Cecil Textbook of Medicine (2-Volume Set) [Volume 4, 21 ed.] 0-7216-7995-1

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Cecil's Textbook of Medicine Part I - MEDICINE AS A LEARNED AND HUMANE PROFESSION

Part II - SOCIAL AND ETHICAL ISSUES IN MEDICINE

Part III - AGING AND GERIATRIC MEDICINE

Part IV - PREVENTIVE HEALTH CARE

Part V - PRINCIPLES OF EVALUATION AND MANAGEMENT

Part VI - PRINCIPLES OF HUMAN GENETICS

Part VII - CARDIOVASCULAR DISEASES

Part VIII - RESPIRATORY DISEASES

Part IX - CRTICAL CARE MEDICINE

Part X - RENAL AND GENITOURINARY DISEASES

Part XI - GASTROINTESTINAL DISEASES

Part XII - DISEASES OF THE LIVER, GALLBLADDER, AND BILE DUCTS

Part XIII - HEMATOLOGIC DISEASES

Part XIV - ONCOLOGY

Part XV - METABOLIC DISEASES

Part XVI - NUTRITIONAL DISEASES

Part XVII - ENDOCRINE DISEASES

Part XVIII - WOMEN'S HEALTH

Part XIX - DISEASES OF BONE AND BONE MINERAL METABOLISM

Part XX - DISEASES OF THE IMMUNE SYSTEM

Part XXI - MUSCULOSKELETAL AND CONNECTIVE TISSUE DISEASES

Part XXII - INFECTIOUS DISEASES

Part XXIII - HIV AND THE ACQUIRED IMMUNODEFICIENCY SYNDROME

Part XXIV - DISEASES OF PROTOZOA AND METAZOA

Part XXV - NEUROLOGY

Part XXV - NEUROLOGY

Part XXVI - EYE, EAR, NOSE, AND THROAT DISEASES

Part XXVII - SKIN DISEASES

Part XXVIII - LABORATORY REFERNCE INTERVALS AND VALUES

About the Publication

Part I - MEDICINE AS A LEARNED AND HUMANE PROFESSION

1 - MEDICINE AS A LEARNED AND HUMANE PROFESSION

About the Publication

Part II - SOCIAL AND ETHICAL ISSUES IN MEDICINE

2 - CLINICAL ETHICS IN THE PRACTICE OF MEDICINE

3 - CARE OF DYING PATIENTS AND THEIR FAMILIES

4 - SOCIAL AND ECONOMIC ISSUES IN MEDICINE

About the Publication

Part III - AGING AND GERIATRIC MEDICINE

5 - BIOLOGY OF AGING

6 - NEUROPSYCHIATRIC ASPECTS OF AGING

7 - DELIRIUM AND OTHER MENTAL STATUS PROBLEMS IN THE OLDER PATIENT

8 - SPECIAL PROBLEMS IN THE GERIATRIC PATIENT

About the Publication

Part IV - PREVENTIVE HEALTH CARE

9 - PRINCIPLES OF PREVENTIVE HEALTH CARE

10 - THE PREVENTIVE HEALTH EXAMINATION

11 - DIET

12 - PHYSICAL ACTIVITY

13 - TOBACCO

14 - VIOLENCE AND INJURY

15 - IMMUNIZATION

16 - ALCOHOLISM AND ALCOHOL ABUSE

17 - DRUG ABUSE AND DEPENDENCE

18 - PRINCIPLES OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE

19 - RADIATION INJURY

20 - ELECTRICAL INJURY

21 - CHRONIC POISONING: TRACE METALS AND OTHERS

About the Publication

Part V - PRINCIPLES OF EVALUATION AND MANAGEMENT

22 - CLINICAL DECISION MAKING: APPROACH TO THE PATIENT

23 - INTERPRETATION OF DATA FOR CLINICAL DECISIONS

24 - APPLICATION OF STATISTICS

25 - PRINCIPLES OF OUTCOME ASSESSMENT

26 - PRINCIPLES OF DRUG THERAPY

Section - Problems of Overarching Importance and Transcending Organ Systems

About the Publication

Part VI - PRINCIPLES OF HUMAN GENETICS

31 - HUMAN HEREDITY

32 - INBORN ERRORS OF METABOLISM

33 - GENE THERAPY

34 - CHROMOSOMES AND THEIR DISORDERS

35 - CONGENITAL ANOMALIES

36 - SYNDROMES INVOLVING MULTIPLE ORGAN SYSTEMS

37 - GENETIC COUNSELING

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Part VII - CARDIOVASCULAR DISEASES

38 - APPROACH TO THE PATIENT WITH POSSIBLE CARDIOVASCULAR DISEASE

39 - EPIDEMIOLOGY OF CARDIOVASCULAR DISEASE

40 - CARDIAC FUNCTION AND CIRCULATORY CONTROL

Section - Specialized Diagnostic Procedures

41 - RADIOLOGY OF THE HEART

42 - ELECTROCARDIOGRAPHY

43 - ECHOCARDIOGRAPHY

44 - NUCLEAR CARDIOLOGY AND COMPUTED TOMOGRAPHY

45 - CARDIAC MAGNETIC RESONANCE IMAGING

46 - CATHETERIZATION AND ANGIOGRAPHY

47 - PATHOPHYSIOLOGY OF HEART FAILURE

48 - MANAGEMENT OF HEART FAILURE

49 - PRINCIPLES OF ELECTROPHYSIOLOGY

50 - ELECTROPHYSIOLOGIC DIAGNOSTIC PROCEDURES

51 - CARDIAC ARRHYTHMIAS WITH SUPRAVENTRICULAR ORIGIN

52 - VENTRICULAR ARRHYTHMIAS AND SUDDEN DEATH

53 - ELECTROPHYSIOLOGIC INTERVENTIONAL PROCEDURES AND SURGERY

54 - ANTIARRHYTHMIC DRUGS

55 - ARTERIAL HYPERTENSION

56 - PULMONARY HYPERTENSION

57 - CONGENITAL HEART DISEASE IN ADULTS

58 - ATHEROSCLEROSIS-THROMBOSIS AND VASCULAR BIOLOGY

59 - ANGINA PECTORIS

60 - ACUTE MYOCARDIAL INFARCTION

60 - ACUTE MYOCARDIAL INFARCTION

61 - CORONARY ANGIOPLASTY

62 - SURGICAL TREATMENT OF CORONARY ARTERY DISEASE

63 - VALVULAR HEART DISEASE

64 - DISEASES OF THE MYOCARDIUM

65 - PERICARDIAL DISEASE

66 - DISEASES OF THE AORTA

67 - ATHEROSCLEROTIC PERIPHERAL ARTERIAL DISEASE

68 - OTHER PERIPHERAL ARTERIAL DISEASES

69 - PERIPHERAL VENOUS DISEASE

70 - MISCELLANEOUS CONDITIONS OF THE HEART: TUMOR, TRAUMA, AND SYSTEMIC DISEASE

71 - CARDIAC TRANSPLANTATION

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Part VIII - RESPIRATORY DISEASES

72 - APPROACH TO THE PATIENT WITH RESPIRATORY DISEASE

73 - RESPIRATORY STRUCTURE AND FUNCTION

74 - ASTHMA

75 - CHRONIC BRONCHITIS AND EMPHYSEMA

76 - CYSTIC FIBROSIS

77 - BRONCHIECTASIS AND LOCALIZED AIRWAY/PARENCHYMAL DISORDERS

78 - INTERSTITIAL LUNG DISEASE

79 - OCCUPATIONAL PULMONARY DISORDERS

80 - PHYSICAL, CHEMICAL, AND ASPIRATION INJURIES OF THE LUNG

81 - SARCOIDOSIS

82 - OVERVIEW OF PNEUMONIA

83 - LUNG ABSCESS

84 - PULMONARY EMBOLISM

85 - PULMONARY NEOPLASMS

86 - DISEASES OF THE DIAPHRAGM, CHEST WALL, PLEURA, AND MEDIASTINUM

87 - OBSTRUCTIVE SLEEP APNEA-HYPOPNEA SYNDROME

88 - RESPIRATORY FAILURE

89 - SURGICAL APPROACH TO LUNG DISEASE

90 - DISORDERS OF VENTILATORY CONTROL

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Part IX - CRTICAL CARE MEDICINE

91 - APPROACH TO THE PATIENT IN A CRITICAL CARE SETTING

92 - RESPIRATORY MONITORING IN CRITICAL CARE

93 - VENTILATOR MANAGEMENT IN THE INTENSIVE CARE UNIT

94 - APPROACH TO THE PATIENT WITH SHOCK

95 - CARDIOGENIC SHOCK

96 - SHOCK SYNDROMES RELATED TO SEPSIS

97 - DISORDERS DUE TO HEAT AND COLD

98 - ACUTE POISONING

99 - RHABDOMYOLYSIS

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Part X - RENAL AND GENITOURINARY DISEASES

100 - APPROACH TO THE PATIENT WITH RENAL DISEASE

101 - STRUCTURE AND FUNCTION OF THE KIDNEYS

102 - FLUIDS AND ELECTROLYTES

103 - ACUTE RENAL FAILURE

104 - CHRONIC RENAL FAILURE

105 - TREATMENT OF IRREVERSIBLE RENAL FAILURE

106 - GLOMERULAR DISORDERS

107 - TUBULOINTERSTITIAL DISEASES AND TOXIC NEPHROPATHIES

108 - OBSTRUCTIVE UROPATHY

109 - SPECIFIC RENAL TUBULAR DISORDERS

110 - DIABETES AND THE KIDNEY

111 - URINARY TRACT INFECTIONS AND PYELONEPHRITIS

112 - VASCULAR DISORDERS OF THE KIDNEY

113 - HEREDITARY CHRONIC NEPHROPATHIES: GLOMERULAR BASEMENT MEMBRANE DISEASES

114 - RENAL CALCULI (NEPHROLITHIASIS)

115 - CYSTIC DISEASES OF THE KIDNEY

116 - ANOMALIES OF THE URINARY TRACT

117 - TUMORS OF THE KIDNEY, URETER, AND BLADDER

118 - DISEASES OF THE PROSTATE

119 - URINARY INCONTINENCE

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Part XI - GASTROINTESTINAL DISEASES

120 - APPROACH TO THE PATIENT WITH GASTROINTESTINAL DISEASE

121 - DIAGNOSTIC IMAGING PROCEDURES IN GASTROENTEROLOGY

122 - GASTROINTESTINAL ENDOSCOPY

123 - GASTROINTESTINAL HEMORRHAGE AND OCCULT GASTROINTESTINAL BLEEDING

124 - DISEASES OF THE ESOPHAGUS

125 - GASTRITIS AND HELICOBACTER PYLORI

126 - PEPTIC ULCER DISEASE: EPIDEMIOLOGY, PATHOPHYSIOLOGY, CLINICAL MANIFESTATIONS, AND DIAGNOSIS

127 - PEPTIC ULCER DISEASE: MEDICAL THERAPY

128 - COMPLICATIONS OF PEPTIC ULCER

129 - PEPTIC ULCER DISEASE: SURGICAL THERAPY

130 - PANCREATIC ENDOCRINE TUMORS

131 - FUNCTIONAL GASTROINTESTINAL DISORDERS: IRRITABLE BOWEL SYNDROME, NON-ULCER DYSPEPSIA, AND NON-CARDIAC CHEST PAIN

132 - DISORDERS OF GASTROINTESTINAL MOTILITY

133 - APPROACH TO THE PATIENT WITH DIARRHEA

134 - MALABSORPTION SYNDROMES

135 - INFLAMMATORY BOWEL DISEASE

136 - MISCELLANEOUS INFLAMMATORY DISEASES OF THE INTESTINE

137 - VASCULAR DISORDERS OF THE INTESTINE

138 - NEOPLASMS OF THE STOMACH

139 - NEOPLASMS OF THE LARGE AND SMALL INTESTINES

140 - CARCINOMA OF THE PANCREAS

141 - PANCREATITIS

142 - DISEASES OF THE PERITONEUM, MESENTERY, AND OMENTUM

143 - DISEASES OF THE RECTUM AND ANUS

143 - DISEASES OF THE RECTUM AND ANUS

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Part XII - DISEASES OF THE LIVER, GALLBLADDER, AND BILE DUCTS

144 - APPROACH TO THE PATIENT WITH LIVER DISEASES

145 - HEPATIC METABOLISM IN LIVER DISEASE

146 - BILIRUBIN METABOLISM, HYPERBILIRUBINEMIA, AND APPROACH TO THE JAUNDICED PATIENT

147 - LABORATORY TESTS IN LIVER DISEASE AND APPROACH TO THE PATIENT WITH ABNORMAL TESTS

148 - TOXIC AND DRUG-INDUCED LIVER DISEASE

149 - ACUTE VIRAL HEPATITIS

150 - CHRONIC HEPATITIS

151 - PARASITIC, BACTERIAL, FUNGAL, AND GRANULOMATOUS LIVER DISEASES

152 - INHERITED, INFILTRATIVE, AND METABOLIC DISORDERS INVOLVING THE LIVER

153 - ALCOHOLIC LIVER DISEASE, CIRRHOSIS, AND ITS MAJOR SEQUELAE

154 - ACUTE AND CHRONIC LIVER FAILURE AND HEPATIC ENCEPHALOPATHY

155 - LIVER TRANSPLANTATION

156 - HEPATIC TUMORS

157 - DISEASES OF THE GALLBLADDER AND BILE DUCTS

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Part XIII - HEMATOLOGIC DISEASES

158 - HEMATOPOIESIS AND HEMATOPOIETIC GROWTH FACTORS

159 - APPROACH TO THE ANEMIAS

160 - APLASTIC ANEMIA AND RELATED BONE MARROW FAILURE SYNDROMES

161 - NORMOCHROMIC, NORMOCYTIC ANEMIAS

162 - MICROCYTIC AND HYPOCHROMIC ANEMIAS

163 - MEGALOBLASTIC ANEMIAS

164 - HEMOLYTIC ANEMIAS: RED CELL MEMBRANE AND METABOLIC DEFECTS

165 - HEMOLYTIC ANEMIAS: AUTOIMMUNE

166 - HEMOLYTIC ANEMIAS: INTRAVASCULAR

167 - HEMOGLOBINOPATHIES: THE THALASSEMIAS

168 - HEMOGLOBINOPATHIES: METHEMOGLOBINEMIAS, POLYCYTHEMIAS, AND UNSTABLE HEMOGLOBINS

169 - SICKLE CELL ANEMIA AND ASSOCIATED HEMOGLOBINOPATHIES

170 - BLOOD TRANSFUSION

171 - DISORDERS OF PHAGOCYTE FUNCTION

172 - LEUKOPENIA AND LEUKOCYTOSIS

173 - EOSINOPHILIC SYNDROMES

174 - MYELOPROLIFERATIVE DISEASES

175 - MYELODYSPLASTIC SYNDROME

176 - THE CHRONIC LEUKEMIAS

177 - THE ACUTE LEUKEMIAS

178 - APPROACH TO THE PATIENT WITH LYMPHADENOPATHY AND SPLENOMEGALY

179 - NON-HODGKIN'S LYMPHOMAS

180 - HODGKIN'S DISEASE

181 - PLASMA CELL DISORDERS

181 - PLASMA CELL DISORDERS

182 - STEM CELL TRANSPLANTATION

183 - APPROACH TO THE PATIENT WITH BLEEDING AND THROMBOSIS

184 - HEMORRHAGIC DISORDERS: ABNORMALITIES OF PLATELET AND VASCULAR FUNCTION

185 - COAGULATION FACTOR DEFICIENCIES

186 - HEMORRHAGIC DISORDERS: MIXED ABNORMALITIES

187 - THROMBOTIC DISORDERS: HYPERCOAGULABLE STATES

188 - ANTITHROMBOTIC THERAPY

About the Publication

Part XIV - ONCOLOGY

189 - INTRODUCTION

190 - CANCER PREVENTION

191 - ONCOGENES AND SUPPRESSOR GENES: GENETIC CONTROL OF CANCER

192 - TUMOR MARKERS

193 - THE EPIDEMIOLOGY OF CANCER

194 - ENDOCRINE MANIFESTATIONS OF TUMORS: "ECTOPIC" HORMONE PRODUCTION

195 - NONMETASTATIC EFFECTS OF CANCER: THE NERVOUS SYSTEM

196 - NONMETASTATIC EFFECTS OF CANCER: THE SKIN

197 - NONMETASTATIC EFFECTS OF CANCER: OTHER SYSTEMS

198 - PRINCIPLES OF CANCER THERAPY

199 - ONCOLOGIC EMERGENCIES

200 - APPROACH TO THE PATIENT WITH METASTATIC CANCER, PRIMARY SITE UNKNOWN

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Part XV - METABOLIC DISEASES

201 - APPROACH TO THE PATIENT WITH METABOLIC DISEASE

Section - Disorders of Carbohydrate Metabolism

202 - GALACTOSEMIA

203 - GLYCOGEN STORAGE DISEASES

204 - FRUCTOSE INTOLERANCE

205 - PRIMARY HYPEROXALURIA

Section - Disorders of Lipid Metabolism

206 - THE HYPERLIPOPROTEINEMIAS

207 - DISORDERS OF PURINE AND PYRIMIDINE METABOLISM

208 - LYSOSOMAL STORAGE DISEASES

Section - Inborn Errors of Amino Acid Metabolism

209 - THE HYPERPHENYLALANINEMIAS AND ALKAPTONURIA

210 - THE HYPERPROLINEMIAS AND HYDROXYPROLINEMIA

211 - DISEASES OF THE UREA CYCLE

212 - BRANCHED-CHAIN AMINOACIDURIAS

213 - HOMOCYSTINURIA

Section - Inherited Disorders of Connective Tissue

214 - THE MUCOPOLYSACCHARIDOSES

215 - MARFAN SYNDROME

216 - EHLERS-DANLOS SYNDROMES

217 - OSTEOGENESIS IMPERFECTA SYNDROMES

218 - PSEUDOXANTHOMA ELASTICUM

Section - Disorders of Porphyrins and Metals

219 - THE PORPHYRIAS

219 - THE PORPHYRIAS

220 - WILSON DISEASE

221 - IRON OVERLOAD (HEMOCHROMATOSIS)

222 - PHOSPHORUS DEFICIENCY AND HYPOPHOSPHATEMIA

223 - DISORDERS OF MAGNESIUM METABOLISM

About the Publication

Part XVI - NUTRITIONAL DISEASES

224 - NUTRITION'S INTERFACE WITH HEALTH AND DISEASE

225 - NUTRITIONAL ASSESSMENT

226 - PROTEIN-ENERGY MALNUTRITION

227 - THE EATING DISORDERS

228 - OBESITY

229 - ENTERAL NUTRITION

230 - PARENTERAL NUTRITION

231 - CONSEQUENCES OF ALTERED MICRONUTRIENT STATUS

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Part XVII - ENDOCRINE DISEASES

232 - PRINCIPLES OF ENDOCRINOLOGY

233 - PROSTAGLANDINS AND RELATED COMPOUNDS*

234 - NATRIURETIC HORMONES

235 - NEUROENDOCRINOLOGY AND THE NEUROENDOCRINE SYSTEM

236 - THE PINEAL GLAND

237 - ANTERIOR PITUITARY

238 - POSTERIOR PITUITARY

239 - THE THYROID

239a - THE THYROID - Part II

240 - THE ADRENAL CORTEX

241 - THE ADRENAL MEDULLA, CATECHOLAMINES, AND PHEOCHROMOCYTOMA

242 - DIABETES MELLITUS

242a - DIABETES MELLITUS - Part II

243 - HYPOGLYCEMIA/PANCREATIC ISLET CELL DISORDERS

244 - MULTIPLE-ORGAN SYNDROMES: POLYGLANDULAR DISORDERS

245 - MULTIPLE-ORGAN SYNDROMES: CARCINOID SYNDROME

246 - DISORDERS OF SEXUAL DIFFERENTIATION

247 - THE TESTIS AND MALE SEXUAL FUNCTION

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Part XVIII - WOMEN'S HEALTH

248 - APPROACH TO WOMEN'S HEALTH

249 - OVARIES AND DEVELOPMENT

250 - MENSTRUAL CYCLE AND FERTILITY

251 - CONTRACEPTION

252 - PREGNANCY: NEOPLASTIC DISEASES

253 - PREGNANCY: HYPERTENSION AND OTHER COMMON MEDICAL PROBLEMS

254 - HIV IN PREGNANCY

255 - HIRSUTISM

256 - MENOPAUSE

257 - OSTEOPOROSIS

258 - BREAST CANCER AND DIFFERENTIAL DIAGNOSIS OF BENIGN NODULES

259 - CERVICAL AND UTERINE CANCER SCREENING

260 - OVARIAN CARCINOMA

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Part XIX - DISEASES OF BONE AND BONE MINERAL METABOLISM

261 - MINERAL AND BONE HOMEOSTASIS

262 - VITAMIN D

263 - OSTEOMALACIA AND RICKETS

264 - THE PARATHYROID GLANDS, HYPERCALCEMIA, AND HYPOCALCEMIA

265 - CALCITONIN AND MEDULLARY THYROID CARCINOMA

266 - RENAL OSTEODYSTROPHY

267 - PAGET'S DISEASE OF BONE (OSTEITIS DEFORMANS)

268 - OSTEONECROSIS, OSTEOSCLEROSIS/HYPEROSTOSIS, AND OTHER DISORDERS OF BONE

269 - BONE TUMORS

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Part XX - DISEASES OF THE IMMUNE SYSTEM

270 - APPROACH TO THE PATIENT WITH IMMUNE DISEASE

271 - COMPLEMENT

272 - PRIMARY IMMUNODEFICIENCY DISEASES

273 - URTICARIA AND ANGIOEDEMA

274 - ALLERGIC RHINITIS

275 - ANAPHYLAXIS

276 - INSECT STING ALLERGY

277 - IMMUNE COMPLEX DISEASES

278 - THE MAJOR HISTOCOMPATIBILITY COMPLEX AND DISEASE SUSCEPTIBILITY

279 - DRUG ALLERGY

280 - MASTOCYTOSIS

281 - DISEASES OF THE THYMUS

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Part XXI - MUSCULOSKELETAL AND CONNECTIVE TISSUE DISEASES

282 - APPROACH TO THE PATIENT WITH MUSCULOSKELETAL DISEASE

283 - CONNECTIVE TISSUE STRUCTURE AND FUNCTION

284 - TISSUE INJURY IN RHEUMATIC DISEASES

285 - SPECIALIZED PROCEDURES IN THE MANAGEMENT OF PATIENTS WITH RHEUMATIC DISEASES

286 - RHEUMATOID ARTHRITIS

287 - THE SPONDYLOARTHROPATHIES

288 - INFECTIOUS ARTHRITIS

289 - SYSTEMIC LUPUS ERYTHEMATOSUS

290 - SCLERODERMA (SYSTEMIC SCLEROSIS)

291 - SJOGREN'S SYNDROME

292 - THE VASCULITIC SYNDROMES

293 - POLYARTERITIS NODOSA GROUP

294 - WEGENER'S GRANULOMATOSIS

295 - POLYMYALGIA RHEUMATICA AND GIANT CELL ARTERITIS

296 - IDIOPATHIC INFLAMMATORY MYOPATHIES

297 - THE AMYLOID DISEASES

298 - BEHCET'S DISEASE

299 - GOUT AND URIC ACID METABOLISM

300 - CRYSTAL DEPOSITION ARTHROPATHIES

301 - RELAPSING POLYCHONDRITIS

302 - OSTEOARTHRITIS (DEGENERATIVE JOINT DISEASE)

303 - THE PAINFUL SHOULDER

304 - SYSTEMIC DISEASES IN WHICH ARTHRITIS IS A FEATURE

305 - MISCELLANEOUS FORMS OF ARTHRITIS

305 - MISCELLANEOUS FORMS OF ARTHRITIS

306 - NON-ARTICULAR RHEUMATISM

307 - ARTICULAR TUMORS

308 - ERYTHROMELALGIA

309 - MULTIFOCAL FIBROSCLEROSIS

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Part XXII - INFECTIOUS DISEASES

310 - INTRODUCTION TO MICROBIAL DISEASE

311 - THE FEBRILE PATIENT

312 - THE PATHOGENESIS OF FEVER

313 - THE ACUTE-PHASE RESPONSE

314 - THE COMPROMISED HOST

315 - NOSOCOMIAL INFECTIONS

316 - ADVICE TO TRAVELERS

Section - Bacterial Diseases

317 - INTRODUCTION TO BACTERIAL DISEASE

318 - ANTIBACTERIAL THERAPY

319 - PNEUMOCOCCAL PNEUMONIA

320 - MYCOPLASMAL INFECTION

321 - PNEUMONIA CAUSED BY AEROBIC GRAM-NEGATIVE BACILLI

322 - ASPIRATION PNEUMONIA

323 - LEGIONELLOSIS

324 - STREPTOCOCCAL INFECTIONS

325 - RHEUMATIC FEVER

326 - INFECTIVE ENDOCARDITIS

327 - STAPHYLOCOCCAL INFECTIONS

Section - Bacterial Meningitis

328 - BACTERIAL MENINGITIS

329 - MENINGOCOCCAL INFECTIONS

330 - INFECTIONS CAUSED BY HAEMOPHILUS SPECIES

Section - Ostoemyelitis

Section - Ostoemyelitis

331 - OSTEOMYELITIS

Section - Whooping Cough

332 - WHOOPING COUGH (PERTUSSIS)

Section - Diphtheria

333 - DIPHTHERIA

Section - Clostridial Diseases

334 - CLOSTRIDIAL MYONECROSIS AND OTHER CLOSTRIDIAL DISEASES

335 - PSEUDOMEMBRANOUS COLITIS

336 - BOTULISM

337 - TETANUS

Section - Anaerobic Bacteria

338 - DISEASES CAUSED BY NON-SPORE-FORMING ANAEROBIC BACTERIA

Section - Enteric Infections

339 - INTRODUCTION TO ENTERIC INFECTIONS

340 - TYPHOID FEVER

341 - SALMONELLA INFECTIONS OTHER THAN TYPHOID FEVER

342 - SHIGELLOSIS

343 - CAMPYLOBACTER ENTERITIS

344 - CHOLERA

345 - ENTERIC ESCHERICHIA COLI INFECTIONS

346 - THE DIARRHEA OF TRAVELERS

347 - EXTRAINTESTINAL INFECTIONS CAUSED BY ENTERIC BACTERIA

Section - Other Bacterial Infections

348 - YERSINIA INFECTIONS

349 - TULAREMIA

350 - ANTHRAX

351 - DISEASES CAUSED BY PSEUDOMONADS

352 - LISTERIOSIS

353 - ERYSIPELOID

354 - ACTINOMYCOSIS

355 - NOCARDIOSIS

356 - BRUCELLOSIS

357 - DISEASE CAUSED BY BARTONELLA SPECIES

Section - Diseases Due To Mycobacteria

358 - TUBERCULOSIS

359 - OTHER MYCOBACTERIOSES

360 - LEPROSY (HANSEN'S DISEASE)

Section - Sexually Transmitted Diseases

361 - INTRODUCTION TO SEXUALLY TRANSMITTED DISEASES AND COMMON SYNDROMES

362 - GONOCOCCAL INFECTIONS

363 - GRANULOMA INGUINALE (DONOVANOSIS)

364 - CHANCROID

365 - SYPHILIS

Section - Spirochetal Diseases Other Than Syphilis

366 - NON-SYPHILITIC TREPONEMATOSES

367 - RELAPSING FEVER

368 - LYME DISEASE

369 - LEPTOSPIROSIS

370 - DISEASES CAUSED BY CHLAMYDIAE

371 - RICKETTSIAL DISEASES

372 - ZOONOSES

Section - Viral Diseases

373 - INTRODUCTION TO VIRAL DISEASES

374 - ANTIVIRAL THERAPY (NON-AIDS)

Section - Viral Infections of the Respiratory Tract

375 - THE COMMON COLD

376 - VIRAL PHARYNGITIS, LARYNGITIS, CROUP, AND BRONCHITIS

377 - RESPIRATORY SYNCYTIAL VIRUS

378 - PARAINFLUENZA VIRAL DISEASE

379 - INFLUENZA

380 - ADENOVIRUS DISEASES

Section - Exanthems and Mumps

381 - MEASLES

382 - RUBELLA (GERMAN MEASLES)

383 - VARICELLA (CHICKENPOX, SHINGLES) (See also Chapter 477)

384 - MUMPS

Section - The Herpes Group of Viruses

385 - HERPES SIMPLEX VIRUS INFECTIONS

386 - INFECTIONS ASSOCIATED WITH HUMAN CYTOMEGALOVIRUS

387 - INFECTIOUS MONONUCLEOSIS: EPSTEIN-BARR VIRUS INFECTION

Section - Retroviruses

388 - RETROVIRUSES OTHER THAN HIV

Section - Enteric Viral Infections

389 - ENTEROVIRUSES

390 - VIRAL GASTROENTERITIS

Section - Hemorrhagic Fever Viruses

Section - Hemorrhagic Fever Viruses

391 - INTRODUCTION TO HEMORRHAGIC FEVER VIRUSES

392 - OTHER ARTHROPOD-BORNE VIRUSES

Section - The Mycoses

393 - INTRODUCTION TO THE MYCOSES

394 - HISTOPLASMOSIS

395 - COCCIDIOIDOMYCOSIS

396 - BLASTOMYCOSIS

397 - PARACOCCIDIOIDOMYCOSIS

398 - CRYPTOCOCCOSIS

399 - SPOROTRICHOSIS

400 - CANDIDIASIS

401 - ASPERGILLOSIS

402 - Pneumocystis Carinii PNEUMONIA

403 - MUCORMYCOSIS

404 - MYCETOMA

405 - DEMATIACEOUS FUNGAL INFECTIONS

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Part XXIII - HIV AND THE ACQUIRED IMMUNODEFICIENCY SYNDROME

406 - INTRODUCTION TO HIV AND ASSOCIATED DISORDERS

407 - IMMUNOLOGY RELATED TO AIDS

408 - BIOLOGY OF HUMAN IMMUNODEFICIENCY VIRUSES

409 - EPIDEMIOLOGY OF HIV INFECTION AND AIDS

410 - PREVENTION OF HIV INFECTION

411 - NEUROLOGIC COMPLICATIONS OF HIV-1 INFECTION

412 - PULMONARY MANIFESTATIONS OF HIV INFECTION

413 - GASTROINTESTINAL MANIFESTATIONS OF AIDS

414 - CUTANEOUS SIGNS OF AIDS

415 - OPHTHALMOLOGIC MANIFESTATIONS OF AIDS

416 - HEMATOLOGY/ONCOLOGY IN AIDS

417 - RENAL, CARDIAC, ENDOCRINE, AND RHEUMATOLOGIC MANIFESTATIONS OF HIV INFECTION

418 - TREATMENT OF HIV INFECTION AND AIDS

419 - MANAGEMENT AND COUNSELING FOR PERSONS WITH HIV INFECTION

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Part XXIV - DISEASES OF PROTOZOA AND METAZOA

420 - INTRODUCTION TO PROTOZOAN AND HELMINTHIC DISEASES

Section - Protozoan Diseases

421 - MALARIA

422 - AFRICAN TRYPANOSOMIASIS (SLEEPING SICKNESS)

423 - AMERICAN TRYPANOSOMIASIS (CHAGAS' DISEASE)

424 - LEISHMANIASIS

425 - TOXOPLASMOSIS

426 - CRYPTOSPORIDIOSIS

427 - GIARDIASIS

428 - AMEBIASIS

429 - OTHER PROTOZOAN DISEASES

Section - Helminthic Diseases

430 - CESTODE INFECTIONS

431 - SCHISTOSOMIASIS (BILHARZIASIS)

432 - LIVER, INTESTINAL, AND LUNG FLUKE INFECTIONS

433 - NEMATODE INFECTIONS

434 - FILARIASIS

435 - ARTHROPODS AND LEECHES

436 - VENOMOUS SNAKE BITES*

437 - VENOMS AND POISONS FROM MARINE ORGANISMS

About the Publication

Part XXV - NEUROLOGY

Section - Evaluation of the Patient

438 - APPROACH TO THE PATIENT

439 - THE NEUROLOGIC HISTORY

440 - CLINICAL DIAGNOSIS AND NEUROLOGIC EXAMINATION

441 - NEUROGENETICS

442 - NEUROLOGIC DIAGNOSTIC PROCEDURES

443 - RADIOLOGIC IMAGING PROCEDURES

Section - Disorders of Cerebral Function

444 - COMA AND DISORDERS OF AROUSAL

445 - PERSISTENT VEGETATIVE STATE

446 - BRAIN DEATH

447 - SYNCOPE

448 - DISORDERS OF SLEEP AND AROUSAL

449 - DISORDERS OF COGNITION

450 - PSYCHIATRIC DISORDERS IN MEDICAL PRACTICE

Section - Pathophysiology and Management of Major Neurologic Symptoms

451 - AUTONOMIC DISORDERS AND THEIR MANAGEMENT

452 - DISORDERS OF MOTOR FUNCTION

453 - MAJOR SENSORY SYMPTOMS

454 - HEADACHES AND OTHER HEAD PAIN

455 - OTHER SPECIFIC PAIN SYNDROMES

Section - Developmental Disorders

456 - NEUROCUTANEOUS SYNDROMES

457 - MALFORMATIONS OF CORTICAL DEVELOPMENT

457 - MALFORMATIONS OF CORTICAL DEVELOPMENT

458 - CONGENITAL ANOMALIES OF THE CRANIOVERTEBRAL JUNCTION, SPINE, AND SPINAL CORD (INCLUDING SYRINGOMYELIA)

Section - The Extrapyramidal Disorders

459 - INTRODUCTION

460 - PARKINSONISM

461 - TREMORS

462 - DYSTONIAS

463 - CHOREAS, ATHETOSIS, AND BALLISM

464 - TICS, MYOCLONUS, AND STEREOTYPIES

Section - Degenerative Diseases of the Nervous System

465 - INTRODUCTION

466 - HEREDITARY CEREBELLAR ATAXIAS AND RELATED DISORDERS

467 - HEREDITARY SPASTIC PARAPLEGIAS

468 - MOTOR NEURON DISEASES

Section - Cerebrovascular Diseases

469 - CEREBROVASCULAR DISEASES--PRINCIPLES

470 - ISCHEMIC CEREBROVASCULAR DISEASE

471 - HEMORRHAGIC CEREBROVASCULAR DISEASE

Section - Infections and Inflammatory Disorders of the Nervous System

472 - INTRODUCTION

473 - PARAMENINGEAL INFECTIONS

474 - NEUROSYPHILIS

475 - ACUTE VIRAL MENINGITIS AND ENCEPHALITIS

476 - POLIOMYELITIS

477 - The Herpesviruses

478 - RABIES

479 - SLOW VIRUS INFECTIONS

Section - Neurologic Disorders Associated with Altered Immunity or Unexplained Host-Parasite Alterations

480 - NEUROLOGIC COMPLICATIONS IN THE IMMUNOCOMPROMISED HOST

481 - REYE'S SYNDROME

Section - The Demyelinating Diseases

482 - MULTIPLE SCLEROSIS AND RELATED CONDITIONS

483 - CENTRAL NERVOUS SYSTEM COMPLICATIONS OF VIRAL INFECTIONS AND VACCINES

Section - The Epilepsies

484 - THE EPILEPSIES

Section - Central Nervous System Tumors and States of Altered Intracranial Pressure

485 - INTRACRANIAL TUMORS

486 - SPECIFIC TYPES OF BRAIN TUMORS AND THEIR MANAGEMENT

487 - SPINAL TUMORS

488 - INTRACRANIAL HYPERTENSION AND HYPOTENSION

Section - Nutritional Disorders of the Nervous System

489 - NUTRITIONAL DISORDERS OF THE NERVOUS SYSTEM

Section - Injury of the Head and Spinal Cord

490 - HEAD INJURY

491 - SPINE AND SPINAL CORD INJURY

Section - Mechanical Lesions of Nerve Roots and Spinal Cord

492 - SPINAL ANATOMY

493 - NECK AND BACK PAIN

494 - INTERVERTEBRAL DISK DISEASE

495 - INFLAMMATORY DISORDERS INVOLVING THE SPINAL CORD

496 - VASCULAR DISORDERS INVOLVING THE SPINAL CORD

Section - Diseases of the Peripheral Nervous System

497 - GENERAL APPROACH TO NERVE DISEASE

498 - PATHOPHYSIOLOGY OF PERIPHERAL NEUROPATHIES

499 - IMMUNE-MEDIATED NEUROPATHIES

500 - HEREDITARY NEUROPATHIES

501 - METABOLIC NEUROPATHIES

502 - TOXIC NEUROPATHIES

503 - NEUROPATHIES ASSOCIATED WITH INFECTIOUS DISEASES

504 - ENTRAPMENT AND COMPRESSIVE NEUROPATHIES

Section - Diseases of Muscle (Myopathies)

505 - GENERAL APPROACH TO MUSCLE DISEASES

506 - MUSCULAR DYSTROPHIES

507 - MORPHOLOGICALLY DISTINCT CONGENITAL MYOPATHIES

508 - METABOLIC MYOPATHIES

509 - CHANNELOPATHIES (NON-DYSTROPHIC MYOTONIAS AND PERIODIC PARALYSES)

510 - INFLAMMATORY AND OTHER MYOPATHIES

Section - Diseases of the Neuromuscular Junction

511 - DISORDERS OF NEUROMUSCULAR TRANSMISSION

About the Publication

Part XXVI - EYE, EAR, NOSE, AND THROAT DISEASES

512 - DISEASES OF THE VISUAL SYSTEM

513 - NEURO-OPHTHALMOLOGY

514 - DISEASES OF THE MOUTH AND SALIVARY GLANDS

515 - UPPER AIRWAY DISEASES

516 - SMELL AND TASTE

517 - HEARING AND EQUILIBRIUM

518 - HEAD AND NECK CANCER

About the Publication

Part XXVII - SKIN DISEASES

519 - STRUCTURE AND FUNCTION OF SKIN

520 - EXAMINATION OF THE SKIN AND AN APPROACH TO DIAGNOSING SKIN DISEASES

521 - PRINCIPLES OF THERAPY

522 - SKIN DISEASES OF GENERAL IMPORTANCE

522a - SKIN DISEASES OF GENERAL IMPORTANCE - Part II

About the Publication

Part XXVIII - LABORATORY REFERNCE INTERVALS AND VALUES

523 - REFERENCE INTERVALS AND LABORATORY VALUES*

Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Part I - MEDICINE AS A LEARNED AND HUMANE PROFESSION

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Chapter 1 - MEDICINE AS A LEARNED AND HUMANE PROFESSION Lee Goldman Fred Plum J. Claude Bennett

Becoming a physician has meaning far beyond completing medical school and residency. It is the entry to a way of life, the one characteristic common to every true profession. It may sound old-fashioned, but the learned professions are really "callings" from which the members cannot separate their lives. There are no part-time professionals; having accepted such a calling, one is bound to live it or leave it. A physician can also be a good spouse, a good parent, and a good citizen of the community; however, the role of spouse, parent, and citizen is inextricably intertwined with the calling of being a physician.

THE SCIENTIFIC INFRASTRUCTURE OF MEDICINE Medicine is not a science, but a profession that encompasses medical science as well as personal, humanistic, and professional attributes. Nonetheless, the delivery of Western medicine depends totally on science and the scientific method. Since Flexner issued his famous report on the subject in 1910, American medical education has striven to develop a strong scientific base as an integral part of medical education at every level: pre-medical, medical, residency, and continuing medical education. Biomedical science is fundamental to understanding disease, making diagnoses, applying new therapies, and appreciating the complexities and opportunities of new technologies. The process of becoming a physician and being committed to lifelong learning requires that an individual possess the scientific base not only to acquire and appreciate new knowledge but also to see new ways for applying it to patient care. The physician must be able to understand reports of current research in the medical literature to grasp and evaluate the newest and latest approaches, no matter how complicated the field may become. This textbook of medicine strongly emphasizes how things work, how they go awry when pathologic processes ensue, and what effect a given therapy can be expected to have in correcting abnormalities. We seek to create in our readers a yearning for a greater depth of understanding and a continuing commitment to stay at the frontier of scientific knowledge throughout their professional lives. Medicine has advanced to an outstanding degree in the past half century. (The 100 years from 1850 to 1950 were characterized--with the important exceptions of the discovery of penicillin, sulfonamides, and insulin--by the application of chemistry and physics to biologic materials, e.g., blood and urine, or to the body, e.g., roentgenography and sphygmomanometry, and by the empiric use of medicinal chemicals.) The advances of the last 50 years have come at the most fundamental levels of science and have reflected the general explosion in scientific knowledge world-wide. True understanding of disease processes depends on levels of scientific knowledge that are just being discovered. For example, an understanding of how proteins are synthesized, fold into their native conformation, and express their various physical properties leads to an understanding of why erythrocytes sickle, the complexities of amyloid formation and how it influences organ function, the nature of protein aggregation as a fundamental process of Alzheimer's disease, and the importance of protein-protein interaction in transmitting messages across cell membranes, within the cytoplasm, and to the nucleus of cells. An appreciation for the way G proteins function explains membrane transport, how messages transfer from the outside to the inside of cells, how microbial toxins operate, how hormones influence cell action, and how cells respond to external stimuli and are regulated in their response. Knowledge of the basic processes of DNA synthesis, mutation, and somatic alteration of gene expression explains inherited diseases and diseases that have their fundamental processes expressed in a continuous pattern of somatic alteration within a given individual. Fundamental science is crucial as a knowledge base for any member of our profession. Fortunately, for a physician studying and learning in this complex environment, medical science has become so fundamental that an understanding of a few basic and critical processes can provide insight into a wide variety of diseases. A list of major clinical achievements in any particular branch of medicine reveals that more than 60% of the enabling discoveries arise from the category of very basic science and that these discoveries were initially made without any particular notion of how they might be applied to human disease. Breakthroughs in infectious diseases, the regulation of blood pressure, fundamental immunology, fundamental genetics, and metabolic regulation by hormones represent milestones in the course of medical history that now provide the tools to help unravel the intricacies of human disease. Despite unbelievable successes, many diseases continue to elude absolute answers: Cancer, Alzheimer's disease, many autoimmune diseases, and most psychiatric diseases are just some examples. Nonetheless, the clues now being ferreted out at the molecular level anticipate solutions of even these disorders, realistically filling future expectations with excitement and anticipation. The scientific infrastructure that we appreciate today is the springboard for the future in which most of the readers of Cecil Textbook of Medicine, 21st edition, will practice. Throughout most of the recorded history of medicine, diagnoses and therapies have not been based on scientific fact, and the degree of certainty with which physicians worked was inexact, if not totally flawed. However, this situation has entirely changed: By 150 years ago things were beginning to change, and by the 20 years spanning the turn of the century, the first fundamental lights began to illuminate the "golden age of microbiology." During this period, Pasteur, working in Paris, and Robert Koch, working in Berlin, began to unravel the intricacies of infectious diseases. To define microorganisms, to understand how they cause infection and transmit diseases, and to understand the host response represented a turning point and forever established the scientific method as the basis for understanding and treating disease. It is an amazing experience to read the scientific papers from Paris and Berlin at that time because in a relatively short period those two schools of thought set us on a pathway from which medicine can never depart--that of demanding precision, of requiring experimental proof, and of building confidence by accumulating irrefutable data. Today's medicine is more than intuition and common sense. It is precision based on a century or more of refining definitions of disease in highly specific terms. We now experience these "golden ages" in more rapid order: the discovery of antibiotics less than 60 years ago; an understanding of immunology in molecular terms 2

within the last 30 years; and now in genetics, not just knowledge at the molecular level, but understanding how to manipulate genes for the immediate benefit of mankind. We are indeed in the age of molecular-biophysical medicine, an influence that permeates and unifies all the traditional disciplines of medicine. Whether one is talking about inborn errors of metabolism, neurotransmitters, cytokines, oncogenes, or hormone regulation, all are being defined with exquisite detail at the molecular level. Programs aimed toward the goal of the human genome project--to sequence all the DNA within the entire genome--are moving forward with accelerating speed. The ability to define every gene, its product, and its role and explicit function has become a shared international goal. Concurrent with these advances in fundamental human biology has been a dramatic shift in the methods for evaluating the application of scientific advances to the patient and to populations. The randomized control trial, sometimes with thousands of patients at multiple institutions, has replaced anecdote as the preferred method

for measuring the benefits and uses of diagnostic or therapeutic interventions. As studies progress from those that demonstrate biologic effect, to those that elucidate dosing schedules and toxicity, and finally to those that assess true clinical benefit, the metrics of measuring outcome have also improved from subjective impressions of physicians or patients to reliable and valid measures of morbidity, quality of life, functional status, and other patient-oriented outcomes. These marked improvements in the scientific methodology of clinical investigation have expedited extraordinary changes in clinical practice, such as reperfusion therapy for acute myocardial infarction, and have demonstrated that reliance on intermediate outcomes, such as a reduction in asymptomatic ventricular arrhythmias with certain drugs, may unexpectedly increase rather than decrease mortality. Just as the physician for the twenty-first century must understand advances in fundamental biology, a similar understanding is needed of the fundamentals of clinical study design as it applies to diagnostic and therapeutic interventions. This pattern of attaining scientific knowledge, beginning with a sick patient and moving first in a reductionist process to individual molecules and fundamental biochemical processes and then back toward an evaluation of scientifically based diagnostic and therapeutic advances, should not reduce our appreciation for the other contributors to the human condition. Advances in molecular and structural biology and the wonders of immunology and genetics must not allow us to neglect the many aspects of human psychology, anthropology, and sociology that influence the world in which we live and that play such a major role in morbidity and eventual mortality. According to the National Center for Health Statistics, behavioral causes--including alcohol, drugs, violence, suicide, smoking, and excessive aggression--generate more than half the cost to the nation for health care. We are only just beginning to grasp the impact of these factors on our nation and the world. In our joy--and sometimes arrogant pride--over achievements in molecular medicine and randomized controlled trials, we must also humbly realize that the sciences that analyze human or population behavior and attempt to improve it, as well as the way that society is structured, are indispensable to the future of medicine and must be incorporated into the discipline of our profession.

THE PHYSICIAN AS A SCIENTIST To use scientific medicine correctly, physicians must be trained as scientists to understand and apply the thinking patterns of the scientific method, to develop an inquiring mind, to know how to design experiments and obtain data, to learn how to analyze the validity and generalizability of those data, and to use this knowledge to ask questions and provide truthful answers within defined limits of precision. Biomedical science becomes the working instrument for the physician who, by definition, practices an analytic profession. Most of these learned skills extend to the management of individual cases at the bedside, i.e., how to gather information, how to synthesize it, how to interpret it to make a full diagnostic story, and how to bring collective wisdom together in the design and execution of appropriate therapy. A central tenet of all sciences is to constantly ask, "Could my conclusion be wrong?" The rigors of the scientific method also provide the physician with learning skills and a process of analysis that are indispensable for dealing with individual patients, as well as provide the opportunity to contribute to medical progress and the improvement of care. The explosion in medical knowledge has led to increasing specialization and subspecialization, defined initially by organ system and more recently by locus of principal activity (inpatient as compared with outpatient), reliance on manual skills (proceduralist as compared with nonproceduralist), or participation in research. More recently, however, it is becoming increasingly clear that the same fundamental molecular and genetic mechanisms are broadly applicable across all organ systems and that the scientific methodologies of randomized trials and careful clinical observation span all aspects of medicine. Every physician must delight in learning the new, correcting the old, and perfecting the future. Much of what medicine now accomplishes depends on large-scale testing of procedures, interventions, vaccines, and new drugs. The fact that many such studies must be conducted in large populations through a multicenter approach provides an opportunity for all physicians to participate in clinical investigation in some way at some time in their professional careers. Indeed, this step is essential for the future of medicine and for physicians to move forward together as a profession. The patient-physician interaction proceeds through a number of phases of clinical reasoning and decision making. The interaction begins with an elucidation of complaints or concerns, followed by inquiries or evaluation to address these concerns in increasingly precise ways. The process commonly requires a careful history or physical examination, ordering of diagnostic tests, integration of clinical findings with the test results, understanding of the risks and benefits of the possible courses of action, and careful consultation with the patient and family to develop future plans. Physicians can increasingly call on a growing literature of evidence-based medicine to guide the process so that benefit is maximized while respecting individual variations among different patients. When this process is approached in a rigorous scientific manner, which does not mean coldly or impersonally, the results become reproducible and generalizable over time. New information, new techniques, and new technology can be brought into the process and their contribution evaluated in a conceptualization of the scientific method often termed continuous quality improvement. Through such constant commitment to advancing the frontiers of medicine, physicians improve health, discover true cures, devise new ways of delivering care, and reduce ultimate health costs.

THE PHYSICIAN AS CAREGIVER Being both professional and caring is an acquired skill. A physician can diagnose and prescribe in a technically correct and scientific, but insensitive way. The patient may be made better, even cured, but still feel unsatisfied with the interaction. In these cases, patients are likely to ask the questions: Does my physician really care? Does what happens to me matter to the physician? Does my doctor show sensitivity and compassion beyond mere technical ability? Patients want and deserve compassion and understanding. They want their physicians to be interested in them as individuals who seek advice, as well as relief from pain, disease, and suffering. They want to sense that they can safely share their deepest thoughts and their most heartfelt confidences with their physicians. In short, they want to value their physician as a trusted friend. Patients also expect to be kept informed while they are receiving competent professional service. As a caregiver, it is this sharing of oneself that is so very important. To some it may seem odd to talk about caring as a learned skill, but it is just that. In studying to be a physician, one must learn both compassion and caring. Easy, supportive interaction with patients and others less fortunate is a skill that comes readily for some and with great difficulty for others. In learning how to demonstrate compassion, Kahlil Gibran taught us: "You give but little when you give of your possessions--it is when you give of yourself that you truly give" (The Prophet). The giving of oneself with ease, with grace, and with meaning is, for most persons, an acquired skill. Sometimes a deep sense of awakening within is required to release the innate sensitivity and compassion that perhaps have not been expressed since childhood. Nevertheless, these traits remain imperatives if the aim is to become a "complete physician."

3

When patients seek medical attention, they entrust their doctors with their very lives. The physician must earn such complete trust. Technical abilities and skilled treatment of disease alone do not suffice. Patients must believe that their physicians care about them as people, not just as patients. Physicians, in turn, must understand that they do far better as professionals if they err on the side of being human with their patients. Dag Hammarskjold told us of "the humility that comes from others having faith in you." Without that touch of humility, physicians may be unable to understand and accept the trust that patients place in us. The physician must be willing to answer the patient's needs and also willing to undertake a long-term commitment to the patient's care. This commitment continues beyond a single insightful diagnosis or the completion of a procedure. The patient still needs care when the data come back from the clinical laboratory, the radiology department, the cardiac catheterization laboratory, or the surgical pathology laboratory. Patients continue to need help in understanding their disease, in dealing with family interactions, and in finding a caring ear when they suffer most. They often need assistance in obtaining necessary additional medical help from specialists or consultants and personal help in dealing with processes involving families and personal situations. Many patients need a link to community or social support systems. A particularly difficult time comes as physicians deal with patients who become old, frail, dependent, crippled, or cognitively impaired. These are the circumstances from which the most sensitive among us truly learn what it means to give of ourselves. Sometimes we may find once again that our patients are the best teachers.

THE PHYSICIAN AS A PROFESSIONAL To help orient our professional compass, the American Board of Internal Medicine has promulgated a definition of "professionalism": Definition: Professionalism in internal medicine comprises those attributes and behaviors that serve to maintain the interest of the patient above one's own self-interest.

A commitment to the highest standards of excellence in the practice of medicine and in the generation and dissemination of knowledge. A commitment to the attitudes and behaviors that sustain the interests and welfare of patients. A commitment to be responsive to the health needs of society. Professionalism aspires to altruism, accountability, excellence, duty, service, honor, integrity, and respect for others.

The interest of the patient lies above self-interest--an indispensable attribute not only of medicine but of all professions. It has to do with our personal behavior transcending our technical abilities, our scientific knowledge, and even our attitudes of compassion and caring. What it means is that we offer to others a special sensitivity--whether they be physician colleagues, students, residents, nonphysician caregivers, patients, or their families. To remain professionals, dignity and understanding must permeate all our interactions--all our thinking, teaching, learning, and listening.

SYSTEMS OF PATIENT CARE FOR THE MILLENNIUM AND BEYOND Students of medicine learn by didactics, observation, and directed participation. As they pass into residency, the avenues of participation become an increasingly independent course of training. In this intellectual experience of growing independence, young physicians learn how to analyze information, organize it, render compassionate and considered care, and deal with their professional colleagues, as well as with patients and their families. This historical independence of thought and action can make it difficult for many physicians who will be entering practice in the future to understand that the evolving changes in the health care delivery system will unavoidably affect that perceived level of independence. The virtually anonymous third-party payers of the past have now emerged as aggressive, prudent purchasers who are highly competitive with other payers. Patient care in the mass is becoming a big business, at least as it relates to insurers, managed care organizations, and groups of employers. Each of these entities has virtual control of large blocks of "covered lives" (patients) and has enormous influence over whether, when, and which physicians and hospitals deliver services. The system has been evolving over the past several years because of the perceived complexity of health care delivery, the increasing costs ascribed to technology and professional subspecialization, and the sheer size of the fraction of gross national product dedicated to health care. American businesses, large and small, realize the need to exert some sort of cost brake on the health care delivery system. The federal Medicare program of health insurance for persons older than 65 years and the federal and state government Medicaid programs of health insurance for defined categories of low-income people have grown as entitlement programs, further adding to the federal deficit and the limitations of budgetary flexibility. Additionally, because this country contains large numbers of uninsured and relatively poor, underinsured people, the government should respond by developing a mechanism for universal coverage and easier access to health care. The changing medical care environment places increasing emphasis on standards, outcomes, and accountability. As purchasers of insurance become more cognizant of value rather than just cost, outcomes ranging from rates of screening mammography to mortality rates with coronary artery bypass graft surgery become metrics by which rational choices can be made. Clinical guidelines and critical pathways derived from randomized control trials and evidence-based medicine can potentially lead to more cost-effective care, as well as better outcomes. However, these major changes in the American health care system bring with them a number of major risks and concerns. If the concept of limited choice among physicians and health care providers is based on objective measures of quality and outcome, the channeling of patients to better providers is one reasonable definition of better selection and enlightened competition. If, however, the limiting of options is based overwhelmingly on cost rather than on measures of quality, outcomes, and patient satisfaction, the historic relationship between the patient and the truly professional physician is fundamentally compromised. In this new environment the physician oftentimes has a dual responsibility: to the health care system as an expert who helps create standards, measures of outcome, clinical guidelines, and mechanisms to ensure high-quality, cost-effective care, as well as to individual patients who entrust their well-being to that physician to promote their best interests within the reasonable limits of the system. A health insurance system that emphasizes cost-effective care, that gives physicians and health care providers responsibility for the health of a population and the resources required to achieve these goals, that must exist in a competitive environment in which patients can choose alternatives if they are not satisfied with their care, and that places increasing emphasis on health education and prevention can have a number of positive effects. In this environment, however, physicians must beware of overt and subtle pressures that could entice them to underserve patients and thereby abrogate their professional responsibilities by putting personal financial reward ahead of their patients' welfare. The physician's responsibility to represent the patient's best interests and avoid financial conflicts by doing too little in the newer systems of capitated care provides different specific challenges but an analogous moral dilemma to the historic American system in which the physician could be rewarded financially for doing too much. In the current health care environment, all physicians and trainees must redouble their commitment to professionalism. At the same time, the challenge to the individual physician to retain and expand the scientific knowledge base and process the vast array of new information is daunting. If, however, physicians can address these various challenges, all citizens should have easier access to outstanding health care. Advances in medical science and increased individual responsibility for health-promoting behavior are both necessary for a fair, equitable, and cost-effective health care system that provides a level of quality acceptable to the American public. Advances in medical science are central to achieving high quality at acceptable cost. It follows that health care delivery systems must seek out proven technology to maintain their competitive position. Physicians in those organizations will have to be educated continually to provide the best professional advice regarding the adoption of new technologic advances, including information not only on their safety and efficacy but also on their effect on medical outcomes, patient satisfaction, and cost-effectiveness. From the standpoint of 4

the physician as a professional, the future is, in a sense, a return to the past when the physician and the patient were not insulated from economic realities and psychosocial contexts. High technology and high caring are not antithetic; they go together. Even though these economic and social changes are coming about in a rather turbulent fashion, the future stands out clearly. The practice of medicine will continue to be an exciting career pursuit and an honored profession that provides physicians a rewarding opportunity to help others. The great diagnosticians will be the ones who also have the greatest access to the newest and most comprehensive therapies. It is comprehensive medicine toward which we must strive rather than generalist medicine or subspecialist medicine; it is doing whatever is necessary to treat all aspects of the patient's disease. Whether it be in the intricacies of gene therapy or in behavior modification to treat substance abuse, "comprehensive" means being able to care for individuals in the best way with the greatest depth of knowledge. For physicians of the new century, this pursuit will be professionally and personally satisfying and will be welcomed by them as well as by society as a whole. American Board of Internal Medicine Committee on Evaluation of Clinical Competence: Project Professionalism. Philadelphia, American Board of Internal Medicine, 1994. Smith R, Hiatt H, Berwick D: A shared statement of ethical principles for those who shape and give health care: A working draft from the Tavistock Group. Ann Intern Med 130:143, 1999. Two careful discussions of professionalism in medicine and how it is a critical part of the health care system.

MD Consult L.L.C. http://www.mdconsult.com Bookmark URL: /das/book/view/882/6.html/top

Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Part II - SOCIAL AND ETHICAL ISSUES IN MEDICINE

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Chapter 2 - CLINICAL ETHICS IN THE PRACTICE OF MEDICINE Peter A. Singer Mark Siegler

Clinical ethics is a practical discipline that contributes to improvement in patient care. It focuses on the central importance of patient preferences and choices in the patient-physician relationship and on the moral obligations of physicians, such as the need for honesty, competence, compassion, and respect for the patient. Clinical ethics teaches physicians about a wide range of specifically ethical issues--informed consent, truth telling, end-of-life decisions, advance directives, and increasing third-party constraints on the autonomy of both patients and physicians. Although in theory these issues have been resolved, in practice they continue to vex conscientious physicians. The most clinically important ethical issues that arise frequently in the practice of internal medicine include decision making by competent patients, substitute decision making (including advance directives) for incompetent patients, end-of-life decisions, futility, and clinical-ethical concerns in an era of cost containment and health care reform.

DECISION MAKING BY COMPETENT PATIENTS During the past generation, the relationship between patients and physicians has become more equal. Most clinical decisions are now reached by a process of shared decision making in which physicians provide information and guidance that allow competent adult patients to base decisions on their own personal preferences, values, and goals. Competent adult patients have an ethical and legal right to accept or refuse medical care recommended by physicians, including life-sustaining treatments. Patients are in control of their own health care. In general, patients accept their physicians' recommendations because physicians and patients share the same goal--improving the patient's health status--and because patients usually trust and have confidence in both physicians' technical abilities and their commitment to the patient's welfare. INFORMED CONSENT. The clinical-ethical process of shared decision making is mirrored by the legal doctrine of informed consent. Informed consent is defined as voluntary acceptance by a competent patient of a plan for medical care after the physician adequately discloses the proposed plan, its risks and benefits, and alternative approaches. The informed consent process applies not only to invasive surgical procedures but to every clinical decision as well. Moreover, the legal and ethical standards of informed consent are not satisfied merely by obtaining the patient's signature on a consent form but require a process of effective communication and education between the physician and patient. If the patient has decision-making capacity (see later), the physician should seek consent from the patient; if the patient lacks decision-making capacity, the physician should seek consent from the appropriate substitute decision maker. The best way for young physicians to learn how to obtain informed consent from patients is by observing a clinician who is recognized for skill in negotiating the consent process. The patient's right to participate in treatment decisions is well recognized in law, philosophy, public policy, and clinical practice. Perhaps the clearest legal statement of this right was enunciated in 1914 by Justice Cardozo: "Every human being of adult years and sound mind has the right to determine what shall be done with his body." The philosophical right of patients to control their own medical care is based on the principle of individual autonomy. In the 1980s, a presidential commission clearly stated that respect for patient preferences should be the basis of public policy in medical ethics. Moreover, evidence from clinical research indicates that patients who participate in their own health care decisions are more likely to implement the shared decision, express greater satisfaction with their physician, and most importantly, have improved functional outcomes in several chronic diseases. DISCLOSURE AND TRUTH TELLING. For the purposes of informed consent, disclosure must include proposed diagnostic tests and treatments, their risks and benefits, and possible alternative approaches. Although standards for disclosure may vary from one jurisdiction to another, the physician should disclose all the information that a reasonable person in the patient's situation would want or need to know before making a decision. For example, physicians would be expected to inform patients about risks that are either highly likely to occur or less likely but very serious when they do occur, e.g., death or permanent disability. Although a subjective standard of disclosure based on an individual patient's personal view is a difficult clinical standard to achieve, physicians should try to know their patients well enough to tailor disclosure to a patient's particular situation. Another aspect of disclosure separate from the need to obtain informed consent involves telling patients the truth about unfavorable diagnoses, such as metastatic cancer, and their prognoses. In the United States, the current medical standard is to be honest with patients and not to conceal bad news. The patient's right to know an unfavorable diagnosis, even if no further tests or treatment is proposed, is grounded in the ethical principle of respect for persons and in the implied promise by physicians to be truthful in their relationships with a patient. The real clinical skill in "telling the truth" or delivering bad news to a patient involves determining exactly what the "truth" is in a particular case and then deciding how and when it should be imparted in a culturally sensitive way that does not destroy the patient's hope. DECISION-MAKING CAPACITY AND COMPETENCY. Decision-making capacity, a clinical concept, is the ability to understand relevant information and appreciate the consequences of a decision. Competency is the parallel legal concept. Patients who have been determined to have decision-making capacity should make their own health care decisions, based on the principle of autonomy, whereas patients determined to lack it should be protected from making bad and sometimes irreversible decisions, based on the principle of beneficence. Decision-making capacity is a dynamic state and may change quickly, as when a patient is admitted stuporous, hypotensive, and with sepsis and lacks this capacity but, 12 hours later, after appropriate treatment, is sitting in bed, conversing normally, and has regained it. Moreover, decision-making capacity is decision specific. For example, patients with substantial cognitive impairment may retain decision-making capacity to decide whether they wish to accept a recommended elective cholecystectomy. Unfortunately, no valid and widely accepted clinical measures are available to assess decision-making capacity. Physicians should assess this capacity by asking patients whether they understand and appreciate their medical problem and the risks and benefits of the proposed treatment and why they have chosen to accept or reject it.

6

The physician or health care team responsible for the patient should determine whether a patient retains or has lost decision-making capacity. When doubt exists,

consultation with a psychiatrist or neurologist may be helpful. Disagreements about decision-making capacity are often brought to the attention of hospital attorneys, ethics committees, or ethics consultants. In cases of irremediable conflict and if clinical circumstances permit, the ultimate judge of a patient's competency is a court. Often, however, the tempo of clinical circumstances may require physicians to make decisions by relying on clinical judgment and assistance from consultants to reach the best and most ethical determination.

SUBSTITUTE DECISION MAKING American legal theory accords incompetent patients the same rights as competent patients to consent to or refuse diagnostic tests and treatment. In practice, however, patients who lack decision-making capacity cannot exercise this right. To address this paradox, substitute decision makers, sometimes called surrogates or proxies, are permitted to make health care decisions for a patient who lacks decision-making capacity. The overall goal of substitute decision making is to approximate the decisions that the patient would make if the patient were still capable of making a decision. Substitute decision-making policies raise two questions: Who should make decisions for a patient who lacks decision-making capacity, and by what standards should the decision be made? The most appropriate person to make substitute decisions is someone designated by the patient while still competent, either orally or through a written proxy advance directive (see later). Other substitute decision makers, in their usual order of priority, include a spouse, adult child, parent, brother or sister, and any other relative or concerned friend. In some jurisdictions, a public official may serve as substitute decision maker for a patient who has no other decision maker available. Many states have now passed health surrogate laws that permit a substitute decision maker to be appointed without going to court when a patient lacks decision-making capacity and has no formal advance directive. The standards for making substitute decisions for patients without decision-making capacity are, in decreasing order of priority, the patient's explicit wishes, values and beliefs, and best interests. A patient's wishes are prior expressions, while competent, that apply to the actual decision that needs to be made, such as whether the patient wants mechanical ventilation in the late stages of amyotrophic lateral sclerosis. Sometimes patients record their specific wishes in an instruction advance directive (see the next section). Values and beliefs are less specific than explicit wishes, but they allow the substitute decision maker to guess what the patient might have decided based on other past choices and the patient's general approach to life. Best interests, which are "objective" estimates of the benefits and burdens of treatment to the patient, are invoked only when the patient's wishes, values, and beliefs are unknown. ADVANCE DIRECTIVES. The two types of advance directives are proxy directives, sometimes called durable powers of attorney for health care, which state whom a person wants to make treatment decisions on that patient's behalf, and instruction directives, sometimes called living wills, which state what treatment the person would or would not want in various situations. The person completes the advance directive when competent, and the directive generally takes effect if the person becomes incompetent. At present, advance directives are recognized legally in every state, and the federal Patient Self-Determination Act requires health care facilities to inquire whether patients have an advance directive and to inform patients of their rights under state law to complete an advance directive. Although public opinion polls indicate strong support for advance directives and although many different advance directive forms are available, relatively few Americans have filled out such directives. Recent evidence has highlighted the limited effect of advance directives on clinical outcomes, such as "do not resuscitate" orders, and on administrative outcomes, such as length of stay. Nevertheless, advance care planning has important psychosocial benefits for patients and families.

END-OF-LIFE DECISIONS With the possible exception of informed consent, no issue in clinical ethics has been as thoroughly analyzed as end-of-life decisions. Nevertheless, the spectrum of end-of-life decisions remains confusing for clinicians and the public. Three distinct practices can be delineated: decisions to forego life-sustaining treatment, euthanasia and physician-assisted suicide, and comprehensive care for dying patients that emphasizes palliation. The right of patients to refuse medical interventions also applies to life-sustaining treatment such as cardiopulmonary resuscitation, mechanical ventilation, dialysis, and artificial nutrition and hydration, even if such a decision results in the patient's death. "Do not resuscitate" orders, in which decisions are reached to forego resuscitation if the patient has a witnessed cardiopulmonary arrest, are by far the most widely used and best-studied examples of withholding potentially life-sustaining interventions. A patient's decision to discontinue (withdraw) or not to initiate (withhold) life-sustaining treatment is not considered the moral or legal equivalent of suicide, and physician participation in such an action is not the equivalent of physician-assisted suicide. These decisions may be made by the patient or substitute decision maker and are legally and ethically permissible when clinicians follow appropriate procedures, as outlined in the previous discussions of decision making by competent patients and substitute decision making. Clinicians must understand that such actions do not place them at legal risk and often reflect the best standards of clinical practice. In contrast to foregoing life-sustaining treatment, euthanasia and physician-assisted suicide are, at the time of this writing, prohibited in almost every legal system in the world, with one notable exception being the state of Oregon, which has legalized physician-assisted suicide. Euthanasia can be defined as an action that leads directly to the death of a patient, e.g., an injection of potassium chloride. Physician-assisted suicide can be defined as providing patients with medical means that the patient uses to commit suicide, e.g., the prescription of a large amount of barbiturates to a patient who then uses the drugs to commit suicide. The main arguments supporting physician-assisted suicide and euthanasia are based on respect for patients' freedom of choice and the claimed right of individuals to enlist a physician's assistance to end their pain and suffering. The main arguments opposing these practices include respect for human life, protection of vulnerable patients, and fear of abuse. Both proponents and opponents of physician-assisted suicide and euthanasia appeal to the role-related responsibility of being a physician to support their arguments. In 1997, the U.S. Supreme Court ruled that physician-assisted suicide is not a constitutional right and therefore state laws prohibiting or permitting the practice are not unconstitutional. Even if assisted suicide and euthanasia receive legal sanction in selected jurisdictions, physicians will still be confronted with the fundamental issue of whether such practices are ethical in a medical context. A third practice in the spectrum of end-of-life decisions is the provision of comprehensive clinical care, including palliative care, for dying patients. Such care should include the skilled use of pain-relieving drugs, as well as attention to the patient's other physical, psychological, social, and spiritual needs. Palliative care is ethically and legally permissible, even mandatory, and is an essential component of quality clinical care of the dying. A practical problem for physicians, however, is to distinguish appropriate palliative care from euthanasia. According to guidelines developed by the Chief Coroner of Ontario, an act is considered palliative care, and not euthanasia, if (1) it is intended solely to relieve the person's suffering, (2) it is administered in response to symptoms or signs of the patient's suffering and is commensurate with that suffering, and (3) it is not the deliberate infliction of death.

FUTILITY In contrast to a patient who refuses treatment is the situation in which patients or families wish to have certain treatments that physicians believe are futile. No ethical or legal framework has been established to address such cases. Despite numerous attempts to define futility, application of these definitions in practice has proved controversial. Physicians should distinguish among patients who are imminently dying (e.g., refractory cardiogenic shock), terminally ill (e.g., metastatic pancreatic cancer), and severely and irreversibly impaired (e.g., persistent vegetative state). When confronted with a futility case, physicians should strive to establish consensus, based on published data where available, among the various members of the health care team regarding the 7

appropriateness of various proposed treatment plans. The physician should communicate with the patient and family to understand their views, including their cultural, religious, and psychological perspectives. Based on this information, the physician may need to negotiate to reach consensus on a treatment plan that is acceptable to the patient and family, as well as the health care team. If consensus is not achievable, an impartial mediator may help resolve the disagreement. As a last resort, arbitration, sometimes via a formal legal approach, may be required. This process will be more effective if formalized as an institutional policy.

CLINICAL-ETHICAL CONCERNS IN MANAGED CARE Profound changes in the financing and organization of health care in recent years have intensified old ethical challenges and posed new ones for physicians. These challenges include but are not limited to access to health care for the uninsured, conflicts of interest, organizational ethics, resource allocation, managed care gag rules, and physician compensation incentives. To maintain ethical integrity, medical practice in a managed care environment should emphasize the ability to provide quality care, the ability of physicians to serve as their patients' advocates, the right of patients to select their own physicians and to make their own health care decisions, the requirement of physicians to disclose financial incentives that could influence their clinical recommendations, and the availability of reasonable appeal

mechanisms for patients or families who believe that their rights have not been honored.

CONCLUSIONS Scientific and technologic developments in medicine have created unprecedented ethical dilemmas for physicians, and the revolution in molecular medicine will generate additional ethical problems. Clinical ethics has emerged as a new and useful component of medical practice by emphasizing that technical and ethical concerns are inseparable in the practice of medicine. Clinical ethics focuses on the continuing centrality of the patient-doctor relationship and on how patients and physicians work within existing administrative and political structures to reach mutual agreement on clinical decisions affecting the patient. In addition, clinical ethics offers a language of discourse that broadens the medical model from one that is narrowly technical to one that takes serious account of individual patient preferences. The language and content of clinical ethics have been adopted not only by patients, physicians, nurses, other health care providers, and medical educators, but also by health economists, hospital administrators, policy developers, and judges. In this regard, ethical considerations in medicine are likely to remain an important component of medical education, clinical practice, biomedical research, and the political evolution of our health care system. Almost 2500 years ago, Plato recognized that good clinical medicine is a marriage of scientific knowledge and human care. In Book IV of The Laws, he described an excellent physician as one who "...treats disease by going into things thoroughly from the beginning in a scientific way and takes the patient and family into confidence. Thus he learns something from the sufferer.... He does not give prescriptions until he has won the patient's support, and when he has done so, he steadfastly aims at providing complete restoration to health by persuading the sufferer into compliance...." The best clinical medicine and patient outcomes are achieved when the patient and physician have established a relationship in which technical and personal aspects of care are integrated. The practice of ethical medicine in the twenty-first century will require nothing more but demand nothing less. www.bioethics.gov/nbac.html Website of the U.S. National Bioethics Advisory Commission. www.acp-asim.org/ethics/index.html Website of the American College of Physicians- American Society of Internal Medicine Center for Ethics and Professionalism. Includes College Ethics Manual. www.ama-assn.org/ethic/ethics.htm Website containing American Medical Association's ethics activities including Council on Ethical and Judicial Affairs, Institute for Ethics, and the Education for Physicians on End-of-life Care Project. www.med.upenn.edu/ bioethic Online information on bioethics from the University of Pennsylvania Center for Bioethics. www.utoronto.ca/jcb Online information on bioethics from the University of Toronto Joint Centre for Bioethics. Jonsen AR, Siegler M, Winslade WJ: Clinical Ethics: A Practical Approach to Ethical Decisions in Clinical Medicine, 4th ed. New York, McGraw-Hill, 1998. A practical guide to help clinicians deal with ethical problems that occur frequently in practice. Provides a clinical decision-making approach along with discussions of informed consent, decision-making capacity, end-of-life decisions, futility, and managed care. Singer PA (ed): Bioethics at the Bedside. Ottawa, Canadian Medical Association, 1999. Covers topics that will be important for clinicians in practice, including the topics in this chapter.

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Chapter 3 - CARE OF DYING PATIENTS AND THEIR FAMILIES Balfour M. Mount

Too many people suffer needlessly at the end of life, both from errors of omission--when caregivers fail to provide palliative and supportive care known to be effective--and from errors of commission--when caregivers do what is known to be ineffective and even harmful. Committee on Care at the End of Life Death calls into question our competence as caregivers, our unconscious premises regarding the omniscience of modern medical science, and the nature of our role in end-of-life care. It raises questions concerning meaning, life, death, and immortality. It may undermine communication with our patients and their family members and result in increased isolation and despair. It is the time when it is erroneously said that "nothing more can be done," yet it is a time to relieve suffering and develop individually tailored support programs. The physician has an unparalleled opportunity to act as a catalyst to enable comfort, communication, integration, and healing.

DEFINITION AND GOALS OF PALLIATIVE CARE Palliative care aims to improve the quality of life when treatment to cure disease and prolong life is no longer a realistic objective. It offers services designed to address the physical, psychological, social, and spiritual needs of dying patients and their families. Its goals are to relieve suffering, attain patient comfort without iatrogenic somnolence or change in affect, assist the patient and family in making the most of decreasing resources, and support those involved in a search for meaning. "Palliative care," in the broad sense of relieving suffering, is not restricted to those who are dying. The term "hospice," or an approach to care that includes medical, psychosocial, and spiritual issues, may also be used in this sense. In addition, hospice may also refer to the site of care or the organization or program that provides end-of-life care. Although this chapter deals with care of the dying in general, a spectrum of dying trajectories may be seen, including those experiencing a sudden unexpected death; those with an anticipated death after a relatively predictable, perhaps rapid, decline; and those facing a chronic illness of uncertain duration that may either be punctuated by acute crises or be relatively stable, only later to face an eventual decline or sudden death. Although the disease trajectory will shape the window of opportunity afforded the caregiver to support the patient, in all these situations the bereavement risk associated with those left behind should be assessed. The variety of possible dying trajectories is also a reminder of the importance of establishing a pattern of open, supportive communication with the patient and family concerning what the future may hold, their goals and aspirations, treatment options with their benefits and burdens, and their preferences for treatment intervention in relevant end-of-life settings. These discussions may lead to the completion of advance directives. They also tend to enhance coping as a result of both lessening the anxiety associated with uncertainty and promoting an enhanced sense of community in the face of adversity. Optimal care demands full-spectrum support--physical, psychosocial, and spiritual. Such comprehensive care must involve the patient, family, and an experienced multidisciplinary team, usually composed of both health care professionals and volunteers. The 8

great majority of terminally ill patients can be appropriately managed by their primary care physician. The primary care physician should have ready access to advice and consultation from local palliative care experts. A minority of patients may require temporary or permanent transfer to the care of a regional palliative care expert for the control of refractory distress. Quality of life--subjective well-being--is the central concern in end-of-life care. It is suggested by the response to "How are you today?" or "How are you in yourself?" or "How is it going these days?" Quality of life does not vary with physical status alone, but is modified by all domains of personal experience--physical, psychological, social, financial, and spiritual. It is what the patient says it is, not what objective observers see.

SYMPTOM CONTROL Attentive control of pain and other symptoms and detailed consideration of psychosocial and spiritual issues should characterize care from the time of diagnosis. When neglected until the late stages of disease, problems in these domains tend to become entrenched, interactive, and increasingly difficult to control. Vigilant prophylaxis of symptoms and attention to the nonphysical factors contributing to suffering lead to enhanced quality of life and diminished drug requirements. The main symptoms associated with terminal illness include pain, the anorexia-cachexia syndrome, weakness and fatigue, dyspnea and cough, nausea and vomiting, mouth problems, skin problems, lymphedema, ascites, confusion, dementia, and anxiety. These symptoms can be easily monitored by physical examination or by using 0 to 10 numerical, verbal, or visual analog scales. This information should be obtained during each visit and graphed in the patient record in a manner similar to the recording of vital signs earlier in the disease process. Physical status and cognitive function should also be regularly monitored with validated instruments because of their potential for rapid change and impact on defining care needs. Chapter 27 provides a detailed review of pain and its management. Because symptoms may change rapidly, frequent re-evaluation is an essential component of effective care of the dying (Table 3-1) . Norms of care are redefined in this setting. Only investigations that may lead to a treatment that will improve quality of life are considered. Blood pressure, pulse, and temperature are not routinely monitored, whereas the frequency of bowel movements is! Attention to detail is required for planning both assessment and care. For one very weak patient, use of a bedside commode or a bedpan and simply accepting occasional incontinence of urine and stool enabled conservation of scant energy reserves for eagerly TABLE 3-1 -- GUIDELINES FOR SYMPTOM CONTROL 1. "Nothing matters more than the bowels" (Saunders). Daily assessment needed. 2. Control of one symptom improves control of all symptoms. 3. Most symptoms are caused by multiple factors. Psychological distress may augment all symptoms. 4. "Assessment must precede treatment" (Twycross). 5. Rule out correctable factors underlying each symptom. 6. Clarify who is bothered by the symptoms: patient, family, or staff. 7. Give a simple explanation for each symptom to the patient and family. Diagrams helpful. 8. Consider the anticipated prognosis, functional status, and the patient's goals in determining appropriate treatment.

9. Discuss treatment options with patient and family and involve them in treatment planning when practical. 10. Determine what was helpful in the past. 11. Use a total-care approach employing nondrug, environmental, and other supportive measures. 12. If needed, use combinations of pharmacologic agents when differing mechanisms of action and toxicity permit. 13. Prescribe drugs prophylactically in individually optimized, regular doses for persistent symptoms. 14. Never say "Nothing more can be done." Consult or refer if comfort is not achieved. anticipated daily visits with his family. Bowel care for the equally weak, fiercely independent man in the next bed involved planned nonintervention while he laboriously struggled unaided to the toilet some 15 ft from his bed. A gentle offer of assistance was given ("When you wish, just let us know"), and a discussion of his need for autonomy was held with family members. Thus, radically different approaches to the details of bowel care were used for two dying men with divergent needs. Competent care of the dying involves meticulous care of skin, mouth, and eyes; adapting activities of daily living, furniture, and utensils to accommodate progressive weakness (a favorite chair raised on blocks, a padded and raised toilet seat, a spoon with a padded handle to accommodate a weak grip); clean smooth sheets; quiet music, flowers, and a few cherished belongings; the reassuring glow of soft lighting at night; and the reliable availability of both skilled nursing and an interested physician. Fears and misunderstandings about existing or anticipated symptoms and the effects of medication are common. The patient and family should participate in both planning and providing care. Clear explanations of symptoms and treatment options give reassurance that "the doctor understands what's going on" and "there is a plan."

COMMUNICATION ISSUES Giving bad news is always difficult. The physician should bring to discussions of prognosis not a set of fixed rules concerning whether "to tell" or "not to tell," but an openness to examining with the patient the reality at hand. Communication that is insensitive in the interest of "telling all" or evasive, falsely optimistic, or otherwise misleading in the interest of "protecting" the patient generally risks seriously undermining the long-range credibility of the physician. Studies suggest that the majority of patients with a serious illness sense the possibility of death, whether or not they have been told. Fears are usually diminished if they can be named. Integrating "bad news" is usually a process, not an event. Grave tidings are often repressed and simply "not heard" at the first airing. The physician should follow the pace of disclosure set by the patient and be sensitive to all forms of communication: plain language ("I fear I may be dying"), symbolic language ("I keep dreaming of a long tunnel with a candle at the end and I am afraid someone is going to blow the candle out"), and nonverbal communication (depressed facial expression, excessive muscle tension). It has been estimated that 80% of communication is nonverbal. The absence of questions does not mean that questions do not exist for the patient. The physician who says "I never tell patients they have cancer unless they ask me" risks leaving the responsibility of broaching the most sensitive and awesome questions to the one who is most vulnerable, the patient. Discussions should be positive, yet reality oriented. "Am I dying? How long do I have?" may be responded to by "I don't know how long any of us have to live. If you are asking if it is serious enough to warrant getting your affairs in order, I would say yes, get your house in order. While you're doing that, you and I will deal with the medical problems you're experiencing." Discussions focused on the goals of treatment minimize uncertainty and foster confidence. Involving the family in these discussions facilitates their subsequent mutual support. Sitting together, the patient, family, and doctor examine what is still possible rather than what has been lost. "There are only three aims we can have in treating any illness, Bill--to cure, to prolong life, and to improve the quality of life. We are not going to be able to cure your tumor in the sense of making it go away permanently. But, you know, there are many medical problems we can't cure--including diabetes, arthritis, and most types of heart disease--yet many people with these conditions live meaningful lives, sometimes for longer periods than we expect. "So `cure' isn't an option. What about the next goal, `to prolong life'? You could undergo surgery, but there is no sense putting you through something that wouldn't be helpful." (Surgery is often used as the first example since it presents a concrete, easily grasped image of futility.) "With treatments as they now stand, the same would be said for chemotherapy, radiotherapy, and immunotherapy." (The phrasing focuses on the limitations of current therapy, not the hopelessness of the illness.)

9

"Does this mean nothing more can be done?" (thus naming the worst fear). "Not at all! It simply means we are at the third goal--that of focusing on the quality of life. How can we make the best of this? Let's examine that. If I understand you, the three complaints you have right now are your backache, that cough, and your loss of appetite. Let's see what we can do about each of these....." The patient and family are left with a clear understanding that the issue is not "to treat or not to treat," but an appropriate shifting in therapeutic goals by a physician who is interested, involved, and undaunted by the specter of this illness. Hope is contagious. Hope is a way through, not a way out. Information about the expected prognosis may aid physicians in making recommendations and help the patient and family make plans, but specific estimates of an individual's survival should generally be avoided because of their inherent uncertainty. No matter how carefully phrased, such pronouncements always unsheathe a sword of Damocles that heightens anxiety and drains the ability to live fully in the moment: "I have only two more months." Accepting the present reality, including the increasing weakness, dependence, uncertain future, and impending loss, frees the patient to choose from available options. Acceptance of that kind is not born out of despair and resignation. It is the transcendent alternative to denial. It is a path to meaning that is possible even in the face of physical deterioration and advancing disease.

FAMILY AS THE UNIT OF CARE Terminal illness is a pressure cooker of family stress. Grief, fear, anger, and guilt abound. Long-standing interpersonal tensions tend to be accentuated. Family meetings to discuss treatment plans and identify problems and fears are a time-efficient tool highly effective in preventing impending crises, clarifying misunderstandings, and building bridges of mutual support. A checklist of areas of inquiry is useful in family assessment (Table 3-2) . Ensure that children and the elderly are informed and involved. Their exclusion often leaves them ill prepared for loss. The bereaved are a high-risk population with an increased incidence of impaired function, medical illness, psychological distress, and even death, especially when other risk factors for bereavement morbidity are present (Table 3-3) . Referral to programs offering bereavement support may be beneficial.

LOCATION OF DYING Death has been moved from the home to the institution in industrial nations, and family members often feel ill prepared to care for dying loved ones. With careful planning, family education, mobilization of community resources, and continuing support, however, both the family and patient may benefit from experiencing this last time together in the home. Even though more than two thirds of patients would prefer to die at home, not all of those expressing this wish will be able to live in comfort at home until death. A home-based death should not become an implied yardstick of success. The goal of care should be to support the patient and family as a unit in adapting to the realities of their needs and resources. Around-the-clock, 7-days-per-week availability of community-based services linked to backup inpatient beds enables the desired balance of maximum quality of life and efficiency in utilization of health care resources. Home care of the dying begins with careful home assessment

TABLE 3-2 -- FAMILY ASSESSMENT ISSUES 1. Identity of nuclear family, extended family, and social network 2. Characteristics of family system: roles, relationships, communication patterns 3. Presence of concurrent life crises 4. History of coping with past crises 5. Values and beliefs about death 6. Response to current illness: changes in roles and relationships 7. Family resources: physical, emotional, financial, social, spiritual 8. Immediate family needs 9. Long-range family needs

TABLE 3-3 -- SELECTED BEREAVEMENT RISK INDICATORS 1. Parental grief 2. Social isolation 3. Timid, dependent personality; poorly developed coping skills 4. Short preparation time (duration of illness) 5. Ambivalent or charged relationship with deceased 6. Concurrent life crisis 7. Pining and clinging in final illness 8. Grief expression repressed by cultural or family norms 9. Disenfranchised grief: mistress, lover, divorcee, loss of a secret relationship performed by an experienced home care team able to direct the family to needed community resources and to recommend modifications in living arrangements and furnishings to simplify care. "You will find it much easier if you rent a hospital bed. They are inexpensive. Try placing it in the living room where she can be quiet, close to the family, and able to see the children passing in the street." "She is weaker now. You will need a handrail and small bench for the bath tub and a walker. I think you would find a commode for the bedside helpful as well." An effective palliative home care program implies the involvement of a team. Regularly scheduled nursing visits are supplemented by emergency visits as required. A trusted physician is essential to consult in the home and collaborate with community-based nurses when the need arises. A social worker, occupational therapist, chaplain, and volunteers may all play a role. Simple, clear routines for medications and treatments are established. A sense of order and safety is fostered by around-the-clock availability of telephone consultation with experienced staff who are aware of recent changes in the patient's condition and medications. Brief respite admissions before family exhaustion sets in may help prolong the capability of home care. A sensitive discussion with the family about what to do when their loved one dies may promote a sense of confidence and preparedness. Acknowledgment of a job well done ("You certainly have done well to keep her at home this long") helps allay feelings of inadequacy and guilt should admission to the hospital become necessary.

AS DEATH APPROACHES During the final weeks or days of a terminal illness, frequent changes in clinical status may occur. Common crises include progressive weakness, inability to swallow, aspiration of oral intake, inability or refusal to take medications, changing levels of consciousness and orientation, restlessness, and urinary or fecal incontinence. Careful planning and prompt response to the request for emergency assistance can avoid unnecessary hospital admission. Individualized reductions in medication doses as death approaches can prolong an alert, interactive, comfortable state, often to the moment of death. Noisy upper airway secretions ("death rattle") are troubling to the family, who will need reassurance, but they are generally not troubling to the patient. They may be reduced by early intervention with hyoscine hydrobromide, 0.4 mg given subcutaneously at intervals of 2 to 4 hours as needed. Questions and fears that the patient and family have about death should be gently explored. The will, funeral arrangements, and a "life review" may be discussed as a means of completing unfinished business and facilitating closure. Encourage family members, including the young, the elderly, and those from out of town, to visit earlier rather than later. Assess bereavement risks and arrange follow-up support if indicated. Decathexis, a protective "separating off" or "turning in" by the patient, is sometimes seen as death approaches. A simple explanation may reassure the concerned family that this is not depression or rejection but a normal protective mechanism. "He doesn't need you to say much now, but your presence will help." Take premonitions of death seriously, and watch for the need for family members to give their lingering loved one permission to die. 10

"It's all right, John. You can let go. You've taken care of everything. We'll miss you, but thanks to you we'll be O.K."

AT THE TIME OF DEATH The hours that surround the death of a family member are charged with meaning for the bereaved and are usually remembered for years to come. Caregivers may use this experience to therapeutic advantage by establishing guidelines for patient and family care that facilitate subsequent grief work. Endeavor to have someone sitting at the bedside of the imminently dying person. If the bedside companion is a family member, be sensitive to the patient's need either for support or for time to be alone with the loved one. Encourage available family members to view the body before it has been moved to the funeral home. Seeing the body facilitates acceptance of the fact of death. When family members arrive, they need support and quiet hospitality, including a handkerchief, a cup of tea, a listening ear. Acknowledge the support given by the bereaved to the deceased during the illness. Allow sufficient time with the body for active grieving. It may be helpful for a caregiver to unobtrusively touch the body and thus indicate that there is nothing frightening about physical contact with the body--an experience that may be highly effective in promoting closure. Discuss whether the family wishes to have an autopsy. Many find the documentation of reality that an autopsy provides to be helpful in the months and years to come. When death occurs in a hospital, ask the family whether they would prefer to collect and pack their loved one's personal effects, particularly if a child has died. A memento of the event such as a lock of hair or a picture may be an aid to bereavement, especially in parental grief. Respect cultural differences in the expression of acute grief. Certain cultural groups may be extremely vocal and demonstrative in their grieving. Wails, screams, fainting attacks, and other dramatic gestures have therapeutic value for many and may be followed in a remarkably short period of time by a sense of composure and evident relief.

Acknowledge the mystery of death without offering "answers" concerning the unknowable. Honor religious rites and prayers meaningful to the bereaved. Attendance at the death or funeral service by the physician who was involved during the illness assists review of the illness, emphasizes the value of the deceased, underscores respect for the family, and assists the physician's own grief.

THE PHYSICIAN AND DEATH In caring for the dying, physicians are challenged in each dimension of their being. What do we do with our accumulated losses as caregivers? How do we establish a new balance in our emotional economy when an important investment has been lost? At what cost? To whom? Do our professional encounters with death leave a need for thicker defensive shells, emotional distancing, intellectualization, and acting out? The risk is minimized if we accept relief of suffering as our mandate rather than the narrower goal of fighting disease and if we attend to our own physical, psychosocial, and spiritual needs. Chochinov HM, Breitbart W: Psychiatric Dimensions of Palliative Medicine. New York, Oxford University Press, 1999. A detailed examination of psychiatric issues relevant to end-of-life care. Doyle D, Hanks GWC, MacDonald N: Oxford Textbook of Palliative Medicine, 2nd ed. New York, Oxford Medical Publications, 1998. The gold standard reference textbook on palliative medicine. Field MJ, Cassel CK: Approaching Death: Improving Care at the End of Life. Washington, National Academy Press, 1997. The Institute of Medicine and Committee on Care at the End of Life offer a detailed report concerning the experience of dying and the conditions that help people attain dignity, meaning, and comfort at the end of life. MacDonald N: Palliative Medicine, a Case-Based Manual. New York, Oxford University Press, 1998. Common clinical issues in palliative care addressed in a case-based format. An ideal resource for group teaching or self-directed learning. Portenoy RK, Bruera E: Topics in Palliative Care. New York, Oxford University Press, 1997. Informative reviews of topics related to delirium in cancer patients, gastrointestinal disorders in patients with advanced cancer, advances in the pharmacotherapy of pain and psychosocial adaptation to cancer.

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Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 4 - SOCIAL AND ECONOMIC ISSUES IN MEDICINE John E. Wennberg

A great deal about medical practice that a physician would like to know is not available in this edition of the Cecil Textbook of Medicine or in other medical texts. Examples of desired but missing information include data on exactly whether and when to hospitalize patients with a broad variety of medical conditions, conclusive evidence on the efficacy of many common surgical procedures, or details about how patients value the outcomes of interventions that physicians are likely to recommend. In the absence of this information and relying on a traditional model of decision making that assumes that the physician is able to act as the rational agent for the patient in choosing among treatment options, the medical system has developed as an economy in which the availability of hospital beds, physicians, and other local resources determines the pattern of care. Experts in economics have long held that the market for medical care differs from that for most goods and services because a competitive market assumes that the consumer is informed about availability, price, and market competition. Patients, by contrast, simply do not have enough information to choose their own care--and patients' widespread use of insurance means that the price of care does not closely modulate the decision to use it. In this market, the traditional remedy is to rely on professionals to control demand and for patients to delegate decision making to their physicians. The tacit agreement between patient and physician is that professionals, in fulfilling their ethical roles, prescribe only needed care. Physicians are also assumed to serve conscientiously as agents for society by ensuring that the supply of resources is adequate--but only adequate--to meet a rational level of demand. Although the physician's understood role as decision-making agent for both patient and society can be compromised by unethically inducing use for self-serving reasons, it has also been assumed that such activity is controlled by agencies, such as the Medicare program's Professional Review Organization, that patrol the market to discipline those who depart from the central consensus about what works and what patients need. It is increasingly apparent, however, that the foundation of much of medical care is not an evidence-based professional consensus about effectiveness and value. The decision to use care, such as hospitalization for a patient with pneumonia, is often driven by availability, not explicit theory. Even when theories of care are explicit--as in treating conditions such as angina pectoris or benign prostatic hypertrophy (BPH) (for which treatment options can range from surgery to drugs or watchful waiting)--the outcomes are often not well understood. Furthermore, physicians are imperfect agents; their own preferences for treatments or outcomes often become entangled with and overpower those of the patient.

FLAWS IN THE SCIENTIFIC AND ETHICAL BASIS OF CLINICAL DECISION MAKING For a number of conditions such as BPH, early-stage prostate cancer, or stable angina, medical theories of efficacy and professional discourse are well organized; opinions are strongly held concerning appropriate treatment, even when experts disagree. Often, disagreements cannot be resolved by appeal to evidence because adequate outcome studies have not been performed. In a market where patients rely on the profession to prescribe treatments, the existence of diverse professional opinions about the value of options invites suppliers to influence demand. In fee-for-service markets, where provider income and the financial stability of institutions depend on the level of utilization, such influence becomes inevitable. The marked variation in the rates of surgery for BPH found in studies conducted in the state of Maine in the early 1980s exposed the lack of consensus about how patients with BPH should be treated. Rates of surgery for BPH ranged between 15% undergoing surgery by age 85 in one town and 50% in another, quite similar 11

community. The rates were physician specific and attributable to at least two widely held and opposing theories about the benefits associated with surgery for BPH among Maine's urologists. The physicians differed in their assumptions about the nature of the underlying illness, as well as the benefits to be derived from surgery. Some believed in a preventive theory: Operate early to avoid later complications, including premature death. Others were more optimistic about untreated BPH. They argued for the quality-of-life theory: Surgery benefits most men by reducing symptoms and improving the quality of life. The unresolved competition between the prevention and the quality-of-life theories reflected indeterminacy rooted in poor clinical science. Subsequent research showed that the preventive theory was incorrect; early surgery appears to lead to a slight decrease in life expectancy because for most men, BPH does not progress to life-threatening obstruction and the small operative mortality risk reduces life expectancy slightly. Moreover, the studies showed that urine flow, the standard used to determine the urologists' estimate of the need for (and the success of) surgery, was an extremely poor indicator of how patients themselves valued their preoperative conditions and their surgical outcomes. What did matter to patients was the degree to which their symptoms bothered them (which was not necessarily related to symptom severity) and the possible negative outcomes of surgery such as impotence and incontinence. When patients are offered an active role in choosing treatment through shared decision making, the link between supply and utilization can be broken. When patients enrolled in two separate pre-paid group practices were informed about their options for treatment of BPH through an interactive videodisk program and were provided with information specific to their own clinical situations, most elected conservative treatment. Among those with severe symptoms, only one in five chose surgery, and the per capita rates of surgery declined about 50%.

THE THRESHOLD EFFECT FOR INTERVENTION Medical practice occurs within a context of available supply that is only rarely known to the participants--physicians generally have no idea how many beds per capita are available in their communities. The exception is the traditional health maintenance organization (HMO)--the closed-staff, pre-paid group practice model exemplified by Kaiser-Permanente and the Group Health Cooperative of Puget Sound. Such organizations know the number of people enrolled in their health plans and use population-based health planning to determine the per capita numbers of beds they provide and health workers they hire. They typically use about 150 hospital beds per 100,000 enrollees and employ physicians according to specialty-specific population-based ratios. Population-based planning is essential because the system receives a fixed amount of money for each enrollee for whom they agree to provide all "necessary" care. A fixed budget requires controlling resources, which is accomplished by setting limits on supply. In fee-for-service markets, by contrast, neither administrators nor health care providers know the size of the population that their organizations serve. Private-sector, population-based health planning that relates supply to consumption is virtually nonexistent. Populations do not "enroll," there are no fixed budgets, and revenue is generated by providing services. The lack of information on the quantity of local resources and the actuarial costs of local consumption supports a dynamic of market growth that is not closely constrained by the size or the health care needs of the population. An institution's growth is determined by its own perceived needs and its assumed roles in the community and the region. Size is influenced by such nonmedical factors as competition, prestige, or the expansion of professional staff to meet the critical mass required to ensure night and weekend coverage. The decision about how many specialists to train is less a function of how many are needed in a community than of the needs (and desires) of the directors of the training programs. Increasingly, the tools of epidemiology, applied to the study of supply and utilization in local health care markets, make it possible to compare resource allocation and utilization rates among communities (and in some cases between individual hospitals) as though they were the closed and countable populations of enrollees in closed-staff HMOs. These studies reveal remarkable differences in the per capita supply of resources, even among demographically similar markets. The studies also show that variations in supply affect the threshold for clinical decision making. The effect of supply of beds on the decision for hospitalization provides a cogent example. For example, although some of Boston's beds (and some of New Haven's) are used to care for people who live outside the city, Boston has nearly 50% more

beds per person in the local population than New Haven does. The differential in population-based availability of hospital resources produces a diffuse effect on the admission threshold for most conditions. A few "demand-driven" conditions, such as myocardial infarction and hip fracture, are unaffected by the available supply of resources (because virtually all physicians, regardless of the context of supply, agree on the need to hospitalize the patient). The increments of beds and other resources in high-resource communities are used for patients with "supply-sensitive" conditions such as pneumonia, congestive heart failure, and bronchitis, which in low-rate markets are more often treated on an outpatient basis. For such conditions, hospitalization rates for people living in Boston are typically 60% higher than for residents of New Haven. Furthermore, capacity and utilization vary substantially from hospital to hospital even within these cities. The threshold effect is not scaled simply on the severity of illness. As capacity increases, populations who are very sick as well as those who are not so sick receive more hospital care. A strong linear relationship exists between capacity and level of investment in terminal care. Yet more is not better in the dimension of life expectancy: Residents of Boston and New Haven experience the same population-based mortality rates. The effects of supply on decision making are subliminal inasmuch as neither administrators, clinicians, nor patients are directly aware of the supply context of local practice. The impact is primarily on the problem-solving tasks of medicine--the care of sick people with conditions about which medical theory is weak and evidence that one course of action is better than another is unproven. The rise of capitation, whereby physicians and hospitals assume total responsibility for patient care for a pre-negotiated price in a variety of practice settings other than traditional HMOs, has provided additional incentives to titrate the provision of medical services to match need rather than to match the historical supply of beds or capacity. While these incentives clearly reduce overutilization, care must be taken to ensure that professionalism, combined with guidelines and perhaps regulation, does not lead to underutilization.

REMEDIES FIND OUT WHAT WORKS. Biomedical science creates the fundamental understanding of the mechanisms of disease at the cellular and molecular levels and is a fruitful source of clinical theory and practice technologies for intervening in the lives of patients. However, its mission as a branch of applied biology does not emphasize evaluation of medical theories or communication about options. It is the job of the evaluative sciences to conduct technology assessments and outcomes research to estimate the probabilities for outcomes that matter to patients and to elucidate the importance of patient preferences in choosing treatment. Although some progress has been made, explicit policies to ensure the orderly evaluation of relevant treatment theories and the education of health professionals in evaluative sciences are not yet in place. FIND OUT WHAT PATIENTS WANT. The success of the biomedical revolution greatly increases medical options and, by doing so, exacerbates the problem of choice in medicine. Although the assumption that physicians can make vicarious decisions that reflect the patient's true preferences may seem naive, throughout most of the history of Western medicine it did not make much difference because there were few choices. Biomedicine and technology have changed the medical landscape; many conditions can now be treated by a number of options that carry different sets of risks and benefits. Rational choice among them depends on learning how to communicate medical options in ways that enable patients to choose among effective treatments according to their own preferences. Although emphasis on the ethical and legal requirements for 12

physicians to share decision making with patients is now greater, the striking variations in rates of surgery among communities and the association between capacity and the intensity of investment in terminal care are reminders that supply-inducing utilization remains a powerful force in medical markets. Successfully implementing shared decision making requires practice environments in which the choices patients make are not in conflict with the financial interests of health care organizations, employers, or individual providers. Creating such an environment is one of the great challenges of health care reform because breaking the link between supply and utilization creates a market in which demand emanates from patients and thus results in different per capita rates of consumption and different demands for resources. LIMIT CAPACITY. Stability in health care markets also requires that capacity be limited in some reasonable way. Many believe that practice guidelines will discipline the decisions of physicians to bring utilization and supply into equilibrium on the basis of medical efficacy. However, the evidence from Boston and New Haven indicates otherwise. The extraordinary variations in hospitalization rates among some of the nation's most prestigious teaching hospitals suggest that the rules have no firm scientific basis; some form of population-based planning is likely to be required. Arrow K: Uncertainty and the welfare economics of medical care. Am Econ Rev 53:941, 1963. A classic presentation of rational agency theory by a Nobel laureate in economics. Fuchs VR: Health care for the elderly: How much? Who will pay for it? Health Aff (Millwood) 18:11, 1999. A review emphasizing the cost implications of our increasing elderly population and increasing technologic capabilities. Katz J: The Silent World of Doctor and Patient. London, Collier Macmillan, 1984. An excellent review of the history of the doctor-patient relationship and the difficulty of establishing shared decision making. Wennberg JE, Cooper MM (eds): The Dartmouth Atlas of Health Care 1998. Chicago, American Hospital Publishing, 1998. Recent national study of small area variations.

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Part III - AGING AND GERIATRIC MEDICINE

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Chapter 5 - BIOLOGY OF AGING Caleb E. Finch Edward L. Schneider

THE LONGEVITY REVOLUTION As part of a remarkable revolution in human biology, the average lifespan has increased beyond 65 years in most human populations, and the fastest-growing age group is the oldest. In the United States since 1950, the age group 65 years and older has grown from 8% to 13% of the general population. The record lifespan is held by a recently deceased French woman, Jeanne Calment, who reached 122 years and 4 months. Despite impairments of vision and hearing, she appeared to be cognitively intact. It is predicted that by 2020 a total of 50 million will live to be at least 65 years of age, i.e., an increase by another 50% (Fig. 5-1) . Thus aging has become a world-wide issue affecting all nations, irrespective of their economic development. The key to maximum lifespan concerns how mortality rates change at later ages. During most of the adult lifespan, the mortality rate accelerates according to the Gompertz equation such that graphs of the log of the mortality rate for each year give a straight line when plotted against age. As a rule, the mortality rate doubles every 8 years throughout the world after puberty. However, new evidence shows that at advanced ages of 100 years or more, the acceleration of mortality rates slows considerably. It is possible that those already at advanced ages will achieve new record lifespans.

ARE DISEASE AND DISABILITY INEVITABLE WITH AGING? We do not fully understand the powerful historical trend for increasing survival to later ages. It seems unlikely that all the improvements can be attributed to the success of medical interventions and improved public health. Obviously, the decline in infant and maternal mortality played a major role in the observed increase in life expectancy at birth during this century. However, the increases in life expectancy at middle age preceded the introduction of antibiotics and other major life-saving interventions. At least some groups in the United States also seem to be aging with greater health, as judged by the declining rates of death from cardiovascular and cerebrovascular disease in the last decades. Lifestyle choices such as smoking, diet, and exercise certainly have a role, but other factors may be found. Major differences exist among populations in age-related diseases and changes that implicate environmental factors. Breast cancer, for example, has approximately a 10-fold higher incidence in Japanese women who live in California versus Japan; this difference continues throughout the adult lifespan. Within the same country, many differences can be seen. Even brain functions are subject to environmental influences, as suggested by the progressive improvement in scores on intelligence tests in different birth cohorts when tested at later ages. These examples imply that the outcomes of aging are subject to a great many environmental influences. Biologists refer to these environmentally influenced differences as plasticity in the aging processes. Alzheimer's disease shows both hereditary and environmental influences. Overall, the risk increases steadily with age and afflicts about 35% of those older than 85 years (see Chapter 449) . Alzheimer's disease is not a new disease, but it is becoming increasingly

Figure 5-1 Past and projected increases in the elderly by decade. (From U.S. Bureau of the Census, Current Population Reports, P25-1092. Population Projections of the U.S. by Age, Sex, Race, and Hispanic Origin. U.S. Government Printing Office, Washington DC, 1992.)

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prominent because of the increased numbers of individuals who are surviving to the eighth, ninth, and tenth decades. Genetic risk factors of different strengths have been mapped precisely. Familial Alzheimer's disease with early onset is strongly associated with rare mutations in the presenilin ( PS) genes on chromosomes 1 ( PS-2) and 14 ( PS-1) and in the amyloid precursor protein on chromosome 21. A more common susceptibility factor is found in the apolipoprotein E gene on chromosome 19. The apoE epsilon4 isoform confers a several-fold higher risk of Alzheimer's disease. Even so, some epsilon4/epsilon4 homozygotes retain mental health at ages beyond 100. Other gene associations (alpha1 -antichymotrypsin, alpha2 -macroglobulin, VLDL receptor, FE65) may differ in effect among populations. Higher education is associated with a lower risk of Alzheimer's disease, perhaps because persons with better cognitive function have more of a functional reserve before declining below an absolute level defined as cognitive impairment. Although education could also be a proxy for environmental effects, the mental demands of higher education may increase the synaptic density that could slow the loss of function.

AGING AND FUNCTIONAL DECLINE Many fears about aging are related to the myth that everything declines with aging. Even genetically identical mice experience heterogeneity in their physiologic responses to aging. In aging humans, the interplay of environment and genetic diversity similarly results in increasing heterogeneity in physiologic responses. Whether drug metabolism or exercise capacity is measured, the heterogeneity of aging is manifested by the substantial increase in differences among individuals. Thus whereas pharmacologic response to specific drugs may be relatively similar among 20-year-olds, predicting the response in 80-year-olds is considerably more difficult. The normal heterogeneity of aging is further compounded in a clinical setting by the diseases acquired during a lifetime and the increased number of medications taken by older patients. Many parameters such as resting cardiac output are relatively stable with normal aging. For other measures such as renal function as assayed by creatinine clearance, the response to aging varies widely--some individuals have a rapid decline with aging, others have moderate declines, and still others have no change at all. Nevertheless, a number of important physiologic variables decline substantially with aging and compromise the individual's ability to respond to pathologic insults. Some of these age-dependent factors include a decrease in vital capacity, immune function, and bronchiolar ciliary movement, as well as an increase in arterial wall stiffness. These changes decrease the ability of an older body to respond to specific insults such as infections or myocardial infarctions. Thus the risk of dying of pneumonia increases remarkably with aging and is probably related to both the decreased ability of the aged immune system to combat the pathogens and the impaired ability of the aged lungs to respond to this injury. The decline in sexual activities after mid-life also illustrates interactions between aging and disease. In women, the post-menopausal loss of estrogen and progesterone causes the reproductive tract mucosa to atrophy and become more subject to low-grade infections, either of which can make coitus painful (dyspareunia). Post-menopausal replacement of female sex steroids reverses many of these trends. Men also become less sexually active, although men have no equivalent of

menopause or universal decline in testosterone to castrate levels. Paternity has been documented in men 94 years old, some 34 years later than the record age for maternity. Vascular disease and diabetes are both associated with an increased risk of impotence. Maximum aerobic exercise capacity declines with aging and is probably responsible for the retirement of star athletes. Marathon times become progressively longer with advancing age, even in devoted athletes. Nonetheless, older individuals who exercise can raise their maximum aerobic capacity to the level of young sedentary individuals. Skeletal muscles, even in the very old, show remarkable capacity for regaining strength with proper exercise. Regular exercise programs can also slow down age-related bone loss and thus partially protect against hip and other fractures in the elderly. Exercise can also improve cardiac performance, as well as diminish the risk of hypertensive disease. These associations suggest that with the decline of so many physiologic functions, one could die of "old age." Some death certificates have even listed "old age" as the cause of death. Careful investigation, however, usually reveals that the patient died of a recognizable disease, such as pneumonia, that might not have killed a 20-year-old but did produce the final blow to an older individual whose physiologic responses had been severely diminished with aging. Another important relationship between aging and disease is the concept that age-dependent loss of specific cell populations may result in specific age-dependent diseases and disorders. For example, with aging comes a loss of cerebral cholinergic neurons that cannot be attributed to vascular disease or Alzheimer's disease alone. The extent of neuron loss during normal aging is controversial and hard to establish, in part because large neurons tend to shrink. Vascular changes, which are common in cerebral arteries, may impair the availability of nutrients, even without clinically recognized strokes, and over time result in damage to neurons. The brains of Alzheimer's disease victims younger than 70 years show a clear distinction from the brains of nondemented patients of the same age in the number of plaques and tangles. At very advanced ages, however, it becomes more difficult for the neuropathologist to distinguish between "normal" aging and Alzheimer's disease.

LESSONS FROM OTHER SPECIES GENETICS OF LIFESPANS. The trends for increased survival to later ages lead to fundamental questions about the biology of aging, particularly about genetic control over the lifespan. Many species of animals have short natural lifespans that are dictated in unknown ways by their particular genes. Laboratory rodents possess the shortest lifespans among mammals, about 5 years at the maximum; domestic cats and dogs and cattle survive in the middle range to 20 years at the most; humans enjoy the upper end. The best-recognized effects of genes on the lifespan are the mutations that cause early-onset diseases. In contrast to mammals, research on invertebrates has identified specific genes that can increase the lifespan, as well as others that decrease it. The fruitfly Drosophila normally lives for about 2 months, but the artificial evolution of short- and long-lived lines of flies was accomplished by choosing individuals that reproduce at younger versus later ages. The resulting selection for lifespan depended on existing genetic variation in the wild-caught flies rather than on new mutations, but the particular survival-influencing genes are still being sought. The nematode Caenorhabditis also possesses "survival" genes that increase the organism's lifespan, which normally takes only 3 weeks from egg to senescence. Mutants have been found that have double the lifespan because of slower acceleration of mortality (Gompertz rate). These studies on flies and nematodes give clues in the search for genes that favor longer lifespans in mammals. Nonetheless, it is sobering to the genetic view that fewer than half of individual variations in adult lifespan can be attributed to genetics in humans, mice, flies, and worms. This observation implies that lifestyle and the environment are more important for most individuals than their inherited genes in how they age. ENVIRONMENTAL INFLUENCES ON THE LIFESPAN. Rodents show clear evidence of environmental influence in outcomes of aging. By reducing their dietary intake to about half ad libitum normal without vitamin or mineral deficiencies, the animals live up to 50% longer, with correspondingly slower acceleration of the mortality rate. Diet restriction also reduces age-related diseases, e.g., the lymphomas and kidney lesions, that usually kill aging rodents. Moreover, diet restriction can delay infertility during aging by slowing the loss of ovarian oocytes. Metabolic changes include a lower blood glucose level and increased insulin efficiency, opposite the usual trend during aging. These examples from other species demonstrate a wide range of environmental interventions that can modify the outcomes of aging. By implication, the recent increase in human life expectancy could be due largely to environmental rather than genetic changes. DO SOME SPECIES ESCAPE AGING? Extremely slow patterns of aging are found in many species, especially plants. Bristlecone pines live at least 4800 years without change in the viability of the seeds that they produce each year, and 1000 years is not unusual in other conifers. Geoducks and quahogs, both bivalve mollusks, live 15

at least 200 years. In the northern Pacific, several species of rockfish can live at least 100 years and show no loss of fertility. Turtles may also exceed 100 years. Although no general signs of age-related dysfunction are known in these long-lived examples, detailed studies remain to be done. To experience a complete absence of aging, an organism would be required to repair all types of injuries and rid itself of abnormal growths. Theoretically, the retention of a complete set of genes by cells throughout the body ("somatic cell genomic totipotency") could lead to replacement of any damaged tissue. Achieving this goal through the control of gene activity, however, would not confer immortality because death still overtakes individuals, even in the absence of age-related disorders. In humans, the safest of all ages occurs at about the time of puberty, when the mortality risk through accidents and disease is about 1:2000 per year. If this risk were maintained indefinitely without the usual acceleration, the life expectancy at birth would be about 1200 years, and the last survivor in a population of 4 billion would be 25,000 years old. Although fantastic improvements over the present human lifespan may be accomplished through disease reduction, humans would still be subject to unavoidable dangers that statistically limit the ultimate lifespan.

EVOLUTIONARY THEORY OF AGING The evolutionary view recognizes that young adults produce the most offspring; even if reproductive capacity were not subject to age-related declines, natural hazards would reduce the older population. Natural selection acts mostly on children and young adults, who are the most responsible for propagation of the species. Correspondingly, the force of natural selection against harmful or disadvantageous genes becomes progressively weaker with advancing age. As a consequence, theory predicts that mutations in the population gene pool are tolerated if any adverse effects are delayed to older ages. Among examples of genes with delayed adverse effects are hereditary Alzheimer's disease and hereditary risks of breast cancer. Many different genes may cause particular diseases of aging.

CELL BIOLOGY OF AGING Numerous theories address specific aging changes in processes ranging from the molecular to the organ system level of function. One of the oldest is the somatic mutation theory, which originally focused on chromosomal genes. There is little doubt that somatic cells accumulate oncogenic mutations on a sporadic and scattered basis during the individual lifespan and that these mutations are of great importance to the age-related increase in cancer. However, relatively few nuclear genes in any cell show evidence of accumulated damage through mutations. The somatic mutation theory has been expanded to include mitochondrial DNA mutations. In certain brain regions with high concentrations of the neurotransmitter dopamine, 1 to 5% of the mitochondria may have DNA deletions that impair adenosine triphosphate production. Free radical theories postulate that endogenously generated and highly reactive free radicals cause the somatic mutations just described. Free radicals can also damage proteins. Slowly replaced proteins such as collagen and elastin tend to show the accumulation of oxidized amino acids and the addition of glucose derivatives (glycosylation), both of which involve free radical chemistry. Some features of diabetes such as diabetic lens opacity are associated with glycosylated proteins. Antioxidants and compounds that trap free radicals may slow or reverse the oxidation of proteins during aging. Oxidative damage from free radicals is increasingly implicated in degenerative diseases of aging. Epidemiologic studies indicate that specific antioxidants may protect individuals who are at risk for coronary artery disease, cataracts, and certain cancers. Neurodegeneration during Alzheimer's disease is also suspected to be driven by free radical mechanisms that are stimulated by beta-amyloid peptide. The gene for familial amyotrophic lateral sclerosis has been mapped to the chromosomal locus for superoxide dismutase, which converts the free radical of oxygen to hydrogen peroxide, which in turn is converted to harmless water and oxygen. Cell-aging theories are based on the finite number of possible divisions made in culture by skin fibroblasts and by most other cells obtained from humans (the Hayflick limit phenomenon). The causes of clonal aging appear to involve the activities of genes that control cell proliferation, some of which are also crucial to malignancy, such

as the p21, p53, and Rb genes, which may normally serve as tumor suppressors but are commonly mutated in human cancers. Most investigators agree that the nondividing status that follows repetitive proliferation does not lead to cell death. If kept carefully, nondividing cells can live for many months in culture dishes. This observation is consistent with the fact that hearts and brains are full of cells that ceased dividing decades ago. Cell senescence may also involve loss of DNA at the ends of chromosomes (telomeres); immortal cancer cells, as well as the germ-like cells in the gonads, are protected against telomere shortening by an enzyme called telomerase. When telomerase is genetically introduced, fibroblasts can bypass the Hayflick limit. It is not yet known whether these cell lines would be malignant in the body. Programmed cell death also relates to aging. During development, excess numbers of neurons, lymphocytes, and other cells die through a genetically programmed sequence of changes called apoptosis. Cell death, however, can arise from other causes such as ischemia or toxins, a process referred to as necrotic cell death. In the aging prostate, apoptosis can be observed among benign proliferating cells. Such natural mechanisms of cell death may protect against the progression of abnormal growths during aging. Immune theories of aging are based on the observation that with aging the primary immune response weakens as reflected by the increasing vulnerability to influenza and other infections. One factor is an increase in memory T cells at the expense of virgin T cells, with a net effect of reducing the response to novel antigens. On the other hand, a general increase is seen in low-grade autoimmune and inflammatory processes such as arthritis. The net result indicates that hyperactivity in some immune functions coexists with hypoactivity in others. Ultimately, this complex situation may be understood in terms of the regulation of genes that control the proliferation of immune cell populations. Endocrine theories account for a wide range of physiologic changes. Certain post-menopausal dysfunctions, as noted earlier, are clearly related to the exhaustion of ovarian follicles that produce estrogen and progesterone. The loss of estrogen accelerates osteoporosis. Moreover, the beneficial effects of estrogen, which also reduces the risk of heart attacks, strokes, and possibly Alzheimer's disease, are lost at menopause. Melatonin and dehydroepiandrosterone are sometimes advertised as "miracle" hormones for aging, but there is little evidence that they benefit the outcomes of normal aging. Neuroendocrine theories address subtle changes in the output of the pituitary that accompany aging. The decreased secretion of growth hormone, for example, is modest in most older adults. Some individuals may suffer growth hormone deficits that cause skeletal muscle atrophy, which can be corrected by growth hormone replacement therapy. Nothing, however, suggests the presence of general deficits of growth hormone that would warrant therapeutic replacement on the scale practiced for estrogen replacement after menopause. Many other age changes could be linked to altered functions of brain centers that influence the autonomic nervous system and metabolism. Such associations are largely speculative in humans. Wear-and-tear theories include mechanical and biochemical features of aging. Insects can wear out their irreplaceable wings. Tooth and joint erosion is common during human aging. At the molecular level, endogenously produced free radicals may damage certain irreplaceable molecules.

SUMMARY Aging changes appear to be very diverse and subject to numerous environmental and genetic influences. Aging processes thus show a great deal of plasticity and potential for modification. With the exception of the ovary, no other organ appears to have a programmed senescence in adult life that leads to predictable complete loss of function during aging in all human populations. Although some individuals carry genes that predispose them to early onset of specific degenerative diseases, there is much reason to 16

anticipate that interventions will be possible. The reduced rates of death from ischemic heart disease in recent decades show the importance of lifestyle in the outcomes of aging. Many biologists and geriatricians are convinced that the potential for successful aging by maintaining health and independence at advanced ages is far greater than recognized by the general public. General Austad SN: Why We Age. What Science Is Discovering About the Body's Journey Through Life. Wiley, New York, 1997. Excellent overview on aging of different organs and processes. Bodnar AG, Ouellette M, Frolkis M, et al: Extension of life-span by introduction of telomerase into normal human cells. Science 279:349, 1998. Breakthrough on clonal senescence. Hazzard WR, et al: Principles of Geriatric Medicine and Gerontology, 4th ed. Healthcare Management Group, 1998. Broad coverage and many special topics. Schneider EL, Rowe JW: Handbook on the Biology of Aging, 4th ed. San Diego, Academic Press, 1996. A regularly updated and authoritative source of reviews by mainstream researchers. Wachter K, Finch CE: From Zeus to the Salmon. The Biodemography of Aging. Washington, DC, National Academy of Sciences, 1997. Current data on the increased human lifespan and biological interpretations of advanced age. Genetics of Aging Finch CE, Tanzi RE: The genetics of aging. Science 278:407, 1997. Summary of recent findings on the genetics of lifespans and mechanisms of aging.

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Chapter 6 - NEUROPSYCHIATRIC ASPECTS OF AGING Sharon K. Inouye

OVERVIEW The process of aging produces important physiologic changes in the central nervous system (Table 6-1) , including neuroanatomic, neurotransmitter, and neurophysiologic changes. These processes in turn result in age-related symptoms and manifestations (Table 6-2) for many older persons. However, these physiologic changes develop at dramatically variable rates in different older persons, the decline being modified by factors such as diet, environment, lifestyle, genetic predisposition, disability, disease, and side effects of drugs. These changes can result in the common age-related symptoms of benign senescence, slowed reaction time, postural hypotension, vertigo or giddiness, presbyopia, presbycusis, stiffened gait, and sleep difficulties. In the absence of disease, these physiologic changes usually result in relatively modest symptoms and little restriction in activities of daily living. However, these changes decrease physiologic reserve and hence increase the susceptibility to challenges posed by disease-related, pharmacologic, and environmental stressors. Neuropsychiatric disorders, the leading cause of disability in older persons, account for nearly 50% of functional incapacity. Severe neuropsychiatric conditions have been estimated to occur in 15 to 25% of older adults world-wide. Importantly, these conditions TABLE 6-1 -- AGE-RELATED PHYSIOLOGIC CHANGES IN THE CENTRAL NERVOUS SYSTEM Neuroanatomic changes Brain atrophy Decreased neuron counts Increased neuritic plaques Increased lipofuscin and melanin Neurotransmitter changes Decline in cholinergic transmission Decreased dopaminergic synthesis Decreased catecholamine synthesis Neurophysiologic changes Decreased cerebral blood flow Electrophysiologic changes (slowing of alpha rhythm, increased latencies in evoked responses)

TABLE 6-2 -- NEUROPSYCHIATRIC MANIFESTATIONS OF AGE-RELATED PHYSIOLOGIC CHANGES MANIFESTATION

SYSTEM Cognition

Forgetfulness Processing speed declines through adult life Neuropsychological declines: selective attention, verbal fluency, retrieval, complex visual perception, logical analysis

Reflexes

Stretch reflexes lose sensitivity Decreased or absent ankle reflexes Decreased autonomic and righting reflexes, postural instability

Sensory

Presbycusis (high-frequency hearing loss), tinnitus Deterioration of vestibular system, vertigo Presbyopia (decreased lens elasticity) Slowed pupil reactivity, decreased upgaze Olfactory system deterioration Decreased vibratory sensation

Gait/balance Gait stiffer, slowed, forward flexed Increased body sway and mild unsteadiness Sleep

Decreased sleep efficiency, fatigue Increased awakenings, insomnia Decrease in sleep stages 3 and 4 Sleep duration more variable, more naps

are due to diseases that increase with age but are not part of the normal aging process. Alzheimer's disease and related dementias occur in approximately 10% of those aged 65 and older and up to 40% of those older than 85 years. Delirium occurs in 5 to 10% of all persons 65 years and older, usually in the setting of acute illness and hospitalization. Severe depression occurs in approximately 5% of older adults, with as many as 15% having significant depressive symptoms. Anxiety disorders occur in 10% of older adults. Common geriatric neuropsychiatric conditions include delirium (Chapter 444) , dementia (Chapter 449 .3), and depression (Chapter 450) . Older individuals are also subject to substantial morbidity and functional disability from cerebrovascular disease (Chapter 470) , Parkinson's disease (Chapter 460) , peripheral neuropathies (Chapter 498) , degenerative myelopathies such as spinal stenosis (Chapter 493) and disk disease (Chapter 494) , giant cell arteritis (Chapter 295) , subdural hematoma (Chapter 471) , seizure disorders (Chapter 484) , sleep apnea (Chapter 87) , falls (Chapter 8) , incontinence (Chapter 119) , and impotence (Chapter 247) . To diagnose these conditions, physicians must understand and perform a mental status examination and an assessment of functional capacity and know the uses and side effects of psychoactive drugs in geriatric patients.

MENTAL STATUS EXAMINATION In addition to a detailed neurologic examination, evaluation of neuropsychiatric disturbances in older persons requires a careful mental status examination, including an assessment of mood, affect, and cognition. Brief screening tests are available to evaluate these domains and to assist in the detection of potential problems requiring further evaluation and treatment. For depression screening, scores of 6 or more on the 15-item short-form Geriatric Depression Scale (Table 6-3) indicate substantial depressive symptoms requiring further evaluation. Alternative depression screening instruments include the Center for Epidemiologic Studies--Depression Scale and

the General Health Questionnaire; for cognitively impaired patients, observer-rated depression scales such as the Hamilton Depression Scale are recommended. Early cognitive deficits can easily be missed during conversation because intellectual impairment can be readily masked with intact social skills. Given the high frequency of cognitive impairment, formal cognitive screening is recommended for all older persons. Ideally, cognitive testing should evaluate at least the general domains of attention, orientation, language, memory, visuospatial ability, and conceptualization. To exclude delirium, attention should be assessed first by asking the patient to perform a task such as repeating five digits or reciting the months backwards; the remainder of cognitive testing will not be useful in an inattentive patient. For further cognitive testing, many brief, practical screening instruments are available. The most widely used instrument is the Mini-Mental 17

TABLE 6-3 -- GERIATRIC DEPRESSION SCALE--SHORT FORM 1. Are you basically satisfied with your life?

yes/ NO

2. Have you dropped many of your activities and interests?

YES /no

3. Do you feel that your life is empty?

YES /no

4. Do you often get bored?

YES /no

5. Are you in good spirits most of the time?

yes/ NO

6. Are you afraid that something bad is going to happen to you?

YES /no

7. Do you feel happy most of the time?

yes/ NO

8. Do you feel helpless?

YES /no

9. Do you prefer to stay home rather than going out and doing new things?

YES /no

10. Do you feel you have more problems with memory than most?

YES /no

11. Do you think it is wonderful to be alive now?

yes/ NO

12. Do you feel pretty worthless the way you are now?

YES /no

13. Do you feel full of energy?

yes/ NO

14. Do you feel that your situation is hopeless?

YES /no

15. Do you think that most people are better off than you are?

YES /no

Scoring: Answers indicating depression are highlighted; six or more highlighted answers indicate depressive symptoms. Adapted from Yesavage J, Brink T, Rowe T, et al: Development and validation of a geriatric depression screening scale: A preliminary report. J Psychiatr Res 17:37, 1983. State Examination, a 19-item, 30-point scale that can be completed in 10 minutes (Table 6-4) . A score of 25 or more generally indicates intact cognitive function, whereas a score of 24 or less requires further evaluation for potential dementia. Further bedside testing can include asking the patient to draw a clock with the hands at a set time to assess visuospatial ability and higher cortical functions. Questions to evaluate judgment and problem-solving ability in hypothetic situations, such as in a fire or when driving, can provide critical insight into the patient's ability to function safely and independently.

FUNCTIONAL ASSESSMENT Functional impairment, defined as difficulty in performing daily activities, is common among elderly persons. Although not routinely evaluated in the standard medical assessment, determination TABLE 6-4 -- MINI-MENTAL STATE EXAMINATION COGNITIVE DOMAIN

MAXIMUM SCORE

Orientation What is the (year) (season) (date) (day) (month)?

5

Where are we (city) (state) (county) (hospital) (floor)?

5

Registration Name 3 objects: 1 sec to say each. Ask the patient for all 3 after you have said them. Give 1 point for each correct answer. Repeat them until all 3 are learned. Count the trials and record the number.

3

Attention and calculation Serial 7s backward from 100 (stop after 5 answers).

5

Alternatively, spell WORLD backward. Recall Ask for the 3 objects repeated above. Give 1 point for each correct answer.

3

Language and praxis Show a pencil and watch, and ask the patient to name them.

2

Ask the patient to repeat the following: "No ifs, ands, or buts."

1

Three-stage command: "Take this paper in your right hand, fold it in half, and put it on the floor."

3

"Read and obey the following: Close your eyes."

1

"Write a sentence."

1

"Copy this design" (interlocking pentagons).

1

A score of 25 or greater signifies intact cognitive function. Adapted from Folstein MF, Folstein SE, McHugh PR: "The Mini-Mental State": A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 12:189, 1975. of the patient's degree of functional incapacity based on medical and neuropsychiatric conditions is critical to understanding the burden of disease and its impact on the individual's daily life. The important relationship of functional status with health in older persons is reflected in the finding that functional measures are stronger predictors of mortality after hospitalization than are admitting diagnoses. Moreover, functional measures strongly predict other important hospital outcomes in the elderly such as length of stay, functional status at discharge, future care needs, caregiver burden, risk for institutionalization, and long-term prognosis. The functional assessment should include an assessment of the patient's ability to carry out basic self-care activities of daily living, as well as higher-level activities needed for independent living, the instrumental activities of daily living. Performance of activities of daily living reflects the ability of the patient to perform basic self-care activities, including feeding, grooming, bathing, dressing, toileting, transferring, and walking. Performance of instrumental activities of daily living reflects the ability of the patient to perform more complex tasks, including shopping, meal preparation, managing finances, housekeeping, using the telephone, taking medications, driving, and using transportation. The functional assessment is carried out with the patient or the family, and the questions ascertain whether the patient can perform these activities independently. Other related domains that should be assessed include vision, hearing, continence, nutritional status, safety, falls, living situation, social supports, and socioeconomic status.

The onset of acute functional decline is often the first and sometimes the only sign of serious acute illness in older persons and warrants immediate medical attention. Similarly, the onset or worsening of related conditions such as delirium, falls, incontinence, depression, or "failure to thrive" heralds the need for prompt medical evaluation.

PSYCHOACTIVE EFFECTS OF DRUGS IN OLDER PATIENTS ADVERSE DRUG EVENTS IN THE ELDERLY. Iatrogenic complications occur in 29 to 38% of older hospitalized patients, with a three- to five-fold increased risk in older as compared with younger patients. Adverse drug events, the most common type of iatrogenic complication, account for 20 to 40% of all complications. The elderly are particularly vulnerable to adverse drug reactions because of multiple-drug regimens, multiple chronic diseases, relative renal and hepatic insufficiency, decreased physiologic reserve, and altered drug metabolism with aging. Moreover, inappropriate drug use has been reported in about 40% of hospitalized older patients, with more than one quarter of these patients having absolute contraindications to the drug and the others being given a drug that was unnecessary. Because 50% of adverse drug events occur in patients receiving inappropriate drugs, the potential for reducing these adverse events is substantial. DRUGS WITH PSYCHOACTIVE EFFECTS. Nearly every class of drugs has the potential to cause delirium in a vulnerable patient, but specific drugs have been most commonly implicated (Table 6-5) and should be used with caution in older patients. Many cases of delirium or cognitive decline in older patients may be preventable through avoidance, substitution, or dose reduction of these psychoactive drugs. Long-acting benzodiazepines (e.g., flurazepam and diazepam) are particularly problematic medications for the elderly and should be avoided whenever possible. If non-pharmacologic approaches to the management of insomnia are unsuccessful, short-term use of an intermediate-acting benzodiazepine without active metabolites (e.g., lorazepam, 0.5 mg, half-life of 10 to 15 hours) is recommended. Drugs with anticholinergic effects (e.g., antihistamines, antidepressants, neuroleptics, antispasmodics) produce a panoply of poorly tolerated side effects in older patients, including delirium, postural hypotension, urinary retention, constipation, and dry mouth. Of the narcotics, meperidine causes delirium more frequently than other agents do because of an active metabolite, normeperidine. Cardiac drugs such as digitalis and antiarrhythmic agents have prolonged half-lives, narrowed therapeutic windows, and decreased protein binding in older patients. The clinician should be aware that toxicity with these agents, e.g., digoxin, can occur even at therapeutic drug levels. The H2 -receptor 18

TABLE 6-5 -- DRUGS WITH PSYCHOACTIVE EFFECTS Sedative/hypnotics Benzodiazepines (especially flurazepam, diazepam) Barbiturates Sleeping medications (chloral hydrate) Narcotics (especially meperidine) Anticholinergics Antihistamines (diphenhydramine, hydroxyzine) Antispasmodics (belladonna, Lomotil) Heterocyclic antidepressants (amitriptyline, imipramine, doxepin) Neuroleptics (chlorpromazine, haloperidol, thioridazine) Antiparkinsonian (benztropine, trihexyphenidyl) Atropine/scopolamine Cardiac Digitalis glycosides Antiarrhythmics (quinidine, procainamide, lidocaine) Antihypertensives (beta-blockers, methyldopa) Gastrointestinal H2 -antagonists (cimetidine, ranitidine, famotidine, nizatidine) Metoclopramide (Reglan) Miscellaneous Nonsteroidal anti-inflammatory drugs Corticosteroids Anticonvulsants Levodopa Lithium Over-the-counter drugs Cold/sinus preparations (antihistamines, pseudoephedrine) Sleep aids (diphenhydramine, alcohol-containing elixirs) Stay Awake (caffeine) Nausea/gastrointestinal (Donnagel, meclizine, H2 -antagonists, loperamide) antagonists (e.g., cimetidine, ranitidine, famotidine, nizatidine) are among the most common causes of drug-induced delirium in the elderly because of their frequent use; clinicians should strongly consider the use of less toxic alternatives (e.g., sucralfate or antacids) or dosage reduction for older patients, especially when the medication is being used for prophylaxis rather than treatment of active disease. Psychoactive drugs account for nearly 50% of preventable adverse drug events, often in patients in whom three or more psychoactive drugs are prescribed, frequently at inappropriately high doses. Delirium and cognitive impairment are the most frequent adverse outcomes of psychoactive drugs. The use of any psychoactive drug is associated with a 4-fold increased risk of delirium or cognitive decline, but the outcomes of delirium and cognitive decline depend on the type or class of drug administered, as well as the total number of drugs received. Sedative-hypnotic drugs are associated with a 3- to 12-fold increased risk for delirium or cognitive decline, narcotics with a 2- to 3-fold increased risk, and anticholinergic drugs with a 5- to 12-fold increased risk. Moreover, when more drugs are used, not only does each carry its own individual risk for adverse outcomes, but the overall risk is also compounded by the heightened potential for drug-drug interactions. For example, if more than three drugs are added in a 24-hour period, the risk of delirium increases 4-fold. Similarly, the risk of cognitive decline increases directly with the number of drugs prescribed, from a 3-fold increased risk with two or three drugs to a 14-fold increased risk with six or more drugs. PRINCIPLES OF DRUG THERAPY IN THE ELDERLY. Physicians should always consider whether non-pharmacologic approaches are appropriate alternatives to medications in older persons. For example, relaxation techniques, massage, and music are highly effective for the treatment of insomnia and anxiety; localized pain can often be effectively managed with local measures such as injection, heat, ultrasound, and transcutaneous electrical stimulation. When drug therapy is required in the elderly, physicians should choose the drug with the least toxic potential and emphasize drugs that have been well tested in elderly

populations (Table 6-6) . Once the drug is chosen, it is often wise to start at 25 to 50% of the standard adult dosage for psychoactive drugs and increase the dose slowly. Drug regimens should be kept as simple as possible, with the fewest drugs and the fewest number of pills possible. Most importantly, the medication list should be reassessed frequently. TABLE 6-6 -- GUIDELINES FOR DRUG THERAPY IN THE ELDERLY General principles: Remember that the elderly are highly sensitive to the psychoactive effects of all drugs. Know the pharmacology of the drugs you prescribe. Know a few drugs well. Recommended approach: 1. Use non-pharmacologic approaches whenever possible. 2. Avoid routine use of "as needed" drugs for sleep, anxiety, pain. 3. Choose the drug with the least toxic potential. 4. Substitute less toxic alternatives whenever possible (antacid or sucralfate for an H2 -blocker, Metamucil/Kaopectate for Lomotil, scheduled acetaminophen/choline magnesium salicylate regimen for pain management). 5. Reduce the dosage. 6. "Start low and go slow." Start with 25-50% of the standard dose of psychoactive drugs in the elderly. Titrate the drug slowly. Set realistic end points: titrate to improvement, not elimination of symptoms. 7. Keep the regimen simple. 8. Regularly reassess the medication list. Have the patient bring in all bottles and review what is being taken. 9. Re-evaluate chronic drug use since the patient is changing. 10. Review over-the-counter medication use. Even long-standing medications should be re-evaluated since the host is changing with age and illness. Chronic usage does not necessarily justify continued usage. The physician should review with the patient all prescribed and over-the-counter medications on a regular basis, preferably by having the patient bring in all medication bottles and indicate how each is being taken. Patients frequently underestimate the toxic potential of over-the-counter medications and may be using a variety of over-the-counter medications that could potentiate the side effects or even directly counteract the desired effects of prescription medications. Leape LL, Brennan TA, Laird N, et al: The nature of adverse events in hospitalized patients: Results of the Harvard Medical Practice Study II. N Engl J Med 324:377, 1991. Landmark study documenting the rate and type of adverse events in over 30,000 hospital admissions. This study revealed that drug complications were the most common type of adverse event and that the rate of adverse events rose with age. Some drugs that cause psychiatric symptoms. Med Lett 40:21, 1998. This article provides a comprehensive listing of drugs with potential psychoactive effects. Tombaugh TN, McIntyre NJ: The Mini-Mental State Examination: A comprehensive review. J Am Geriatr Soc 40:922, 1992. This study provides a detailed review of 26 years of information on the Mini-Mental State Examination, the most widely used cognitive screening test, including its psychometric properties, strengths, and limitations.

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Chapter 7 - DELIRIUM AND OTHER MENTAL STATUS PROBLEMS IN THE OLDER PATIENT Sharon K. Inouye

EVALUATION OF MENTAL STATUS CHANGE IN THE OLDER PATIENT Mental status change, one of the most common presenting symptoms in acutely ill elders, is estimated to account for up to 30% of emergency evaluations for older patients. Importantly, mental status often serves as a barometer of the overall underlying health of an elderly patient and is commonly the only symptom of serious underlying disease. A broad range of medical, neurologic, and psychiatric conditions can lead to mental status changes (see Chapters 444 , 449 , and 450) , and a systematic approach aids in the evaluation of suspected mental status change in an older patient (Fig. 7-1) . 19

Figure 7-1 Algorithm for evaluation of suspected mental status change in an older patient.

The first step in evaluating suspected altered mental status in an older patient is to obtain a detailed history from a reliable informant to establish the patient's baseline level of cognitive function and the clinical course of any cognitive changes. Chronic changes, i.e., changes occurring over months to years, most likely represent an underlying dementing illness, which should be evaluated accordingly (see Chapter 449) . Acute changes, i.e., changes occurring over days to weeks--even if superimposed on an underlying dementia--should be further evaluated by detailed cognitive assessment to determine whether delirium is present. If features of delirium (e.g., inattention, disorganized thinking, altered level of consciousness, fluctuating symptoms) are not present, further evaluation for depression, acute nonorganic psychotic disorders, or other psychiatric conditions is indicated.

20

DELIRIUM Delirium, a clinical syndrome characterized as an acute disorder of attention and cognitive function, is the most frequent complication of hospitalization for elders and a potentially devastating problem. Delirium is often unrecognized despite sensitive methods for its detection, and its complications may be preventable. DEFINITIONS. The definition and diagnostic criteria for delirium continue to evolve. The Diagnostic and Statistical Manual, Version IV, of the American Psychiatric Association has been widely used (Table 7-1) , but development of the criteria in this manual was based on expert consensus, and their diagnostic sensitivity and specificity have not been determined. The Confusion Assessment Method provides a simple, operationalized diagnostic algorithm with a sensitivity of 94 to 100% and a specificity of 90 to 95%. ETIOLOGY. Similar to other common geriatric syndromes (see Chapter 8) , delirium is usually of multifactorial etiology. A search for the innumerable potential underlying contributors requires clinical astuteness and a thorough medical evaluation, especially since many of these factors are treatable but, if untreated, may result in substantial morbidity and mortality. The process is made more challenging by the frequently nonspecific, atypical, or muted features of the underlying illness in older persons. In fact, delirium is commonly the only initial sign of underlying life-threatening illness such as pneumonia, urosepsis, or myocardial infarction in the geriatric population. The development of delirium usually involves a complex interrelationship between a vulnerable patient with pertinent predisposing factors and exposure to noxious insults or precipitating factors. Thus delirium may develop in patients who are highly vulnerable to delirium--such as the cognitively impaired or severely ill--after a relatively benign insult such as a single dose of sleeping medication. Conversely, patients who are not vulnerable would be relatively TABLE 7-1 -- DIAGNOSTIC CRITERIA FOR DELIRIUM DSM-IV Diagnostic Criteria A. Disturbance of consciousness (i.e., reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention. B. A change in cognition (such as memory deficit, disorientation, language disturbance) or the development of a perceptual disturbance that is not better accounted for by a pre-existing, established, or evolving dementia. C. The disturbance develops over a short period (usually hours to days) and tends to fluctuate during the course of the day. D. Evidence from the history, physical examination, or laboratory findings indicates that the disturbance is caused by the direct physiologic consequences of a general medical condition. The CAM Diagnostic Algorithm * Feature 1. Acute onset and fluctuating course This feature is usually obtained from a family member or nurse and is shown by positive responses to the following questions: Is there evidence of an acute change in mental status from the patient's baseline? Did the (abnormal) behavior fluctuate during the day, that is, tend to come and go, or increase and decrease in severity? Feature 2. Inattention This feature is shown by a positive response to the following question: Did the patient have difficulty focusing attention, for example, being easily distractible, or have difficulty keeping track of what was being said? Feature 3. Disorganized thinking This feature is shown by a positive response to the following question: Was the patient's thinking disorganized or incoherent such as rambling or irrelevant conversation, unclear or illogical in flow of ideas, or unpredictable and switching from subject to subject? Feature 4. Altered level of consciousness This feature is shown by any answer other than "alert" to the following question: Overall, how would you rate this patient's level of consciousness (alert [normal], vigilant [hyperalert], lethargic [drowsy, easily aroused], stupor [difficult to arouse], or coma [unarousable])? DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Version IV; CAM = Confusion Assessment Method.

From Inouye SK, van Dyck CH, Alessi CA, et al: Clarifying confusion: The Confusion Assessment Method. A new method for detection of delirium. Ann Intern Med 113:941, 1990. *The diagnosis of delirium by CAM requires the presence of features 1 and 2 and either 3 or 4.

resistant, and delirium would develop only after exposure to multiple noxious insults. Moreover, previous studies have demonstrated that the effects of these risk factors may be cumulative. The importance of this multifactorial causation to the clinician is that removing or treating one factor in isolation will not usually be sufficient to resolve the delirium. Instead, the full spectrum of vulnerability and precipitating factors should be addressed. Predisposing, or vulnerability, factors identified consistently in previous studies include pre-existing cognitive impairment or dementia, severe underlying illness, high levels of comorbidity, functional impairment, advanced age, chronic renal insufficiency, dehydration, malnutrition, and vision or hearing impairment. Dementia is an important and consistent risk factor for delirium, with demented patients having a two- to five-fold increased risk for delirium. Moreover, 30 to 50% of delirious patients have underlying dementia. Delirious patients commonly have evidence of underlying chronic brain disease, particularly conditions associated with cognitive impairment such as Parkinson's disease, cerebrovascular disease, and space-occupying lesions. Medications, the most common remediable cause of delirium, contribute to delirium in up to 40% of cases (see Chapter 6) . Insufficiency or failure of any major organ system, particularly renal or hepatic failure, can precipitate delirium. Both hypoxemia and hypercarbia have been associated with delirium. Clinicians must be attuned to occult respiratory failure, which in the elderly often lacks the usual signs and symptoms of dyspnea and tachypnea and can be missed by measuring oxygen saturation alone. Acute myocardial infarction or congestive heart failure can be manifested as delirium in an elderly patient without the usual symptoms of chest pain or dyspnea. Occult infection is a particularly notable cause of delirium. Older patients frequently fail to mount the febrile or leukocytotic response to infection, and clinicians must carefully assess for signs of pneumonia, urinary tract infection, endocarditis, abdominal abscess, or infected joints. A variety of metabolic disorders may contribute to delirium, including hypernatremia or hyponatremia, hypercalcemia, acid-base disorders, hypoglycemia and hyperglycemia, and thyroid or adrenal disorders. Immobilization and immobilizing devices (e.g., indwelling bladder catheters, physical restraints) have been demonstrated to be important factors precipitating delirium. Dehydration and volume depletion, as well as nutritional decline during hospitalization (e.g., decline in weight, fall in serum albumin), are well-documented factors contributing to delirium. Drug and alcohol withdrawal are important and often unsuspected causes of delirium in the elderly. Environmental factors such as an unfamiliar environment, sleep deprivation, deranged schedule, frequent room changes, sensory overload, or sensory deprivation may aggravate delirium in the hospital setting. Psychosocial factors such as depression, psychological stress, pain, or lack of social supports may also precipitate delirium. INCIDENCE AND PREVALENCE. In the elderly, the prevalence of delirium at hospital admission can range from 10 to 40%. Delirium can develop in as many as 25 to 56% of patients during hospitalization. Higher rates are found when frequent surveillance is performed in older, surgical, and intensive care populations. EPIDEMIOLOGY. The associated hospital mortality rates for delirium range from 25 to 33%, rates as high as those associated with acute myocardial infarction and sepsis. The problem of delirium in hospitalized elderly patients has assumed particular prominence because patients aged 65 years and older currently account for more than 40% of all inpatient days of hospital care. Based on recent U.S. vital health statistics and a conservative delirium rate of 20%, delirium will complicate hospital stays for over 2.3 million older persons, involve over 17.5 million inpatient days, and account for over $4 billion of hospital expenditures each year. Substantial additional costs are incurred after hospital discharge because of the increased need for rehabilitation services, nursing home placement, and home care. These extrapolations highlight the extensive economic and health policy implications of delirium. PATHOGENESIS. The basic pathogenesis of delirium remains unclear. Most investigators agree that delirium appears to be a functional rather than structural lesion. Electroencephalographic studies demonstrate global functional derangements in patients with delirium, characterized by generalized slowing of cortical background (alpha) activity. The leading current hypotheses view delirium as the final common pathway of many different pathogenic mechanisms 21

culminating in a widespread reduction in cerebral oxidative metabolism with resultant impairment of cholinergic transmission. Proposed mediators examined in previous studies have included beta-endorphin, somatostatin, lymphokines, tryptophan, phenylalanine metabolites, and cortisol. Although delirium has long been considered a transient syndrome, several of these basic mechanisms may not be completely reversible, particularly those resulting in hypoxic damage. Moreover, the dose and duration of the noxious insults, along with the degree of vulnerability of the patient, may also exert great influence on the ultimate reversibility of the delirium. CLINICAL MANIFESTATIONS. The cardinal features of delirium include acute onset and inattention. Establishing the acuity of onset requires accurate knowledge of the patient's baseline cognitive function. Patients are inattentive, that is, they have difficulty focusing, maintaining, and shifting attention. They appear easily distracted and have difficulty maintaining conversation and following commands. Objectively, patients may have difficulty with simple repetitive tasks, digit spans, and recitation of months backward. Other key features include disorganization of thought processes, which is usually a manifestation of underlying cognitive or perceptual disturbances, and an altered level of consciousness, typically lethargy with reduced clarity of awareness of the environment. Although not cardinal elements, other features frequently occurring during delirium include disorientation, cognitive deficits, psychomotor agitation or retardation, perceptual disturbances such as hallucinations and illusions, paranoid delusions, and sleep-wake cycle reversal. DIAGNOSIS AND EVALUATION. The cornerstone of evaluation of delirium is a comprehensive history and physical examination. The first step in evaluation (Table 7-2) should be to establish the diagnosis of delirium through cognitive assessment and determine whether the present condition represents an acute change from the patient's baseline cognitive function. Because cognitive impairment may not be apparent during conversation, brief cognitive screening tests such as the Mini-Mental Status Examination should be used. Attention should be further assessed with simple tests such as a forward digit span (inattention indicated by an inability to repeat five digits forward) or recitation of the months backward. The history, which should be obtained from a reliable informant, is targeted to establish the patient's baseline cognitive function and the time course of any mental status change, as well as to obtain clues about potential precipitating factors such as recent medication changes, intercurrent infections, or medical illnesses. Physical examination should include a detailed neurologic examination for TABLE 7-2 -- EVALUATION OF DELIRIUM IN ELDERLY PATIENTS 1. Cognitive testing and determination of baseline cognitive functioning. Establish the diagnosis of delirium 2. Comprehensive history and physical examination, including careful neurologic examination for focal deficits and search for occult infection 3. Review the medication list: discontinue or minimize all psychoactive medications. Check the side effects of all medications 4. Laboratory evaluation (tailored to the individual): complete blood count, electrolytes, blood urea nitrogen, creatinine, glucose, calcium, phosphate, liver enzymes, oxygen saturation 5. Search for occult infection: physical examination, urinalysis, chest radiography, selected cultures (as indicated) 6. When no obvious cause is revealed from the above steps, further targeted evaluation is considered in selected patients: Laboratory tests: Magnesium, thyroid function tests, B12 level, drug levels, toxicology screen, ammonia level Arterial blood gas: Indicated in patients with dyspnea, tachypnea, any acute pulmonary process, or history of significant respiratory disease Electrocardiogram: Indicated in patients with chest or abdominal discomfort, shortness of breath, or cardiac history

Cerebrospinal fluid examination: Indicated when meningitis or encephalitis is suspected Brain imaging: Indicated in patients with new focal neurologic signs or with a history or signs of head trauma Electroencephalogram: Useful in diagnosing occult seizure disorder and differentiating delirium from nonorganic psychiatric disorders focal deficits and a careful search for signs of occult infection or an acute abdominal process. A crucial difficulty in the differential diagnosis of delirium is distinguishing a long-standing confusional state (dementia) from delirium alone or delirium superimposed on dementia. These two conditions are differentiated by the acute onset of symptoms in delirium (dementia is much more insidious) and the impaired attention and altered level of consciousness associated with delirium. The differential diagnosis also includes depression and nonorganic psychotic disorders. Although paranoia, hallucinations, and affective changes can occur with delirium, the key features of acute onset, inattention, altered level of consciousness, and global cognitive impairment will assist in the recognition of delirium. At times, the differential diagnosis can be quite difficult--particularly with an uncooperative patient or when an accurate history is unavailable. Because of the potentially life-threatening nature of delirium, it is prudent to manage the patient as having delirium and search for underlying precipitants (e.g., intercurrent illness, metabolic derangements, drug toxicity) until further information can be obtained. Review of the medication list, including over-the-counter medications, is critical, and use of medications with psychoactive effects should be discontinued or minimized whenever possible. In the elderly, these medications may cause psychoactive effects even at dosages and measured drug levels that are within the "therapeutic range." Consideration should be given to the possibility that withdrawal from alcohol or other medications is a contributor to delirium. Laboratory evaluation must be tailored to the individual situation (see Table 7-2) . In patients with pre-existing cardiac or respiratory diseases or related symptoms, an electrocardiogram or arterial blood gas determination may be indicated. The need for cerebrospinal fluid examination remains controversial except when clearly indicated, such as in a febrile delirious patient. Brain imaging should be reserved for patients with new focal neurologic signs, for those with a history or signs of head trauma, or for patients without another identifiable cause of the delirium. The electroencephalogram, with its false-negative rate of 17% and false-positive rate of 22% in distinguishing delirious and nondelirious patients, has a limited role and is most useful for detecting an occult seizure disorder and differentiating delirium from nonorganic psychiatric disorders. TREATMENT. In general, nonpharmacologic approaches should be used in all delirious patients and will usually be successful for symptom management. Pharmacologic approaches should be reserved for the occasional patient in whom the delirium symptoms may result in interruption of needed medical therapies (e.g., intubation, intravenous lines) or may endanger the safety of the patient or other persons. However, no drug is ideal for the treatment of delirium symptoms; any choice may further cloud the patient's mental status and obscure efforts to monitor the course of the mental status change. Thus any drug chosen should be given in the lowest dose for the shortest time possible. Neuroleptics are the preferred agents of treatment, with haloperidol and thioridazine being the most widely used agents. Haloperidol causes less orthostatic hypotension and fewer anticholinergic side effects than thioridazine does and is available in parenteral form; however, it has a higher rate of extrapyramidal side effects and acute dystonias. If parenteral administration is required, intravenous use results in rapid onset of action with a short duration of effect, whereas intramuscular use will have a more optimal duration of action. Thioridazine, which is more sedating, may be beneficial in agitated patients; its elixir form can be given by the oral or nasogastric route. The recommended starting dose is 0.5 to 1.0 mg haloperidol orally or parenterally or thioridazine, 10 to 25 mg orally, and then repeating the dose every 30 minutes after the vital signs have been rechecked until sedation has been achieved. The end point should be an awake but manageable patient. The average elderly patient who has not previously been treated with neuroleptics should require a total loading dose of no more than 3 to 5 mg of haloperidol or 50 to 100 mg of thioridazine. Subsequently, a maintenance dose consisting of half of the loading dose should be administered in divided doses over the next 24 hours, with doses tapered over the next few days as the agitation resolves. Benzodiazepines are not recommended for the first-line treatment 22

of delirium because of their tendency to cause oversedation and exacerbate the confusional state. However, they remain the drugs of choice for treatment of withdrawal syndromes from alcohol and sedative drugs (see Chapters 16 and 17) . Non-pharmacologic management techniques recommended for every delirious patient include encouraging the presence of family members, using "sitters" to be orienting influences, or transferring a disruptive patient to a private room or closer to the nurse's station for increased supervision. Interpersonal contact and communication, including verbal reorientation strategies, simple instructions and explanations, and frequent eye contact, are vital. Patients should be involved in their own care and allowed to participate in decision making as much as possible. Eyeglasses and hearing aids may reduce sensory deficits. Mobility, self-care, and independence should be encouraged, and physical restraints should be avoided, if possible, because of their tendency to increase agitation, their questionable efficacy, and their potential to cause injury. Attention must be focused on minimizing the disruptive influences of the hospital environment. Clocks and calendars should be provided to assist with orientation. Room and staff changes should be kept to a minimum. A quiet environment with low-level lighting is optimal for delirious patients. Perhaps the most important intervention is to allow an uninterrupted period for sleep at night. Nonpharmacologic approaches to relaxation, including music, relaxation tapes, and massage, can be highly effective. PROGNOSIS. Delirium is an important independent determinant of prolonged length of hospital stay, increased mortality, increased rates of institutional placement, and functional and cognitive decline--even after controlling for age, gender, dementia, illness severity, and baseline functional status. Delirium had previously been considered to be a reversible, transient condition, but recent studies on the duration and persistence of delirium symptoms document that delirium may be much more persistent than previously believed. In fact, delirium duration of 30 days or more is typical, and as few as 20% of patients may have complete resolution of all delirium symptoms at 6-month follow-up. Moreover, a prolonged transitional phase characterized by abnormalities in cognition, affect, or behavior appears to be quite common. In addition, delirium appears to have greater deleterious effects in patients with underlying cognitive impairment. The long-term detrimental effects are most probably related to the duration, severity, and underlying cause(s) of the delirium, as well as the vulnerability of the host (i.e., baseline cognitive impairment). PREVENTION. The most effective intervention strategy to reduce delirium and its associated complications is primary prevention of delirium before it occurs. Ideally, preventive strategies should address important delirium risk factors and target patients at moderate

RISK FACTOR Cognitive impairment

TABLE 7-3 -- DELIRIUM RISK FACTORS AND POTENTIAL INTERVENTIONS INTERVENTIONS Therapeutic activities program Reality orientation program (reorienting techniques, communication)

Sleep deprivation

Noise reduction strategies Scheduling of nighttime medications, procedures, and nursing activities to allow uninterrupted period of sleep

Immobilization

Early mobilization (e.g., ambulation or bedside exercises) Minimizing immobilizing equipment (e.g., bladder catheters)

Psychoactive medications Restricted use of "as needed" sleep and psychoactive medications (e.g., sedative-hypnotics, narcotics, anticholinergic medications) Nonpharmacologic protocols for management of sleep and anxiety Vision impairment

Provision of vision aids (e.g., magnifiers, special lighting)

Provision of adaptive equipment (e.g., illuminated phone dials, large-print books) Hearing impairment

Provision of amplifying devices Repair of hearing aids

Dehydration

Early recognition and volume repletion

to high risk for delirium at baseline (Table 7-3) . On a larger scale, preventive efforts for delirium will require system-wide changes to educate physicians and nurses to improve recognition and heighten awareness of the clinical implications, provide incentives to change practice patterns that lead to delirium (e.g., immobilization, use of sleep medications, bladder catheters, and physical restraints), and create systems that enhance high-quality geriatric care (e.g., geriatric expertise, case management, clinical pathways, and quality monitoring). Cole MG, Primeau FJ: Prognosis of delirium in elderly hospital patients. Can Med Assoc J 149:41, 1993. Systematic review with a meta-analysis of eight studies involving 573 delirious patients on outcomes associated with delirium. Elie M, Cole MG, Primeau FJ, Bellavence F: Delirium risk factors in elderly hospitalized patients. J Gen Intern Med 13:204, 1998. Review emphasizing that advanced age, underlying dementia, and serious medical illness are the principal risk factors for delirium in the hospital. Francis J: Delirium in older patients. J Am Geriatr Soc 40:829, 1992. An outstanding review of the recent literature on delirium with an extensive reference list. Inouye SK, Bogardus ST, Charpentier PA, et al: A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 340:669, 1999. Clinical trial of a multiple risk factor reduction approach for prevention of delirium in hospitalized older medical patients. Rummans TA, Evans JM, Krahn LE, Fleming KC: Delirium in elderly patients: Evaluation and management. Mayo Clin Proc 70:989, 1995. Recent review of aspects of clinical findings and management approaches.

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Chapter 8 - SPECIAL PROBLEMS IN THE GERIATRIC PATIENT Judith C. Ahronheim

Biologic and chronologic ages are not well matched. Nevertheless, physiologic changes and the higher prevalence of overt and subclinical disease in late life create specific vulnerabilities and special problems.

DRUGS AND RISKS CLINICAL PHARMACOLOGY. The elderly experience more adverse drug events than any other age group does because their exposure to larger numbers of medications provides more opportunities for medication errors and drug-drug interactions and because their altered pharmacokinetics results in enhanced sensitivity to many agents. PHARMACOKINETIC CHANGES.

Age-related physiologic changes, especially in renal function, that occur in late life reduce drug elimination, prolong drug half-life, and increase the risk of drug toxicity. Although the average glomerular filtration rate (GFR) declines approximately 50% between the third and ninth decades of life primarily as a result of hypertension and diabetes, many individuals maintain normal or nearly normal GFR in late life. Serum creatinine does not reflect the age-related decline in GFR or predict individual renal function because muscle mass, the source of serum creatinine, also declines with age. In general, the loading dose of medications should not be altered in the presence of renal dysfunction, but subsequent doses, especially for medications that have narrow therapeutic-to-toxic ratios and are eliminated by the kidney, such as digoxin and aminoglycosides, must be adjusted according to actual renal function for any medication. Formulas such as

for rapid estimation of GFR have been validated in subgroups of elderly patients and should be used when dosing decisions are rapidly needed. However, these estimates may be inaccurate in debilitated patients with muscle wasting and in the dynamic setting of acute illness. Serum drug levels should be obtained to guide dosing of drugs with a narrow therapeutic-to-toxic ratio.

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Hepatic blood flow may decrease with advancing age, but controversy exists over the extent to which age-related hepatic changes affect drug metabolism. Some but not all studies have demonstrated a decline in hepatic oxidative processes ("phase I" metabolism) in the elderly. Likewise, unanimity is lacking over whether the inducibility or inhibition of the cytochrome P-450 system, which is responsible for most oxidative drug metabolism, changes with age. In contrast, it is generally agreed that hepatic conjugation ("phase II" metabolism) is unaltered with age. Unlike oxidized metabolites, which are often active, metabolites produced by conjugation are usually inactive. Diazepam undergoes oxidation to long-acting, renally excreted metabolites, and repeated dosing may lead to delayed toxicity. In contrast, lorazepam undergoes conjugation and inactive metabolites are produced. It should not be assumed that normal conjugation of medications such as lorazepam guarantees safety because the effects of certain drugs may be enhanced in the elderly regardless of the metabolic pathway. With advancing age, lean body mass declines and body fat increases. Thus the volume of distribution tends to be lower for water-soluble drugs and higher for fat-soluble drugs. The onset of action of a water-soluble drug such as alcohol may be earlier than expected, and the steady-state concentrations of a lipid-soluble drug such as diazepam may not be reached until later than expected. In the latter situation, toxicity may occur in a delayed and unexpected fashion, especially in the presence of active metabolites. Serum albumin remains normal in the healthy elderly but may decline swiftly during illness owing to inflammation, impaired protein synthesis, and diminished reserves in late life. When serum albumin levels are low, standard clinical laboratory assays of drugs highly bound to albumin (such as phenytoin) may be misleading because they reflect total (bound plus free) drug and hence might prompt the clinician to raise the dose and create the potential for toxicity. PHARMACODYNAMICS.

Although the effects of some agents at the tissue level may decrease in late life, most alterations involve enhanced effects on the target or non-target organ, probably related to physiologic changes as well as the presence of overt or silent disease. Whether caused by reduced elimination (altered pharmacokinetics) or alterations in the receptor or tissue itself (pharmacodynamics), the known side effects of essentially all medications may be potentiated in the elderly.

BOWEL AND BLADDER PROBLEMS CONSTIPATION AND FECAL IMPACTION. Contrary to popular belief, there is little evidence to indicate an increased prevalence of constipation among the community-dwelling elderly, although the use of laxatives is increased, perhaps because of traditional beliefs about what constitutes normal bowel function. Constipation may be increased among the institutionalized elderly, however, because of immobility, decreased intake of fluid and fiber, prolonged intestinal transit time, impaired anorectal sensation, neurologic disease, bowel lesions, and the use of constipating medicines. Constipating medications include but are not limited to tricyclic antidepressants, anticholinergics, some antihypertensive agents, calcium channel antagonists, opioid analgesics, aluminum-containing antacids, and bile acid resins. An important consequence of constipation is fecal impaction, which may be manifested as fever, altered mental status, agitation, urinary retention, or paradoxical diarrhea caused by leakage around the impaction. Because of these features, fecal impaction can be mistaken for other problems and hence be treated inappropriately. Fecal impaction can usually be treated with suppositories, enemas, or manual disimpaction, but in extreme cases mechanical bowel obstruction may require surgical intervention. Prevention consists of strict attention to the patient's bowel habits, adequate hydration, adequate but not excessive dietary fiber, avoidance of constipating medications when possible, and judicious use of laxatives. PROBLEMS WITH MICTURITION. URINARY INCONTINENCE.

Urinary incontinence affects 10 to 30% of the community-residing elderly (Table 8-1) . The prevalence rises among the oldest elderly and reaches at least 60 to 70% among elderly persons residing in nursing homes. The most common cause of urinary incontinence in elderly men and women is overactivity of the bladder detrusor. In

this condition (called "detrusor instability"), the detrusor muscle TABLE 8-1 -- COMMON FORMS OF URINARY INCONTINENCE IN THE ELDERLY CAUSE OR ASSOCIATION

TYPE Urge (detrusor instability)

Post-menopause, old age, CNS disease

Stress

Increased intra-abdominal pressure superimposed on

"True"

Incompetent urethral sphincter

Reflex

Overdistended bladder

Mixed urge and stress

See above

Overflow

Incomplete bladder outlet obstruction (e.g., BPH), bladder atony (e.g., long-standing diabetes)

Pseudoincontinence

Inability to toilet, confusional states

CNS = central nervous system; BPH = benign prostatic hypertrophy. contracts in response to inappropriately small volumes of urine, often preceded by a sense of urgency. Incontinence results if the patient is unable to get to the toilet on time or when other problems coexist such as urethral incompetence or bladder inflammation. Detrusor instability is believed to be caused by lack of inhibition of the brain stem detrusor reflex by higher cerebrocortical centers. However, most affected elderly have no clinically apparent neurologic disease. The symptoms of detrusor instability--frequency and urge incontinence--may be ameliorated by "bladder training," which consists of prolonging the interval between voidings by using behavioral techniques. Patients who are physically disabled or cognitively impaired should be toileted frequently or on a schedule, and incontinence garments (adult diapers) may be used. Antispasmodic agents such as oxybutynin, which relaxes the bladder wall and promotes the storage of urine, presumably by inhibiting cholinergically mediated detrusor contractions, may be useful. Other medications with anticholinergic activity, such as imipramine, have been suggested for this purpose but, owing to central nervous system effects and other actions, are less well tolerated in geriatric patients. In elderly women, post-menopausal changes in pelvic musculature contribute to urinary incontinence by leading to loss of the extrinsic support of pelvic organs and the bladder neck. Pelvic and distal urethral tissue contain estrogen and progesterone receptors, and the urethra may become patulous after menopause. In this setting, intra-abdominal pressure may easily surpass intraurethral pressure and lead to leakage of urine. This "true stress incontinence" (i.e., occurring in the absence of a detrusor contraction) typically occurs immediately after a cough or sneeze or, in severe cases, merely upon arising from a sitting position. Stress incontinence may respond to treatment with exogenous estrogens, but data in patients 75 years and older are limited. Other treatment approaches include pelvic muscle exercises and alpha-adrenergic agents such as phenylpropanolamine, which act on urethral alpha-adrenergic receptors to increase urethral tone. Urodynamic studies are not routinely required to evaluate incontinence, but testing ranging from simple bedside observation to a series of complex tests should be considered when the history and clinical evaluation fail to explain the cause. Asymptomatic patients may exhibit involuntary detrusor contractions on cystometric testing, whereas patients with detrusor instability may have a falsely negative test if they are psychologically inhibited from emptying their bladders under testing conditions. Likewise, urodynamic testing may not be predictive of who will benefit from a specific treatment, especially in patients with multiple abnormalities. Chronic indwelling catheters should not be used in the management of incontinence, even in patients with decubitus ulcers, because urinary tract infection develops in virtually 100% of chronically catheterized patients and chronic antibiotic suppression merely leads to the production of resistant strains of organisms. When indwelling catheters are the only alternative (as in urinary retention that cannot be managed with intermittent catheterization), antibiotic treatment should be reserved for symptomatic illness or unexplained lethargy. URINARY RETENTION.

Urinary retention is far more common in men, in whom it is most often related, at least in part, to prostatic 24

outlet obstruction caused by benign prostatic hyperplasia. Acute urinary retention may occur in elderly men and less often in women as a result of fecal impaction, the bedridden state, immobility, or anticholinergic drugs such as tricyclic antidepressants, disopyramide, first-generation antihistamines, and drugs used to treat urinary incontinence. Diuretics can also lead to urinary retention when they produce a volume of urine that overwhelms the compromised bladder. Urinary retention may be precipitated following surgery by the prolonged effects of anesthetic agents and opioid analgesics. Urinary retention that first begins in the hospital can persist for some time but generally resolves when the the patient does not have an antecedent history of retention. Long-standing diabetes mellitus may be associated with a "cystopathy" caused by peripheral neuropathy of the afferent limb of the spinal detrusor reflex and the resulting detrusor areflexia. However, most elderly diabetics with bladder dysfunction do not suffer from diabetic cystopathy, perhaps because of shorter disease duration in adult-onset diabetes. It is important to distinguish frank urinary retention (the inability to void) from increased residual urine, defined as a post-void residual urine volume greater than approximately 50 mL. For example, in elderly women, anatomic problems such as cystocele may increase residual urine. Other patients may have incomplete bladder emptying because of modest detrusor hyporeflexia. Frank urinary retention, which may be manifested as "overflow incontinence," requires immediate attention, whereas increased post-void residual urine, which is often asymptomatic, does not in and of itself require treatment.

FALLS AND FRACTURES Approximately one third of people 75 years and older fall at least once annually, and a key aspect of management in elderly patients is the prevention of falls. When fall-related injury occurs, it is just as important to assess the reason for the fall as to address the injury. Falls among the elderly are most commonly caused by acute or chronic neurologic disease, arthritis, musculoskeletal impairments, poor balance, postural instability, cardiac arrhythmias, generalized weakness from acute or chronic medical illness (including acute myocardial infarction), orthostatic hypotension, or impaired coordination hampering the ability to fall "well." Additional factors are visual impairments, dementia, medications with sedating properties, and antihypertensive medications, especially when they lead to overcorrection of hypertension. The probable cause of the fall can be ascertained in 95% of cases with a careful history and physical examination alone. Further diagnostic work-up should be guided by this initial evaluation. Although most falls in the elderly result in trivial or minor injury, approximately 5% result in injury serious enough to require hospitalization. Falls are by far the most important accidental cause of death in the geriatric population; the death rate from falls is approximately 10 per 100,000 population between the ages of 65 and 74 years, but it rises to approximately 150 per 100,000 after age 85. Wrist and hip fractures are almost always related to a fall, whereas vertebral wedging and fractures may occur without obvious trauma. The incidence of wrist (Colles') fracture increases in mid-life among women but reaches a plateau by age 60. In contrast, the incidence of hip fracture rises steadily after age 60, and approximately 17% of men and 30% of women sustain a hip fracture by age 90. These fracture patterns may be partly related to the mechanism of falling in that an older person may lack the coordination to break a fall by quickly throwing out the arm. In addition, reduced muscle mass and subcutaneous fat may contribute to diminished absorption of energy on impact. Hip fractures in the elderly are a surgical emergency. Initial radiographs sometimes fail to reveal a fracture. When an elderly patient has fallen and cannot stand or bear weight or has severe pain on weight bearing, the hip must be deemed fractured until proved otherwise. If repeat radiography fails to reveal a fracture on frontal and lateral views, a bone scan or magnetic resonance imaging should be done. Surgery should be performed as soon as the patient is medically stabilized because morbidity and mortality rise exponentially if surgery is delayed beyond approximately 48 hours. Assiduous medical management of these frail patients is essential and should be directed at prevention or treatment of pneumonia, deep vein thrombosis, pulmonary embolus, pressure sores, urinary tract infection, and fecal impaction. Post-operative delirium (see Chapter 7) is common and may be due to one or more medical problems, to medications, or to prolonged effects of anesthesia. The increased risk of fracture with aging is due not only to the tendency to fall but also to bone loss, which begins to occur after the fourth decade of life in both sexes. At the time of menopause, the rate of bone loss in women accelerates for approximately 7 years. The accelerated phase is manifested first in trabecular bone of the vertebrae and the extreme ends of long bones. In the absence of trauma, the rate of spinal compression fractures is about eight times higher, and the rate of wrist and

hip fracture from all causes is about twice as high in women as in men. Recent evidence indicates that bone loss further accelerates in the last decades of life in both men and women. Age-related bone loss is due largely to osteoporosis (see Chapter 257) , but many geriatric patients also have osteomalacia (Chapter 263) . Osteomalacia in the elderly is most often due to vitamin D deficiency, usually coexists with osteoporosis, and resembles the latter clinically. Vitamin D deficiency may be due to inadequate sunlight exposure, impairment in intestinal vitamin D absorption, and a reduced capacity to manufacture vitamin D in the skin. Osteomalacia is preventable and treatable. Only about 15 minutes of sunlight exposure twice per week is needed to optimize the vitamin D status in light-skinned adults. The elderly may require somewhat more, and still more time is required in deeply pigmented persons, in whom ultraviolet light does not penetrate the melanin layer as quickly. Elderly people, regardless of race, should ingest a minimum of 800 IU/day of vitamin D and higher doses if vitamin D deficiency is documented. Much higher doses should be continued only until the deficiency is corrected because of the danger of toxicity. Excessive sunlight exposure does not produce hypervitaminosis D but should be avoided to minimize skin damage. Substantial advances have been made in the prevention and treatment of osteoporosis in the elderly, with special emphasis on estrogen in women and biphosphonates in both women and men (see Chapter 257) . Weight bearing and resistive exercise also retard bone loss. A sensible exercise program tailored to the needs and limitations of the individual patient also helps maintain mobility, muscle tone, and cardiovascular function. It is always important to identify and address preventable causes of bone loss such as primary hyperparathyroidism, vitamin D deficiency, phosphate depletion, use of corticosteroids or heparin, cigarette smoking, excessive alcohol intake, and marginal calcium intake. Correction of negative calcium balance in elderly men and women generally requires a daily total intake of 1500 mg elemental calcium from dietary sources and supplements.

FLUID BALANCE AND ELECTROLYTE DISORDERS Geriatric patients may become easily dehydrated after a variety of insults such as excessive environmental heat, diarrhea, or febrile illness. Underlying factors are an impaired renal concentrating ability and impaired urinary sodium conservation in response to salt deprivation as a result of progressive loss of nephrons, especially in the renal cortex, an increase in basal and stimulated levels of atrial natriuretic hormone, and a decrease in the responsiveness of the renin-angiotensin-aldosterone system. In addition, the thirst response to dehydration is diminished even among healthy elderly. All these problems are accentuated in neurologically impaired patients, who are even less likely to seek water when dehydrated. A variety of medical illnesses may therefore be complicated by or be manifested as hypernatremia, hyperosmolarity, and obtundation. Even more common is hyponatremia caused by an exaggerated release of arginine vasopressin after an osmotic stimulus and a decreased ability to excrete a water load, in part related to the reduced GFR. Elderly patients also have a higher rate of disorders that predispose to hyponatremia, such as congestive heart failure, central neurologic impairments, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The disproportionate occurrence of SIADH among the elderly is probably related to enhanced physiologic release of arginine vasopressin, as well as exposure to the many pharmacologic agents known to produce this syndrome.

25

Enteral tube feeding is also frequently associated with hyponatremia. Although hypotonic feeds may be partly to blame, hyponatremia in tube-fed patients may also be a marker for underlying central nervous system disease, which has been associated with SIADH. In neurologically impaired, tube-fed patients, attention must be paid to the amount of free water added to the feed or used to flush the feeding tube, and serum sodium must be monitored. When saline solutions are given to correct dehydration, salt deficits, or fluid-electrolyte imbalance, they must be infused cautiously and with careful monitoring to avoid heart failure.

PRESSURE SORES Most pressure sores (decubitus ulcers) occur within the first 2 weeks of hospitalization or institutionalization. The prevalence among nursing home patients is approximately 11%, but as many as 20% of these patients have hospital-acquired pressure sores when they are admitted to the nursing home. Pressure sores develop when extrinsic pressure on the skin exceeds the mean capillary pressure (32 mm Hg), thereby reducing blood flow and tissue oxygenation. In recumbent patients, pressures over the sacrum or greater trochanter reach as high as 100 to 150 mm Hg. Moisture, friction, and shear contribute to skin breakdown under these circumstances. Advanced age may increase the risk because of changes in the skin, including decreased thickness and vascularity of the dermal layer, delayed wound healing, and redistribution of fat from the subcutaneous to deeper layers. Conditions that increase risk include immobility, arterial insufficiency, poor nutrition, and zinc, iron, or vitamin C deficiency. Neurologic impairments reduce the spontaneous movements that normally occur during sleep. Associated urinary and fecal incontinence exacerbate the problem by creating moisture and irritation. Pressure sores can occur anywhere on the body. Typical sites include dependent areas possessing minimal subcutaneous fat and bony prominences such as the sacrum, greater trochanter, scapula, lateral malleolus, thoracic spine, and heels. The hallmark of prevention is avoidance of pressure, and patients at risk should be identified early. Bedridden patients should be lifted, not dragged, across the sheet. Normal skin should be kept clean and dry without the use of indwelling catheters because they do not avoid the problem of fecal soilage and may reduce nursing vigilance. An effort should be made to restore nutritional deficiencies, but nutritional repletion is not a substitute for removal of pressure and meticulous skin care. Shallow ulcer craters should be kept clean and covered with a dressing if indicated. Uncomplicated blisters should be managed without debridement or dressing because blister fluid may enhance wound healing. Ulcers involving subcutaneous tissue may generate substantial necrotic tissue, which should be debrided. Debridement can be accomplished mechanically with dressings or enzymatically with debriding agents. Ulcers extending through fascia or involving bone, muscle, or supporting tissue require surgical debridement and often skin grafting. A variety of appliances, dressings, and debriding methods may supplement meticulous nursing care, although clinical trials to prove their efficacy or cost-effectiveness are often lacking. Foam "egg crate" pads and mattresses redistribute pressure, and sheepskin padding absorbs moisture. Air-fluidized beds (warm air flowing through silicon beads) and alternating air pressure mattresses redistribute and reduce extrinsic pressure. Although the air-fluidized bed may help speed ulcer healing, it is expensive and difficult to clean. Wet-to-dry dressings enhance debridement of necrotic tissue, but if the dressing is not exposed to air, it macerates healthy skin and enlarges the ulcer. Inappropriate use of wet-to-dry dressings desiccates underlying tissue. Occlusive hydrocolloid dressings may enhance healing, avoid the problem of desiccation, and protect a pressure sore from external soilage. A covered wound cannot be inspected, however, and sophisticated dressings should not create a false sense of security or reduce nursing vigilance when the key to treatment lies in removal of pressure. Ulcer craters should not be treated with topical antibiotics, which promote antimicrobial resistance without enhancing wound healing. Systemic antibiotics should be used only if obvious cellulitis or evidence of systemic infection related to the skin lesion is present.

MEDICAL DECISION MAKING FOR COGNITIVELY IMPAIRED ELDERLY Patients have a fundamental right to accept or refuse any medical treatment. The physician must inform patients of the risks, benefits, and alternatives of proposed treatments and determine whether they have the capacity to decide. Many geriatric patients lack decisional capacity because of dementia or other neurologic impairments. Nevertheless, they have the right to refuse treatment either through an advance directive (written or oral) or through an authorized surrogate decision maker (see Chapter 2) . All efforts should be made to involve the patient in the decision-making process. Patients with limited capacity, such as those with early dementia, may still have the ability to make their own medical decisions. Decisional capacity is patient specific and decision specific and is a clinical judgment that can usually be made by a primary care physician. Family members and others often try to "protect" elderly patients out of concern that bad news will be harmful. In extreme situations, the delivery of bad news can be harmful to certain patients (such as a severely depressed patient at risk for suicide). However, in most situations, patients wish to be fully informed and participate in their own care, so it is important for the physician to assess the patient's desire for information and deliver news sensitively. Despite the general consensus that patients may refuse any form of medical treatment, controversy surrounds the refusal of long-term enteral tube feeding, a treatment often given to patients with advanced neurologic impairment. Although the 1990 U.S. Supreme Court Cruzan decision affirmed the right of patients with decisional capacity to refuse tube feeding and other medical treatments, the Court left it up to individual states to set specific legal standards for refusal by patients lacking decisional capacity. Some states require a high level of evidence of a patient's previously expressed wishes to refuse life-sustaining treatment, whereas other states

have separate legal standards for refusal of tube feeding. Physicians should familiarize themselves with state regulations. As of this writing, lower courts have twice upheld family requests for treatment deemed medically futile by physicians. The arguments supporting such "futile" treatment have hinged on the need to maintain patient autonomy and affirm the family as the rightful decision makers for incompetent patients; they have not addressed the authority of physicians to make futility determinations. Demands for treatment in such extreme cases are rare and in the courts have been vastly outnumbered by "right-to-die" disputes, in which patients or their surrogates have refused life-prolonging treatments imposed by physicians or institutions. It is uncertain whether recent changes in the health care system and cost-cutting maneuvers will increase the number of conflicts in which patients or families demand care that the health care system is unwilling to provide. When conflict exists, health professionals who morally object to the withdrawal of life-sustaining treatments have the right to transfer care of the patient to another physician or facility that will uphold the patient's or family's decision. They do not, however, have the right to decide unilaterally what treatments patients should have. Ahronheim JC: Artificial nutrition and hydration in the terminally ill patient. Clin Geriatr Med 12:379, 1996. Critical review of medical aspects with an emphasis on enteral feeding of patients with advanced neurologic impairments. Arnaud MJ, Baumgartner R, Morley JE, et al: Hydration and Aging. New York, Springer, 1998. Monograph reviewing the clinical aspects and physiology of sodium and water metabolism in late life and treatment approaches in various disease states. Close J, Ellis M, Hooper R, et al: Prevention of falls in the elderly trial (PROFET): A randomised controlled trial. Lancet 353:93, 1999. An interdisciplinary approach reduced recurrent falls in the elderly. Schwartz JB: Clinical pharmacology. In Hazzard WR, Blass JP, Ettinger WH, et al: Principles of Geriatric Medicine and Gerontology, 4th ed. New York, McGraw-Hill, 1999, pp 303-331. Critical review of age-related pharmacologic principles with specific attention given to medications frequently prescribed in geriatric practice. Thomas DR, Allman RM (eds): Pressure ulcers. Clin Geriatr Med 13:421, 1997. Volume devoted to the epidemiology, assessment, and management of pressure ulcers with extensive references. Urinary Incontinence Guideline Panel: Urinary Incontinence in Adults: Clinical Practice Guidelines. Rockville, MD, Agency for Health Care Policy and Research, 1996, AHCPR Publication No. 96-0682. Consensus panel guidelines with extensive references.

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Part IV - PREVENTIVE HEALTH CARE

26

Chapter 9 - PRINCIPLES OF PREVENTIVE HEALTH CARE Albert Oberman

A growing body of evidence links personal health behavior and preventive services to the reductions in mortality from the leading causes of death and disability in the United States. Advances in understanding the determinants of risk, the demand for preventive measures in health reform, and the remarkable overall downward mortality trend (Table 9-1) provide the momentum for further primary preventive efforts. Reductions in cardiovascular mortality accounted for much of the decline in total mortality. Yet life expectancy at birth in the United States (78.9 years for women and 72.5 years for men) remains considerably below that of many developed countries. Other causes of preventable morbidity and mortality such as cancer, chronic obstructive pulmonary disease, human immunodeficiency virus (HIV) infection, and homicide have escalated. Men have higher age-adjusted death rates for every cause, especially for HIV infection. Death rates strongly correlate with socioeconomic status and are higher for blacks than for whites for 8 of the 10 leading causes of death. Furthermore, there is a broad spectrum of health care delivery and prevention within the country. Use of clinical preventive services is less among those without a usual source of health care, those in lower income and education groups, and older adults.

PREVENTION STRATEGIES The two complementary strategies for prevention are a population approach and a clinical, high-risk approach. A strong rationale exists for the population approach, in which interventions are offered on a broad scale to all segments of the population, because much of the current burden of ill health comes from the large numbers of those at moderate individual risk rather than from the few who demonstrate marked abnormalities. Since the risk for chronic diseases is generally continuous and often curvilinear, this approach shifts the entire population's risk to a lower level. Chronic diseases commonly arise from the interaction of multiple risk factors at moderate levels rather than from single aberrant risk factors. For example, most hypertensive complications and preventable deaths come from the many persons with mild to moderate hypertension (see Chapter 55) rather than the relatively few with severe hypertension. Estimates indicate that a 3-mm Hg downward shift in the average systolic blood pressure in the United States might reduce the annual mortality from all causes by 4%, from coronary heart disease by 5%, and from stroke by 8%. The high-risk strategy targets individuals in whom disease is judged most likely to develop and who would therefore benefit from intervention. This strategy, which is more compatible with usual medical practice, avoids the inefficiency of the population approach with its need to intervene in many who neither desire such help nor are likely to benefit. Preventive policies that focus on high-risk individuals offer substantial benefits for these individuals, but the potential impact on the total burden of disease is often disappointing. Despite the rationale for emphasizing prevention, studies indicate that major gaps exist in the delivery of preventive health services. The main barriers include the time required, the lack of reimbursement, skepticism toward attempting behavioral change, and a health system geared to illness.

CLINICAL PREVENTIVE SERVICES Clinical preventive services include counseling, immunization, screening tests, and reduction of the susceptibility to disease by interventions such as chemoprevention. Preventive services are often classified as primary, secondary, or tertiary. Primary prevention is directed toward preventing disease or injury before it develops; secondary prevention deals with early detection and treatment to impede the progress of pre-clinical disease. In contrast, tertiary prevention refers to rehabilitative activities after the onset of disease to minimize complications and disability. Distinguishing among these phases of prevention may be confusing. Detecting and treating hypertension could be considered secondary prevention of hypertensive disease but primary prevention of congestive heart failure and stroke. In any event, prevention can be perceived along a continuum from modification of predisposing factors, to preventing disease, to avoiding premature death and disability. The sooner the prevention, the more likely unnecessary illness, disability, and TABLE 9-1 -- DEATH RATES* FOR 1995, MALE-FEMALE AND BLACK-WHITE RATIOS FOR 1995, AND PER CENT CHANGE IN DEATH RATES 1950 TO 1995 FOR 10 LEADING CAUSES OF DEATH -- UNITED STATES RANK/CAUSE AGE-ADJUSTED 1995 DEATH RATE MALE-FEMALE RATIO BLACK-WHITE RATIO % CHANGE 1950- 1995 All causes

503.9

1.7

1.6

-40.1

1. Diseases of heart

138.3

1.8

1.5

-55.0

2. Malignant neoplasms

129.9

1.4

1.4

+3.6

3. Accidents

30.5

2.5

1.3

-47.0

4. Cerebrovascular diseases

26.7

1.2

1.8

-69.9

5. Chronic obstructive pulmonary disease

20.8

1.5

0.8

+372.7

6. HIV infection

15.6

5.0

4.7

+59.2

7. Diabetes mellitus

13.3

1.2

2.4

-7.0

8. Pneumonia and influenza

12.9

1.6

1.4

-50.8

9. Suicide

11.2

4.5

0.6

+1.8

10. Homicide and legal intervention

9.4

3.7

6.1

+74.1

From National Center for Health Statistics: Health, United States, 1996-97 and Injury Chartbook. Hyattsville, MD, Public Health Service, 1997. *Per 100,000 population, age adjusted to the 1940 U.S. population. Based on death rates. Per cent change for 1990 to 1995. Categories for coding were introduced in 1987.

27

TABLE 9-2 -- ESTIMATION OF NON-GENETIC CONTRIBUTIONS TO DEATH IN THE UNITED STATES DISEASES AND INJURIES POTENTIAL CONTRIBUTING FACTORS Tobacco

Diet and Exercise

Cancer

X

X

X

X

Cardiovascular disease

X

X

X

X

Diabetes mellitus Digestive diseases/cirrhosis

Alcohol Microbes Toxins Firearms

Motor Vehicles

Illicit Drugs

X X

X X

Accidents

X X

X

HIV infection Hepatitis

X

Infectious/parasitic diseases Respiratory diseases

Sexual Behavior

X

X

X

X

X

X

X

X

X X

X

Renal diseases

X

X

X

Neurologic diseases

X

X

Pneumoconioses

X

X

Homicide/suicide

X

X

Sexually transmitted diseases

X

X

X

X

X

X

Infant mortality

X

Modified from McGinnis MJ, Foege WH: Actual causes of death in the United States. JAMA 270:2207-2212, 1993. premature death can be avoided. Therefore, increasing emphasis has been placed on preventing risk factors themselves. The term "primordial" prevention has been introduced for this concept. Indiscriminate screening without adequate advice and follow-up serves no useful purpose. The periodic health examination (see Chapter 10) has evolved from a broad-based, uniform protocol to an approach that targets the prevention, detection, and treatment of specific diseases or risk factors for pre-determined age, gender, and racial groups. Changes in the health care system and the development of national guidelines will probably draw greater attention to health promotion, disease prevention, and the interface of physician-based medical care with the public health system. Physicians should consider each disorder in terms of the potential for prevention as compared with the possibility of adverse effects from the preventive intervention. Ample evidence connects identifiable and oftentimes preventable factors to the morbidity and mortality associated with major health problems (Table 9-2) . About half of all deaths, morbidity, and disability can be attributed to such non-genetic factors, and many lifestyle changes benefit multiple systems and disorders. For example, cigarette smoking has been estimated to contribute to one in five deaths in the United States (see Chapter 13) ; dietary changes (see Chapter 39) may lower the occurrence of atherosclerosis, diabetes, osteoporosis, and cancer. Other important personal behavior factors affecting health include physical activity, alcohol, illicit drug use, sexual practices, and exposure to environmental toxins. Several common misconceptions impede preventive health care. Many believe that diseases with a strong heritable component cannot be altered, but susceptibility to disease often requires the interaction of multiple genes and environmental factors for expression (see Chapter 31) . In addition, chronic diseases are multifactorial, so other factors can be changed to compensate for an elevated genetic risk. The notion that prevention is less useful in older persons excludes many who would benefit most from prevention. The elderly have a greater absolute risk of disease and have been shown to adhere and respond favorably to preventive measures. In addition, life expectancy is frequently underestimated in the elderly--those who reach 65 years can now expect to live into their 80s. With a larger aging population, decreasing fatality rates, and improved treatment of many disorders, it is essential that the focus be on primary prevention. Otherwise, the prevalence and associated morbidity of major diseases will increase and further consume available medical resources. It should be clearly understood that the purpose of prevention is not only to postpone illness to a later age but also often to prevent the diseases themselves and the resultant disability. On average, U.S. citizens spend 85% of their 75+ years of life expectancy in a healthy state unimpaired by disabilities, disease, or injuries. The leading causes of disability-adjusted loss of years of life in developed countries over the next 25 years will probably continue to be atherosclerotic diseases, but the impact of depression, smoking-related disease, accidents, alcohol, and degenerative neurologic and rheumatologic diseases will also be substantial (Table 9-3) . TABLE 9-3 -- TEN PROJECTED LEADING CAUSES OF DISABILITY-ADJUSTED LIFE YEARS IN 2020 ACCORDING TO BASELINE PROJECTION BY REGION DEVELOPED REGIONS DEVELOPING REGIONS Rank/Disease or Injury

DALYs * ( × 106 )

All causes

160.5

1. Ischemic heart disease

Rank/Disease or Injury All causes

18.0 1. Unipolar major depression

DALYs ( × 106 ) 1228.3 68.8

2. Cerebrovascular disease

9.9 2. Traffic accidents

64.4

3. Unipolar major depression

9.8 3. Ischemic heart disease

64.3

4. Trachea, bronchus, and lung cancers

7.3 4. Chronic obstructive pulmonary disease

52.7

5. Traffic accidents

6.9 5. Cerebrovascular disease

51.5

6. Alcohol use

6.1 6. Tuberculosis

42.4

7. Osteoarthritis

5.6 7. Lower respiratory infections

41.1

8. Dementia and other degenerative and hereditary CNS disorders

5.5 8. War injuries

40.2

9. Chronic obstructive pulmonary disease

4.9 9. Diarrheal diseases

37.0

10. Self-inflicted injuries

3.9 10. HIV

34.0

DALYs = disability-adjusted life years; CNS = central nervous system; HIV = human immunodeficiency virus. From Murray CJL, Lopez AD: Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 349:1498-1504, 1997. *Sum of the years of life lost to death and reduction in the value of years of life lived because of disability.

28

All U.S. citizens should be able to reach the objective for Healthy People 2000--to attain at least 65 years of healthy life.

Murray CJL, Lopez AD: Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 349:1498, 1997. One of a four-part series by the authors on the Global Burden of Disease Study, which predicts worldwide trends in mortality and morbidity. National Center for Health Statistics: Health, United States, 1998, with Socioeconomic and Health Status Chartbook. Hyattsville, MD, Public Health Service, 1998. A report on the health status and trends of the nation. National Center for Health Statistics: Healthy People 2000 Review, 1997. Hyattsville, MD, Public Health Service, 1997. Most recent data and modifications to the objectives for Healthy People 2000: National Health Promotion and Disease Prevention Objectives. Report of the US Preventive Services Task Force: Guide to Clinical Preventive Services: An Assessment of the Effectiveness of 169 Interventions, 2nd ed. Baltimore, Williams & Wilkins, 1996. The most recent authoritative recommendations for clinical preventive services.

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Chapter 10 - THE PREVENTIVE HEALTH EXAMINATION Richard K. Riegelman

Integrating prevention into the practice of adult medicine is an intellectual and administrative challenge. The annual physical examination has been replaced by the periodic health examination, with intervals adjusted by age group. The complete physical examination and multiphasic screening laboratory work-up have been replaced by a focused screening history and physical examination designed to detect risk factors for disease. Laboratory testing is now guided by principles designed to select tests that are likely to produce substantial benefit to groups of individuals at affordable cost. In addition, the preventive health examination should include active therapeutic interventions, including counseling, vaccination, and chemoprophylaxis. To help accomplish these multiple goals, groups such as the American College of Physicians, the Canadian Task Force, and the U.S. Preventive Services Task Force (USPSTF) have developed guidelines for the preventive health examination. The widely used USPSTF recommendations have been intentionally limited to procedures with adequate supportive evidence. A recommendation to screen for a disease, for instance, generally requires evidence that the disease causes substantial morbidity or mortality, that detection at the asymptomatic stage is feasible, and that early detection can alter outcome. Thus it is important to view the USPSTF recommendations as a minimum set of guidelines that are likely to increase in number over time as further evidence accumulates and new approaches are introduced. Other organizations, especially those with a specific disease or professional focus, generally recommend more intensive or aggressive examinations.

INDIVIDUALIZING THE PREVENTIVE HEALTH EXAMINATION In the USPSTF screening guidelines, the recommended history, physical examination, and laboratory tests for any individual are derived by considering that person's age, gender, and risk factors (Table 10-1) . Of note is that efforts to base preventive approaches on evidence have led to the absence of recommendations for many tests that were previously recommended by many, such as chest radiography to detect lung cancer even among smokers, because any early detection that may occur does not generally alter a patient's prognosis. Other tests that are explicitly not recommended for asymptomatic, normal-risk individuals include the electrocardiogram, exercise stress testing, multiple chemistry screens, and sputum cytology testing. CHANGES IN THE PREVENTIVE HEALTH EXAMINATION. The guidelines of the USPSTF, which is now affiliated with the Agency for Healthy Care Policy and Research, are currently undergoing a new cycle of review. Their review of colon cancer screening implies new recommendations, including annual fecal occult blood testing and periodic flexible sigmoidoscopy to reduce colorectal cancer mortality in individuals 50 years and older. The use of mammography between the ages of 40 and 50 years has been very controversial despite efforts to obtain consensus. In the absence of consensus, decisions should be left to individual patients TABLE 10-1 -- U.S. PREVENTIVE SERVICES TASK FORCE PERIODIC EXAMINATION RECOMMENDATIONS: SCREENING HISTORY, PHYSICAL EXAMINATION, AND LABORATORY WORK--AGES 19 AND OLDER Schedule every 1 to 3 yrs of age 19-64 and every year if 65 or older The recommended schedule applies only to the periodic visit itself. The frequency of the individual preventive services is left to clinical discretion except as indicated. The table indicates recommended ages and high-risk (HR) groups for whom the recommendations are made. Recommendations are applicable to age groups indicated in parentheses HISTORY

PHYSICAL EXAMINATION

Dietary intake ( 19) Physical activity ( 19) Tobacco/alcohol/drug use ( 19) Sexual practices (19-64) Functional status ( 65)

Height and weight ( 19) Blood pressure ( 19) Visual acuity ( 65) Hearing ( 65) Clinical breast exam ( 50) and HR 19- 49 --Annually over 50, women aged 35 and older with a family history of premenopausally diagnosed breast cancer in a first-degree relative Testicular exam (HR 19- 39)--Men with a history of cryptorchidism, orchiopexy, or testicular atrophy Symptoms of TIA ( 65) Complete skin exam (HR 19)--Persons with a family or personal history of skin cancer, increased occupational or recreational exposure to sunlight, or clinical evidence of precursor lesions (e.g., dysplastic nevi, certain congenital nevi) Thyroid for nodules (HR 19)--Persons with a history of upper body irradiation Auscultation for carotid bruits (HR 40)--Persons with risk factors for cerebrovascular or cardiovascular disease (e.g., hypertension, smoking, coronary disease, atrial fibrillation, diabetes) or those with neurologic symptoms (e.g., TIAs or a history of cerebrovascular disease) Complete oral cavity exam (HR 19)--Persons with exposure to tobacco or excessive amounts of alcohol or those with suspicious symptoms or lesions detected through self-examination LABORATORY WORK

Nonfasting total cholesterol ( 19) Papanicolaou smear (19- 64, HR 65)--Pap smear every 1-3 yr. At 65 and older, only women who have not had previous documented screening in which smears have been consistently negative Fasting glucose (HR 19)--The markedly obese, persons with family history of diabetes, or women with a history of gestational diabetes Rubella antibodies (HR 19- 39)--Women lacking evidence of immunity VDRL (HR 19- 64)--Prostitutes, persons who engage in sex with multiple partners in areas in which syphilis is prevalent, or contacts of persons with active syphilis Urinalysis for bacteremia (HR 19- 64)--Persons with diabetes Dipstick urinalysis ( 65)

Mammography (HR 35- 49; 50)--Women aged 35 and older with a family history of premenopausally diagnosed breast cancer in a first-degree relative; otherwise every 1-2 yr beginning at age 50. See text Chlamydial testing (HR 19- 64)--Persons who attend clinics for sexually transmitted diseases, attend other high-risk health care facilities (e.g., adolescent and family planning clinics), or have other risk factors for chlamydial infection (e.g., multiple sexual contacts or a sexual partner with multiple sexual contacts, age younger than 20). Gonorrhea culture (HR 19- 64)--Prostitutes, persons with multiple sexual partners or a sexual partner with multiple contacts, sexual contacts of persons with culture-proven gonorrhea, or persons with a history of repeated episodes of gonorrhea Counseling and testing for HIV infection (HR 19- 64)--Persons seeking treatment for sexually transmitted disease; homosexual and bisexual men; past or present IV drug users; persons with a history of prostitution or multiple sexual partners; women whose past or present sexual partners were HIV infected, bisexual, or IV drug users; persons with long-term residence or birth in an area with high prevalence of HIV infection; or persons with a history of transfusion between 1978 and 1985 Hearing (HR 19- 64)--Persons exposed regularly to excessive noise PPD (HR 19)--Household members of persons with tuberculosis or others at risk for close contact with the disease (e.g., staff of tuberculosis clinics, shelters for the homeless, nursing homes, substance abuse treatment facilities, dialysis units, correctional institutions); recent immigrants or refugees from countries in which tuberculosis is common, migrant workers; residents of nursing homes, correctional institutions, or homeless shelters; or persons with certain underlying medical disorders (e.g., HIV infection) Fecal occult blood/sigmoidoscopy (HR)--Persons 50 and older who have first-degree relatives with colorectal cancer; a personal history of endometrial, ovarian, or breast cancer; or a previous diagnosis of inflammatory bowel disease, adenomatous polyps, or colorectal cancer Colonoscopy (HR 19- 39)--Persons with a family history of familial polyposis coli or cancer family syndrome Fecal occult blood/colonoscopy (HR 40)--Persons with a family history of familial polyposis coli or cancer family syndrome Fecal occult blood/sigmoidoscopy ( 50)--See text Bone mineral content (HR 40- 64)--Premenopausal women at increased risk for osteoporosis (e.g., white race, bilateral oophorectomy before menopause, slender build) and for whom estrogen replacement therapy would otherwise not be recommended Electrocardiogram ( 19)--Men who would endanger public safety were they to experience sudden cardiac events, e.g., commercial airline pilots. Men >40 with 2 or more cardiac risk factors (high blood cholesterol, hypertension, cigarette smoking, diabetes mellitus, family history of coronary artery disease) or sedentary or high-risk men planning to begin a vigorous exercise program Thyroid function tests (women 65) Glaucoma testing by eye specialist ( 65) TIA = transient ischemic attack; HIV = human immunodeficiency virus; PPD = purified protein derivative. From U.S. Preventive Services Task Force: Guide to Clinical Preventive Services, 2nd ed. Alexandria, VA, International Medical Publishing, 1996. 40 to 50 years old and their physicians. The use of screening tests for prostate cancer has not been endorsed by the USPSTF or the National Cancer Institute. COUNSELING AS PART OF THE PREVENTIVE HEALTH EXAMINATION. The periodic preventive examination is an opportunity to provide counseling as well as screen for risk factors and disease. However, prevention and counseling should not be confined to the periodic preventive examination, and all encounters should be viewed as opportunities to identify or monitor risk factors and provide counseling. The USPSTF has identified a series of high-priority areas of counseling, which are summarized in Table 10-2 .

IMPLEMENTING THE PREVENTIVE HEALTH EXAMINATION Successful implementation of the periodic health examination requires that physicians endorse, participate in, and share responsibility for the process with the patient. The preventive health examination TABLE 10-2 -- PREVENTIVE SERVICES TASK FORCE--MAJOR ROUTINE COUNSELING RECOMMENDATIONS FOR INDIVIDUALS 19 AND OLDER Ask to describe the use of alcohol and other drugs and counsel regarding the danger of alcohol and tobacco use in any form. Patients with increased exposure to sunlight should be advised to protect their lips and skin. Counsel about car safety belt use and avoidance of driving while using or after the use of alcohol or other drugs. Regular injury prevention counseling is suggested for all older adults or their caretakers. Obtain a history of sexual practices and provide counseling on prevention of unintended pregnancy and contraceptive options to all sexually active women who do not want to become pregnant and men who do not want to have a child, as well as counseling regarding high-risk behavior and prevention of sexually transmitted diseases and HIV infection. Routinely provide nutrition assessment and counseling. Routinely assess patients' physical activity practices and advise a program of regular physical activity that is tailored to their health status and lifestyle. Counsel regarding regular dental visits, brushing and flossing, use of fluoride, and avoiding foods high in sugar. Encourage patients to keep an up-to-date list of medications with dosage and usage schedules. should not be viewed as a one-shot effort. For some patients it may be best integrated into visits for specific problems. For example, patients may be most receptive to smoking cessation recommendations when they are recovering from bronchitis. The physician may be aided by flowsheets or checklists to organize the preventive recommendations and serve as a reminder. Many interventions can be implemented by non-physicians as a routine part of the physician's practice. Active involvement by patients is essential to successful prevention. The recent introduction of Personal Health Guides allows patients to share in the responsibility for putting prevention into practice. US Preventive Services Task Force: Guide to Clinical Preventive Services, 2nd ed. Baltimore, Williams & Wilkins, 1995. A review of the methods, evidence, and recommendations of the USPSTF. US Public Health Service: The Clinician's Handbook of Preventive Services. Washington, DC, International Medical Publishing, 1994. A guide to accompany the Office of Disease Prevention and Health Promotion's Put Prevention into Practice program, which also includes Personal Health Guides and patient educational materials. Websites increasingly provide the most up-to-date information on changes in recommendations. The following websites are useful sources of information on the USPSTF and National Institutes of Health consensus reports, respectively: http://www.ahcpr.gov

http://www.odp.od.nih.gov/consensus/statements

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Chapter 11 - DIET Roland L. Weinsier

By 1996, annual health care expenditures in the United States surpassed $1 trillion and were more than 13.5% of the gross national product. Only a tiny fraction is invested in preventing disease and promoting health despite the fact that better control of fewer than 10 risk factors, including increasing exercise, decreasing smoking, wearing seat belts, and improving diet, could prevent 40 to 70% of all premature deaths, one third of all cases of acute disability, and two thirds of all cases of chronic disability. In support of this notion is the fact that age-adjusted mortality rates 30

from coronary heart disease in the United States have decreased by more than 40% over the past 25 years; up to one third of this decline is probably attributable to diet-induced reductions in serum cholesterol levels.

NUTRITION IN DISEASE PREVENTION Dietary recommendations aimed at reducing disease risk of the entire population can be of major benefit for the nation's health because even a relatively small reduction in risk in a large number of moderate-risk people could lead to greater benefit for the total population than a large reduction in risk for a small number of high-risk people. For example, population-wide dietary changes are especially worthwhile because most coronary disease occurs in people who have only moderate elevations in serum cholesterol (i.e., 6

>70%

>60%

*Ratio of the metabolic rate during activity to the resting metabolic rate. One MET is defined as the energy expended while sitting quietly. Percentage of maximum heart rate. Percentage of maximum aerobic capacity.

EPIDEMIOLOGY National and state-based surveys indicate that approximately 30% of American adults are completely sedentary during their leisure time and another 30% to 40% are minimally active. Fewer than 40% of adults report being physically active at the recommended levels (20 minutes or more of vigorous activity at least three times per week or 30 minutes or more of moderate-intensity activity five or more times per week). Participation in leisure time physical activity appears to have increased from the 1960s through the 1980s but has reached a plateau over the past decade. Participation in physical activity declines with age and tends to be slightly higher among men than women and among whites than among members of other racial or ethnic groups. Higher levels of education and income are associated with greater participation in physical activity and account for most of the racial and ethnic differences observed for leisure time physical activity.

HEALTH BENEFITS OF PHYSICAL ACTIVITY The physiologic and metabolic responses to exercise are at the root of the multiple health benefits associated with physical activity. Physical activity requires increased energy expenditure and imposes demands and stresses on multiple organ and enzyme systems. These demands lead to acute responses and to long-term adaptations of the circulatory, respiratory, nervous, endocrine, and skeletal systems. The most direct benefits of physical activity are cardiovascular and musculoskeletal adaptations, which increase functional capacity in these organ systems. Increased aerobic capacity and muscular strength and endurance have been well documented following training programs in individuals of all ages. Maintenance of functional capacity and strength may be especially important for preventing disability and maintaining independence among older adults. Many disease- and risk factor-specific benefits of physical activity have also been postulated. Convincing data link regular physical activity to lower rates of coronary heart disease (CHD) and colon cancer and to improvements in mental health, glucose metabolism, and bone density, but much research is needed to evaluate other possible health consequences of physical activity. CORONARY HEART DISEASE. Classic epidemiologic studies demonstrated that heart disease was less likely to develop in conductors on double-decker buses in London than in less active drivers and that among longshoremen, the most active men had the least risk of CHD. Longitudinal studies of college alumni have shown a reduced incidence of CHD and lower CHD and all-cause mortality among regularly active men as compared with their sedentary counterparts. Previously sedentary men who initiated regular physical activity in middle age also reduced their risk of death from CHD and all causes when compared with men who remained sedentary. Increased physical fitness has been linked with lower all-cause and CHD mortality for both men and women. Overall, the risk of CHD in sedentary men is about twice that of men who are habitually active. To date, no randomized clinical trial of physical activity for the primary prevention of CHD has been conducted. However, the association of regular physical activity with reductions in CHD meets strict epidemiologic criteria for causality--the association is strong, consistent, graded, temporally appropriate, and biologically plausible (Table 12-2) . The evidence for a causal role of regular physical activity in the secondary prevention of CHD is at least as strong as that for primary prevention. Patients with CHD who engage in regular physical activity as part of a cardiac rehabilitation program have lower all-cause and CHD mortality than do non-participants 1 to 3 TABLE 12-2 -- MECHANISMS BY WHICH PHYSICAL ACTIVITY PREVENTS CORONARY HEART DISEASE Reduces elevated systolic blood pressure Reduces elevated diastolic blood pressure Raises HDL cholesterol Reduces triglycerides Reduces weight gain and enhances weight maintenance and fat distribution Increases glucose uptake and insulin sensitivity Reduces platelet adhesion Enhances fibrinolysis May reduce thrombosis

Decreases sympathetic and increases parasympathetic drive, which reduces myocardial oxygen demand May reduce ventricular arrhythmias May increase myocardial oxygen supply HDL = high-density lipoprotein. years after initial hospitalization. Exercise-based cardiac rehabilitation programs have also been shown to increase functional capacity and reduce CHD symptoms and may improve quality of life. Appropriate physical activity should be a part of the management and rehabilitation of most patients with CHD (see Chapter 60) . WEIGHT CONTROL. Individuals who are regularly active tend to weigh less and have a lower percentage of body fat than do sedentary individuals despite the fact that physically active persons are consistently observed to consume more calories than sedentary individuals. Regular physical activity increases caloric expenditure indirectly by raising the resting metabolic rate after activity, as well as directly by the activity itself. A combined program of diet and regular physical activity appears to be the most effective means of maintaining ideal body weight. Regular physical activity appears to alter body fat distribution beneficially, independent of its effects on body weight and total adiposity. DIABETES. Physical activity increases muscle glucose uptake directly and also increases insulin sensitivity. Physical activity is commonly prescribed for managing non-insulin-dependent diabetes mellitus (NIDDM). Physical activity may also prevent NIDDM through its effects on insulin and glucose metabolism and maintenance of body weight (see Chapter 242) . In well-conducted longitudinal studies, the incidence of NIDDM has been observed to be lower in regularly active male college alumni, physicians, and female nurses than their sedentary counterparts. OSTEOPOROSIS. Physical activity may play an important role in maintaining bone mineral density, preventing osteoporosis, and reducing fractures (see Chapter 257) . Bone density is reduced by bed rest and can be increased by weight-bearing activity. Regular physical activity has been demonstrated to increase bone mass in young women and reduce the decline in bone mass seen in postmenopausal women and may increase bone density in patients with osteoporosis. Postmenopausal women who walk approximately 1 mile per day have higher bone mineral density and slower rates of bone loss than do sedentary women. Regular physical activity also increases muscle mass and strength, perhaps reducing the risk of falls and protecting against fractures when falls do occur. CANCER. Both regular physical activity and physical fitness have been associated with lower mortality from cancer in longitudinal studies. Although data for most specific cancers are limited, studies of occupational and leisure time activity indicate that physical activity is protective against colon cancer. Several studies suggest a reduced risk of breast cancer in regularly active women, but a nearly equal number of studies have failed to demonstrate this relationship. The protective effects may be mediated by reduced intestinal transit time (colon cancer) and altered endocrine function. MENTAL HEALTH. Regular physical activity and physical fitness are positively associated with mental health and well-being. Persons who are regularly active report less anxiety and depression and lower levels of stress than do sedentary persons. Exercise programs may be useful as an adjunctive therapy for treating mild to moderate depression.

HEALTH RISKS Physical activity is associated with risks as well as benefits. Musculoskeletal overuse injuries of the lower extremity are the most common negative consequences of physical activity. Three factors are strongly associated with a risk of musculoskeletal injury: 33

previous injuries, increased duration of activity, and exercise intensity. The risk of injury is considerably higher with vigorous activity than with moderate activity. The clinician can reduce patients' risk of injury by making them aware of these associations and by advocating moderate physical activity and gradual increases in duration of activity. Major cardiac events, although rare, have been associated with vigorous physical activity. The risk of cardiac arrest is transiently elevated during exercise both for those who are regularly active and to a greater extent for individuals who are irregularly active. However, the overall risk of cardiac arrest is reduced in men who are regularly active. The incidence of sudden death associated with jogging has been estimated at 1 per 360,000 hours of jogging. The majority of these deaths are due to underlying CHD. Physical activity may also exacerbate medical conditions such as asthma, and irregular exercise may make insulin dosing more challenging in diabetic patients. Nevertheless, most individuals with underlying disease or disability may still safely exercise if appropriate precautions are taken.

MEDICAL EVALUATION Appropriate medical evaluation depends on the individual's age and health status and the type of activity undertaken. Individuals who are free of disease and who are initiating moderate-intensity physical activity such as regular walking do not require medical evaluation. Men older than 40 years and women older than 50 who wish to become vigorously active should undergo a medical examination. Persons of any age with symptomatic cardiovascular disease or multiple risk factors for cardiovascular disease require medical evaluation. Evaluation of patients with known cardiovascular disease should include a physician-supervised, symptom-limited exercise test with blood pressure and electrocardiographic monitoring; such testing is not generally thought to be mandatory in asymptomatic adults without known cardiovascular disease.

ASSESSMENT AND COUNSELING Health professionals should routinely counsel patients to adopt and maintain an active lifestyle. The exercise prescription should consider an individual's age, health, current activity level, and readiness to initiate behavior change. Research on both quitting smoking and initiating physical activity has shown that patients move along a behavioral continuum from pre-contemplation, to contemplating change, to making a change, and finally to maintaining the new behavior. Physicians have greater success in changing their patient's physical activity practices if they can target their counseling to the patient's current activity level and behavioral stage. Brief, specific physical activity counseling reinforced by other providers, follow-up appointments, or educational materials can increase physical activity. How much and what type of physical activity should be prescribed? The traditional exercise prescription calls for 20 or more minutes of continuous aerobic activity three to five times per week at moderate to vigorous intensity (60% of maximum heart rate or 50% of aerobic capacity). This prescription is appropriate for increasing fitness and improving health status. Reassessment of epidemiologic and clinical data on the health aspects of physical activity reveals that many of the health benefits attributable to physical activity are associated with the total quantity of activity performed even if the activity is discontinuous and of only moderate intensity. Moderate activities such as brisk walking, gardening, and stair climbing on a daily basis can have major health impacts. The Centers for Disease Control and Prevention, National Institutes of Health, Surgeon General, and the American College of Sports Medicine currently recommend that American adults participate in 30 minutes or more of moderate-intensity physical activity on most and preferably all days of the week. The physical activity prescription can take the traditional vigorous exercise approach or follow the recommendation for daily moderate physical activity (Table 12-3) . Both provide significant health benefits. Tailoring recommendations for physical activity to the patient's individual goals, interests, skills, available time, and barriers to activity increases the chance for success. Most persons are aware that they should be more active. The physician can encourage patients to become regularly active by TABLE 12-3 -- THE EXERCISE PRESCRIPTION

Type of physical activity Continuous or intermittent Primarily aerobic Stretching for flexibility Resistance exercise for strength Intensity Moderate (40-60% relative to capacity, "brisk walk") OR Vigorous (>60% relative to capacity) Duration 20-60 min/d 150-300 kcal/d Frequency Daily for intermittent moderate activity Three or more times per week for continuous, vigorous activity Session For planned exercise: Warm-up, 3-5 min Conditioning, 15-40 min Cool-down, 2-5 min For lifestyle activity: Incorporate activity into the daily routine. "Pulses" of activity should be at least 10 min long and at an intensity equal to brisk walking Progression Increase duration, intensity, and frequency gradually Evaluate progress each visit Warning signs Severe musculoskeletal pain Claudication Chest pressure, pain, or discomfort Unusual shortness of breath Dizziness, nausea, vomiting reinforcing the importance of physical activity to health, working with the patient to help build the skills and self-confidence needed to be active, and designing a program of physical activity that fits into the individual's lifestyle. Dunn AL, Marcus BH, Kampert JB, et al: Comparison of lifestyle and structured interventions to increase physical activity and cardiorespiratory fitness: A randomized trial. JAMA 281:327, 1999. Lifestyle changes are as effective as a structured exercise program. Simons-Morton DG, Calfas KJ, Oldenburg B, Burton NW: Effects of interventions in health-care settings or physical activity on cardiorespiratory fitness. Am J Prev Med 15:413, 1998. A review and discussion of all the controlled trials of physical activity counseling for primary and secondary prevention. This issue of the American Journal of Preventive Medicine also includes up-to-date reviews of physical activity interventions in a variety of settings (schools, workplace, communities) and for special populations. US Department of Health and Human Services: Physical Activity and Health: A Report of the Surgeon General. Atlanta, US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, 1996. An authoritative review of the health effects of physical activity and current patterns and trends of participation in physical activity in the United States.

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Chapter 13 - TOBACCO Neal L. Benowitz

EPIDEMIOLOGY Currently, about 45 million individuals in the United States are cigarette smokers, including 28% of men and 23% of women. People who are less well educated and/or have unskilled occupations are more likely to smoke. Smoking is responsible for about 430,000 preventable U.S. deaths annually. A lifelong smoker has about a one in three chance of dying prematurely from a complication of smoking. Smoking is the major preventable cause of death in developed countries. Other forms of tobacco use include pipes and cigars (used by 8.7% of men and 0.3% of women) and smokeless tobacco (5.5% of men and 1% of women). Smokeless tobacco use in the United 34

States is primarily oral snuff and chewing tobacco, whereas nasal snuff is used to a greater extent in the United Kingdom.

HARMFUL CONSTITUENTS OF TOBACCO Tobacco smoke is an aerosol of droplets (particulates) containing water, nicotine and other alkaloids, and tar. Tobacco smoke contains several thousand different chemicals, many of which may contribute to human disease. Major toxic chemicals in the particulate phase of tobacco include nicotine, benzo(a)pyrene and other polycyclic hydrocarbons, N -nitrosonornicotine, beta-naphylamine, polonium-210, nickel, cadmium, arsenic, and lead. The gaseous phase contains carbon monoxide, acetaldehyde, acetone, methanol, nitrogen oxides, hydrogen cyanide, acrolein, ammonia, benzene, formaldehyde, nitrosamines, and vinyl chloride. Tobacco smoke may produce illness via systemic absorption of toxins and/or cause local pulmonary injury by oxidant gases.

TOBACCO ADDICTION Tobacco use is motivated primarily by the desire for nicotine. Drug addiction is defined as compulsive use of a psychoactive substance, the consequences of which are detrimental to the individual or society. Understanding addiction is useful in providing effective smoking cessation therapy. Nicotine is absorbed rapidly from tobacco smoke into the pulmonary circulation; it then moves quickly to the brain, where it acts on nicotinic cholinergic receptors to produce its gratifying effects, which occur within 10 to 15 seconds after a puff. Smokeless tobacco is absorbed more slowly and results in less intense pharmacologic effects. With long-term use of tobacco, physical dependence develops as a result of an increased number of nicotinic cholinergic receptors in the brain. When tobacco is unavailable, even for only a few hours, withdrawal symptoms often occur, including anxiety, irritability, difficulty concentrating, restlessness, hunger, craving for tobacco, disturbed sleep, and in some people, depression. Addiction to tobacco is multifactorial, including a desire for the direct pharmacologic actions of nicotine, relief of withdrawal symptoms, and learned associations. Smokers report a variety of reasons for smoking, including pleasure, arousal, enhanced vigilance, improved performance, relief of anxiety or depression, reduced hunger, and control of body weight. Environmental cues--such as a meal, a cup of coffee, talking on the phone, an alcoholic beverage, or friends who smoke--often trigger an urge to smoke. Smoking and depression are strongly linked. Smokers are more likely to have a history of major depression than non-smokers are. Smokers with a history of depression are also likely to be more highly dependent on nicotine and have a lower likelihood of quitting. When they do quit, depression is more apt to be a prominent withdrawal symptom. Most tobacco use begins in childhood or adolescence. Risk factors for youth smoking include peer and parental influences, behavioral problems (e.g., poor school performance), and personality characteristics such as rebelliousness or risk taking, depression, and/or anxiety, as well as genetic influences. Adolescent desire to appear older and more sophisticated, such as emulating more mature role models, is another strong motivator. Environmental influences such as advertising are also thought to contribute. Whereas smoking rates among adults have been declining over the past 30 years, initiation rates for youth have remained constant for the past 15 years. Approaches to preventing tobacco addiction in youth include educational activities in schools or in the media, reducing accessibility of tobacco to youth (such as taxation, enforcing restrictions against youth purchasing tobacco), changing the social and environmental norms, and deglamourizing smoking (restricting indoor smoking, educating parents not to smoke around children).

TOBACCO-RELATED DISEASES Tobacco use is a major cause of death from cancer, cardiovascular disease, and pulmonary disease (Table 13-1) . Smoking is also a major risk factor for peptic disease, osteoporosis, reproductive disorders, and fire-related injuries. TABLE 13-1 -- HEALTH HAZARDS OF TOBACCO USE (RISKS INCREASED BY SMOKING) Cancer See Table 13-2 Cardiovascular Disease Sudden death Acute myocardial infarction Unstable angina Stroke Peripheral arterial occlusive disease Aortic aneurysm Pulmonary Disease Lung cancer Chronic bronchitis Emphysema Asthma Increased susceptibility to pneumonia Increased morbidity from viral respiratory infection Gastrointestinal Disease

Peptic ulcer Esophageal reflux Reproductive Disturbances Reduced fertility Premature birth Lower birth weight Spontaneous abortion Abruptio placentae Premature rupture of membranes Increased perinatal mortality Oral Disease (Smokeless Tobacco) Oral cancer Leukoplakia Gingivitis Gingival recession Tooth staining Other Earlier menopause Osteoporosis Cataract Premature skin wrinkling Aggravation of hypothyroidism Altered drug metabolism or effects

CANCER. Smoking is the single largest preventable cause of cancer (Table 13-2) . It is responsible for about 30% of cancer deaths. A number of chemicals in tobacco smoke may contribute to carcinogenesis as tumor initiators, co-carcinogens, tumor promoters, or complete carcinogens. Lung cancer is the leading cause of cancer deaths in the United States and is predominantly attributable to cigarette smoking. The risk of lung and other cancers is proportional to how many cigarettes are smoked per day and the duration of smoking. Workplace exposure to asbestos or alpha-radiation (see Chapter 18) (the latter in uranium miners) synergistically increases the risk of lung cancer in cigarette smokers. Alcohol use (see Chapter 16) interacts synergistically with tobacco in causing oral, laryngeal, and esophageal cancer. The mechanism of interaction may involve alcohol-solubilizing tobacco carcinogens and/or alcohol-related induction of liver or gastrointestinal enzymes that metabolize and activate tobacco carcinogens. The tobacco-related risks of bladder and kidney cancer are enhanced by occupational exposure to aromatic amines, such as found in the dye industry. Cervical cancer is more common in women who smoke, presumably the result of exposure to carcinogens in cervical secretions. Smoking appears to be involved in 20 to 30% of leukemia cases in adults, including both lymphoid and myeloid leukemia. TABLE 13-2 -- SMOKING AND CANCER MORTALITY TYPE OF CANCER

RELATIVE RISK AMONG SMOKERS Current

Lung Larynx Oral cavity Esophagus Pancreas Bladder Kidney Stomach Leukemia Cervix

MORTALITY ATTRIBUTABLE TO SMOKING

Former

Percentage

Number

Male

22.4

9.4

90

82,800

Female

11.9

4.7

79

40,300

Male

10.5

5.2

81

2,400

Female

17.8

11.9

87

700

Male

27.5

8.8

92

4,900

Female

5.6

2.9

61

1,800

Male

7.6

5.8

78

5,700

Female

10.3

3.2

75

1,900

Male

2.1

1.1

29

3,500

Female

2.3

1.8

34

4,500

Male

2.9

1.9

47

3,000

Female

2.6

1.9

37

1,200

Male

3.0

2.0

48

3,000

Female

1.4

1.2

12

500

Male

1.5

?

17

1,400

Female

1.5

?

25

1,300

Male

2.0

?

20

2,000

Female

2.0

?

20

1,600

Female

2.1

1.9

31

1,400

Adapted from Newcomb PA, Carbone PP: The health consequences of smoking: Cancer. Med Clin North Am 76:305, 1992.

35

CARDIOVASCULAR DISEASE. Cigarette smoking accounts for about 20% of cardiovascular deaths in the United States. Risks are increased for coronary heart disease, sudden death, cerebrovascular disease, and peripheral vascular disease, including aortic aneurysm. Cigarette smoking accelerates atherosclerosis and promotes acute ischemic events. The mechanisms of the effects of smoking are not fully elucidated but are believed to include (1) hemodynamic stress (nicotine increases the heart rate and transiently increases blood pressure), (2) endothelial injury and dysfunction (nitric oxide release and resultant vasodilation are impaired), (3) development of an atherogenic lipid profile (smokers have on average higher low-density lipoprotein, more oxidized low-density lipoprotein, and lower high-density lipoprotein cholesterol than non-smokers do), (4) enhanced coagulability, (5) arrhythmogenesis, and (6) relative hypoxemia because of the effects of carbon monoxide. Carbon monoxide reduces the capacity of hemoglobin to carry oxygen and impairs the release of oxygen from hemoglobin to body tissues, both of which combine to result in a state of relative hypoxemia. To compensate for this hypoxemic state, polycythemia develops in smokers, with hematocrits often 50% or more. The polycythemia also increases blood viscosity, which adds to the risk of thrombotic events. Cigarette smoking acts synergistically with other cardiac risk factors to increase the risk of ischemic heart disease. Although the risk of cardiovascular disease is roughly proportional to cigarette consumption, the risk persists even at low levels of smoking, that is, one to two cigarettes per day. Cigarette smoking reduces exercise

tolerance in patients with angina pectoris and intermittent claudication. Vasospastic angina is more common and the response to vasodilator medication is impaired in patients who smoke. The number of episodes and total duration of ischemic episodes as assessed by ambulatory electrocardiographic monitoring in patients with coronary heart disease are substantially increased by cigarette smoking. The increase in relative risk of coronary heart disease because of cigarette smoking is greatest in young adults, who in the absence of cigarette smoking would have a relatively low risk. Women who use oral contraceptives and smoke have a synergistically increased risk of both myocardial infarction and stroke. After acute myocardial infarction, the risk of recurrent myocardial infarction is higher and survival is half over the next 12 years in persistent smokers as compared with quitters. Smoking interferes with revascularization therapy for acute myocardial infarction. After thrombolysis, the reocclusion rate is four-fold higher in smokers who continue than in those who quit. The risk of reocclusion of a coronary artery after angioplasty or occlusion of a bypass graft is increased in smokers. Cigarette smoking is not a risk factor for hypertension per se but does increase the risk of complications, including the development of nephrosclerosis and progression to malignant hypertension. PULMONARY DISEASE. More than 80% of chronic obstructive lung disease in the United States is attributable to cigarette smoking. Cigarette smoking also increases the risk of respiratory infection, including pneumonia, and results in greater disability from viral respiratory tract infections. Pulmonary disease from smoking includes the overlapping syndromes of chronic bronchitis (cough and mucus hypersecretion), emphysema, and airway obstruction. The lung pathology produced by cigarette smoking includes loss of cilia, mucous gland hyperplasia, increased number of goblet cells in the central airways, inflammation, goblet cell metaplasia, squamous metaplasia, mucus plugging of small airways and destruction of alveoli, and a reduced number of small arteries. The mechanism of injury is complex and appears to include direct injury by oxidant gases, increased elastase activity (a protein that breaks down elastin and other connective tissue), and decreased antiprotease activity. A genetic deficiency of alpha1 -antiprotease activity produces a similar imbalance between pulmonary protease and antiprotease activity and is a risk factor for early and severe smoking-induced pulmonary disease. OTHER COMPLICATIONS. Cigarette smoking increases the risk of duodenal and gastric ulcers, delays the rate of ulcer healing, and increases the risk of relapse after ulcer treatment. Smoking is also associated with esophageal reflux symptoms. Smoking produces ulcer disease by increasing acid secretion, reducing pancreatic bicarbonate secretion, impairing the gastric mucosal barrier (related to decreased gastric mucosal blood flow and/or inhibition of prostaglandin synthesis), and/or reducing pyloric sphincter tone. Cigarette smoking is a risk factor for osteoporosis in that it reduces the peak bone mass attained in early adulthood and increases the rate of bone loss in later adulthood. Smoking antagonizes the protective effect of estrogen replacement therapy on the risk of osteoporosis in postmenopausal women. Cigarette smoking is a major cause of reproductive problems and results in approximately 4600 U.S. infant deaths annually. Growth retardation from cigarette smoking has been termed the "fetal tobacco syndrome." Cigarette smoking causes reproductive complications by causing placental ischemia mediated by the vasoconstricting effects of nicotine, the hypoxic effects of chronic carbon monoxide exposure, and/or the general increase in coagulability produced by smoking. Other adverse effects of cigarette smoking include premature facial wrinkling, an increased risk of cataracts, olfactory dysfunction, and fire-related injuries, the latter of which contribute significantly to the economic costs of tobacco use. Smoking reduces the secretion of thyroid hormone in women with subclinical hypothyroidism and increases the severity of clinical symptoms of hypothyroidism in women with subclinical or overt hypothyroidism, the latter effect reflecting antagonism of thyroid hormone action. Cigarette smoking also potentially interacts with a variety of drugs by accelerating drug metabolism or by the antagonistic pharmacologic actions that nicotine and/or other constituents of tobacco have with other drugs (Table 13-3) .

HEALTH HAZARDS OF SMOKELESS TOBACCO Smokeless tobacco refers to snuff and chewing tobacco. Oral snuff is placed (as a "pinch") between the lip and gum or under the tongue; chewing tobacco is actively chewed and generates saliva that is spit out (hence the term "spit tobacco"). Smokeless tobacco products are usually flavored, many with licorice, and also contain sodium bicarbonate to keep the local pH alkaline to facilitate buccal absorption of nicotine. Nicotine absorption from smokeless tobacco is similar in magnitude to that absorbed from cigarette smoking. In addition, other chemicals, including sodium, glycyrrhizinic acid (from licorice), and potentially carcinogenic chemicals such as nitrosamines are absorbed systemically. Smokeless tobacco is addictive and is associated with an increased risk of oral cancer at the site where the tobacco is usually placed (inside the lip, under the cheek or tongue) or nasal cancer in nasal snuff users. Other oral diseases also associated with smokeless tobacco include leukoplakia, gingivitis, gingival recession, and staining of the teeth. Cardiovascular effects of smokeless tobacco include acute aggravation of hypertension or angina pectoris as a result of the sympathomimetic effects of nicotine, hypokalemia, hypertension secondary to the effects of glycyrrhizinic acid (a potent mineralocorticoid), and excessive sodium absorption resulting in aggravated hypertension or sodium-retaining disorders.

ENVIRONMENTAL TOBACCO SMOKE Considerable evidence indicates that exposure to environmental tobacco smoke (ETS) (i.e., passive smoking) is harmful to the health of non-smokers (Table 13-4) . Recently, the U.S. Environmental Protection Agency classified ETS as a class A carcinogen, which means that it has been shown to cause cancer in humans. ETS consists of smoke that is generated while the cigarette is smoldering, as well as mainstream smoke that has been exhaled by the smoker. Seventy-five per cent or more of the total combustion product from a cigarette enters the air. The constituents of ETS are qualitatively similar to those of mainstream smoke. However, some toxins such as ammonia, formaldehyde, and nitrosamines are present in much higher concentrations in ETS than in mainstream smoke. The Environmental Protection Agency has estimated that ETS is responsible for approximately 3000 lung cancer deaths annually in non-smokers in the United States, is causally associated with 150,000 to 300,000 cases of lower respiratory tract infection in infants and young children up to 18 months of age, and is causally associated with the aggravation of asthma in 200,000 to 1 million children. An appreciation of the hazards of ETS is important to the physician because it provides a basis for advising parents 36

TABLE 13-3 -- INTERACTION BETWEEN CIGARETTE SMOKING AND DRUGS INTERACTION (EFFECTS COMPARED WITH NON-SMOKERS)

DRUG(S) Antipyrine Caffeine Desmethyldiazepam Estradiol Estrone Flecainide Heparin Imipramine

Lidocaine Oxazepam Pentazocine Phenacetin Phenylbutazone Propranolol Theophylline

SIGNIFICANCE

Accelerated metabolism

May require high doses in smokers, reduced doses after quitting

Oral contraceptives

Enhanced thrombosis, increased risk of stroke and myocardial infarction

Do not prescribe to smokers, especially if older than 35

Cimetidine and other H2 blockers

Lower rate of ulcer healing, higher ulcer recurrence rates

Consider using mucosal protective agents

Propranolol

Less antihypertensive effect, less antianginal efficacy; more effective Consider the use of cardioselective in reducing mortality following myocardial infarction beta-blockers

Nifedipine (and probably other calcium blockers)

Less antianginal effect

May require higher doses and/or multiple-drug antianginal therapy

Diazepam, chlordiazepoxide (and possibly other sedative-hypnotics)

Less sedation

Smokers may need higher doses

Chlorpromazine (and possibly other neuroleptics)

Less sedation, possibly reduced efficacy

Smokers may need higher doses

Propoxyphene

Reduced analgesia

Smokers may need higher doses

not to smoke when children are in the home, for insisting that child care facilities be smoke-free, and for recommending smoking restrictions in work sites and other public places.

BENEFITS OF QUITTING The benefits of quitting smoking are substantial for smokers of any age. A person who quits smoking before age 50 has half the risk of dying in the next 15 years than a continuing smoker has. Smoking cessation reduces the risks of development of lung cancer, with the risk falling to half that of a continuing smoker by 10 years and one sixth that of a smoker after 15 years' cessation. The risk of acute myocardial infarction falls rapidly after quitting smoking and approaches non-smoker levels within a year of abstinence. Cigarette smoking produces a progressive loss of airway function over time that is characterized by an accelerated loss of forced expiratory volume in 1 second (FEV1 ) with increasing age. FEV1 loss to cigarette smoking cannot be regained by cessation, but the rate of decline slows after smoking cessation and returns to that of non-smokers. Women who stop smoking during the first 3 to 4 months of pregnancy reduce the risk of having a low-birthweight baby to that of a woman who has never smoked. After quitting, smokers gain an average of 5 to 7 lb, which is perceived as undesirable and a reason not to quit by some smokers. Smokers tend to be thinner because of the effects of nicotine to increase energy expenditure and reduce compensatory increases in food consumption. After they quit smoking, ex-smokers tend to reach the weight expected had they never smoked. On balance, the benefits of quitting far outweigh the risks associated with weight gain, and patients should be counseled accordingly.

TREATMENT OF NICOTINE ADDICTION Seventy per cent of cigarette smokers would like to quit. Spontaneous quit rates are about 1% per year. Simple physician advice to TABLE 13-4 -- HEALTH HAZARDS OF ENVIRONMENTAL TOBACCO SMOKE IN NON-SMOKERS CHILDREN ADULTS Hospitalization for respiratory tract infection in first year of life

Lung cancer

Wheezing

Myocardial infarction

Middle ear effusion

Reduced pulmonary function

Asthma

Irritation of eyes, nasal congestion, headache

Sudden infant death syndrome

Cough

quit increases the quit rate to 3%. Minimal-intervention programs increase quit rates to 5 to 10%, whereas more intensive treatments, including smoking cessation clinics, can yield quit rates of 25 to 30%. A practical office smoking cessation program developed by the National Cancer Institute consists of "4 A's": (1) ask about smoking at every opportunity; (2) advise all smokers to stop; (3) assist the patient in stopping and maintaining abstinence; and (4) arrange follow-up to reinforce non-smoking. Assistance in quitting should include providing self-help material or quit kits, which are widely available from governmental health agencies, professional societies, and local organizations such as cancer, heart, and lung associations. The physician may offer additional education and counseling through the office (most efficiently provided by office staff and through teaching aids such as videotapes) or through referral to community smoking cessation programs. Smokers who are interested may be offered nicotine replacement or other pharmacologic therapy. Currently, two medications have been approved for smoking cessation: nicotine and bupropion. All types of smoking cessation medications, if used properly, double smoking cessation rates when compared with placebo treatments. Nicotine replacement medications include 2- and 4-mg nicotine polacrilex gum, transdermal nicotine patches, nicotine nasal spray, and nicotine inhalers. A smoker should be instructed to quit smoking entirely before beginning nicotine replacement therapies. Optimal use of nicotine gum includes instructions not to chew too rapidly, to chew 8 to 10 pieces per day for 20 to 30 minutes each, and to use it for an adequate period for the smoker to learn a lifestyle without cigarettes, usually 3 months or longer. Side effects of nicotine gum are primarily local and include jaw fatigue, sore mouth and throat, upset stomach, and hiccups. Several different transdermal nicotine preparations are marketed--three deliver 21 or 22 mg over a 24-hour period, and one delivers 15 mg over a period of 16 hours. All have lower-dose patches for tapering. Patches are applied in the morning and removed either the next morning or at bedtime, depending on the patch. Full-dose patches are recommended for most smokers for the first 1 to 3 months, followed by one to two tapering doses for 2 to 4 weeks each. Nicotine nasal spray, one spray into each nostril, delivers about 0.5 mg nicotine systemically and can be used every 30 to 60 minutes. Local irritation of the nose commonly produces burning, sneezing, and watery eyes during initial treatment, but tolerance develops to these effects in 1 to 2 days. The nicotine inhaler actually delivers nicotine to the throat and upper airway, from where it is absorbed similarly to nicotine from gum. It is marketed as a cigarette-like plastic device and can be used ad libitum.

37

Bupropion, also marketed as an antidepressant drug, is dosed at 150 to 300 mg/day for 7 days prior to stopping smoking and then at 300 mg/day for the next 6 to 12 weeks. Bupropion can also be used in combination with a nicotine patch. Bupropion in excessive doses can cause seizures and should not be used in individuals with a history of seizures or with eating disorders (bulimia or anorexia). On average, nicotine medications or bupropion treatment doubles the cessation rates found with placebo treatment, and absolute rates of smoking cessation have increased from 12% (placebo) to 24% (active medication) in clinical trials. Follow-up office visits and/or telephone calls during and after active treatment increase long-term smoking cessation rates. Even in the best treatment circumstances, 70% or more of smokers relapse. Most smokers go through a quitting process three or four times before they finally succeed. When a quit attempt fails, the health care provider should encourage patients to try again as soon as they are ready. Cost-effectiveness studies find average costs per year of life saved of $1000 to $2000 for brief physician counseling alone and $2000 to $4000 for counseling plus medication to aid cessation. Smoking cessation treatment is much less costly per year of life saved than other widely accepted preventive therapies, including treatment of mild to moderate hypertension or hypercholesterolemia. Benowitz NL: Pharmacology of nicotine: Addiction and therapeutics. Annu Rev Pharmacol Toxicol 36:597, 1996. A review of the human pharmacology of nicotine, its role in producing tobacco addiction, and the basis for pharmacotherapy for nicotine addiction. Hughes JR, Goldstein MG, Hurt RD, Shiffman S: Recent advances in the pharmacotherapy of smoking. JAMA 281:72, 1999. Recommends that pharmacotherapy should be made available to all smokers who wish to quit. Hurt RD, Sachs DPL, Glover ED, et al: A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 337:1195, 1997. Clinical trial demonstrating the benefit of bupropion in smoking cessation therapy. Law MR, Morris JK, Walk NJ: Environmental tobacco smoke exposure and ischemic heart disease: An evaluation of the evidence. BMJ 315:973, 1997. Reviews environmental tobacco smoke as a cause of cardiovascular disease. The Smoking Cessation Clinical Practice Guideline Panel and Staff: The Agency for Health Care Policy and Research Smoking Cessation Clinical Practice Guideline. JAMA 275:1270, 1996. Consensus recommendations on implementing smoking cessation for primary care clinicians, smoking cessation specialists, and health care administrators.

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Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 14 - VIOLENCE AND INJURY Elizabeth McLoughlin

DEFINITIONS Violence in the United States is a public health emergency and can be caused by institutional and personal actions. The root causes of violence include inequitable social and economic conditions. Personal violence is the intentional use of physical or psychological force against another person or against oneself that may result in injury or death. An injury is damage to tissue usually caused by excessive energy transfer. That energy can be kinetic (causing fractures, lacerations, and contusions), thermal (burns and scalds), electrical (electrocutions), or chemical (poisonings). The mechanism is somewhat different for drowning and suffocation, which result when tissue is deprived of oxygen. Injuries may be classified in many ways, primarily by type, by cause, and by intent. Type of injury includes, for example, a fracture, laceration, or burn. Cause groupings distinguish among, for example, injuries caused by a car crash, a bullet, poisons, or a fall. Intent categories address whether the injury was unintentional, intentionally self-inflicted (the most severe outcome being suicide), or intentionally inflicted by another (the most severe outcome being homicide). Violent injuries such as homicide and suicide are positioned at the intersection of violence in general and all injuries.

EPIDEMIOLOGY In 1995, 6% of all deaths in the United States were caused by an injury; 8% of all hospital discharges had a first listed diagnosis of injury and 37% of all emergency department visits were for injuries. Figure 14-1 presents the burden of injury at four levels of severity. Suicide and homicide account for about 35% of deaths from injury (Table 14-1) . The leading external causes of injury death, regardless of intent, are motor vehicle traffic crashes, firearms, poisoning (primarily by drug overdose), suffocation (which includes suicide by hanging), falls, drownings, and fire. Although firearms slightly exceed motor vehicles as the primary mechanism for injury death for males, the age-related profiles are remarkably alike across the age range (Fig. 14-2) . Among firearm deaths, the peak in young men is primarily homicide, whereas the peak in older men is primarily suicide. Motor vehicle deaths exceed firearm deaths in the young and the very elderly, age groups that are vulnerable to pedestrian as well as vehicle occupant deaths. The external causes of fatal and non-fatal injury differ dramatically. In states with databases where one can compare the causes of fatal and non-fatal injury, for example, in California in 1995, falls accounted for fewer than 10% of the deaths but over one third of the hospitalizations for injury. In comparison, motor vehicles and firearms together accounted for more than half of the deaths but fewer than 20% of the hospitalizations. Violence in families is an increasingly recognized and complex problem. Children's Protective Services determined that over 1 million children were victims of abuse or neglect in 1995. The National Family Violence Surveys estimate that 116 per 1000 women experience a violent act and 34 per 1000 experience severe violence at the hands of an intimate partner. No estimates of the prevalence of elder abuse have been made, but the problem is serious and may be increasing as the population ages. Alcohol consumption is a major risk factor for all types of injury. In 1987, the estimated percentage of unintentional injury deaths associated with alcohol were 42% for motor vehicles, 20% for other road vehicles, 20% for water transport, 16% for air transport, 35% for falls, 45% for fires, and 38% for drowning. For suicide and homicide, the percentages of deaths associated with alcohol are estimated to be 28% and 46%, respectively.

SECULAR TRENDS IN INJURIES Injuries are preventable. Data on injury deaths from 1910 to 1995 show a significant decrease in other (i.e., non-motor vehicle) unintentional injury death rates (Fig. 14-3) . This decrease was due in part to improved safety design of occupational machinery and other protective measures, the mechanization of agriculture and

Figure 14-1 Burden of injury: United States, 1995. (Data from National Vital Statistics System, National Hospital Discharge Survey, National Hospital Ambulatory Medical Care Survey, National Health Interview Survey. Reprinted from Fingerhut LA, Warner M: Injury Chartbook. Health, United States 1996 - 97 . Hyattsville, MD, National Center for Health Statistics, 1997.)

38

TABLE 14-1 -- NUMBERS* AND RATES OF INJURY DEATHS IN THE UNITED STATES (1995) BY INTENTIONALITY AND MECHANISM BY GENDER DEATHS TOTAL MALES No. All deaths

Rate

No.

Rate

FEMALES No.

%

Rate

147,891 56.3 105,645 78.4 42,246 25.4 100.0

Distribution by Intentionality Unintentional

90,402 34.4

60,066 43.3 30,336 16.8

61.1

Suicide

31,284 11.9

25,369 18.6

5,915

4.1

21.2

Homicide

22,552

8.6

17,408 14.5

5,144

4.0

15.2

3,653

1.3

851

0.5

2.5

Other

2,802

2.0

Distribution by Mechanism Motor vehicle traffic

42,452 16.2

28,490 22.2 13,962

9.9

28.7

Firearms

35,957 13.7

30,724 24.1

5,233

4.0

24.3

Poisoning

16,307

6.2

11,568

8.4

4,739

3.2

11.0

Falls

11,275

4.3

6,387

3.6

4,888

1.4

7.6

Suffocation

10,376

4.0

7,106

5.1

3,270

1.7

7.0

Drowning

5,071

1.9

4,015

3.1

1,056

0.8

3.4

Fire

4,235

1.6

2,528

1.8

1,707

1.1

2.9

22,218

6.7

14,827 10.2

7,391

3.4

15.0

Other

From National Vital Statistics System, 1995. Atlanta, National Center for Health Statistics, Centers for Disease Control and Prevention, 1998. *Excludes adverse event-related deaths (International Classification of Diseases, Injuries, and Causes of Death codes E870-E879 and E930-E949) Per 100,000 population. Crude rates are used for "total rate"; age-adjusted rates are used for "gender rate."

industry, labeling and packaging of drugs and toxic products, and improved medical care. Between 1912 and 1995, unintentional work deaths per 100,000 population were reduced 90%, from 21 to 2. In 1912, an estimated 18,000 to 21,000 workers' lives were lost. In 1996, in a work force more than triple in size and producing 13 times the goods and services, there were only 4800 work-related deaths. The death rate from motor vehicle crashes increased 10-fold from 1910 to 1930 as cars became the primary form of transportation. However, this death rate has decreased 30% in the last two decades owing in part to improved safety features in vehicles and roads, temporary lowering of speed limits, increased legal drinking age, and public intolerance of drinking and driving. The homicide rate increased from 6 per 100,000 population in 1910 to 9 in 1930, decreased during World War II and the post-war period (1940s to 1960s) to approximately 5, and then increased to 10 in the 1980s and 1990s. Recent increases are attributed to the enormous number of guns in circulation, currently estimated to be from 150 to 200 million, one third of which are handguns. The suicide rate has shown less variability but has been consistently higher than the homicide rate throughout this century.

WAYS TO REDUCE INJURY An example of the effectiveness of a public policy to prevent injury is the reduction in deaths and non-fatal head injuries in motorcyclists after enactment of the mandatory helmet laws. Hospital charges for injuries to California motorcyclists declined markedly in the 2 years (1992 to 1993) following enactment of the law, with charges related to head injuries falling by 58%. Certain personal and family actions can prevent injury from known hazards (Table 14-2) , and enactment of certain public policies has the potential to reduce injury: MOTOR VEHICLE CRASHES. Wear seat belts to maximize the protection offered by air bags, keep children properly restrained in the back seat, wear helmets while riding motorcycles and bicycles, and drive sober. POLICIES.

Enact or maintain motorcycle helmet laws; improve public transportation to reduce dependence on cars. FIREARMS. Remove guns from the home (or at least store unloaded, locked, and out of reach of children). POLICIES.

Restrict the purchase and possession of handguns in the home, up to and including bans (official policy of the American

Figure 14-2 Firearms and motor vehicle traffic crashes: male death rates by age groups, United States, 1995. (Data drawn from 1995 Injury Mortality Data, National Center for Health Statistics, Centers for Disease Control and Prevention, 1998.)

39

Figure 14-3 Trends in injury death rates, United States, 1910 to 1995. (Updated from Baker SP, O'Neill B, Ginsburg MJ, et al: The Injury Fact Book. 2nd ed. New York, Oxford University Press, 1992.)

Academy of Pediatrics and the American Public Health Association). FIRE AND BURN INJURIES. Install and maintain smoke detectors or residential sprinklers; reduce the temperature settings in residential hot water heaters to 125° F. POLICIES.

Establish mandatory flammability performance standards for cigarettes to prevent furniture ignition. DROWNING. Wear flotation devices while boating. POLICIES.

Require four-sided isolation fences with self-latching gates on all residential pools. FALLS. Install guards on balconies and windows in high-rise buildings; improve lighting and install handgrip devices in the home. ALCOHOL-RELATED INJURY. Avoid binge drinking, promote alcohol moderation, and drive sober. POLICIES. Permit community control over the number and location

INJURY Motor vehicle

TABLE 14-2 -- SOME KEY MEASURES TO PREVENT INJURY FOR PUBLIC POLICY Enact and enforce seat belt, child restraint, and motorcycle helmet laws.

FOR PATIENTS

Use seat belts, child restraints Use helmets when riding bicycles and motorcycles

Firearms

Ban assault weapons Enforce waiting period for firearm purchase

Remove firearms from home If gun in home, store locked and unloaded

Fire and burns

Mandate fire-safe cigarettes

Maintain smoke detectors; install sprinklers

Drowning

Mandate 4-sided fencing of pools

Wear flotation devices when boating

Falls Alcohol

Install guards on balconies, windows; install handrails in elders' homes Advocate for local control of alcohol outlets Restrict alcohol advertising that appeals to children

Drive sober Avoid binge drinking

Actions for physicians Counsel patients about injury and prevention (see above). Identify and refer abused patients to social/legal services. Insist on adequate physical/occupational rehabilitation. Improve injury databases and use them to design preventive strategies. Become knowledgeable about and advocate sound public policies.

40

of alcohol outlets in neighborhoods; restrict alcohol advertising that is attractive and available to children. Violence and injuries are complex, pervasive problems that must be reduced through comprehensive, multidisciplinary interventions. As is the case with preventing diseases such as smoking-associated cancers and acquired immune deficiency syndrome, preventing violence and injuries requires that physicians intervene both at the individual level and in the social and political processes that determine the prevalence of these conditions.

IMPLICATIONS FOR MEDICAL PRACTICE Traditionally, physicians have focused on treating and counseling individual patients and have concentrated on knowledge, attitudes, and behaviors. Evidence from successful injury prevention efforts suggests that equal attention should be given to public policies to prevent injury. To reduce violence and injuries, physicians can do the following: 1. Counsel patients about injury risk and prevention. All physicians, regardless of specialty, have the opportunity to advise patients and families about actions they can take to prevent injury. The American Academy of Pediatrics has developed injury prevention messages for parents that emphasize a child's developmental stages and how to avoid age-specific risks. Although physician-patient counseling may not always result in behavior change, it can be a powerful educational message delivered by a trusted authority. 2. Identify and refer abused patients. Hospitals, clinics, and doctors' offices may provide the first opportunity for abused patients, particularly adult women, to acknowledge the abuse, receive support, find protection, and break the cycle of violence. Medical and nursing professional organizations have prepared guidelines for institutionalizing the health care response to family violence through the development of model protocols, staff training materials, and proposed modification of intake forms for hospitals and clinics (e.g., American Medical Association guidelines). Policies and procedures should be adapted to individual hospital needs and address state-specific regulations about reporting abuse to authorities. Health care providers can best assist abused patients by working collaboratively with local social and legal services and by referring patients to these resources. 3. Emphasize rehabilitation and community follow-up. Tertiary prevention involves minimizing functional disability, a consequence of serious injury. Physicians can help their patients return to productive lives by ensuring that patients receive appropriate physical and occupational therapy and that they have access to community services after discharge. The independent living movement and local centers for independent living, as well as state departments of rehabilitation, can provide role models and resources for people with disabilities. Because community social and mental health services are essential for prevention and rehabilitation, physicians can serve their patients by publicly speaking out in support of these services. 4. Improve the injury database for research and prevention. Information about the mechanisms and intentionality of injury must be gathered by coroners, medical examiners, and health care providers through history taking and documentation in official records. The usefulness of non-fatal injury data would be increased if all states established centralized hospital and emergency department databases that included external cause of injury codes. 5. Advocate for public policy solutions to the violence and injury problem. Physicians have played a leadership role in injury control in such diverse areas as traffic safety, burns from tap water and clothing ignition, and firearms policy. Today's injury problems call for augmented medical leadership in policy areas. Legislators and journalists turn to physicians for information about disease and injury because physicians have daily contact with sick and injured people and can thus speak from personal experience about the problem. Informed physicians can advocate for solutions by testifying at legislative hearings, by granting media interviews, by making presentations at professional meetings, and by teaching medical students and residents about injury prevention principles and strategies. The World Wide Web sites suggested in the reference section provide the most recent data on statistics, policies, and programs related to violence and injury. The following agencies can direct investigators to additional sources of data, background materials, rationale for specific policies, and updates on the current status of policy initiatives and program interventions. For Violence and Firearm Injury Control Policies The Pacific Center for Violence Prevention, San Francisco General Hospital, San Francisco, CA 94100; Web: www.pcvp.org. Federal government information about criminal justice from the Justice Information Center at www.ncjrs.org. For Motor Vehicle Injury Control Policies Advocates for Highway and Auto Safety, 750 First Street, NE, Suite 901, Washington, DC 20002; Web: www.saferoads.org. Federal government information from the National Highway Traffic Safety Administration at www.nhtsa.dot.gov. For Falls Control Policies (and for Injury in General) The National Center for Injury Prevention and Control (Centers for Disease Control and Prevention), Office of Communications Resources, Mailstop K65, 4770 Buford Highway NE, Atlanta, GA 30341-3724; Web: www.cdc.gov/ncipc. For Flame/Burn Control Policies (and for Injury in General) Trauma Foundation, San Francisco General Hospital, San Francisco, CA 94100; Web: www.tf.org. Federal government information from the US Fire Administration at www.usfa.fema.gov. For Alcohol Control Policies The Marin Institute for the Prevention of Alcohol and Other Drug Problems, 24 Belvedere Street, San Rafael, CA 94901; Web: www.marininstitute.org.

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Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 15 - IMMUNIZATION Walter A. Orenstein

Immunization is one of the most cost-effective means of preventing morbidity and mortality from infectious diseases. Routine immunization, particularly of children, has resulted in decreases of 90% or more in reported cases of measles, mumps, rubella, congenital rubella syndrome, polio, tetanus, diphtheria, and pertussis. In many circumstances, immunization not only prevents morbidity and mortality but also, in the long run, reduces health care costs.

GENERAL CHARACTERISTICS OF IMMUNIZATIONS Immunization protects against disease or the sequelae of disease through the administration of an immunobiologic: vaccines, toxoids, immune globulin preparations, and antitoxins. Protection induced by immunization can be active or passive. ACTIVE IMMUNIZATION. Administering a vaccine or toxoid causes the body to produce an immune response against the infectious agent or its toxins. Vaccines consist of suspensions of live (usually attenuated) or inactivated microorganisms or fractions thereof. Toxoids are modified bacterial toxins that retain immunogenic properties but lack toxicity. Active immunization generally results in long-term immunity, although the onset of protection may be delayed because it takes time for the body to respond. With live attenuated vaccines, small quantities of living organisms multiply within the recipient until an immune response cuts off replication. In contrast, inactivated vaccines and toxoids contain large quantities of antigen. In the majority of recipients, a single dose of a live vaccine generally induces an immune response that closely parallels natural infection and induces long-term immunity. Killed vaccines, in contrast, often require multiple doses. PASSIVE IMMUNIZATION. Passive immunization using immune globulins or antitoxins delivers pre-formed antibodies to provide temporary immunity. Immune globulins obtained from human blood may contain antibodies to a variety of agents, depending on the pool of human plasma from which they are prepared. Specific immune globulins are made from the plasma of donors with high levels of antibodies to specific antigens, such as tetanus immune globulin. Most immune globulins must be injected intramuscularly. Antitoxins are solutions of antibodies derived from animals immunized 41

with specific antigens (e.g., diphtheria antitoxin). Passive immunization is usually indicated to protect individuals immediately before anticipated exposure or shortly after known or suspected exposure to an infectious agent (Table 15-1) , when active immunization either is not possible or has not been adequate. ROUTE AND TIMING OF VACCINATION. Each immunobiologic has a preferred site and route of administration. In adults, vaccines containing adjuvants should be injected intramuscularly, preferably in the deltoid muscle. For men, a 1-inch needle is adequate, whereas for women, recommended needle lengths vary from 5/8 inch for women weighing less than 60 kg to 1 inch for those weighing 60 to 90 kg and 1.5 inches for women heavier than 90 kg. Use of the buttocks is discouraged except when large volumes are required both because of the potential for damage to the sciatic nerve and because of diminished immune response to some vaccines, such as hepatitis B. Subcutaneous vaccines are also usually administered in the deltoid area, and intradermal vaccines are usually given on the volar surface of the forearm. In general, inactivated vaccines and toxoids can be given simultaneously at different sites. With vaccines that frequently cause side effects, such as cholera and inactivated typhoid vaccines, it may be best to separate administration by at least a week. With the exception of cholera and yellow fever vaccines, which should ideally be administered at least 3 weeks apart, live and inactivated vaccines can be administered at the same time. For example, measles, mumps, and rubella (MMR) vaccine can be administered with oral polio vaccine (OPV). However, with the exception of MMR and OPV, which can be administered at any interval, live vaccines not delivered on the same day should be separated by at least 1 month because immune globulin may also interfere with the take of live vaccines other than OPV; ideally, such vaccines should be administered at least 2 weeks prior or 3 to 11 months after immune globulin. ADVERSE REACTIONS. Hypersensitivity to vaccine components such as animal proteins, antibiotics, preservatives, and stabilizers can lead to local and systemic reactions ranging from mild to severe. The egg protein contained in vaccines grown in chicken eggs (influenza and yellow fever vaccines) may cause reactions in persons allergic to eggs. In general, persons without anaphylactic-type allergies to eggs can be given these vaccines safely, but persons with anaphylactic reactions to eggs should not generally receive these vaccines except when absolutely necessary and then only under established protocols by physicians who are expert in such situations. Even though measles and mumps vaccines are grown in chick embryo tissue culture, the risk of anaphylaxis even in those with severe hypersensitivity to eggs is very low, so such persons can be vaccinated without prior testing but should be observed for at least 20 minutes and preferably 90 minutes after immunization. No vaccine is completely safe or completely effective. Two major groups make comprehensive, detailed recommendations regarding immunization of adults: (1) the Task Force on Adult Immunization of the American College of Physicians (ACP) and The Infectious Diseases Society of America (IDSA), which publishes the Guide for Adult Immunization, and (2) the Advisory Committee on Immunization Practices of the U.S. Public Health Service. The latter group publishes its information in Morbidity and Mortality Weekly Report. Suspected adverse events temporally related to vaccinations should be reported to the Vaccine Adverse Events Reporting System (1-800-822-7967). GENERAL CONSIDERATIONS. Immunizations for adults depend on age, lifestyle, occupation, and medical conditions (Table 15-2) . All adults should have a primary series of tetanus and diphtheria toxoids with boosters of combined toxoids (Td) every 10 years. Persons born in or after 1957 should have evidence of immunity to measles, mumps, and rubella. Vaccination of susceptible adolescents and adults against varicella is desirable. Pneumococcal vaccine

DISEASE

TABLE 15-1 -- PASSIVE IMMUNIZATIONS FOR ADULTS NAME OF MATERIAL COMMENTS AND USE

Tetanus

Tetanus immune globulin, human

Management of tetanus-prone wounds in persons without adequate prior active immunization and treatment of tetanus

Cytomegalovirus

Cytomegalovirus immune globulin, intravenous

Prophylaxis for bone marrow and kidney transplant recipients

Diphtheria

Diphtheria antitoxin, equine

Treatment of established disease, high frequency of reactions to serum of non-human origin

Rabies

Rabies immunoglobulin, human

Post-exposure prophylaxis of animal bites

Measles

Immune globulin, human

Prevention or modification of disease in contacts of cases, not for control of epidemics

Hepatitis A

Immune globulin, human

Protection of household contacts, pre-exposure prophylaxis for travelers who need protection before immunity can be achieved with hepatitis A vaccine

Hepatitis B

Hepatitis B immune globulin, human

Prophylaxis for needlestick or mucous membrane contact with HBsAg-positive persons, for sexual partners with acute hepatitis B or hepatitis B carriers, for infants born to mothers who are carriers of HBsAg, for infants whose mother or primary caregiver has acute hepatitis B

Varicella

Varicella-zoster immune globulin

Persons with underlying disease and at risk of complications from chickenpox who have not had varicella or varicella vaccine and who are exposed to varicella. May be given post-exposure to known susceptible adults, particularly if antibody-negative

Vaccinia

Vaccinia immune globulin

Treatment of eczema vaccinatum, vaccinia necrosum, and ocular vaccinia following vaccinia (smallpox) vaccination

Erythroblastosis fetalis

Rh immune globulin

Rh-negative women who give birth to Rh-positive infants or who abort

Hypogammaglobulinemia

Immune globulin, intravenous Maintenance therapy

Idiopathic thrombocytopenic purpura

Immune globulin, intravenous Therapy for acute episodes

Botulism

Trivalent A, B, and E antitoxin, Treatment of botulism equine

Snakebite

Antivenin, equine (North American coral snake antivenin)

Specific for North American coral snake, Micrurus fulvius

Crotalidae, polyvalent

Effective for viper and pit viper bites, including rattlesnakes, copperheads, moccasins

Antivenin, equine

Specific for black widow spider, Latrodectus mactans, and other members of the genus

Spider bite

HBsAg = hepatitis B surface antigen.

42

DISEASE

IMMUNIZING AGENT

TABLE 15-2 -- SELECTED IMMUNIZING AGENTS INDICATED FOR ADULTS* INDICATIONS SCHEDULE MAJOR CONTRAINDICATIONS AND PRECAUTIONS

Cholera

Inactivated vaccine

Meeting international travel requirements

Two 0.5-mL doses SC or IM or two 0.2-mL doses ID 1 wk to 1 mo apart; booster dose every 6 mo

Diphtheria

Tetanus and diphtheria toxoids combined

All adults

Two doses IM 4 wk apart, 3rd dose 6-12 mo after 2nd dose for primary series, booster every 10 yr; no need to repeat if schedule is interrupted

Hepatitis A

Inactivated hepatitis A vaccine

Travelers to highly or 2 doses at least 6 mo intermediately endemic apart for persons countries, men who have sex 2 years of age with men; illegal drug users (injectors and non-injectors), persons who work with virus-infected primates or do research with the virus, persons with chronic liver disease, recipients of clotting factors

Hepatitis B

Inactivated virus vaccine

Adolescents, health care and IM; three doses at 0, 1, public safety workers and 6 mo potentially exposed to blood, clients and staff of institutions for the developmentally disabled, hemodialysis patients, sexually active homosexual men; users of illicit injectable drugs, recipients of clotting factors, household and sexual contacts of HBV carriers, inmates of long-term correctional facilities, heterosexuals treated for sexually transmitted diseases or with multiple sexual partners, travelers with close contact for 6 mo with populations with high prevalence of HBV carriage

Influenza

Inactivated influenza virus vaccine

All adults Annual vaccination; see 65 yr; other adults with annual ACIP high-risk conditions; adults recommendation caring for persons with high-risk conditions, including medical personnel (see text); women who will be in 2nd or 3rd trimester of pregnancy during influenza season

COMMENTS

Of limited effectiveness; cholera and yellow fever vaccine should be administered at least 3 wk apart History of neurologic or severe hypersensitivity reaction following a previous dose

Hypersensitivity to vaccine components

Should be considered for outbreak control for children and adolescents in communities with intermediate to high underlying transmission

Pregnancy should not be considered a contraindication if the woman is otherwise eligible. Health care workers who have contact with patients or blood should be tested 1-2 mo after vaccination to determine serologic response

Anaphylactic hypersensitivity to eggs

Japanese encephalitis

Inactivated virus vaccine

Lyme disease

Inactivated outer surface Primarily persons who live, protein A (OspA) work, or visit areas at high or moderate risk for Lyme disease and who will have frequent or prolonged exposure to a tick-infested habitat during transmission season.

Three doses IM at 0, 1 month, and 12 months

Measles

Live-virus vaccine

All adults born after 1956 without history of live vaccine on or after 1st birthday, physician-diagnosed measles, or detectable measles antibody; persons born before 1957 can generally be considered immune

One dose sufficient for most adults; 2 doses at least 1 mo apart indicated for persons entering college or medical facility employment, traveling abroad, or at risk of measles during outbreaks

Meningococcal Polysaccharide vaccine disease containing tetravalent A, C, W135, and Y

Terminal complement component deficiencies, anatomic or functional asplenia, travelers who will live in areas with hyperendemic or epidemic diseases; may be useful during localized outbreaks

One dose

Mumps

All adults born after 1956 One dose without history of live vaccine on or after 1st birthday, physician-diagnosed mumps, or detectable mumps antibody; persons born before 1957 can generally be considered immune

Live-virus vaccine

Travelers to Asia spending at Three 1-mL doses SC on least 1 mo in endemic areas days 0, 7, 30; shortened during transmission season schedule of 0, 7, 14 days may be used when necessary. Booster doses may be given after 2 yr

Persons with histories of urticaria at greater risk of adverse reactions to vaccine; pregnancy

No data exist on concurrent administration with vaccines other than DTP, drugs (e.g., chloroquine, mefloquine), or other biologics

Duration of immunity and need for boosters are unknown.

Altered immunity (e.g., leukemia, lymphoma, generalized malignancy, congenital immunodeficiency, immunosuppressive therapy), immune globulin or other blood products within prior 3-11 mo depending upon dose of immune globulin or blood product received, untreated tuberculosis, anaphylactic hypersensitivity to neomycin or gelatin, pregnancy, thrombocytopenia

Persons with anaphylactic allergies to eggs may be vaccinated (see text). Vaccine should be administered to persons with asymptomatic HIV infection and should be considered for symptomatic HIV patients, except those with severe immunocompromise

Consider revaccination after 3-5 yr for adults at increased risk of disease

Altered immunity (e.g., leukemia, lymphoma, generalized malignancy, congenital immunodeficiency, immunosuppressive therapy), immune globulin or other blood products within prior 3-11 mo, anaphylactic hypersensitivity to neomycin or gelatin, pregnancy, thrombocytopenia if administered with measles vaccine

Although persons born before 1957 are generally immune, vaccine can be given to adults of all ages and may be particularly indicated for post-pubertal males who are thought to be susceptible. Persons with anaphylactic allergies to eggs may be vaccinated.

Pneumococcal 23-valent polysaccharide Adults with cardiovascular disease vaccine disease, pulmonary disease, diabetes mellitus, alcoholism, cirrhosis, cerebrospinal fluid leaks, splenic dysfunction or anatomic asplenia, Hodgkin's disease, lymphoma, multiple myeloma, chronic renal failure, nephrotic syndrome, immunosuppression, HIV infection; high-risk populations such as certain Native Americans and all adults 65 yr

One dose IM or SC. A 2nd dose should be considered 5 or more yr later for adults at high risk of disease (e.g., asplenic patients), as well as those who lose antibody rapidly (e.g., nephrotic syndrome, renal failure, transplant recipients). Revaccinate adults who received a first dose when 5 L), whereas valproic acid has a relatively small V D (0.15 L). As discussed later, the V D is a useful pharmacokinetic term for calculating the loading dose and in appreciating how various changes can affect a drug's half-life. ELIMINATION.

Drugs are removed from the body by two major mechanisms: hepatic elimination, in which drugs are metabolized in the liver and excreted through the biliary tract, and renal elimination, in which drugs are removed from the circulation by either glomerular filtration or tubular secretion. For the vast majority of drugs, the rates of hepatic and renal elimination are proportional to the plasma concentration of the drug. This relationship is often described as a "first-order" process. Two measurements are used to evaluate elimination: clearance and half-life. CLEARANCE.

The efficiency of elimination can be described by assessing how the drug clears from the circulation. Drug clearance is a measure of the volume of plasma cleared of drug per unit of time. It is similar to the measurement used clinically to assess renal function--the creatinine clearance--which is the volume of plasma from which creatinine is removed per minute. Total drug clearance (Cltot ) is the rate of elimination by all processes (Eltot ) divided by the plasma concentration of the drug (Cp ):

Drugs may be cleared by several organs, with renal and hepatic clearance being the two major mechanisms. Total drug clearance (Cltot ) can therefore be best described as the sum of clearances by each organ. For must drugs this is essentially the sum of the renal and hepatic clearance:

Table 26-1 demonstrates the wide variation in clearance values among commonly used medications, with some drugs (e.g., ethosuximide and phenobarbital) having relatively low clearances (500 mL/min). Amikacin, gentamicin, and tobramycin are almost entirely cleared by the kidneys, whereas drugs such as aspirin, carbamazepine, and phenytoin are cleared less than 5% by the kidneys. Drug clearance is affected by several factors, including (1) blood flow through the organ of clearance; (2) protein binding to the drug; and (3) the activity of the clearance processes in the organs of elimination (e.g., glomerular filtration rate [GFR] and tubular secretion in the kidney or enzyme activity in the liver). Drug clearance is not affected by distribution of drug throughout the body (V D) because clearance mechanisms act only on drug in the circulation. HALF-LIFE.

The amount of time needed to eliminate a drug from the body depends on both the clearance and the volume of distribution. The first-order elimination constant (ke ) represents the proportion of the apparent volume of distribution that is cleared of drug per unit of time during the exponential disappearance of drug from the plasma over time (elimination phase).

Figure 26-2 Representative "concentration versus time" plot used in pharmacokinetic studies where concentration of drug is plotted with a logarithmic scale on the ordinate and time is plotted with a linear scale on the abscissa. The resultant curve is seen to have two phases: the distribution phase, the initial portion of the plotted line when the concentrations of drug decrease rapidly; and the elimination phase, the later phase when there is exponential disappearance of drug from the plasma with time. The dotted line extrapolated from the elimination phase back to time zero is used to calculate CPO . During the elimination phase, the half-life can be calculated as the time it takes to decrease the concentration by half (shown here as the time needed to decrease from concentration Ca to ½ Ca ).

94

TABLE 26-1 -- PHARMACOKINETIC PARAMETERS FOR SOME COMMONLY USED DRUGS VD PROTEIN BINDING TOTAL Cl % OF CltotAS RENAL Cl HALF-LIFE (liters/kg) (% ) (ml/min) (hr) Amikacin

THERAPEUTIC RANGE (mg/L)

0.25

3 units of blood) will require urgent endoscopy. Endoscopy in these patients is best performed in the intensive-care unit because they are at particular risk for aspiration and may require emergent intubation for respiratory protection and ventilation. Patients with slower or inactive bleeding may be evaluated by endoscopy in a "semi-elective" manner (usually within 12-20 hours), but a case can be made to perform endoscopy very early even in these stable patients (perhaps in the emergency department itself) to allow triage decisions to be made more confidently. Most bleeding from upper gastrointestinal lesions can be effectively controlled endoscopically. The endoscopist considers factors such as age (older patients have a higher risk of rebleeding) and the severity of the initial hemorrhage (which has a direct correlation with the risk of rebleeding) in addition to the appearance of the lesion when determining the need for endoscopic therapy. Non-variceal bleeding vessels can be treated with a variety of means including injections of various substances (epinephrine, saline, sclerosants) or thermal coagulation (laser or electrocautery). In the United States, the most popular approach to a bleeding peptic ulcer lesion is a

combination of injection with dilute epinephrine and electrocoagulation. Initial hemostasis can be achieved in 90% or more of cases; rebleeding, which may recur in up to 20% of cases, will respond about half of the time to a second endoscopic procedure. Patients who continue to bleed (typically patients with large ulcers in the posterior wall of the duodenal bulb) are usually managed angiographically (with embolization of the bleeding vessel) or surgically. Variceal bleeding is also effectively managed endoscopically, with a similar success rate as with bleeding ulcers (Color Plate 2 A). Hemostasis is achieved using either band ligation (Fig. 122-1) , sclerotherapy, or a combination of both. Increasingly, patients who do not respond to endoscopic treatment are then considered candidates for a transjugular intrahepatic portosystemic shunt; traditional shunt surgery for bleeding varices is rarely performed. Even if initial endoscopic hemostasis is successful, long-term prevention of rebleeding requires a program of ongoing endoscopic sessions until variceal obliteration is complete. Ligation is the preferred approach in this setting because it is associated with fewer side effects. ACUTE LOWER GASTROINTESTINAL BLEEDING (see Chapter 123) . The most common cause of acute lower gastrointestinal bleeding is angiodysplasia, followed by diverticulosis, neoplasms, and colitis. In about 10% of patients presenting with hematochezia, a small bowel lesion may be responsible. In contrast to upper gastrointestinal bleeding, there is no single best test for acute lower gastrointestinal bleeding (see Fig. 123-1) . In young patients (1 L/day) (100%), which is secretory and occurs during fasting. Hypokalemia (80-100%) and dehydration (83%) commonly occur because of the volume of the diarrhea. Achlorhydria was originally reported, but hypochlorhydria is more usually found (54-76%). Flushing occurs in 20% of patients, hyperglycemia in 25 to 50%, and hypercalcemia in 25 to 50%. Steatorrhea is uncommon (16%) despite the volume of diarrhea. PATHOLOGY AND PATHOPHYSIOLOGY. VIPomas in adults are in the pancreas in 80 to 90% of cases, with rare cases due to intestinal carcinoids, ganglioneuromas, ganglioneuroblastomas, or pheochromocytomas. VIPomas are usually large and solitary; 50 to 75% occur in the pancreatic tail and 40 to 70% have metastasized at diagnosis. VIPomas frequently secrete both VIP and peptide histidine methionine, but VIP is responsible for the symptoms. VIP is a potent stimulant of secretion in both the small and large intestine, and this action is responsible for the cardinal features of the syndrome. VIP also relaxes gastrointestinal smooth muscle, and this often causes dilated loops of bowel as well as a dilated, atonic gallbladder. Hypochlorhydria is thought to be due to the inhibitory effect of VIP on acid secretion; flushing is due to the vasodilatory

effects of VIP; and hyperglycemia is due to the glycogenolytic effect of VIP. The mechanism of the hypercalcemia remains unclear. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS. Because the diarrhea of VIPomas characteristically persists during fasting and is large in volume (>3 L/day, 70-80%), the diagnosis is excluded when fasting stool volume is less than 700 mL/day. To differentiate VIPomas from other causes of large-volume, fasting diarrhea, fasting plasma VIP levels should be determined. The normal value in most laboratories is less than 190 pg/mL, and elevated levels are present in 90 to 100% of patients in various series. The differential diagnosis of large-volume, fasting diarrhea (>700 mL/day) includes the ZE syndrome, diffuse islet-cell hyperplasia, surreptitious use of laxatives, the pseudopancreatic cholera syndrome, and, rarely, human immunodeficiency virus infections. TREATMENT. The symptoms of the VIP can be controlled in more than 85% of patients by octreotide, but increased doses may be required over time. Tumor localization studies with somatostatin receptor scintigraphy and surgical resection are preferred if possible; chemotherapy with streptozotocin and doxorubicin, hepatic chemoembolization, or hepatic embolization may benefit patients with unresectable or residual tumor.

SOMATOSTATINOMAS Somatostatinomas are endocrine tumors in the pancreas or upper small intestine that ectopically secrete somatostatin, which causes a distinct clinical syndrome of diabetes mellitus, gallbladder disease, diarrhea, steatorrhea, and weight loss. These symptoms occur three to four times more commonly (80-95% of all cases) in patients with pancreatic than in patients with intestinal somatostatinomas. Duodenal somatostatinomas are frequently reported in patients with von Recklinghausen's disease and are usually asymptomatic. Although these von Recklinghausen tumors are commonly called somatostatinomas because of the immunocytochemical finding of somatostatin in the tumor, the plasma somatostatin level is not usually elevated, and they are not clinical somatostatinomas. PATHOLOGY AND PATHOPHYSIOLOGY. Sixty per cent of somatostatinomas occur in the pancreas and 40% occur in the duodenum/jejunum. Pancreatic somatostatinomas occur in the pancreatic head in 60 to 80% of cases, 70 to 92% have metastasized at diagnosis, and they are usually large (mean, 5 cm), solitary tumors. In contrast, duodenal somatostatinomas are smaller (mean, 2.4 cm), are frequently associated with psammoma bodies on histologic examination, and less frequently have metastases at diagnosis (30-40%). Duodenal somatostatinomas without von Recklinghausen's disease have elevated plasma somatostatin levels in 70% of cases. In the gastrointestinal tract, somatostatin inhibits basal and stimulated gastric acid secretion, pancreatic secretion, intestinal absorption of amino acids, gallbladder contractility, and release of numerous hormones, including cholecystokinin and gastrin. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS. Somatostatinomas are usually found by accident, particularly at exploratory laparotomy 687

for cholecystectomy, during endoscopy, or on imaging studies. The diagnosis requires the demonstration of increased plasma and tumor concentrations of somatostatin-like immunoreactivity, which is also found with endocrine tumors outside the pancreas or intestine, including small cell lung cancer, medullary thyroid carcinoma, pheochromocytomas, and paraganglioma. TREATMENT. Treatment is difficult, and octreotide is of little benefit. Somatostatinomas can be imaged using somatostatin receptor scintigraphy or, if needed, other conventional imaging studies to assess tumor location and extent. Surgery, if possible, or chemotherapy, hepatic chemoembolization, or hepatic embolization may be of value.

GRFOMAS GRFomas are endocrine tumors that frequently originate in the pancreas but also occur in other extrapancreatic locations and ectopically release growth hormone-releasing factor (GRF), which causes acromegaly that is clinically indistinguishable from that due to a pituitary adenoma. GRFomas are an uncommon cause of acromegaly, occurring in none of 177 unselected patients with acromegaly in one study. The intra-abdominal features of GRFoma are due to its metastases and are typical of any malignant pancreatic endocrine tumor. PATHOLOGY AND PATHOPHYSIOLOGY. GRFomas most commonly occur in the lung (54%), with most of the remainder occurring in the gastrointestinal tract, including 30% in the pancreas. Pancreatic GRFomas are usually large (mean, 6 cm), 39% are metastatic at diagnosis, 40% occur in combination with the ZE syndrome, and 33% occur in patients with MEN-1. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS. Any patient with acromegaly with abdominal complaints, acromegaly without a pituitary tumor, or acromegaly with hyperprolactinemia (which occurs in 70% of persons with GRFomas) should be suspected of having a GRFoma. The diagnosis is confirmed by performing a plasma assay for GRF and growth hormone. TREATMENT. The effects of the GRF can be controlled with octreotide in more than 90% of patients. Treatment should be directed at the GRFoma per se, as described earlier for the pancreatic endocrine tumors.

NON-FUNCTIONAL PANCREATIC ENDOCRINE TUMORS Non-functional pancreatic endocrine tumors originate in the pancreas and either secrete no peptides or their secreted products do not cause clinical symptoms. The symptoms and signs are due to the tumor per se and include abdominal pain, hepatosplenomegaly, cachexia, and jaundice. In 20% of asymptomatic patients, tumors are found incidentally at surgery. PATHOLOGY AND PATHOPHYSIOLOGY. More than 60% of the tumors have metastasized to the liver at presentation. Most are large (70% > 5 cm), and 70% occur in the pancreatic head. Frequently secreted, non-functional peptides include chromogranin A (100%), chromogranin B (100%), pancreatic polypeptide (60%), and the alpha-subunit (40%) and beta-subunit of human chorionic gonadotropin. Immunocytochemically, the tumors contain these peptides as well as insulin (50%), glucagon (30%), and somatostatin (13%). DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS. Non-functional pancreatic endocrine tumors are frequently diagnosed only late in the disease course after the patient presents with symptoms or signs of metastatic disease, and a liver biopsy reveals a metastatic neuroendocrine tumor. Any patients with a long survival (>5 years) after a diagnosis of metastatic pancreatic adenocarcinoma should be suspected of having a non-functional pancreatic endocrine tumor. An elevated plasma chromogranin A or pancreatic polypeptide level or positive somatostatin receptor scintigraphy are strong evidence that a pancreatic mass is a pancreatic endocrine tumor. TREATMENT. Tumor localization, surgical resection, and chemotherapy with streptozotocin and doxorubicin, hepatic embolization, or chemoembolization are useful, as described

earlier.

ACTHOMAS AND OTHER UNCOMMON PANCREATIC ENDOCRINE TUMORS Pancreatic endocrine tumors ectopically secreting adrenocorticotropic hormone (ACTH) explain 4 to 16% of cases with ectopic Cushing's syndrome. Cushing's syndrome occurs in 5% of cases of the ZE syndrome and invariably reflects metastatic disease to the liver. Occasional cases benefit from the use of octreotide, but prognosis is poor even with chemotherapy. Paraneoplastic hypercalcemia can result from a pancreatic endocrine tumor that releases parathormone-related peptide or an unknown hypercalcemic substance. Tumors are generally large and metastatic to the liver at diagnosis. Octreotide may help control the hypercalcemia, but surgery, chemotherapy, hepatic embolization, or chemoembolization are the mainstays of therapy. Jensen RT: Gastrin-producing tumors. Cancer Treat Res 89:293-334, 1997. Summary of recent advances in gastrinoma with emphasis on the tumor biology. Jensen RT, Norton JA: Endocrine neoplasms of the pancreas. In Yamada T, Alpers DH, Owyang C, et al (eds): Textbook of Gastroenterology, 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 1999. A general chapter covering all aspects of pancreatic endocrine tumors. O'Shea D, Bloom SR (guest eds): Gastrointestinal endocrine tumours. Bailliere's Clinical Gastroenterology 10:571-766, 1996. Covers recent advances of the pathology and surgical and medical management of all pancreatic endocrine tumors with individual sections on VIPomas, insulinomas, glucagonomas, gastrinomas, and carcinoids.

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Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 131 - FUNCTIONAL GASTROINTESTINAL DISORDERS: IRRITABLE BOWEL SYNDROME, NON-ULCER DYSPEPSIA, AND NON-CARDIAC CHEST PAIN Nicholas J. Talley

In clinical practice, the majority of patients who present with chronic or recurrent gastrointestinal symptoms do not have a structural or biochemical explanation identified by routine diagnostic tests. These patients are labeled as having a functional gastrointestinal disorder. Functional does not imply a psychiatric disturbance or absence of disease but rather a known or suspected underlying disorder of gut function. Based on clinical and epidemiologic studies, the functional gastrointestinal disorders have been classified according to the presumed anatomic site of the disorder (Table 131-1) . The most widely recognized functional gastrointestinal disorders are the irritable bowel syndrome, functional (or non-ulcer) dyspepsia, and functional (or non-cardiac) chest pain.

IRRITABLE BOWEL SYNDROME DEFINITION. In the past, most patients with unexplained abdominal pain or bowel dysfunction were labeled as having irritable bowel syndrome, but irritable bowel syndrome is now considered to be characterized by chronic or recurrent abdominal pain and an erratic disturbance of defecation. Bloating is also common. EPIDEMIOLOGY. Symptoms consistent with irritable bowel syndrome are reported by one in six Americans, and similar prevalence rates have been found in Europe, Australia, and Asia. The prevalence is greater in women but is similar in whites and blacks; it is lower in people older than age 60 years. Approximately 30% of persons with irritable bowel syndrome become asymptomatic over time. Only about one third of persons with irritable bowel syndrome consult a physician, but the condition still accounts for about 12% of primary care visits. The first presentation is typically between the ages of 30 and 50 years. Those who seek care for irritable bowel syndrome tend to have more severe abdominal pain, a greater frequency and severity of non-gastrointestinal symptoms, such as headache, fatigue, or menstrual pain, and greater psychological distress. PATHOGENESIS. Accumulating evidence suggests that irritable 688

TABLE 131-1 -- ROME CLASSIFICATION OF FUNCTIONAL GASTROINTESTINAL DISORDERS AND ESTIMATED PREVALENCE IN THE UNITED STATES* DISORDER APPROXIMATE U.S. PREVALENCE (% ) Functional bowel disorders Irritable bowel syndrome

15

Abdominal pain or discomfort, relieved with defecation or associated with a change in the frequency or consistency of stools, and An irregular pattern of defecation (at least 25% of the time) consisting of two or more of the following: altered stool frequency, altered stool form, mucus, bloating, or feeling of distention Functional abdominal bloating

30

Functional constipation

10 g/24 hr. Sensitivity drops with stool fat in the range of 6-10 g/24 hr.

14

C-triolein breath test

D-xylose

A test of fat absorption. Normally, 99% of triglycerides ingested are absorbed, and the labeled fat is metabolized to 14 CO2 , which appears in the breath. With fat malabsorption, there is a reduction in 14 CO2 in the breath. Sensitivity and specificity are 85-95% when compared with the quantitative fecal fat test. False-positive test results are often recorded in the irritable bowel syndrome, which limits its usefulness.

test A test of small intestinal mucosal absorption, which is used to distinguish mucosal malabsorption from malabsorption due to pancreatic insufficiency. An oral dose of D-xylose (25 g/500 mL water) is administered and D-xylose excretion is measured in a 5-hr urine collection. Normally >4 g of D-xylose is excreted in the urine over 5 hr. The test may also be positive in bacterial overgrowth owing to metabolism of D-xylose by bacteria in the intestinal lumen. False-positive test results occur with renal failure, ascites, and an incomplete urine collection. Blood levels at 1 and 2 hr improve sensitivity. May be normal with limited mucosal disease.

Hydrogen breath test

Most useful in the diagnosis of lactase deficiency. An oral dose of lactose (1 g/kg body weight) is administered following measurement of basal breath hydrogen levels. A late peak (within 3-6 hr) of >20 ppm of exhaled hydrogen following lactose ingestion is suggestive of lactose malabsorption. Absorption of other carbohydrates (e.g., sucrose, glucose, fructose) can be tested as well.

SPECIFIC TESTS FOR MALABSORPTION Tests for Pancreatic Function Secretin stimulation test The gold standard test of pancreatic function with which all other tests are compared. Requires duodenal intubation with a double lumen tube and collection of pancreatic juice in response to IV secretin. Allows measurement of HCO3 - and pancreatic enzymes. A sensitive test of pancreatic function, but labor intensive and invasive. Tests for Bacterial Overgrowth Quantitative culture of small intestinal aspirate

Gold standard test for bacterial overgrowth. Greater than 105 colony-forming units/mL in the jejunum suggests bacterial overgrowth. Requires special anaerobic sample collection, rapid anaerobic and aerobic plating, and care to avoid oropharyngeal contamination. False-negative results occur with focal jejunal diverticula or when overgrowth is distal to the site aspirated.

14

C- D-xylose breath test

Diagnostic sensitivity and specificity is comparable to or better than quantitative culture for the diagnosis of bacterial overgrowth except perhaps in those with motility disorders. Following an oral dose of 14 C- D-xylose (1 g), overgrowth of gram-negative bacteria metabolizes 14 D-xylose with release of CO2 , which is absorbed and exhaled. An increase of breath 14 CO2 at 30 min is most indicative of a positive test. Cannot be used in pregnant women or children. Development of a nonradioactive 13 C- D-xylose breath test is under way.

Hydrogen breath test Has a lower sensitivity and specificity when compared with intestinal culture and the D-xylose breath test. The nonabsorbable sugar lactulose (1 g/kg body weight) or glucose is administered orally. When bacterial overgrowth is present, increased hydrogen is excreted in the breath. An early peak (within 2 hr) of >20 ppm of exhaled hydrogen is suggestive of bacterial overgrowth. Tests for Mucosal Injury

Small bowel biopsy Often obtained for a specific diagnosis when there is a high index of suspicion for small intestinal disease or when a D-xylose test result is abnormal. Several biopsies (4-5) must be obtained to maximize the diagnostic yield. Duodenal biopsies are usually adequate for diagnosis, but occasionally enteroscopy with jejunal biopsies is necessary. Small intestinal biopsy provides a specific diagnosis in some diseases, e.g., intestinal infection, Whipple's disease, abetalipoproteinemia, agammaglobulinemia, lymphangiectasia, lymphoma, and amyloidosis. In other conditions such as celiac disease and tropical sprue, the biopsy shows characteristic findings but the diagnosis is made on improvement after treatment. Permeability studies A test of mucosal integrity. These tests are gaining favor as a screening test for small intestinal disease and to follow response to treatment. The study is performed by administering an oral dose of nonabsorbable markers, e.g., mannitol/lactulose, or lactulose/51 Cr-EDTA, and measuring urinary excretion. Currently a research tool. Tests of Ileal Function Schilling test A test of vitamin B12 absorption. Performed as part I, followed by parts II, III, and IV if needed. Part I: A saturating dose (1 mg IM) of vitamin B 12 is given followed by an oral dose of radioactive cyanocobalamin (0.5-2 mug). Urine is collected for 24 hr because of a poorly understood delay in the passage of cobalamins across ileal cells. Part I is abnormal in all individuals with vitamin B12 deficiency except those with dietary deficiency and food-cobalamin malabsorption. Part II: The test is repeated with a dose of intrinsic factor (IF). Distinguishes lack of IF from other causes of vitamin B12 malabsorption. Part III: The test is repeated with pancreatic enzymes. Can be used as a test for pancreatic insufficiency. In such individuals, administration of exogenous enzymes frees cyanocobalamin from R-proteins, reverting the Schilling test to normal. Part IV: The test is repeated with antibiotics. When parts I and II are low, bacterial overgrowth can be distinguished from ileal disease by repeating the test after a 5-d course of antibiotics. *Not all of these tests are readily available. A strong suspicion for any disease may warrant foregoing an extensive work up and obtaining the test with highest diagnostic yield. In some cases, empiric treatment, such as removing lactose from the diet of an otherwise healthy individual with lactose intolerance, is warranted without any testing.

717

Figure 134-2 Strategy for obtaining a diagnosis when malabsorption is suspected.

with selective nutrient deficiencies without diarrhea. When this is suspected, antibody tests (see later discussion) and intestinal biopsy should be performed. When malabsorption is suspected in patients hospitalized for severe diarrhea or malnutrition, a more streamlined evaluation usually includes a stool for culture, ova and parasites, and fat; an abdominal imaging study; and a biopsy of the small intestine.

MALABSORPTIVE SYNDROMES Conditions That Impair Intraluminal Digestion IMPAIRED MIXING.

Surgical alterations such as partial gastrectomy with gastrojejunostomy (a Billroth II anastamosis) result in the release of biliary and pancreatic secretions into the intestine at a site remote from the site of entry of gastric chyme into the jejunum. This imbalance can result in impaired lipolysis and impaired micelle formation, with subsequent fat malabsorption. Rapid transit through the jejunum contributes to the malabsorption of nutrients. Individuals with these conditions also have surgical anastamoses that predispose to bacterial overgrowth. IMPAIRED LIPOLYSIS.

A deficiency in pancreatic lipase can be due to the congenital absence of pancreatic lipase or due to destruction of the pancreatic gland from alcohol-related pancreatitis, cystic fibrosis, or pancreatic cancer. Pancreatic lipase can also be denatured by excess secretion of gastric acid (e.g., Zollinger-Ellison syndrome). Chronic pancreatitis (see Chapter 141 ) is the most common cause of pancreatic insufficiency and impaired lipolysis. In the United States, chronic pancreatitis is most commonly due to alcohol abuse; in contrast, tropical (nutritional) pancreatitis is most common worldwide. Malabsorption of fat does not occur until more than 90% of the pancreas is destroyed. Individuals typically present with steatorrhea, abdominal pain, and diabetes, although some present with diabetes in the absence of gastrointestinal symptoms. Weight loss, when it occurs, is usually due to decreased oral intake to avoid abdominal pain or diarrhea and less commonly to malabsorption. Fat malabsorption due to chronic pancreatitis usually causes bulky, fat-laden stools. These individuals have more than 30 g/day of fat loss in the stool. Stools are not usually watery because undigested triglycerides form large emulsion droplets with little osmotic force and, unlike fatty acids, do not stimulate water and electrolyte secretion in the colon. Deficiency of fat-soluble vitamins is seen only rarely, presumably because gastric and residual pancreatic lipase generates enough fatty acids for some micelle formation. Clinical manifestations of carbohydrate and protein malabsorption are also rare in pancreatic insufficiency. However, in severe disease, subclinical protein malabsorption, manifested by the presence of undigested meat fibers in the stool, and subclinical carbohydrate malabsorption, manifested by gas-filled, floating stools, can occur. About 30 to 40% of individuals with chronic pancreatitis due to alcohol abuse have calcifications on abdominal radiographs. A qualitative or quantitative test for fecal fat will be positive in individuals whose pancreas is more than 90% destroyed. There are no convenient laboratory tests for the diagnosis of milder 718

cases of chronic pancreatitis, which often manifest with chronic abdominal pain without fat malabsorption. Pancreatic enzyme replacement and analgesics are the mainstays of treatment. Standard pancreatic enzyme preparations (6 to 8 tabs with each meal) or enteric-coated enzymes (three capsules with each meal) improve fat absorption and may reduce abdominal pain. IMPAIRED MICELLE FORMATION.

Bile salt concentrations in the intestinal lumen can fall below the critical concentration (5 to 15 mM) needed for micelle formation because of decreased bile salt synthesis (severe liver disease), decreased bile salt delivery (cholestasis), or removal of luminal bile salts (bacterial overgrowth, terminal ileal disease or resection, cholestyramine therapy, acid hypersecretion). Fat malabsorption due to impaired micelle formation is generally not as severe as that due to pancreatic lipase deficiency, presumably because fatty acids and monoglycerides can form lamellar structures, which to a certain extent can be absorbed. However, malabsorption of fat-soluble vitamins (D, A, K, E) may be marked because micelle formation is required for their absorption. Decreased Bile Salt Synthesis and Delivery:

Malabsorption can occur in individuals with cholestasic liver disease or bile duct obstruction. The clinical consequences of malabsorption are most often seen in women with primary biliary cirrhosis because of the prolonged nature of the illness. Although these individuals can present with steatorrhea, bone disease is the most common presentation. Osteoporosis is more common than osteomalacia. The etiology of bone disease in these individuals is poorly understood and often not related to vitamin D deficiency. Treatment of bone disease is with calcium supplements (and vitamin D if a deficiency is documented), weight-bearing exercise, and hormone therapy. Intestinal Bacterial Overgrowth:

In health, only small numbers of lactobacilli, enterococci, gram-positive aerobes, or facultative anaerobes can be cultured from the upper small bowel lumen. Motility and acid are the most important factors in keeping the number of bacteria in the upper small bowel low. Any condition that produces local stasis or recirculation of

colonic luminal contents allows development of a predominantly "colonic" flora (coliforms and anaerobes such as Bacteroides and Clostridia) in the small intestine (Table 134-5) . Anaerobic bacteria cause impaired micelle formation by releasing cholyl-amidases, which deconjugate bile salts. The unconjugated bile salts, with their higher pKa, are more likely to be in the protonated form at the normal upper small intestinal pH of 6 to 7 and can therefore be absorbed passively. As a result, the concentration of bile salts decreases in the intestinal lumen and can fall below the critical micellar concentration to TABLE 134-5 -- ABNORMALITIES CONDUCIVE TO BACTERIAL OVERGROWTH STRUCTURAL Surgical Afferent loop dysfunction following gastrojejunostomy Ileocecal valve resection Surgical loops (end-to-side intestinal anastomoses) Anatomic Duodenal and jejunal diverticula Obstruction Strictures (Crohn's disease, radiation enteritis) Adhesions (postsurgical) Gastrojejunocolic fistulas MOTOR Scleroderma Diabetes mellitus Idiopathic pseudo-obstruction HYPOCHLORHYDRIA Acquired immune deficiency syndrome Atrophic gastritis Proton pump inhibitors Acid-reducing surgery for peptic ulcer disease MISCELLANEOUS Immunodeficiency states Pancreatitis Cirrhosis cause fat and fat-soluble vitamin malabsorption. Vitamin B12 deficiency and carbohydrate malabsorption can also occur with generalized bacterial overgrowth. Anaerobic bacteria ingest vitamin B12 and release proteases that degrade brush border disaccharidases. Lactase is the disaccharidase normally present in lowest abundance and is therefore the first affected. Although anaerobic bacteria utilize vitamin B12 , they synthesize folate. Therefore, individuals with bacterial overgrowth usually have low serum vitamin B12 levels but normal or high folate levels, which help distinguish bacterial overgrowth from tropical sprue--in which both vitamin B12 and folate levels are usually low owing to decreased mucosal uptake. Individuals with bacterial overgrowth can present with diarrhea, abdominal cramps, gas and bloating, weight loss, and signs and symptoms of vitamin B12 and fat-soluble vitamin deficiency. Watery diarrhea occurs because of the osmotic load of unabsorbed carbohydrates and stimulation of colonic secretion by unabsorbed fatty acids. The diagnosis of bacterial overgrowth should be considered in the elderly and in individuals with predisposing underlying disorders. The identification of greater than 105 colony-forming units/mL in a culture of small intestinal aspirate remains the gold standard in diagnosis. The noninvasive test with a sensitivity and specificity equal to or better than intestinal culture is the [14 C]D-xylose breath test; in individuals with low vitamin B12 levels, a Schilling test before and after antibiotic therapy can be diagnostic (see Table 134-4 ). The goal of treatment is to correct the structural or motility defect if possible, eradicate offending bacteria, and provide nutritional support. Acid-reducing agents should be stopped if possible. Treatment with antibiotics should be based on culture results when possible; otherwise, empiric treatment is given. Tetracycline (250 to 500 mg orally [po] four times a day [qid]) or a broad-spectrum antibiotic against aerobes and enteric anaerobes (ciprofloxacin, 500 mg po twice a day [bid], amoxicillin/clavulanic acid, 250 to 500 mg po three times a day [tid], cephalexin, 250 mg po qid, with metronidazole, 250 mg tid) should be given for 14 days. Prokinetic agents such as metoclopramide (10 mg po qid), cisapride (10 to 20 mg po qid), or erythromycin (250 to 500 mg po qid) can be tried to treat small bowel motility disorders but often are not efficacious. Octreotide (50 mug subcutaneously every day [qd]) may improve motility and reduce bacterial overgrowth in individuals with scleroderma. When the structural abnormality or motility disturbance cannot be corrected, patients are at risk for malnutrition and vitamin B12 and fat-soluble vitamin deficiencies. Cyclic treatment (1 week out of every 4 to 6 weeks) with rotating antibiotics may be required in these patients to prevent recurrent bouts of bacterial overgrowth. If supplemental calories are needed, medium-chain triglycerides should be given, as they are not dependent on micelle formation for their absorption. Monthly treatment with vitamin B12 should be considered, along with supplemental vitamins D, A, K, and E and calcium. Ileal Disease or Resection:

Disease of the terminal ileum is most commonly due to Crohn's disease (which may also lead to ileal resection) but can also be caused by radiation enteritis, tropical sprue, tuberculosis, Yersinia infection, and idiopathic bile salt malabsorption. These diseases cause bile salt wasting. Bile salt losses of up to 3 g/day can be offset by increased hepatic synthesis. The clinical consequences of bile salt malabsoption are directly related to the length of the diseased or resected terminal ileum. In an adult, if less than 100 cm of ileum is diseased or resected, watery diarrhea results owing to stimulation of colonic fluid secretion by unabsorbed bile salts. Fat absorption remains normal because increased bile salt synthesis in the liver compensates for bile salt losses, and micelle formation is preserved. Such individuals can be treated with cholestyramine (2 to 4 g taken at breakfast, lunch, and dinner), an antimotility agent (loperamide or diphenoxylate hydrochloride), and a multiple vitamin and mineral supplement. When more than 100 cm of ileum is diseased or resected, bile salt losses in the colon exceed the capacity for increased bile salt synthesis in the liver; the bile salt pool shrinks, micelle formation is impaired, and steatorrhea and diarrhea develop. Individuals with these conditions can be treated with a low-fat diet, vitamin B12 injections, dietary supplements of calcium, and a multiple vitamin-mineral supplement. An antimotility agent should be administered for diarrhea. The patient should be screened for fat-soluble vitamin deficiencies (vitamins A and E, 25-(OH) vitamin D, and prothrombin 719

time) and bone disease (bone densitometry, serum calcium, and intact parathyroid hormone). Malabsorption in Crohn's disease also can be due to bacterial overgrowth from strictures or enterocolic fistula. Gastrocolic or enteroenteric/colic fistulas can also bypass segments of small intestine and significantly decrease the surface area available for absorption. Three long-term complications of chronic bile salt wasting and fat malabsorption are renal stones, bone disease (osteoporosis and osteomalacia), and gallstones. Oxalate renal stones occur as a consequence of excess free oxalate absorption in the colon. Free oxalate is generated when unabsorbed fatty acids bind luminal calcium, which is then unavailable for binding oxalate. Renal oxalate stones can sometimes be avoided with a low-fat, low-oxalate diet and calcium supplements. Bone disease is due to impaired micelle formation with a resulting decrease in absorption of vitamin D; year-round sun exposure reduces this complication. Vitamin D and calcium supplements should be given to susceptible individuals, but vitamin D levels and urinary calcium should be monitored for response to treatment because excess vitamin D can be toxic. The mechanism of gallstone formation in these individuals is unclear; pigmented gallstones are most common.

Diseases That Impair Mucosal Absorption Mucosal malabsorption can be caused by specific (usually congenital) brush border enzyme or nutrient transporter deficiencies or by generalized diseases that damage the small intestinal mucosa or result in surgical resection or bypass of small intestine. The nutrient(s) malabsorbed in these general malabsorptive diseases depend on the site of intestinal injury (proximal, distal, or diffuse) and the severity of damage. The main mechanism of malabsorption in these conditions is a decrease in surface area available for absorption. Some conditions (infection, celiac disease, tropical sprue, food allergies, and graft versus host disease) are characterized by intestinal inflammation and villus flattening; other conditions by ulceration (ulcerative jejunitis, nonsteroidal anti-inflammatory drugs), infiltration (amyloidosis), or ischemia (radiation enteritis, mesenteric ischemia). LACTASE DEFICIENCY.

Acquired lactase deficiency is the most common cause of selective carbohydrate malabsorption. Most individuals, except those of northern European descent, begin to lose lactase activity by the age of 5 years. The prevalence of lactase deficiency is highest (85 to 100%) in Asians, African blacks, and Native Americans. In most individuals, lactase deficiency is due to decreased synthesis of the enzyme. In some, however, intracellular transport and glycosylation of lactase is defective. Adults with lactase deficiency typically complain of gas, bloating, and diarrhea after the ingestion of milk or dairy products but do not lose weight. Unabsorbed lactose is osmotically active, drawing water followed by ions into the intestinal lumen. On reaching the colon, bacteria metabolize lactose to short-chain fatty acids, carbon dioxide, and hydrogen gas. Short-chain fatty acids are transported with sodium into colonic epithelial cells, facilitating the reabsorption of fluid in the colon. If the colonic capacity for the reabsorption of short-chain fatty acids is exceeded, an osmotic diarrhea results (see Chapter 133 ). The diagnosis of lactase deficiency can be made by empirical treatment with a lactose-free diet, which results in resolution of symptoms, or by the hydrogen breath test after oral administration of lactose. A number of intestinal diseases cause secondary reversible lactase deficiency, such as viral gastroenteritis, celiac disease, giardiasis, and bacterial overgrowth. CONGENITAL ENTEROPEPTIDASE (ENTEROKINASE) DEFICIENCY.

Enteropeptidase is a brush border protease that cleaves trypsinogen to trypsin, thereby triggering the cascade of pancreatic protease activation in the intestinal lumen. The rare congenital deficiency of enteropeptidase results in the inability to activate all pancreatic proteases and leads to severe protein malabsorption. It manifests in infancy as diarrhea, growth retardation, and hypoproteinemic edema. ABETALIPOPROTEINEMIA.

Formation and exocytosis of chylomicrons at the basolateral membrane of intestinal epithelial cells are necessary for the delivery of lipids to the systemic circulation. One of the proteins required for assembly and secretion of chylomicrons is the microsomal triglyceride transfer protein, which is mutated in individuals with abetalipoproteinemia. Children with this disorder suffer from fat malabsorption and, in particular, from the consequences of vitamin E deficiency (retinopathy and spinocerebellar degeneration). Biochemical tests show low plasma levels of apoprotein B, triglyceride, and cholesterol. Membrane lipid abnormalities result in red blood cell acanthosis ("burr cells"). Intestinal biopsy is diagnostic and characterized by engorgement of epithelial cells with lipid droplets. Calories are provided by treatment with a low-fat diet containing medium-chain triglycerides. Medium-chain fatty acids are easily absorbed and released directly into the portal circulation, thereby bypassing the defect of abetalipoproteinemia. Poor absorption of long-chain fatty acids can sometimes result in essential fatty acid deficiency. High doses of fat-soluble vitamins, especially vitamin E, are often needed. CELIAC DISEASE.

Celiac disease, also called celiac sprue, nontropical sprue, and gluten-sensitive enteropathy, is an inflammatory condition of the small intestine precipitated by the ingestion of wheat, rye, and barley in individuals with certain genetic predispositions. The prevalence of celiac disease in the United States, based on the number of individuals presenting with typical gastrointestinal symptoms, is estimated at 1:4500. However, recent screening studies for the antigliadin and antiendomysial antibodies that are associated with celiac disease suggest a much higher prevalence in Northern Ireland (1:122), as well as in Europe and the United States (about 1:250). High-risk groups for celiac disease include first-degree relatives and individuals with type I diabetes mellitus and autoimmune thyroid disease. Virtually 100% of individuals with dermatitis herpetiformis have gluten-sensitive enteropathy. Both environmental and genetic factors are important in the development of celiac disease. The alcohol-soluble protein fraction of wheat gluten, the gliadins, and similar prolamins in rye and barley trigger intestinal inflammation in susceptible individuals. Oat grains, which have prolamins rich in glutamine but not proline, appear to be less toxic. The specific peptide sequence or sequences responsible for triggering intestinal inflammation and the processes leading to villus flattening remain unknown. Approximately 15% of first-degree relatives of affected individuals are found to have celiac disease. Predisposition to gluten sensitivity has been mapped to the HLA-D region on chromosome 6. Ninety per cent of individuals with celiac disease have the DQ2 heterodimer encoded for by alleles DQA1*0501 and DQB1*0201 compared with 20 to 30% of controls. The DQ2 protein is expressed on antigen-presenting cells, but the site on DQ2 that interacts with gliadin and host T-cell receptors, thereby sensitizing the intestine to gluten, has not been identified. The diagnosis of celiac disease is made by characteristic changes found on small intestinal biopsy and improving when a gluten-free diet is instituted (Figs. 134-3 and 134-4) . Mucosal flattening can be observed endoscopically as reduced duodenal folds or duodenal scalloping. Characteristic features found on intestinal biopsy include the absence of villi, crypt hyperplasia, increased intraepithelial lymphocytes, and infiltration of the lamina propria with plasma cells and lymphocytes. Serologic markers for celiac disease are useful in supporting the diagnosis, in screening first-degree relatives, and in following the response to a gluten-free diet. Antigliadin IgG and IgA antibodies are sensitive but not specific. Antiendomysial IgA antibodies (antibodies against tissue transglutaminase) are highly sensitive (90%) and specific (90 to 100%) for active celiac disease in skilled laboratory testing. Antiendomysial and antigliadin IgA antibodies will be negative in the small percentage of individuals with selective IgA deficiency. Celiac disease usually manifests early in life at about 2 years of age, after wheat has been introduced into the diet, or later in the third or fourth decades of adult life. Individuals with significant mucosal involvement present with watery diarrhea, weight loss or growth retardation, and the clinical manifestations of vitamin and mineral deficiencies. All nutrients, most notably carbohydrate, fat, protein, electrolytes, fat-soluble vitamins, calcium, magnesium, iron, folate, and zinc, are malabsorbed. Cobalamin malabsorption is rare, as the disease most often affects the proximal small intestine more than the distal. Some individuals also have impaired pancreatic 720

Figure 134-3 Intestinal biopsy appearance of flattened villi and hyperplastic crypts. (Courtesy of Heidrun Rotterdam, MD.)

enzyme secretion owing to impaired release of CCK and secretin from the diseased intestinal mucosa. Diarrhea is due to a number of mechanisms, including a decreased surface area for water and electrolyte absorption, the osmotic effect of unabsorbed luminal nutrients, and the stimulation of intestinal fluid secretion by inflammatory mediators and unabsorbed fatty acids. A significant number of adults with celiac disease present with anemia or osteoporosis without gastrointestinal symptoms. These individuals likely have proximal disease that impairs iron, folate, and calcium absorption but an adequate surface area in the remaining intestine for absorption of other nutrients. Other extraintestinal manifestations of celiac disease include rash (dermatitis herpetiformis), neurologic disorders (myopathy, epilepsy), psychiatric disorders (depression, paranoia), and reproductive disorders (infertility, spontaneous abortion). Treatment consists of a lifelong gluten-free diet. Wheat, rye, and barley grains should be excluded from the diet. Rice and corn grains are tolerated, and a moderate amount of oat grain (if not contaminated by wheat grain) may be tolerated as well. Early referral to a celiac support group is often helpful in maintaining dietary compliance. Owing to secondary lactase deficiency, a lactose-free diet should be recommended until symptoms improve. All individuals with celiac disease should be screened for vitamin and mineral deficiencies and have bone densitometry. Seventy per cent of individuals with celiac disease have osteopenia. Documented deficiencies of vitamins and minerals should be replenished (Table 134-6) , and women of childbearing age should take folic acid supplements.

Up to 90% of patients with celiac disease treated with a gluten-free diet experience symptomatic improvement within 2 weeks. The most common cause of a poor dietary response is continued ingestion of gluten. Other possibilites include an overlooked intestinal infection, other food allergies (cow's milk, soy protein), ulcerative jejunitis, or intestinal lymphoma. In a small percentage of individuals, collagen deposition is found beneath the surface epithelium (collagenous sprue), or a hypoplastic mucosa demonstrates both villus and crypt atrophy; individuals with these conditions characteristically have severe disease refractory to a gluten-free diet. Although some with collagenous sprue respond to steroid treatment, a hypoplastic mucosa is indicative of irreversible (end-stage) intestinal disease. Individuals with celiac disease are at increased risk for intestinal T-cell lymphoma and carcinomas; a strict gluten-free diet for life may lessen this risk. Lymphoma should be suspected in individuals who have abdominal pain and a recurrence of symptoms despite a gluten-free diet. TROPICAL SPRUE.

Tropical sprue is an inflammatory disease of the small intestine associated with the overgrowth of predominantly coliform bacteria. It occurs in residents or travelers to the tropics, especially India and Southeast Asia. Individuals classically present with diarrhea as well as megaloblastic anemia due to vitamin B12 and folate deficiency, but some have anemia only. Intestinal biopsy characteristically shows subtotal and patchy villus atrophy in the proximal and distal small intestine, which may be due to the effect of bacterial toxins on gut structure or to the secondary effects of vitamin B12 deficiency on the gut (megaloblastic gut). Diagnosis is based on history, documentation of vitamin B12 and/or folate deficiency, and the presence of an abnormal small intestinal biopsy report. Treatment is a prolonged course of broad-spectrum antibiotics, oral folate, and vitamin B12 injections until symptoms resolve. Relapses occur mainly in natives of the tropics. INFECTION.

Giardia lamblia, the most common protozoal infection in the United States, can cause malabsorption in individuals infected with a large number of trophozoites, especially the immunocompromised or IgA-deficient host. Malabsorption occurs when a large number of organisms cover the epithelium and cause mucosal inflammation, which results in villus flattening and a decrease in absorptive surface area. Stool for ova and parasites at this stage of infection is often negative because of the attachment of organisms

Figure 134-4 Regeneration of villi 4 weeks after initiation of a gluten-free diet. (Courtesy of Heidrun Rotterdam, MD.)

721

TABLE 134-6 -- VITAMIN AND MINERAL DOSES USED IN THE TREATMENT OF MALABSORPTION ORAL DOSE PARENTERAL DOSE Vitamin A

*

Water-soluble A 25,000 U/d §

Vitamin E

Water-soluble E 400-800 U/d §

Vitamin D

25,000-50,000 U/d

Vitamin K

5 mg/d

Folate

1 mg/d

Calcium

1500-2000 mg elemental calcium/d Calcium citrate, 500 mg calcium/tab § Calcium carbonate, 500 mg calcium/tab §

Magnesium

Liquid magnesium gluconate § 1-3 tbsp (12-36 mEq magnesium) in 1-2 L of ORS or sports drink sipped throughout the day

Zinc

Zinc gluconate § 20-50 mg elemental zinc/d |

Iron

150-300 mg elemental iron/d Polysaccharide-iron complex § Iron sulfate or gluconate

2 mL of a 50% solution (8 mEq) both buttocks IM

Iron dextran as calculated for anemia (IV or IM)

B-complex vitamins 1 megadose tab/d Vitamin B12

2 mg/d

1 mg IM or SC/month #

IM = intramuscular; IV = intravenous; ORS = oral rehydration solution; SC = subcutaneous. *Monitor serum vitamin A level to avoid toxicity, especially in those with hypertriglyceridemia. §Form best absorbed or with least side effects. Monitor serum calcium and 25-OH vitamin D levels to avoid toxicity. Monitor 24-hr urine calcium to assess adequacy of dose. ||If intestinal output is high, additional zinc should be given. #For vitamin B12 deficiency 1 mg IM or SC twice a week for 4 weeks, then once a month.

in the proximal small intestine. Diagnosis can be made by a stool antigen capture ELISA test but may require duodenal aspiration and biopsies. Diarrhea, malabsorption, and wasting are common in individuals with the acquired immune deficiency syndrome (AIDS) but are seen less frequently with improved anti-retroviral therapy (Chapter 413) . Malabsorption is usually due to infection with cryptosporidia, Mycobacterium avium-intracellulare complex (MAC), Isospora belli, and microsporidia. AIDS enteropathy (a term used when no organism is identified) can also cause malabsorption. An organism can be identified by stool examination or intestinal biopsy about 50% of the time. In individuals with AIDS and diarrhea, fecal fat and D-xylose absorption study results are frequently abnormal. Serum albumin, vitamin B12 , and zinc levels are often low. Low serum levels of vitamin B12 have been reported in human immunodeficiency virus (HIV)-infected individuals without AIDS as well. Vitamin B12 deficiency is mainly due to ileal disease, but low IF and decreased TC II may be contributing factors. Management of malabsorption should focus on restoring the immune system by treating the underlying HIV infection with antiviral therapy. When possible, the offending organism should be treated with antibiotics. If the organism cannot be eradicated, chronic diarrhea and malabsorption will result; treatment in such cases consists of antimotility agents and a lactose-free, low-fat diet. If supplemental calories are needed, liquid oral supplements that are predigested and high in medium-chain triglycerides are best tolerated. Vitamin and mineral deficiencies should be screened for and treated. Whipple's disease, a rare cause of malabsorption, manifests with gastrointestinal complaints in association with systemic symptoms such as fever, joint pain, or neurologic manifestations. Occasionally, individuals present with ocular or neurologic disease without gastrointestinal symptoms. The organism responsible for causing Whipple's disease is a gram-positive actinomycete, Tropheryma whippelii. The HLA-B27 gene is more common in Whipple's disease patients. Small intestinal biopsy shows villus blunting and infiltration of the lamina propria with large macrophages that stain positive with the periodic acid-Schiff method and are filled with the organism. It is important to distinguish these macrophages from macrophages infected with MAC, which stain positive on acid-fast staining and are found in individuals with AIDS. Treatment is with a prolonged course of broad-spectrum antibiotics. Relapses are common. RADIATION ENTERITIS.

Gastrointestinal dysfunction is common after radiation treatment to the pelvis or abdomen. Most individuals have an increased frequency of bowel movements for life. Diarrhea and abdominal cramps can develop up to 20 years after radiation treatment. Radiation damage to the intestine, characterized histologically by an obliterative endarteritis of the small vessels, can result in intestinal ulceration, strictures, and fistula formation. A small number of individuals develop malabsorption due to bacterial overgrowth, intestinal bypass, or bile salt wasting. Rapid transit may also contribute to malabsorption and diarrhea. Treatment is often unsatisfactory. Antimotility

agents, cholestyramine, antibiotics, steroids, and sulfasalazine can be tried. GRAFT VERSUS HOST DISEASE (GVHD).

Diarrhea occurs frequently after allogeneic bone marrow or stem cell transplantation. Immediately after transplant, diarrhea is due to the toxic effects of cytoreductive therapy on the intestinal epithelium. At 20 to 100 days after transplant, diarrhea is usually due to GVHD or infection. Individuals with GVHD present clinically with a skin rash, buccal mucositis, anorexia, nausea, vomiting, abdominal cramps, and diarrhea. The diagnosis of GVHD in the gastrointestinal tract can be made on biopsy of the stomach, small intestine, or colon. In mild cases, the mucosa appears normal on inspection at endoscopy, but apoptosis of gastric gland or crypt cells can be found on biopsy. In severe cases, denuding of the intestinal epithelium results in diarrhea and malabsorption and often requires parenteral nutritional support. Octreotide (50 to 250 mug subcutaneous tid) may be helpful in controlling voluminous diarrhea. Treatment of GVHD is with steroids and antithymocyte globulin combined with parenteral nutrition support until intestinal function returns. SHORT BOWEL SYNDROME.

Malabsorption due to small bowel resection or surgical bypass is referred to as the short bowel syndrome. The most common causes in the United States are Crohn's disease, radiation enteritis, and mesenteric ischemia. The severity of malabsorption depends on the site and extent of resection, the capacity for bowel adaptation, and the function of the residual bowel. Adaptive changes to enhance absorption in the remaining bowel include hyperplasia, dilation, and elongation. Mechanisms of malabsorption after small bowel resection include a decreased absorptive surface area, decreased luminal bile salt concentration, rapid transit, and bacterial overgrowth. Limited jejunal resection is usually best tolerated because bile salt and vitamin B12 absorption remain normal. Ileal resection is less well tolerated because of the consequences of bile salt wasting and the limited capacity of the jejunum to undergo adaptive hyperplasia. When fewer than 100 cm of jejunum remain, the colon takes on an important role in caloric salvage and fluid reabsorption. Malabsorbed carbohydrates are digested by colonic bacteria to short-chain fatty acids, which are absorbed in the colon. Parenteral nutrition may be avoided by a diet rich in complex carbohydrates, oral rehydration solution, and an antimotility agent. In comparison, individuals 722

with fewer than 100 cm of jejunum and no colon have high jejunostomy outputs and often require intravenous fluids or parenteral nutrition to survive. These individuals waste sodium, chloride, bicarbonate, magnesium, zinc, and water in their ostomy effluent. Diet modifications should include a high-salt, nutrient-rich diet given in small meals and taken separately from fluids. An oral rehydration solution with a sodium concentration greater than 90 mmol is best absorbed. Oral vitamin and mineral doses higher than the usual U.S. recommended daily allowances are required (see Table 134-6 ). Vitamin B12 should be given parenterally. Magnesium deficiencies are often difficult to replenish with oral magnesium because of its osmotic effect in the intestinal lumen. A liquid magnesium preparation added to an oral rehydration solution and sipped throughout the day may minimize magnesium-induced fluid losses. Potent antimotility agents such as tincture of opium are often needed to slow transit and maximize contact time for nutrient absorption. High-volume jejunostomy outputs can be lessened by inhibiting endogenous secretions with a proton pump inhibitor and, in severe cases, octreotide (50 to 100 mug subcutaneous tid). The benefit of octreotide may be offset by its potential to inhibit intestinal adaptation and impair pancreatic enzyme secretion. In the most severe cases, supplemental calories must be provided by nocturnal tube feeding or parenteral nutrition. Long-term complications include bone disease, renal stones (oxalate stones if the colon is present, urate stones with a jejunostomy), gallstones, bacterial overgrowth, fat-soluble vitamin deficiencies, essential fatty acid deficiency, and D-lactic acidosis. Small bowel transplantation should be considered in individuals who require parenteral nutrition to survive and then develop liver disease or venous access problems.

DISEASES THAT IMPAIR NUTRIENT DELIVERY TO THE GENERAL CIRCULATION IMPAIRED LYMPHATIC DRAINAGE. Diseases that cause intestinal lymphatic obstruction, such as primary congenital lymphangiectasia (malunion of intestinal lymphatics), or those that result in secondary lymphangiectasia (lymphoma, tuberculosis, Kaposi's sarcoma, retroperitoneal fibrosis, constrictive pericarditis, severe heart failure) result in fat malabsorption. The increased pressure in the intestinal lymphatics leads to leakage and sometimes rupture of lymph into the intestinal lumen with the loss of lipids, gamma globulins, albumin, and lymphocytes. The diagnosis of lymphangiectasia can be made by intestinal biopsy, but the specific cause may be more difficult to identify. Individuals with lymphangiectasia malabsorb fat and fat-soluble vitamins and have protein loss into the intestinal lumen. The most common presentation is hypoproteinemic edema. Nutritional management includes a low-fat diet and supplementation with medium-chain triglycerides, which are absorbed directly into the portal circulation. Fat-soluble vitamins should be given if deficiencies develop. PROTEIN-LOSING ENTEROPATHY. Protein-losing enteropathy can result from a variety of inflammatory diseases and some as yet ill-defined mechanisms (see Chapter 133 ). Feldman M, Scharschmidt BT, Sleisenger MH (eds): Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 6th ed. Philadelphia, WB Saunders, 1998, Chaps. 16 , 26 - 28 , 48 , 86 - 89 , 91 - 94 , 100 , 101 . Comprehensive discussion of diseases that cause maldigestion and malabsorption, including pathophysiology, diagnosis, and management. Murray JA: The widening spectrum of celiac disease. Am J Clin Nutr 69:354, 1999. Excellent review of pathophysiology, genetics, immunology, and clinical diagnosis and management.

MD Consult L.L.C. http://www.mdconsult.com Bookmark URL: /das/book/view/882/137.html/top

Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 135 - INFLAMMATORY BOWEL DISEASE William F. Stenson

DEFINITION. Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease, are chronic inflammatory diseases of the gastrointestinal tract. They are diagnosed by a set of clinical, endoscopic, and histologic characteristics, but no single finding is absolutely diagnostic for one disease or the other. Moreover, some patients have a clinical picture that falls between the two diseases and are said to have indeterminate colitis. The inflammatory response in ulcerative colitis is largely confined to the mucosa and submucosa, but in Crohn's disease the inflammation extends through the intestinal wall from mucosa to serosa. Ulcerative colitis is confined to the colon, and colectomy is a curative procedure. Crohn's disease, in contrast, can involve any part of the gastrointestinal tract, although the distal small bowel and the colon are most commonly involved. Resection of the inflamed segment is not curative in Crohn's disease, and inflammation is likely to recur.

EPIDEMIOLOGY. The incidence and prevalence of Crohn's disease and ulcerative colitis vary with geographic location; the highest rates are for white populations in northern Europe and North America, where the incidence for each disease is about 5 per 100,000 and the prevalence is about 50 per 100,000. Rates in central and southern Europe are lower, and in South America, Asia, and Africa lower still. Crohn's disease and ulcerative colitis are both more common in Jews than non-Jews. In the United States, the incidence of IBD in the black population has been one fifth to one half that in the white population, but in recent years that gap has narrowed. In northern Europe and North America, the incidence of ulcerative colitis has leveled off but that of Crohn's disease is still increasing. For both diseases, the incidence is equal in men and women. The peak age at onset is between 15 and 25 years of age, with a second, lesser peak between 55 and 65 years of age. Both diseases occur in childhood, although the incidence before 15 years of age is low. The risk of developing ulcerative colitis is increased among both non-smokers and former smokers compared with current smokers. Whether initiation of smoking improves symptoms is unclear, although success has been reported with nicotine patches. In contrast, the incidence of smoking is higher among Crohn's disease patients than the general population, and patients who continue to smoke may be less likely to respond to medical therapy.

ETIOLOGY AND PATHOGENESIS. The most important risk factor for IBD is a positive family history. Approximately 15% of IBD patients have affected first-degree relatives, and the incidence among first-degree relatives is 30 to 100 times that of the general population. The best estimates of the lifetime risk of developing IBD among first-degree relatives of affected individuals is 3 to 9%. The increased incidence among first-degree relatives contrasts to the absence of an increased incidence in spouses of patients. Dizygotic twins have the same rate of concordance as would be expected for siblings, whereas monozygotic twins have higher rates of concordance for both diseases. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. In IBD, the lamina propria is infiltrated with lymphocytes, macrophages, and other cells of the immune system. An intensive search for the antigens that trigger the immune response has yet to identify a specific microbial pathogen. Anticolon antibodies of unclear significance have been identified in the sera of ulcerative colitis patients. IBD may also be related to a failure to suppress (or "down-regulate") the normal, finely tuned, low-grade chronic inflammation of the intestinal lamina propria in response to its chronic exposure to luminal antigens. Whatever the antigenic trigger, activated lamina propria T cells are involved in the pathogenesis of IBD. In Crohn's disease, the activated lymphocytes appear to be primarily Th1 lymphocytes that produce interferon (IFN)-gamma. Proinflammatory cytokines including interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha amplify the immune response. Intravenous infusion of an antibody to TNF-alpha is clinically effective in Crohn's disease. Large numbers of neutrophils enter the inflamed mucosa attracted by chemotactic agents including IL-8 and leukotriene B4 . Epithelial injury in IBD appears to be due to reactive oxygen species from neutrophils and macrophages, as well as to cytokines including TNF-alpha and IFN-gamma. Mice develop colitis when the genes for IL-2, IL-10, or TGFbeta1 are knocked out or when there are certain T-cell receptor mutants, and transgenic rats develop colitis if the human HLA-B27 gene has been introduced. If the same animals are raised in a germ-free environment, colitis does not develop.

PATHOLOGY. Ulcerative colitis and Crohn's disease each have a characteristic pathologic appearance, but in any given case the 723

TABLE 135-1 -- COMPARISON OF ULCERATIVE COLITIS AND CROHN'S DISEASE ULCERATIVE COLITIS

CROHN'S DISEASE

Pathology Rectal involvement

Always

Common

"Skip lesions"

Never

Common

Transmural involvement

Rare

Common

Granulomas

Occasional

Common

Perianal disease

Never

Common

"Cobblestone" mucosa

Rare

Common

"Collar button" ulcers

Common

Occasional

Small intestinal involvement

Never

Common

Discontinuous involvement

Never

Common

Fistulas

Never

Common

Strictures

Occasional

Common

Radiology

Endoscopy

Aphthous ulcers

Never

Common

Discontinuous involvement

Never

Common

Rectal sparing

Never

Common

Linear or serpiginous ulcers

Never

Common

Ulcers in terminal ileum

Never

Common

pathologic picture may not be specific enough to distinguish between them or to differentiate them from other diseases such as infectious colitis or ischemic colitis (Table 135-1) . In IBD, the pathologic assessment of disease activity may not correlate with the clinical and endoscopic assessments. In ulcerative colitis, inflammation begins in the rectum, extends proximally a certain distance, and then abruptly stops, with a clear demarcation between involved and uninvolved mucosa. In mild disease, there are superficial erosions, whereas in more severe disease, ulcers may be large but superficial, penetrating the muscularis mucosa only in very severe disease. Inflammatory polyps or pseudopolyps may be present. Most of the pathologic findings in ulcerative colitis are limited to the mucosa and submucosa; the muscularis propria is affected only in fulminant disease. Active ulcerative colitis is marked by neutrophils in the mucosa and submucosa and clumps of neutrophils in crypt lumens (crypt abscesses). There is mucus depletion, mucosal edema, and vascular congestion with focal hemorrhage. In addition to signs of acute activity, there are also signs of chronicity, with lymphoid aggregates, plasma cells, mast cells, and eosinophils in the lamina propria. In Crohn's disease, the bowel wall is thickened and stiff. The mesentery, which is thickened, edematous, and contracted, fixes the intestine in one position. Transmural inflammation may cause loops of intestine to be matted together. All layers of the intestine are thickened, and the lumen is narrowed. "Skip lesions" with two involved areas separated by a length of normal intestine suggest Crohn's disease. Colonic inflammation with rectal sparing is more consistent with Crohn's disease than with ulcerative colitis. The earliest lesion of Crohn's disease is the aphthous ulcer, which typically occur over Peyer patches in the small intestine and over lymphoid aggregates in the colon. As the disease progresses, aphthous ulcers enlarge and become stellate or serpiginous. Eventually, the stellate ulcers coalesce to form longitudinal and transverse linear ulcers. The remaining islands of non-ulcerated mucosa give a cobblestone appearance. Fissures develop from the base of ulcers and extend down through the muscularis to the serosa. Lymphoid aggregates are found in the submucosa and external to the muscularis propria. Granulomas are common in Crohn's disease but not in ulcerative colitis.

ULCERATIVE COLITIS: CLINICAL FINDINGS AND NATURAL HISTORY. The dominant symptom in ulcerative colitis is diarrhea, which is usually associated with blood in the stool (Table 135-2) . Bowel movements are frequent but small in volume as a result of irritability of the inflamed rectum. Urgency and fecal incontinence

Mild:

TABLE 135-2 -- CRITERIA FOR SEVERITY IN INFLAMMATORY BOWEL DISEASE Fewer than four bowel movements per day with little or no blood, no fever, and sedimentation rate less than 20 mm/hr.

Moderate: Between mild and severe. Severe:

Six or more bowel movements per day with blood, fever, anemia, and sedimentation rate greater than 30 mm/hr.

may limit the patient's ability to function in society. Other symptoms include fever and pain, which may be in either lower quadrant or in the rectum. Systemic features--fever, malaise, and weight loss--are more common if all or most of the colon is involved and may have a greater effect than diarrhea on the patient's ability to function. Some patients, especially elderly persons, complain of constipation rather than diarrhea because rectal spasm prevents the passage of stool. The initial attack of ulcerative colitis may be fulminant with bloody diarrhea, but more commonly the disease begins indolently, with non-bloody diarrhea progressing to bloody diarrhea. Ulcerative colitis can present initially with any extent of anatomic involvement, from disease confined to the rectum to pancolitis. Most commonly, ulcerative colitis follows a chronic intermittent course with long periods of quiescence interspersed with acute attacks lasting weeks to months; however, a significant percentage of patients suffer a chronic continuous course. In ulcerative colitis of mild to moderate severity, there may be tenderness over the affected area of the colon, and rectal examination may reveal tenderness or blood on the glove. In severe disease the patient is more likely to be febrile and tachycardic. Anemia and an elevated leukocyte count and erythrocyte sedimentation rate are useful in confirming severe disease and in following the clinical course of a severe exacerbation. Electrolyte disorders, particularly hypokalemia, are seen with severe diarrhea.

CROHN'S DISEASE: CLINICAL FINDINGS AND NATURAL HISTORY. Crohn's disease presents with one of three major patterns: (1) disease in the ileum and cecum (40% of patients); (2) disease confined to the small intestine (30%); and (3) disease confined to the colon (25%). Much less commonly, Crohn's disease involves more proximal parts of the gastrointestinal tract--the mouth, the tongue, the esophagus, the stomach, and the duodenum. The predominant symptoms are diarrhea, abdominal pain, and weight loss; any of these three symptoms may be most prominent in a given individual. The initial presentation may not be dramatic; patients may complain for months or years with vague abdominal pain and intermittent diarrhea before the diagnosis is considered. Diarrhea occurs in almost all those with Crohn's disease, but the pattern varies with the anatomic location of the disease. In patients with colonic disease, especially with rectal involvement, diarrhea is of small volume and associated with urgency and tenesmus. Inflammation in the rectum causes a loss of distensibility; the entry of even a small amount of stool into a non-distensible rectum causes an immediate and urgent need to defecate. Prolonged inflammation and scarring in the rectum can leave it so rigid and non-distensible that the patient is incontinent. In disease confined to the small intestine, stools are of larger volume and not associated with urgency or tenesmus. Patients with severe involvement of the terminal ileum and those who have had surgical resections of the terminal ileum may have bile salt diarrhea or steatorrhea. The location and pattern of pain correlate with disease location. In patients with ileal disease, cramping right lower quadrant pain occurs after eating and is related to partial intermittent obstruction of a narrowed intestinal lumen. Abdominal distention, nausea, and vomiting may accompany the pain. Weight loss of some degree, which occurs in most patients with Crohn's disease irrespective of anatomic location, is a product of malabsorption or diminished intake because of pain, diarrhea, or anorexia. Fever and chills often accompany disease activity; a low-grade fever may be the patient's first warning sign of a flare. Induction of remission by drugs or surgery is invariably associated with increased energy and a sense of well-being. Crohn's disease, like ulcerative colitis, is a relapsing and remitting disease. About 30% of placebo-treated patients with Crohn's disease of mild to moderate activity go into remission within 4 months. Conversely, of patients in remission and on no therapy, about 30% will relapse within 1 year and 50% at 2 years. Physical findings in Crohn's disease vary with the distribution and severity of the disease. Aphthous ulcers of the lips, gingiva, or buccal mucosa are common. The abdomen may be tender, typically over the area of disease activity. Thickened bowel loops, thickened mesentery, or an abscess may cause a mass, often in the right lower quadrant. The presence of perianal disease is suggested by fistulous openings, induration, redness, or tenderness near the anus. Laboratory findings are largely non-specific. Anemia may result 724

from chronic disease, blood loss, or nutritional deficiencies (of iron, folate, or vitamin B12 ). A modestly elevated leukocyte count is indicative of active disease, but a marked elevation suggests the presence of an abscess or other suppurative complication. The erythrocyte sedimentation rate has been used to follow disease activity, and it tends to be higher in colonic disease than ileal disease. Hypoalbuminemia is an indication of malnutrition. Ileal disease or resection of more than 100 cm of ileum results in a diminished serum vitamin B12 level because of malabsorption.

EXTRAINTESTINAL MANIFESTATIONS. Although IBD primarily involves the bowel, it is associated with manifestations in other organ systems. The extraintestinal manifestations (e.g., sclerosing cholangitis or ankylosing spondylitis) may be more problematic than the bowel disease. The extraintestinal manifestations can be divided into two major groups: (1) those in which the clinical activity follows the activity of the bowel disease and (2) those in which the clinical activity is unrelated to the clinical activity of the bowel disease.

The most common extraintestinal manifestation of IBD is arthritis, including colitic arthritis and ankylosing spondylitis. Colitic arthritis, a migratory arthritis that affects knees, hips, ankles, wrists, and elbows, parallels the course of the bowel disease; successful treatment of the intestinal inflammation results in improvement in the arthritis. Ankylosing spondylitis (see Chapter 287) presents with morning stiffness, low-back pain, and stooped posture; it can be relentlessly progressive and crippling. Patients with ulcerative colitis have a 30-fold increase in the incidence of ankylosing spondylitis compared with the general population. Non-steroidal anti-inflammatory drugs reduce inflammation and pain but do not halt the progression of the disease. Medical treatment of the IBD and colectomy are not helpful in managing ankylosing spondylitis. Sacroiliitis, which is inflammation of the joint between the sacrum and the ilium, occurs in conjunction with ankylosing spondylitis but is more often seen alone. In ulcerative colitis, 15% of patients have radiographs consistent with sacroiliitis but most are asymptomatic. The hepatic complications of IBD include fatty liver, pericholangitis, chronic active hepatitis, and cirrhosis. The biliary tract complications are sclerosing cholangitis (ulcerative colitis) and gallstones (Crohn's disease). Cholesterol gallstones occur in patients with ileal disease or ileal resections because of malabsorption of bile salts and the resultant decrease in the size of the bile salt pool. Pericholangitis is the most common hepatic complication of IBD; patients with pericholangitis are usually asymptomatic. Elevations of alkaline phosphatase are seen frequently; elevations of bilirubin are less common. Sclerosing cholangitis (see Chapter 157) is a chronic cholestatic liver disease marked by fibrosing inflammation of the intrahepatic and extrahepatic bile ducts. While it occurs in only 1 to 4% of patients with ulcerative colitis and with lower frequency in Crohn's disease, the majority of patients with sclerosing cholangitis have IBD. Colectomy and medical therapy of the bowel disease do not ameliorate the course; sclerosing cholangitis is now one of the most common indications for liver transplantation (see Chapter 155) in adults. The two common dermal complications of IBD are pyoderma gangrenosum (see Chapter 522) and erythema nodosum (see Chapter 522) . The lesions of pyoderma gangrenosum almost always develop during a bout of acute colitis and usually resolve with control of the colitis by oral corticosteroids or with intradermal corticosteroids; in rare cases, colectomy is required. The activity of erythema nodosum, which is seen particularly in association with Crohn's disease in children, follows the activity of the bowel disease. The ocular complications of IBD are uveitis and episcleritis (see Chapter 512) . Local therapy with corticosteroids and agents that dilate the pupil helps to prevent scarring and blindness.

RADIOGRAPHY. In both ulcerative colitis and Crohn's disease, radiographic findings may not correlate well with disease activity. The patient's clinical response or endoscopic findings are more useful for this purpose. In early ulcerative colitis, the barium enema may be normal or there may be limited distensibility of the involved segment, resulting in a narrowed, shortened, and tubular form of the lumen. The haustral markings disappear, and the normally tortuous appearance

Figure 135-1 Air contrast barium enema demonstrating luminal narrowing and loss of haustral markings in the sigmoid and descending colon in a patient with ulcerative colitis.

of the colon is straightened (Fig. 135-1) . Air contrast examination reveals a fine granular appearance to the mucosa, with a slightly irregular surface. In more severe disease, the granularity becomes coarser and eventually nodular; ulcers penetrate through the mucosa and can be seen in profile as small collar-button collections of barium extending beyond the colonic lumen. The earliest form of Crohn's disease detectable by air contrast barium enema is marked by the presence of aphthous ulcers, which appear as small discrete collections of barium surrounded by radiolucent halos of inflammatory infiltrate. These small ulcers are usually multiple, and the intervening mucosa is normal. As Crohn's disease becomes more severe, the aphthous ulcers enlarge, deepen, and connect with one another to form linear ulcers; the intervening mucosa develops a nodular appearance on a radiograph, a process termed cobblestoning. Progressive deepening of ulcers can lead to abscess formation or fistulization. Contrast studies are more likely than endoscopic studies to identify fistulas. Transmural inflammation and fibrosis lead to limited distensibility, with decreased luminal diameter and stricture formation. Like fistulas, strictures are more easily appreciated on radiographic studies than by endoscopy. Transmural inflammation and fibrosis result in thickening of the bowel wall, with wide gaps between the barium-filled lumens of loops of inflamed small bowel (Fig. 135-2) . Small bowel Crohn's disease can be evaluated by small bowel follow-through or by enteroclysis. Computed tomography and ultrasonography are useful in identifying abscesses and other fluid collections and in assessing the thickness of the bowel wall.

ENDOSCOPY. The earliest endoscopic manifestations of ulcerative colitis are the development of diffuse erythema and loss of the fine vascular pattern seen in the normal rectal mucosa (Color Plate 2 B). Erythema is usually accompanied by mucosal edema, which is manifested endoscopically by blunting of the rectal valves, loss of normal vasculature, and development of granular-appearing mucosa. Inflammation is associated with the presence of yellowish exudate on the mucosa. The inflamed mucosa bleeds easily if touched with the endoscope; this easy bleeding is termed friability. In more severe disease, the mucosa bleeds spontaneously and small ulcerations appear. An important aspect of the endoscopic findings in ulcerative colitis is their distribution: inflammation begins in the rectum, extends proximally a certain distance, and then stops; all the mucosa proximal to that point is normal, and all the mucosa distal to it is abnormal. The earliest endoscopic manifestation of Crohn's disease is the aphthous ulcer, a small discrete ulcer a few millimeters in diameter surrounded by a thin red halo of edematous tissue (Color Plate 725

Figure 135-2 Small bowel follow-through in a patient with Crohn's disease of the ileum demonstrating luminal narrowing, mucosal ulceration, and separation of the barium-filled loops due to thickening of the bowel wall.

2 G). Ulcers may be rounded or long and serpiginous. Longitudinal and transverse ulcers may intersect to form a grid with intervening cobblestone-like areas of non-ulcerated mucosa. Large, deep, penetrating ulcers can be surrounded by areas of normal-appearing mucosa. The diffuse mucosal irregularities of erythema, edema, and granularity, which are prominent in ulcerative colitis, occur less commonly and later in the course of Crohn's disease. The rectum may or may not be involved in Crohn's disease. Areas of involvement are typically interspersed with normal "skip" areas.

DIFFERENTIAL DIAGNOSIS. For many therapeutic decisions, it is not particularly important to know whether the patient has ulcerative colitis or Crohn's disease. However, when surgery is contemplated, the distinction is important. For example, a colectomy and ileoanal anastomosis could be recommended as a curative procedure if the physician were confident the patient had ulcerative colitis rather than Crohn's colitis. The anatomic distribution of the inflammatory response may be helpful in distinguishing ulcerative colitis from Crohn's disease. In ulcerative colitis, inflammation is seen in the rectum and extends proximally for some distance; in extensive disease, inflammation extends to the cecum. Although ulcerative colitis does not involve the small intestine, there may be a few centimeters of inflamed mucosa without ulceration in the terminal ileum. If the rectum is spared or if there are areas of uninflamed mucosa (skip areas) between areas of inflamed mucosa, then Crohn's colitis is more likely. Ulcerative colitis is not only continuous along the longitudinal axis of the colon, but the degree of inflammation is also consistent and symmetric circumferentially at any level. In contrast, in Crohn's colitis, deep linear ulcers may be separated by areas of normal mucosa. A major distinguishing mark in favor of Crohn's disease is the presence of transmural inflammatory changes; in ulcerative colitis, inflammation is confined to the mucosa and submucosa. Extensive perianal involvement with fistulas and abscesses point to Crohn's disease. The presence of non-caseating granulomas suggests Crohn's disease, but even in Crohn's disease, most patients have no granulomas on biopsy. Despite all these differences, there is a small but significant number of patients with IBD who cannot be assigned with confidence to one disease category or the other; these patients are considered to have indeterminate colitis. Infections with Shigella, Amoeba, Giardia, Escherichia coli O157:H7, and Campylobacter organisms can present with bloody diarrhea, cramps, and an endoscopic picture identical to ulcerative colitis (Chapter 339) . An important distinction between these infectious diseases (excepting amebiasis) and IBD is that the diarrhea in the

infectious diseases tends to be limited to a period of days to a few weeks, whereas the diarrhea of IBD is typically of longer duration. Stool cultures for bacterial pathogens and serologic tests for amebiasis help distinguish infectious diarrhea from IBD. In patients who present with prolonged diarrhea, other protozoal diseases, such as giardiasis, must be considered. Pseudomembranous colitis presents as profuse watery diarrhea and may last from a few days to months; the presence of small membranous plaques adherent to the mucosa on sigmoidoscopy is pathognomonic. As part of the initial evaluation of patients with acute exacerbation of IBD, it is appropriate to check the stool for C. difficile toxin, especially if there has been recent antibiotic exposure. Mild ulcerative colitis, in which rectal bleeding is the primary manifestation, can be confused with hemorrhoids or anal fissures (Chapter 143) . The presence of urgency or diarrhea is more consistent with ulcerative colitis. Sigmoidoscopy should easily differentiate ulcerative colitis from these perianal problems. Collagenous colitis is a chronic inflammatory disease marked pathologically by the presence of a thick collagen deposition in the subepithelial layer of the colonic mucosa (Chapter 133) . The typical clinical presentation is chronic watery diarrhea in a middle-aged woman. Endoscopically, the mucosa appears mildly inflamed or, more commonly, absolutely normal; biopsy with histology provides the diagnosis. Ischemic colitis is part of the differential diagnosis of the initial bout of IBD and should be considered in elderly persons or others at particular risk for ischemic disease (Chapter 137) . Diverticulitis, which may be difficult to separate from acute Crohn's colitis, tends to be a more acute problem without a chronic inflammatory state (Chapter 136) . Intestinal lymphoma can mimic the symptoms of Crohn's disease; in lymphoma, small bowel radiographs may show diffuse involvement with masses in the bowel wall. If Crohn's disease has a long, indolent course with relatively mild symptoms, it may be difficult to differentiate from irritable bowel syndrome, and some patients may have both (Chapter 131) .

DRUGS USED IN IBD. GENERAL SUPPORTIVE THERAPY. Antidiarrheal agents, usually loperamide or diphenoxylate, are useful in patients with mild IBD to reduce the number of bowel movements and to relieve rectal urgency. Anticholinergics (tincture of belladonna, clidinium, propantheline bromide, and dicyclomine hydrochloride) may reduce cramps, pain, and rectal urgency. An especially effective combination of an antidiarrheal and an antispasmodic is powdered opium (25 mg) and belladonna (15 mg). Antidiarrheal agents and antispasmodics are contraindicated in severe colitis because of the risk of precipitating toxic megacolon. The chronic use of narcotics for pain should not be part of the management of IBD. Sometimes antidepressants can be helpful. Non-steroidal anti-inflammatory drugs can exacerbate the clinical activity of IBD and should be used cautiously. Nutritional management plays only a small role in ulcerative colitis. Patients should avoid specific foods (typically high-fiber foods) that worsen their symptoms. Nutritional management plays a much larger role in Crohn's disease, in which many patients have diminished caloric intake and vitamin B12 , vitamin D, calcium, magnesium, zinc, and iron may be malabsorbed. Both total parenteral nutrition and elemental enteral diets can decrease intestinal inflammation by reducing the antigen load in the lumen. AMINOSALICYLATES. Sulfasalazine is composed of 5-aminosalicylic acid (5-ASA) joined by an azo bond to sulfapyridine (Table 135-3) . Colonic bacteria split the azo bond to release 5-ASA, the active ingredient, into the colonic lumen. 5-ASA is not absorbed from the colon; it appears to have a local therapeutic effect by acting intraluminally. Sulfasalazine has been used successfully as a single agent in mild to moderate acute attacks of ulcerative colitis and Crohn's colitis; it is the drug of choice in mild cases. Success rates with sulfasalazine are dose related, with better success rates at doses of 4 g/day or more. Patients who respond to sulfasalazine usually do so in 2 to 3 weeks, although some take 4 weeks or longer to respond. Dose-related toxic effects (headache, nausea, vomiting, and abdominal discomfort) are related to serum sulfapyridine levels, but hypersensitivity reactions (rash, fever, aplastic anemia, 726

TABLE 135-3 -- PREPARATIONS OF 5-AMINOSALICYLIC ACID DELIVERY DISTRIBUTION

PREPARATION

DOSE*

Topical Mesalamine suppository

Direct

Rectum

500 mg once or twice a day

Mesalamine enema

Direct

Left colon

4 g in 60 mL at bedtime

Sulfasalazine

Bacterial azo reductase

Colon

4-6 g in divided doses

Dipentum

Bacterial azo reductase

Colon

1.5-3.0 g in divided doses

Asacol

Release at pH > 7

Distal ileum, colon

2.4-4.8 g in divided doses

Pentasa

Time-release ethyl cellulose microgranules

Ileum, colon

3-4 g in divided doses

Oral

*Doses given are for active disease; similar doses can be given for maintenance therapy, although some practitioners use lower doses for maintenance.

pancreatitis, lupus-like rash, nephrotoxicity, hepatitis, agranulocytosis, and autoimmune hemolysis) are not. Sulfasalazine commonly causes changes in sperm morphology and number, leading to reversible infertility. Sulfasalazine inhibits folic acid absorption and is a competitive inhibitor of folate conjugase in the jejunal brush border; folic acid supplementation of 1 to 2 mg/day is commonly recommended. If 5-ASA alone is administered orally, it is rapidly absorbed, and significant luminal concentrations are not achieved. 5-ASA is available in the United States as an enema and as a suppository. Several oral formulations provide 5-ASA to the colon by binding two 5-ASAs through an azo linkage, by coating 5-ASA in granules that dissolve at pH 7 or above in the colon and terminal ileum, or by encapsulating 5-ASA in a semipermeable membrane that releases 65% of its 5-ASA in the colon and 35% in the small intestine. CORTICOSTEROIDS. Oral corticosteroids are effective in mild to moderate ulcerative colitis and Crohn's disease. Parenteral therapy is reserved for moderate to severe disease. The typical initial dose of prednisone is 40 mg/day in moderate to severe disease. The patient is left on high doses of corticosteroids until symptoms begin to diminish, after which the dose is gradually reduced. If an inadequate initial dose of prednisone is used because of the fear of side effects, the likelihood of a positive response diminishes. In some patients, disease activity flares when the dose of prednisone is reduced below a certain level (steroid dependence). For most patients, administration of oral prednisone in a single morning dose is as effective as divided doses. Corticosteroids should not be used in patients with undrained abscesses or when symptoms are due to a stricture or fibrotic process. Maintenance therapy with corticosteroids is ineffective to prevent recurrences in ulcerative colitis or Crohn's disease in remission. The many side effects of corticosteroids (see Chapter 28) are the major factor limiting their use in IBD. IMMUNOMODULATORS. Immunomodulator drugs act by blocking lymphocyte proliferation, activation, or effector mechanisms. There is extensive experience with azathioprine and its metabolite 6-mercaptopurine (6-MP) to treat IBD and lesser experience with cyclosporine and methotrexate. Azathioprine and 6-MP are effective in treating active Crohn's disease and in maintaining remission; their roles in ulcerative colitis are less clear. Typical initial doses are 1 to 1.5 mg/kg for 6-MP and 2.0 to 2.5 mg/kg for azathioprine. The delay between the initiation of therapy and the clinical response is typically 3 to 6 months. These drugs are used in patients who have active disease that is unresponsive to corticosteroids (refractory patients) and in corticosteroid-dependent patients. In these patients, 6-MP or azathioprine is added to corticosteroid therapy; then after 3 or 4 months, when the 6-MP and azathioprine are likely to have taken effect, the dose of corticosteroids is gradually tapered. Most clinicians maintain patients on 6-MP or azathioprine for several years if remission is induced by these drugs. The major limiting factor in the use of 6-MP and azathioprine is their toxicity; both commonly cause leukopenia, may cause pancreatitis, and may increase the risk of lymphoma. Methotrexate, given either orally or parenterally, is effective in active Crohn's disease. Cyclosporine, given intravenously, is effective in reducing inflammation in patients with severe ulcerative colitis who are facing colectomy. ANTIBIOTICS.

Except in cases of overt sepsis, there is little role for antibiotics in the management of ulcerative colitis. Antibiotics do not affect the remission rate; moreover, the risk of inducing antibiotic-associated pseudomembranous colitis must be considered. Antibiotics play a larger role in Crohn's disease; they are used in the management of the suppurative complications, especially abscess formation and perianal disease, although surgical drainage is the primary therapy for abscesses. Metronidazole (10 to 15 mg/kg/day) is effective in perianal Crohn's disease and is as effective as sulfasalazine in Crohn's colitis. The major side effect of metronidazole is peripheral neuropathy, which is dose dependent and usually resolves when the drug is discontinued. Ciprofloxacin at 500 mg twice a day for a few weeks is also effective in some patients.

MEDICAL MANAGEMENT OF ULCERATIVE COLITIS (Fig. 135-3) . PROCTITIS. For active ulcerative proctitis, a relatively effective and rapidly-acting approach is the nightly administration of 5-ASA retention enemas or suppositories, often supplemented with an oral aminosalicylate. Corticosteroid enemas can also be used. Either 5-ASA suppositories or corticosteroid foam is appropriate for disease of up to 20 cm of distal colon; 5-ASA or corticosteroid retention enemas can be used for active disease, involving up to 60 cm of distal colon. Another approach to proctitis or distal colitis is an oral aminosalicylate, although a response may not be evident for 3 to 4 weeks. EXTENSIVE COLITIS. For patients with colitis of mild to moderate activity and extension proximal to the sigmoid colon, the initial drug of choice is an oral aminosalicylate; efficacy increases with increasing doses. For patients with more active disease (>5-6 bowel movements per day), patients in whom a more rapid response is desired, or patients who have not responded to 3 to 4 weeks of aminosalicylates, the treatment of choice is oral prednisone. Patients with severe diarrhea, systemic symptoms, or significant amounts of blood in the stool should be started on 40 mg/day; most patients respond to oral corticosteroids within a few days. After the symptoms are controlled, prednisone can be gradually tapered by 5 to 10 mg every 1 to 2 weeks. Patients who respond to oral prednisone and can be fully withdrawn from it should be maintained on an aminosalicylate. For patients who do not respond to corticosteroids (steroid-refractory) or who do respond but whose disease flares whenever the corticosteroids are withdrawn (steroid-dependent), options include indefinite corticosteroids, an immunomodulator (azathioprine or 6-MP), or colectomy. Continuation of high-dose corticosteroid therapy for too long a time is the most common serious error in the management of ulcerative colitis. If the patient is on a substantial dose (>15 mg/day of prednisone) for more than 6 months, a trial of an immunomodulator or colectomy should be given serious consideration. The most common reason for hospitalization is intractable diarrhea, although blood loss is also a common problem. Patients with severe active ulcerative colitis should be evaluated for toxic megacolon. Anticholinergics and antidiarrheal agents are contraindicated in severe ulcerative colitis because of the risk of precipitating toxic megacolon. The mainstays of therapy for severe ulcerative colitis are bed rest, rehydration with intravenous fluids, and intravenous corticosteroids (hydrocortisone 300 mg/day; prednisolone, 60-80 mg/day, or methylprednisolone, 48-60 mg/day). Total parenteral nutrition may be necessary if there is malnutrition. Patients with peritoneal signs or signs of systemic infection should be treated with parenteral antibiotics. Patients who do not improve in 7 to 10 days should be considered for either colectomy or a trial of intravenous cyclosporine. MAINTENANCE THERAPY. Aminosalicylates reduce the incidence of recurrences in patients with ulcerative colitis; almost all patients 727

Figure 135-3 Treatment algorithm for ulcerative colitis.

should receive maintenance therapy. The efficacy of sulfasalazine at 3 to 4 g/day is greater than the efficacy of 2 g/day even though 2 g/day is the usual recommended maintenance dose. Corticosteroids are not effective as maintenance therapy and should not be used. Most of the experience with 6-MP as maintenance therapy in ulcerative colitis is in patients whose acute disease has been brought under control with 6-MP; withdrawal of 6-MP from these patients results in a high incidence of exacerbation.

MEDICAL MANAGEMENT OF CROHN'S DISEASE (Fig. 135-4) . GENERAL APPROACH. It is difficult to develop generally applicable guidelines for the management of Crohn's disease because of the great variety of anatomic locations, clinical presentations, and gastrointestinal complications such as fistulas, abscesses, strictures, and perforations. Response to therapy is monitored by empiric clinical assessment directed at the problem that is most troublesome for the patient. A common problem in the management of Crohn's disease is a marked discrepancy between the severity of the patient's symptoms and the objective signs of disease activity. Patients with severe pain and diarrhea may have minimal findings on endoscopy or radiographic studies. Patients who have undergone ileal resections may have significant diarrhea on the basis of their surgery alone. ACTIVE DISEASE. For colonic or ileocolic Crohn's disease with mild to moderate activity, an aminosalicylate is a reasonable first therapy. Pentasa, an oral 5-ASA preparation with greater availability of 5-ASA in the ileum than sulfasalazine or Asacol, may be a better choice for patients with ileitis or ileocolitis. Metronidazole, given by mouth at a dose of 10 to 15 mg/kg/day, is an alternative to aminosalicylates for Crohn's colitis. Prednisone is the drug of choice for patients who have failed to respond to aminosalicylates or metronidazole, for patients with ileal disease, and for patients with highly active colonic or ileocolic disease. The response to prednisone is usually more rapid than that to aminosalicylates. Before corticosteroids are given to a Crohn's disease patient with abdominal pain, fever, and a high leukocyte count, an abdominal computed tomographic scan should be obtained to exclude an abscess. For patients who have been brought into clinical remission on corticosteroids, the rate at which the dose is tapered is arbitrary and not defined by controlled trials. Usually the prednisone dose can be tapered from 40 mg/day to 20 mg/day relatively rapidly (5-10 mg/1-2 weeks) without inducing a flare of disease activity. If the patient has not been on a 5-ASA preparation, one should be added to increase the likelihood of a successful corticosteroid withdrawal. Once the dose of prednisone has reached 20 mg/day, the taper is slowed to 5 mg every 10 to 14 days; if symptoms flare, the dose of prednisone is increased. At this point, the best approach for most patients is a trial of an immunomodulator, either 6-MP or azathioprine; corticosteroid therapy is continued for 3 to 4 months and then tapered gradually. Approximately 60% of corticosteroid-dependent patients will be able to withdraw from corticosteroids using this approach; the alternative is surgery if there is a stricture or a focal area of involvement. The approach to severe Crohn's disease is similar to the approach to severe ulcerative colitis. The patient is hospitalized, given nothing by mouth, rehydrated with intravenous fluids, and given parenteral corticosteroids. Patients who respond to parenteral corticosteroids are switched to high-dose oral corticosteroids (prednisone 40 mg/day), and the dose of prednisone is gradually reduced. Patients with severe Crohn's disease who do not respond to parenteral corticosteroids within a week should be considered for surgery. A course of total parenteral nutrition may be useful as adjunctive therapy. MAINTENANCE THERAPY. Maintenance therapy with aminosalicylates is recommended for those brought into remission on corticosteroids or with surgery; however, the efficacy of aminosalicylates as maintenance therapy is less well established in Crohn's disease than in ulcerative colitis. Maintenance with 6-MP or azathioprine is recommended for patients brought into remission on those drugs or who were corticosteroid dependent and then converted to those drugs. There is no role for cortricosteroids as maintenance therapy.

SURGERY. Twenty to 25 per cent of patients with extensive ulcerative colitis eventually undergo colectomy, usually because their disease has not responded adequately to medical therapy. In ulcerative colitis, colectomy is a curative procedure. Emergency colectomy may be required in toxic megacolon or in a severe fulminant attack without toxic megacolon. The standard operation for ulcerative colitis is a proctocolectomy and Brooke's ileostomy. The most popular alternative operation is the proctocolectomy and ileoanal anastomosis; in this procedure, a pouch is constructed from the terminal 30 cm of ileum, and the distal end of the pouch is pulled through the anal canal. The decision for or against colectomy is influenced by the patient's age, social circumstances, and duration of disease. The risk of developing malignancy enters into the equation when considering colectomy in those with long-standing ulcerative colitis; if the other indications are equivocal, the risk of malignancy may push the balance in favor of colectomy. Within 10 years of diagnosis, approximately 60% of patients with Crohn's disease undergo surgery for their disease. Because surgical resection is not curative in Crohn's disease and recurrences 728

Figure 135-4 Treatment algorithm for Crohn's disease.

are likely, the approach is more conservative in terms of the amount of tissue removed. Failure of medical management is a common cause for resection in Crohn's disease, as it is in ulcerative colitis, but complications (e.g., obstruction, fistula, abscess) are often indications for resection in Crohn's disease. Surgery is also performed to allow patients to stop taking medications (usually corticosteroids). For small bowel Crohn's disease, the most common surgical procedure is segmental resection for obstruction or fistula. The incidence of recurrence severe enough to need repeat surgery after ileal or ileocolic resection is about 50% after 10 years and 75% after 15 years. Endoscopic and histologic surgical approaches to Crohn's colitis include segmental resection, subtotal colectomy with ileoproctostomy, and total colectomy with ileostomy. For patients with extensive colonic disease including the rectum, the procedure of choice is total proctocolectomy with a Brooke's ileostomy. Total colectomy with ileoanal anastomosis is not appropriate in Crohn's colitis because recurrence of Crohn's disease in the ileal segment forming the new pouch would require a repeat operation and loss of a long segment of ileum.

COMPLICATIONS. The most severe complication of ulcerative colitis is toxic megacolon, that is, dilatation of the colon to a diameter of greater than 6 cm associated with a worsening of the patient's clinical condition and the development of fever, tachycardia, and leukocytosis. Physical examination may reveal postural hypotension, tenderness over the distribution of the colon, and absent or hypoactive bowel sounds. Antispasmodics and antidiarrheal agents are likely to initiate or exacerbate toxic megacolon. Medical therapy is designed to reduce the likelihood of perforation and to return the colon to normal motor activity as rapidly as possible. The patient is given nothing by mouth, and nasogastric suction is begun. Intravenous fluids should be administered to replete water and electrolytes, broad-spectrum antibiotics are given in anticipation of peritonitis resulting from perforation, and parenteral corticosteroids are given at a dose equivalent to more than 40 mg of prednisone per day. Signs of improvement include a decrease in abdominal girth and the return of bowel sounds. Deterioration is marked by the development of rebound tenderness, increasing abdominal girth, and cardiovascular collapse. If the patient does not begin to show signs of clinical improvement during the first 24 to 48 hours of medical therapy, the risk of perforation increases markedly, and surgical intervention is indicated. Abscesses and fistulas, which are common complications in Crohn's disease, are products of the extension of a mucosal fissure or ulcer through the intestinal wall and into extraintestinal tissue. Leakage of intestinal contents through a fissure into the peritoneal cavity results in an abscess. Extension of the inflammatory process through the wall of adjacent viscera or through the abdominal wall to the exterior results in a fistula. Abscesses occur in 15% to 20% of patients with Crohn's disease and are especially common in the terminal ileum. The typical clinical presentation of intra-abdominal abscess is fever, abdominal pain, tenderness, and leukocytosis. Abdominal abscess is most often diagnosed by computed tomography. Broad-spectrum antibiotic therapy, including anaerobic coverage, is indicated. Percutaneous drainage of abscesses in patients with Crohn's disease may improve the clinical picture but will not provide adequate therapy because of persistent communication between 729

the abscess cavity and the intestinal lumen. Resection of the portion of involved intestine containing the communication is usually required for definitive therapy. The prevalence of fistulas is 20% to 40% in Crohn's disease. Most fistulas are enteroenteric or enterocutaneous, with smaller numbers that are enterovesical or enterovaginal. Total parenteral nutrition or immunomodulator therapy may induce fistula closure; however, the fistulas often recur after the total parenteral nutrition or immunomodulator is stopped. Surgical therapy includes resection of the segment involved with active disease. Obstruction is a common complication of Crohn's disease, particularly in the small intestine, and is a leading indication for surgery. Small bowel obstruction in Crohn's disease may be caused by mucosal thickening from acute inflammation, by muscular hyperplasia and scarring as a result of previous inflammation, or by adhesions. Obstruction may also occur because of impaction of a bolus of fibrous food in a stable, long-standing stricture. Obstruction presents with cramping abdominal pain and diarrhea that worsen after meals and resolve with fasting. Strictures may be evaluated by oral contrast studies, barium enema, or colonoscopy, depending on anatomic location. Corticosteroids are useful if acute inflammation is an important component of the obstructive process, but not if the obstruction is due to fibrosis. A common error in the management of Crohn's disease is treatment with long courses of corticosteroids in patients who have obstructive symptoms from fixed anatomic lesions. If the obstruction does not resolve with nasogastric suction and corticosteroids, surgery is necessary. Perianal disease is an especially difficult complication of Crohn's disease. A complex of problems is caused by ulcers in the anal canal and the resulting fistulas. The fistulous openings are most commonly in the perianal skin but can be in the groin, the vulva, or the scrotum. Fistulas present as drainage of serous or mucous material. If the fistula does not drain freely, there is local accumulation of pus (perianal abscess) with redness, pain, and induration. The pain of perianal abscesses is exacerbated by defecation, sitting, or walking. The typical physical presentation of abscess is redness with tenderness on digital examination. Adequate evaluation of perianal disease usually requires proctoscopic examination under anesthesia. Computed tomography is useful in defining the presence and extent of perianal abscesses. The goals of therapy in perianal disease are relief of local symptoms and preservation of the sphincter. Limited disease can be approached with sitz baths and metronidazole, but in most cases adequate external drainage is also required. Persistent severe perianal Crohn's disease can result in destruction of the anal sphincter and fecal incontinence.

COLON CANCER, DYSPLASIA, AND COLONOSCOPIC SURVEILLANCE. Patients with extensive ulcerative colitis have a markedly increased risk for colon cancer compared with the general population beginning 8 to 10 years after diagnosis and increasing with time. The risk of malignancy is also a function of the anatomic extent of the disease; the risk is much greater with pancolitis than with left-sided disease. Patients with long-standing ulcerative colitis are at risk for developing cancer even if their symptoms have been relatively mild; that is, colon cancer is seen in patients whose disease has been quiescent for 10 to 15 years. In ulcerative colitis, colon cancers are frequently submucosal and may be missed at colonoscopy. Colon cancer in ulcerative colitis is associated with dysplastic changes in the mucosa at other sites in the colon. Dysplasia cannot be identified by visual inspection; microscopic examination of biopsy specimens is required. Some practitioners perform surveillance colonoscopies with random biopsies in patients with long-standing ulcerative colitis beginning 8 to 10 years after the onset of disease and repeated every 1 to 2 years. If the specimens show dysplasia, the patient is sent for colectomy. Although it is clear that dysplasia is associated with colon cancer in ulcerative colitis, the utility of surveillance colonoscopy has not been firmly established. The risk of colon cancer in Crohn's colitis is less than in ulcerative colitis but greater than in the general population. The utility of surveillance in Crohn's colitis is unproven.

PREGNANCY AND INFLAMMATORY BOWEL DISEASE. Fertility in women with IBD is normal or only minimally impaired, and the incidences of prematurity, stillbirth, and developmental defects in IBD are similar to those of the general population. The incidence of fetal complications may be somewhat higher in cases in which the mother's disease is clinically active, irrespective of drug therapy. Previous proctocolectomy or the presence of an ileostomy is not an impediment to the successful completion of a pregnancy. Many women have taken sulfasalazine throughout the course of pregnancy, and there is no evidence for its causing harm to the fetus. Pregnant women have an increased requirement for folic acid, and sulfasalazine interferes with folate absorption. Therefore, women taking sulfasalazine who are pregnant or considering pregnancy should receive folate supplementation (1 mg twice daily) to ensure that the fetus receives amounts adequate for normal development. The use of corticosteroids by pregnant women with IBD is not associated with an increased rate of fetal complications. In general, it appears that the risks to the pregnancy of treatment with sulfasalazine or corticosteroids are less than the risks of allowing disease activity to go untreated. Most of the data on azathioprine and 6-MP in pregnancy come from the transplant literature and involve higher doses than are commonly used in IBD. Reported fetal effects in the transplant population include congenital malformations,

immunosuppression, prematurity, and growth retardation; risks in the IBD population are not known. The effects of pregnancy on IBD depend on disease activity. If the patient's disease is inactive at the time of conception, it is likely that it will remain inactive during the course of the pregnancy. If the disease is active at the time of conception, the course is harder to predict. Ulcerative colitis that is active at the time of conception tends to worsen. In two thirds of Crohn's disease cases that are active at conception, the degree of activity remains the same; among the other third, some improve clinically and others deteriorate. Hanauer SB: Drug therapy: Inflammatory bowel disease. N Engl J Med 334:841, 1996. A useful summary of drug therapy in IBD. Jewell DP: Ulcerative colitis. In Feldman M, Scharschmidt BF, Sleisenger MH (eds): Gastrointestinal and Liver Disease, 6th ed. Philadelphia, WB Saunders, 1997, p 1735. A comprehensive overview of ulcerative colitis. Kirsner JB, Shorter RG (eds): Inflammatory bowel disease, 4th ed. Philadelphia, Lea & Febiger, 1995. A multi-authored textbook on IBD. Kornbluth A, Sachar D, Salomon P: Crohn's disease. In Feldman M, Scharschmidt BF, Sleisenger MH (eds): Gastrointestinal and Liver Disease, 6th ed. Philadelphia, WB Saunders, 1997, p 1708. A comprehensive overview of Crohn's disease. Stenson WF: Inflammatory bowel disease. In Yamada T (ed): Textbook of Gastroenterology, 3rd ed. Philadelphia, Lippincott-Raven, 1999. A comprehensive overview of IBD, including pathogenesis and treatment.

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Chapter 136 - MISCELLANEOUS INFLAMMATORY DISEASES OF THE INTESTINE C. Mel Wilcox

ACUTE APPENDICITIS (INCLUDING THE ACUTE ABDOMEN) DEFINITION. Appendicitis is an acute inflammatory disorder of the vermiform appendix. It is uncommon at the extremes of age, with the highest incidence in the 2nd and 3rd decades. Because of its prevalence, varied manifestations mimicking other intra-abdominal diseases, and curability, appendicitis provides a framework for an understanding of the causes and approach to the acute abdomen. ETIOLOGY AND PATHOGENESIS. Although not demonstrable in all cases, obstruction of the appendiceal lumen by a fecalith is the usual inciting event. Less common causes include neoplasms (carcinoid tumors, adenocarcinoma, Kaposi's sarcoma) and infections ( Enterobius vermicularis, cytomegalovirus). With appendiceal obstruction, normally secreted mucus becomes impacted and causes appendiceal distention, thrombosis, and subsequently, bacterial invasion of the wall; the end result is gangrene and perforation. CLINICAL FINDINGS. The clinical manifestations follow a stereotypic course paralleling these pathologic events. Almost invariably, abdominal pain is the first manifestation. Initially, mild pain may be discounted as indigestion. It is often poorly localized to the periumbilical area or epigastrium; appendiceal distention results in this poorly localized visceral type of periumbilical discomfort. The 730

pain is at first colicky, then steady, and increases in severity as the inflammatory process progresses. When the parietal peritoneum becomes inflamed, usually hours after the initial onset of symptoms, the pain becomes localized in the right iliac region. Right iliac pain is typical of appendicitis; however, pelvic pain (pelvic appendix) or right upper quadrant pain may result, depending on the location of the appendix. Anorexia is frequent, and the urge to eat argues against the diagnosis of appendicitis. Vomiting is not a prominent symptom. PHYSICAL EXAMINATION. Physical findings depend on the stage of the inflammatory process, location of the appendix, and in some cases, the age of the patient. Acute abdominal conditions have notoriously atypical manifestations in the elderly and in patients receiving corticosteroid therapy. The most consistent physical finding is tenderness in the right iliac region at McBurney's point (one fingerbreadth from the anterosuperior iliac spine toward the umbilicus). The area of tenderness, however, corresponds to the location of the inflamed appendix. With a retrocecal appendix, tenderness may be mild. Rectal examination may disclose tenderness anteriorly with a pelvic appendix or a bulge in the pelvic wall from an abscess. An inflamed parietal peritoneum results in localized rebound tenderness and rigidity. Only with generalized peritonitis are diffuse rebound tenderness and peritoneal signs elicited. Rarely, a mass is palpable in the right lower quadrant. Rotating a flexed right hip when supine (obturator sign) or raising a straightened leg against resistance (psoas sign) may elicit pain. Bowel sounds can be heard unless peritonitis and ileus are present. Fever occurs only in the later stages of inflammation; fever at the onset of abdominal pain should suggest another diagnosis. LABORATORY STUDIES. Leukocytosis with increased polymorphonuclear leukocytes is a consistent finding only in the later stages of appendicitis. Urinalysis is usually normal. Standard abdominal radiography is frequently normal, although it may demonstrate localized loops of bowel, obliteration of the psoas shadow, or a soft tissue mass; however, these latter findings represent abscess formation. Fewer than 10% of patients have a calcified fecalith seen in the region of the appendix by abdominal imaging. DIFFERENTIAL DIAGNOSIS OF APPENDICITIS AND THE ACUTE ABDOMEN. Although the differential diagnosis of acute appendicitis and acute abdomen is broad, a systematic history and physical examination, combined with selected laboratory tests and abdominal imaging studies, in most cases lead to a diagnosis. For an acutely ill patient, early surgical consultation is mandatory. Although a firm diagnosis before laparotomy is the rule today, surgical exploration when the appendix is normal is entirely acceptable given the increase in morbidity and mortality with appendiceal rupture. Indeed, 5 to 10% of patients with suspected acute appendicitis have a normal appendix at the time of laparotomy. A variety of disorders cause a subacute to acute right lower quadrant pain syndrome mimicking acute appendicitis (Table 136-1) . In young children, bacterial infections may result in a mesenteric adenitis or terminal ileitis or involve the right colon. Crohn's ileitis or ileocolitis frequently masquerades as acute appendicitis (see Chapter 135) . Meckel's or cecal diverticulitis may be impossible to distinguish from acute appendicitis. Special consideration should be given to female patients. Pelvic inflammatory disease is infrequently unilateral but may mimic appendicitis. Ectopic pregnancy, ruptured endometrioma, or torsion of an ovarian cyst may cause unilateral pain. A ruptured graafian follicle would occur in TABLE 136-1 -- CAUSES OF RIGHT LOWER QUADRANT PAIN SYNDROMES INFLAMMATORY DISORDERS NEOPLASMS Appendicitis

Carcinoid

Crohn's ileitis/colitis

Lymphoma

Cecal diverticulitis

Cecal adenocarcinoma (perforated)

OTHER Gynecologic disorders

Meckel's diverticulitis Yersinia ileocolitis Amebic colitis Tuberculous colitis mid-cycle without fever and leukocytosis. Appendicitis may be difficult to diagnose during pregnancy because the appendix moves toward the right upper quadrant. CHARACTERISTICS OF PAIN.

Acute severe abdominal pain most often results from perforation of an abdominal viscus (peptic ulcer), small bowel obstruction, choledocholithiasis, nephrolithiasis, or rupture and dissection of an abdominal aortic aneurysm. Subacute onset of pain is more typical of intestinal ischemia, cholecystitis, pancreatitis, diverticulitis, Crohn's

disease, and appendicitis. Pain of a constant nature is seen with cholecystitis, pancreatitis, intestinal ischemia, and other inflammatory disorders (see Chapters 137 , 141 , and 157) . Colicky pain occurs with nephrolithiasis or intestinal obstruction. Although more typical of nephrolithiasis, pain radiating to the groin may rarely be seen in appendicitis. Radiation of pain to the back suggests pancreatitis, peptic ulcer disease, or biliary tract disease. Shoulder pain results from diaphragmatic irritation (pancreatitis, cholecystitis). Significant vomiting is seen with pancreatitis or obstruction of the stomach or small bowel. PHYSICAL EXAMINATION.

Careful observation of the patient may provide clues to the cause. With peritonitis, the patient attempts to lie quietly. In contrast, patients with intermittent visceral-type pain (nephrolithiasis or choledocholithiasis) are restless during the attack. Tachycardia is non-specific. Hypotension suggests bleeding (ruptured aneurysm), sepsis, or severe pancreatitis. Low-grade fever occurs with any inflammatory process, including acute pancreatitis. Abdominal inspection should include attention to scars that may suggest hernias or to masses (aneurysm, abscess). Absence of bowel sounds suggests ileus, whereas "rushes and tinkles" occur with small bowel obstruction. Abdominal palpation should begin opposite the point of subjective pain to minimize voluntary guarding, which may limit the examination. Coughing may cause local pain with peritonitis. Diffuse abdominal rigidity, unequivocal rebound tenderness, or severe localized tenderness with rebound represents generalized peritonitis and indicates a need for urgent surgical exploration. Involuntary guarding or referred rebound suggests a focal peritoneal process. Abdominal ischemia causes subjective pain disproportionate to the findings on examination until infarction and perforation occur. Abdominal distention and tympany are found with dilation of either the large or small bowel. Femoral artery or abdominal bruits suggest vascular disease (ischemic disease or aneurysms). Rectal and pelvic examinations may help evaluate for a pelvic appendix and peritonitis or gynecologic disorders. LABORATORY STUDIES.

In patients with an acute abdomen, the following studies should be performed: complete blood cell count with differential, serum electrolytes, blood urea nitrogen and creatinine, serum amylase, liver chemistry tests, urinalysis, and a pregnancy test in women of childbearing potential. An elevated polymorphonuclear leukocyte count points to infection (appendicitis, cholecystitis), tissue necrosis (bowel infarction), or other inflammatory processes (pancreatitis). Anemia may result from gastrointestinal bleeding secondary to carcinoma or peptic ulcer. Pyuria and bacteriuria indicate a urinary tract infection, and microscopic or gross hematuria suggests nephrolithiasis. Fecal white blood cells or blood in the stool is seen with colitis (ischemia, inflammatory bowel disease, infection); fecal white cells are not present in acute appendicitis. Mildly elevated serum amylase (less than two times the upper limit of normal) is non-specific and occurs with a variety of intra-abdominal disorders (see Chapter 141) . ABDOMINAL IMAGING.

Radiographic films of the chest and supine/upright abdominal series are useful to evaluate for free peritoneal air, bowel gas pattern, and the presence of calculi (nephrolithiasis, 80%; gallstones, 15%; appendicolith, 5%; or pancreatic calcification). Pneumonia or another basilar pulmonic process may mimic an abdominal syndrome. Abdominal sonography may demonstrate gallstones and a thickened gallbladder wall (acute cholecystitis), a dilated common bile duct (choledocholithiasis), or pancreatic calcifications (chronic pancreatitis). Recent studies suggest that in experienced hands, sonography has a sensitivity and specificity of greater than 90% in diagnosing acute appendicitis. Abdominal computed tomographic (CT) scanning has been invaluable in the evaluation of patients with an acute abdomen. Localized inflammatory processes of the right lower quadrant may suggest appendicitis or possibly Crohn's disease if the terminal ileum and/or right colon is thickened; however, overlap between these two entities may occur. CT also helps exclude diverticulitis, acute pancreatitis, biliary obstruction, luminal disorders such as 731

small bowel or colonic infarction, and aortic dissection, as well as unsuspected processes of the liver and spleen. Because of its ability to evaluate essentially all intra-abdominal organs, CT has become the imaging modality of choice in patients with an acute abdomen. Helical CT with both oral and intravenous contrast, if no contraindications are present, has the highest diagnostic yield. A variety of other non-surgical conditions may cause an acute abdominal pain syndrome. Disorders "above the diaphragm" include myocardial infarction, bacterial pneumonia, and acute pericarditis. Severe right heart failure and a distended liver may cause mild to moderate right upper quadrant pain. Acute hepatitis rarely results in severe abdominal pain and should be suspected by marked elevations of serum aminotransferase concentrations. Marked transient elevations in serum aminotransferases, however, are commonly seen with acute biliary obstruction (choledocholithiasis). Systemic disorders with abdominal manifestations include sickle cell crisis, acute intermittent porphyria, diabetic neuropathy, heavy metal poisoning, and cutaneous herpes zoster. TREATMENT. Surgical therapy is curative. Mortality is minimal when the diagnosis is rapidly established and appendectomy performed. Mortality rates increase significantly with frank perforation, particularly in the elderly. For patients with a typical history, no confirmatory studies may be necessary before surgical exploration. When the diagnosis is in doubt, careful observation for 6 to 12 hours may be diagnostic. Broad-spectrum antibiotics directed toward gram-negative rods and anaerobes should be given before surgery or at the time of CT-guided drainage. In some patients, acute appendicitis resolves with localized perforation alone; however, subsequent relapse is frequent (chronic appendicitis), so elective appendectomy should be performed.

DIVERTICULITIS OF THE COLON Colonic diverticula are mucosal outpouchings occurring where arteries penetrate the muscularis to reach the submucosa and mucosa. Because these areas are inherently weak and under stress, prolapse of mucosa and submucosa may occur. Diverticula form throughout the entire colon, although more commonly in the left colon, particularly the sigmoid. Diverticulitis results when a fecalith becomes impacted in a diverticulum, with erosion through the serosa resulting in perforation. CLINICAL FINDINGS. Diverticulitis of the colon typically affects patients 50 years and older because the prevalence of diverticulosis increases with age. The pain is usually subacute and constant and located in the left lower quadrant (sigmoid diverticulitis). However, the location of pain depends on the colonic segment involved. Fever is almost invariably present. High-grade fever and sepsis occur when the perforation is not contained or when the peritonitis is generalized. Constipation or loose stools may be reported. Rectal bleeding is distinctly unusual. DIFFERENTIAL DIAGNOSIS. Constant left lower quadrant pain and fever in the elderly are highly suggestive of acute diverticulitis. Lower abdominal pain, fever, and bloody diarrhea suggest a bacterial colitis (Shigella, Salmonella, Campylobacter), ischemic colitis, or other inflammatory bowel disease (see Chapters 135 , 137 , and 339) . With generalized peritonitis, the differential diagnosis becomes that of the acute abdomen (see above). Gynecologic disorders may be localized to the left lower quadrant and should always be considered in females. DIAGNOSTIC STUDIES. Leukocytosis is common, although non-specific. Urinalysis may demonstrate non-specific findings such as protein or rare white blood cells. If significant diarrhea is reported, fecal leukocytes should be searched for. Abdominal radiographs may indicate a displaced colon, extraluminal gas, or colonic mucosal abnormalities. These studies are probably more helpful in excluding other potential causes of left lower quadrant pain. Diagnostic barium enema has been used for many years and is safe when carefully performed. Typical findings include spiculation of the mucosa, spasm, or frank perforation and abscess. These findings are relatively specific for acute diverticulitis but may be difficult to differentiate from carcinoma. Abdominal CT, which has become the test of choice, may demonstrate bowel wall thickening, abscess formation, and diverticula (Fig. 136-1) . Barium enema and CT are complementary because neither is 100% sensitive and specific.

Figure 136-1 CT scan showing marked thickening of the distal end of the descending colon with surrounding inflammatory changes (straight arrow) and extraluminal gas (curved arrow) diagnostic of diverticulitis.

Endoscopic examination is contraindicated with diverticulitis given the theoretic potential to exacerbate perforation; however, when carcinoma or inflammatory bowel disease is highly suspected, sigmoidoscopy is appropriate. TREATMENT. Initial therapy includes broad-spectrum antibiotics such as a 3rd-generation cephalosporin combined with anaerobic coverage (metronidazole). For mild disease, oral antibiotics and bowel rest can be used in the outpatient setting. Early surgical consultation is important, especially in the presence of more significant pain or an acute abdomen. If a large abscess is identified by CT imaging, percutaneous catheter drainage can be a temporary measure before subsequent definitive surgical therapy. Complications of diverticulitis include colonic stricture, bleeding, or fistula formation to the small bowel, colon, bladder, or vagina.

RADIATION ENTEROCOLITIS Although radiation is commonly used to palliate abdominal and pelvic malignancies, clinically significant radiation injury in the gastrointestinal tract is unusual. Injury usually develops when the total dosage exceeds 50 Gy. PATHOGENESIS. Given the high turnover rate of gastrointestinal epithelium, it is not unexpected that the gut, particularly replicating cells in the crypts, would be affected by radiation. If the dose of radiation does not exceed 50 Gy, minor mucosal injury (edema, erosions) may be temporary. With more intense therapy, damage to submucosal blood vessels results in an arteritis and, secondarily, mucosal ischemia. Late complications include fibrosis, strictures, and diffuse vascular ectasia in the affected segments. CLINICAL FINDINGS. During the early phases of radiation therapy, patients may report nausea, vomiting, and diarrhea, which may be bloody. Symptoms caused by the complications of high-dose radiation are not seen for months or even years following therapy (intestinal ulcerations with bleeding, obstruction from fibrosis and stricture, fistulas to other pelvic organs or abscesses, or chronic gastrointestinal bleeding and anemia from vascular ectasia). If a significant amount of small bowel is in the radiation field, malabsorption may be noted. DIAGNOSIS. In the appropriate setting, the diagnosis is relatively straightforward. Symptoms early in the course of therapy suggest acute injury. Endoscopic features include mucosal edema, ulceration (early), and diffuse vascular ectasia and stricture (late). Although non-specific, barium enema may demonstrate mucosal edema, fistula formation, and strictures. In an older patient with a stricture, carcinoma must be excluded. TREATMENT. Treatment options are limited. Iron deficiency anemia from bleeding (vascular ectasia) should be treated with chronic iron therapy. For symptomatic distal colonic strictures, dilation may be attempted, although surgery is usually required. Diarrhea can be treated with antimotility agents. Abscess and fistula formation requires surgical resection. Surgery should be performed 732

only when necessary given the potential for further complications after anastomosis owing to the involvement of adjacent bowel segments.

INTESTINAL AND COLONIC ULCERATION Small intestinal and colonic ulceration is uncommon. Ulcerations may be isolated or diffuse and may be located anywhere throughout the small bowel. The location of disease and the character of the ulcers suggest the underlying cause. Isolated proximal small bowel ulcerations are most commonly caused by medications such as slow-release potassium pills or non-steroidal anti-inflammatory drugs (NSAIDs). Other disorders include infections, collagen-vascular diseases (Behcet's disease, systemic lupus erythematosus), and ulcerated neoplasms. Multiple ulcers may be caused by Zollinger-Ellison syndrome and have been associated with celiac disease. In some cases they are idiopathic. Because of their small size, these ulcers are difficult to identify by routine small bowel barium radiographs. Enteroclysis (see Chapter 121) is more sensitive in defining these abnormalities. Small bowel enteroscopy is time consuming and not widely available, although it is the best method to visualize the proximal end of the small bowel directly. Diffuse processes (celiac sprue, lymphoma, or Crohn's disease) are more reliably identified by these radiographic studies. Ulceration(s) in the right colon has recently been documented to result from NSAIDs. These ulcerations may result in one or multiple circumferential strictures, termed diaphragms, and may also appear in the small bowel. Infections such as tuberculosis, amebiasis, or rarely bacterial infections may produce right colonic ulceration. Ischemia usually produces diffuse segmental ulceration. Distal colonic ulcers result from ischemia, infections, or inflammatory bowel disease, particularly Crohn's colitis. Rectal ulcers, when solitary, may be seen with chronic constipation (stercoral ulcer) or trauma or may be idiopathic. Barium enema may suggest Crohn's disease or ischemia. Colonoscopy with ulcer biopsy may demonstrate characteristic histopathologic changes in Crohn's disease or the solitary rectal ulcer syndrome. Anderson RE, Hugander AP, Ghazi SH, et al: Diagnostic value of disease history, clinical presentation, and inflammatory parameters of appendicitis. World Surg 23:133, 1999. This prospective study documents the diagnostic utility of the history, physical examination, and parameters of inflammation in suggesting the diagnosis of appendicitis. Choi YH, Fischer E, Hoda SA, et al: Appendiceal CT in 140 cases: Diagnostic criteria for acute and necrotizing appendicitis. Clin Imaging 22:252, 1998. The overall accuracy of CT was 98% and it had a 90% positive predictive accuracy for necrotizing appendicitis. Hellberg A, Rudberg C, Kullman E, et al: Prospective randomized multicentre study of laparoscopic versus open appendectomy. Br J Surg 86:48, 1999. Laparoscopic appendicectomy is as safe as open appendicectomy and has the advantage of allowing a quicker recovery.

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Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 137 - VASCULAR DISORDERS OF THE INTESTINE Lawrence J. Brandt

Vascular disorders may present either with ischemic damage consequent to insufficient blood flow or by bleeding caused by a focal or diffuse increase in vascularity. The development of sophisticated radiologic imaging techniques has expanded the spectrum of clinically relevant vascular disorders.

ISCHEMIC DISORDERS Three major vessels supply almost all of the blood to the gastrointestinal tract, albeit with incredible variation in anatomy. The celiac axis and its branches supply the liver, biliary tract, spleen, stomach, duodenum, and pancreas; the superior mesenteric artery (SMA) gives off branches to the duodenum and pancreas and then supplies the entire small intestine as well as the ascending colon and a part of the transverse colon; the inferior mesenteric artery (IMA) delivers blood to the rectum and descending colon and then anastomoses with the superior mesenteric artery to supply the transverse colon. In some areas such as the stomach, duodenum, and rectum, collateral circulation is abundant and ischemia is unusual, whereas in other regions, such as the splenic flexure and sigmoid, anastomoses are more limited and segmental ischemic damage is common. Ischemic injury of the bowel is influenced by the health of the cardiovascular system; the potential for collateral flow; the response of the vasculature to autonomic stimuli and circulating vasoactive substances; local modulation of blood flow; and a host of exogenous agents causing vasoconstriction (digitalis glycosides, vasopressin, and alpha-adrenergic agonists) or vasodilation (beta-adrenergic agonists, papaverine, calcium channel blockers, aminophylline). The types of intestinal ischemia and their approximate incidences are colonic (60%), acute mesenteric (30%), focal segmental (5%), and chronic mesenteric (5%). Ischemic injury may be occlusive (due to an anatomic obstruction to blood flow) or non-occlusive (mediated by vasoconstriction), but these two processes often coexist. When a major vessel is suddenly occluded, collaterals open immediately in response to the fall in arterial pressure. Increased blood flow through these collaterals continues as long as the pressure in the vascular bed distal to the obstruction remains below systemic pressure. However, after several hours of ischemia, vasoconstriction develops in the involved vascular bed, elevating its pressure and reducing collateral flow. If the ischemia and vasoconstriction are prolonged, the vasoconstriction can persist even after the cause of the ischemia is corrected. The bowel may tolerate a remarkable reduction in blood flow without damage. Normal oxygen consumption can be maintained with only 20 to 25% of normal blood flow, but below this critical level, oxygen consumption falls because increased oxygen extraction can no longer compensate for diminished blood flow. Acute Mesenteric Ischemia Intestinal ischemia can be acute or chronic and of venous or arterial origin. Acute mesenteric ischemia is much more common than chronic mesenteric ischemia, and ischemia of arterial origin is much more frequent than venous disease. Acute mesenteric ischemia is caused by superior mesenteric arterial embolus (50%), non-occlusive mesenteric ischemia (25%), superior mesenteric artery thrombosis (10%), focal segmental ischemia (5%), and acute mesenteric venous thrombosis (10%). ARTERIAL FORMS OF ACUTE MESENTERIC ISCHEMIA.

SMA emboli usually originate from a left atrial or ventricular thrombus and lodge distal to the origin of a major branch. Many patients with SMA emboli have had previous peripheral emboli, and approximately 20% have synchronous emboli to other arteries. Non-occlusive mesenteric ischemia usually results from splanchnic vasoconstriction hours to days after some cardiovascular event (e.g., acute myocardial infarction, heart failure, arrhythmia, or shock). Patients with chronic renal diseases, especially those requiring hemodialysis and those undergoing major cardiac or intra-abdominal operations, are also at risk. SMA thrombosis occurs at severe atherosclerotic narrowings, most often at the SMA origin. The acute episode is commonly superimposed on chronic ischemia, and 20 to 50% of these patients have a history suggesting intestinal angina during the weeks to months preceding the acute event. CLINICAL ASPECTS OF SEVERE ACUTE MESENTERIC ISCHEMIA.

Sudden severe abdominal pain developing in a patient with heart disease and arrhythmias, long-standing and poorly controlled heart failure, recent myocardial infarction, or hypotension should suggest the possibility of acute mesenteric ischemia. Early on, the pain is accompanied by a paucity of physical findings. Increasing abdominal tenderness and muscle guarding indicate infarcted bowel. Right-sided abdominal pain associated with maroon or bright red blood in the stool, although characteristic of colonic ischemia, also can suggest acute mesenteric ischemia because the blood supply to both the right colon and small bowel originates from the SMA. Leukocytosis, metabolic acidemia, and elevations of serum phosphate, amylase, lactate dehydrogenase, creatine kinase, and intestinal 733

alkaline phosphatase are seen with advanced ischemic bowel injury. Early in the course of disease, plain films of the abdomen usually are normal. Later, formless loops of small intestine, ileus, or "thumbprinting" of the small bowel or right colon due to submucosal hemorrhage may develop. Duplex ultrasonography of the celiac axis and SMA may demonstrate partial or complete occlusion of these vessels but is not reliable to evaluate peripheral blood flow. Abdominal computed tomography (CT) is helpful in some cases, especially those caused by mesenteric venous thrombosis, but early signs are non-specific and later signs develop only with necrosis and gangrene. Selective mesenteric angiography is the mainstay of diagnosis and initial treatment of both occlusive and non-occlusive acute mesenteric ischemia. The approach to diagnosing and managing acute mesenteric ischemia is based on several observations: (1) if the diagnosis is not made before intestinal infarction, the mortality rate is 70 to 90%; (2) both occlusive and non-occlusive forms can be diagnosed by angiography; (3) vasoconstriction may persist even after the initial cause of the ischemia is corrected; and (4) vasoconstriction can be relieved by vasodilators infused into the SMA. Early and liberal use of angiography and the incorporation of intra-arterial papaverine are therefore the cornerstones in the treatment of both occlusive and non-occlusive mesenteric ischemia. Initial management of patients suspected of having acute mesenteric ischemia includes resuscitation, abdominal plain films, and selective angiography. Resuscitation includes relieving acute heart failure and correcting hypotension, hypovolemia, and cardiac arrhythmias. Mesenteric blood flow cannot be improved if low cardiac output, hypovolemia, or hypotension persists. Broad-spectrum antibiotics are begun immediately. Plain films of the abdomen are obtained, not to establish the diagnosis of acute mesenteric ischemia but to exclude other causes of abdominal pain. A normal plain film does not exclude acute mesenteric ischemia. If no alternative diagnosis is made on the abdominal films, selective SMA angiography is performed. Based on the angiographic findings and the presence or absence of peritoneal signs, treatment can be planned (Fig. 137-1) . Even when the decision to operate has been made based on clinical grounds, a preoperative angiogram should be obtained. Relief of mesenteric vasoconstriction is essential in treating emboli, thromboses, and "low flow" states and is accomplished by infusing papaverine at 30 to 60 mg/hour through the indwelling SMA angiography catheter (Fig. 137-2) . Laparotomy is performed in acute mesenteric ischemia to restore arterial flow after an embolus or thrombosis, to resect irreparably damaged bowel, or both. Except in the case of mesenteric venous thrombosis, heparin should not be used immediately postoperatively. However, late thrombosis after embolectomy or arterial reconstruction occurs frequently enough that anticoagulation 48 hours postoperatively is advisable. Survival is in the range of 55%; 90% of patients with acute

mesenteric ischemia diagnosed angiographically before the development of peritonitis survive. MESENTERIC VENOUS THROMBOSIS.

Mesenteric venous thrombosis accounts for 5 to 10% of intestinal ischemia. Underlying causes have been identified in more than 80% of patients and include antithrombin III, protein S and C deficiencies, and hypercoagulable states associated with polycythemia vera, myeloproliferative disorders, pregnancy, and neoplasms. Oral contraceptives account for less than 10% of cases. As many as 60% of patients have a history of peripheral vein thromboses. Mesenteric venous thrombosis can have an acute, subacute (weeks to months), or chronic onset; the latter is unaccompanied by symptoms unless and until late complications occur. Acute mesenteric venous thrombosis resembles arterial forms of acute mesenteric ischemia because it presents as abdominal pain that, early on, is typically out of proportion to the physical findings. However, the tempo of illness is slower than that with arterial ischemia, and the mean duration of pain before hospital admission is 5 to 14 days. Nausea and vomiting are common, and lower gastrointestinal bleeding or hematemesis indicating bowel infarction is found in 15%. Abdominal plain film signs of mesenteric venous thrombosis are similar to those of other forms of acute mesenteric ischemia and almost always reflect the presence of infarcted bowel. Characteristic findings on small bowel series include luminal narrowing from congestion and edema of the bowel wall, separation of loops due to mesenteric thickening, and "thumbprinting" due to submucosal hemorrhage and edema. Selective mesenteric arteriography can differentiate venous thrombosis from arterial forms of ischemia, but ultrasonography, CT, and magnetic resonance imaging (MRI) are more commonly used to demonstrate thrombi in the superior mesenteric vein (SMV) and portal vein. If patients with suspected acute mesenteric ischemia have features suggesting mesenteric venous thrombosis, a contrast medium-enhanced CT scan is obtained before SMA angiography; a history of deep vein thrombosis or a family history of an inherited coagulation defect also suggest CT as the initial imaging study. In the few patients with no physical findings of intestinal infarction in whom a diagnosis of mesenteric venous thrombosis is made by ultrasonography, CT, or MRI, a trial of anticoagulant or thrombolytic therapy is worthwhile. All other patients should have prompt laparotomy, resection of non-viable bowel, and heparinization. The mortality of acute mesenteric venous thrombosis is lower than that of the other forms of acute mesenteric ischemia, varying from 20 to 50%. Recurrence rates of 20 to 25% fall to 13 to 15% if heparin is begun promptly. Subacute mesenteric venous thrombosis is a condition in which patients have abdominal pain for weeks to months but have no intestinal infarction. It is caused by either extension of thrombosis at a rate rapid enough to cause pain but slow enough to allow collaterals to develop before infarction occurs or by acute thrombosis of a sufficiently small portion of the venous drainage system to permit recovery from ischemic injury. Diagnosis usually is made on imaging studies done for other suspected diagnoses. Non-specific abdominal pain usually is the only symptom, and physical examination and laboratory tests are normal. In chronic mesenteric venous thrombosis, there usually are no symptoms at the time of thrombosis, and the patient may remain asymptomatic or may develop gastrointestinal bleeding. If the portal vein is involved, physical findings are those of portal hypertension, but if only the SMV is involved, there may be no abnormal findings. Laboratory studies may show hypersplenism with pancytopenia or thrombocytopenia. Treatment of chronic mesenteric venous thrombosis is aimed at controlling bleeding, which is usually from esophageal varices. No treatment is indicated for patients with asymptomatic chronic mesenteric venous thrombosis. The natural history of chronic mesenteric venous thrombosis is not known, but from postmortem studies it appears that almost 50% of patients do not have bowel infarction and most are without symptoms. Focal Segmental Ischemia of the Small Bowel Vascular insults to short segments of small bowel produce a broad spectrum of clinical features without the life-threatening complications associated with more extensive ischemia. Focal segmental ischemia usually is caused by atheromatous emboli, strangulated hernias, vasculitis, blunt abdominal trauma, radiation, or oral contraceptives. With focal segmental ischemia there usually is adequate collateral circulation to prevent transmural infarction, and patients present with one of three clinical patterns: (1) acute enteritis often simulating appendicitis (see Chapter 136) , (2) chronic enteritis resembling Crohn's disease (see Chapter 135) , and (3) intestinal obstruction often with bacterial overgrowth and a "blind loop" syndrome. Treatment is resection of the involved bowel. Colon Ischemia Colon ischemia is the most common ischemic injury to the gastrointestinal tract. A spectrum of colon ischemic injury is recognized, including reversible colopathy (submucosal or intramural hemorrhage) (at least 30 to 40%); transient colitis (at least 15-20%); chronic ulcerating colitis (20-25%); stricture (10-15%); gangrene (15-20%); and fulminant universal colitis (2 cm) Post-gastrectomy stumps Gastric epithelial dysplasia Menetrier's disease (hypertrophic gastropathy) Chronic peptic ulcer

739

atrophic gastritis, occurring naturally or due to predisposing factors such as pernicious anemia or H. pylori, leads to achlorhydria, which in turn favors the growth of bacteria capable of converting nitrates to nitrites. The nitrosamine MNNG ( N-methyl- N -nitro- N-nitrosoguanidine) causes a high rate of induction of adenocarcinoma in the glandular stomach of rats. Genetic Recent advances in molecular genetics have uncovered a large number of structurally altered genes in clonal human tumors that are presumed to play important roles in carcinogenesis. It has been very difficult from the study of human gastric tumors alone to determine the true order of events and, in particular, to demonstrate a causal function for each genetic alteration at a specific stage of tumor development. Nonetheless, it is clear that genetic factors do play a role. For example, blood group A is associated with a higher incidence rate of gastric cancer, even in nonendemic areas. There is a threefold increase in gastric cancer among first-degree relatives of gastric cancer patients. Furthermore, germline or inherited mutations in the E-cadherin gene have been described in familial gastric cancer. In addition, in hereditary nonpolyposis colorectal cancer (HNPCC) type II, there are associated extracolonic cancers, including gastric cancer. Predisposing Conditions Atrophic gastritis with or without intestinal metaplasia is seen in association with gastric cancer (see Table 138-1) , especially in endemic areas. Pernicious anemia is associated with a several-fold increase in gastric cancer. Atrophic gastritis and gastric cancer share a number of common environmental risk factors. It is likely that atrophic gastritis and intestinal metaplasia represent intermediary steps to gastric cancer. At the same time, most patients with atrophic gastritis do not develop gastric cancer, suggesting that neither atrophic gastritis nor achlorhydria alone is responsible.

Benign gastric ulcers do not appear to predispose patients to gastric cancer. However, patients who have a gastric remnant after subtotal gastrectomy for benign disorders have a 1.5 to 3.0 relative risk of gastric cancer by 15 to 20 years after surgery. Incidence and Prevalence Whereas gastric cancer was the most common cancer in the United States in the 1930s, its annual incidence rate has steadily decreased; the annual incidence is now fewer than 20,000 new cases per year. The age-adjusted mortality rate for males and females decreased by 25% from 1973 to 1985. Typically, gastric cancer occurs between ages 50 to 70 years and is uncommon before age 30 years. The rates are higher in males than females by 2 to 1. Five-year survival is less than 20%. Pathology and Pathogenesis Gastric adenocarcinomas can be divided into two types: intestinal and diffuse. The intestinal type is typically in the distal stomach with ulcerations, is often preceded by premalignant lesions, and is declining in incidence in the United States. In contrast, the diffuse type involves widespread thickening of the stomach, especially in the cardia, and often affects younger patients; this form may present as "linitis plastica," a nondistensible stomach with absence of folds and narrowed lumen due to infiltration of the stomach wall with tumor. The prognosis is generally worse in the diffuse type. The classification of gastric cancer into these two types is helpful in considering the causes of gastric cancer. Key histopathologic features of gastric cancer include degree of differentiation, invasion through the gastric wall, lymph node involvement, and presence or absence of signet-ring cells within the tumor itself. Other pathologic manifestations include a polypoid mass, which may be difficult to distinguish from a benign polyp. Early gastric cancer, a condition that is not uncommon in Japan and that has a relatively favorable prognosis, consists of superficial lesions with or without lymph node involvement. A number of potential mechanisms have been postulated to explain how H. pylori predisposes to gastric cancer. The leading hypothesis is that the increased cancer risk is due to the induction of an inflammatory response, which itself is genotoxic. Chronic inflammatory states have been associated with a number of gastrointestinal malignancies, such as ulcerative colitis with colon cancer, Barrett's esophagus with adenocarcinoma, and chronic hepatitis/cirrhosis with liver cancer. It is also possible that chronic H. pylori infection leads to chronic atrophic gastritis with resulting achlorhydria, which in turn favors bacterial growth that can convert nitrates (dietary components) to nitrites. These nitrites, in combination with genetic factors, promote abnormal cellular proliferation, genetic mutations, and eventually cancer. It now appears several genetic mechanisms are important in gastric cancer: oncogene activation, tumor suppressor gene inactivation, and DNA microsatellite instability. For example, loss of heterozygosity of the APC (adenomatous polyposis coli) gene has been observed in gastric cancers. The p53 tumor suppressor gene product regulates the cell cycle at the G1/S phase transition and likely also functions in DNA repair and apoptosis (programmed cell death). The p53 gene is mutated not only in gastric cancer but also in gastric precancerous lesions, suggesting that mutation of the p53 gene is an early event in gastric carcinogenesis. Microsatellite DNA alterations or instability in dinucleotide repeats that were originally identified in HNPCC also occur frequently in sporadic gastric carcinoma. Mutations in oncogenes and tumor suppressor genes may accumulate as a result of DNA microsatellite instability. Clinical Manifestations (Table 138-2) In its early stages, gastric carcinoma may often be asymptomatic or have only nonspecific symptoms, thereby making early diagnosis difficult. Later symptoms include bloating, dysphagia, epigastric pain, or early satiety. Early satiety or vomiting may suggest partial gastric outlet obstruction, although gastric dysmotility may contribute to the vomiting in nonobstructive cases. Epigastric pain, reminiscent of peptic ulcer, occurs in about one fourth of patients; but in the majority of patients with gastric cancer, the pain is not relieved by food or antacids. Pain that radiates to the back may indicate that the tumor has penetrated into the pancreas. When dysphagia is associated with gastric cancer, this symptom suggests a more proximal gastric tumor at the gastroesophageal junction or in the fundus. Signs of gastric cancer include bleeding, which can result in anemia that produces the symptoms of weakness, fatigue, and malaise as well as more serious cardiovascular and cerebral consequences. Perforation due to gastric cancer is unusual. Metastatic gastric cancer to the liver can lead to right upper quadrant pain, jaundice, and/or fever. Lung metastases can cause cough, hiccups, and hemoptysis. Peritoneal carcinomatosis can lead to malignant ascites unresponsive to diuretics. In the earliest stages of gastric cancer, the physical examination may be unremarkable. At later stages, patients become cachectic, and an epigastric mass may be palpated. If the tumor has metastasized to the liver, then hepatomegaly with jaundice and ascites may TABLE 138-2 -- TNM STAGING OF GASTRIC CANCER TUMOR T1: Tumor confined to the mucosa or submucosa T2: Tumor extending into the muscularis propria T3: Tumor extending through the serosa without involving contiguous structures T4: Tumor extending through the serosa and involving contiguous structures NODES N0: No lymph node metastases N1: Regional lymph node involvement within 3 cm of the tumor along the greater or lesser curvature N2: Regional lymph node involvement more than 3 cm from the primary tumor N3: Involvement of other intra-abdominal lymph nodes not removable at surgery METASTASES M0: No distant metastases M1: Distant metastases

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be present. Portal or splenic vein invasion can cause splenomegaly. Lymph node involvement in the left supraclavicular area is termed Virchow's node, and periumbilical nodal involvement is called Sister Mary Joseph's node. The fecal occult blood test may be positive. Paraneoplastic syndromes may precede or occur concurrently with gastric cancer. Examples include Trousseau's syndrome (see Chapter 197) , which is recurrent migratory superficial thrombophlebitis indicating a possible hypercoagulable state; acanthosis nigricans, which presents in flexor areas with skin lesions that are raised and hyperpigmented; neuromyopathy with involvement of the sensory and motor pathways; and central nervous system involvement with altered mental status and ataxia. Laboratory studies may reveal iron deficiency anemia. Predisposing pernicious anemia can progress to megaloblastic anemia. Microangiopathic hemolytic anemia has been reported. Abnormalities in liver function tests generally indicate metastatic disease. Hypoalbuminemia is a marker of malnourishment. Protein-losing enteropathy is rare but can be seen in Menetrier's disease (see Chapter 125) , another predisposing condition. Serologic test results, such as those of carcinoembryonic antigen and CA 72.4, may be abnormal. Although these tests are not recommended for original diagnosis, they may be useful for monitoring disease after surgical resection. Diagnosis On upper gastrointestinal barium contrast studies, a benign gastric ulcer is suggested by a smooth, regular base. In contrast, a malignant ulcer is manifested by a surrounding mass, irregular folds, and an irregular base. The location of the ulcer does not necessarily help to predict benign versus malignant disease because there is about equal frequency of malignancy on the greater and lesser curvatures. It is important for the radiologist to assess for rigidity, poor distensibility, ragged contour, and lack of peristalsis that suggest an ulcer is malignant. Extensive infiltration of the stomach wall may result in linitis plastica. For modern diagnosis, an upper endoscopy with biopsy and cytology is mandatory whenever a gastric ulcer is found on the radiologic study, even if the ulcer has benign characteristics.

The diagnostic accuracy of upper endoscopy with biopsy and cytology is far greater than upper gastrointestinal series, approaching 95 to 99% for both types of gastric cancer. Cancers may present as small mucosal ulcerations, a polyp, or a mass (Color Plate 3 C). Staging of gastric cancer, and at times diagnosis, has been greatly enhanced by the advent of endoscopic ultrasound. The extent of tumor, including wall invasion and local lymph node involvement, can be assessed by endoscopic ultrasonography (Fig. 138-1) , which provides complementary information to computed tomographic (CT) scans. Endoscopic ultrasonography can help guide aspiration biopsies of lymph nodes to determine their malignant features, if any. CT scans of the chest and abdomen should be performed to document lymphadenopathy and extragastric organ (especially lung and liver) involvement. In some centers, staging of gastric cancer will entail bone scans because of the proclivity of gastric cancer to metastasize to bone. Treatment The only chance for cure of gastric cancer remains surgical resection, assuming no evidence of distant metastatic disease. Complete resection is possible in only 25 to 30% of cases, however. If the tumor is confined to the distal stomach, subtotal gastrectomy is performed with resection of lymph nodes in the porta hepatis and in the pancreatic head. In contrast, tumors of the proximal stomach merit total gastrectomy to obtain an adequate margin and to remove lymph nodes; distal pancreatectomy and splenectomy are usually also performed as part of this procedure, which carries with it higher mortality and morbidity rates. Limited gastric resection is necessary for patients with excessive bleeding or obstruction. If cancer recurs in the gastric remnant, then limited resection may again be necessary for palliation. Most recurrences in both types of gastric cancer are in the local or regional area of the original tumor. Gastric cancer is one of the few gastrointestinal cancers that is somewhat responsive to chemotherapy. Single-agent treatment with

Figure 138-1 Endoscopic ultrasound depicting a large gastric mass that is compressing the liver and gallbladder wall (A) and, on a different view, the left lobe of the liver (B).

5-fluorouracil, doxorubicin, mitomycin-C, or cisplatin provides partial response rates of 20 to 30%. When used in combination, certain chemotherapeutic regimens, such as doxorubicin and mitomycin-C, doxorubicin and cisplatin, or doxorubicin and high-dose methotrexate, yield partial response rates of 35 to 50%. However, it is not clear if combination chemotherapy translates into prolonged survival. Postoperative adjuvant chemotherapy after curative intent does not currently offer any survival advantage. Radiation therapy is ineffective and generally employed only for palliative purposes in the setting of bleeding, obstruction, or pain. The combination of chemotherapy with radiation therapy or intraoperative radiation therapy has yet to be supported by prospective clinical trials. Gene therapy or immune-based therapy are currently only investigational in animal models. Implicit in the management of the patient with gastric cancer is meticulous attention to nutrition (jejunal enteral feedings or total parenteral nutrition), correction of metabolic abnormalities that arise from vomiting or diarrhea, and treatment of infection from aspiration or spontaneous bacterial peritonitis. To maintain lumen patency, endoscopic laser treatment or prosthesis placement can be utilized in a palliative fashion. Prognosis Approximately one third of patients who undergo a curative resection are alive after 5 years. In the aggregate, the overall 5-year survival rate of gastric cancer is less than 10%. Prognostic factors 741

include anatomic location and nodal status (see Table 138-2) ; distal gastric cancers without lymph node involvement carry a better prognosis compared with proximal gastric cancers with or without lymph node involvement. Other prognostic factors include depth of penetration and tumor cell DNA aneuploidy. Linitis plastica and infiltrating lesions carry a much worse prognosis than polypoid disease or exophytic masses. In the subset of mostly Japanese patients with the entity of early gastric cancer that is confined to the mucosa and submucosa, surgical resection may be curative and definitely improves the 5-year survival rate to more than 50%. In fact, when early gastric cancer is confined only to the mucosa, studies are investigating the adequacy of endoscopic resection.

LYMPHOMA OF THE STOMACH Gastric lymphoma represents about 5% of all malignant gastric tumors and is increasing in incidence. The majority of gastric lymphomas are non-Hodgkin's lymphomas, and the stomach is the most common extranodal site for non-Hodgkin's lymphomas. Patients with gastric lymphoma are generally younger than those with gastric adenocarcinoma but retain the male predominance. Patients commonly present with symptoms and signs similar to those of gastric adenocarcinoma. Lymphoma in the stomach can be a primary tumor or can be due to disseminated lymphoma. B-cell lymphomas of the stomach are most commonly large cell with a high-grade type. Low-grade variants are noted in the setting of chronic gastritis and are termed mucosa-associated lymphoid tissue (MALT). MALT lesions are strongly associated with H. pylori infection. Radiographically, gastric lymphoma usually presents as ulcers or as exophytic masses; a diffusely infiltrating lymphoma is more suggestive of secondary lymphoma. Thus, upper gastrointestinal barium studies usually show multiple nodules and ulcers for a primary gastric lymphoma and typically have the appearance of linitis plastica with secondary lymphoma. As with gastric adenocarcinoma, however, upper endoscopy with biopsy and cytology are required for diagnosis and have an accuracy of nearly 90%. Apart from conventional histopathologic analysis, immunoperoxidase staining for lymphocyte markers is helpful in diagnosis. As for gastric adenocarcinoma, proper staging of gastric lymphoma involves endoscopic ultrasonography, chest and abdominal CT scans, and bone marrow biopsy as needed. Treatment of large cell gastric lymphoma is best pursued with subtotal gastrectomy followed by combination chemotherapy (see Chapter 179) , especially where there is lymph node involvement. In this context, 5-year survival rates of 40 to 60% have been reported. Trials of chemotherapy alone or radiation therapy alone are in progress. Prognosis is better if the lymphoma contains small lesions limited to the stomach, is well-differentiated, does not have lymph node involvement, and is associated with only superficial penetration of the gastric wall. In contrast, HIV-associated gastric lymphoma and disseminated gastric lymphoma carry a poor prognosis. For MALT lesions, early data suggest that eradication of H. pylori infection with antibiotics induces regression of the tumor, but longer-term follow-up will be needed to be confident that such therapy is sufficient. The efficacy of combined chemotherapy and radiation therapy is not yet established for MALT lesions.

OTHER MALIGNANT TUMORS OF THE STOMACH Leiomyosarcomas, which constitute about 1% of all gastric cancers, usually present as an intramural mass with central ulceration. Symptoms may include bleeding accompanied by a palpable mass. Leiomyosarcomas are often relatively indolent; surgical resection yields a 5-year survival rate of about 50%. Metastasis can occur to lymph nodes and the liver. Other gastric sarcomas include liposarcomas, fibrosarcomas, myosarcomas, and neurogenic sarcomas. Recently, some gastrointestinal stromal tumors have been associated with activating mutations in the c-kit gene. Carcinoid tumors may begin in the stomach and are curable by removal if they have not yet spread to the liver. Primary tumors can also spread to the stomach. In addition to lymphomas, other tumors found in the stomach include primary lung and breast cancers as well as malignant melanoma.

LEIOMYOMAS AND BENIGN TUMORS Leiomyomas, which are smooth-muscle tumors of benign origin, occur with equal frequency among men and women and are typically located in the middle and distal stomach. Leiomyomas can grow into the lumen with secondary ulceration and resulting bleeding. Alternatively, they can expand to the serosa with extrinsic compression. On upper gastrointestinal series, leiomyomas are usually smooth with an intramural filling defect, with or without central ulceration. Endoscopy may reveal a mass that has overlying mucosa or mucosa replaced by ulceration. However, benign leiomyomas can be difficult to distinguish from their malignant counterparts radiographically or endoscopically; tissue diagnosis is imperative. Symptomatic leiomyomas should be removed, but those without associated symptoms do not require therapy. Other benign gastric tumors include lipoma, neurofibroma, lymphangioma, ganglioneuroma, and hamartoma, the latter associated with Peutz-Jeghers syndrome or

juvenile polyposis (restricted to the stomach).

ADENOMAS Gastric adenomas and hyperplastic polyps are unusual but may be found in middle-aged and elderly patients. Polyps may be sessile or pedunculated and are also found in nearly 50% of patients with familial adenomatosis polyposis or Gardner's syndrome. Gastric adenocarcinoma arising in the antrum has been described in such patients. Although isolated gastric adenomatous polyps are generally asymptomatic, some patients may have dyspepsia, nausea, or bleeding. Gastric adenomas and hyperplastic polyps are smooth and regular on upper gastrointestinal series, but the diagnosis must be confirmed by upper endoscopy with biopsy. Pedunculated polyps that are >2 cm or that have associated symptoms should be removed by endoscopic snare cautery polypectomy, whereas large sessile gastric adenomatous polyps may merit segmental surgical resection. If polyps progress to an intermediary stage of severe dysplasia or culminate in cancer, the treatment is the same as for gastric adenocarcinoma. Agboola O: Adjuvant treatment in gastric cancer. Cancer Treat Rev 20:217, 1994. This article provides an overview on different therapeutic modalities for gastric cancer. Fuchs C, Mayer R: Gastric carcinoma. N Engl J Med 333:32, 1995. An excellent comprehensive overview of gastric cancer. Muir CS, Harvey JC: Cancer of the stomach. GI Cancer 1:213, 1996. This review concentrates on epidemiologic features of gastric cancer. Rustgi AK: GI cancers: Biology, diagnosis, and therapy. Philadelphia, Lippincott-Raven, 1995. The section on gastric cancer encompasses individual chapters on clinical manifestations, pathology, biology, surgery, and chemotherapy/radiation therapy.

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Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 139 - NEOPLASMS OF THE LARGE AND SMALL INTESTINES Bernard Levin

NEOPLASMS OF THE LARGE INTESTINE Cancer of the large bowel (colon and rectum) is the most common malignancy of the gastrointestinal tract, and together with breast and lung cancer it is one of the three most frequent malignancies in the United States. With more than 570,000 new cases each year, it is also a worldwide health problem of great importance, particularly in Western countries. Approximately 131,000 cases of cancer of the colon and rectum were diagnosed in the United States in 1998; only half of patients survive 5 years or longer. During the period 1973 to 1989, colorectal cancer mortality in the United States decreased by 20% in white women and by 8.5% in white men; in contrast, mortality increased in black men by 22.5% and by 2.6% in black women. The reasons for this 742

disparity are not clear, although it may be attributable in part to late diagnosis and less access to appropriate medical care. Incidence trends also show substantial increases for black men and women but substantially lower incidence rates for white men and women. New insight into the genetics and molecular biology of this neoplasm has been gained since the late 1980s; advances have also been made in methods of prevention, diagnosis, and treatment. The large bowel also may be involved by other malignant tumors. These include anal carcinoma (squamous or transitional cell types), lymphoma, leiomyosarcoma, malignant carcinoid tumor, and Kaposi's sarcoma. The large bowel may also be involved through direct invasion by malignancies from adjacent sites, such as prostate, ovary, uterus, and stomach. The most frequent tumors that occur in the large intestine are benign polyps. Except for lipomas of the ileocecal valve, other benign tumors are very unusual. Polyps of the Colon A polyp is any lesion that arises from the surface of the gastrointestinal tract and protrudes into the lumen. Polyps in the large intestine, whether noted at sigmoidoscopy, colonoscopy, or during barium enema, may be single or multiple, pedunculated or sessile, and sporadic or part of an inherited syndrome. Polyps become clinically significant because of bleeding or because of their potential for malignant transformation. PATHOLOGY.

In addition to adenocarcinoma, which may present as a polypoid mass, three distinct types of benign polyps arise from colonic epithelium: hyperplastic (metaplastic), inflammatory, and neoplastic (adenomatous). Hyperplastic polyps, which tend to be small and asymptomatic, account for about one-fifth of all polyps in the colon and for most of the polyps in the rectum and distal sigmoid colon. They are not considered neoplastic. Inflammatory polyps occur in chronic ulcerative colitis and also are not neoplastic (see Chapter 135) . Juvenile polyps, which are hamartomas of the lamina propria, may be single or multiple and occur most commonly in the rectum. They are susceptible to hemorrhage and autoamputation. Adenomatous Polyps

PREVALENCE AND DISTRIBUTION.

The incidence of colonic adenomas increases with age in countries with a high or intermediate risk for colorectal cancer, occurring in 30% to 40% of individuals older than 60 years in the United States. Adenomas are uncommon in areas where the incidence of cancer is low; for example, the prevalence of adenomas varies from almost zero among black South Africans to 10% in Japan and Colombia. The low incidence of cancer in some countries, such as Japan, is probably related to the small number of large adenomas as well as to the total number of adenomas. The presence of adenomas does not necessarily convey a high risk because the propensity for neoplastic transformation is related to size and histologic characteristics (dysplasia). MACROSCOPIC AND MICROSCOPIC APPEARANCE.

Adenomas may be separated into tubular, villous, and intermediate tubulovillous types. The typical tubular adenoma is small and spherical and has a stalk. Its surface is roughly separated into lobules by intercommunicating clefts. In contrast, the villous adenoma may be large and sessile with a velvety surface. Histologically the tubular adenoma consists of closely packed tubular glands that divide and branch. In the villous adenoma, finger-like projections of neoplastic epithelium project toward the bowel lumen. The tubulovillous lesions consist of a mixture of tubular and villous patterns. About 60% of adenomas are tubular, 20 to 30% are tubulovillous, and about 10% are villous. All adenomas are dysplastic, and dysplasia in adenomas may be graded into mild, moderate, and severe. This classification is based on the presence of cytologic (mainly nuclear) abnormalities and glandular architectural changes. DEVELOPMENT.

In the normal adult, the epithelial tissue of the colon actively renews itself with a turnover period of about 3 to 8 days. DNA synthesis occurs primarily in cells in the lower one-third of crypts. Normally cells replicate and migrate up the crypt, subsequently to be exfoliated from the mucosal surface. In adenomas, immature cells are found higher up the colonic crypt than normal and are associated with unrepressed DNA synthesis, which represents abnormal cell renewal along the surface of the crypt and the entire length of the crypt. DNA-synthesizing cells can accumulate on the luminal surface, thus forming new adenomatous tissue. RELATIONSHIP OF COLONIC ADENOMAS TO CANCER.

Colonic adenomas appear to have malignant potential: (1) the epidemiology of adenomas and carcinoma is similar; (2) adenocarcinomas and adenomas occur in the same anatomic distribution in the colon; (3) residual adenomatous tissue is observed quite commonly in small cancers; (4) the incidence of cancer increases as the size of the adenoma increases; (5) the adenoma-to-cancer transition has been observed in familial polyposis, hereditary nonpolyposis colorectal carcinoma, and in experimental animals treated with a carcinogen; (6) the risk for colorectal cancer is higher in patients with a history of adenomas and is significantly lessened if the adenoma is removed; (7) a period of approximately 5 years elapses between the diagnosis of adenoma and the development of carcinoma. Fewer than 5% of adenomas develop into carcinomas. Several important factors in this transformation can be identified, especially size, histologic type, and epithelial dysplasia. The frequency of cancer in adenomas under 1 cm is 1 to 3%; in those between 1 to 2 cm, 10%; and in those over 2 cm, more than 40%. The highest malignancy rate is associated with a villous growth pattern. Invasive neoplasm has been found in 40% of the villous tumors, in fewer than 5% of the tubular adenomas, and in 23% of the tubulovillous variety. The malignant potential of adenomas also increases with increasing degrees of dysplasia. Most adenomas smaller than 1 cm show only mild dysplasia and have a low malignant potential. With severe dysplasia, the rate of malignant transformation rises to 27%. Cancer in adenomas is usually well differentiated and occurs most commonly in the tip of a pedunculated adenoma without invasion of the muscularis mucosae. These lesions are usually satisfactorily treated by polypectomy. Occasionally cancers in adenomas invade the muscularis mucosae, grow down the stalk, invade lymphatic vessels and adjacent lymph nodes, and metastasize. The roles of autocrine factors, tumor suppressor genes, and oncogenes in the development of adenomas and

their malignant transformation are currently under study. CLINICAL MANIFESTATIONS.

Most adenomatous polyps are asymptomatic, but they may cause hematochezia. Some adenomatous polyps are diagnosed after the detection of occult blood loss in asymptomatic individuals who are screened for colon cancer. Adenomas may also be detected by fiberoptic sigmoidoscopy or colonoscopy or by double-contrast barium enema examination. MANAGEMENT AND FOLLOW-UP.

Because of the association of adenomas with the development of adenocarcinomas, colonic polyps should usually be removed or destroyed. In individual clinical circumstances (e.g., age of patient, location of lesion) this rule may rarely have to be modified. Pedunculated polyps, even if large, can be removed by electrocautery snare, whereas small sessile polyps (1 to 8 mm) should be biopsied and destroyed with the "hot biopsy" forceps. For sessile polyps with a wide-based attachment to the colonic wall, several electrocautery sessions may be required for complete excision. Endoscopic removal may not be safe or possible if a lesion is in a relatively inaccessible location. The endoscopic appearances that suggest carcinomatous invasion include ulceration, an irregular surface contour, firm consistency, and friability. If a diagnosis of malignancy is made after polypectomy, a decision has to be made about the adequacy of the polypectomy. In the presence of poorly differentiated histologic features, penetration of the muscularis mucosa, vascular or lymphatic invasion, or a resection margin containing cancer, the risk of regional lymph node involvement is approximately 5%. The mortality from surgical resection is less than 2% in patients aged 50 to 69 years and 4.4% for those older than 70 years, so any decision to recommend surgical resection must take into account individual operative risk. FOLLOW-UP AFTER COLONOSCOPIC POLYPECTOMY.

Ideally, all adenomas should be removed from the colon at the time of the initial colonoscopy. A follow-up colonoscopy is appropriate at 3 years to evaluate for the presence of any lesions missed at the previous procedure or to discover new lesions. If the colon is free of polyps at this examination, an interval of 3 years is appropriate before the next colonoscopy. Chemopreventive strategies aimed at preventing adenoma recurrence are being studied, including diet, nonsteroidal anti-inflammatory drugs (NSAIDs), supplemental calcium, folic acid, and ursodeoxycholic acid.

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Inherited Polyposis Syndromes

Recent advances in genetics and molecular biology have accentuated our interest in the inherited risk of colorectal cancer. The polyposis syndromes account for approximately 1% of colorectal cancer, whereas the nonpolyposis inherited conditions may be responsible for up to 6%. ADENOMATOUS POLYPOSIS SYNDROMES.

The adenomatous polyposis syndromes include familial adenomatous polyposis and Gardner's syndrome; in both hereditary disorders, hundreds to thousands of colonic adenomas are present (Color Plate 3 A). The adenomas begin to appear early in the second decade of life. Gastrointestinal symptoms occur in the third or fourth decade. Almost all patients with familial polyposis develop carcinoma of the colon by age 40 years if the colon has not been removed. Some cases occur without a family history and may represent spontaneous mutations. Gardner's syndrome differs from familial adenomatous polyposis in that affected individuals exhibit benign extraintestinal growth, including osteomas (especially mandibular) and soft tissue tumors (lipomas, sebaceous cysts, fibrosarcomas). Other associated features include supernumerary teeth, desmoid tumors, and mesenteric fibromatosis (Figs. 139-1 and 139-2) . The colonic adenomas are similar to those of familial adenomatous polyposis and have the same potential for malignancy. In both familial adenomatous polyposis and Gardner's syndrome, upper gastrointestinal polyps are commonly found. Multiple gastric "fundic gland polyps" are found in 50 to 100% of affected individuals. Adenomatous duodenal polyps are present in up to 80% of individuals with familial adenomatous polyposis or Gardner's syndrome, and periampullary cancer develops in approximately 10%. Adenomas occur in the small bowel distal to the duodenum but rarely undergo malignant transformation. Familial adenomatous polyposis and Gardner syndrome are inherited as autosomal dominant disorders with incomplete penetrance. The mutant gene for both conditions is on the long arm of chromosome 5. Different mutations at that locus may account for the phenotypic differences between the syndromes. The APC (adenomatous polyposis coli) gene mutations lead to the formation of a truncated protein. Gene abnormalities can be detected by a blood test in 87% of affected individuals, thereby enabling screening within affected families to be much more accurate. Genetic counseling should always precede and accompany genetic testing. SCREENING RECOMMENDATIONS.

Flexible proctosigmoidoscopy should be performed annually in all first-degree relatives, from age 12 years until age 40 years, and every 3 years thereafter. Screening is appropriate for those with the mutant gene. Because gene markers are not yet 100% specific and sensitive, screening is also indicated for those without the mutant gene, although considerably less often. Surveillance with a side-viewing endoscope for gastric and duodenal polyps should begin when the diagnosis of colonic polyposis is made and should continue every 2 to 3 years thereafter, and possibly yearly if prominent lesions are apparent in the duodenum. MANAGEMENT.

Surgery is the primary management option in FAP. Total proctocolectomy with conventional ileostomy or ileal pouch-anal anastomosis is more often used as opposed to the older procedure of subtotal colectomy with ileo-rectal anastomosis. Pharmacologic interventions such as the use of cyclooxygenase-2 inhibitors are under study. Hereditary Nonpolyposis Colorectal Cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by germline mutations in DNA nucleotide mismatch repair genes (hMLH, hMSH2, PMS, PMS2, and GTBP) located on chromosome 2, 3, or 7, and is inherited in a highly penetrant autosomal dominant fashion. HNPCC has been classically defined as colorectal cancer in three or more family members, two of whom are first-degree relatives of the third, and involving people in at least two generations, with at least one person diagnosed with colorectal cancer before age 50 years. This definition may be too restrictive, and other variants of this classic pedigree exist. Several adenomas may be present despite the name of the syndrome, but diffuse adenomatosis is not found. The average age at diagnosis of cancer is the mid-40s, and it is characteristic to find multiple synchronous cancers with a majority of lesions proximal to the splenic flexure. Individuals with genetic mutations that can lead to HNPCC are also at high risk for cancers of the ovary, uterus, ureter, pancreas, and stomach. Genetic tests are now available to detect the major mutations that lead to HNPCC, and these should be considered after appropriate counseling for individuals with a suggestive family history. Individuals in families with HNPCC who have a positive genetic test or in whom genetic testing has not been performed, should undergo colonoscopy every

Figure 139-1 Schematic representation of the intestinal and extraintestinal manifestations of familial adenomatous polyposis (FAP) and Gardner's syndrome. The primary features of Gardner's syndrome consist of a triad of colonic polyposis, bone tumors (particularly in the skull and mandible), and soft tissue tumors, but the phenotypic overlap between FAP and Gardner's syndrome is considerable. (From Itzkowitz SH, Kim YS: In Feldman M, Scharschmidt BF, Sleisenger MH [eds]: Sleisinger and Fordtran's Gastrointestinal and Liver Disease, 6th ed. Philadelphia, WB Saunders, 1998, p 1844.)

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Figure 139-2 Schematic representation of Peutz-Jeghers syndrome. Mucocutaneous pigmentation and benign gastrointestinal polyposis are the primary features of the syndrome. (From Itzkowitz SH, Kim YS: In Feldman M, Scharschmidt BF, Sleisenger MH [eds]: Sleisinger and Fordtran's Gastrointestinal and Liver Disease, 6th ed. Philadelphia, WB Saunders, 1998, p 1844.)

2 years from ages 21 to 40 years, then annually thereafter. In asymptomatic women from families with HNPCC who are found by gene testing to be HNPCC gene carriers or who have not undergone genetic testing, pelvic examinations should be performed every 1 to 3 years beginning at age 18 years; at age 25 years, women should have annual pelvic examination and transvaginal ultrasonography. Endometrial biopsy may also be necessary. The Peutz-Jeghers syndrome is characterized by melanotic spots on the lips, buccal mucosa, and skin, and by multiple hamartomatous polyps throughout the gastrointestinal tract from the stomach to the rectum. It is inherited in an autosomal dominant fashion but it has a variable expressivity. Recently, the gene responsible has been localized to chromosome 19p, where mutations in a novel serine-threonine gene ( STKII) are believed to be causative. Usually polyps are fewer in number than in familial adenomatous polyposis. Microscopically, these polyps consist of elongated branching glands lined by benign epithelium native to the location of the polyps. The most distinctive feature is the presence of an arborizing proliferation of smooth muscle in the lamina propria. Rarely, intestinal malignancies have been described, with a preponderance in the small intestine. Other manifestations include ovarian sex cord stromal tumors and polyps of the gallbladder, ureter, and nose. Intestinal symptoms of recurrent, colicky abdominal pain may appear in adolescence, and intussusception may require surgical removal of a polyp. Gastrointestinal bleeding may occur, causing iron deficiency anemia. Turcot's syndrome, inherited as an autosomal recessive or dominant condition, is rare and is characterized by hereditary adenomatous polyposis with a low number of polyps (20 to 300) and tumors of the central nervous system. These neoplasms include medulloblastoma, glioblastoma, and ependymoma. Recent evidence implicates abnormalities of both the adenomatous polyposis coli (APC) gene and nucleotide mismatch repair genes in the pathogenesis of this condition. Juvenile polyposis is inherited as an autosomal dominant trait, with an occasional case occurring spontaneously. A subset of juvenile polyposis families carry germ line mutations in the gene SMAD4 (also known as DPC4) located on chromosome 18q21.1; this gene normally encodes a critical cytoplasmic mediator in the transforming growth factor-beta signaling pathway. Mutations in the PTEN gene have also been described. PTEN, which codes for a protein tyrosine phosphatase, is a tumor suppressor gene on chromosome 10q23. The number of polyps is less than in familial adenomatous polyposis, averaging 25 to 40. Polyps may be found throughout the gastrointestinal tract or may be restricted to the colon. Symptoms may begin in childhood or adolescence with rectal bleeding, anemia, abdominal pain, or intussusception. A variety of extraintestinal symptoms including congenital abnormalities, and pulmonary arteriovenous malformations have been described in association with juvenile polyposis. The hamartomas of juvenile polyposis are morphologically distinct from those found in Peutz-Jeghers syndrome. Foci of adenomatous epithelium may be present in these polyps, or adenomas may coexist. The true risk of malignancy in these patients is unknown, but carcinoma of the gastrointestinal tract has developed in 10% of reported patients with juvenile polyposis. Subtotal colectomy may occasionally be warranted in those with severely dysplastic adenomas. Cronkhite-Canada syndrome is a nonfamilial disorder of adults characterized by diffuse gastrointestinal polyposis, alopecia, dystrophy of the fingernails, and cutaneous hyperpigmentation. The polyps resemble juvenile polyps and are in greatest density in the stomach and colon. Watery diarrhea, anorexia, abdominal pain, cachexia, protein-losing enteropathy, and carcinoma of the gastrointestinal tract (in up to 14% of cases) have been reported. Cowden's syndrome (multiple hamartoma syndrome) is transmitted in an autosomal dominant manner and is characterized by multiple facial tricholemmomas, oral papillomas, keratoses of the hands and feet, and a high rate of associated systemic malignancies, particularly of thyroid and breast. The polyps are not dysplastic, and the risk of gastrointestinal malignancy is not increased. Mutations in the PTEN gene have recently been identified in Cowden's syndrome. Adenocarcinoma of the Large Bowel Carcinoma of the colon and rectum varies widely in frequency in different parts of the world. Large bowel cancers occur commonly in North America, northwestern Europe, and New Zealand, whereas in South America, southwest Asia, equatorial Africa, and India, the risk is much less. The incidence varies from 3.5 per 100,000 in India to 32.3 per 100,000 in Connecticut. Colorectal cancers display regional differences within the United States, with the highest 745

incidence in the Northeast. Rectal cancer is more common in men in most, but not all, areas of the world. In the United States, rectal cancer incidence has declined during the past 50 years. Overall mortality from colorectal cancer has also declined in the United States during the past 20 years. Migrants from parts of the world with a low incidence to regions with a higher risk, such as the United States or Canada, show a rapid increase in incidence. This change is also exemplified by the higher incidence in Puerto Ricans who have migrated to the mainland compared with those in Puerto Rico and in first- and second-generation Chinese and Japanese immigrants to Hawaii and the mainland United States compared with Japanese in Japan and Chinese in the Peoples' Republic of China. ETIOLOGY.

Both inherited predisposition and environmental factors seem to be implicated in carcinogenesis in the colon and rectum, but in ways yet to be clearly delineated. Of the environmental factors, diet has been the most extensively studied. Both the amount and type of fat intake correlate with the risk for colorectal cancer in many, but not all, studies. Consumption of saturated fat (with a high content of animal fat) has been reported to be correlated positively with colon cancer incidence. Other studies suggest that diets containing predominantly monounsaturated fats as a lipid source may exert a protective effect against the development of colorectal cancer, but other components of the diet may also play a role. In countries with a high incidence of colon cancer, the average fat content in the diet is about 40% of total calories, in contrast to the dietary fat content of 15 to 20% or less of total calories in countries with a low cancer incidence. If fat in the colon does promote cancer, the effect might be related to increased biliary sterol excretion leading to increased colonic epithelial proliferation, to modification of cell membranes, or to stimulation of the synthesis of prostaglandins that induce cellular proliferation. The possible role of dietary fiber in reducing colonic carcinogenesis has been suggested but has not been firmly established. Fiber is not a single chemical substance. Certain components of fiber found in vegetables, cereals, and fruits may be helpful in reducing the risk of cancer by diluting and binding carcinogens in the lumen, by modifying colonic bacterial flora, and by acidifying the colonic lumen because fiber is metabolized to short-chain fatty acids. Naturally occurring anticarcinogens found in fruits and vegetables (indoles, thioethers, dithiothiones, carotenoids) are being investigated. Other factors that have been postulated to play a role in colonic carcinogenesis are excess caloric intake, low physical activity level, obesity, and inadequate intake of calcium and vitamin D. Aspirin and other NSAIDs that modulate the formation of prostaglandins appear to protect against the development of colorectal neoplasms. AGE.

The risk of colorectal cancer begins to increase at the age of 50 years and rises sharply at age 60 years. With each succeeding decade the risk doubles, reaching a peak by age 75 years. ASSOCIATION WITH INFLAMMATORY BOWEL DISEASE

(see Chapter 135) . Among all patients diagnosed as having a large bowel adenocarcinoma, only about 1% give an antecedent history of inflammatory bowel disease. In chronic ulcerative colitis, carcinoma of the colon occurs more commonly (approximately 10 to 20 times) than in the general population. The duration of disease and the extent of colonic involvement correlate with the subsequent development of colon cancer. Approximately 2 to 4% of all patients with chronic ulcerative colitis develop colorectal carcinoma, with a cumulative incidence of about 12% after 25 years. Patients with ulcerative proctitis have no increase in risk, and the risk for patients with left-sided colitis may be delayed until approximately 10 years later. In ulcerative colitis, mucosal dysplasia, defined as an unequivocal neoplastic alteration of the colonic epithelium, is the recognized precursor for development of carcinoma. Dysplastic epithelium may overlie an area of malignancy associated with direct invasion into the submucosa. The dysplastic area may be flat or proliferative, and the likelihood of carcinoma increases significantly in the presence of a dysplasia-associated lesion or mass. Whether routine colonoscopic surveillance is useful in patients with long-standing inflammatory bowel disease is still under evaluation. Nevertheless, many authorities favor periodic colonoscopy with multiple biopsies to diagnose dysplasia in individuals with more than 8 years of symptoms and extensive colonic involvement. The availability of newer surgical procedures, such as ileoanal pouches, favors a trend toward earlier colectomy in high-risk individuals. The demonstration of low- or high-grade dysplasia or a dysplasia-associated lesion or mass, even in the presence of low-grade dysplasia, warrants prophylactic colectomy because the risk of an associated carcinoma may be as high as 50 or 60%. Newer epithelial biomarkers, such as flow cytometry, and oncogene and tumor suppressor gene mutations and deletions, are being studied in an attempt to define the biology of neoplastic transformation and to identify individuals at high risk before cancer develops. Patients with Crohn's colitis (see Chapter 135) are also at higher risk (approximately four to seven times that of the general population) for the development of colorectal cancer, but this risk is probably lower than in ulcerative colitis. Colonic surveillance has not been widely used, but guidelines similar to those for surveillance of patients with chronic ulcerative colitis are applicable to patients with extensive colonic involvement. HEREDITY AND COLONIC CANCER.

Inherited risk is an important consideration in formulating screening guidelines. The adenomatous polyposis syndromes and hereditary nonpolyposis colorectal cancer together account for approximately 7% of colon cancers. The remainder of colon cancers are referred to as "sporadic," but this term is a misnomer. Population studies have demonstrated a twofold or threefold increased risk of colon cancer in first-degree relatives of individuals with colon cancer. A similar risk is present in first-degree relatives of individuals with adenomatous polyps. In fact, as many as 50% or more of "sporadic" adenomas and cancers may exhibit a partially penetrant autosomal dominant inheritance. MOLECULAR GENETICS OF COLORECTAL CANCER.

The genetic events surrounding the development of colorectal cancer are now understood with ever increasing sophistication (Fig. 139-3) . The gene for familial adenomatous polyposis has been mapped to chromosome 5. Deletions of DNA sequences at the same locus are also frequently observed in adenocarcinomas from "sporadic" cases and may be the earliest change in the neoplastic process. K-ras mutations follow the chromosome 5 changes and are observed more commonly in larger adenomas and cancers. Chromosome 17 (p53 gene) and chromosome 18 (DCC gene) deletions are often present and may be important in malignant transformation. Mutations of the nucleotide mismatch repair genes have been identified in both inherited and sporadic colorectal cancers. The total accumulation of genetic changes (allelic deletions, oncogene mutations) may be more important than a particular sequence of events in the development of invasive cancer. PATHOLOGY.

The vast majority of colorectal cancers are adenocarcinomas. The tumors exhibit varying degrees of glandular differentiation and produce variable amounts of mucin. Gross morphologic features may be divided into two major groups: polypoid and annular constricting lesions. The polypoid type is most commonly found on the right side, and the annular constricting lesion is more common on the left side of the colon. Adenocarcinomas of the rectum may be sessile or polypoid. Approximately 75% of colorectal cancers occur in the descending colon, rectosigmoid, and rectum. Approximately 50% are within the reach of the 60-cm fiberoptic sigmoidoscope. The cecum and ascending colon are involved in 15% and the transverse colon in 10% (Fig. 139-4) . Carcinoma of the colon spreads by direct extension through the wall of the bowel into the pericolonic fat and mesentery, by invasion of surrounding organs, by way of the lymphatics to the regional lymph nodes, and via the portal vein to the liver. Additionally, the tumor may spread throughout the peritoneal cavity and through the blood stream to the lungs and bones. Rectal cancers may directly invade the perirectal fat, vagina, prostate, bladder, ureters, and bony pelvis and may metastasize to the lungs and liver. CLINICAL MANIFESTATIONS.

The major symptoms of colorectal cancer are rectal bleeding, pain, and change in bowel habit. The clinical presentation in an individual patient is related to the size and location of the tumor. Those on the right side are often asymptomatic, and bleeding may be occult. Tumors of the cecum and ascending colon rarely obstruct early. Changes in bowel habit, with reduction in stool caliber or progressive constipation, and hematochezia are more common with left-sided lesions. Adenocarcinomas of the colon may present with a localized perforation and with signs of peritonitis. An abdominal mass or symptoms and signs of liver metastasis may be the earliest clinical manifestations of an underlying colorectal cancer. Rectal or anal cancers may present with rectal bleeding, perineal 746

Figure 139-3 Correlation between stages of progression of colorectal carcinoma and recognized mutational events affecting specific colon cancer-associated genes. MMR = mismatch repair genes; TGFIIR = tumor growth factor-beta receptor II; IGF (RII) = insulin-like growth factor receptor II; APC = adenomatous polyposis coli tumor suppressor gene; DCC = deleted in colon cancer tumor suppressor gene; P53 = p53 tumor suppressor gene; ras = Ki-ras oncogene; COX-2 = cyclo-oxygenase 2; PLA2 = phospholipase A2; and SMAD = signaling components that control TGF-beta mediated gene transcription. JV-18-1/MADR2 are tumor suppressor genes located on chromosome 18q (as are DCC and SMAD4). (Adapted from Powell SM: Genes driving the colonoscope. Energ. Technol Gastro Endosc 7:293-311, 1997.)

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Figure 139-4 Distribution of large bowel cancer by anatomic segment according to the Third National Cancer Survey. (Data from Schottenfeld D, Fraumeni J Jr [eds]: Cancer Epidemiology and Prevention. Philadelphia, WB Saunders, 1982, p 703.)

pain, or change in bowel habit. Presenting symptoms may also include those referable to invasion of adjacent organs, including hematuria, renal insufficiency (obstructive uropathy), and vaginal fistulas. Colorectal cancer must be suspected when patients present with rectal bleeding, a change in bowel habit, decrease in stool caliber, iron deficiency anemia, or unexplained abdominal pain. Rectal bleeding may be caused by other conditions, including hemorrhoids, angiodysplasia, diverticulosis, and other benign and malignant tumors (see Chapter 123) . Beyond age 40 years, the frequency of neoplasia increases significantly. Unexplained iron deficiency in both older men and women always requires a thorough evaluation to exclude gastrointestinal cancer. METASTATIC COLON CANCER.

Metastases may be clinically apparent before or after resection of the primary colorectal cancer. Massive hepatomegaly may occur with pain due to distention of the liver capsule. Spread within the abdomen may cause small and large bowel obstruction and ascites. Pelvic spread may cause bladder dysfunction, sacral or sciatic nerve pain, and vaginal discharge or bleeding. Distant spread to lungs and bone may be silent until a very advanced stage is reached. Intestinal recurrences are uncommon and usually result from tumor implants, related to the original resection, growing from the serosa into the lumen. DIAGNOSIS.

A careful history, physical examination, and selected use of laboratory and radiologic tests facilitate the diagnosis of colorectal cancer. The history includes the patient's symptoms, prior removal of an adenoma or cancer, previous or present inflammatory bowel disease, or a family history of one of the inherited colorectal cancer syndromes. Special emphasis should be paid to first-degree relatives with a history of colorectal neoplasia. Physical examination may reveal evidence of Peutz-Jeghers or Gardner's syndrome and may provide substantiation of spread to lymph nodes, liver, or peritoneal cavity. A digital rectal examination is essential in determining the presence of a distal rectal cancer or of peritoneal or pelvic spread. A complete pelvic examination must be performed. Laboratory tests may reveal iron deficiency anemia or an abnormality of liver enzymes. In evaluating patients with symptoms or signs of colorectal cancer, colonoscopy is now the generally preferred approach; the other option is flexible sigmoidoscopy followed by double-contrast barium enema (Fig. 139-5) . In the patient with inflammatory bowel disease, a barium enema or even colonoscopy may be deferred briefly until acute inflammation has been controlled. Colonoscopy is more sensitive than double-contrast barium enema in detecting small adenomas and cancers (Color Plate 1 C) and is also valuable for evaluating patients in whom an abnormality has been detected by barium enema. In addition, the presence or absence of synchronous cancers and adenomas can be determined. Colonoscopy can be used to remove adenomas (Color Plate 2 C), to perform biopsy of suspected cancers, and to obtain brush biopsies of suspected malignancies and colonic strictures for cytologic examination. Endoscopic ultrasonography is being used with increasing frequency to help in the staging of rectal cancers. Depth of invasion can often be accurately determined. Computed tomographic (CT) scanning of the abdomen and pelvis can help define the extent of tumor involvement and may be the initial mode of diagnosis in patients with abdominal pain or symptoms that could be caused by other conditions, such as diverticulitis. A chest radiograph will help evaluate the possibility of lung metastases; CT scanning can detect possible liver metastasis, especially in patients with abnormal liver enzyme levels. MANAGEMENT.

The modern approach to management is multidisciplinary and includes not only consideration of the immediate clinical problem but also a long-term approach to the patient, including preoperative and postoperative adjuvant treatment, future plans for assessment of local recurrence or distant metastasis, and attention to family

members at increased risk. SURGERY.

The most important goal of treatment for primary malignancies of the colon and rectum is complete removal. Surgical resection of the affected segment, including omentum and lymph nodes, is performed. Laparoscopic resection is being used, although long-term follow-up data regarding its effectiveness are still being collected. Cancers of the right and left portions of the colon are treated by hemicolectomy; cancers of the sigmoid and upper rectum (above 6 cm from the anal verge) are resected anteriorly with removal of a margin of normal colon above and below the tumor. Stapling techniques have facilitated anastomoses within the pelvis. Although 3-cm proximal and distal margins have been previously emphasized, an adequate radial margin is equally important. Lesions within 5 cm of the anal verge are usually treated by a combined abdominoperineal resection and permanent colostomy. Newer approaches for small, early rectal cancers include sphincter-saving procedures using local excision followed, in some instances,

Figure 139-5 Annular constructing lesion of the rectosigmoid ("apple-core") visualized on barium enema. (Adapted from DuBrow RA: Diagnostic Imaging. U.T. M.D. Anderson Cancer Center, Houston, 1998.)

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by chemotherapy and radiation therapy to the pelvis. Preoperatively, combined radiation therapy and chemotherapy may facilitate resection, including sphincter-saving procedures. For anal cancers the standard approach is to use a combination of radiation and chemotherapy, which usually shrinks or obliterates the cancer. HIV-infected patients or those with AIDS may be more susceptible to treatment-related toxicity. Surgical resection is now usually reserved for lesions that do not respond to chemoradiation and for those that recur. Surgery may be required for palliation as well as for cure. Colonic obstruction may necessitate a palliative colostomy, although a primary resection and colostomy can often be accomplished at the same operation. A perforated carcinoma is usually managed by primary resection and colostomy with later closure of the colostomy. For selected medically fit patients with one to three hepatic metastases, surgical resection of part of the tumor-bearing liver is often possible. Careful preoperative radiologic staging and intraoperative ultrasonography of the liver facilitate these technically demanding procedures. Laser photoablation is being increasingly used to relieve colonic or rectal obstruction or to stop bleeding in patients with unresectable tumors or extensive metastatic disease. RADIATION THERAPY.

Radiation therapy plays an important role in the management of rectal cancer. Preoperative radiation therapy is often combined with fluorouracil and leucovorin in an effort to decrease local recurrence and distant spread. It may also be used to reduce tumor size and enable otherwise unresectable lesions to be resected. The postoperative administration of radiation (50 Gy) and chemotherapy is now standard therapy and has been shown to decrease local recurrence and distant metastasis. Biochemical modulation of fluorouracil by leucovorin is also being incorporated. Radiation therapy is useful in palliation of recurrent rectal cancer (pain or bleeding) or bone or brain metastases. CHEMOTHERAPY.

Patients with resected colonic cancer with lymph node spread have improved survival if treated with the combination of fluorouracil and leucovorin for 6 months. For patients with metastatic spread, the combination of fluorouracil and leucovorin increases tumor shrinkage compared with fluorouracil alone. New drugs such as topoisomerase I inhibitors (camptothecins) and oxaliplatin have therapeutic activity for palliation in patients with metastatic spread. In patients with liver metastases, hepatic arterial therapy with implantable pumps or via injection ports using floxuridine alone or in combination with other drugs, such as leucovorin, produces an enhanced tumor shrinkage in the liver. Increased duration and quality of survival have not yet been convincingly demonstrated for this costly intervention. PROGNOSIS AND FOLLOW-UP.

The 10-year survival for patients with colorectal cancer after surgical resection is approximately 50%. Several histopathologic staging systems (e.g., the Dukes or TNM system) describe the extent of the malignancy (Table 139-1) , and survival correlates well with the stage of the disease: 80 to 90% 10-year survival for cancer confined to the mucosa; 70 to 80% 10-year survival for cancer extending through all areas of the bowel wall; and 30 to 55% 10-year survival for

Stage 0

TABLE 139-1 -- AMERICAN JOINT COMMITTEE ON CANCER: CLASSIFICATION OF COLON/RECTAL CANCER Carcinoma in situ; the cancer does not extend beyond the smooth muscle that separates the mucosa from the submucosa (Tis, N0, M0)

Stage I

Cancer confined to the mucosa, submucosa, or external muscle; the cancer does not extend through the bowel wall (T1 or T2, N0, M0)

Stage II

Cancer that penetrates all layers of the bowel wall, with or without invasion of adjacent tissues (T3, N0, M0)

Stage III Cancer involving regional lymph nodes or extending into nearby tissues or organs without spread to lymph nodes (any T, N1-N3, M0; or T4, N0, M0) Stage IV Cancer that has spread to distant sites, usually the liver or lungs (any T, any N, M1) TNM = tumor/node/metastasis. cancer involving the regional lymph nodes. Cancers of the distal rectum with lymph node involvement have a poorer prognosis. Prior to surgical resection, the entire colon should be examined, preferably by colonoscopy, for the presence of synchronous adenomas. If not possible preoperatively, colonoscopy should be performed postoperatively, usually within 2 to 3 months of the surgical procedure. Colonoscopy should be repeated a year later and every 3 years thereafter because new adenomas require 3 years or more to develop into large adenomas with malignant potential. After surgical resection, patients without known systemic metastases are evaluated for adjuvant therapy. Patients with colonic cancer and lymph node involvement should receive fluorouracil and leucovorin, and those with rectal cancer and spread through the wall or with lymph node involvement should receive radiation plus chemotherapy. While receiving chemotherapy or radiation therapy, patients should be followed up very carefully according to protocol guidelines. For those not receiving any specific therapy, periodic follow-up, including interim history, physical examination, and laboratory tests (e.g., liver enzymes, hematocrit), should be performed every 3 months for the first 3 years, then every 6 months until the fifth year. Considerable controversy exists concerning the cost-effectiveness of obtaining periodic chest radiographs or CT scans of the abdomen and pelvis as part of routine follow-up care in the absence of symptoms or laboratory test abnormalities. CARCINOEMBRYONIC ANTIGEN.

Carcinoembryonic antigen (CEA) levels in the blood may rise before symptoms or other laboratory test abnormalities are evident in patients with recurrent or metastatic colonic cancer. Some authorities favor periodic CEA determinations (e.g., every 3 months) after colorectal cancer resection, but this very expensive approach is helpful only in a minority of patients. Occasionally, a rising CEA level may detect a localized, surgically resectable metastasis. Certainly, its routine use should be confined to those individuals who do not have co-morbid conditions that would preclude subsequent resections of isolated liver or lung metastases. In conjunction with conventional radiologic techniques (CT scan, MRI, or PET scans), radiolabeled monoclonal antibodies to CEA may be helpful in localizing such metastases. PREVENTION.

Many colorectal cancers are first brought to medical attention by the patient's recognition of symptoms. For improved survival, the diagnosis should ideally be made earlier, in an asymptomatic phase. A greater emphasis is now being placed on preventive measures. Primary prevention is identification of factors, either genetic or environmental, responsible for colorectal cancers. Secondary prevention refers to identification and eradication of premalignant lesions and detection and resection of

cancer while it is still curable. Although definitive evidence of effectiveness is still lacking, the following dietary guidelines have been developed to try to reduce the risk of colorectal cancer: (1) reduce fat intake to fewer than 30% of calories; (2) increase dietary fiber to 20 to 30 g/day; (3) include a variety of vegetables and fruits in the diet; (4) avoid obesity; (5) consume alcohol in moderation, if at all; and (6) avoid cigarettes and tobacco. In addition, regular physical activity may also reduce risk. Chemopreventive measures such as aspirin or NSAIDs are being studied. Implicit in the concept of secondary prevention is the need for improved techniques for screening for early cancer or premalignant adenomas. Effective screening requires the availability and application of simple and economic measures to a large number of asymptomatic individuals to identify those with these lesions. Screening for colorectal cancer can be classified as general screening of patients at average risk and screening of patients in high-risk groups. Screening recommendations for patients at high risk because of ulcerative colitis, familial polyposis, HNPCC syndromes, or a personal history of colorectal adenomas or cancer have been discussed earlier in the chapter. For persons with a personal history of Crohn's colitis or a family history of sporadic colon cancer, recommendations vary and should include periodic evaluation of the entire colon. AVERAGE-RISK PATIENTS.

Currently, testing for fecal occult blood and flexible sigmoidoscopy in asymptomatic individuals are used for detecting early colorectal cancer. Testing for occult blood using guaiac-based methods detects lesions earlier in screened subjects compared with controls, and in three randomized controlled trials in the United States, Denmark, and the United Kingdom, colorectal mortality was significantly reduced (by 15 to 33%) by annual or bi-annual testing for fecal occult blood and appropriate 749

colonoscopic follow-up. Newer immunochemical tests for human hemoglobin in the stool, currently under clinical trial, are likely to be more specific. Randomized controlled trials of flexible sigmoidoscopy have not been performed on a large scale. Case-control studies have demonstrated significant effectiveness of flexible sigmoidoscopy in reducing mortality (by 70%) from distal colorectal cancer. Flexible sigmoidoscopy can identify and eradicate premalignant and malignant lesions in the area examined and also can identify individuals who may have more proximal synchronous adenomas and carcinomas. Current guidelines include a number of options. One is to test for fecal occult blood annually after age 50 years; patients with abnormal findings require careful diagnostic evaluation, including colonoscopy. The American Cancer Society's recommendations include several alternatives. One is to test for fecal occult blood annually combined with flexible sigmoidoscopy every 5 years, both beginning at age 50 years. Patients with abnormal findings, e.g., positive fecal occult blood test or distal adenomas, should be referred for colonoscopic evaluation. Alternative screening approaches beginning at age 50 years include colonoscopy every 10 years or double contrast barium enema every 5 to 10 years.

NEOPLASMS OF THE SMALL BOWEL Benign and malignant tumors of the lining epithelium and mesenchymal tissues may arise in the small intestine, or these areas may be secondarily involved by direct invasion from surrounding structures or by metastases. The small bowel represents almost 90% of the mucosal surface of the gut, but small intestinal cancers account for only 1 to 2% of all gastrointestinal neoplasms. Only about 2000 cases occur in the United States each year. RISK FACTORS. Patients with regional enteritis, especially those who have had segments of intestine surgically bypassed, have an increased incidence of small bowel carcinoma. Individuals with Gardner's syndrome have an increased risk of periampullary adenocarcinoma. In patients with Peutz-Jeghers syndrome, the relative risk of small intestinal adenocarcinoma is 16 times that expected, with a lifetime incidence of 2%. Patients with celiac disease of long duration have an increased incidence of intestinal lymphoma, as do patients with AIDS and other immunodeficiency states. Mediterranean abdominal lymphoma (immunoproliferative small intestinal disease) has been widely reported among Arabs and Jews of Middle Eastern origin and also occurs sporadically throughout the world, including in blacks in southern Africa. Why small bowel neoplasms, especially adenocarcinomas, are so uncommon compared with large bowel cancers is uncertain. It is possible that the rapid transit time with a resultant decreased exposure time to carcinogens, lower numbers of bacteria, and dilution of potential carcinogens by the large volume of enteric liquids may contribute. PATHOLOGY. BENIGN.

These lesions include adenomas, leiomyomas, lipomas, and angiomas. Brunner's gland adenomas are not neoplastic but represent hyperplasia or hypertrophy of submucosal duodenal glands; these lesions appear as small nodules in the duodenal mucosa detected at endoscopy or on barium radiographs. MALIGNANT.

Adenocarcinomas, carcinoids, lymphomas, and leiomyosarcomas account for more than 90% of malignant small bowel tumors. Adenocarcinomas are most common in the proximal small intestine, whereas lymphomas and carcinoids are most common in the distal small intestine. CLINICAL MANIFESTATIONS. More than half of all benign bowel tumors remain asymptomatic and may be discovered only incidentally at laparotomy or autopsy. Lack of symptoms is attributable to the liquid contents of the small intestine and distensibility of the small intestine. Large tumors may lead to partial or complete mechanical obstruction from intussusception or volvulus. Adenocarcinomas account for about half of the malignant tumors of the small intestine, with a peak incidence in the sixth and seventh decades. The duodenum is the most frequently affected site. When postbulbar in location, adenocarcinoma may simulate peptic ulcer disease; when in the periampullary region, it may cause obstructive jaundice. More distally, adenocarcinomas may remain silent until symptoms of intestinal obstruction or gastrointestinal hemorrhage occur. Carcinoids are the most frequently occurring small intestinal neoplasm, with more than half found incidentally either at autopsy or at operation for other diseases. Small carcinoid tumors may be asymptomatic, but larger carcinoid tumors can obstruct the lumen or bleed (Color Plate 3 D). Once metastasis occurs to the liver, features of the carcinoid syndrome become apparent (see Chapter 245) . Weight loss, intestinal obstruction, fever, bleeding, and evidence of malabsorption syndrome are features of lymphoma. Massive hemorrhage and intestinal perforation may be the presenting symptoms of large sarcomas. SIGNS. Physical examination may be unremarkable in patients with benign tumors, unless the neoplasm is large enough to present with a mass. Loud borborygmi, visible peristalsis, and abdominal distention may be present in intestinal obstruction. In patients with malignant small bowel neoplasms, more obvious physical findings may be evident. Cachexia, hepatomegaly, ascites, and jaundice may be found. Peripheral lymphadenopathy or splenomegaly may be found in those with extensive lymphoma. DIFFERENTIAL DIAGNOSIS. The initial symptoms may be vague and poorly defined. Once bleeding occurs, causes such as peptic ulceration, Meckel's diverticulum, and vascular anomalies need to be considered (see Chapter 137) . Obstructive jaundice may occur with periampullary neoplasms, bile duct cancer, impacted common duct stones, pancreatitis, and pancreatic cancer (see Chapter 140) . Intestinal obstruction may be due to adhesions, particularly in patients who have had prior abdominal operations, internal

hernias, volvulus, or intussusception. LABORATORY AND RADIOLOGIC STUDIES. Hypochromic, microcytic anemia is quite common. Elevation of alkaline phosphatase and bilirubin levels may occur if the ampulla of Vater is obstructed or if liver metastases are present. Elevated levels of plasma serotonin or urinary 5-hydroxyindoleacetic acid occur in the carcinoid syndrome (see Chapter 245) . Dysproteinemia is a typical feature of Mediterranean lymphoma and is characterized by the presence of abnormal fragments of immunoglobulin A (Ig) A in the serum and urine that is devoid of light chains (see Chapter 179) . Upper gastrointestinal tract barium radiographs and selective nasoenteric intubation (enteroclysis), which permits the introduction of barium and air into a relatively localized segment, may be useful in localizing tumors. Abdominal ultrasonography and CT may determine the extent of hepatic involvement, aid in the work-up of jaundice, and assess intra-abdominal and retroperitoneal spread. Intestinal lymphoma may occasionally be diagnosed by peroral intestinal biopsy, but the disease mainly involves the lamina propria and usually requires a full-thickness surgical biopsy. A thorough staging of lymphoma involves bone marrow biopsy, laparotomy with splenectomy, and biopsies of regional lymph nodes and liver. ENDOSCOPIC EVALUATION. Front-viewing and side-viewing fiberoptic endoscopes are used to examine the duodenum; suspicious lesions can be biopsied and brushed. Endoscopic ultrasound may be helpful in defining depth of involvement of a specific lesion. Periampullary lesions can be well visualized; the pancreatic and biliary trees can be studied by contrast radiography after endoscopic cannulation. The terminal ileum can also be viewed at colonoscopy. Small bowel enteroscopy is sometimes helpful in localizing a small bleeding lesion. THERAPY. Treatment is primarily surgical for symptomatic benign tumors, adenocarcinomas, leiomyosarcomas, malignant carcinoids, and those with secondary involvement of the small intestine. Duodenal carcinomas or large villous adenomas are treated by pancreaticoduodenal resection (Whipple's procedure). In patients with localized lymphoma (stage I), surgical excision is recommended. Combination chemotherapy is used for more extensive lymphoma (see Chapter 179) . Radiation therapy may be helpful for bulky tumors or localized recurrences. PROGNOSIS AND PREVENTION. The prognosis for benign tumors of the intestine is good if surgical resection can alleviate bleeding and obstruction. The prognosis of small intestinal adenocarcinomas is generally poor. The prognosis for leiomyosarcomas and primary lymphomas is good if surgical resection is complete, but this is rarely possible. Patients with malignant carcinoid tumors may survive for long periods, even in the presence of extensive hepatic involvement. Primary small intestinal lymphomas occurring in populations in the Middle East could possibly be decreased by public health measures that decrease parasitic infestation. Earlier diagnosis and adequate 750

treatment of celiac disease (gluten-free diet) may reduce the frequency of malignancy. Surgical bypass should not be performed in patients with Crohn's disease. In patients with familial polyposis syndromes, duodenal and periampullary adenomas should be monitored periodically. Prophylactic endoscopic or surgical removal may be appropriate for large or dysplastic lesions. Epidemiology Potter JD: Epidemiologic, environmental and lifestyle issues in prevention and early detection of colorectal cancer. In Young GP, Rozen P, Levin B (eds): Prevention and Early Detection of Colorectal Cancer. Philadelphia, WB Saunders, 1996, p 23. A concise but critical summary of current evidence. Schottenfeld D, Islam SS: Cancers of the small intestine. In Schottenfield D, Fraumeni JF Jr (eds): Cancer Epidemiology and Prevention, 2nd ed. New York, Oxford University Press, 1996, p 806. An extensive discussion of current state of knowledge. Primary Prevention Kelloff GH, Boone CW, Sigman CC, et al: Chemoprevention of colorectal cancer. In Young GP, Rozen P, Levin B (eds): Prevention and Early Detection of Colorectal Cancer. Philadelphia, WB Saunders, 1996, p 115. The authors classify and describe the multiple natural and chemical compounds that are being evaluated in clinical trials and their mechanisms of action. Schatzkin A: Dietary prevention of colorectal cancer. In Young GP, Rozen P, Levin B (eds): Prevention and Early Detection of Colorectal Cancer. Philadelphia, WB Saunders, 1996, p 103. The author reviews the evidence that dietary intervention can influence the development of adenomas and cancer. Screening and Early Detection Byers T, Levin B, Rothenberger D, et al: American Cancer Society Guidelines for Screening and Surveillance for Early Detection of Colorectal Polyps and Cancer: Update 1997. CA Cancer J Clin 47:154, 1997. A summary of current guidelines. Midgley R, Kerr D: Colorectal cancer. Lancet 353:391-399, 1999. A concise review of the current state of clinical practice. Wagner JL, Tunis S, Brown M, et al: Cost-effectiveness of colorectal cancer screening in average-risk adults. In Young GP, Rozen P, Levin B (eds): Prevention and Early Detection of Colorectal Cancer. Philadelphia, WB Saunders, 1996, p 321. The authors provide an extensive discussion about the cost-effectiveness of colorectal cancer screening. Winawer SJ, Fletcher RH, Muller L, et al: Colorectal cancer screening: Clinical guidelines and rationale. Gastroenterology 112:594, 1997. A definitive, evidence-based analysis of the theoretical basis of screening measures and their practical application. Molecular Biology and Genetics Bellacosa A, Genuardi M, Anti M, et al: Hereditary nonpolyposis colorectal cancer: Review of clinical, molecular genetics, and counseling aspects. Am J Med Genet 62:353, 1996. Reviews advances in molecular aspects of colorectal cancer. Lieters GJ, Tollenaar RA, Cleton-Jansen AM: Molecular staging of colorectal cancer: A step forward. Gastroenterology 116:769-770, 1999. Utility of molecular markers to aid in estimating prognoses in colon cancer. Tomlinson I, Ilyas M, Novelli M: Molecular genetics of colon cancer. Cancer Metastasis Rev 16:67, 1997. Adenomas and Their Management Bond JH: Polyp guidelines: Diagnosis, treatment and surveillance for patients with non-familial colorectal cancer. Ann Intern Med 119:836, 1993. An authoritative review of this topic with practical management guidelines. Zauber AG, Bond JH, Winawer SJ: Surveillance of patients with colorectal adenomas or cancer. In Young GP, Rozen P, Levin B (eds): Prevention and Early Detection of Colorectal Cancer. Philadelphia, WB Saunders, 1996, p 195. An extensive discussion of the natural history and clinical approaches.

Therapy Cohen AM, Winawer SJ (eds): Cancer of the Colon, Rectum, and Anus. New York, McGraw-Hill, 1995. A detailed multi-authored text that provides in-depth discussions of surgery, radiation therapy, and chemotherapy as well as newer experimental approaches. Small Intestine Jones DV, Levin B, Salem P: Intestinal lymphomas, including immunoproliferative small intestinal disease. In Feldman M, Scharschmidt BF, Sleisenger MH (eds): Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 6th ed. Philadelphia, WB Saunders, 1997, p 1844. A summary of the pathogenesis, diagnosis, and management of intestinal lymphomas. Jones DV, Skibber J, Levin B: Adenocarcinoma and other small intestinal neoplasms, including benign tumors. In Feldman M, Scharschmidt BF, Sleisenger MH (eds): Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 6th ed. Philadelphia, WB Saunders, 1997, p 1858. A summary of the multidisciplinary approach to tumors of the small bowel.

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Chapter 140 - CARCINOMA OF THE PANCREAS Eugene P. DiMagno

DEFINITION. Ductal adenocarcinoma, which accounts for 90% of pancreatic cancers, is a relentlessly progressive and fatal disease. Most tumors are moderately well differentiated mucinous carcinomas arising from the cuboid epithelium of pancreatic ducts. The remaining 10% of pancreatic cancers are endocrine tumors (see Chapter 130) ; acinar cell, giant cell, and epidermoid cancers; adenoacanthomas; sarcomas; and cystadenocarcinomas.

INCIDENCE AND EPIDEMIOLOGY. In the past generation the incidence of pancreatic cancer has increased from fewer than 5 to between 11 and 12 per 100,000 population. Currently, pancreatic cancer kills more Americans than any other neoplasm except breast, colorectal, lung, and prostate cancers. Each year, pancreatic cancer develops in approximately 27,000 Americans and 25,000 die. The median survival after diagnosis is 4 to 8 months. The overall 5-year survival rate is less than 1%. Resecting the tumor improves median survival to 17 to 20 months, but the 5-year survival rate remains less than 10%. Pancreatic cancer is associated with certain demographic characteristics and risk factors (Table 140-1) . Pancreatic cancer occurs more frequently in men (1.5:1), and 80% occur between the ages of 60 and 80; the disease is unusual in people younger than 40 years. Patients with chronic pancreatitis and members of families with hereditary pancreatitis or the non-polyposis colon cancer syndrome are at increased risk. Patients with chronic pancreatitis have more than a nine-fold risk of pancreatic cancer, and the cumulative risk increases 2% per decade. Patients with hereditary pancreatitis have a cumulative risk of 40% by 70 years of age. Intraductal papillary mucinous tumor, which may mimic chronic pancreatitis clinically, carries a 50% risk of invasive cancer and is considered a pre-malignant neoplasm. Environmental factors are probably associated with an increased risk of pancreatic cancer, but coffee consumption, alcohol abuse, diabetes mellitus, and previous cholecystectomy or gastrectomy do not appear to increase the risk. Eliminating cigarette smoking and eating a diet low in cholesterol, with olive oil and fish as the main sources of fat, may reduce the risk. The most common molecular abnormalities (>90%) in human pancreatic cancer are mutations in codon 12 of the K- ras gene, which is probably involved in cancer growth. A high proportion of pancreatic cancers also have deletions and mutations in the p53 gene. Gene mutations result in loss of function, failure of inactivation, and intranuclear accumulation of the p53 protein. Epidermal growth factor and erb-b2 receptor pathways are also altered and may have a role in the pathogenesis of pancreatic cancer.

PATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONS. In pancreatic ductal adenocarcinoma, well-differentiated to poorly differentiated duct glands are embedded in a dense network of fibrous tissue. As it extends into the pancreas and surrounding tissue, the tumor envelopes and fixes vessels and invades fat, lymph channels, and perineural areas. Symptoms and signs of pancreatic cancer are related to the location of the tumor within the gland and to extension of the tumor to the stomach, duodenum, bile duct, retroperitoneum, and porta hepatis. Pain occurs in 90% of patients. It may be vague and rather non-specific and may occur up to 3 months before the onset of jaundice. Early in the course the pain may be ignored by both the patient and the examining physician. The tumor most commonly extends to the retroperitoneal space and produces visceral pain variously described as persistent, disagreeable, aching, increased by TABLE 140-1 -- RISK FACTORS FOR PANCREATIC CANCER Definite Age >60 yr Male sex Cigarette smoking Chronic pancreatitis Non-polyposis colon cancer syndrome Probable High-cholesterol and high-fat diet with high linoleic acid content Chemical exposure (coal tar derivative, coke, benzidine, beta-naphthylamine) Unlikely Diabetes mellitus Coffee Alcohol Prior cholecystectomy, gastrectomy

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TABLE 140-2 -- DIAGNOSTIC ACCURACY (%) OF IMAGING TESTS IN DIAGNOSIS OF PANCREATIC CANCER TEST SENSITIVITY SPECIFICITY PREDICTIVE VALUE Positive

Negative

Ultrasonography

74

84

78

79

Computed tomography

79

64

76

78

Endoscopic retrograde cholangiopancreatography

95

90

87

97

lying supine or by eating, and causing the patient to awaken at night. Relief is sometimes obtained by bending forward, by lying on the side and drawing the knees to the chest or chin, and by crouching forward on all four extremities. Jaundice caused by obstruction of the common bile duct occurs early in the course of the disease in 60 to 70% of carcinomas of the head of the pancreas. When carcinoma of the head of the pancreas arises in its central part or in the uncinate process, jaundice is not an early manifestation. In cancer of the body and tail,

jaundice occurs late and may be caused by hepatic metastases or obstruction of the bile duct at the porta hepatis by lymphadenopathy. Painless jaundice is unusual. Weight loss greater than 10% of ideal body weight, almost universal, is usually due to both malabsorption and decreased food intake. Seventy-five per cent of patients malabsorb fat, and 50% malabsorb protein. Malabsorption occurs in patients who have a carcinoma of the head of the pancreas that obstructs the pancreatic duct, thereby producing pancreatic exocrine insufficiency (see Chapters 134 and 141) . Glucose intolerance from increased plasma levels of islet amyloid polypeptide producing insulin resistance may be present in up to 80% of patients with pancreatic cancer, but in most patients the diabetes is mild. Fewer than 5% of patients have hyperphagia, polydipsia, and polyuria. Other symptoms and signs include depression, light-colored stool (60% of patients with carcinoma of the pancreatic head), constipation, and emotional lability (27% of patients with carcinoma of the pancreatic tail). Vomiting and weakness occur in one third of patients. More rarely, patients exhibit superficial thrombophlebitis (Trousseau's syndrome) or gastrointestinal bleeding caused either by direct extension of the tumor into the stomach or duodenum or by varices secondary to splenic vein obstruction. Rarely, metastases from pancreatic cancer of the body and tail to the testicles, temporal bone, or esophagus may cause testicular enlargement and pain, sudden profound hearing loss, or dysphasia, respectively. Hepatomegaly combined with jaundice is present in 80 and 30% of patients with carcinoma of the head and carcinoma of the body TABLE 140-3 -- DIFFERENTIAL DIAGNOSIS OF PANCREATIC CANCER Benign Conditions Chronic pancreatitis Extrahepatic jaundice Common bile duct stones Bile duct stricture (secondary to previous biliary tract surgery or sclerosing cholangitis) Cholecystitis Intrahepatic cholestatic jaundice Alcoholic hepatitis Toxins Cysts Abscess Posterior penetrating duodenal or gastric ulcers Depression Functional bowel disorders Malignant Conditions Retroperitoneal lymphomas Bile duct cancer Ampullary cancer Gynecologic malignancies Carcinoma of the duodenum or small intestine and tail, respectively. A palpable gallbladder (Courvoisier's sign) is present in 30% of patients with carcinoma of the head of the pancreas. An abdominal mass or ascites is present in fewer than 20% of patients. Ascites, splenomegaly, and peripheral edema may be caused by occlusion of the portal vein by tumor, whereas compression of the aorta or splenic artery may produce an abdominal bruit.

DIAGNOSIS. The preferred imaging test for diagnosing pancreatic cancer is a computed tomographic (CT) scan. If a tumor is highly suspected but not found by CT scan, the most sensitive test is endoscopic ultrasonography (US) (Table 140-2) . Other imaging tests such as US or endoscopic retrograde cholangiopancreatography are not usually needed for diagnosis. As a group, patients with pancreatic cancer have higher values for serum lipase, amylase, and glucose than do other patients, but these tests do not distinguish between pancreatic cancer and pancreatitis. Similarly, serum alkaline phosphatase, aspartate aminotransferase, and bilirubin are commonly elevated, but these tests lack specificity to exclude hepatic disorders. Non-specific findings on the chest radiograph and abdominal films may be present in patients with pancreatitis or pancreatic cancer. Pancreatic calcifications have a sensitivity of 95% for diagnosing chronic pancreatitis, but primary ductal carcinoma, mucinous cystadenocarcinoma (curvilinear calcification), benign serous cystadenoma (central, "sunburst" calcification), and solid and papillary epithelial neoplasms can also calcify. If obvious pulmonary or bony metastases are found, further diagnostic tests may not be needed. If the cancer is deemed resectable, endoscopic US or laparoscopy may be considered to determine whether vascular invasion and lymph node metastases are present or whether peritoneal seeding and small liver metastases have occurred, respectively. The availability of endoscopic US is increasing, and it may be as useful as laparoscopy in staging tumors preoperatively. When compared with traditional US, CT, and angiography, endoscopic US is more sensitive for detecting portal vein involvement and lymph node metastasis. Laparoscopy correctly identifies 85% of unresectable tumors. Aspiration cytology of the pancreatic mass with US or CT guidance is 90% sensitive but should not be performed unless the cancer is clearly unresectable because the procedure may cause intra-abdominal seeding of tumor cells. New tests that have appeared in the last 5 to 10 years are magnetic resonance imaging, magnetic resonance cholangiopancreatography, and positron emission tomography. The role of these tests in the diagnosis of pancreatic cancer is evolving. Magnetic resonance imaging may be as accurate as CT but is not widely used. No serologic marker (see Chapter 192) is sufficiently accurate to serve as a screening test for pancreatic cancer. CA 19-9 (the most commonly used marker), carcinoembryonic antigen, galactosyltransferase, pancreatic oncofetal antigen, and pancreatic cancer-associated antigen each have a sensitivity of 50 to 85%, but false-positive tests occur in up to 46% of patients with benign diseases and in up to 65% of those with other malignancies. Other markers such as plasma islet amyloid polypeptide and K- ras mutations in pancreatic secretions are under study.

DIFFERENTIAL DIAGNOSIS. The initial symptoms and signs of pancreatic cancer are non-specific (Table 140-3) . Indeed, most patients with weight loss and abdominal pain, with or without jaundice, do not have pancreatic cancer. In patients without jaundice, the abdominal pain and weight loss of pancreatic cancer may be difficult to distinguish from many other disorders. In jaundiced patients, pancreatic cancer must be distinguished from potentially treatable benign conditions such as chronic pancreatitis obstructing the common bile duct and from causes of extrahepatic and intrahepatic cholestasis.

TREATMENT. Surgical resection of pancreatic cancer offers the only chance of cure. Unfortunately, only 10% of all pancreatic cancers are resectable, and the 5-year survival rate after resection is only 10%. Resection of tumors smaller than 2 cm in diameter is associated with a 20 to 37% 5-year survival rate. Pancreaticoduodenectomy is the surgical procedure of choice. In experienced hands, surgical mortality is 2 to 5%. Other surgical procedures such as total pancreatectomy and regional pancreatectomy are not commonly performed because of higher operative mortality and morbidity 752

and 5-year survival rates that do not exceed those of pancreaticoduodenectomy. The pylorus-preserving pancreaticoduodenal resection may be performed in patients with a small cancer of the pancreatic head, but it does not improve nutrition when compared with standard pancreaticoduodenectomy. Adjuvant chemoradiation after

resection prolongs survival, and preoperative neoadjuvant chemoradiation is under study. Palliative procedures relieve symptoms of biliary obstruction, duodenal obstruction, or both. To relieve biliary obstruction, cholecystojejunostomy and a gastroenterostomy should be performed unless the cystic duct enters the common duct close to the tumor. In this case, choledochojejunostomy should be performed. To decompress the biliary tree, endoscopic stenting is as successful as surgical decompression and may have lower morbidity, but jaundice is more likely to recur late in the disease. An endoscopic stent should be placed if the patient has a high surgical risk or a short life expectancy (1 to 3 months). In contrast, cholecystojejunostomy and gastroenterostomy should be performed if an unresectable tumor is found at the time of surgery or if the patient has a life expectancy of 6 to 7 months because complete duodenal obstruction occurs in 5 to 15% of patients--usually as a pre-terminal event. Incomplete or functional gastric outlet obstruction occurs in 40 to 60% of patients; in such patients, the combination of a cholinergic (bethanechol, 25 mg three times per day) and a prokinetic agent (metoclopramide or cisapride, 10 mg four times per day) may alleviate the symptoms of gastric stasis by enhancing gastric emptying. Gemcitabine is the only single agent that may prolong survival; it has a low response rate, but a small improvement in overall survival in comparison to 5-fluorouracil (5-FU) (5.7 versus 4.4 months and a 1-year survival rate of 18% versus 2%). No other single agent or combination of chemotherapeutic drugs prolongs or enhances the quality of life. 5-FU produces a partial response rate in 10 to 15% of patients, but its use is associated with a median survival of less than 20 weeks. Other agents have a similar effect (mitomycin), less effect (streptozotocin, doxorubicin, epirubicin, ifosfamide, methyl-CCNU [lomustine], and high-dose methotrexate), or no effect (actinomycin D, doxorubicin, BCNU [carmustine], standard-dose methotrexate, cisplatin, melphalan, and L-asparaginase). The combination of external beam radiation with 5-FU or with streptozotocin, mitomycin, and 5-FU improves survival when compared with radiation or chemotherapy alone. Intraoperative electron beam radiation and 125 I implants do not improve survival in comparison to external beam radiation. These modalities may limit local tumor extension, but they do not control liver and peritoneal metastases. Pain can usually be successfully managed if adequate doses of analgesics are prescribed on a regular basis and adjuvant drugs are used when necessary. Mild to moderate pain can be controlled with aspirin, acetaminophen, and non-steroidal anti-inflammatory agents. If these drugs fail to relieve pain, opioid analgesics should be used (see Chapter 27) . Intraoperative or percutaneous neurolytic celiac plexus block is remarkably effective in controlling pain. If patients have intolerable pain, subcutaneous patient-controlled analgesia or epidural narcotics afford pain relief. Malabsorption can be reasonably well controlled by ingesting eight tablets of pancrealipase with meals (the total dose of lipase should be 30,000 IU). Two tablets should be taken immediately after eating a few bites, two tablets at the end of the meal, and four tablets interspersed during the meal (see Chapter 141) . Burris HA, Moore HJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first line therapy for patients with advanced pancreatic cancer: A randomized trial. J Clin Oncol 15:2403, 1997. First demonstration of a single agent that improves survival. Loftus EV, Olivares-Pazkad BA, Batts KP, et al: Intraductal papillary-mucinous tumors of the pancreas: Clinicopathological features, outcome, and nomenclature. Gastroenterology 110:1909, 1996. IPMT is a dysplastic and pre-malignant lesion, separate from mucinous cystic neoplasm and often diagnosed as chronic pancreatitis, that if possible, should be treated with complete surgical excision because it is impossible to distinguish non-invasive IPMT from invasive cancer preoperatively. Urrutia R, DiMagno EP: Pancreatic cancer: Cellular and molecular mechanisms. In Bertino JR (ed): Encyclopedia of Cancer, vol 2 (G-Q). San Diego, Academic Press, 1996, pp 1201-1211. A review of the molecular bases of pancreatic cancer. Yeo CJ, Cameron JL: Pancreatic cancer. Curr Prob Surg 36:59-152, 1999. A useful review from the surgical perspective.

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Chapter 141 - PANCREATITIS Konrad H. Soergel

ANATOMY AND PHYSIOLOGY OF THE PANCREAS The pancreas first appears as ventral and dorsal budding evaginations of the primitive foregut at 5 weeks' gestation. The right portion of the ventral bud, including the common bile duct, migrates posteriorly with rotation of the duodenum. Both anlagen and their ducts fuse by the seventh week of gestation, with the ventral anlage forming the pancreatic head and uncinate process and the dorsal anlage forming the body and tail. Incomplete fusion results in two separate pancreatic ducts: the dorsal duct of Santorini draining through the minor papilla and a short ventral duct (Wirsung) ending at the major papilla of Vater. This anomaly, termed pancreas divisum, is present in 5 to 10% of the population. Fixation of the ventral bud while the duodenum rotates results in a band of pancreatic tissue encircling the descending duodenum, the resulting annular pancreas is very rare and may cause duodenal obstruction or pancreatitis. The retroperitoneal location and the absence of a capsule surrounding the pancreas are important factors in understanding how pancreatitis evolves. Pancreatic inflammation and fibrosis may spread unimpeded by anatomic barriers to involve the spleen, the splenic artery and vein, the duodenum and distal common bile duct, the mesocolon and small bowel mesentery, the diaphragm and pararenal spaces, the lesser omental sac, and the celiac and superior mesenteric ganglia. The acinar cells of the exocrine pancreas synthesize approximately 20 digestive enzymes, colipase, a secretory trypsin inhibitor, and lithostathine S2-5 , a protein that inhibits the precipitation of CaCO3 from pancreatic juice. These secretory proteins are sorted into condensing vacuoles, which then become zymogen granules. The granules fuse with the apical cell membrane and discharge their contents into the acinar lumen by exocytosis by a process controlled by cholecystokinin (CCK) which acts via central vagal pathways and gastropancreatic and enteropancreatic cholinergic reflexes. CCK is released from endocrine I cells in the duodenal and proximal jejunal mucosa during fat and protein digestion. All digestive enzymes, except alpha-amylase, lipase, ribonuclease, and deoxyribonuclease, are secreted as inactive zymogens. Trypsinogen is activated by enterokinase, which is secreted by the duodenum; trypsin then activates all other zymogens within the duodenal lumen. The centroacinar, ductular, and pancreatic duct epithelial cells represent a functional unit that exchanges HCO3 - for Cl- , with increasing flow rates of pancreatic secretion. This process involves the intracellular generation of carbonic acid by carbonic anhydrase and the actions of a Cl- /HCO3 - exchanger and a Cl- channel, the cystic fibrosis transmembrane regulator (CFTR), at the luminal cell border. The excess intracellular H+ ions are removed by a basolaterally located Na+ /H+ exchanger. Secretion of alkaline, bicarbonate-rich pancreatic juice is stimulated by acetylcholine and by the hormone secretin, which is released from mucosal S cells when the duodenal pH decreases to 4.5. Premature activation of zymogens within the pancreas is the key event in the pathogenesis of acute pancreatitis. Protein and CaCO3 precipitates within the pancreatic duct system play a major role in the development of chronic pancreatitis.

ACUTE PANCREATITIS DEFINITIONS. Acute pancreatitis is an acute inflammatory process with variable involvement of adjacent and remote organs. Although pancreatic function and structure usually return to normal, the risk of recurrent attacks is 20 to 50% unless the precipitating cause is removed. The annual incidence of acute pancreatitis is close to 10 per 100,000 in the adult population. Initial manifestations and exacerbations of chronic pancreatitis may be indistinguishable from attacks of acute pancreatitis, and they should be treated as such. The inflammation begins in the perilobular and peripancreatic fatty tissue, manifested by edema and spotty fat necrosis. The disease may progress to the peripheral acinar cells, 753

Figure 141-1 The pathophysiology of pancreatic autodigestion. IL = interleukin; TNF = tumor necrosis factor. (Modified from Sleisenger MH, Fordtran JS [eds]: Gastrointestinal Disease, 5th ed. Philadelphia, WB Saunders, 1993, p 1631.)

pancreatic ducts, blood vessels, and bordering organs. In severe cases, patchy areas of the pancreatic parenchyma become necrotic. Local complication are defined as (1) acute fluid collections, which are common and frequently multiple, occur early in the course, and lack a defined wall--the majority of these collections resolve spontaneously; (2) pancreatic necrosis: focal or diffuse necrosis of pancreatic parenchyma, frequently associated with peripancreatic fat necrosis--the necrotic tissue may be sterile or infected; and (3) pancreatic abscess: a rare complication that arises late in the course of acute pancreatitis. Ambiguous terms that should be discarded include pancreatic phlegmon, acute and infected pseudocysts, and edematous and hemorrhagic acute pancreatitis. Severe pancreatitis is defined as a local complication and/or organ failure generally associated with an APACHE II (Acute Physiology and Chronic Health Evaluation) score of 8 or more. PATHOGENESIS. Premature activation of zymogens and the escape of activated enzymes from acinar cells and pancreatic ducts set the stage for the autodigestive process that represents acute pancreatitis (Fig. 141-1) . Proteases released into the blood are inactivated by circulating inhibitors, including alpha2 -macroglobulin, alpha1 -antitrypsin, and the C1 -esterase inhibitor. In addition, trypsin activates kallikrein, a peptidase, which then cleaves several peptides, including bradykinin and kallidin, from their inactive precursors in blood plasma. These peptides, termed kinins, have various deleterious effects including vasodilatation, increased vascular permeability, pain, and neutrophil accumulation. Two mechanisms may trigger pancreatic autodigestion. The first is zymogen activation within the pancreatic acinar cell (Fig. 141-2) . The rate of exocytosis is decreased while acinar protein synthesis continues undiminished, leading to intracellular accumulation of

Figure 141-2 Synthesis, sorting, and secretion of hydrolytic enzymes and zymogens in the pancreatic acinar cell. A, Normal. B, Abnormalities observed in various models of experimental pancreatitis: (1) crinophagy; condensing vacuoles and lysosomes coalesce; (2) absent compartmentalization; (3) autophagic vacuole; (4) autoactivation; (5) increased lysosomal hydrolase secretion; (6) exocytosis block; (7) secretion across basolateral cell wall. Interrupted lines indicate abnormal events. (From Sleisenger MH, Fordtran JS [eds]: Gastrointestinal Disease, 5th ed. Philadelphia, WB Saunders, 1993, p 1630.)

754

zymogens. A variety of errors in intracellular traffic result in co-localization of zymogens and lysosomal enzymes in large autophagic vacules. Lysosomal enzymes and the acidic pH within these vacuoles activate the zymogens, which then undergo misdirected secretion across the basolateral wall of the acinar cell. The second is increased pancreatic duct permeability. A rise in intraductal pressure, acute hypercalcemia, and orally administered acetylsalicylic acid or ethanol makes the pancreatic duct epithelium permeable to molecules of up to 25 kD. Severe pancreatitis results when the pancreatic duct is then perfused with active pancreatic enzymes, particularly when microvascular permeability is increased by the actions of histamine or prostaglandins. Thus, pancreatic zymogen activation and increased pancreatic duct permeability may act sequentially in initiating acute pancreatitis. Reflux of duodenal contents or bile into the pancreatic duct does not cause acute pancreatitis but obstruction of the pancreatic duct near the ampulla of Vater may explain many episodes of acute pancreatitis.

ASSOCIATED FACTORS. Among clinical conditions, medications, and toxins known to precipitate acute pancreatitis (Table 141-1) , choledocholithiasis and ethanol abuse account for 70 to 80% of all cases. The number attributed to the idiopathic type varies with the clinician's astuteness in identifying one of the factors listed. All remaining causes combined account for 10% or less of the total. Alcoholic and familial pancreatitis are discussed under "Chronic Pancreatitis." GALLSTONES.

Gallstones may cause pancreatitis by impacting in the ampulla of Vater. The stones usually pass spontaneously into the duodenum, and small gallstones can be found in the stools of 92% of patients with gallstone pancreatitis. Persistent stone impaction can cause severe pancreatitis combined with ascending cholangitis. The incidence of gallstone-associated pancreatitis parallels TABLE 141-1 -- FACTORS ASSOCIATED WITH ACUTE PANCREATITIS Obstructive Causes Choledocholithiasis Ampullary obstruction by tumor or sphincter of Oddi hypertension Choledochocele Periampullary duodenal diverticulum Pancreas divisum (?); annular pancreas Primary or metastatic pancreatic tumor Parasites in pancreatic duct: Clonorchis, Ascaris Toxins Ethanol Methanol Organophosphorus insecticides Scorpion venom ( Tityus trinitatis) Drugs Definite association: azathioprine/6-mercaptopurine; valproic acid; estrogens; metronidazole; loop diruetics, including thiazides, furosemide, bumetanide; pentamidine; sulfonamides, including sulfasalazine; methyldopa; L-asparaginase; tetracyclines, cytarabine, dideoxyinosine Probable association: chlorthalidone; mesalamine; ethacrynic acid; phenformin; angiotensin-converting enzyme inhibitors; nitrofurantoin; cocaine and amphetamine abuse; acetaminophen, cimetidine. Metabolic Causes Hypertriglyceridemia Hypercalcemia Trauma Blunt abdominal trauma Endoscopic retrograde cholangiopancreatographic procedures Abdominal operations, cardiopulmonary bypass Infections Viral; mumps, coxsackie B, hepatitis A and B Bacterial: Mycoplasma, Salmonella, Campylobacter jejuni Vascular Shock-hypoperfusion Vasculitis Cholesterol emboli Miscellaneous Penetrating duodenal ulcer Organ transplantation Crohn's disease of duodenum Familial pancreatitis Idiopathic that of cholelithiasis: it peaks at ages 50 to 70, and women outnumber men by 2 to 1. As with other types of acute pancreatitis, chronic pancreatitis rarely results from multiple episodes of pancreatitis associated with gallstones. Pancreatitis during pregnancy usually occurs during the third trimester and is caused by gallstones in approximately 90% of instances. DRUG-INDUCED PANCREATITIS.

This complication characteristically occurs within the first 2 months of exposure; it is not dose related, and the pancreatitis usually is mild. Most commonly implicated are azathioprine/6-mercaptopurine, valproic acid in children, sulfur-containing diuretics, and pentamidine and dideoxyinosine in patients with the acquired immunodeficiency syndrome. HYPERTRIGLYCERIDEMIA.

The presence of lipemia, with serum triglyceride levels more than 1000 mg/dL, represents a cause, not an effect, of pancreatitis. Causes include estrogen therapy, alcoholism, intravenous lipid infusions, and primary hyperlipidemias. MISCELLANEOUS FACTORS.

Acute hypercalcemia may trigger acute pancreatitis during intravenous calcium infusions, during cardiopulmonary bypass, and with vitamin D poisoning. Blunt abdominal trauma causes pancreatitis by disrupting the duct; it is the most common cause of pancreatitis in children. Postoperative pancreatitis may follow intra- and extra-abdominal surgery and carries a high mortality rate of 25 to 50%. Patients after organ transplantation are at increased risk of acute and chronic pancreatitis. It is unclear whether this is entirely attributable to azathioprine/6-mercaptopurine therapy; infected pancreatic necrosis is common and the mortality is high. Pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) is usually mild unless it is complicated by duodenal perforation during endoscopic sphincterotomy. Pancreatic infections are an exceedingly rare and poorly documented cause of pancreatitis. Whether pancreas divisum predisposes to recurrent acute pancreatitis remains controversial. The available evidence favors the decision to proceed with surgical or endoscopic decompression of the dorsal pancreatic duct in these patients. CLINICAL PRESENTATION.

Steady, dull, or boring midepigastric pain associated with nausea and vomiting is the classic presentation of acute pancreatitis. The pain reaches peak intensity within 15 minutes to 1 hour from onset, in contrast to the more abrupt onset of pain with a perforated viscus. It radiates straight to the midline of the lower thoracic vertebral region in about 50% of patients and is usually worse in the supine position. Painless acute pancreatitis is very rare but carries a grave prognosis because the patients frequently present in shock. Initial physical examination reveals mild fever and tachycardia; hypotension is present in 30 to 40% of patients. There is marked tenderness to deep palpation of the upper abdomen, but signs of peritoneal irritation are absent. Paralytic ileus with abdominal distention may develop during the first few days, signifying extension of the inflammatory process into the small intestinal and colonic mesentery. One to 2 weeks after the onset, large ecchymoses rarely appear in the flanks (Grey Turner's sign) or the umbilical area (Cullen's sign); these represent blood dissecting from the pancreas along fascial planes. Similarly, inflammatory masses, large fluid collections, or a pancreatic abscess may become palpable later in the course of the disease. DIAGNOSIS. The diagnosis of acute pancreatitis rests on a combination of clinical, laboratory, and radiologic findings, none of which is infallible. The goals of diagnostic studies are to exclude other acute conditions that may require urgent surgical management; to assess the prognosis; to detect local and systemic complications early; and to identify a precipitating cause. LABORATORY TESTS. AMYLASE.

Total serum amylase activity is the test most frequently used to diagnose acute pancreatitis. The level rises 2 to 12 hours after onset of symptoms and remains elevated for 3 to 5 days in most cases. Values more than five times the upper limit of normal are highly specific for acute pancreatitis but are found in only 80 to 90% of cases. The magnitude of the rise in serum amylase does not correlate with the severity of the attack, nor does prolonged hyperamylasemia indicate developing complications. Marked hypertriglyceridemia, sufficient to give the serum a lipemic appearance, masks elevations in serum amylase and lipase; dilution of these sera lead to a paradoxical rise in the measured enzyme values. Separation of total serum amylase into its pancreatic (P) and salivary (S) isoenzymes and measurements of urinary amylase output add little to the diagnostic information. The 755

TABLE 141-2 -- ADDITIONAL CAUSES OF ELEVATIONS IN SERUM PANCREATIC ENZYMES Levels may be similar to those in acute pancreatitis Chronic pancreatitis; pancreatic pseudocyst; carcinoma of the pancreas; perforation of stomach, duodenum, jejunum; mesenteric infarction; brain and spinal cord injury. Minor amylase and lipase elevations Acute cholecystitis; burn injury; end-stage renal disease; acute and chronic alcohol abuse. Isolated amylase elevation Salivary adenitis; ovarian neoplasm; tubal pregnancy; metabolic acidosis; admission to an intensive care unit; acute hepatitis; anorexia nervosa; upper gastrointestinal endoscopy; incidental finding. amylase-creatinine clearance ratio (ACR) (the ratio of amylase concentration in urine over plasma, divided by the corresponding values for creatinine) is useful in diagnosing asymptomatic macroamylasemia, in which aggregates of circulating amylase escape glomerular filtration and the ACR is abnormally low. Serum amylase levels may be elevated in many other clinical conditions (Table 141-2) , illustrating the fact that the diagnosis of acute pancreatitis should not be based only on laboratory results. Lipase.

Serum lipase assays, especially those using colipase, have similar specificity and sensitivity as serum amylase. The serum lipase levels tend to remain elevated longer than the amylase levels during the healing phase of pancreatitis. Combinations of Serum Enzyme Tests.

The combination of serum amylase and lipase determinations is more accurate than either test alone (Table 141-3) . The diagnostic accuracy can be improved further by calculating cut-off values that lie above the upper limit of normal. Serum immunoreactive cationic trypsin, elastase, and phospholipase A2 do not improve the diagnostic information obtained from serum amylase and lipase values. Measurements of trypsin activation peptide and serum anionic trypsinogen promise increased diagnostic accuracy but are not widely available. Other Blood Tests.

Leukocytosis of up to 25,000 cells/mm3 is present in 80% of patients; the hematocrit is frequently elevated due to hemoconcentration. Hypocalcemia occurs in up to 30% of patients due to a combination of hypoalbuminemia and calcium precipitation in areas of fat necrosis. The ionized calcium concentration remains normal, and symptoms of tetany are extremely rare. Pre-existing hypercalcemia may, however, be obscured by the calcium-lowering effect of pancreatitis. Transient, mild hyperglycemia is common and does not require insulin treatment. Serum triglyceride levels should be obtained in all patients because of their etiologic implications and to help interpret unexpectedly normal serum amylase and lipase levels. Elevated alanine aminotransferase (ALT) and alkaline phosphatase values suggest gallstone-associated pancreatitis (see later). The serum aspartate aminotransferase (AST) is elevated in approximately 50% of patients, owing to alcoholic liver disease or to the pancreatic inflammation itself. IMAGING TESTS. Plain Films of the Abdomen.

Plain films should be obtained routinely to rule out the presence of free air caused by perforation of a viscus and "thumbprinting" of the intestinal wall, suggesting mesenteric infarction. Changes caused by pancreatitis include localized ileus of a loop of jejunum ("sentinel loop"), generalized paralytic ileus, spasm of the transverse colon with absent colonic gas beyond ("colon cut-off sign"), and calcifications indicating the existence of underlying chronic pancreatitis. Chest Radiographs.

Pleural effusion and basilar atelectasis indicate diaphragmatic involvement by acute pancreatitis but are not necessarily confined to the left side. Interstitial fluffy infiltrates are the hallmark of the adult respiratory distress syndrome (see later). Barium contrast studies of the upper gastrointestinal tract are of little diagnostic value. Abdominal Ultrasonography (US) and Computed Tomography (CT).

US is the method of choice for detecting cholelithiasis and for TABLE 141-3 -- DIAGNOSIS OF ACUTE PANCREATITIS BY SERUM ENZYME ELEVATIONS IN PATIENTS WITH ACUTE ABDOMINAL PAIN AMYLASE LIPASE EITHER BOTH Sensitivity

80-90%

90%

95%

--

Specificity

70%

70%

--

90%

determining the diameter of the extrahepatic and intrahepatic bile ducts. Dilatation of these ducts suggests recent or persisting impaction of a stone in the distal common bile duct or the ampulla of Vater. US also very accurately detects acute cholecysitis. For the diagnosis of acute pancreatitis, an abdominal CT scan should be obtained only when clinical impression and laboratory results are conflicting; but when the clinical diagnosis is made, the CT scan is far superior to US for assessing the extent and local complications of pancreatitis. With rapid intravenous bolus injection of contrast material, a dynamic CT scan will reveal extension of peripancreatic inflammation, involvement of adjacent organs, venous thrombosis, and fluid collections. Most important, pancreatic necrosis can be identified and quantitated by the lack of contrast medium enhancement after the bolus injection. The abdominal CT scan may be normal, however, in about 10% of patients with early, mild pancreatitis. DIFFERENTIAL DIAGNOSIS.

There is no single absolute criterion for the diagnosis of acute pancreatitis. The differential diagnosis should focus on other conditions presenting with acute upper abdominal pain that require specific therapy, including perforated peptic ulcer, acute cholecystitis, and mesenteric vascular occlusion. A gallstone impacted in the ampulla of Vater may not only delay the resolution of biliary pancreatitis but also cause complicating ascending cholangitis and obstructive jaundice. The combination of positive US findings (gallstones or bile duct dilatation) with a positive biochemical score is indicative of this situation. A positive score consists of three or more of the following tests exceeding the stated limit: (1) alkaline phosphatase greater than upper limit of normal (ULN); (2) total bilirubin greater than ULN; (3) gamma glutamyltransferase greater than two times ULN; (4) ALT greater than one and one-half times ULN; and (5) ALT/AST greater than 1.0. PROGNOSTIC ASSESSMENT. Several scoring systems predict the morbidity and mortality of acute pancreatitis attacks (Table 141-4) , based on clinical and laboratory observations obtained during the first 48 hours after admission to the hospital. Examples include the Ranson and the modified Glasgow criteria developed specifically for pancreatitis and the APACHE II (Acute Physiology and Chronic Health Evaluation) and SAPS (Simplified Acute Physiology) scores. These scoring systems are only 70 to 80% accurate in predicting a mild or a severe course. Their use cannot replace the careful observation of the individual patient. Recent reports indicate that elevation of serum C-reactive protein to more than 120 mg/L is an accurate predictor for the development of pancreatic necrosis. CLINICAL COURSE AND THERAPY. MILD PANCREATITIS.

Mild acute pancreatitis is defined by the absence of systemic and local TABLE 141-4 -- ADVERSE PROGNOSTIC FACTORS IN ACUTE PANCREATITIS RANSON'S CRITERIA* MAINLY ETHANOL-INDUCED On Admission:

Within 48 hours:

Age > 55 WBC > 16,000/mm

GLASGOW CRITERIA ALL CAUSES Age > 55

3

WBC > 15,000/mm3

Glucose > 200 mg/dL

Glucose > 180 mg/dL

LDH > 350 IU/L

LDH > 600 IU/L

AST > 250 IU/L

BUN > 45 mg/dL Albumin < 3.2 g/dL

Within 48 hours:

Calcium > 8 mg/dL

Hematocrit decrease > 10%

Arterial PO2 < 60 mm Hg

BUN rise > 5 mg/dL Calcium < 8 mg/dL Arterial PO2 < 60 mm Hg Base deficit > 4 mEq/L Fluid deficit > 6 L Three or more positive criteria predict a complicated clinical course; mortality rises when 4 criteria are met. LDH = lactic dehydrogenase; AST = aspartate aminotransferase; BUN = blood urea nitrogen. *Ranson JHC, Rifkind KM, Turner JW: Prognostic signs and nonoperative peritoneal lavage in acute pancreatitis. Surg Gynecol Obstet 143:209, 1976. Blamey SL, Imrie CW, O'Neill WH, et al: Prognostic factors in acute pancreatitis. Gut 25:1340, 1984. No pre-existing hyperglycemia.

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complications. About 80% of patients belong to this category and require less than 1 week of hospitalization. Treatment consists of general supportive care and close monitoring for signs of systemic complications; local complications tend to manifest during the second and third weeks of illness. The intravascular volume deficit may exceed 30% due to peripancreatic fluid sequestration and vomiting. Volume restoration must be rapid and efficient to maintain regular monitored urine output of more than 40 mL/hr. The patient receives nothing by mouth, with the goal of resting the pancreas. Nasogastric aspiration is indicated in the presence of vomiting or developing ileus; it need not be initiated routinely. The patient should receive sufficient analgesic medications to alleviate pain. Opiates should not be withheld because of their potential for raising the sphincter of Oddi pressure. They may, however, cause or worsen paralytic ileus. Neither total parenteral nutrition nor routine prophylactic antibiotic therapy is indicated. Small feedings of a high carbohydrate diet are begun once the pain has subsided and bowel sounds have reappeared. SYSTEMIC COMPLICATIONS.

Most systemic complications (Table 141-5) occur during the first week of illness and are treated by standard medical measures. Close patient monitoring is the key to their timely recognition. Circulatory shock arises by a combination of volume depletion and hyperdynamic circulatory state with decreased peripheral vascular resistance (see Chapter 94) . The management includes transfer to an intensive-care unit, volume replacement, and vasopressor substances. The occurrence of shock is frequently followed by pancreatic necrosis. Acute renal failure may be caused by circulatory shock and a selective increase in renal vascular resistance. The treatment is that of acute tubular necrosis arising in any setting (see Chapter 103) . The leading cause of respiratory insufficiency during acute pancreatitis is the adult respiratory distress syndrome, although respiratory depression caused by opiate medications, pleural effusions, intravascular volume overload, and shallow respirations due to abdominal "splinting" may contribute. The pathogenesis probably involves damage to the pulmonary surfactant layer by circulating phospholipase A and free fatty acids. Sepsis is most commonly caused by infection of the bile ducts, of areas of pancreatic necrosis, or of peripancreatic fluid collections (see later). LOCAL COMPLICATIONS.

Ascending cholangitis and severe biliary pancreatitis present overlapping features and may coexist. Gram-negative bacteremia and spiking fevers are more common with infection of the biliary tract, whereas hyperbilirubinemia may be mild or absent in both situations. Appropriate antibiotic therapy should be instituted (e.g.,

gentamicin, ampicillin, and metronidazole) (see Chapter 157) . The main therapeutic objective is to clear the gallstones without delay. Pancreatic Necrosis.

Pancreatic necrosis is found by dynamic CT in approximately 80% of patients (16% of the total) with clinically severe disease, usually during the second or third week of illness (Fig. 141-3) but is present in approximately 40% of patients within 4 days of symptom onset. Pancreatic necrosis resolves without incident in nearly 60% of patients who develop it. Therapy and prognosis of the severely ill patient depend crucially on whether the necrotic tissue is infected (Fig. 141-4) . This question should be answered by fine-needle aspiration of necrotic areas under CT guidance. A Gram stain of the aspirate is more than 95% accurate in predicting the final results of bacterial cultures. The bacteria represent enteric flora that gained access to mesenteric lymphatics by TABLE 141-5 -- COMPLICATIONS OF ACUTE PANCREATITIS LOCAL

SYSTEMIC Circulatory shock

Impacted common bile duct stones

Respiratory insufficiency

Pancreatic necrosis ± infection

Acute renal failure

Fluid collections ± infection

Sepsis

Pancreatic abscess

Coagulopathy (DIC)

Colonic necrosis

Hyperglycemia

Bleeding

Hypocalcemia

Splenic vein thrombosis Splenic necrosis

Conditions in italics are life-threatening; they require prompt recognition and management. DIC = disseminated intravascular coagulation.

Figure 141-3 Dynamic CT scan of patient with pancreatic necrosis. Interposed between normally perfused portions of the pancreas (p) are non-perfused necrotic areas (arrows). The pancreas is surrounded by fluid in the retroperitoneum, which extends into the small bowel mesentery. A = contrast medium-enhanced aorta. Failure of tissue enhancement during bolus injection with rapid scanning outlines areas of necrosis. (From Sleisenger MH, Fordtran JS [eds]: Gastrointestinal Disease, 5th ed. Philadelphia, WB Saunders, 1993, p 1642.)

translocating across the colonic mucosa. Antibiotics with high penetration into pancreatic tissue include the fluoroquinolones, imipenem/cilastatin, and metronidazole. The mortality of patients with infected pancreatic necrosis treated conservatively is 60 to 100%. Immediately removing necrotic tissue (necrosectomy), combined with continued lavage of the necrotic space, lowers the mortality to about 20%, but patients frequently require re-operation for continuing necrosis and other local complications, such as bleeding and fistula formation. The management of patients with sterile pancreatic necrosis remains controversial. Repeat CT with fine-needle aspiration reveals the later development of infection in over 40% of these patients. Prophylactic intravenous antibiotic therapy (e.g., ofloxacin, 200 mg twice daily plus metronidazole 500 mg twice daily) appears to decrease the risk of conversion to infected pancreatic necrosis and, thus, of mortality. Fluid Collections.

Fluid collections occur within or around the pancreas in up to 50% of patients with severe pancreatitis. The majority resolve spontaneously; collections that persist for more than 6 weeks develop a wall of granulation tissue and are then called pseudocysts (see "Chronic Pancreatitis"). Collections that continue to expand or become infected require percutaneous drainage. Pancreatic abscesses contain liquid pus and may be considered to represent infected fluid collections. The presence of extraluminal gas bubbles on radiographs or CT is a specific but rare clue

Figure 141-4 Management and prognosis of severe acute pancreatitis. PN = pancreatic necrosis; FNA = fine-needle aspiration of necrotic areas under CT guidance with Gram stain and culture of aspirate.

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to their presence. Pancreatic ascites reflects involvement of peritoneal surfaces by the inflammatory process and, rarely, the rupture of a pancreatic duct with pancreatic juice entering into the peritoneal cavity. There are several causes of bleeding during acute pancreatitis. Hemorrhage may occur into necrotic intrapancreatic and peripancreatic tissue and into fluid collections. Brisk hemorrhage occurs with erosion of the splenic or gastroduodenal arteries. At times, the blood gains access to a disrupted pancreatic duct and empties into the duodenum. Diffuse mucosal bleeding from the antrum and duodenum is common but rarely severe. Finally, bleeding may signal perforation of peripancreatic inflammation into any portion of the gastrointestinal tract from esophagus to colon. The spleen may become involved by direct extension of the inflammatory process or, secondarily, by splenic vein thrombosis. The latter complication leads to gastric fundic varices. PREVENTING RECURRENCES. The search for the precipitating cause begins during the acute attack. Serum calcium and triglyceride levels are determined and the medication list is reviewed (see Table 141-1) . An abdominal US examination is performed routinely. If gallstones are detected, the patient should undergo early cholecystectomy, preferably before discharge from the hospital. The absence of choledocholithiasis must be ascertained before or during this surgical procedure. At this stage, approximately 20% of patients are assumed to have idiopathic pancreatitis. After a second attack, ERCP with sphincter of Oddi manometry should be performed and will identify correctable obstructive causes of the pancreatitis attack in approximately one third of patients. Bile aspirated from the common bile duct or the duodenum from the remaining patients should undergo microscopic analysis. Cholesterol crystals, calcium bilirubinate granules, or microspheroliths may be detected, and the majority of these patients will develop biliary "sludge" or gallstones on serial US examinations. Treatment options include cholecystectomy, endoscopic papillotomy, or oral dissolution therapy with bile acids. This systematic search for obstructive causes of acute pancreatitis leaves only 5 to 10% of patients designated as having "idiopathic pancreatitis."

CHRONIC PANCREATITIS DEFINITION AND PATHOGENESIS. Chronic pancreatitis is marked by progressive fibrosis, leading to loss of exocrine and endocrine (islets of Langerhans) tissue and irregular dilatation of pancreatic ductal structures (Table 141-6) . Episodes of acute pancreatitis may be interspersed, especially during the early years of alcoholic pancreatitis. Chronic calcifying pancreatitis is the most common form, by far. It is characterized by irregular distribution within the gland with varying degrees of obstruction of the primary and secondary pancreatic ducts. The initiating event may be fibrillar proteins precipitating in small pancreatic duct branches; these protein plugs calcify by surface accretion. Later on, similar lamellar protein precipitates form in the major pancreatic duct and calcify as well. The plugs and concretions cause acinar atrophy, chronic inflammation with metaplasia of the ductal epithelium, periductal fibrosis, and irregular dilatation of major and secondary pancreatic ducts. The initiating event may be deficient acinar secretion of lithostathine, a protein that inhibits calcium precipitation from the supersaturated pancreatic juice. Alternatively, lithostathine may undergo proteolytic cleavage that yields an insoluble residue, LH1 , that forms fibrillar precipitates and no longer keeps calcium in solution. Chronic obstructive pancreatitis is caused by obstruction TABLE 141-6 -- ETIOLOGIC ASSOCIATIONS WITH CHRONIC PANCREATITIS Chronic Calcifying Pancreatitis Chronic alcoholism Tropical pancreatitis Hereditary

Senile/pancreatic atrophy Metabolic: hypercalcemia, hyperlipemia, post-renal transplant Idiopathic Obstructive Chronic Pancreatitis Tumors Duct strictures Pancreas divisum (?) Note: Hereditary isolated pancreatic enzyme deficiencies, congenital pancreatic insufficiency with neutropenia, and cystic fibrosis are separate nosologic entities. of the main pancreatic duct and leads to uniform dilatation of the duct system, rarely accompanied by protein plugs and intraductal calcifications. ETIOLOGIC ASSOCIATIONS. ALCOHOL.

Fully 70 to 80% of patients with chronic pancreatitis are chronic alcohol abusers. Alcoholic pancreatitis, even when it presents as an acute episode, is a chronic, progressive disease. Typically, the initial symptoms appear at ages 35 to 45, but some patients may experience their first attack before age 25. Alcoholic liver disease develops in 40 to 50% of patients and frequently becomes manifest 5 to 10 years after the onset of pancreatitis. Alcohol abstinence offers moderate and unpredictable benefits in terms of pain relief and the later development of diabetes mellitus but does not alter the progression of pancreatic fibrosis and exocrine insufficiency. The mechanism of alcohol-induced pancreatic injury remains unknown. TROPICAL PANCREATITIS.

Calcific chronic pancreatitis occurs in children and young adults in certain tropical areas, including southern India, Indonesia, and Central Africa. Although abdominal pain is common, the diagnosis is frequently made on the basis of newly discovered diabetes or pancreatic calcifications. Although malnutrition is suspected to play a role, this form of chronic pancreatitis is not found in other areas where malnutrition is equally common. There is no relationship to alcohol consumption. HEREDITARY PANCREATITIS.

Pancreatitis inherited as an autosomal dominant trait with 40 to 80% penetrance accounts for approximately 2% of patients with chronic pancreatitis. Episodes of abdominal pain usually start at ages 5 to 12. The etiology is amino acid substitutions in the cationic trypsin molecule. Families with hereditary pancreatitis have reduced degradation of trypsin, so active trypsin accumulates within the pancreas and causes repeated acute attacks and ultimately chronic pancreatitis. SENILE PANCREATITIS/ATROPHY.

Ten to 20% of patients with chronic pancreatitis are older than 60 at initial presentation. Pancreatic calcifications and malabsorption are common, but pain is commonly absent. Smoking and obesity, but not alcohol abuse, have been implicated. Senile atrophy and lipomatosis of the pancreas probably represent the same poorly understood entity. The clinical course is benign and generally non-progressive. METABOLIC CAUSES.

Chronic pancreatitis develops in up to 15% of patients with primary hyperparathyroidism and frequently is clinically silent. Hyperlipidemia and renal transplantation are rare causes of chronic pancreatitis. OBSTRUCTION.

Obstruction of the pancreatic duct by tumors, post-traumatic strictures, pancreatic duct calculi, or a "tight" minor papilla in patients with pancreas divisum may lead to chronic pancreatitis. The progression of the disease is halted when the obstructing lesion can be removed. IDIOPATHIC.

The remaining 10 to 25% of patients are in the "idiopathic" category. They present the full spectrum of the disease, from mild functional disturbances to advanced calcific disease. Notably, gallstone-associated acute pancreatitis is not a cause of chronic pancreatitis. CLINICAL PRESENTATION AND COURSE. In approximately 40% of patients, chronic pancreatitis initially presents with episodes that are indistinguishable from acute pancreatitis. Insidious onset of pain heralds the disease in another 40%, and malabsorption, diabetes, or complications of chronic pancreatitis lead to the diagnosis in the remainder. Pain is minor or absent in 7 to 15% of patients during the course of the disease. PAIN.

Pain is intermittent or chronic; it is boring and dull, often accompanied by nausea and vomiting. It is perceived in the epigastrium and/or the left and right subcostal areas and radiates straight through to the back in approximately one half of patients. Pain may be aggravated by eating and on the day after a drinking bout. Pancreatic pain fibers pass through the celiac plexus and the paravertebral sympathetic ganglia. Events that may trigger the pain of chronic pancreatitis are raised intraductal and pancreatic parenchymal pressure due to ductal obstruction and perineural inflammation with fibrosis. Pain is the predominant symptom; it may keep the patient from work, impair social and family relationships, and frustrate attempts at abstaining from alcohol. Spontaneous pain relief occurs in approximately 60% of patients within 6 to 12 years after the onset of symptoms. Pancreatic calcifications, diabetes mellitus, and malabsorption frequently appear when the pain begins to diminish.

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WEIGHT LOSS.

Weight loss is common during the course of the disease. Contributing causes include anorexia caused by pain or analgesics, funds being spent on alcohol rather than food, untreated diabetes, and malabsorption due to pancreatic exocrine insufficiency. Malabsorption develops in about 40% of patients, usually 5 to 10 years after the onset of pain. Most patients can compensate for weight loss due to malabsorption by increasing their food intake. DIABETES MELLITUS.

Progressive loss of islets of Langerhans eventually leads to diabetes in 70% of patients, half of whom require insulin treatment. Patients with chronic pancreatitis and diabetes are at increased risk of hypoglycemia because of concomitant glucagon deficiency, poor dietary habits, and the hypoglycemic effects of alcohol. CARCINOMA.

The incidence of adenocarcinoma of the pancreas is increased in chronic pancreatitis, particularly the hereditary type. Early diagnosis is rarely possible and the prognosis is dismal. MORTALITY.

The 10-year survival is 65% in alcoholics and 80% in patients with non-alcoholic chronic pancreatitis. Only 10 to 20% of deaths are directly related to the disease. Major contributors to the excess mortality are extrapancreatic and pancreatic carcinoma, hypoglycemia, and the effects of alcoholism. DIAGNOSIS. IMAGING STUDIES.

Plain anteroposterior and oblique views of the abdomen may reveal localized or diffuse intraductal calcifications of the pancreas. Abdominal CT may detect small calcifications missed on plain radiographs, dilatation of the main pancreatic duct, and pseudocysts. Differentiation from cancer of the pancreas may be difficult. Early in the course, ERCP may show blunting and dilatation of pancreatic duct branches, but the pancreatogram may be normal in up to 10% of patients. The main value of ERCP is to identify potentially correctable lesions, such as large ductal stones, pseudocysts, and duct strictures. Endoscopic US may detect early stages of the disease. BLOOD TESTS.

Serum amylase and lipase concentrations frequently remain normal during attacks of pain. Serum levels of pancreatic isoamylase and trypsin may be decreased, but these changes are not sufficiently reliable for the early diagnosis of chronic pancreatitis. PANCREATIC FUNCTION TESTS.

The so-called secretin test is the most sensitive test for chronic pancreatitis. Duodenal contents are aspirated after the intravenous administration of secretin ± cholecystokinin or cerulein. The calculated pancreatic output of bicarbonate and enzymes is decreased in approximately 85% of patients, and the test accuracy is 87%. In the simpler Lundh test, trypsin concentration is determined in the proximal jejunum after a liquid test meal. Both tests are time consuming, and neither is widely used. OTHER TESTS.

The bentiromide (NBT-PABA) test assesses intestinal tryptic activity by quantitating the urinary excretion of p-amino benzoic acid after oral dosing with the test compound. This test and measurement of stool chymotrypsin concentration are reliably abnormal only with advanced pancreatic insufficiency. Vitamin B12 absorption may be impaired due to decreased liberation of this vitamin bound to gastric R-proteins by duodenal trypsin (see Chapter 163) . An abnormal Schilling test of vitamin B12 (cobalamin) absorption that corrects with administration of pancreatic enzymes is a specific, but not a sensitive, test for chronic pancreatitis. Clinical vitamin B12 deficiency develops rarely. SEQUENCE OF TESTS.

Diagnosis depends on symptoms, tests of pancreatic function, and radiologic studies, including ERCP. In general, the documentation of any two of these three manifestations is sufficient for making the diagnosis. An example is the presence of pancreatic calcifications on a plain film of the abdomen in a patient with chronic upper abdominal pain. Abdominal CT frequently provides additional information regarding the presence and possible complications of chronic pancreatitis. Two diagnostic dilemmas generally require expert consultation. The first is to rule out early, mild chronic pancreatitis. Because neither the duodenal secretin test nor the ERCP examination is 100% sensitive, both tests plus endoscopic US may have to be performed. The second is to differentiate chronic pancreatitis from adenocarcinoma or a cystic tumor of the pancreas. When imaging methods, cytologic testing of percutaneous aspirates from a pancreatic mass, and diagnostic laparoscopy fail to provide the answer, surgical exploration and resection may be required. THERAPY. PAIN.

Control of abdominal pain is the most important and difficult task in treating chronic pancreatitis. Narcotics are frequently required and should not be withheld because of concerns about evolving addiction and concomitant alcoholism. Acute attacks of pain require hospitalization with no oral intake, parenteral analgesics, and renewed efforts at achieving abstinence from alcohol. The rationale for a trial of pancreatic enzymes is the inhibition of cholecystokinin release by intraduodenal trypsin, leading to decreased meal-stimulated pancreatic secretion. Non-enteric-coated preparations of pancrelipase should be used, such as Viokase, Cotazyme, or Ilozyme, at doses of 6 tablets per meal. Concomitant suppression of gastric acid secretion with an H2 -receptor blocker is advisable to minimize the destruction of the enzyme supplement at low gastric pH. Pain relief has been reported in some patients with mild non-alcoholic chronic pancreatitis, that is, without pancreatic calcifications or steatorrhea. Percutaneous destruction of the celiac plexus by alcohol or phenol injection reduces pain in approximately 60% of patients, but the effect is transient and the procedure has potential complications. Patients with intractable chronic or intermittent pain should be considered for a surgical procedure based on ERCP and CT evaluation of the duct system. When the pancreatic duct is dilated to 8 mm or more in diameter, decompression may be attempted by endoscopic stent placement across the ampulla of Vater. Most patients, however, require permanent duct decompression by longitudinal pancreaticojejunostomy. In the absence of a dilated pancreatic duct, partial pancreatectomy, such as pancreaticoduodenectomy (Whipple procedure), can be performed when severe changes are confined to the head of the pancreas. When expertly performed and limited to patients who abstain from alcohol, these operations relieve pain in approximately 70% of patients. MALABSORPTION.

Malabsorption is a late manifestation of chronic pancreatitis and occurs when pancreatic secretion of digestive enzymes is reduced by 90% or more. Fat malabsorption due to lipase deficiency is the predominant abnormality. The condition is documented by a stool fat content of more than 7 g/d (steatorrhea). The indication for treatment is weight loss that cannot be corrected by increasing the caloric intake. Reducing or eliminating steatorrhea is difficult to achieve due to the low potency of available porcine pancreatic extracts and their irreversible denaturation at gastric pH values of less than 4. Enzymes can be taken as described earlier. Alternatively, enteric-coated enzyme preparations such as Pancrease or Creon, which are released only in the alkaline milieu of the duodenum, can be prescribed in doses of two to three capsules per meal. COMPLICATIONS. PSEUDOCYSTS.

Pancreatic pseudocysts contain high concentrations of pancreatic enzymes and are encapsulated by a rim of chronic inflammation and fibrosis; they are without an epithelial lining. Pseudocysts may represent fluid collections that developed during acute pancreatitis but failed to resolve over a period of 6 to 8 weeks. More commonly, they result from obstruction of small pancreatic ducts, a type of retention cyst formed during the course of chronic pancreatitis. Pseudocysts are located within or around the pancreas but may dissect retroperitoneally to the mediastinum or pelvis; pseudocysts in the head of the pancreas may compress the common bile duct. Pseudocysts can be diagnosed by abdominal US, CT, or endoscopic US, but their differentiation from rare uniloculated pancreatic cystic neoplasms is difficult. One or more pseudocysts appear in up to 60% of patients with chronic pancreatitis. Life-threatening but rare complications include infection, hemorrhage into the cystic space, and rupture of the pseudocyst. The contribution of a pseudocyst to the pain of chronic pancreatitis is difficult to assess. Treatment should be considered for large pseudocysts (>5 cm in diameter). Internal drainage into the stomach, duodenum, or jejunum yields excellent results. Successful treatment by percutaneous or endoscopic aspiration and drainage for several weeks has also been reported. PANCREATIC ASCITES.

Ascites and pleural effusions during the course of chronic pancreatitis are the result of leakage from a disrupted pancreatic duct. The amylase and lipase content is many times higher than in the blood. The majority of these patients require surgical correction of the leak by providing drainage into a loop of jejunum or by partial pancreatectomy. OBSTRUCTION OF ADJACENT ORGANS.

Several structures adjacent

759

to the pancreas may become obstructed by fibrosis or a developing pseudocyst. Common bile duct obstruction with slowly developing jaundice requires a biliary-enteric drainage procedure to prevent the development of secondary biliary cirrhosis and ascending cholangitis. Gastric outlet obstruction can be bypassed by a gastrojejunostomy; a vagotomy should be added. Compression or thrombosis of the splenic vein leads to gastric fundic varices that may bleed; splenectomy is curative. Fernandez-del Castillo C, Rattner DW, Makary MA, et al: Debridement and closed packing for the treatment of necrotizing pancreatitis. Ann Surg 228:676, 1998. An account of the complexity and management problems presented by necrotizing acute pancreatitis. Gorry MC, Gabbaizedeh D, Furey W, et al: Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis. Gastroenterology 113:1063, 1997. Identification of the second single nucleotide mutation in families with hereditary pancreatitis. The mutations predict resistance of active trypsin to autodegradation within the pancreas.

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Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 142 - DISEASES OF THE PERITONEUM, MESENTERY, AND OMENTUM Michael R. Lucey

PERITONEAL DISORDERS Abdominal pain and ascites are characteristic clinical features in disorders of the peritoneum. Ascites Ascites, the accumulation of serous fluid in the peritoneal cavity, has many causes (Table 142-1) . More than 90% of cases of ascites are due to portal hypertension, usually as a result of cirrhosis (see Chapter 153) . Perhaps half of the remainder, i.e., 5% of all cases of ascites, are due to peritoneal disease. CLINICAL FEATURES OF ASCITES.

Increasing abdominal girth and rapid weight gain are the most common symptoms associated with new-onset ascites. Dullness in the flanks when the patient is supine, shifting dullness during percussion of the abdomen, and a fluid wave are useful clinical signs to detect ascites, but volumes smaller than 1500 mL are often clinically undetectable. When it is clinically important to confirm the presence of suspected ascites, sonography or computed tomographic (CT) scanning of the abdomen is advisable. The investigation of new-onset ascites, especially if unexplained by standard clinical examination and tests, should always include paracentesis (Table 142-2) . Ascitic fluid can be examined for biochemical content and cytology and sent for culture. In specific cases, such as suspected tubercular peritonitis, biopsy of the peritoneum during laparoscopy is valuable (see below). The mechanism of ascites formation in portal hypertension is complex (see Chapter 153) and includes such factors as altered Starling forces in the portal circulation (increased portal venous hydrostatic pressure, reduced portal venous oncotic pressure), altered renal sodium handling, and increased hepatic and possibly splanchnic lymph formation. Portal oncotic pressure is reduced in cirrhotic patients because of hypoalbuminemia, which is due to hepatic synthetic failure. In contrast, obstructed outflow of normal lymphatics appears to be a principal causative factor in the development of ascites secondary to peritoneal carcinomatosis or malignant chylous ascites. Medical management using diuretics and salt restriction is often effective in patients with portal hypertension. Conversely, ascites caused by peritoneal inflammation or malignancy alone does not respond to salt restriction and diuretics. In the past, portal hypertensive ascites was distinguished from other forms of ascites by determining whether the ascitic fluid was a transudate or an exudate. This concept assumes that in portal hypertension, protein-poor ascitic fluid transudes from the normal peritoneal surface, whereas in peritoneal disease such as peritoneal TABLE 142-1 -- CAUSES OF ASCITES CAUSES OF ASCITES

COMMENTS

Portal hypertension Cirrhosis

Accounts for 80% of ascites in the United States

Fulminant hepatic failure

Rarely causes ascites

Hepatic outflow obstruction

Ascites is a characteristic clinical feature of hepatic outflow obstruction

Congestive heart failure Constrictive/restrictive cardiomyopathy Budd-Chiari syndrome--hepatic vein and/or IVC occlusion

Most commonly associated with an underlying thrombotic disorder

Veno-occlusive disease

Important cause of ascites in bone marrow transplant recipients

Portal vein occlusion

Rarely causes ascites

Malignancy

Accounts for 10% of ascites in the United States. Peritoneal carcinomatosis causes 50% of malignant ascites

Infection Peritoneal tuberculosis

See Tables 142-6 and 142-7

Fitz-Hugh-Curtis syndrome

Perihepatitis associated with fibrous perihepatic exudate usually due to Neisseria gonorrhoeae or Chlamydia trachomatis

Infectious peritonitis in HIV-infected patients Renal Nephrotic syndrome

Covert cirrhosis should be excluded

Nephrogenous in hemodialysis recipients

Covert cirrhosis should be excluded

Endocrine Myxedema Meigs' syndrome Strauma ovarii Ovarian stimulation syndrome Pancreatic Ascites

Associated with pancreatitis, raised ascitic amylase concentration

Biliary Leak

Previous surgery, including laparoscopic cholecystectomy, gangrenous gallbladder, trauma, percutaneous liver biopsy

Urine ascites

Urinary leak into the peritoneum

Systemic lupus erythematosus Miscellaneous

Idiopathic chronic non-specific peritonitis in HIV-infected patients

See text

Mixed causes

IVC = inferior vena cava; HIV = human immunodeficiency virus. inflammation or malignancy, protein-rich ascitic fluid exudes from the abnormal peritoneal surface. Consequently, ascitic fluid with a protein content greater than 2.5 g/dL was designated an exudate, and fluid with a protein content less than 2.5 g/dL was termed a transudate. However, the transudate-exudate characterization is flawed because many patients with spontaneous bacterial peritonitis (SBP), in which ascitic fluid is infected, nonetheless have low ascitic fluid protein rather than the expected high protein content (see below) and many samples of ascites from portal hypertension secondary to cardiac failure have a high protein content rather than the expected low protein content. The preferred method to distinguish ascites associated with portal hypertension from other forms of ascites is the serum-ascites albumin gradient, which is calculated by subtracting the ascitic albumin concentration from the serum albumin concentration. Ascites associated with portal hypertension has a serum-ascites albumin gradient greater than 1.1 g/dL, whereas ascites caused by peritoneal inflammation or malignancy has a serum-ascites albumin gradient less than 1.1 g/dL (Table 142-3) . Many patients have more than one potential cause of ascites, so-called mixed ascites, such as cirrhosis and peritoneal tuberculosis; the serum-ascites albumin gradient 760

TABLE 142-2 -- DIAGNOSTIC TESTS IN ASCITES FEATURE

Portal hypertension

Malignancy

DIAGNOSIS

ASCITIC WHITE BLOOD CELL COUNT (per mm3 )

ASCITIC RED BLOOD CELL COUNT

CYTOLOGY (% POSITIVE NEOPLASTIC CELLS)

BIOCHEMICAL ANALYSIS

SERUM-ASCITES ALBUMIN GRADIENT (g/dL)

COMMENTS

Cirrhosis

250 PMN

Few or none

0

Albumin 1.1

--

Cardiac ascites

2.5 g/dL

>1.1

--

Peritoneal carcinomatosis

75% have >500

Few or none

100

Protein usually >2.5 g/dL

1.1

80

Serum alkaline phosphatase 350 mU/mL

Triglycerides >200 mg/dL

Usually 300

Few or none

0

Hepatoma plus ascites

Often >500

Commonly increased

0

Infection

Tuberculous peritonitis

80% >500, predominantly lymphocytes

Frequently present

0

Miscellaneous

Pancreatic ascites

Frequently increased

0

--

>1.1

Elevated serum alpha-fetoprotein

Ascitic adenosine deaminase 32.3 U/L or LDH >90 mu/L

50% have >1.1 (i.e., may have cirrhosis)

See Table 142-6

Ascitic amylase greatly increased

Variable

--

PMN = polymorphonuclear leukocytes; SBP = spontaneous bacterial peritonitis; MHM = massive hepatic metastases; LDH = lactate dehydrogenase. usually reflects the presence of portal hypertension even when other causes of ascites are also present. Portal hypertensive ascites that fails to respond to salt restriction and diuretics is termed refractory ascites. Serial large-volume paracentesis is the simplest approach to management. The value of intravenous infusions of albumin to counter the volume contraction caused by paracentesis is controversial but reasonable in patients with accompanying renal insufficiency, defined as a serum creatinine content greater than 1.5 mg/dL. Rapid removal of ascitic fluid occasionally results in peritoneal hemorrhage. Placement of a transjugular intrahepatic portosystemic shunt also improves ascitic control in cirrhotic patients with refractory ascites, albeit with the risks of encephalopathy and decompensation in hepatic function associated with this procedure. MALIGNANT ASCITES.

Malignant ascites constitutes a small fraction of all cases of ascites and represents a heterogeneous group of disorders and mechanisms. Peritoneal carcinomatosis, the most common form of malignant ascites, arises from primary peritoneal disease such as mesothelioma or from the metastatic spread of a wide variety of malignant processes (Table 142-4) . On occasion, in addition to malignant studding of the peritoneum, a tumor also TABLE 142-3 -- CLASSIFICATIONS OF ASCITES BY SERUM-ASCITES ALBUMIN CONCENTRATION GRADIENT HIGH GRADIENT (> 1.1 g/dL)

LOW GRADIENT (< 1.1 g/dL)

Cirrhosis

Peritoneal carcinomatosis

Alcoholic hepatitis

TB peritonitis (without cirrhosis)

Congestive restrictive heart failure

Pancreatic ascites (without cirrhosis)

Massive hepatic metastases

Bile leak

Fulminant hepatic failure

Nephrotic syndrome

Budd-Chiari syndrome

Systemic lupus erythematosus

Veno-occlusive disease

Bowel obstruction or infarction

Portal vein occlusion Acute fatty liver of pregnancy Myxedema TB = tuberculous. produces massive hepatic metastases sufficient to cause portal hypertension. Whenever ascites is due to malignant infiltration of the peritoneum, either alone or accompanied by massive hepatic metastases, shedding of malignant cells into the ascites is almost invariable (see Table 142-2) . In contrast, massive hepatic metastases without peritoneal studding or multilocular primary hepatocellular carcinoma arising in a cirrhotic liver rarely cause shedding of malignant cells into the ascitic fluid. Thus cytologic analysis of the ascitic fluid is extremely valuable when attempting to identify peritoneal malignancy. Mesothelioma is an exception to this rule because it produces cytologic results that are often difficult to interpret. The serum-ascites albumin gradient in malignant ascites reflects the presence or absence of portal hypertension. Therefore, the serum-ascites gradient is low in patients with peritoneal carcinomatosis and normal portal pressure, whereas ascites associated with massive hepatic metastases irrespective of peritoneal studding or with primary hepatocellular carcinoma arising in a cirrhotic liver is associated with a serum-ascites albumin gradient greater than 1.1 g/dL, which reflects the presence

of portal hypertension. The underlying cause of malignant ascites is determined after a thorough clinical TABLE 142-4 -- CAUSES OF PERITONEAL CARCINOMATOSIS Primary disorders of the peritoneum Mesothelioma Metastatic spread from Gastrointestinal tumors Stomach Colon Pancreas Other intra-abdominal organs Ovary Pseudomyxoma peritonei Extra-abdominal primary tumors Breast Lung Hematologic malignancy Lymphoma

761

evaluation, which often includes laboratory tests and imaging procedures; for example, massive hepatic metastases are invariably associated with a marked elevation in serum alkaline phosphatase, usually greater than 350 IU/mL. The presence of ascites with positive neoplastic cytologic findings indicating peritoneal carcinomatosis signifies an expected survival of 6 months or less. Therapy is palliative. In certain causes, such as mesothelioma, instilling antitumor agents into the peritoneal cavity may be part of a therapeutic program directed against the underlying tumor. Diuretics and salt restriction are ineffective in controlling ascites caused by peritoneal carcinomatosis. Serial paracentesis is the simplest method to control symptomatic malignant ascites. Occasionally, a peritoneovenous shunt may provide valuable, albeit temporary palliation. When malignant ascites is associated with portal hypertension, the prognosis is always poor. Salt restriction and diuretics may effectively control the ascites; when diuretics are ineffective, serial paracentesis is often the best method for rapid palliation. CHYLOUS ASCITES.

Chylous ascites is milky in appearance because of leakage of lymph into the peritoneal cavity; the triglyceride concentration is markedly elevated, always greater than 200 mg/dL and often greater than 1000 mg/dL. New-onset chylous ascites is most often due to underlying malignancy, especially lymphoma. Occasionally, chylous ascites occurs after trauma, intra-abdominal surgery, heart failure, and peritoneal infection such as tuberculosis (TB). Rarely, it occurs as an incidental unexplained finding in cirrhotic patients. Except in cases of known trauma, investigation is focused on identifying an underlying malignant process, even though malignant chylous ascites rarely contains malignant cells (see Table 142-2) . Appropriate tests include abdominal CT or magnetic resonance imaging (MRI) and bone marrow aspiration. Lymphangiography does not identify intra-abdominal lymphadenopathy when CT or MRI has failed to do so. Chylous ascites, whether of malignant or benign origin, responds poorly to salt restriction or diuretics, except in rare idiopathic cases associated with cirrhosis and portal hypertension. Paracentesis offers simple palliative therapy. In the majority of cases, treatment is directed at the underlying lymphoma. Fat in the diet can be replaced with medium-chain triglycerides that are absorbed directly into the portal blood stream and bypass the lymphatics. Occasional patients may be placed on a regimen of total parenteral nutrition to reduce the formation of chylous ascites. PANCREATIC ASCITES.

Pancreatic ascites is due to leakage of pancreatic juice into the peritoneal cavity. It occurs in patients after pancreatitis when a pseudocyst ruptures into the peritoneum and causes pancreatic ascites (see Chapter 141) . Because alcohol is a frequent cause of pancreatitis and is the most common cause of chronic liver failure, it may be difficult to distinguish pancreatic ascites secondary to alcoholic pancreatitis from ascites secondary to alcoholic cirrhosis in someone with concomitant alcoholic pancreatitis. Paracentesis reveals a high serum-ascites albumin gradient in the presence of portal hypertensive ascites, which suggests cirrhosis rather than pancreatitis as the source of ascites, or a very elevated amylase concentration, usually considerably greater than the serum level (see Table 142-2) in pancreatic ascites. In pancreatic ascites, the ascitic amylase concentration remains elevated even after the serum level declines toward normal. Endoscopic retrograde cholangiopancreatography is useful in pancreatic ascites, especially in trauma cases, to identify a disrupted pancreatic duct. Surgery to drain the pseudocyst and repair the duct is necessary in traumatic pancreatic ascites, but a conservative approach is often adopted in alcoholic and other non-traumatic cases. ENDOCRINE ASCITES.

In rare circumstances, ascites is a principal manifestation of an endocrine disorder. Examples include myxedema (which causes an elevated serum-ascites albumin gradient), struma ovarii, Meigs' syndrome (see Chapter 86) with ascites and pleural effusion caused by benign ovarian neoplasms, and ovarian overstimulation syndrome, which occurs in women receiving fertility-enhancing drugs such as clomiphene citrate, human chorionic gonadotropin, human menopausal gonadotropin, follicle-stimulating hormones, and luteinizing hormone-releasing hormone. RENAL ASCITES.

Nephrotic syndrome is a rare cause of ascites in the absence of liver disease when the serum albumin concentration falls below 2.0 g/dL. However, whenever this diagnosis is considered, a careful search for underlying liver disease is mandatory. Hepatitis B surface antigen and anti-hepatitis C antibodies (see Chapters 149 and 150) should be measured because hepatitis B or C may produce glomerulonephritis as well as cirrhosis and the resulting ascites may be due to any combination of portal hypertension, poor albumin synthesis, and renal albumin wasting. CONNECTIVE TISSUE DISORDERS.

Occasionally, systemic lupus erythematosus is associated with the development of ascites in the absence of liver disease and portal hypertension. The ascites may respond to therapy for the underlying disease. ASCITES IN HIV-INFECTED PATIENTS.

When new-onset ascites occurs in patients with acquired immune deficiency syndrome (AIDS), causes of portal hypertension such as alcoholism or chronic viral hepatitis should be sought. Other sources of ascites in patients with AIDS include abdominal lymphoma, Kaposi's sarcoma, or peritoneal infection. Among the infections reported to cause ascites in human immunodeficiency virus (HIV)-infected patients are TB, Mycobacterium avium complex, cryptococcal disease, and coccidioidomycosis. Patients with a reduced peripheral CD4+ count may have ascites secondary to intestinal perforation or acute appendicitis without other more typical features of intestinal catastrophe. In addition, ascites develops in some HIV-infected patients as a result of a chronic non-specific peritonitis for which no infectious or malignant cause is identified. Acute Peritonitis DEFINITION.

Acute peritonitis is inflammation of the peritoneum or peritoneal fluid from bacteria or intestinal contents (including gastric acid, gastrointestinal luminal contents, bile, or

pancreatic juice) in the peritoneal cavity. Secondary peritonitis results from any definable cause, such as perforation of a viscus owing to acute appendicitis or diverticulitis, perforation of an ulcer (peptic ulcer, Crohn's disease, malignancy), and trauma, including iatrogenic intervention (e.g., surgery, needle biopsies). Primary peritonitis, including SBP, refers to peritonitis arising without a recognizable preceding cause. Tertiary peritonitis, which is persistent intra-abdominal sepsis without a discrete focus of infection, generally follows surgical treatment of prior severe peritonitis and occurs in severely ill patients in intensive care, especially patients who are immunosuppressed. PROGNOSTIC FACTORS.

Peritonitis after acute appendicitis or a perforated peptic ulcer occurring in an otherwise healthy patient is associated with a low mortality, whereas peritonitis after elective surgery, trauma, or pancreatitis has a high mortality irrespective of the patient's overall clinical setting. The prognosis for severe peritonitis has not changed in the past 50 years despite the advent of broad-spectrum antibiotics, critical care units, and radical approaches to eliminate bacterial contamination of the peritoneal cavity. The outcome in severe peritonitis is dictated by the patient's overall health, including nutritional status, immunocompetence, and systemic factors such as cardiac and renal function. CLINICAL FEATURES.

The classic features of acute peritonitis are abdominal pain, abdominal tenderness, and the absence of bowel sounds. Severe, sudden-onset abdominal pain suggests a ruptured viscus. The clinical signs of peritoneal irritation include abdominal tenderness, rebound tenderness, and eventually, abdominal rigidity. In florid cases, these signs and symptoms are accompanied by fever, hypotension, tachycardia, and acidosis. Although this clinical pattern is characteristic, acute peritonitis may frequently lack these features. For example, SBP arising in ascites is often very subtle in manifestation (see below). Acute peritonitis arising in elderly or immunosuppressed patients may lack the features of peritoneal irritation or systemic decompensation. Similarly, in patients with tertiary peritonitis, classic signs and symptoms may be absent or suppressed and the diagnosis suggested only by persistent leukocytosis or fever. In these atypical circumstances, a high index of suspicion is necessary. DIAGNOSIS.

Plain abdominal radiographs can determine the presence of free air in the abdominal cavity, a characteristic finding of a perforated viscus. CT and/or ultrasonography can identify the presence of free fluid or an abscess. When peritonitis is associated with ascites, paracentesis is mandatory (see Table 142-2) . THERAPY.

The three key elements of therapy for acute peritonitis 762

are resuscitation, laparotomy, and antibiotics. Resuscitation with intravenous fluids and correction of metabolic and electrolyte disturbances are the initial steps. Laparotomy is a cornerstone of therapy for secondary or tertiary acute peritonitis to identify and repair the cause of the acute catastrophe, to evacuate pus, and to irrigate the peritoneal cavity. In some patients, when biliary peritonitis is accompanied by little systemic disturbance, careful conservative management with intravenous fluids and broad-spectrum antibiotics is adequate, and laparotomy can be avoided. However, the threshold for proceeding to laparotomy should be low, even in these circumstances. Broad-spectrum systemic antibiotics are critical to cover bowel flora, including anaerobic species (see Chapter 157) . When peritonitis persists despite all standard measures, antifungal agents (such as amphotericin B or fluconazole) are appropriate for possible candidal infections. Spontaneous Bacterial Peritonitis DEFINITION.

SBP, which has no obvious precipitating cause, occurs almost exclusively in cirrhotic patients but may occasionally complicate acute hepatic failure. SBP is a marker of severe hepatic failure and usually occurs in patients with low ascitic protein content and elevated serum bilirubin. For example, SBP develops in approximately 25% of patients with an ascitic fluid total protein content of less than 1 g/dL during 3 years of subsequent observation. The mechanism of SBP development is related to deficient opsonic activity in ascitic fluid. The offending organisms are almost always enteric gram-negative aerobes such as Escherichia coli or Klebsiella pneumoniae or gram-positive aerobes, particularly Streptococcus pneumoniae. Anaerobic organisms rarely cause SBP. CLINICAL FEATURES.

The clinical manifestation of SBP is often subtle. It must be suspected not only whenever a cirrhotic patient has fever and abdominal pain more typical of acute peritonitis but also whenever a cirrhotic patient with ascites has a sudden deterioration in hepatic or renal function, worsening malaise, encephalopathy, or unexplained persistent leukocytosis, even in the absence of abdominal signs or symptoms typical of acute peritonitis. A high index of suspicion is also necessary whenever a patient with known established liver disease has features of sepsis or hepatic deterioration despite the absence of clinical ascites; small pockets of infected ascites may be present and detectable only by ultrasound or CT scan, and a presumptive diagnosis of SBP followed by empirical antibiotic therapy may be the wisest course. DIAGNOSIS.

The key to establishing SBP is diagnostic paracentesis in which the ascitic fluid is found to have 250 or more polymorphonuclear (PMN) cells per cubic millimeter. A very elevated PMN cell count in ascites (for example, >5000/mm3 ) suggests an intra-abdominal abscess or a secondary cause of peritonitis. Demonstrating an organism in the ascitic fluid is helpful but not required for diagnosis. The chances of identifying an organism in ascites are enhanced by directly transferring ascitic fluid to blood culture media bottles before incubation, but even then no organism is identified in 30 to 50% of cases. SBP is usually caused by a single species, so multiple organisms on ascitic culture suggest a perforated viscus. In addition to inspecting and culturing ascitic fluid, all patients suspected of having SBP should have blood cultures, chest radiography, and urine microscopy and culture to identify blood-borne sepsis and to look for additional sites of infection. THERAPY.

Antibiotics are the cornerstone of managing SBP, and laparotomy has no place in therapy for SBP. Three to 5 days of intravenous treatment with broad-spectrum antibiotics is usually adequate, at which time efficacy can be determined by estimating TABLE 142-5 -- RISK FACTORS FOR INTRA-ABDOMINAL TUBERCULOSIS HIV infection Immunosuppressive therapy Advanced age Intravenous drug use/alcoholism/cirrhosis Immigration from an endemic area Poverty Incarceration/long-stay care Peritoneal dialysis

TABLE 142-6 -- CLINICAL CHARACTERISTICS OF PERITONEAL TUBERCULOSIS* (%) Ascites

80-100

Abdominal swelling

65-100

Abdominal pain

36-93

Weight loss

37-87

Fever

56-100

Diarrhea

9-27

Abdominal tenderness

65-87

Anemia

46-68

Positive PPD test

55-100

PPD = purified protein derivative. *The percentages represent the frequency with which these features have been observed in peritoneal tuberculosis. These data antedate studies of TB in HIV-infected persons.

the ascitic fluid PMN cell count; the use of intravenous antibiotics can be discontinued if the count is less than 250/mm3 . The most important negative prognostic factors are the presence of renal failure, onset of SBP while in the hospital, and elevated serum aminotransferase levels. SBP recurs in 70% of patients in the first year after their initial episode unless prophylactic antibiotics are used. The frequency of recurrence is greatest in patients with a low ascitic fluid total protein content and impaired hepatic synthetic function. The incidence of SBP can be markedly reduced, both in patients who are at risk for a first episode and in those who have already had SBP, with prophylactic antibiotics that cleanse the gut microflora, such as quinolones (norfloxacin once per day or ciprofloxacin once per week) or trimethoprim-sulfamethoxazole. Although prophylaxis reduces the incidence of SBP, mortality is related to the underlying hepatic dysfunction and is not affected. Peritoneal Tuberculosis TB is an important cause of peritonitis worldwide and, with advent of the AIDS epidemic, has re-emerged in the developed world (Table 142-5) . Patients with peritoneal TB frequently have concomitant cirrhosis, which may incorrectly be implicated as the source of ascites and obscure the presence of tuberculous peritonitis. The serum-ascites albumin gradient is low in patients with peritoneal TB without portal hypertension or cirrhosis, but it is variably high or low in cirrhotic patients with TB. TB in HIV-infected patients is characterized by newly acquired infection rather than a recrudescence of quiescent infection, a high likelihood of TB among at-risk persons who are exposed to TB, a high rate of clinical rather than quiescent TB, rapidly progressive TB that frequently has extrapulmonary involvement, and finally, the emergence of TB strains that are resistant to one or more of the standard antituberculous chemotherapeutic agents. CLINICAL FEATURES.

Ascites is almost invariable, whereas abdominal swelling and pain are common (Table 142-6) . Many patients have accompanying systemic signs and symptoms such as fever, weight loss, and anemia. DIAGNOSIS.

Paracentesis reveals a lymphocytosis but rarely shows acid-fast bacilli on smear (Table 142-7) . Culture of ascitic fluid has a somewhat higher diagnostic yield, but with a 4- to 6-week delay; the potential immediate value of molecular diagnostic

DIAGNOSTIC TEST

TABLE 142-7 -- DIAGNOSTIC TESTS OF PERITONEAL TUBERCULOSIS COMMENT

Paracentesis With smear

62% in males; > 50% in females) and ferritin (more than twice normal). However, both of these parameters are prone to false-positive elevations and must be interpreted with caution. Transferrin saturation can be falsely elevated in non-fasting patients, in those with active liver necrosis, and even in heterozygotes for hemochromatosis. Ferritin also increases non-specifically with hepatocellular necrosis and may cause particular confusion in patients with alcoholic liver disease. To diagnose hereditary hemochromatosis with certainty, experts recommend a liver biopsy with quantitation of total hepatic iron. Patients with hereditary hemochromatosis who have clinical

evidence of liver disease will have a hepatic iron index (micromoles of hepatic iron per gram of dry tissue divided by age in years) greater than 1.9. Genetic testing can also be performed for the C282Y mutation in HFE, but treatment is generally reserved for patients with confirmed iron overload on liver biopsy. Phlebotomy (see Chapter 221) is the mainstay of therapy and can prevent or even reverse hepatic fibrosis. Fully developed cirrhosis is not usually reversible, although phlebotomy can enhance the survival of patients with cirrhosis. Unfortunately, patients with cirrhosis are at high risk of developing hepatocellular carcinoma, whether or not they undergo iron depletion therapy. Hepatocellular carcinoma is currently the leading cause of death among patients with hereditary hemochromatosis. Family members of probands are screened by genetic testing and by serial measurements of transferrin saturation and ferritin. Because of the high frequency of the genetic defect, screening the general population with iron studies or genetic tests is now recommended.

PROTOPORPHYRIA Protoporphyria is an inherited disorder marked by a profound reduction in ferrochelatase, the final enzyme in the pathway of heme synthesis. The mode of inheritance is debated. The primary clinical features of protoporphyria are cutaneous photosensitivity and scarring of sun-exposed skin; patients can also develop pigment gallstones, frequently at a young age. Parenchymal liver disease has been reported in fewer than 30 patients. Protoporphyria can be diagnosed by measuring elevated protoporphyrin levels in erythrocytes or feces. Patients with the highest levels of protoporphyrin (> 1000 mug/dL in erythrocytes) may be predisposed to liver disease and should undergo liver biopsy. Histology reveals birefringent deposits of protoporphyrin in hepato-cytes and Kupffer cells. Development of jaundice predicts rapid deterioration and demise. Treatment of the liver disease of protoporphyria is aimed at reducing production and increasing excretion of protoporphyrin. Hematin appears to decrease protoporphyrin production and has been useful in selected patients. Both cholestyramine and activated charcoal bind protoporphyrin in the gut, preventing enterohepatic recirculation and promoting excretion. For patients with severe liver disease and jaundice, liver transplantation should be considered.

CYSTIC FIBROSIS Cystic fibrosis (see Chapter 76) manifests rarely in infants as a syndrome of obstructive jaundice. Older children and adolescents are more likely to develop liver disease, although the reported prevalence varies from 2.2 to 16%. Patients usually have established hepatic fibrosis at the time of diagnosis. Biochemical tests often fail to predict liver injury; indeed, a catastrophe such as variceal hemorrhage is sometimes the first evidence for hepatic disease. Because chronic liver disease may be the initial manifestation of cystic fibrosis, the diagnosis should be considered in any child or adolescent with hepatic fibrosis of unknown cause. Therapy for portal hypertension follows that for other liver diseases.

GLYCOGEN STORAGE DISEASES Most of the glycogen storage diseases (see Chapter 203) are accompanied by hepatic glycogen accumulation and hepatomegaly. Only four of these (types O, I, III, and IV) result in clinical liver disease. Type O (glycogen synthetase deficiency) is extremely rare. Type IV (alpha-1,4-glucan-6-glycosyltransferase deficiency) leads to mortality from cirrhosis in early childhood. Types I and III are the two most likely to be encountered in adults. Type I glycogenosis (glucose-6-phosphatase deficiency) is characterized by hepatic glycogen accumulation and marked hepatic steatosis. Biochemical studies reveal profound hypoglycemia and hypertriglyceridemia. Hepatic aminotransferases are only mildly increased. Patients treated with a high glucose diet can survive to adulthood but are at extremely high risk for developing hepatic adenomas. Adenomas are present in 75% of patients by age 30; malignant transformation is rare. Rigorous therapy designed to maintain the blood glucose level above 75 mg/dL at all times may prevent or reverse adenoma formation. Type III glycogenosis (debrancher enzyme deficiency) differs from type I in that hypoglycemia and hyperlipidemia are much milder. Liver biopsy does not reveal steatosis but frequently demonstrates fibrosis, which rarely progresses to cirrhosis or portal hypertension. Supplemental feedings are recommended for patients with progressive liver injury.

AMYLOIDOSIS Hepatic involvement is common in patients with systemic amyloidosis (see Chapter 297) . Localized disease in the liver is rare but has been reported. Features of hepatic amyloidosis include hepatomegaly and increased serum alkaline phosphatase, each of which are found in 60% of patients with biopsy-proven liver involvement; clinical liver disease, however, is rarely encountered. A small number of patients with hepatic amyloidosis develop severe intrahepatic cholestasis with jaundice. This syndrome portends a poor prognosis, although death results from extrahepatic (primarily renal) disease. Liver biopsy is not required to confirm hepatic involvement in patients with known systemic amyloidosis. If the diagnosis is uncertain, liver biopsy may be useful and can be performed safely if clotting parameters are normal and any history of a bleeding disorder is excluded.

SARCOIDOSIS Sarcoidosis is one of the most common granulomatous diseases affecting the liver. Hepatic granulomas can be identified in approximately two thirds of patients with sarcoidosis, placing the liver behind only the lung and lymph nodes as the primary sites of 803

involvement (see Chapter 81) . Nevertheless, clinical symptoms of liver disease are rare in sarcoidosis. Liver involvement is usually recognized because of hepatomegaly or an elevated alkaline phosphatase level. A small minority of patients can develop a cholestatic syndrome characterized by pruritus and jaundice or can have hepatic failure and portal hypertension in the event the disease progresses to cirrhosis. Liver biopsy can be useful in establishing a diagnosis of sarcoidosis, because granulomas are so numerous as to be sampled even with a random needle core. Occasionally, portal granulomas can destroy intrahepatic bile ducts, mimicking primary biliary cirrhosis. The latter can be distinguished by the presence of antimitochondrial antibodies in serum. When sarcoidosis progresses to hepatic fibrosis, connective tissue deposition is more extensive than around the granulomas alone. Corticosteroids alleviate the symptoms of sarcoidosis but have not been proven to alter liver histology or the tendency toward hepatic fibrosis. Therapy should therefore be reserved for symptomatic patients in whom tuberculosis and other infectious diseases have been excluded.

TOTAL PARENTERAL NUTRITION The most common hepatobiliary complication of total parenteral nutrition (TPN) is hepatic steatosis. Fatty liver occurs in 25 to 100% of patients receiving TPN; the lesion is heralded by an increase in serum aminotransferase levels with a smaller increase in alkaline phosphatase. Enzymes peak at around 2 weeks of therapy and then decline even if TPN is continued without modification. Steatosis is completely reversible on cessation of the infusion. Long-term TPN poses a risk of chronic liver injury in adults. The most common abnormality is steatohepatitis; cholestasis and hepatic fibrosis have also been observed. Because steatohepatitis and cholestasis can both progress to hepatic fibrosis, their development is considered by many an indication to discontinue therapy. Chronic liver injury may be prevented by avoiding caloric excess, by infusing TPN cyclically, and by providing small amounts of enteral nutrition when possible. Adults receiving TPN for more than 30 days are at risk of forming biliary sludge and gallstones. Fifty per cent of patients develop sludge after 6 weeks, and virtually 100% of patients are affected after 3 months. Both acalculous and calculous cholecystitis can occur. Although the pathophysiology of sludge and stone formation in the setting of TPN is due in part to decreased bile flow, gallbladder stasis plays an important role. Stasis may be ameliorated by cholecystokinin, by pulsed infusions of amino acids, or by small enteral feedings.

LIVER DISEASE IN PREGNANCY

Pregnant women are susceptible to the full range of hepatic diseases. For the most part, pregnancy does not pose an increased risk of acute liver disease, nor does it alter the natural history of hepatic illnesses contracted during gestation. Notable exceptions are viral hepatitides caused by the herpes simplex, herpes zoster, and hepatitis E viruses. Herpes simplex hepatitis has a higher incidence in pregnant women than in the population at large. All three agents can provoke severe illness in pregnant women, with mortality rates as high as 20% in the case of hepatitis E. LIVER DISEASES UNIQUE TO PREGNANCY (Table 152-1) . Transient elevations in hepatic aminotransferase levels may accompany hyperemesis gravidarum. Biochemical cholestasis, defined as an increase in circulating bile acids, can be detected in as many as 10% of normal gestations. Symptomatic cholestasis occurs in only 1 to 5% of pregnant women and is generally confined to the second and third trimesters. Most patients complain only of pruritus (pruritus gravidarum); a minority exhibit a more severe syndrome with disabling pruritus, jaundice, and steatorrhea. The latter may have an inherited predisposition toward cholestasis, with women of South American Indian and Swedish descent being at high risk. Cholestasis of pregnancy is a self-limited syndrome that resolves spontaneously after delivery. Whereas mild disease poses no risk to either mother or fetus, severe disease places women at increased risk of premature delivery and fetal death. Symptoms of mild gestational cholestasis can be treated with antihistamines or cholestyramine. Severe disease warrants close monitoring and possible early delivery. Patients should be counseled that the syndrome often recurs with future pregnancies. Acute fatty liver of pregnancy is characterized by microvesicular fat accumulation in hepatocytes and hepatic necrosis. It mimics diseases caused by impairment of mitochondrial fatty acid oxidation, and in some instances it has been linked to fetal long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. The incidence is estimated from 1 in 6,000 to 1 in 13,000 gestations. Roughly half of affected women are primiparas. A specific diagnosis can be made only by demonstrating microvesicular fat droplets in hepatocytes; liver biopsy, however, is not essential for management and may be precluded by coagulopathy. Because acute fatty liver almost always resolves spontaneously post partum, prompt delivery of the fetus is the treatment of choice. Patients deteriorating despite delivery should be considered for liver transplantation. Fatty liver of pregnancy tends not to recur with subsequent gestations, although with fetal LCHAD deficiency the predicted recurrence rate is 25%. HELLP syndrome is the name given to a disorder of pregnancy characterized by hemolysis, elevated liver enzymes, and low platelets. This microangiopathic disorder of the liver occurs in the setting of severe preeclampsia or eclampsia with a frequency of 2 to 12%. Older, multiparous patients are at increased risk of HELLP syndrome; of note is that the classic triad of hypertension, proteinuria, and edema need not be present to make the diagnosis. Patients can develop HELLP syndrome in the second or third trimester or even post partum. Symptoms are similar to those of acute fatty liver of pregnancy, including abdominal pain, nausea, and vomiting. In rare instances, subcapsular hematomas can occur and lead to hepatic rupture and circulatory collapse. Laboratory abnormalities are not specific but often include anemia (hematocrit 5 mg/dL, prolonged prothrombin time *

Rare

Elevated AST/ALT (60-1500 U/L), platelets 600 U/L, microangiopathic anemia

3-25%

2, 3, or post partum Abdominal pain, nausea, vomiting

AST = aspartate aminotransferase; ALT = alanine aminotransferase. * Useful diagnostic distinction from HELLP syndrome, in which prothrombin time, partial thromboplastin time, and fibrinogen are usually normal.

804

maturity and to permit delivery as early as practical. The syndrome usually resolves rapidly post partum; in patients with persistent thrombocytopenia, plasmapheresis may be successful. The recurrence rate of HELLP syndrome in two large series varied between 3 and 25%. PREGNANCY WITH CHRONIC LIVER DISEASE. Fertility is reduced in women with chronic liver disease and particularly in those with cirrhosis. Nevertheless, pregnancies can occur in women with advanced liver disease and are encountered with some frequency in women with mild to moderate liver disease. In general, pregnancy does not alter the course of underlying liver disease. Nevertheless, severe underlying liver disease places the mother at risk of gestational complications such as variceal hemorrhage and fetal death. Prophylaxis of gastrointestinal bleeding is not warranted in patients with cirrhosis. Patients receiving specific medications, however, such as corticosteroids for autoimmune chronic active hepatitis or copper chelators for Wilson's disease, should continue them throughout gestation. Cuthbert JA: Wilson's disease: A new gene and an animal model for an old disease. J Invest Med 43:323, 1995. A comprehensive review of the disease and its genetics. Powell LW, George DK, McDonnell SM, Kowdley KV: Diagnoses of hemochromatosis. Ann Intern Med 129:925, 1998. One of a series of articles on the detection and management of hemochromatosis. Teckman JH, Qu D, Perlmutter DH: Molecular pathognesis of liver disease in alpha1 -antitrypsin deficiency. Hepatology 24:1504, 1996. An elegant summary that places new scientific information into cellular models of disease. Wolf JL: Liver disease in pregnancy. Med Clin North Am 80:1167, 1996. Concise review with 86 references.

MD Consult L.L.C. http://www.mdconsult.com Bookmark URL: /das/book/view/882/155.html/top

Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 153 - ALCOHOLIC LIVER DISEASE, CIRRHOSIS, AND ITS MAJOR SEQUELAE Scott L. Friedman

OVERVIEW DEFINITION AND GENERAL FEATURES. Cirrhosis consists of fibrosis of the hepatic parenchyma resulting in nodule formation. It represents the consequences of a sustained wound-healing response to chronic liver injury from a variety of causes (Table 153-1) , including toxins (e.g., alcohol), chronic viral infection, cholestasis, and metabolic disorders. The clinical manifestations of cirrhosis vary widely, from lack of symptoms to liver failure, and are determined by both the nature and severity of the underlying liver disease as well as the extent of fibrosis. Clinical manifestations can be broadly classified into those resulting from impaired hepatocellular function, such as jaundice and coagulopathy, and those that result from physical disruption of the parenchyma, such as gastroesophageal varices and ascites. EPIDEMIOLOGY. Up to 40% of patients with cirrhosis are asymptomatic. In these individuals, cirrhosis may be discovered during routine examination or at autopsy. The overall incidence of cirrhosis in the United States is estimated at 360 per 100,000 population, or approximately 900,000 total patients. Of these, the large majority have either alcoholic liver disease or chronic viral infection. Cirrhosis is the most common non-neoplastic cause of death among hepatobiliary and digestive diseases in the United States, accounting for approximately 30,000 deaths per year. An additional 10,000 deaths occur due to liver cancer, the majority of which involve underlying cirrhosis, and deaths due to liver cancer have increased in the past decade. Mortality in patients with alcoholic disease is considerably higher than in patients with other forms of cirrhosis. Death rates are also higher in men than in women. Since 1980, overall cirrhosis mortality has decreased by 25% in the United States, possibly reflecting decreasing alcohol consumption and, to a lesser extent, the advent of hepatitis B vaccination, improved supportive care, and availability of liver transplantation (see Chapter 155) . TABLE 153-1 -- CLASSIFICATION OF HEPATIC FIBROSIS AND CIRRHOSIS I. Presinusoidal fibrosis A. Schistosomiasis B. Idiopathic portal fibrosis II. Parenchymal (sinusoidal) fibrosis (true cirrhosis) A. Drugs and toxins 1. Alcohol 2. Methotrexate 3. Isoniazid 4. Vitamin A 5. Amiodarone 6. Perhexiline maleate 7. alpha-Methyldopa 8. Oxyphenisatin B. Infections 1. Chronic hepatitis B or C 2. Brucellosis 3. Echinococcosis 4. Congenital or tertiary syphilis C. Autoimmune 1. Autoimmune chronic hepatitis--types 1, 2, and 3 D. Vascular abnormalities 1. Chronic, passive congestion due to right-sided heart failure, pericarditis 2. Hereditary hemorrhagic telangiectasias (Osler-Weber-Rendu) E. Metabolic/genetic diseases 1. Wilson's disease 2. Hemochromatosis 3. alpha 1 -Antitrypsin deficiency 4. Carbohydrate disorders (e.g., fructose intolerance, galactosemia, glycogen storage diseases) 5. Lipid disorders (e.g., Wolman's disease, abetalipoproteinemia) 6. Urea cycle defects (e.g., ornithine transcarbamylase) 7. Porphyria 8. Amino acid disorders (e.g., tyrosinosis) 9. Bile acid disorders (e.g., Byler's disease) F. Biliary obstruction 1. Primary biliary cirrhosis 2. Secondary ("mechanical") biliary obstruction a. Primary sclerosing cholangitis b. Neoplasm of bile ducts or pancreas c. Iatrogenic or inflammatory biliary stricture

3. Cystic fibrosis 4. Biliary atresia/neonatal hepatitis 5. Congenital biliary cysts G. Idiopathic/miscellaneous 1. Non-alcoholic steatonecrosis (including jejuno-ileal bypass, obesity) 2. Indian childhood cirrhosis 3. Granulomatous liver disease 4. Polycystic liver disease III. Post-sinusoidal fibrosis A. Veno-occlusive disease

CLASSIFICATION AND ETIOLOGY. Cirrhosis has traditionally been classified as either macronodular (> 3-mm nodules) or micronodular (4 years) is lacking, the drug clearly improves survival free of liver transplantation in patients with moderate or severe disease. Cyclosporine had shown early promise in a small controlled trial, but longer-term usage led to only modest efficacy combined with an adverse effect on renal function, which has dampened enthusiasm for its use. Other immunosuppressive agents have met with modest success in some patients, including azathioprine, methotrexate, chlorambucil, and prednisone. In addition to specific agents against the disease, management should include correcting vitamin A, D, E, and K deficiencies and using antipruritics, including cholestyramine (16 to 32 g/day). In rare cases of intractable pruritus, opioid antagonists and plasmapheresis may be beneficial. Liver transplantation offers excellent quality of life in most patients with end-stage disease. Although transplantation is usually curative, rare cases of disease have recurred after transplant. SECONDARY BILIARY CIRRHOSIS. Secondary biliary cirrhosis occurs in response to chronic biliary obstruction from a variety of causes (see Chapter 157) . Neither the mechanism of scarring nor the duration and severity of obstruction required for irreversible fibrosis are established. In general, at least 6 months of obstruction are required for cirrhosis to develop, but shorter intervals have been reported. ETIOLOGY.

Cholestasis may be intrahepatic or extrahepatic, the latter also referred to as "mechanical" cholestasis. Primary sclerosing cholangitis is the most common cause of intrahepatic cholestasis besides PBC (see Chapter 157) . Cholestasis in this condition is incomplete but progressive and leads to cirrhosis in most patients within 10 years. Patients with associated inflammatory bowel disease who have undergone bowel resection may develop peristomal varices. In cystic fibrosis, intrahepatic cholestasis with focal biliary cirrhosis may complicate up to 25% of patients by the time of death, although liver disease is often asymptomatic. The precirrhotic lesion is marked by biliary proliferation and ductal occlusion. Cholestatic syndromes of infancy and childhood are frequently complicated by rapid progression of fibrosis within 10 to 12 weeks of birth even when recognized promptly. These disorders represent a spectrum of pathologic changes often involving atresia of either intrahepatic or extrahepatic ducts. There is overlap both clinically and histologically with neonatal hepatitis. Fibrosis often progresses even after successful biliary decompression and normalization of bilirubin, with biopsy specimens revealing a pattern resembling congenital hepatic fibrosis. Extrahepatic cholestasis in adults most commonly results from structural or mechanical obstruction. Common lesions include choledocholithiasis, biliary or pancreatic cancer, iatrogenic stricture, or chronic pancreatitis. A variant form of cholangiohepatitis in Asians is characterized by intrahepatic obstruction from biliary sludge, which can lead to recurrent cholangitis and secondary cirrhosis; the cause is unknown. PATHOLOGY.

The progression of histologic changes in chronic cholestasis has been well characterized. Hepatocyte degeneration with formation of cellular rosettes and ductular proliferation may be followed by inflammatory biliary necrosis and early periductal fibrosis. Inspissated bile within ductal lumens, formation of bile lakes, and periductular bile infarcts are classic late features. Early ductular changes are reversible, but persistent obstruction ultimately leads to portal-central septa and nodule formation typical of irreversible fibrosis. CLINICAL AND LABORATORY FEATURES.

Clinical consequences of secondary biliary cirrhosis will initially be determined by the underlying disease. With progression, jaundice may become the prominent symptom. Pruritus is variable in severity. Fat malabsorption with steatorrhea and deficiencies of vitamins A, D, E, and K occur in long-standing obstruction. Osteomalacia or osteoporosis may occur because of vitamin D malabsorption and calcium deficiency. Disproportionately increased hepatic alkaline phosphatase (fourfold to fivefold increase) relative to other liver tests is typical of secondary biliary cirrhosis. Other results of serum tests of biliary injury may be similarly elevated, including gamma-glutamyl transpeptidase and 5 -nucleotidase. Aminotransferase levels are increased less than twofold. Hypercholesterolemia is common. Associated markers of immunologic disease or bacterial cholangitis may be evident in patients with sclerosing cholangitis or mechanical obstruction, respectively. TREATMENT.

Recognizing and treating the underlying cause of cholestasis is the mainstay of therapy. For extrahepatic obstruction, biliary decompression, either by surgical drainage or by placement of a biliary stent for neoplasms, is usually required. Intrahepatic cholestasis is less amenable to surgical drainage, with management limited to treating complications. Pruritus can be controlled with cholestyramine (16 to 32 g/day in two divided doses) or, in severe cases, opioid antagonists (e.g., naloxone, nalmefene). Calcium and vitamin D supplementation may be required for bone disease. Parenteral replacement of vitamins A, E, and K is sometimes required. Regular exposure to sunlight enhances the conversion of 7-dehydrocholesterol to vitamin D and can reduce the development of osteomalacia. Current single-agent medical therapy for primary sclerosing cholangitis is not effective. For example, UDCA improves biochemical parameters but does not retard disease progression; future approaches may use combination therapy (e.g., UDCA and methotrexate). Liver transplantation is highly successful in most patients with secondary biliary cirrhosis and deteriorating liver function (see Chapter 155) .

VASCULAR DISORDERS ASSOCIATED WITH CIRRHOSIS CHRONIC RIGHT-SIDED HEART FAILURE. Long-standing right-sided heart failure due to cardiomyopathy, tricuspid valve 809

insufficiency, pulmonary disease, or pericardial constriction can lead to hepatic fibrosis; however, this late sequela is uncommon. The clinical picture is usually dominated by cardiac or pulmonary dysfunction. Liver abnormalities may be typical of hepatic congestion, with disproportionate elevation of bilirubin (up to 10-fold) and

prothrombin time (2 to 6 seconds prolonged) yet modest aminotransferase elevations (less than threefold). Gross inspection of affected liver characteristically reveals focal areas of congestion (nutmeg liver). HEPATIC VENO-OCCLUSIVE DISEASE. This syndrome occurs most commonly as a complication of bone marrow transplantation and/or pyrrolizidine alkaloid therapy and is characterized clinically by rapid onset of hepatomegaly, weight gain, and ascites. Hyperbilirubinemia and increased aminotransferase levels are typical. There is deposition of a fibronectin-rich matrix around terminal hepatic (central) veins, with evidence of endothelial cell injury. Because of its characteristic presentation, however, biopsy is rarely necessary to establish the diagnosis. The lesion is not a true cirrhosis, yet the clinical consequences are rapid and profound because the deposition of extracellular matrix occurs in a critical site of sinusoidal outflow. BUDD-CHIARI SYNDROME. Like veno-occlusive disease, Budd-Chiari syndrome is not a true cirrhosis but rather an acute or subacute obstruction to hepatic venous outflow. Fibrous webs are one of the many causes of the disorder, but these are usually extrahepatic, and parenchymal fibrosis is uncommon.

MISCELLANEOUS DISORDERS ASSOCIATED WITH CIRRHOSIS A variety of poorly understood chronic liver diseases are associated with cirrhosis. Non-alcoholic steatonecrosis is a clinicopathologic syndrome remarkably similar to alcoholic liver disease, but it occurs in the absence of alcohol use. The disorder, which is often identified incidentally, is found with several conditions, including diabetes mellitus, morbid obesity, jejunoileal bypass surgery, Weber-Christian disease, and abetalipoproteinemia. Amiodarone, diethylstilbestrol, perhexiline maleate, total parenteral nutrition, and synthetic estrogens have also been implicated. Cirrhosis develops in at least one third of patients if the precipitant is not removed. Indian childhood cirrhosis is a significant cause of preschool pediatric morbidity, occurring in up to 1 in 4000 live births in the Indian subcontinent. Marked hyaline accumulation, increased copper deposition, and extensive fibrosis are typical histologic features. The underlying defect is unknown. D-Penicillamine has been used to slow progression in some patients. Polycystic liver disease is usually associated with renal cysts and is characterized by macroscopic or microscopic hepatic cysts associated with fibrosis. Granulomatous liver diseases, including sarcoidosis (see Chapter 151) , may progress to cirrhosis in some patients. In addition to medications associated with non-alcoholic steatonecrosis, drug-induced hepatic fibrosis may also be seen in patients taking isoniazid or antimetabolites, especially methotrexate. The latter is associated with dose-dependent fibrosis in patients treated for psoriasis or rheumatoid arthritis for at least 2 years. Continuous therapy is more fibrogenic than intermittent dosing, and coexisting liver disease or heavy alcohol intake amplifies the risk of fibrosis. Surveillance liver biopsies are required in patients whose cumulative dose exceeds 1.5 to 2 g, because considerable fibrosis may develop in the absence of symptoms.

MAJOR SEQUELAE OF CIRRHOSIS (Table 153-2) PORTAL HYPERTENSION. FEATURES OF THE PORTAL CIRCULATION AND CLASSIFICATION OF PORTAL HYPERTENSION.

The portal circulation is a low-pressure system ( 5.5 and serum creatinine > 3.4 mg/dL

Acute liver failure not caused by acetaminophen poisoning

INR > 6.5 or any three of the following: Age < 10 or > 40 years Cause: non-A, non-B, non-C hepatitis; halothane hepatitis; idiosyncratic drug reaction; Wilson's disease, ischemia Duration of jaundice before encephalopathy < 7 days INR > 3.5 Serum bilirubin > 17.6 mg/dL

INR = International normalized ratio acute hepatic necrosis due to drugs, alcohol, viral infections, or ischemia. It is important to distinguish reversible precipitating factors from the inexorable progression of chronic liver disease. ETIOLOGY, INCIDENCE, AND PREVALENCE. The most common causes of end-stage liver disease include alcohol abuse, viral hepatitis (B, C, D) (see Chapter 150) , primary biliary cirrhosis (see Chapter 153) , primary sclerosing cholangitis (see Chapter 157) , hemochromatosis (see Chapter 221) , alpha1 -antitrypsin deficiency (see Chapter 152) , Wilson's disease (see Chapter 220) , Budd-Chiari syndrome, schistosomiasis, drugs and toxins (see Chapter 148) , steatohepatitis, and cryptogenic liver cirrhosis. The exact prevalence of chronic liver failure is unknown, but chronic liver failure is much more common than acute liver failure and probably accounts for most liver-related deaths. PATHOGENESIS. Loss of more than 70% of functioning liver cells results in the covert redistribution of splanchnic blood flow, an energy-deficient state, and the failure of multiple secondary organs. Chronic liver injury eventually results in the death of hepatocytes followed by the accumulation of fibrous tissue. The fibrous tissue distorts the architecture of the organ, causing portal hypertension and the development of portosystemic shunting. CLINICAL MANIFESTATIONS. Clinical manifestations of chronic liver failure evolve over many months to years and eventually include recurrent episodes of hepatic encephalopathy, progressive metabolic derangements (hypoalbuminemia, osteodystrophy, hyponatremia, acidosis, hyperbilirubinemia, glucose intolerance, and hypoglycemia), worsening of portal hypertension and its life-threatening complications (variceal bleeding, ascites, spontaneous bacterial peritonitis), severe pruritus, hematologic abnormalities (coagulopathy, leukopenia, thrombocytopenia, anemia, folate deficiency, hemoptysis), altered metabolism of endogenous hormones and drugs, and the development of functional renal failure (i.e., the hepatorenal syndrome). The Child-Pugh classification, which was developed to assess the severity of chronic liver failure, is based on five equally weighted clinical-laboratory parameters (encephalopathy, ascites, serum albumin, serum bilirubin, nutritional status) with a maximal possible score of 15 (Table 154-3) . Patients with compensated chronic liver failure are Child-Pugh A (score 1-5), whereas those with advanced cirrhosis are Child-Pugh C (score 11-15). DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS. The distinction between chronic liver failure and acute liver failure is based on clinical evidence of chronic liver disease: the stigmata of portal hypertension (ascites, splenomegaly, spider angiomas, varices), palmar erythema, gynecomastia, Dupuytren's contractures, testicular atrophy, and malnutrition. Multiple laboratory abnormalities (e.g., coagulopathy, hyperbilirubinemia, hypoproteinemia, and hypoalbuminemia)

PARAMETER/CLASS

TABLE 154-3 -- CHILD-PUGH CLASSIFICATION OF LIVER CIRRHOSIS B

A

Encephalopathy

Absent Mild

Severe

Ascites

Absent Moderate, easily treated

Severe, refractory to treatment

Serum albumin

>3.5

3-3.5

100 cm) results in bile salt losses that exceed the maximum capacity of the liver to synthesize bile salts, leading to diminution of the bile salt pool, decreased concentrations of intestinal bile salts, fat maldigestion, and steatorrhea.

CHOLESTASIS Pathophysiology Cholestasis is the clinical condition that results from impairment of bile secretion. A variety of pathophysiologic mechanisms have been implicated in cholestasis. Functional abnormalities of hepatocytes seen in cholestasis include depressed activity of sinusoidal membrane Na+ ,K+ -ATPase, reductions in fluidity of the hepatocyte plasma membrane, decreased basolateral uptake of bile salts and organic anions, altered function of bile salt carrier proteins and microtubules, release of calcium from intracellular stores, and abnormal mitochondrial function with altered cellular redox state and decreased availability of ATP. Canalicular abnormalities may include reduction in microvilli of the canalicular membrane, dilation of the canalicular space, alterations in canalicular membrane fluidity, and disruption of pericanalicular actin microfilaments. Perhaps most important, disruption of tight junctions sealing the canalicular space abolishes both anionic and osmotic gradients necessary for the generation of bile flow and permits back-diffusion of secreted bile components into the plasma. Many of the biochemical abnormalities associated with obstructive cholestasis appear to result from reflux of bile from the canaliculus into the plasma. Biochemically, cholestasis is characterized by accumulation in plasma of compounds normally secreted into the bile (bilirubin, bile salts) (Table 157-1) . Elevated levels of serum bile salts are the most sensitive indicators of cholestasis; this determination is not routinely available and therefore not used widely. Serum cholesterol is commonly increased in cholestasis, reflecting increased cholesterol synthesis and appearance in plasma of lipids normally secreted into bile. The hyperlipidemia of cholestasis is associated with appearance in plasma of lipoprotein X, a discoidal particle 824

Figure 157-4 Enterohepatic circulation of bile salts. Bile salts are secreted by the liver in the biliary radicles and stored in the gallbladder. After meals and the release of cholecystokinin, bile salts are expelled from the gallbladder and into the intestines where they participate actively in the intestinal digestion of fat. Small amounts of bile salts are passively absorbed from the jejunum; they are actively absorbed in the ileum and return to the liver via portal circulation. Following uptake at the sinusoids, bile salts are transferred to the canalicular membrane through the cytosol by binding to bile salt binding proteins and secreted through the canalicular membrane. The total bile acid pool (BAP) circulating in the enterohepatic circulation is 2 to 3 g in normal adults. In steady state, daily bile salt turnover (K) averages 20 to 30% of the bile salt pool.

containing phosphatidylcholine, free cholesterol, albumin, and specific apolipoproteins. Exclusion of bile from the intestine in severe cholestasis has several consequences. In the absence of bile salts, there is moderate malabsorption of fat and severe malabsorption of cholesterol and fat-soluble vitamins. Cholestasis may be associated with specific vitamin deficiency disorders such as night blindness (vitamin A), osteomalacia (vitamin D), neuropathy (vitamin E), or coagulopathy (vitamin K). Generalized osteoporosis also commonly occurs for unknown reasons. Because bilirubin degradation products are responsible for the normal brown color of stools, pale "acholic" stools are occasionally present in advanced cholestatic disorders. Urobilinogen normally is formed in the colon by bacterial metabolism of bilirubin and is subsequently absorbed and excreted into urine; disappearance of urobilinogen from the urine of a jaundiced patient is indicative of cholestasis. Certain canalicular membrane enzymes, including alkaline phosphatase, 5 nucleotidase, and gamma-glutamyl transpeptidase, also commonly accumulate in plasma of cholestatic patients. These enzymes normally are present on the luminal surface of the canalicular TABLE 157-1 -- PATHOPHYSIOLOGY OF CHOLESTASIS Retention of Bile Components in Plasma Conjugated hyperbilirubinemia with bilirubinuria Hypercholesterolemia (lipoprotein X) with xanthoma formation Elevated serum bile salts Pruritus Osteoporosis Exclsuion of Bile Salts From the Intestine Malabsorption of fat with steatorrhea Malabsorption of fat-soluble vitamins Vitamin A--night blindness Vitamin D--osteomalacia Vitamin E--neuropathy Vitamin K--coagulopathy Malabsorption of cholesterol Acholic stools Osteoporosis

Hepatic Injury Release of canalicular membrane enzymes into the plasma (alkaline phosphatase, 5 -nucleotidase, alpha-glutamyltransferase) Retention of bile salts can contribute to liver injury Biliary ductular proliferation Cirrhosis plasma membrane. When canalicular pressure rises (as when flow of bile is obstructed), these enzymes are synthesized in increased amounts, accumulate on the sinusoidal membrane, and are released into the blood. Disproportionately elevated blood levels of these enzymes are useful in establishing the diagnosis of extrahepatic or intrahepatic obstructive cholestasis. Acute obstruction of the common bile duct also can be associated with transient hepatocellular necrosis. For this reason, elevations of serum aminotransferase and lactate dehydrogenase levels may predominate during the early hours after acute biliary obstruction. With time, however, the levels of these enzymes decline, while alkaline phosphatase and other canalicular enzymes rise, producing the typical "cholestatic pattern." Because of their detergent properties, hydrophobic bile salts retained in cholestasis may contribute to hepatic injury. Bile salt synthesis paradoxically increases in cholestasis, possibly contributing to hepatotoxicity. The liver is not left without defense because it has the capacity to convert hydrophobic bile salts by phase I (cytochrome P-450-mediated hydroxylation) and phase II (sulfation, glucuronidation) pathways to hydrophilic bile acid conjugates, which are eliminated in urine. In high-grade cholestasis, urinary excretion may become the major pathway of bile salt elimination, as compared with the normal situation in which bile acids are eliminated through the feces. Although the role of bile salts in perpetuation of liver injury in cholestasis has not been established with certainty, the administration of hydrophilic bile salts such as ursodeoxycholic acid (UDCA) improves liver function test results, clinical symptoms, and histology. Patients with advanced cholestasis experience generalized malaise, weakness, easy fatigability, nausea, anorexia, and pruritus. The underlying cause responsible for pruritus in cholestasis is unknown. Although pruritus has been attributed to cutaneous toxicity of retained bile salts, its severity does not correlate with cutaneous bile salt concentrations and treatment with cholestyramine is not invariably helpful in relieving the symptoms. An unknown endogenous opiate receptor agonist is retained in the cholestatic patient and may cause pruritus through direct effects on cutaneous neurons; in recent experimental trials, the severity of pruritus was relieved by administration of opiate antagonists. Introduction of bacteria into bile above an obstructing lesion can lead rapidly to purulent infection of the biliary tree and liver, termed ascending cholangitis. Contributing factors include high biliary pressure and stasis. In the absence of infection, cholestasis may be well tolerated for very long periods of time. Although 825

patients typically do not feel well, hepatic functions unrelated to bile secretion (such as intermediary metabolism, protein synthesis, and toxin degradation) are initially well preserved. If biliary obstruction can be relieved, symptoms and biochemical abnormalities will resolve. However, if allowed to persist, chronic biliary obstruction, regardless of cause, eventually leads to cirrhosis with all its complications. The mechanism by which increased bile secretory pressure leads to cirrhosis has not as yet been established, but it can occur with either extrahepatic or intrahepatic obstruction. Approach to the Cholestatic Patient In general, cholestasis may result from conditions affecting large bile ducts (extrahepatic cholestasis) or from disorders of small bile ducts, canaliculi or hepatocytes (intrahepatic cholestasis). The distinction is useful because it has important clinical implications. In extrahepatic cholestasis, bile flow is impaired because of mechanical obstruction of the larger bile ducts due to benign or malignant processes. Increased biliary pressure above the obstruction leads to ductal dilatation. Obstruction of large ducts is usually localized and therefore can be addressed with mechanical measures to effect drainage. In contrast, intrahepatic cholestasis involves either diffuse injury to small bile ducts or metabolic derangements in the bile secretory apparatus at the level of the hepatocyte and canaliculus. Intrahepatic cholestasis is typically not associated with ductal dilatation and is not amenable to mechanical interventions. Diagnostic evaluation of cholestasis begins with routine blood tests of liver enzymes and liver function to establish the pattern and severity of liver injury. Liver tests typically exhibit a disproportionate elevation of canalicular enzymes such as alkaline phosphatase, 5 -nucleotidase, and gamma-glutamyl transpeptidase. Functional abnormalities typically include conjugated hyperbilirubinemia and hypercholesterolemia. Loss of synthetic function manifested by hypoalbuminemia occurs only in patients in whom chronic cholestasis progresses to cirrhosis, but an abnormal prothrombin time may occur relatively early in cholestasis because of malabsorption of vitamin K, which occurs due to decreased concentrations of bile acids in the intestines. Additional blood tests may indicate a specific cause for the cholestasis, such as primary biliary cirrhosis (PBC) (antimitochondrial antibody) (see Chapter 153) or sarcoidosis (see Chapter 81) . Once a cholestatic pattern of liver disease has been established, imaging techniques such as ultrasonography are indicated to determine if there is evidence of large duct obstruction with proximal ductal dilatation. Ultrasonography can also demonstrate the location and nature of the obstructing lesion. This diagnostic modality is a very sensitive and accurate test for detection of gallstones, a common cause of obstructive cholestasis, and also may detect focal mass lesions such as primary or secondary tumors in the liver. Computed tomography (CT) and magnetic resonance imaging (MRI) are more expensive tests that at present offer no advantage over ultrasonography for detection of large duct obstruction. These studies, however, provide additional information about the nature of the obstructing lesion. If cancer is strongly suspected, it may be preferable to image initially with CT or MRI to obtain sectional images of the entire abdomen with high-resolution views of the retroperitoneum and pancreas. The most precise information regarding biliary anatomy is obtained by direct cholangiography (percutaneous transhepatic cholangiography [PTC] or endoscopic retrograde cholangiopancreatography [ERCP]) (Fig. 157-5) ; these tests may be necessary if non-invasive methods are inconclusive. Very recently, a new non-invasive technique, magnetic resonance cholangiopancreatography (MRCP), was reported to be as useful for diagnosis as ERCP. If the large bile ducts appear normal with imaging studies, liver biopsy usually is indicated to look for evidence of a parenchymal process. In disorders that diffusely involve the small bile ducts, the pattern of tissue injury on liver biopsy may be diagnostic. Obstruction to bile flow produces a typical histologic pattern that includes retention of bilirubin granules in the hepatic cytoplasm and inspissated "bile plugs" in canaliculi, most prominent in the pericentral zone. Scattered hepatocyte injury, possibly attributable to bile salts, is manifested as feathery degeneration with focal necrosis. Mild edema and polymorphonuclear inflammation of portal tracts may be seen. With prolonged obstruction, the characteristic finding of proliferation of bile ductules is observed. If the duct obstruction is not relieved, an increasing amount of fibrosis occurs around the portal tracts, accompanied by atrophy of hepatocytes. True cirrhosis with regenerative nodules occurs after months to years of biliary obstruction. The small sample of liver tissue obtained on a percutaneous biopsy is not always representative of the entire liver, and information from a single biopsy must be interpreted with caution. General principles for therapy of cholestasis include the following: 1. Specific therapy to cure or control the underlying disorder usually should be undertaken whenever possible. For example, curative resection is indicated if feasible for an obstructing neoplasm; if clinically indicated, common bile duct exploration will allow cure of gallstones; and repair of biliary strictures may restore normal biliary drainage. Drugs that cause cholestasis should be discontinued. Immune-mediated bile ductular injury may respond to immunosuppressive therapy. 2. Relief of biliary obstruction is generally worthwhile for relief of symptoms of cholestasis (pruritus, jaundice), to prevent or relieve ascending cholangitis, and to prevent progression to biliary cirrhosis, even if the underlying disease cannot be cured. Drainage may be achieved by surgical resection or bypass of the obstructed segment, typically by means of a Roux-en-Y choledochojejunostomy. Alternatively, percutaneous and endoscopic approaches may be employed. Strictures may be dilated using balloon catheters passed over guide wires. Malignant biliary obstruction commonly is managed by stenting. In general, the endoscopic retrograde approach is preferable to the percutaneous approach because of the risk of hemorrhage or bile leak with liver puncture. 3. Palliation of symptoms and supportive measures are currently the mainstay of treatment for chronic cholestatic disorders such as primary sclerosing cholangitis (PSC) or PBC. Drugs such as rifampin and phenobarbital induce hepatic phase I and phase II drug metabolizing enzymes; therapy with these agents may relieve cholestasis somewhat by enhancing detoxification and elimination of a variety of retained lipophilic compounds, including bile salts. Bile salt-binding resins such as cholestyramine sometimes provide symptomatic relief from pruritus, which may be a serious problem in the more advanced cases. Opiate receptor antagonists such as naloxone may be helpful for treatment of pruritus. Patients with chronic cholestasis and fat maldigestion also require dietary fat restriction, fat-soluble vitamin supplements, and calcium supplements. Complications of cirrhosis should be identified and treated. UDCA, the 7beta-epimer of chenodeoxycholic acid, is a naturally occurring bile salt in the bear. In contrast to chenodeoxycholic acid, it is a poor detergent because its 7-hydroxyl group projects toward the hydrophobic surface of the molecule, impeding hydrophobic interactions with other lipids. UDCA is intrinsically non-toxic even at supraphysiologic concentrations. It was originally used for dissolution of cholesterol gallstones but was serendipitously found to improve cholestasis and liver injury in a variety of chronic cholestatic liver diseases. It reduces serum bilirubin, transaminase, and alkaline phosphatase levels and can improve clinical symptoms and liver histology. UDCA in various experimental models attenuates toxicity of more hydrophobic bile salts. It also may have direct protective effects on the liver and may alter immunologic function. It is unclear whether UDCA can slow the progression of cholestatic liver disease to biliary

cirrhosis. 4. Hepatic transplantation (see Chapter 155) can provide a 1-year survival of nearly 90% in certain types of end-stage cholestatic diseases (PBC, PSC, and biliary atresia). Indications for transplantation include intractable symptoms, complications of cirrhosis, or deterioration of prognostic indicators. The healthier the patient at the time of transplantation, the better the outcome; conversely, patients with complications of liver disease frequently die while awaiting transplantation.

DISORDERS ASSOCIATED WITH CHOLESTASIS Intrahepatic Causes of Cholestasis Intrahepatic cholestasis may occur because of diffuse obliteration of small bile ducts or because of generalized disorders affecting bile secretion at the level of the hepatocytes or canaliculi. Obliteration 826

Figure 157-5 Cholangiographic appearance of cholestatic disorders. A, Normal cholangiogram and pancreatogram. B, Pancreatic cancer. The tumor is obstructing the common bile duct and the pancreatic duct, producing proximal dilatation of both (double duct sign). A cannula extending from the endoscope has been passed through the area of obstruction and its tip lies in the proximal common hepatic duct. C, Choledocholithiasis. A large cholesterol gallstone in the common bile duct appears as a radiolucent shadow outlined by radiodense contrast material. The common bile duct is dilated. D, Primary sclerosing cholangitis. Multiple strictures are present in both the intrahepatic and extrahepatic biliary tree. Intrahepatic ducts are attenuated and reduced in number. Beadlike areas of dilatation can be noted between areas of stricture, but the fibrotic process in the liver prevents generalized dilatation of the proximal biliary ducts. The gallbladder is filled with contrast material and appears normal.

of small bile ducts usually leads to chronic progressive cholestasis and biliary cirrhosis. Small duct obliterative disorders, often collectively termed vanishing bile duct syndromes, include infiltrating neoplasms (discussed later); granulomatous disorders such as sarcoidosis; and the immune-mediated bile duct destruction of PBC, hepatic allograft rejection, and chronic graft-versus-host disease. Cholestasis of metabolic origin may be seen commonly in severely ill patients and is associated with trauma, surgery, sepsis, and parenteral hyperalimentation. Numerous drugs and estrogen also can produce cholestasis either as a direct effect or as an idiosyncratic reaction (see Chapter 148) . Cholestasis of pregnancy appears to reflect sensitivity to the direct cholestatic effects of estrogen. Non-caseating granulomas are a common and non-specific finding in the liver. In sarcoidosis (see Chapter 81) , an idiopathic disease characterized by non-caseating granulomas in lung and other tissues, liver involvement is common. Usually these patients are symptom free with mild abnormalities of liver function tests. Granulomas in the portal tracts may produce fibrotic obliteration of small bile ducts. Rarely, bile duct obliteration may be sufficiently 827

severe to produce biliary cirrhosis. Although some experts consider hepatic involvement in sarcoidosis to be an indication for glucocorticoid therapy, glucocorticoids have not been proven to alter the natural history of sarcoidosis involving the liver. Primary biliary cirrhosis (see Chapter 153) is a progressive cholestatic disorder characterized by autoimmune destruction of small interlobular bile ducts. Injury is thought to occur as a result of cytotoxic T cell-mediated immune attack directed against bile ductular epithelial cells. PBC is primarily a disease of middle-aged women (>10:1 female/male ratio). It may be associated with other autoimmune disorders. A characteristic marker of this disease is antimitochondrial antibody, which is found in 90% of patients with PBC and only rarely in other disorders. PBC generally progresses slowly but relentlessly to cirrhosis and hepatic failure. Progressive familial intrahepatic cholestasis typically presents as mild to moderate cholestasis in infancy or childhood. Liver biopsy specimens appear generally unremarkable except that bile ductules can be identified in fewer than 50% of portal tracts. The disorder may occur in sporadic or hereditary forms and it may be part of a hereditary condition termed Alagille's syndrome or arteriohepatic dysplasia. Severity and prognosis are variable: some patients develop biliary cirrhosis requiring transplantation in childhood, whereas others have an indolent course. A variety of genetic defects in pathways of bile acid synthesis or biliary lipid secretion have been implicated in the pathogenesis of this disorder. Chronic graft-versus-host disease occurs when T cells from an allogenic source are infused into an immunodeficient patient, most typically at the time of bone marrow transplantation (see Chapter 182) . Liver involvement is characterized by mononuclear infiltration of portal tracts with obliteration of small bile ductules, similar to that seen in PBC. Intensive immunosuppression may control the graft-versus-host reaction, and if this fails, UDCA may improve cholestasis; however, the cholestasis often progresses to biliary cirrhosis. After hepatic transplantation (see Chapter 155) , chronic hepatic allograft rejection is associated with immunologic injury to biliary ductules and hepatic arterioles. Like PBC and graft-versus-host disease, chronic allograft rejection is associated with T-cell infiltration of the portal tracts and destruction of bile ductules. Arterial intimal injury leading to intimal hyperplasia may compromise hepatic circulation and accelerate the progression of liver injury. A benign intrahepatic cholestasis of metabolic origin is seen commonly in severely ill patients. Predisposing factors include major trauma or surgery, severe infection, and parenteral hyperalimentation. The mechanism responsible for cholestasis is unknown. Serum bilirubin often is markedly elevated, whereas elevations of the alkaline phosphatase typically are modest, and aminotransferase levels usually are near normal. Liver synthetic function usually is well preserved. Liver biopsy specimens reveal only minimal abnormalities. The etiology of the syndrome is unknown. With elimination of the precipitating factors, cholestasis typically resolves over a few weeks. Intrahepatic cholestasis of pregnancy is a relatively common disorder that usually appears late during the third trimester of pregnancy, disappears after delivery, and can occur in subsequent pregnancy. In its usual form, the only manifestation is generalized itching (pruritus gravidarum), but more severe cases it may be accompanied by jaundice. It is associated with an increased risk of fetal loss. The pathogenesis is uncertain, but estrogens may cause impaired intracellular transport and/or canalicular excretion of bile salts. There appears to be a familial predisposition to the development of intrahepatic cholestasis of pregnancy. Drug-induced cholestasis may be a complication of treatment with a number of therapeutic agents (see Chapter 148) . Cholestasis induced by estrogens or cyclosporine is not associated with inflammation and is thought to result from metabolic effects at the level of the hepatocyte. Chlorpromazine typically produces an acute febrile illness accompanied by elevation of both aminotransferase and alkaline phosphatase levels; a hypersensitivity mechanism is thought to be responsible. Other common drugs that can produce idiosyncratic cholestatic liver injury include captopril, sulindac, and benoxaprofen. The recognition that drugs frequently can cause intrahepatic cholestasis is important because, in most instances, simple withdrawal of offending agents will result in normalization of liver function tests and clinical symptoms. Diseases of the Large Bile Ducts and Gallbladder Primary and Secondary Neoplasms Involving the Bile Ducts

Neoplasms are among the most common and important causes of extrahepatic biliary obstruction. Primary malignancies of the liver, bile ducts, gallbladder, ampulla of Vater, and pancreas in aggregate account for over 50,000 deaths annually in the United States, and patients with these cancers most typically present with jaundice caused by bile duct obstruction. Malignancies classically produce painless obstructive jaundice, but it is more typical for neoplasms involving the liver, bile ducts, or pancreas to cause vague pain in the epigastrium or back; this pain may precede the onset of jaundice. The common bile duct may be obstructed distally by pancreatic cancer or ampullary carcinoma, proximally by hepatocellular carcinoma or gallbladder carcinoma, or anywhere along its length by cholangiocarcinoma. Rare benign neoplasms that may obstruct the common bile duct distally include pancreatic cystadenoma and villous adenoma of the papilla of Vater. Metastatic tumor from any source to lymph nodes in the porta hepatis can also cause extrinsic compression of the proximal common bile duct; this complication is a common cause of cholestasis in patients with cancers of the breast, lung, colon or stomach. Not all cholestasis caused by malignancies is extrahepatic: extensive tumor metastases within the liver parenchyma may produce intrahepatic cholestasis by obstructing smaller intrahepatic ducts. Diffuse infiltration of malignant cells along hepatic sinusoids with consequent cholestasis also may occur, especially in small cell carcinoma of the lung and in lymphoma. Rarely a non-obstructive metabolic cholestasis may occur as a paraneoplastic syndrome complicating extrahepatic malignancies such as lymphoma or renal cell carcinoma (Stauffer's syndrome).

Cholangiocarcinoma is a form of adenocarcinoma that arises from the intrahepatic or extrahepatic biliary epithelium. It occurs somewhat more commonly in males than females. There is a high incidence in the Far East, related to infestation by liver flukes and Oriental cholangiohepatitis. In Western countries there is an increased incidence in patients with PSC or choledochal cysts. Grossly, three patterns of growth are described: polypoid, sclerosing, and infiltrative. Most cancers of the extrahepatic ducts appear as poorly defined gray-white thickenings of the bile duct wall; the lumen is narrowed, often resembling fibrous strictures or sclerosing cholangitis radiographically. Cholangiocarcinomas tend to grow slowly and to infiltrate the wall of the duct and dissect along tissue planes. Perineural invasion and metastasis to regional nodes are common. Tumors at the bifurcation of the common hepatic duct (termed Klatskin tumors) commonly invade the liver by direct extension. The usual presentation of cholangiocarcinoma involving the common hepatic or common bile duct is progressive obstructive jaundice. More proximal lesions, which produce localized obstruction of intrahepatic branches of the biliary tree, may cause vague abdominal pain associated with marked elevation of the serum alkaline phosphatase without jaundice. Ultrasonography and CT typically reveal dilated intrahepatic bile ducts with focal narrowing of the biliary tree, sometimes accompanied by a mass. The most useful imaging study is cholangiography, which typically demonstrates segmental narrowing or obstruction. In patients with PSC, diagnosis of cholangiocarcinoma is suggested by rapid worsening of jaundice with a new dominant stricture on cholangiography. Diagnosis may be confirmed by endoscopic brush cytology or needle aspiration, but in some cases the diagnosis can be established only at laparotomy. Only one third of cholangiocarcinomas are resectable for cure at the time of presentation. The 5-year survival after attempted curative resection is about 20%. The best results are obtained with tumors of the distal bile duct and polypoid tumors; absence of lymph node metastases and clear surgical margins also indicate a better prognosis. Radical surgical attempts to cure intrahepatic cholangiocarcinoma by total hepatectomy with hepatic transplantation were disappointing because of a high rate of postoperative recurrence, and this approach has been abandoned by consensus. Response to chemotherapy or radiation is limited, although brachytherapy (intraductal radiation) holds promise as a palliative measure for some patients. Most patients die of local hepatic invasion rather than distant metastases. Overall survival for cholangiocarcinoma is less than 10% at 5 years. Gallbladder adenocarcinoma is an uncommon malignancy in the United States. Most patients are older than 70 years of age, and women are affected more than men, by a 3:1 ratio. There is a strong association of gallstones with carcinoma of the gallbladder (80-90% of carcinomatous gallbladders have stones), and the risk factors for gallbladder carcinoma by and large are the same as the 828

risk factors for gallstones. In some groups of Native Americans who are genetically predisposed to develop gallstones with very high frequency at relatively young ages, gallbladder adenocarcinoma is 5 to 10 times more common than in the general population. The duration and severity of cholelithiasis appear to correlate with the risk of gallbladder carcinoma. Gallbladder cancer is especially associated with very large gallstones (greater than 3 cm in diameter) or calcification of the chronically inflamed gallbladder wall (porcelain gallbladder), and these findings are therefore considered by many experts to be indications for cholecystectomy even in the asymptomatic patient. However, because the incidence of adenocarcinoma of the gallbladder in patients with cholelithiasis is less than 1 per 1000 patient-years, the prevention of gallbladder cancer currently is not considered a sufficient indication for cholecystectomy in most patients with asymptomatic gallstones. Early symptoms of gallbladder cancer are non-specific and similar to those of cholelithiasis or cholecystitis; later, patients develop persistent pain and unremitting jaundice as the tumor invades the liver and bile ducts. Imaging studies such as ultrasonography, CT, and cholangiography can reveal features suggestive of gallbladder cancer, such as thickening or mass of the gallbladder wall or extension of mass to involve the liver, but over 80% of gallbladder cancers are undiagnosed preoperatively. Tumors that are localized to the gallbladder may be cured by cholecystectomy, but these tumors represent fewer than 20% of all patients with gallbladder cancers. Extension to adjacent bile ducts or liver or metastasis to portahepatic lymph nodes or distant organs is common at initial presentation. By the time patients develop jaundice, 85% are unresectable. Chemotherapy and radiation therapy currently are of little benefit. Overall 5-year survival is less than 10%. New onset of cholestasis over days to weeks in any adult, especially older than age 50, is worrisome for cancer. A palpable, dilated, non-tender gallbladder (Courvoisier's sign) suggests cancer obstructing the common bile duct. Laboratory studies most typically reveal a rapid and progressive increase in serum alkaline phosphatase and bilirubin values. Because cancers are common and may sometimes present as atypical symptoms or laboratory findings, most adults with new onset of abnormal liver tests or jaundice should undergo imaging of the liver and bile ducts to look for masses or ductal dilatation. Ultrasonography is generally the first imaging procedure in a cholestatic patient, but it may be preferable to go directly to CT or MRI if the clinical picture is strongly suggestive of cancer, because these procedures provide more information about the nature and level of the obstructing lesion and the presence of metastases. Further evaluation depends on the initial findings. In patients who appear to be candidates for surgical resection, it may be appropriate to proceed with surgery. The diagnosis of cancer can be established by intraoperative biopsy, and at laparotomy the surgeon can choose between a radical, potentially curative resection, a drainage procedure for palliation of unresectable cancer, or correction of a benign obstructing process. Additional preoperative diagnostic techniques such as cholangiography (see Fig. 157-5 B), endoscopic ultrasonography, and angiography may sometimes be helpful in determining resectability and in resolving diagnostic uncertainties. If patients are poor candidates for surgery or have unresectable disease, a diagnosis can be established by CT-guided needle aspiration biopsy of the primary lesion or a metastasis. When obstructing malignancy is not resectable for cure, relief of cholestasis usually represents a major goal of palliation. Advances in therapeutic radiology and endoscopy over the past decade now permit relief of bile duct obstruction by placement of internal stents without surgery in most patients. Two types of stents are commonly used. Flexible plastic stents ranging in diameter from 7 to 14 French are inexpensive but occlude over a period of months from accumulation of bacterial biofilm and minerals on their inner surface; they must be removed and replaced periodically. Permanently implanted self-expanding metallic mesh stents, introduced in the past few years, provide a much wider lumen (on the order of 1 cm) and occlude less commonly; however they are expensive, and tumors can grow in through the openings in the mesh. Other Disorders of the Large Bile Ducts

Choledochal cysts are congenital anatomic malformations of the bile duct. Five forms of choledochal cysts are described: type I--fusiform or saccular dilatation of the extrahepatic tree; type II--diverticular common bile duct cyst; type III--choledochocele; type IV--diffuse dilation of common bile duct and hepatic ducts; and type V--intrahepatic ductal dilatation (Caroli's disease). Histologic examination demonstrates a thick-walled structure of very dense connective tissue with smooth muscle fibers. A pericystic inflammatory process or cholangitis frequently accompanies the choledochal cyst. The mechanism of cyst formation is uncertain. If the common bile duct is blocked, patients may present with cholestasis in infancy, resembling patients with biliary atresia. If the common bile duct is patent, patients may remain asymptomatic into adulthood. About half of patients with choledochal cysts present after age 10. In the adult form, the triad of abdominal pain, jaundice, and a palpable mass is the classic presentation. Fever may be present as a result of bile stasis with cholangitis. Complications include primary formation of brown pigment gallstones in the cyst and liver abscesses. Abdominal ultrasonography and CT often demonstrate dilated bile ducts. However, the best method to establish the diagnosis is endoscopic retrograde cholangiopancreatography (ERCP) or MRCP. Once the diagnosis of choledochal cyst is established, the therapy is surgical. Simple cystenterostomy can provide drainage and prevent cholangitis. However, whenever possible, complete surgical excision of the cyst is desirable because there is a high incidence of cholangiocarcinoma in choledochal cysts. Benign biliary strictures, which are fibrotic narrowings of the large bile ducts, occur as a result of trauma, inflammation, infection, or ischemia. Surgical injury to the bile ducts, although uncommon, is a major technical complication of cholecystectomy. Repair of bile duct injuries is technically difficult, and postsurgical strictures are associated with significant chronic morbidity, including biliary cirrhosis. Chronic pancreatitis commonly produces fibrotic narrowing of the common bile duct where it passes through the head of the pancreas (see Chapter 141) . Although proximal ductal dilatation and alkaline phosphatase elevation are common, significant cholestasis is unusual, and liver failure from biliary cirrhosis is quite uncommon. In patients with chronic pancreatitis who have elevations of serum alkaline phosphatase level or common bile duct dilatation on ultrasound examination, periodic liver biopsy has been recommended to detect progressive hepatic fibrosis. Surgical drainage (choledochojejunostomy) usually is successful in relieving ductal obstruction and halting the progression of biliary cirrhosis in chronic pancreatitis in the few cases in which it is required. Strictures of the bile ducts have been noted after hepatic irradiation, possibly secondary to vascular endothelial injury and ischemia. Similarly, strictures have been reported after chemotherapy employing intrahepatic arterial infusion of floxuridine or mitomycin C. Surgical drainage is preferred to endoscopic or percutaneous stenting in most patients with benign strictures because of uncertainties regarding long-term patency and late complications of stents. Liver flukes (see Chapter 432) are trematode parasites that are ingested in food, taken up from the gut, travel through the circulation to the liver, and from there pass into bile. The adult flukes mature in the biliary tree, where they can reside for decades and release eggs into bile. Mild infections usually are asymptomatic; heavier infections may produce fever and eosinophilia initially and later may cause signs and symptoms of biliary obstruction. Chronically, liver flukes may cause ductal fibrosis and strictures. The diagnosis can be established by identifying ova in stool. Clonorchis sinensis and Opisthorchis viverrini are common in east Asia, where they are acquired through ingestion of raw fish. Praziquantel is the treatment of choice. Fasciola hepatica is found throughout the world. It is acquired from eating wild watercress on which encysted metacercariae have been deposited by snails. The recommended treatment is bithionol. Liver flukes have been implicated in the pathogenesis of Oriental cholangiohepatitis, a chronic inflammatory disorder of the biliary tree associated with bile duct strictures, recurrent episodes of obstructive jaundice and ascending cholangitis, development of brown pigment gallstones in the intrahepatic and extrahepatic bile ducts, and biliary cirrhosis. This disorder is common in east Asia, including China and Japan, and is seen in the United States with some frequency in areas with large Asian immigrant populations. Not all patients have evidence of infection with liver flukes, and other pathogenic factors may be important. The disease is associated with lower socioeconomic class and malnutrition, and its frequency appears to have fallen dramatically in Japan, Hong Kong, and Taiwan

829

since the 1950s. Patients typically are younger than 50 years of age, with males and females affected equally. The usual presentation is an attack of ascending cholangitis associated with fever, right upper quadrant pain, and jaundice. Some attacks respond spontaneously or with antibiotic treatment alone; in others, sepsis may develop and surgical drainage may be required. Attacks may recur at irregular intervals of days to years. Long-term management includes eradication of parasites and elimination of stones and strictures. Intrahepatic stones that cannot be extracted may necessitate resection of hepatic segments. The prognosis varies with the extent of involvement, but death from complications of sepsis and cirrhosis is common. Cholangiopathy from the acquired immunodeficiency syndrome (AIDS) describes a number of biliary tract abnormalities associated with infection with the human immunodeficiency virus (HIV) (see Chapter 413) . Patients with advanced immunodeficiency may develop acalculous cholecystitis, focal distal biliary stenosis at the ampulla of Vater, or multifocal stenoses of the biliary tree resembling PSC. Although the pathogenesis of this complication is not known with certainty, AIDS cholangiopathy is strongly associated with colonization of bile with cryptosporidia or microsporidia. Patients typically complain of right upper quadrant abdominal pain and often have abnormal liver test results, particularly that of alkaline phosphatase. The diagnosis may be suggested when an ultrasound examination of the gallbladder reveals edema of the wall; ERCP demonstrates strictures and delayed emptying and may permit direct sampling of bile for pathogens. No specific therapy is of proven benefit. Cholangiopathy is a late complication of AIDS; although rarely fatal of itself, it portends a poor prognosis. Biliary atresia is a disorder of infants. Typically, the bile duct is normal at the time of birth; but over the next 6 to 12 weeks, its lumen gradually becomes obliterated and the duct becomes a fibrotic cord. The etiology is unknown. Infants become jaundiced at 4 to 6 weeks of age. Without treatment, over 90% of affected children will die before the age of 1 year from the complications of biliary cirrhosis. If the diagnosis is established promptly, a surgical portoenterostomy (Kasai procedure) can be of benefit. In this procedure, a core of tissue is removed from the hilum of the liver and the ends of the transected bile ducts are allowed to drain into a loop of jejunum. The Kasai procedure improves cholestasis and prolongs survival if performed early in infancy. Even after this procedure, most affected children progress to cirrhosis over the next few years. Biliary atresia is the most common indication for hepatic transplantation in young children. PSC is a disorder characterized by a patchy obliterative inflammatory fibrosis of the large bile ducts. Chronic inflammation leads to extensive bile duct strictures, cholestasis, and gradual progression to biliary cirrhosis. The etiology of PSC is not known, but both genetic and immunologic abnormalities have been implicated. About 50% of all cases of PSC occur in association with inflammatory bowel disease (see Chapter 135) . The frequency of HLA-B8 and HLA-DR3, which are associated with a number of autoimmune diseases, is higher in PSC than in normal subjects. Autoantibodies directed against an epitope present on colonic and biliary epithelial cells have been described in some patients. Unlike other extraintestinal manifestations of ulcerative colitis, PSC shows little correlation with the severity of bowel inflammation and does not remit after colectomy. The definitive diagnostic study for PSC is ERCP (or MRCP), which in classic cases demonstrates multiple areas of irregular stricturing and beadlike dilatations of the intrahepatic and extrahepatic ducts (see Fig. 157-5 D). Because the fibrotic process may diffusely involve both intrahepatic and extrahepatic ducts, it is not uncommon for ultrasonography to reveal non-dilated bile ducts. The diagnosis of PSC also may be suggested by liver biopsy showing portal and periportal inflammation with small and large lymphocytes as well as periductular inflammation with epithelial destruction. With the progression of the disease, concentric "onionskin" fibrosis develops around disappearing bile ducts. Liver biopsy staging may be useful to characterize the stage and rate of progression of disease. Patients with PSC typically present with insidious onset of chronic cholestasis, including jaundice, pruritus, fatigue, and malaise. The disease is often detected in a preclinical stage by routine blood tests revealing marked elevation of the serum alkaline phosphatase level, although in some patients with early disease the alkaline phosphatase value may be normal. About 15% of patients have manifestations suggestive of recurrent bacterial cholangitis, with episodes of fever, chills, night sweats, right upper quadrant pain, and jaundice. Often the associated inflammatory bowel disease dominates the clinical picture. There is no specific therapy for sclerosing cholangitis. Corticosteroids, azathioprine, penicillamine, and antibiotics have been proven ineffective. Administration of UDCA often improves liver function tests and sometimes may alleviate symptoms; it has not yet been demonstrated that UDCA retards the progression of the disease. Immunosuppressive therapy with methotrexate and cyclosporine are under study. Antibiotics are indicated for recurrent bacterial cholangitis. Surgical therapy has been directed toward improving biliary drainage. In recent years, endoscopic stenting or balloon dilatation of focal strictures have largely replaced surgery in this disease. Endoscopic drainage in selected cases may improve cholestasis and expedite clearing of biliary infections, but the long-term benefit is generally only marginal. PSC is a common indication for liver transplantation. Several large trials indicate that the mean interval from diagnosis of PSC to death from complications of biliary cirrhosis is 10 to 12 years. In the absence of hepatic transplantation, independent indicators of prognosis include age, serum bilirubin level, histologic stage, and presence of splenomegaly. Twenty to 30 per cent of patients with advanced PSC may develop secondary cholangiocarcinoma, which is often very difficult to diagnose. Cholangiocarcinoma should be suspected in any patient with this disease who exhibits an abrupt worsening of cholestasis or in whom cholangiography indicates a single dominant stricture. Even with close evaluation and follow-up, cholangiocarcinoma is found incidentally in 10 to 15% of patients with PSC undergoing hepatic transplantation. Gallstones

Gallstones are concretions that form in the biliary tree, usually in the gallbladder, when certain biliary solutes (cholesterol, calcium) precipitate as solid crystals that subsequently grow and aggregate within the mucin layer lining the gallbladder. The prevalence of gallstones in the U.S. adult population is 10 to 15%, and gallstone disease is responsible for about 10,000 deaths annually. Each year over 500,000 gallbladders are removed at a cost in excess of $6 billion because of gallstone-related disease. In the United States, cholesterol gallstones or cholesterol mixed with calcium bilirubinate account for 80% of stones, whereas the remaining 20% are pigmented or calcium bilirubinate stones. PATHOGENESIS.

The pathophysiology of gallstone formation begins when bile becomes supersaturated with cholesterol or calcium. Next, the solute must nucleate from solution and precipitate as solid crystals (cholesterol or bilirubin). Third, crystals must aggregate and fuse to form stones; this growth and aggregation of crystals occurs in a mucus gel along the wall of the gallbladder. Fourth, gallstone formation may be associated with impaired gallbladder motility, which is thought to be secondary to cholesterol accumulation in the gallbladder muscle, resulting in impaired contractile response to cholecystokinin. Cholesterol gallstones are yellow-brown and range in size from a few millimeters to 2 to 3 cm. Greater than 50% of their dry weight (often over 90%) consists of crystalline cholesterol monohydrate, but variable amounts of other components, including mucin glycoproteins and calcium bilirubinate, are also present. Cholesterol gallstones can form when the amount of cholesterol secreted into bile exceeds the amount that can be held in stable micellar solution by the concentrations of bile salts and lecithin present. The degree of cholesterol saturation of bile is commonly expressed by a cholesterol saturation index, with index values greater than one indicating supersaturation. In unsaturated bile, newly secreted vesicles containing cholesterol and lecithin are dissolved completely by bile salts as bile is concentrated in the gallbladder. In contrast, as supersaturated bile is concentrated, vesicles fail to dissolve completely and instead fuse to form large, cholesterol-rich multilamellar liquid crystals, from which excess cholesterol may precipitate as plate-like cholesterol monohydrate crystals. The causes of biliary cholesterol supersaturation generally can be divided into those associated with a primary increase in biliary secretion of cholesterol, by far a more predominant underlying cause, and those associated with deficiency of bile salts. Estrogen causes an increase in absolute rates of biliary cholesterol secretion 830

into bile most likely as a result of up-regulation of low-density lipoprotein receptors and enhanced uptake of cholesterol by the hepatocyte. This fact probably accounts for the two-fold increased risk of cholesterol gallstones in women during their childbearing years and the increased risk of gallstones in multiparous women and women taking oral contraceptives. Progesterone also may play a part in gallstone pathogenesis by impairing gallbladder contractions and by inhibiting an enzyme responsible for esterification of free cholesterol. Obesity is associated with increased biliary cholesterol secretion possibly as a result of an increase in cholesterol synthesis. Some hypocholesterolemic drugs, such as the fibric acid derivatives clofibrate and gemfibrizol, directly stimulate secretion of cholesterol into bile and are associated with increased risk of cholesterol gallstones. Decrease in bile acid pool size may be responsible for increased incidence of cholesterol cholelithiasis in Crohn's disease, in which excessive bile salt losses occur due to ileal resection or diseased ileum. Many non-obese patients with cholelithiasis have a small bile salt pool and lower than normal rates of bile salt synthesis. Bile salt synthesis decreases and biliary cholesterol saturation increases with age, and this trend may account for the progressive increase in prevalence of gallstones with age. Gallstones develop more commonly in first-degree relatives of cholesterol gallstone patients. The high risk of cholesterol gallstones in Native Americans of the southwestern U.S. (greater than 80%) also appears to have a genetic basis. The nature of the genetic predisposition is not well understood, but oversensitive negative feedback regulation of bile salt biosynthesis has been postulated. Pigment gallstones account for about 20% of U.S. gallstones. The predominant components of these gallstones are calcium salts of organic and inorganic anions, especially bilirubin. Ionized calcium is present in bile at concentrations similar to those of plasma. Unconjugated bilirubin has a low solubility product with calcium, and its presence in bile even in small amounts favors precipitation of calcium bilirubinate. Two subtypes of pigment gallstones have different composition, different

pathogenesis, and different risk factors. Black pigment gallstones are hard, dense, brittle concretions composed of calcium bilirubinate along with inorganic calcium salts of carbonate and phosphate. The bilirubin in these stones becomes oxidized and polymerized, producing a mixture of altered pigments that absorb light over the entire visible spectrum, thus giving these stones a characteristic jet-black color. The major predisposing factor appears to be an increased heme turnover leading to increased biliary secretion of unconjugated bilirubin, as occurs in hemolytic disorders, hypersplenism (cirrhosis), or disorders associated with ineffective erythropoiesis. Brown pigment (earthy) gallstones have a soft, claylike consistency. In addition to calcium bilirubinate, they contain a substantial proportion of calcium soaps of fatty acids. Brown pigment gallstones occur in chronically infected bile in areas of stasis, where bacterial cleavage of phospholipid and conjugated bilirubin releases unconjugated bilirubin and fatty acids. Factors predisposing to this type of stone include biliary strictures, biliary infestation with parasites, Oriental cholangiohepatitis, and choledochal cysts. Most stones forming primarily in the bile ducts are of the brown pigment type. In addition to bile supersaturation, a variety of other abnormalities contribute to formation of both cholesterol and pigment gallstones (Fig. 157-6) . Precipitation of crystals from supersaturated bile requires the formation of an initial solid nidus (nucleation) with subsequent deposition of solute on the surface leading to crystal growth. Many individuals who secrete supersaturated bile have very slow nucleation and do not develop gallstones. Nucleation and growth of cholesterol crystals is much more rapid in bile of gallstone patients than in gallstone-free controls for equal degrees of cholesterol supersaturation. A number of proteins in bile can accelerate or retard the nucleation and growth of crystals, and abnormal levels of these proteins may account for the abnormally rapid crystal appearance in bile of gallstone patients. Nascent cholesterol crystals precipitating from vesicles or mixed micelles are trapped in a mucin gel lining of the gallbladder. Over time these crystals fuse to form macroscopic stones. Mucus secretion is stimulated by prostaglandins; in animal models the prevention of excessive mucin secretion by cyclooxygenase inhibitors can prevent cholesterol gallstone formation. Lastly, many patients with gallstones have defective gallbladder emptying and an abnormally high residual

Figure 157-6 Pathogenesis of cholesterol gallstones. Canalicular secretion of bile containing excess cholesterol relative to bile salts and phospholipids (supersaturated bile) is necessary but not sufficient. Additional requirements for stone formation are nucleation and growth of crystals, trapping of crystals in a mucin gel, and gallbladder stasis with retention of sludge permitting gradual aggregation and fusion of crystals to form macroscopic stones. Abnormalities in each of these areas have been noted in gallstone patients. In principle, eliminating any of these four steps should prevent gallstone formation.

volume after administration of cholecystokinin. Conditions in which gallbladder stasis occurs, such as parenteral alimentation, low-fat weight-reducing diets, and pregnancy are associated with a high rate of rapid gallstone formation. CLINICAL MANIFESTATIONS.

Gallstone disease can be divided conceptually into four stages (Table 157-2) . In the first stage ("lithogenic"), no discrete stones have yet formed but the necessary conditions for stone formation (bile supersaturated with cholesterol, rapid nucleation and crystal growth, mucus, and gallbladder stasis) are in place. Identification of patients at high risk for gallstones in this early stage may allow targeted use of preventive therapies. In the second stage, the gallstones have already been formed but are still asymptomatic. Several epidemiologic studies have shown that the majority of gallstones are asymptomatic and may remain so for decades. Onset of symptoms heralds the third stage of gallstone disease. The typical symptom-complex associated with gallstones is termed biliary colic. Biliary colic is thought to result from increased wall tension in the gallbladder and/or bile ducts due to impaction of a stone in the cystic duct or distal common bile duct. It is characterized by continuous severe pain in the epigastrium or right upper quadrant, sometimes radiating to the back or scapula, and typically lasting for more than 30 minutes. The pain is unrelieved by changes in position and often causes the patient to seek emergent medical attention. Biliary colic is frequently associated with nausea and vomiting. Biliary colic is the only pattern of pain that is consistently associated with gallstones; in large prospective studies, the frequency of non-specific symptoms such as vague abdominal discomfort, bloating, and flatulence in individuals with gallstones has been no higher than in the general population. Examination of the abdomen during attacks of biliary colic usually reveals right upper quadrant tenderness but no evidence of peritonitis, and the TABLE 157-2 -- STAGES OF GALLSTONE DISEASE Lithogenic bile (stage 1)

Asymptomatic gallstones (stage 2)

Symptomatic gallstones (stage 3)

Complications of gallstones (stage 4) Acute: Acute cholecystitis (localized peritonitis, perforation, abscess, sepsis) Choledocholithiasis (obstructive jaundice, acute pancreatitis, ascending cholangitis) Chronic: Chronic cholecystitis Choledochoduodenal fistula with gallstone ileus Gallbladder adenocarcinoma

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patient is afebrile. Transient elevation of bilirubin, alkaline phosphatase, and aspartate and alanine aminotransferase levels are sometimes noted. In patients who have experienced at least one attack of biliary colic, about two thirds will experience additional attacks of pain during the next 2 years, and biliary colic therefore is commonly an indication for cholecystectomy. The fourth and most serious stage of gallstone disease is marked by onset of complications. Acute cholecystitis (inflammation of the gallbladder) typically presents as acute onset of constant, dull, right upper quadrant pain, fever, shaking chills, nausea, and vomiting. Abdominal pain is often aggravated by coughing or moving; these symptoms are due to localized peritonitis over the area of the gallbladder. A characteristic physical finding is Murphy's sign, defined as tenderness of the gallbladder to palpation during examination of the abdomen. Patients with cholecystitis develop leukocytosis with marked shift to the left, but bilirubin and alkaline phosphatase levels are usually not elevated. In most cases, the cholecystitis develops as a result of impaction of a stone in the neck of the gallbladder. In about 10% of cases, however, no gallstones are present; such acalculous cholecystitis may result from impaction of mucus or sludge, from ischemia in vasculitic disorders, or from direct infection of the gallbladder bile. Some cases are sterile, but in the majority bacteria can be cultured from the gallbladder. The usual organisms present are Escherichia coli and other enteric gram negatives. If untreated, the gallbladder may become empyematous, develop gangrene, and perforate, leading to peritonitis, subphrenic abscess, and septic shock. Sometimes infection with gas-forming anaerobic organisms may produce emphysematous cholecystitis with air in the gallbladder wall. Acute cholecystitis requires prompt hospitalization. Antibiotic therapy will usually treat the infection and allow for elective surgery. However, acute cholecystitis should be considered a surgical disease requiring a surgical cure as promptly as it can be done safely. Patients with long-standing gallstone disease frequently develop chronic cholecystitis. The evolution of chronic cholecystitis is obscure. It may be the result of repeated bouts of acute cholecystitis in some cases, but many patients cannot relate a history of acute cholecystitis. Often patients note vague, poorly defined, non-specific intermittent epigastric discomfort, but many are asymptomatic. The gallbladder is thickened, fibrotic, and contracted and frequently cannot be seen by oral cholecystography. A chronic inflammatory infiltrate is present, and mucosal pseudodiverticula termed Rokitansky-Aschoff sinuses are seen histologically. In long-standing cases, deposition of calcium in the fibrotic gallbladder wall may give an eggshell appearance on a radiograph, termed porcelain gallbladder. Chronic cholecystitis, particularly with porcelain gallbladder, is thought to predispose to adenocarcinoma of the gallbladder. In an occasional patient, impaction of a large stone in the cystic duct with persistent obstruction may gradually lead to distention of the gallbladder with clear mucus, a condition termed gallbladder hydrops (mucocele). Calcium salts may become concentrated in the hydropic gallbladder, producing a limy or milk-of-calcium bile, which may be visible on plain abdominal radiographs. Rarely in chronic cholecystitis a large gallstone will erode through the wall of the gallbladder or common bile duct into the duodenum, producing a choledochoenteric fistula. In the absence of prior biliary surgery, this unusual condition is strongly suggested by the finding of air in the biliary tree on plain radiographs. The large stone frequently impacts in the ileum, and patients then present with small bowel obstruction, a phenomenon termed gallstone ileus. Fistulization also can occur into other

structures adjacent to the gallbladder such as colon, stomach, or abdominal wall. Gallstones in the common bile duct (choledocholithiasis) may impact at the level of the ampulla of Vater to produce obstructive jaundice and biliary colic (see Fig. 157-5 C). Bacterial infection above an obstructing stone in the common bile duct is common and leads to ascending cholangitis. Patients with ascending cholangitis typically present with acute onset of high fever and signs of sepsis, right upper quadrant pain and tenderness, and jaundice (Charcot's triad). Leukocytosis with shift to the left, conjugated hyperbilirubinemia, abnormally high alkaline phosphatase, and elevated aminotransferase levels are common. Bacteria often can be cultured from the blood. In severe cases, pus may be present in the biliary tree, and patients may develop multiple hepatic abscesses. The usual pathogens observed in ascending cholangitis are enteric gram-negative bacteria, anaerobes, or occasionally enterococci. Antibiotics are indicated but frequently fail to control sepsis in severe, suppurative cases. Symptoms usually respond rapidly to biliary drainage through surgical, radiographic, or endoscopic means. Endoscopic sphincterotomy with stone extraction and/or temporary stent placement is the least invasive and most rapid way of achieving biliary decompression in most cases of ascending cholangitis. Attacks of acute pancreatitis (see Chapter 141) may be triggered by passage of a gallstone through the ampulla of Vater. The pathogenesis of acute gallstone pancreatitis is not completely understood. It has been speculated that transient obstruction of the pancreatic duct orifice where it joins the common bile duct leads to an increase in pancreatic ductal pressure, which may cause premature activation of proteolytic enzymes within the pancreatic acinar cells. Gallstones are responsible for most cases of pancreatitis in the non-alcoholic. Data suggest that episodes of recurrent acute pancreatitis previously thought to be idiopathic may be caused by small gallstones that are below the limits of detection of the common imaging techniques. A search for cholesterol microcrystals in duodenal bile may be useful in making the diagnosis of microlithiasis. Diagnostic Studies in Gallstone Disease A variety of diagnostic imaging studies are of value in patients with suspected gallbladder disease (Fig. 157-7) . Plain radiographs may reveal calcium-containing (pigment) gallstones, which are usually radiopaque. Occasionally, foci of calcification either in the core or around the rim also can be seen in predominantly cholesterol stones. Air in the biliary tree can be caused by gas-forming organisms or by fistulas between the bowel and biliary tract. Calcification of the gallbladder ("porcelain gallbladder") indicates chronic cholecystitis. Ultrasonography is a sensitive, specific, non-invasive, and inexpensive test for diagnosis of gallstones. In general, ultrasonography is the only diagnostic procedure needed to make the diagnosis of gallstones in the gallbladder, but it usually will not detect stones in the common bile duct; it may, however, provide clues to the presence of choledocholithiasis, such as dilatation of the major bile ducts. The typical gallstone on ultrasound evaluation appears as an echogenic focus that casts a sound "shadow." Biliary sludge also is diffusely echogenic and located in the dependent gallbladder but lacks acoustic shadowing. In acute cholecystitis, ultrasonography may reveal edema of the gallbladder wall and pericholecystic fluid. The accuracy of ultrasound in diagnosis of gallstones is about 95%. However, ultrasonography does not provide accurate information on the type of gallstone (cholesterol vs. pigmented), number of gallstones, or cystic duct obstruction. For an oral cholecystogram, patients are given an oral radiocontrast agent, iopanoic acid. The contrast agent is absorbed from the intestine, taken up by the liver, and secreted into the bile. When concentrated by the gallbladder overnight, the contrast agent outlines most of the gallbladder. Radiolucent gallstones appear as negative shadows within the gallbladder. Failure of the gallbladder to visualize generally suggests chronic cholecystitis with loss of gallbladder mucosal function or cystic duct obstruction. Acute and chronic liver disease may also be associated with failure to visualize the gallbladder. The size and type of stones can be estimated with reasonable accuracy by this test. Typical cholesterol gallstones are radiolucent and floating. Because of more extensive information provided by oral cholecystography on the type and size of gallstones and gallbladder visualization, this procedure should be used in evaluating those patients who may be candidates for gallstone dissolution. Hepatobiliary radionuclide scans employ a variety of iminodiacetic acid (IDA) derivatives (e.g., HIDA, DISIDA, or PIPIDA) to assess the patency of the cystic duct and the common bile duct. These organic anions are administered intravenously, taken up by the liver, and excreted rapidly into bile. Failure of these isotopes to enter the gallbladder or the intestine suggests obstruction of the cystic or common bile ducts, respectively. This test is very useful in the diagnosis of cholecystitis with cystic duct obstruction. Contrast material may be injected directly into the biliary tree through either a percutaneous, fluoroscopically guided approach (PTC) or a retrograde approach (ERCP). These tests represent the gold standards for examination of the biliary tree and generally will 832

Figure 157-7 Images of gallstones. A, Plain radiograph reveals calcified pigment gallstones. The more common cholesterol gallstones are not detectable on plain radiographs. B, Oral cholecystogram showing contrast material outlining multiple radiolucent cholesterol stones in a normally functioning gallbladder. C, Ultrasound examination showing a large gallstone as an echogenic focus that casts a sonic "shadow."

reveal stones or stenosis that are not detectable by other means. In occasional patients in whom gallstones are strongly suspected but all routine studies are negative, microscopic examination of a sample of bile aspirated at ERCP may reveal the presence of calcium bilirubinate or cholesterol crystals. Therapy for Gallstones

No treatment is usually required for asymptomatic gallstones because of their low propensity to become symptomatic. Longitudinal studies have shown that conversion from asymptomatic to symptomatic stones takes place at the rate of no more than 1 to 2% per year, and risk-benefit analyses indicate that surgery for asymptomatic gallstones generally causes more morbidity than it prevents. Exceptions to this rule may include very large gallstones (>3 cm in diameter) and porcelain gallbladder, both of which have been associated with an increased risk of gallbladder carcinoma. Some experts also would recommend prophylactic cholecystectomy for asymptomatic gallstones in patients with diabetes mellitus or spinal cord injury because gallstone complications such as acute cholecystitis may be more severe and more often life threatening in these groups. Symptomatic gallstones are cured by cholecystectomy. Surgical removal of the gallbladder is indicated in all instances of acute cholecystitis or in symptomatic patients with non-visualized gallbladder on oral cholecystography. Laparoscopic cholecystectomy is now preferred because of shorter hospitalization time and quicker recovery. Serious bile duct injury, often requiring reconstructive surgery, occurs in about 0.5% of cases but decreases in frequency as the surgeon gains experience with laparoscopic surgery. Gallstones in the common bile duct may be removed by the surgeon at the time of cholecystectomy. More recently, development of methods for direct choledochoscopy and stone extraction during surgery have reduced the need for common duct exploration (Color Plate 2 D). Alternatively, stones up to 1.5 cm in diameter can be extracted from the common bile duct by endoscopic methods after endoscopic sphincterotomy. Larger stones can be crushed and extracted in pieces. These techniques are of value when patients are acutely ill with ascending cholangitis or acute pancreatitis or when stones are inadvertently left in the common duct after cholecystectomy. Ascending cholangitis is treated aggressively with antibiotics and endoscopic sphincterotomy, which removes the obstructed stones and allows for normalization of bile flow. The drainage of infected bile combined with appropriate antibiotic therapy results in quick recovery, after which the patient ordinarily should have an elective cholecystectomy. In patients at high surgical risk, cholecystectomy can be deferred indefinitely after sphincterotomy and stone extraction with only a few per cent per year risk of subsequent gallstone complications. In addition to surgical therapy, cholesterol gallstones may be treated medically. Oral administration of certain bile salts (chenodeoxycholic acid or UDCA) reduces biliary cholesterol saturation. If the cholesterol saturation index of bile can be brought below 1 with administration of these two bile salts, the gallstone-forming process can be reversed and undersaturated micelles in bile can slowly "leach" cholesterol from the stones. Over a period of time (6 months to 1 year) of continuous therapy, pure cholesterol gallstones will gradually dissolve. Bile salt therapy is most successful in patients with pure cholesterol gallstones and does not work with calcified stones and even mixed stones. Other critical factors for success include small stones, a normally functioning gallbladder, and adequate bile salt dosage. In an ideal group of patients with small, radiolucent, floating stones, 75% dissolution of gallstones within 1 year has been observed. Chenodeoxycholic acid is moderately toxic; it may cause mild to moderate elevations of liver function tests and serum cholesterol. In therapeutic doses, chenodeoxycholic acid is frequently associated with disabling diarrhea. Because of these side effects, the use of chenodeoxycholic acid in patients with gallstones has been abandoned in the United States. UDCA, a 7beta-epimer of chenodeoxycholic acid, is a weak detergent and essentially without toxicity; it is equally as efficacious in dissolving gallstones as chenodeoxycholic acid but has practically no side effects. Administration of UDCA is associated with a marked decrease in biliary cholesterol secretion and desaturation of bile with cholesterol; it also

appears to stabilize cholesterol-rich lecithin vesicles and liquid crystals in bile. Because oral dissolution therapy is slow and often not successful, it generally is reserved for patients with mildly symptomatic gallstones who are at high risk for surgery or who are otherwise reluctant to undergo cholecystectomy. UDCA is also effective for primary prevention of rapidly forming 833

gallstones in patients with morbid obesity who are experiencing rapid weight loss. Prophylactic administration of UDCA during this period reduces gallstone incidence by more than 80%. Experimental medical therapies for gallstones include solvent dissolution and extracorporeal shock wave lithotripsy. Cholesterol gallstones can be dissolved rapidly (within hours) when organic solvents such as methyl-tert-butyl ether or ethyl propionate are instilled directly into the gallbladder by percutaneous transhepatic approach. The dissolution rate for non-calcified stones using this modality is close to 100% and the side effects are few. This approach has not gained wide acceptance because of its invasive nature and labor intensity. Extracorporeal shock wave lithotripsy was first introduced with great success for treatment of renal stones and, later, in the mid 1980s, was modified to permit shattering of stones in the gallbladder. Gallstone fragments after lithotripsy are eliminated with bile or can be dissolved with concurrent oral bile salt treatment. This therapy is particularly effective for solitary gallstones. Biliary colic after lithotripsy occurs relatively frequently as a result of elimination of small fragments of pulverized stones; in about 1% of patients, passage of stone fragments causes acute pancreatitis. No gallstone lithotripsy device has been approved for general use in the United States; and with the advent of laproscopic cholecystectomy, this technology has largely been abandoned. A major limitation of all medical treatments of cholesterol gallstones (bile salt dissolution, solvent dissolution, lithotripsy) is gallstone recurrence, which averages about 50% over a period of 5 years. However, only 7.5% of the recurrent stones become symptomatic, and continuous low-dose UDCA administration may prevent or decrease the incidence of stone recurrence. Other Benign Disorders of the Gallbladder A number of benign gallbladder wall abnormalities sometimes may mimic cholelithiasis. Cholesterolosis of the gallbladder is usually an asymptomatic condition in which cholesterol accumulates within histiocytes in the mucosa of the gallbladder. Aggregates of these lipid-laden macrophages distend and enlarge the mucosal folds. The accumulation of lipid at the tips of these folds is readily visible grossly as yellow streaks or flecks that resemble the seeds of a strawberry, hence the common name "strawberry gallbladder." There is usually no inflammation or calculi. The reason for the accumulation of cholesterol is unknown. Focal aggregation of cholesterol laden macrophages may produce polyps that may be visible on ultrasonography. Other benign gallbladder lesions that may produce polyps of the gallbladder wall include benign adenomas and adenomyomatous hyperplasia. In general, these lesions are asymptomatic and require no treatment. Postcholecystectomy Disorders After cholecystectomy, a small fraction of patients develop mild diarrhea. Increased circulation of the bile salt pool with increased delivery of bile salts to the colon has been implicated in post-cholecystectomy diarrhea, and patients with this syndrome often respond well to treatment with cholestyramine. More difficult is the problem of recurrent upper abdominal pain, which is noted in about 5% of patients after cholecystectomy. In some instances, pain may be secondary to retained gallstones in the common bile duct or abscess or other complications of surgery. In the absence of such a specific etiology, biliary type pain after gallbladder removal is termed post-cholecystectomy syndrome. This term is a misnomer, since in most cases the pain probably is unrelated to gallstones or cholecystectomy but rather due to an error in the original diagnosis. The prevalence of gallstones is so great that many patients with abdominal pain from other causes are coincidentally found to have TABLE 157-3 -- CRITERIA FOR DIAGNOSIS OF BILIARY DYSKINESIA Right upper quadrant pain associated with transient elevation of alkaline phosphatase, bilirubin, aspartate aminotransferase, and alanine aminotransferase Diameter of common bile duct >11 mm (ultrasound) Delayed emptying of common bile duct (>45 min) after endoscopic retrograde cholangiopancreatography or quantitative hepatobiliary scintigraphy Elevated basal sphincter of Oddi pressure (by manometry) gallstones. When these patients undergo cholecystectomy, persistence of symptoms is not surprising. Recurrence of abdominal pain after cholecystectomy should lead the physician to consider other, overlooked causes of pain such as irritable bowel syndrome, peptic ulcer, pancreatitis, and biliary dyskinesia. Biliary Dyskinesia Biliary dyskinesia refers to a syndrome of repeated attacks of biliary colic resulting from motor dysfunction of the sphincter of Oddi. Bile flow is regulated by the sphincter of Oddi by a combination of phasic contractions superimposed on tonic pressure. The motor activity of the sphincter of Oddi is influenced by hormonal and neural factors. The principal hormone involved in the regulation of sphincter of Oddi and gallbladder contraction is cholecystokinin, which contracts the gallbladder and at the same time relaxes the sphincter of Oddi. After cholecystectomy with loss of the gallbladder reservoir, modest increases normally have been noted in the sphincter of Oddi tone, bile ductal pressure, and common bile ductal diameter. Rarely, patients may develop abnormalities of sphincter of Oddi function, including increased basal tone or increased amplitude and frequency of phasic contraction, which may episodically impede efflux of bile and trigger typical attacks of biliary colic. The association of sphincter of Oddi motor abnormalities with symptoms and signs of functional biliary obstruction is termed biliary dyskinesia (Table 157-3) . Clinically, biliary dyskinesia produces episodic right upper quadrant abdominal pain mimicking an attack of choledocholithiasis. The diagnosis is suspected when symptoms and laboratory abnormalities suggest intermittent common bile duct obstruction at the level of the ampulla of Vater (elevated alkaline phosphatase, aspartate aminotransferase, and/or bilirubin; dilatation of the common bile duct), but cholangiography reveals no evidence of gallstones. Additional objective signs that support this diagnosis are delayed emptying of the common bile duct at ERCP and abnormal sphincter of Oddi manometry showing an increase in basal pressure to greater than 40 mm Hg. Once the diagnosis is established, endoscopic sphincterotomy is the therapy of choice. Bates MD, Bucuvalas JC, Alonso MH, Ryckman FC: Biliary atresia: Pathogenesis and treatment. Semin Liver Dis 18:281-293, 1998. Detailed review of the clinical presentation and therapy of this disorder of 1 per 10,000 live births. Czaja AJ: Frequency and nature of the variant syndromes of autoimmune liver disease. Hepatology 28:360-365, 1998. A clinical review summarizing the similarities and differences among autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. Heuman DM, Moore EW, Vlahcevic ZR: Pathogenesis and dissolution of gallstones. In Zakim D, Boyer DT (eds): Hepatology, 3rd ed. Philadelphia, WB Saunders, 1996. A current review of gallstone pathogenesis, with particular emphasis on factors involved in pathogenesis of gallstone formation. Kaplan MM: The use of methotrexate, colchicine, and other immunomodulatory drugs in the treatment of primary biliary cirrhosis. Semin Liver Dis 17:129-136, 1997. Review of present modalities of therapy for primary biliary cirrhosis. Ko CW, Sekijima JH, Lee SP: Biliary sludge. Ann Intern Med 130:301-311, 1999. A review of the clinical significance of this ultrasonographic finding. Ponsioen CIJ, Tytgat NJ: Primary sclerosing cholangitis: A clinical review. Am J Gastroenterol 93:515-523, 1998. A detailed review of the natural history of this disease.

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Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Part XIII - HEMATOLOGIC DISEASES

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Chapter 158 - HEMATOPOIESIS AND HEMATOPOIETIC GROWTH FACTORS Peter Quesenberry

Lymphohematopoiesis is a tightly regulated system in which production of the various blood cell types responds to specific functional demands: red cell production in response to hypoxia, granulocyte/monocyte production in response to infection, lymphocyte production in response to antigen challenge, and platelet production in response to hemorrhage. In this system (or tissue), early multipotent stem cells with extensive proliferative potential, but few differentiated features, reside largely in the bone-encased marrow cavity. These stem cells have the potential, with appropriate inductive signals, to differentiate and give rise to populations of progenitor cells with progressively restricted renewal, proliferative, and lineage potential but with increasing functional characteristics defining a variety of specific lineages (Fig. 158-1) . This process eventuates in the cell lineages recognizable by standard Wright-Giemsa stains as erythroid, granulocytic, monocytic, lymphoid, or megakaryocytic. These events occur continuously with a large turnover of differentiated cells, as illustrated by the blood lifespans of human erythrocytes (120 days), platelets (10 days), and granulocytes (9 hours). Lymphocyte (T and B cells) lifespans vary tremendously from hours to years. The production of active blood cell types occurs predominantly in the bone marrow. However, the spleen, lymph nodes, and accessory lymphoid tissues are also ongoing sites of cell production, predominately lymphoid; under stress, myeloid cell production also occurs at these sites. The end cells produced in the marrow are released into the blood stream under various stimuli and circulate in the blood. With the exception of erythrocytes and platelets, they emigrate to the tissues where they have variable lifespans: granulocytes measured in days and monocytes/macrophage/lymphocytes measured in weeks to years.

LYMPHOHEMATOPOIESIS The classically recognizable differentiated marrow lineages represent the end stages of a carefully orchestrated production system. Progenitors feed into the various blast compartments (myeloblast, proerythroblast, lymphoblast, and megakaryoblast), which, in turn, feed into lineages that show increasingly differentiated characteristics while losing proliferative potency. Myeloblasts become promyelocytes, which then differentiate into myelocytes, the stage at which neutrophilic (Fig 158-2) , eosinophilic, and basophilic lineages are distinguished. Erythrocyte and platelet lineages result in anucleate functional cells, whereas B and T lymphocyte lineages give rise to a variety of effector cell populations. This system is an irreversible in-out production system with final demise of end cells in the blood stream (platelets and red cells) or tissues (all others). The primitive lymphohematopoietic stem cell is the basis for the

Figure 158-1 Hierarchical model of lymphohematopoiesis. RBC-red blood cell; NK cell-natural killer cell.

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Figure 158-2 Neutrophil production system. PMN-polymorphonuclear leukocyte.

ongoing production of lymphohematopoiesis (Table 158-1) . The stem cell is defined as a cell with tremendous proliferative potential, the capacity to renew itself on a population basis, and the ability to give rise to large numbers of differentiated progeny eventuating in the end cells just detailed. It immediately gives rise to a wide variety of committed progenitors, ranging from those capable of giving rise to most lineages to progenitors restricted to a single lineage.

STEM CELL ONTOGENY Early multipotent stem cells are present in the yolk sac and in mesenchymal tissues. These stem cells subsequently traffic predominantly to the liver (and to a lesser extent the kidney), followed by the establishment of marrow as the major site of active hematopoiesis. The earlier in ontogeny stem cells are harvested, the greater their proliferative potential, as illustrated by the proliferative and growth potential of fetal liver and cord blood cells in clinical transplantation. The hematopoietic cell in both murine and human species has been characterized as to surface proteins and physical, metabolic, and cell cycle characteristics; and these characteristics have been utilized physically to purify stem cells (Fig. 158-3) . Early stem cells do not express differentiated lineage markers, but they express certain classes of receptor proteins or other markers; in humans, CD34 and c- kit have been proposed as stem cell-specific markers. Studies have indicated that CD34-negative cells (1) have significant stem cell potential but contain no progenitor cells and (2) may give rise to CD34-positive cells. The most primitive stem cells tend to be dormant in G0 or prolonged G1 phases and also to show strong activity of the p170 pump, the multidrug resistance pump that exudes certain chemotherapeutic agents and the dyes rhodamine and Hoechst, from cells. Thus the most primitive stem cells are characterized by very low staining with rhodamine and Hoechst. LYMPHOHEMATOPOIETIC STEM CELL. The existence of a stem cell, common to all lymphoid and myeloid lineages, was established by studies in mice in which the infusion of a single cytogenetically or retrovirally marked stem cell gave rise to all cell lineages, which then persisted over time. Sustained in vivo engraftment is the gold standard for the true stem cell, although different subpopulations may show different engraftment kinetics, ranging from weeks to over a year in the mouse. The engrafting cell, which is quiescent or dormant, appears to have high p170 pump activity (stains low for rhodamine, a p170-pumped dye). The existence of a similar multipotent stem cell in humans was inferred from studies of marrow and blood cells from patients with chronic myelogenous leukemia, in whom all lineages were marked with the Philadelphia chromosome, and from glucose-6-phosphate dehydrogenase studies of patients with myeloproliferative disorders. Unfortunately, there is no in vivo engraftment assay in humans, but three in vitro assays appear to measure relatively primitive multilineage cells and have been proposed as true surrogates for the long-term renewal lymphohematopoietic stem cell. The colony-forming unit-blast (an assay in which marrow cells give rise to small colonies of primitive blast cells) with extensive proliferative and differentiative potential may in fact be a good surrogate, but unfortunately few laboratories have mastered this technique, so it is not generally applicable. The high proliferative potential colony-forming cell, an assay in which marrow cells proliferate in the presence of combinations of growth factors to give rise to large (>0.5 mm) colonies in vitro, also appears to be a reasonable surrogate

CHARACTERISTIC

TABLE 158-1 -- STEM AND PROGENITOR CELLS STEM CELL

PROGENITOR CELL

Proliferative potential

Tremendous

More limited

Renewal

On a population basis

Probably none

Potential for differentiation

All lymphohematopoietic lineages

Restricted

Differentiated characteristics

Minimal--lineage negative

Progressively increases

Cycle status

Dormant

Cycling

Cytokine responsiveness

Large number of cytokines needed for expression of phenotype

Restricted

Cell of origin

Unknown

Stem cell

Staining with rhodamine and Hoechst dyes (partial measure of p170 pump activity)

Active p170 pump--stains dimly

Less active p170 pump--rhodamine "bright"

Producing long-term hematopoiesis after in vivo transplant

Defines cells

Limited to none

Adheres to marrow stroma

Yes

No or limited

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Figure 158-3 Characteristics of the lymphohematopoietic stem cell.

and probably the best generally available. The stromal-based assays, long-term culture-initiating cell (LTC-IC) and cobblestone-forming assays, are of interest but appear to monitor both primitive and more differentiated cells and are difficult to reproduce. These assays, in which marrow cells grow on an adherent stromal layer, remain interesting research areas without practical applications, although the recently described LTC-IC extended (a 60+ day assay) may come closer to the real stem cell. Human marrow and cord blood cells have been infused into immunodeficient mice to establish engraftment. Studies with non-obese diabetic-severe combined immunodeficient mice, an immunodeficient animal that will accept human marrow cell engraftment, have been particularly impressive, but the lineages are skewed to lymphoid cells, and engraftment is variable. Thus, this assay has not yet been established as a valid human stem cell assay. REGULATION AND CYTOKINES. Utilizing both in vitro and in vivo assays, a large number of cytokines have been characterized and shown to affect lymphohematopoiesis. The availability of cloned molecules has provided sufficient quantities of cytokines for in vivo studies and clinical application. Regulation of lymphohematopoiesis is based on a large number of circulating and membrane based cytokines, as well as integrin modulation and antigen presentation to B and T cells. Over 70 cytokines maintain, stimulate, or inhibit various aspects of lymphohematopoiesis (Table 158-2) . Cytokines exert a wide variety of actions on diverse cell types both within and outside specific differentiation lineages, but many TABLE 158-2 -- CHARACTERISTICS OF LYMPHOHEMATOPOIETIC CYTOKINES Are glycoproteins Act on cell surface receptors Initiate complex second messenger and tanscriptional and post-transcriptional regulation May act on stem cell, progenitor cell, and differentiated cells of the same lineage. May act on multiple different lineages (e.g., erythroid, granulocyte, and lymphoid). Stimulate or inhibit proliferation, apoptosis, differentiation, or function Usually act on neoplastic counterpart of normal target cell have predominant or primary actions, especially when evaluated after in vivo administration (Table 158-3) . Erythropoietin (erythroid), macrophage-colony-stimulating factor (M-CSF), and granulocyte-CSF (G-CSF) are examples of cytokines with a relatively high degree of specificity. Most cytokines, however, have multiple actions. Examples include interleukin (IL)-6, which acts on primitive stem cells as well as lymphoid, granulocyte, megakaryocyte, and macrophage lineages, and IL-3, which impacts virtually all lineages. IL-1 induces many other cytokines and illustrates the difficulty in ascertaining primary or secondary effects, especially with the potential for paracrine or autocrine loops. These cytokines are produced by a large variety of tissues and cell types. Most cells produce multiple cytokines, which can be differentially induced by various stimuli, including other cytokines, such as IL-1. The suggestion that "everything makes everything" is perhaps too drastic, but also not too far off target. The key is in differential production in response to different stimuli, and probably in local production. Monocytes, T lymphocytes, endothelial cells, fibroblasts, and "marrow stromal" cells are important sources of lymphohematopoietic cytokines. Erythropoietin production is an exception to the general rule, because it is largely produced in the kidney in response to hypoxia, although it can also be produced by the liver. Stimuli that induce white blood cell formation are, in general, related to exposure to foreign or noxious agents, whereas platelet production occurs in response to hemorrhage, anemia, and thrombocytopenia. Perhaps the best way to define the cytokine responsiveness of a particular cell class is to characterize cytokine receptor expression. Each cytokine has its private receptor, but different cytokines may share class-specific signal transducers. Many receptors dimerize on cytokine binding and then activate tyrosine kinase, promoting phosphorylation of intracellular proteins; other receptors do not have intrinsic enzymatic activity but induce protein phosphorylation through associated non-receptor-type tyrosine kinase activities, such as JAK2, Fes, and Lyn. Receptors are expressed in low numbers and do not exceed a few hundred per cell. The multipotent repopulating stem cell possesses receptors for most cytokines, but more mature cells have a more restricted distribution of receptors.

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CYTOKINE

TABLE 158-3 -- CYTOKINES ACTIVE ON LYMPHOHEMATOPOIETIC STEM CELLS PRINCIPAL OR HIGHLIGHTED ACTIVITY

Interleukins IL-1

Induces production of other cytokines from many cells: co-stimulates early stem cells with other cytokines; modulates immune response.

IL-2

T-cell growth factor; inhibits myelopoiesis and erythropoiesis.

IL-3

Multi-lineage stimulator--myeloid, erythroid, lymphoid, and megakaryocytic; in vivo increases blood monocytes and granulocytes including eosinophils and platelets.

IL-4

Stimulates B cells and dendritic cells and modulates immune response; co-stimulates CFU-GM and CFU-E.

IL-5

Simulates B cells and eosinophils.

IL-6

Stimulates megakaryopoiesis and synergizes with IL-1, IL-2, IL-3, IL-4, GM-CSF, and CSF-1; enhances plasma cell proliferation; role in Castleman's disease and atrial myxoma.

IL-7

Stimulates pre-B cells (with steel factor) and early stem cells.

IL-8

Stimulates production and function of neutrophils; acts as proinflammatory factor.

IL-9

Co-stimulates CFU-GM and CFU-MIX; stimulates BFU-E with erythropoietin; enhances T cell production and, with IL-3, mast cell production.

IL-10

Inhibits cytokine production, modulates immune cells, and stimulates mast cells.

IL-11

Shares most of activities of IL-6; increases neutrophils and platelets in blood in primate model.

IL-12

Increases generation of immunocompetent cells.

IL-13

Enhances steel factor-induced proliferation of Lin- Sca+ murine marrow stem cells; inhibits cytokine production by monocytes; stimulates B cells and activates T cells.

IL-14

B-cell growth factor.

IL-15

Modulates T-cell activity.

IL-16

Acts as immunomodulator.

IL-17

Induces production of other cytokines such as IL-6, IL-8, and G-CSF, and enhances expression of adhesion molecules.

IL-18

Induces GM-CSF and interferon gamma production; inhibits IL-10 production.

Colony-Stimulating Factors, Erythropoietin, and Early Acting Factors CSF-1

Enhances production and function of monocytes.

G-CSF

Stimulates granulocyte production and function; co-stimulates early progenitors in synergy with a number of cytokines; stimulates pre-B cells; in vivo stimulates granulocyte production.

GM-CSF

Stimulates GM-CFC and production of monocytes, granulocytes, eosinophils, and basophils; synergizes with IL-4 to produce dendritic cells; co-stimulates many types of progenitors, including early multipotent stem cells.

Erythropoietin

Stimulates erythrocyte production in vitro and in vivo; co-stimulates BFU-E and CFU-MEG and stimulates CFU-E.

FLT-3 ligand

Co-stimulates multipotential stem cells, especially with thrombopoietin and steel factor; stimulates generation of dendritic cells.

Steel factor

Similar to FLT-3; enhances generation of mast cells.

Thrombopoietin, c-mpl ligand

Major regulator of proliferation and differentiation of megakaryocytes; co-stimulates multipotential stem cells in combination with steel factor and IL-11; promotes erythropoiesis in synergy with erythropoietin.

Cytokine Inhibitory Factors and Others MIP-1 alpha

Inhibits early multipotent colony formation but stimulates that of committed precursors.

TGF-beta

Suppresses early multipotent progenitors but stimulates later progenitors.

MCAF, platelet factor 4, H-ferritin Similar to TGF-beta TNF-alpha

Similar to TGF-beta, but a more pronounced effect on BFU-E and CFU-E.

Activin

Enhances IL-3 and erythropoietin stimulated BFU-E and CFU-E; inhibits IL-3 stimulated CFU-GM.

Inhibin

Inhibits CFU-MIX, CFU-GM, and BFU-E.

Interferon- alpha, beta, and gamma

Co-inhibits CFU-MIX, CFU-GM, and BFU-E; inhibits production of cytokines; immune modulator.

Prostaglandin E2

Suppresses CFU-M with less or no activity on CFU-GM and CFU-G; enhances BFU-E indirectly through CD8+ lymphocytes.

Glu-Glu-Asp-Asp-Lys (pentapeptide)

Inhibits CFU-S proliferation and CFU-GM.

N-acetyl-Ser-As-Lys-Pro (tetrapeptide)

Inhibits CFU-S and other progenitors entry into cell cycle.

Leukemia inhibitory factor

Inhibits GM-CSF and G-CSF stimulated CFU-GM and CFU-G, respectively.

Insulin-like growth factor II

Stimulates erythroid and granulocyte progenitors.

Hepatocyte growth factor (scatter Synergistic activity on progenitors. factor) Basic fibroblast growth factor

Acts in concert with other cytokines on early multipotential and megakaryocyte progenitors.

Platelet-derived growth factor

Stimulates erythroid and granulocyte progenitors.

CFU-GM = colony-forming unit-granulocyte-macrophage; CFU-E = colony-forming unit-erythroid; GM-CSF = granulocyte-macrophage colony-stimulating factor; BFU-E = blast-forming unit-erythroid; G-CSF = granulocyte colony-stimulating factor; GM-CFC = granulocyte-macrophage colony-forming; CFU-MEG = colony-forming unit-megakaryocytes; MIP-1 = macrophage inhibitory protein-1; TGF-beta = transforming growth factor-beta; TNF-alpha = tumor necrosis factor-alpha; CFU-M = colony-forming unit-macrophage; CFU-G = colony-forming unit-granulocyte; CFU-S = colony-forming unit.

Two major receptor families have been described. First, the hematopoietic receptor family includes IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, G-CSF, granulocyte-macrophage CSF (GM-CSF), and erythropoietin. The extracellular binding domains of these receptors contain four conserved cysteine residues and a WS-X-WS motif (X is a variable non-conserved amino acid). Some also have an immunoglobulin-like structure. Receptors for GM-CSF, IL-3, and IL-5 each contain specific low-affinity alpha-chains, but a high-affinity beta-chain is shared by all three receptors. The common beta-chain plays a role in the competitive binding of these ligands. Second, the tyrosine kinase receptor family includes receptors for FLT3-ligand, steel factor (c- kit ligand), CSF-1, and thrombopoietin. These receptors have an immunoglobulin-like structure and 10 conserved cysteines in the extracellular domain, with tyrosine kinase activity in the cytoplasmic domain. Receptors not fitting into these families include those for IL-1 and IL-8. Signaling through these receptors activates transcription factors that then may direct differentiation toward specific lineages. For example, GATA-1 and FOG promote erythroid and megakaryocyte differentiation, whereas SCL, AML-1, and GATA-2 regulate primitive stem cell differentiation. Adhesion molecules function both to bind cells or extracellular matrix and as signaling molecules. Steel factor, IL-3, and GM-CSF activate very late antigens 4 and 5 (VLA-4 and VLA-5), which are adhesion molecules expressed on CD34-positive cells. This activation results in promotion of the ability of VLA-4 and VLA-5 to bind fibronectin. Stromal or microenvironmental cells are major regulators of hematopoiesis, both by positioning stem/progenitor 838

Figure 158-4 Hierarchical model of stem cell regulation.

cells and by signaling with secreted and membrane-based cytokines. Homing studies indicate that long-term repopulating lymphohematopoietic stem cells move closely adjacent to osteogenic surfaces; others have suggested that bone cells are major stem cell regulators. These regulatory influences affect hematopoietic lineages in a variety of ways. An important effect of erythropoietin on erythropoietin progenitors and precursors is to prevent apoptosis and thus maintain the viability of these cells. Cell-cycle transit and the induction of proliferation are major effects of many of the early-acting cytokines, such as steel factor, and all lineages exhibit cytokine-modulated differentiation. Erythropoietin induces erythroid hemoglobulization; G-CSF causes the acquisition of myeloid enzymes in granulocytes; and thrombopoietin induces the expression of platelet-specific proteins. Thus, differentiation is a general feature,

although whether this is specifically cytokine-mediated induction from a multipotent cell or simply a manifestation of survival of cells with a genetic probability of differentiation into a specific lineage remains an area of controversy. Regulatory influences also affect the function of many end cells, such as granulocytes, monocytes, T cells, B cells, and dendritic cells. These data, in toto, suggest a hierarchical model of stem cell regulation (Fig. 158-4) . However, there is persuasive evidence that, at least at the more primitive stem cell stages, there may be a cell-cycle component to regulation. Studies have shown that a percentage of daughter cells derived from a single cell from a hematopoietic colony and grown under "permissive" conditions will give rise to totally different lineages. These data suggest that critical commitment decisions are made during one cell-cycle transit. In addition, primitive engrafting stem cells stimulated by cytokine to traverse the cell cycle show dramatic and reversible fluctuations in their ability to engraft and maintain hematopoiesis as they transit the cell cycle. These observations form the basis for the cell-cycle model presented in Figure 158-5 . MOBILIZATION OF STEM/PROGENITOR CELLS. Engraftable, long-term repopulating stem cells and their progenitors are easily mobilized into the peripheral blood by a number of cytokines, including G-CSF, steel factor, FLT-3, IL-11, IL-12, IL-3, IL-8, IL-7, MIP-1alpha, and erythropoietin. In addition, previous exposure to cyclophosphamide or other cytotoxic agents also mobilizes stem cells, presumptively through the actions of cytokines. Pretreatment with cyclophosphamide, followed by treatment with steel factor and G-CSF, may be the most potent regimen for mobilizing stem/progenitor cells. In general, mobilized stem/progenitor cells appear to restore hemopoiesis more rapidly than unstimulated marrow, although marrow "primed" with in vivo cytokines may be equivalent to mobilized peripheral blood cells for rapid engraftment. Whether these mobilized stem cells will have the same long-term repopulation capacity as marrow cells remains to be established. STEM/PROGENITOR CELL EXPANSION. The ability to expand lymphohematopoietic stem cells in vitro has immediate implications for strategies of repetitive transplant, immunotherapy, and gene

Figure 158-5 Cell-cycle-based model of stem cell regulation.

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therapy. A large number of studies have established that exposure of marrow cells in liquid culture to a variety of cytokines leads to differentiated and progenitor cell expansion. These cells can also be effective in transplantation, but as yet no study has established expansion of long-term engraftable stem cells, and studies have shown that cytokine stimulation of marrow stem cells can lead to fluctuations in engraftment phenotype that are reversible and correlate with phase of cell cycle; engraftment tends to be lost in the late S/early G2 phase. HOMING AND ENGRAFTMENT OF STEM CELLS. Conventional dogma holds that marrow transplant recipients need to be treated with cytotoxic agents, usually irradiation and/or cytotoxic drugs, to open space in the marrow for stem cells to engraft. This turns out to not be the case. Marrow stem cells engraft quantitatively in non-treated hosts, and the final ratio of donor to host cells after transplantation appears to be determined simply by the ratio of donor to host stem cells. Homing to marrow appears complete within 20 hours (probably sooner), and engrafted stem cells rapidly enter cell cycle after intravenous infusion (within 12 hours). They subsequently move to the bone surface, giving rise to both hematopoietic and bone cells. The blood stream clears quickly of stem cells, and there appears to be virtually no primary thymic engraftment, although later secondary engraftment of thymus occurs.

THERAPEUTIC USES OF STEM CELLS AND CYTOKINES DIAGNOSIS. A number of diseases appear to be stem cell or cytokine diseases. Diseases of deranged or deficient stem cells are usually manifest as cancers or as cell deficiency states (Table 158-4) . THERAPY. Marrow transplantation (see Chapter 182) represents one of the major therapeutic advances of the past 20 years. It has been successfully used to cure marrow deficiency states (largely aplastic anemia), genetic marrow diseases (hemoglobinopathies, enzymopathies), osteopetrosis, and a variety of predominately marrow or lymphoid malignancies. It was initially used to restore deficient cell production (or deficient products from cells) or to restore cell populations after otherwise lethal damage by high-dose radiotherapy/chemotherapy was used to eliminate malignant cell populations; marrow transplantation circumvented the first barrier (killing of marrow stem cells) to dose escalation. More recent studies have indicated that a graft-versus-tumor effect is a major component of the therapeutic efficiency of allogeneic brother/sister transplantation, thus indicating that transplantation may work in part by mediating a cellular immune attack against cancer cells. Marrow cells were the initial source of stem cells for transplantation, but pheresis of peripheral blood stem cells has supplemented marrow in autologous transplantation and is rapidly replacing it in allogeneic transplantation. Fetal liver has been utilized as a source of stem cells, and umbilical cord blood is becoming a major source of cells, especially for unrelated transplantation. Stem cells from these sources are also the most attractive vehicles for a variety of gene therapy approaches, although this is still an evolving area of research.

CYTOKINES IN THERAPY Interleukin 2 and interferon have been used successfully in therapy for solid tumors and chronic myelogenous leukemia, respectively. The first successful use of a cytokine in the therapy for a cytokine deficiency state was that of erythropoietin to treat the anemia of renal failure. Renal failure represents a true cytokine deficiency state, and thus this is an ideal target for cytokine therapy. Administration of erythropoietin to patients with renal failure corrects or partially corrects the anemia and restores a better state of well-being. Erythropoietin is also used in other settings, where its benefits are less clear (Table 158-5) . Unfortunately, other cytokine deficiency states have been hard to document, and the results of cytokine therapy of other diseases (despite Food and Drug Administration [FDA] approval) are equivocal at best. A major emphasis has been placed on the use of G-CSF and GM-CSF (Table 158-6) for marrow recovery after cytotoxic therapy of cancer. Initial trials escalating the dose of chemotherapy agents in small cell carcinoma indicated that administration of G-CSF enhanced granulocyte recovery and decreased febrile infectious complications. All trials since have been variations TABLE 158-4 -- STEM CELL DISEASES DISEASE

MECHANISM

Aplastic anemia

Deficient multipotent stem cell: multiple causes (cell killing or immune)

Neutropenia--Kostmann's, cyclic, and others

Genetic deficiency or regulatory abnormality

Myelodysplastic syndrome

Marrow damage progressing to neoplasm

Acute myelogenous leukemia

Cytogenetic abnormality at stem cell level

Paroxysmal nocturnal hemoglobinuria

Defective glycosylphosphatidylinositol-anchored membrane proteins and mutation in the PIG-A gene

Chronic myelogenous leukemia

9:22 translocation moves abl oncogene adjacent to bcr

Myeloproliferative disorders: polycythemia vera, myelofibrosis, myeloid metaplasia, Neoplasms of multipotent stem cells primary thrombocytosis on this theme. The critical flaw in these studies is that the dose escalation has not led to better cancer control, and thus the use of G-CSF or GM-CSF has not been of benefit to the underlying problems of these patients. Furthermore, these cytokines may not be cost effective. Although the FDA has approved them for certain indications in cancer, G-CSF and GM-CSF are best treated as interesting experimental therapies at this time. Neither G-CSF nor GM-CSF has proven effective in other

conditions such as in active infection; this is not surprising because endogenous levels of G-CSF are already quite high in febrile neutropenic and infected patients. G-CSF, probably with steel factor or others, has a role in stem cell mobilization and appears effective in certain severe chronic neutropenic states, including Kostmann's neutropenia and cyclic neutropenia. Evolution to leukemia in patients with Kostmann's neutropenia, however, is a real problem. The malignant counterparts of the marrow cells usually retain the cytokine responsiveness of the normal cells, and it is clear that many neoplastic cells will proliferate in response to cytokines. Tumor progression is a risk, but cytokine manipulation of tumor growth, possibly in concert with therapy to kill cycling cells, is an opportunity. G-CSF and TABLE 158-5 -- INDICATIONS FOR THERAPY WITH ERYTHROPOIETIN DISEASE/CONDITION

THERAPEUTIC EFFICACY

Anemia of renal failure

Improves quality of life and decreases transfusion requirement; there is clinical benefit.

Anemia with human immunodeficiency virus induced by zidovudine with erythropoietin levels < 500/mL

Approved for use in United States but clinical benefit not clear

Chemotherapy-induced anemia

Approved in United States for non-myeloid malignancies. May be of use in selected cases with possible increased quality of life; overall benefit in this setting still unclear

Anemia of inflammation (rheumatoid arthritis and inflammatory bowel disease)

Increases hematocrit without clinical benefit; should not be used

Other conditions under evaluation: perioperative setting; autologous blood collection; anemia of prematurity; anemia of myelodysplasia, lymphoma, or leukemia; anemia with allogeneic transplantation; anemia of pure red cell aplasia; induction of hemoglobin F in sickle cell anemia or thalassemia; and adjuvant for phlebotomy

May be considered in selected individuals but benefit not established (perioperative setting with restrictions has Food and Drug Administration approval)

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TABLE 158-6 -- G-CSF AND GM-CSF USE IN CLINICAL THERAPY CONDITION

ESTABLISHED BENEFIT G-CSF

GM-CSF

Chronic neutropenia (cyclic, idiopathic and Kostmann's)

Yes

No

Cancer chemotherapy-induced neutropenia

Uncertain

Uncertain

Stem cell mobilization

Yes

Yes

Active infection

No

No

Other inflammatory conditions

No

No

Drug-induced (not chemotherapy) neutropenia

No

No

GM-CSF stimulate a wide variety of cell types of both hematopoietic and non-hematopoietic origin and, not surprisingly, have a wide variety of side effects, including bone pain; fever and chills; pleural and pulmonary effusions/infiltrates; vasculitis; rashes, including neutrophilic dermatitis (Sweet's syndrome); splenic enlargement, hypersplenism, and, rarely, splenic rupture; and proteinuria. Recently, agents that stimulate in vivo platelet production have entered clinical trials, and one has been released for clinical use: IL-11 enhances platelet recovery after chemotherapy for cancer. As with G-CSF and GM-CSF, and despite FDA approval, it remains unclear what clinical benefit will accrue from the use of this agent. The ligand for C-mpl or thrombopoietin should also soon be approved for stimulating platelet production. Thus, at present, powerful biologics can increase the red cell, neutrophil, eosinophil, basophil, monocyte, and platelet counts. These are intriguing drugs with great potential, but, with the exceptions of erythropoietin (for the anemia of renal failure) and G-CSF (for chronic neutropenia), their true roles in clinical therapy remain uncertain.

PLATE 5 HEMATOLOGIC DISEASES

Figure 158- A, Normal peripheral blood smear. The red cells are normocytic (normal size) and normochromic (normal hemoglobin pigment), with central areas of pallor that should occupy less than one half of the diameter of the cells.

Figure 158- B, Reticulocytes. Special supravital (methylene blue) staining of the blood smear reveals dark purple reticulin, representing residual RNA in immature red cells.

Figure 158- C, Aplastic anemia. Bone marrow biopsy shows a virtually empty marrow.

Figure 158- D, Iron deficiency anemia. Many red cells are microcytic (smaller than the nucleus of the normal lymphocyte near the center of the field) and hypochromic (with central areas of pallor that exceed one half of the diameter of the cells).

Figure 158- E, Megaloblastic anemia. Peripheral blood with oval macrocytes (large red cells) and marked neutrophil hypersegmentation.

Figure 158- F, Megaloblastic anemia. Bone marrow aspirate shows red cell precursors that are giant megaloblasts, with nuclear-cytoplasmic dissociation (nuclear maturation lagging behind cytoplasmic maturation). Megaloblastic changes in the leukocyte series are demonstrated by the "giant C metamyelocyte."

Figure 158- G, Hereditary spherocytosis. Peripheral smear shows a predominance of microspherocytes (small, densely staining red cells with loss of the central areas of pallor) alongside larger, grayish, "polychromatic" cells that probably represent

reticulocytes.

Figure 158- H, Microangiopathic hemolytic anemia. Peripheral smear shows fragmented red cells or "schistocytes" in a variety of shapes and sizes.

Figure 158- I, Thalassemia minor. Smear shows hypochromic red cells with many target cells.

Figure 158- J, Sickle cell anemia. Homozygous SS disease with a predominance of sickled red cells in the peripheral smear.

Figure 158- K, Hemoglobin SC disease. Peripheral smear shows frequent target cells interspersed with sickled red cells that are sometimes more plump in appearance than sickle cells in SS disease.

Figure 158- L, Pelger-Huet anomaly. Mature neutrophil with a two-lobed nucleus that has a dumbbell or "pince-nez" appearance. Pseudo-Pelger-Huet anomaly occurs in acquired conditions (e.g., myelodysplasia, myeloproliferative disorders,

infections).

PLATE 6 HEMATOLOGIC DISEASES

Figure 158- A, Infectious mononucleosis. Peripheral smear shows pleomorphic, atypical (or reactive) lymphocytes.

Figure 158- B, Myeloproliferative disorder. Bone marrow shows megakaryocytic clusters seen in essential thrombocythemia and other conditions associated with clonal thrombocytosis.

Figure 158- C, Myeloproliferative disorder. A peripheral blood smear in agnogenic myeloid metaplasia showing a leukoerythroblastic picture. The characteristic findings are teardrop-shaped red cells (dacryocytes), nucleated red cells (erythroblasts), and immature granulocyte precursors.

Figure 158- D, Myeloproliferative disorder. A bone marrow biopsy in agnogenic myeloid metaplasia shows reticular fibrosis.

Figure 158- E, Sideroblastic anemia. Prussian blue iron stain of the bone marrow shows ringed sideroblasts, which are nucleated red cell precursors with perinuclear rings of iron-laden mitochondria.

Figure 158- F, Chronic lymphocytic leukemia. Peripheral smear shows that the predominant leukocytes are "normal" mature-appearing lymphocytes, with occasional "smudge" cells.

Figure 158- G, Hairy cell leukemia. Peripheral smear shows hairy cells with blue-gray cytoplasm and fine, hairlike projections (resembling ruffles), and oval or slightly indented nuclei with loose chromatin and indistinct nucleoli.

Figure 158- H, Chronic myelogenous leukemia, stable phase. Peripheral smear shows leukocytosis, with representation by the entire spectrum of leukocyte differentiation, ranging from myeloblasts to mature neutrophils.

Figure 158- I, Acute leukemia. Left, Acute lymphoblastic leukemia (ALL). Right, Acute myelogenous leukemia (AML). Lymphoblasts in ALL are smaller, with a higher nuclear:cytoplasmic ratio and less distinct nucleoli than myeloblasts in AML. The nucleoli in the myeloblasts are clear and "punched out."

Figure 158- J, Acute non-lymphoblastic leukemia. The myeloblasts in the smear show Auer rods as cytoplasmic inclusions.

Figure 158- K, Multiple myeloma. Bone marrow aspirate with predominance of plasma cells.

Figure 158- L, Thrombotic thrombocytopenic purpura (TTP). Peripheral smear shows fragmented red cells alongside larger, polychromatophilic cells and a nucleated red cell that reflect hemolysis, as well as a paucity of platelets.

Habibian HK, Peters SO, Hsieh CC, et al: The fluctuating phenotype of the lymphohematopoietic stem cell with cell cycle transit. J Exp Med 188:393-398, 1998. A focus on stem cell engraftment. Kaushansky K: Thrombopoietin: The primary regulator of platelet production. Blood 86:419, 1995. A review of thrombopoietin. Ogawa M: Differentiation and proliferation of hematopoietic stem cells. Blood 81:2844, 1995. A focus on newer concepts of stem cells. Quesenberry PJ: Hemopoietic stem cells, progenitor cells and cytokines. In Lichtman M, Kipps T (eds): Williams Textbook of Hematology, 5th ed. New York, McGraw Hill, 1994, p 211. Review of hemopoiesis.

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Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 159 - APPROACH TO THE ANEMIAS Kenneth S. Zuckerman

DEFINITIONS Anemia, which is defined as a reduction in the number of circulating erythrocytes, is a common manifestation of primary bone marrow disorders, primary abnormalities of erythrocytes, immunologic disorders, nutritional deficiencies, and a broad spectrum of systemic diseases that secondarily result in anemia. Any condition that can impair the production or increase the rate of destruction or loss of erythrocytes can result in anemia, if the bone marrow is unable to compensate for the rate of loss of red blood cells (RBCs). At least some degree of anemia is detectable in 20 to 40% of hospitalized patients. A considerable amount of information that is useful in determining severity, pathophysiology, and etiology of anemia is provided by electronic, automated blood cell counters (Table 159-1) . The hemoglobin (Hgb), measured in grams per deciliter, represents the total amount of hemoglobin in all of the erythrocytes in 100 mL of blood. The hematocrit (Hct) is the percentage of the total blood volume that is composed of erythrocytes. The mean corpuscular or cell volume (MCV) is measured directly on automated cell counters but can be calculated as MCV (mu3 or fL) = Hct (%) × 10/RBC count (×106 /muL of whole blood). The mean cell hemoglobin (MCH) is calculated by automated cell counters as MCH (pg) = Hgb (g/dL) × 10/RBC (×106 /muL). The mean cell hemoglobin concentration (MCHC) is calculated by automated cell counters as MCHC = Hgb (g/dL) × 100/Hct (%). The MCH and MCHC are of limited value because of relatively poor sensitivity for any individual disorders, whereas the MCV is extremely useful in classification and determination of the etiology of anemia. The RBC distribution width (RDW/CV) is a ratio of the width of the RBC size distribution curve at 1 standard deviation from the mean size divided by the MCV. Because this value is a ratio with the MCV as denominator, it tends to magnify any variation in cell size in patients with microcytosis but is relatively insensitive to mild or early macrocytosis. A less frequently used value, the RDW-SD, is the width of the RBC size distribution curve, encompassing 80% of the erythrocytes in the measured population. This latter measurement is particularly sensitive even to small populations of microcytic or macrocytic RBCs. In addition to these standard measurements, automated absolute reticulocyte counts per microliter of blood or evaluations of new methylene blue-stained peripheral blood smears for the percent of positive-staining erythrocytes (reticulocytes) give a measure of the number of newly released (generally 1- to 2-day old) erythrocytes. These newly formed erythrocytes still contain residual ribosomal RNA, which can be recognized easily on supravital staining with new methylene blue. Because the ribosomal RNA is lost from the cell within the first 1 to 2 days in the circulation and erythrocytes in the blood survive an average of about 120 days, reticulocytes comprise about 1% of all erythrocytes in the circulation; a normal, non-anemic adult has 40,000 to 100,000 reticulocytes per microliter of blood. Automated blood cell counters also provide total white blood cell (WBC) count, WBC differential count, and platelet count. All of this information is useful in assessing the mechanism of anemia.

ETIOLOGY AND PATHOGENESIS Normal Erythropoiesis The circulating erythrocyte under normal conditions has an average lifespan of approximately 120 days. It is a non-nucleated, non-dividing cell, in which more than 90% of the protein content is the oxygen-carrying molecule, hemoglobin. The erythrocyte's sole responsibility is to deliver oxygen to the tissues of the body. Thus, the primary consequence of anemia is tissue hypoxia. Erythropoiesis is driven by a feedback loop. Oxygen-sensing cells in the area of the juxtaglomerular apparatus of the kidney respond to local tissue hypoxia by increasing production of erythropoietin (EPO), which is the primary regulatory hormone for erythropoiesis. EPO plays little, if any, role in maintaining or producing early hematopoietic precursors or even the earliest detectable erythroid progenitor cells, known as burst forming units-erythroid (BFU-E); however, EPO is absolutely essential for the maturation of BFU-E to late erythroid progenitor cells, known as colony-forming units-erythroid (CFU-E), and to proerythroblasts in the bone marrow. The main mechanism of action of EPO is to prevent apoptosis, also known as programmed cell death, of erythroid precursor cells and to permit their proliferation and subsequent maturation. Once erythroid precursor cells mature to the level of proerythroblasts, further maturation to normoblasts, reticulocytes, and mature erythrocytes no longer requires the presence of EPO. Under normal circumstances, the RBC mass is maintained at a nearly constant level by means of the EPO feedback loop's ability to match new erythrocyte production to the rate of natural senescence and loss of RBCs. Although total absence of EPO in the circulation never or almost never occurs, severe depression of circulating EPO levels results in near cessation of erythrocyte production. Hypoxia, as sensed in the kidney, results in increased production of EPO, which leads to increased erythrocyte production by the bone marrow. When the local tissue hypoxia is due to a reduction in the number of circulating erythrocytes and amount of hemoglobin and the consequent decreased total-body oxygen-carrying capacity, the increased EPO produced by the kidney stimulates the bone marrow to produce increased numbers of erythrocytes to compensate for the existing deficiency of RBCs. Once an increase in EPO levels in the circulation occurs in response to acute onset of anemia, new proerythroblasts and normoblasts appear in the bone marrow within 2 to 4 days, and new reticulocytes begin to appear 841

TABLE 159-1 -- NORMAL VALUES FOR RED BLOOD CELL MEASUREMENTS MEASUREMENT UNITS NORMAL RANGE (APPROXIMATE)* Hemoglobin

g/dL

Males: 13.5-17.5 Females: 12.0-16.0

Hematocrit

%

Males: 40-52 Females: 36-48

Red blood cell (RBC) count

× 106 /muL of blood

Males: 4.5-6.0 Females: 4.0-5.4

Mean cell volume (MCV)

fL

81-99

Mean cell hemoglobin (MCH)

pg

30-34

Mean cell hemoglobin concentration (MCHC)

g/dL

30-36

RDW-CV

%

12-14

RDW-SD

%

37-47

Reticulocyte count (absolute number)

No./muL of blood

40,000-100,000

Reticulocyte percentage

% of RBCs

0.5-1.5

Red blood cell size distribution width

*Actual normal ranges for many of these values may vary slightly, depending on such factors as the location and type of equipment used, altitude above sea level, and patient age.

in the peripheral blood within 3 to 7 days. Re-establishment of normal numbers of circulating erythrocytes and normal tissue oxygenation results in reduced production of EPO and then a reduced rate of production of erythrocytes back to the normal basal level that is required to maintain a stable, normal number of erythrocytes in the blood. When hypoxia is caused by decreased ambient oxygen concentration, impaired delivery of oxygen through the lungs and to hemoglobin molecules in erythrocytes, venous to arterial shunting of blood, hemoglobin mutants with increased oxygen affinity and decreased ability to release oxygen in the tissues, or

localized renal disease that the renal sensor cannot distinguish from generalized hypoxemia, the increase in EPO results in increased erythropoiesis, erythrocytosis, and secondary polycythemia. Pathogenesis of Anemias The basic mechanisms of anemia can be divided into those conditions that result in accelerated destruction or loss of RBCs and those in which the primary abnormality is impaired ability of the bone marrow to produce sufficient numbers of erythrocytes to replace those that are lost. Although this classification makes it easier to understand the pathophysiology of anemia and to determine the proper diagnostic studies to perform, in many patients more than one mechanism may occur simultaneously. ANEMIAS DUE TO IMPAIRED PRODUCTION OF ERYTHROCYTES BY THE BONE MARROW.

If there is a reduced erythrocyte mass due to impaired production of erythroid precursors and mature RBCs by the bone marrow, the number of reticulocytes in the circulating blood and the number of normoblasts in the bone marrow will be lower than would be appropriate in the presence of the existing degree of anemia. A wide variety of conditions can be responsible for impaired erythropoiesis (Table 159-2) . ERYTHROPOIETIN DEFICIENCY.

Insufficient production of EPO results in failure of an otherwise normal bone marrow to produce the required number of erythrocytes, despite the production of normal numbers of other hematopoietic cells such as neutrophils and platelets. The prototype for impaired EPO production is renal failure (with particularly severe EPO deficiency after bilateral nephrectomies), in which only very low levels of EPO, generally less than 10% of normal, are produced. The small amount of EPO produced in nephrectomized patients is derived from the liver and is sufficient to generate only a small portion of the required numbers of erythrocytes. Thus, patients with chronic renal failure, and particularly those who have had bilateral nephrectomies, have severe anemia, with Hgb values less than 5 g/dL in the absence of exogenous EPO therapy or RBC transfusions. Rare patients with autoantibodies against EPO have extremely low to undetectable circulating EPO levels and severe anemia, with pure red cell aplasia in the bone marrow. Patients with chronic infectious or inflammatory diseases or cancer can also have anemia that is associated with inappropriately low levels of EPO for their degrees of anemia; in these circumstances, cytokines such as interleukin (IL)-1, IL-6, or tumor necrosis factor (TNF)-alpha might be responsible, at least in part, for the impaired EPO production. QUANTITATIVE DEFICIENCY OF HEMATOPOIETIC STEM CELLS AND/OR COMMITTED ERYTHROID PROGENITOR CELLS.

A second mechanism of anemia due to reduced production of cells by the bone marrow is deficiency of hematopoietic stem cells and/or committed erythroid progenitor cells. Any condition that is characterized by a deficiency of hematopoietic stem cells and/or committed erythroid precursor cells also will result in anemia. Even if EPO production is appropriately increased for the degree of anemia, anemia will result if the target marrow precursor cells are deficient in number. In almost all such cases, the defect is a more generalized bone marrow abnormality that results in reduced production of all lineages of bone marrow-derived cells, particularly erythrocytes, granulocytes, and platelets. Idiopathic bone marrow failure, commonly known as aplastic anemia, is the prototype of such disorders (see Chapter 160) . Bone marrow aplasia or hypoplasia also may occur as a result of toxic substances such as benzene, cancer chemotherapeutic agents, other pharmacologic agents such as chloramphenicol or gold salts, ionizing radiation, or certain viral infections such as Epstein-Barr virus, human immunodeficiency virus (HIV), hepatitis (non-A, non-B, non-C) virus, or dengue virus. TABLE 159-2 -- PATHOPHYSIOLOGIC CLASSIFICATION OF ANEMIAS DUE TO IMPAIRED PRODUCTION OF ERYTHROCYTES BY THE BONE MARROW Erythropoietin (EPO) deficiency (normocytic anemias) Renal insufficiency (worse after bilateral nephrectomies) Pure red cell aplasia due to anti-EPO antibodies (extremely rare) Anemia of chronic disease (inappropriately low EPO level is a partial contributing factor) Quantitative deficiency of hematopoietic/erythroid progenitor cells (normocytic anemias) Idiopathic bone marrow aplasia/hypoplasia Secondary bone marrow aplasia/hypoplasia (drugs, toxins, infections, radiation, malnutrition) Myelofibrosis (primary or secondary) Bone marrow replacement by neoplastic cells (myelophthisis) Myelodysplasia (minority of myelodysplasia patients) Paroxysmal nocturnal hemoglobinuria (10-15% of PNH patients) Pure red cell aplasia (anti-erythroid precursor cell antibodies, parvovirus B19 infection) Impaired erythroid precursor cell division and DNA synthesis (macrocytic/megaloblastic anemias) Cobalamin (vitamin B12 ) deficiency Folate deficiency Myelodysplasia Cancer chemotherapeutic drugs and some immunosuppressive and antimicrobial drugs Impaired heme synthesis in differentiating erythroid cells (microcytic anemias) Iron deficiency Anemia of chronic disease/inflammation Sideroblastic anemias (particularly hereditary forms) Impaired globin synthesis in differentiating erythroid cells (microcytic anemias) Thalassemias

842

Other conditions such as bone marrow fibrosis (myelofibrosis) or extensive replacement of the bone marrow by neoplastic cells also can result in deficiencies of hematopoietic stem and progenitor cells and/or impaired ability of these cells to proliferate and to differentiate into mature hematopoietic cells. Patients with severe malnutrition, including anorexia nervosa, also may have bone marrow hypoplasia. A minority of patients with myelodysplasia or paroxysmal nocturnal hemoglobinuria also have significant bone marrow hypoplasia. Selective anemia is also seen in pure red cell aplasia; this disorder usually has an immunologic basis, with selective immune-mediated destruction of erythroid progenitor cells and absence or near absence of detectable nucleated erythroid precursors in the bone marrow despite elevated levels of circulating EPO. Viral infection, particularly with parvovirus B19, which selectively infects committed erythroid progenitor cells, also can cause transient or prolonged pure red cell aplasia because of the cytotoxic effect of this virus on the infected erythroid precursor cells. IMPAIRED ABILITY OF ERYTHROID PROGENITORS TO RESPOND TO ERYTHROPOIETIN.

A third general mechanism responsible for reduced erythrocyte production by the bone marrow is impaired responsiveness of erythroid precursors to appropriate circulating EPO concentrations. This category covers a broad range of disorders, including intrinsic erythrocyte abnormalities, exogenous inhibitory effects, and nutritional deficiencies. No mutations or abnormalities of EPO receptors or in EPO-related signal transduction pathways in erythroid precursors have been identified as causes of anemia. There are many potential ways to categorize this large, diverse group of anemias. One method is to divide these conditions pathophysiologically into those in which there is impaired DNA synthesis and cell division and those in which there is impaired synthesis of hemoglobin. DISORDERS CHARACTERIZED BY IMPAIRED DNA SYNTHESIS: MEGALOBLASTIC ANEMIAS.

Impaired DNA synthesis and the resulting impaired cell division by erythroid precursors result in red cell macrocytosis (increased MCV) and variable degrees of anemia (see Chapter 163) . These abnormalities may occur whenever there is a significant deficiency of key substrates in the DNA synthetic pathways, as is caused by deficiencies of cobalamin (vitamin B12 ) and folate. Folate deficiency frequently may be due to insufficient dietary intake but also may be due to diffuse intestinal disorders and to drugs that interfere with folate metabolism, such as ethanol, sulfonamides or sulfa-related drugs, trimethoprim, methotrexate, anticonvulsants, and possibly oral contraceptives. Folate deficiency may occur in patients with an increased requirement for folate in such conditions as chronic hemolytic anemias, pregnancy, and in childhood. In addition, severe alcoholics, patients with general malnutrition from any cause, and patients with certain unconventional dietary habits are susceptible to developing folate deficiency. A severely folate-deficient diet will result in clinically significant folate deficiency within about 6 weeks. Cobalamin deficiency almost never occurs because of lack of dietary cobalamin intake; instead, it most often is due to impaired absorption of cobalamin due to lack of intrinsic factor, gastric atrophy, and abnormalities of cobalamin absorption in the terminal ileum. Because of substantial stores and very low daily requirements for cobalamin in normal individuals, deficiency of cobalamin usually takes at least 3 to 5 years to become manifest. In patients with myelodysplasia, one of the mechanisms of anemia and other hematopoietic cell deficiencies can be a moderately severe to severe impairment of DNA synthesis, with development of megaloblastosis and macrocytosis of RBCs. A broad range of cancer chemotherapeutic agents impair DNA synthesis in the short term, and some cause stem cell damage that can result in a long-term adverse effect on DNA synthesis, which may result in mild to moderate anemia or may be manifested only by an increased MCV. In association with the reduced DNA synthesis and delays in or decreased number of cell divisions in megaloblastic anemias, there generally is intramedullary death of hematopoietic precursors, predominantly by apoptosis, and reduced numbers of mature erythrocytes and sometimes granulocytes and platelets released into the blood. This condition of hypercellular bone marrow combined with death of precursors before full maturation of hematopoietic cells is called ineffective hematopoiesis, or, in the case of RBCs alone, ineffective erythropoiesis. IMPAIRED HEMOGLOBIN SYNTHESIS: DISORDERS CHARACTERIZED BY DIMINISHED HEME SYNTHESIS.

Impaired hemoglobin synthesis occurs with disorders in which there is reduced production of either heme or globin, and, when sufficiently severe, results in microcytic anemias (decreased MCV). The heme synthetic pathway and its defects are described in more detail in other chapters. Most or all of the rare disorders collectively known as hereditary sideroblastic anemias appear to be due to mutations in the coding regions of genes for the erythroid-specific forms of heme synthetic pathway enzymes or erythroid-specific promoters (especially ALA synthase, HMB synthase, and possibly ferrochelatase); the result is reduced heme synthesis in erythroid cells. Iron is required for the final stage of synthesis of heme, and iron deficiency impairs heme synthesis and results in anemia. Although iron-deficiency anemia is associated classically with microcytosis, most patients with mild iron-deficiency anemia actually have normocytic erythrocytes. Over time, iron-deficient patients commonly have a progressive decrease in the MCV within the normal range, and microcytosis occurs generally in the most severe 20 to 30% of cases. In patients with chronic infectious or inflammatory diseases or with cancer, the responsiveness of erythroid precursors to endogenous and exogenous EPO may be impaired. The mechanism for this impaired responsiveness to EPO is unknown, but it is thought to be due to inhibitory cytokines and chemokines. One of the hallmarks of anemia of chronic disease or inflammation is impaired transfer of iron into developing erythroid cells, resulting in a functional iron deficiency in normoblasts even when iron stores in the bone marrow and the rest of the body are adequate. The result is impaired heme synthesis and a mild to moderate normocytic or microcytic anemia. In many of the circumstances in which anemia of chronic disease/inflammation occurs, there also may be concomitant iron deficiency. IMPAIRED HEMOGLOBIN SYNTHESIS: DISORDERS CHARACTERIZED BY IMPAIRED GLOBIN SYNTHESIS--THALASSEMIAS.

Impaired synthesis of alpha-globin chains in alpha-thalassemias or beta-globin chains in beta-thalassemias results in unbalanced synthesis of globin chains and a reduction in the number of hemoglobin alpha2/beta2 hemoglobin tetramers (see Chapter 167) . Because of the reduced numbers of hemoglobin tetramer molecules in each cell, thalassemia patients have a microcytic anemia. The unpaired excess beta-chains in the erythrocytes of patients with alpha-thalassemia and unpaired excess alpha-chains in patients with beta-thalassemia tend to aggregate, precipitate, and form insoluble cytoplasmic inclusion bodies that result in oxidative damage to the membranes of developing normoblasts and death of a large proportion of these developing erythroid cells within the marrow, resulting in anemia due to ineffective erythropoiesis. Furthermore, the normoblasts that do survive produce erythrocytes that contain similar inclusions (Heinz bodies), which lead to premature destruction of these cells in the spleen and liver, resulting in a hemolytic component of the anemia. The overall degree of anemia is related to the severity of the defect in globin synthesis, so that patients who have deletion of only one of their four alpha-globin genes generally have microcytosis but no anemia, those with deletion of two alpha-globin genes have microcytosis and mild anemia, and those who are heterozygous for beta-thalassemia have microcytosis and mild anemia. INEFFECTIVE ERYTHROPOIESIS.

Ineffective erythropoiesis is defined as anemia with increased numbers of erythroid precursor cells in the bone marrow but decreased numbers of mature circulating erythrocytes being released from the bone marrow. Thus, in ineffective erythropoiesis, there are inappropriately low numbers of reticulocytes in the blood. This condition usually is caused by defects that are present in the maturing proerythroblasts and normoblasts in the bone marrow and result in their premature death within the bone marrow. The most common causes of anemia due to ineffective erythropoiesis are myelodysplasia, megaloblastic anemias, and thalassemias. ANEMIAS DUE TO ACCELERATED DESTRUCTION, CONSUMPTION, OR LOSS OF CIRCULATING ERYTHROCYTES.

Any intrinsic defects of erythrocytes or extrinsic conditions that cause erythrocytes to be damaged intravascularly, removed from the circulation prematurely by the spleen or liver, or lost through bleeding result in increased EPO production, increased numbers of maturing erythroid precursors in the bone marrow, and release of increased numbers of newly formed reticulocytes into the blood. Thus, in a patient with a normal bone marrow, accelerated loss of circulating erythrocytes always will be associated with increased erythropoiesis, 843

which can be judged by the presence of an increased reticulocyte count. An increased reticulocyte count implies that there is at least a mildly increased rate of loss or destruction of erythrocytes; if the bone marrow is able to keep up with the increased demand for replacement erythrocytes, the patient will not have a decreased RBC mass. Anemia occurs only if the rate of production of erythrocytes by the bone marrow is unable to compensate completely for the loss or destruction of RBCs. Although chronic hemolysis or blood loss is associated with compensatory increased erythropoiesis (assuming no additional abnormalities of bone marrow, kidney, or required nutrients), signs of compensatory increased erythropoiesis will not appear until several days after acute hemolysis or blood loss. HEMOLYTIC ANEMIAS DUE TO INTRINSIC RED CELL MEMBRANE DEFECTS.

Abnormalities of RBC membrane proteins and lipids lead to deformed erythrocytes, which are prone to be removed prematurely from the circulation, primarily by the filtering functions of the spleen (see Chapter 164) . The most common membrane protein abnormalities involve spectrin, ankyrin, band 3 protein, and protein 4.1, and lead to the RBC membranopathies known as hereditary spherocytosis, hereditary elliptocytosis, and hereditary pyropoikilocytosis. In each of these disorders, the decreased deformability of RBCs results in their premature clearance from the blood, primarily in the spleen. Abnormalities of the lipid bilayer of the erythrocyte membrane lead to bizarrely shaped RBCs, which have poor deformability and cytoplasmic projections and also result in an increased rate of destruction of erythrocytes, primarily in the spleen. One abnormality of the lipid bilayer is acanthocytosis or spur cell anemia, which may be caused by hereditary lipoprotein defects such as abetalipoproteinemia, cholesterol metabolism abnormalities that occur in patients with severe liver disease, or the McLeod phenotype of severely deficient Kell blood group antigen on erythrocytes. Stomatocytes or xerocytes result from imbalance in the size of the outer and inner portions of the membrane lipid bilayer and dehydration of erythrocytes; abnormalities of membrane phospholipids or absence of Rh antigens on the surface of RBCs (Rh null phenotype) result in these morphologic abnormalities that may result in mild hemolysis. In paroxysmal nocturnal hemoglobinuria, a defect in a critical membrane-anchoring molecule (glycosylphosphatidylinositol [GPI]), which is responsible for anchoring many cell surface proteins, results in absence of at least three surface proteins that are critical to prevention of complement-mediated cell damage and lysis. The absence or significant reduction in decay accelerating factor (DAF, CD55), membrane inhibitor of reactive lysis (MIRL, CD59), and C8-binding protein result in variably increased susceptibility of these defective cells to lysis by complement. HEMOLYTIC ANEMIAS DUE TO INTRINSIC RED CELL ENZYMOPATHIES.

Red cell enzymopathies (see Chapter 164) that may lead to hemolytic anemia generally fall into two groups. Defects in enzymes in the hexose monophosphate shunt (e.g., glucose-6-phosphate dehydrogenase) or those responsible for maintaining reduced glutathione (e.g., gamma-glutamylcysteine synthetase) to prevent oxidative injury to RBCs tend most frequently to be associated with episodic hemolysis during times of physiologic stresses, such as surgery, infections, or oxidants in foods or pharmacologic agents. The oxidant damage causes Heinz body formation. In contrast, deficiencies of enzymes in the Embden-Meyerhof pathway (e.g., pyruvate kinase and glucose phosphate isomerase) or enzymes responsible for supporting nucleotide metabolism (e.g., adenosine deaminase and pyrimidine 5 -nucleotidase) tend to cause chronic hemolytic anemias, presumably as a result of adenosine phosphate deficiency, which leads to impaired homeostasis of water, sodium, potassium, and calcium. Because erythrocytes are unable to synthesize new proteins, older erythrocytes are most likely to have the lowest levels of enzymes that are susceptible to intracellular degradation and thus are the most likely to be removed from the circulation.

HEMOLYTIC ANEMIAS DUE TO HEMOGLOBIN VARIANTS WITH REDUCED SOLUBILITY OR PROTEIN INSTABILITY.

More than 100 different structural variants of hemoglobin exhibit either reduced solubility (e.g., hemoglobins S, C, O-Arab, and D-Los Angeles) or a higher susceptibility than normal to oxidation of amino acids within the globin chains (e.g., hemoglobins Zurich, Koln, Hammersmith, and Gun Hill) (see Chapter 168) . The less soluble and unstable hemoglobins tend to form abnormal hemoglobin polymers or crystals, to precipitate, and to form cytoplasmic Heinz bodies, which then become attached to the cell membrane and decrease erythrocyte deformability; the result is membrane damage, followed by sequestration and destruction of erythrocytes in the spleen. HEMOLYTIC ANEMIAS DUE TO ABNORMALITIES EXTRINSIC TO THE RED CELL.

Erythrocytes can be sequestered or destroyed prematurely as a result of other conditions that secondarily cause damage to otherwise normal RBCs. In autoimmune hemolytic anemia, antibodies form against red cell membrane antigens (most commonly Rh-D antigen for so-called warm IgG antibodies and I or i antigen for so-called cold, complement-fixing IgM antibodies) (see Chapter 165) . These antibody-coated erythrocytes are recognized by Fc or complement receptors on macrophages in the spleen (especially IgG) or liver (especially C3 complement). IgG-coated red cells usually undergo repeated partial phagocytosis with progressive loss of red cell membrane until the cells that survive and re-enter the circulation are spherocytes, which have decreased deformability and eventually are sequestered and removed permanently from the circulation. A long list of drugs can result in hemolysis by similar mechanisms by causing antierythrocyte antibodies or by causing antidrug antibodies that lead to subsequent immune complex deposition on erythrocytes, which also results in hemolysis by similar mechanisms. Alloimmune hemolysis may result from transfusion of blood with "minor" blood group mismatches into recipients previously sensitized to those antigens by prior transfusions and/or pregnancies. Severe acute intravascular hemolysis (see Chapter 166) can occur from transfusion of ABO incompatible blood and less commonly from transfusion of blood that has Rh or so-called minor blood group antigen mismatches. Microangiopathic hemolysis with fragmented erythrocytes, intravascular release of hemoglobin and other erythrocyte contents, and intravascular and splenic destruction of RBCs occurs in the presence of fibrin deposition in small arterioles, in such conditions as thrombotic thrombocytopenic purpura and disseminated intravascular coagulation, as well as in the presence of diffuse small vessel vasculitis, eclampsia, or malignant hypertension. Prosthetic heart valves or arterial grafts with roughened endothelial surfaces also can cause mechanical fragmentation of erythrocytes. Other causes of mechanical damage to otherwise normal erythrocytes are trauma (e.g., march hemoglobinuria), thermal injury from severe burns, and osmotic lysis due to freshwater drowning or mistaken intravenous infusion of high volumes of hypotonic fluids. Certain infections such as malaria, bartonellosis, and babesiosis can cause direct intravascular destruction of infected erythrocytes, and clostridial sepsis can result in release of toxins that directly damage red cell membrane phospholipids and lyse the cells. Certain snake and spider venoms can cause hemolysis (i.e., cobra venom via phospholipases that destroy the erythrocyte membrane and pit vipers and brown recluse spider venoms via induction of disseminated intravascular coagulation). Finally, a number of drugs and ingested toxins, including nitrofurantoin, phenazopyridine, sulfones, amyl nitrite, naphthalene mothballs, paraquat, and hydrogen peroxide can cause direct oxidative damage to erythrocytes. Several cancer chemotherapeutic agents also probably cause oxidant and/or membrane damage, which can result in anemia within a few days after drug administration. BLOOD LOSS.

Although acute blood loss can result in anemia, it may be much more difficult to document slow, chronic blood loss, in which case the bone marrow almost always is able to compensate until the patient becomes iron deficient. The gastrointestinal tract is a major site of chronic blood loss: malignancies, gastritis, peptic ulcer disease, inflammatory bowel disease, diverticulitis, proctitis, hemorrhoidal bleeding, angiodysplasia, arteriovenous malformations, and hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) are among the major causes of chronic or intermittent gastrointestinal blood loss (see Chapter 123) . Chronic excessive menstrual blood loss, chronic urinary tract bleeding, and recurrent epistaxis also can lead to iron deficiency and anemia. Because of the substantial consumption of maternal iron by the developing fetus, multiple pregnancies also may contribute to the development of iron deficiency and anemia. Patients with chronic intravascular hemolysis (e.g., paroxysmal nocturnal hemoglobinuria, malaria; or traumatic hemolysis from a prosthetic cardiac valve) lose hemoglobin in the urine and may become iron deficient and anemic. The blood drawn from and lost by a hospitalized 844

patient can also contribute to an otherwise unexplained recent anemia, especially in patients who are unable to mount a reticulocyte response. DILUTIONAL PSEUDOANEMIA.

Certain conditions lead to an expansion of plasma volume, which results in a decreased hemoglobin, hematocrit, and RBC count without any decrease in the patient's total RBC mass. For example, the chronic intravascular volume expansion that occurs in pregnancy can reduce the hemoglobin to a level of as low as about 10 g/dL. Acute volume overload also can cause a dilutional decrease in the concentration of RBCs, which resolves after equilibration and diuresis occur. Certain medications, particularly some cytokines, such as IL-2, IL-11, and granulocyte-macrophage colony-stimulating factor (GM-CSF), also may cause acute dilutional pseudoanemias.

CLINICAL MANIFESTATIONS There are three main types of clinical manifestations of anemia. In anemia that has developed very rapidly, symptoms related to hypotension may develop as a result of loss of blood volume. In both chronic and acute anemias, tissue and organ hypoxia is a major source of symptoms, although eventually orthostatic and non-orthostatic hypotension and tachycardia may occur due to chronically decreased blood volume. In hemolytic anemias, the products of lysed erythrocytes also may result in separate clinical findings. The specific signs and symptoms of anemia may vary widely from patient to patient with the same degree and tempo of anemia. The major factors that determine the specific response of each individual to anemia include severity of anemia, rapidity of onset of anemia, age of the patient, overall physical condition, and co-morbid events or disorders. Mild anemia often is associated with no clinical symptoms and may be discovered only when a complete blood cell count is done for another reason. The earliest clinical symptoms of mild to modest anemia tend to be a sense of fatigue, generalized weakness, and loss of stamina, followed by tachycardia and exertional dyspnea. In young, healthy patients, these symptoms frequently are not noticed until the hemoglobin level falls to below 7 or 8 g/dL. However, in elderly patients and those with cardiovascular or pulmonary disease, symptoms may occur even with modest degrees of anemia and hemoglobin levels in the range of 9 to 11 g/dL. Physiologic Compensatory Mechanisms in Anemia The five main physiologic compensatory responses to anemia vary in prominence depending on rapidity of onset and duration of anemia and the condition of the patient. First, in acute-onset anemia with severe loss of intravascular volume, peripheral vasoconstriction and central vasodilatation preserve blood flow to vital organs. Second, over time and with increasingly severe anemia, systemic small vessel vasodilatation results in increased blood flow to ensure better tissue oxygenation. These vascular compensations result in decreased systemic vascular resistance, increased cardiac output, and tachycardia, which result in a higher rate of delivery of oxygen-bearing erythrocytes to the tissues. Third, RBCs develop an increased level of 2,3-diphosphoglycerate, which interacts with hemoglobin molecules to cause a rightward shift of the hemoglobin oxygen dissociation curve, which in turn enhances the release of oxygen to the tissues at any given partial pressure of oxygen. Fourth, in chronic anemias there is a compensatory increase in plasma volume, which serves to maintain the total blood volume and to enhance tissue perfusion. The fifth compensatory response in otherwise normal individuals is stimulation of EPO production, which in turn stimulates new erythrocyte production. The latter occurs if the stem cells and erythroid precursors are normal, the erythroid precursors are able to respond normally to EPO, and the developing normoblasts are normal. Clinical Manifestations of Chronic Anemia Weakness, fatigue, lethargy, decreased stamina, palpitations, dyspnea on exertion, and orthostatic light-headedness are common symptoms in patients with chronic anemia, although the compensatory mechanisms described earlier may prevent these symptoms from being manifested in mild or moderate anemias. Occasional patients with slowly developing or long-standing anemia may report being asymptomatic even with hemoglobin levels as low as 5 or 6 g/dL, although virtually all such patients notice a distinct improvement in their performance status after correction of anemia. As is true of acute anemias, co-morbid conditions, particularly with impaired blood supply or oxygenation of specific organs, may result in symptoms and signs resulting from organ-specific dysfunction. Thus, anemic patients with prior myocardial dysfunction may have more pronounced edema, dyspnea, orthopnea, tachycardia, fatigue, and loss of stamina. In patients with coronary artery disease, anemia may result in onset or worsening of angina or may even precipitate a myocardial infarction. Anemic patients with significant peripheral arterial disease may develop new or worsening claudication. Anemic patients with cerebrovascular disease may experience more frequent or severe transient ischemic events or strokes. The most prominent general physical examination findings that may occur in patients with significant anemia include pallor of skin and mucosal surfaces, orthostatic hypotension, resting or orthostatic tachycardia, systolic ejection murmur, increased prominence of the cardiac apical impulse, bounding pulses, and wide pulse pressure. The presence of splenomegaly or history of prior splenectomy raises the possibility of a chronic hemolytic anemia. A right upper quadrant surgical scar or history of gallstones and/or cholecystectomy also should raise the possibility of a chronic hemolytic state with formation of bilirubin-containing gallstones. In patients who are anemic without an immediately obvious etiology, careful probing of the patient's past medical history and family history is essential. In particular, it is important to obtain results of previous blood cell counts to determine whether the anemia is of recent to even life-long duration. A careful, in-depth discussion of personal and family history can be very helpful, particularly if positive for anemia, splenectomy, cholecystectomy, gallstones, and/or jaundice at birth or later in life. However, the new mutation rate for congenital/hereditary hemolytic anemias is sufficiently high that a lack of family history should not deter one from the search for such conditions, if the

remainder of the clinical picture is compatible with a congenital hemolytic anemia. Mild hereditary and congenital hemolytic anemias sometimes escape detection until patients are elderly or until a second event compromises the ability of the patient's bone marrow to compensate for the chronic, excessive rate of destruction of erythrocytes. In some patients, past treatment may have been inappropriate or ineffective because of inadequate evaluation and incorrect diagnosis. General Clinical Manifestations of Acute Development of Anemia from Blood Loss or Hemolysis In a patient with acute severe hemolysis or blood loss, prominent early symptoms include resting or orthostatic hypotension due to a decrease in total blood volume, with subsequent light-headedness or syncope, exertional, orthostatic, and/or resting tachycardia and palpitations, diaphoresis, anxiety, agitation, generalized severe weakness and lethargy, and possibly decreased mental function. All of the physical examination findings described earlier for chronic anemias tend to be more pronounced with anemias of very rapid onset that also are complicated by acute loss of intravascular blood volume. Depending on the severity of the anemia and blood volume depletion, co-morbid conditions, age, and overall patient health, there also may be signs of oxygen deprivation in one or multiple organ systems. Loss of 25 to 35% of the total blood volume in 12 to 24 hours cannot be ameliorated by the normal compensatory mechanisms, and loss of more than 40% of blood volume in 12 hours leads to profound symptoms due more to intravascular volume depletion than to anemia. Diseases of Other Body Systems that Can Cause or be Associated with Anemia A broad spectrum of disorders of other organ systems can give rise to anemia. Any chronic infection, chronic inflammatory disease, or malignant disease can result in anemia of chronic disease or inflammation. Patients with lymphoproliferative and rheumatologic diseases may develop autoimmune hemolytic anemia. Any cause of moderate to severe renal insufficiency can cause anemia due to impaired EPO production. Any cause of marked splenomegaly, including myeloproliferative and lymphoproliferative disorders, certain chronic infectious diseases (e.g., malaria, tuberculosis), portal 845

Figure 159-1 Algorithm for diagnosis of anemias. TTP = thrombotic thrombocytopenic purpura; HUS = hemolytic-uremic syndrome; HELLP = hepatomegaly- elevated l iver (function tests)- l ow platelets; DIC = disseminated intravascular coagulation.

vein thrombosis, or portal hypertension may cause excessive red cell sequestration and destruction. Gastritis, peptic ulcer disease, gastrointestinal angiodysplasia, and hereditary hemorrhagic telangiectasia frequently are associated with chronic blood loss that leads to iron deficiency and anemia. Iron deficiency also can be caused by removal or significant dysfunction (e.g., Whipple's disease, Crohn's disease) of the duodenum, which is the major site of iron absorption. Anti-gastric parietal cell antibodies, gastric achlorhydria, prior gastrectomy, intestinal bacterial overgrowth, or dysfunction (e.g., inflammatory bowel disease) or surgical removal of the terminal ileum can result in cobalamin deficiency and anemia. Patients with hypopituitarism or hypothyroidism may have a mild macrocytic anemia. Severe alcoholics may develop folate deficiency from poor dietary intake, iron deficiency from chronic gastric blood loss, or even toxic suppression of the bone marrow, resulting in decreased erythropoiesis. Patients with severe liver disease often have shortened RBC survival due to splenomegaly caused by portal hypertension or due to excess deposition of unesterified cholesterol on erythrocyte membranes and the resulting formation of acanthocytes and schistocytes that are cleared from the blood prematurely. Anemia is a common manifestation of HIV infection and may be multifactorial, including contributions from cytokine-mediated anemia of chronic disease, relative EPO deficiency, malnutrition, myelodysplastic changes in the bone marrow, bone marrow fibrosis and necrosis, immune-mediated hemolysis, and drug (e.g., zidovudine)-induced myelosuppression.

DIAGNOSIS The initial diagnostic evaluation (Fig. 159-1) of anemia is based on using readily available information, including a careful in-depth evaluation of the patient's past medical history and family history (Table 159-3) , physical examination (splenomegaly is the single most important physical finding in the anemic patient), complete blood cell count, reticulocyte count, and microscopic evaluation of the peripheral blood smear (Table 159-4) . More specialized laboratory tests are indicated only after these screening studies have been obtained. In the patient with anemia, the first distinction to be made is whether the primary cause of the anemia is failure of the bone marrow to produce sufficient numbers of erythrocytes or accelerated loss or destruction of erythrocytes. A single test, the reticulocyte count, often provides the answer to this question. An elevated absolute reticulocyte count in an anemic patient indicates that the bone marrow is responding to the requirement for new erythrocyte production to replace prematurely destroyed or lost erythrocytes from hemolysis or blood loss. A reticulocyte count that is below normal or in the normal range for non-anemic individuals indicates that the primary cause of the anemia is the inability of the bone marrow to maintain the rate of production of RBCs required to compensate for those lost or destroyed. Microscopic examination of the morphology of RBCs in a peripheral blood smear is an essential part of the evaluation of both defective production and excessive destruction of RBCs (Color 846

TABLE 159-3 -- USE OF THE PERSONAL AND FAMILY MEDICAL HISTORY IN DIAGNOSIS OF ANEMIAS HISTORY: SIGNS AND SYMPTOMS POSSIBLE ETIOLOGY OF ANEMIA Known normal complete blood cell count in past

Probably not hereditary/congenital disorder

Anemia known since childhood

Inherited/congenital hemolytic anemia or (less likely) bone marrow hypoplasia

Splenectomy, gallstones, and/or jaundice

Chronic hemolytic anemia, liver disease

Family history of splenectomy, gallstones, and/or jaundice

Hereditary hemolytic anemia (RBC enzyme or membrane disorder, thalassemia, or hemoglobinopathy)

Poor or unconventional diet, malnutrition, or severe alcoholism

Bone marrow hypoplasia, folate deficiency

Paresthesias, foot numbness, loss of balance, altered mental status

Cobalamin (vitamin B12 ) deficiency

Gastrectomy, surgical removal of ileum, chronic malabsorption disorder

Cobalamin (vitamin B12 ) deficiency

Chronic gastritis, peptic ulcer disease, chronic use of ASA or NSAID, recurrent epistaxis or rectal bleeding, melena, menorrhagia, metrorrhagia, multiple pregnancies, duodenal surgery, gastrectomy

Iron deficiency

Chronic rheumatologic, immunologic, infectious, or neoplastic disease

Anemia of chronic disease, autoimmune hemolytic anemia

Decreased urine output

Anemia due to renal insufficiency

Dark urine

Hemolytic anemia (intravascular hemolysis)

Recent onset of infections, mucosal and skin bleeding, easy bruising, oral ulcerations

Bone marrow aplasia/hypoplasia, acute leukemia, myelodysplasia, myelophthisis

Occupational/environmental toxin exposure (benzene, ionizing radiation, lead)

Bone marrow aplasia/hypoplasia, acute leukemia, myelodysplasia, lead poisoning

Drug/medication exposure: Penicillin, cephalosporin, procainamide, quinidine, quinine, sulfonamide

Drug-induced immune hemolytic anemia

Fava beans, dapsone, naphthalene

Oxidant-induced hemolysis (G6PD deficient)

Cancer chemotherapeutic drugs (recent use)

Bone marrow aplasia/hypoplasia, oxidant damage, fluid retention/dilutional anemia, megaloblastic anemia

Cancer chemotherapeutic drugs (past use)

Bone marrow hypoplasia, myelodysplasia, acute myeloid leukemia

Chloramphenicol, gold salts, sulfonamides, anti-inflammatory drugs

Bone marrow aplasia/hypoplasia

Ethanol, chloramphenicol

Acute reversible bone marrow toxicity

Methotrexate, azathioprine, pyrimethamine, trimethoprim, zidovudine, sulfa drugs, hydroxyurea

Bone marrow aplasia/hypoplasia, megaloblastic anemia

RBC = red blood cells; ASA = aspirin; NSAID = non-steroidal anti-inflammatory drug; G6PD = glucose-6-phosphate dehydrogenase. Plate 5 A). In a patient with an elevated reticulocyte count, specific morphologic changes in the RBCs observed on microscopic examination often make the diagnosis readily apparent or reduce the list of possible diagnoses considerably. For example, the finding of sickle cells should lead to a hemoglobin electrophoresis, which will confirm the type of sickling disorder (Color Plate 5 J). A predominant finding of spherocytes means that the patient almost certainly has autoimmune or alloimmune hemolysis or hereditary spherocytosis (Color Plate 5 G); the evaluation includes a careful past medical and family history (for duration of anemia, medications, history of blood transfusions, anemia in other family members, and history of splenectomy, cholecystectomy, gallstones, and jaundice in the patient and family members), examination of the patient (for splenomegaly, jaundice, or signs of autoimmune disorders), and laboratory studies (including direct and indirect antiglobulin [Coombs] tests or more sensitive tests of antierythrocyteantibodies and total and indirect bilirubin). Microcytic RBCs in a patient without an elevated reticulocyte count suggest iron deficiency (Color Plate 5 D), anemia of chronic disease, or thalassemia trait (Color Plate 5 I) (or, in more severe cases, homozygous beta-thalassemia or hemoglobin H disease) as the most likely causes. Sideroblastic anemia with or without myelodysplasia and lead poisoning are rare causes of microcytic anemia in adults. In microcytic anemia, the history of the anemia (including duration; prior menstrual and pregnancy history in females; dietary history; occupational history; history of gastrointestinal, upper respiratory, or urinary tract bleeding; history of chronic infections or autoimmune or chronic inflammatory disorders; response to prior therapy for anemia) and family history of anemia can help greatly to distinguish among these possible causes. A low or low normal RBC count and normal RDW favors anemia TABLE 159-4 -- RED BLOOD CELL MORPHOLOGIC ABNORMALITIES AS CLUES TO THE DIAGNOSIS OF ANEMIAS RED BLOOD CELL (RBC) REPRESENTATIVE CAUSES OF ANEMIA MORPHOLOGY Microcytosis

Iron deficiency, anemia of chronic disease, thalassemia, and (rarely) lead poisoning, vitamin B6 deficiency, or hereditary sideroblastic anemias

Macrocytosis

Polychromatophilia (reticulocytes), vitamin B12 (cobalamin) or folate deficiency, myelodysplasia, use of drugs that inhibit DNA synthesis

Basophilic stippling

Hemolysis, lead poisoning, thalassemia

Target cells

Thalassemia, hemoglobins C, D, E, and S, liver disease, abetalipoproteinemia

Microspherocytes

Autoimmine hemolytic anemia, alloimmune hemolysis, hereditary spherocytosis, some cases of Heinz body hemolytic anemias

Schistocytes and fragmented RBCs

Thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, vasculitis, malignant hypertension, eclampsia, traumatic hemolysis due to prosthetic heart valve or damaged vascular graft, thermal injury (burns), post-splenectomy

Teardrop cells

Myelofibrosis, myelophthisis (bone marrow infiltration by neoplastic cells)

Sickle cells

Hemoglobin SS, SC, or S-beta-thalassemia

Acanthocytes (spur cells)

Severe liver disease, malnutrition, McLeod blood group phenotype

Echinocytes (burr cells)

Renal failure, hemolysis due to malnutrition with hypomagnesemia and hypophosphatemia, pyruvate kinase deficiency, common in vitro artifact

Stomatocytes

Alcoholism, hereditary stomatocytosis

"Bite" cells or "blister" cells

Glucose-6-phosphate dehydrogenase deficiency, other oxidant-induced hemolysis, unstable hemoglobins

Howell-Jolly bodies

Post-splenectomy, hyposplenism

Intraerythrocytic parasitic or bacterial inclusions

Malaria (parasites), babesiosis (parasites), bartonellosis (gram-negative coccobacilli)

Agglutinated red blood cells

Cold agglutinin disease, in vitro artifact

Rouleaux formation

Multiple myeloma, monoclonal gammopathy of undetermined significance

847

TABLE 159-5 -- LABORATORY TESTS TO DISTINGUISH IRON DEFICIENCY FROM ANEMIA OF CHRONIC DISEASE (ACD) MEASUREMENT UNITS NORMAL VALUES IRON DEFICIENCY ACD ACD + IRON DEFICIENCY Serum iron

mug/dL

50-150

Low normal-

Serum total iron-binding capacity

mug/dL

250-400

Low normal-

Low normal-

Transferrin saturation

%

20-50

Normal-

Low normal-

Serum ferritin

mug/L

20-350

Normal-

Normal-

Serum soluble transferrin receptor

nM

9-28

Normal

Bone marrow iron stores

0-4+

2-3+

Normal

Iron-containing normoblasts in the bone marrow

%

20-80%

of chronic disease; an elevated RDW in this setting favors iron deficiency; and a high normal or elevated RBC count and normal RDW favors thalassemia. Serum iron, iron-binding capacity, and ferritin levels often can distinguish between anemia of chronic disease and iron-deficiency anemia (Table 159-5) ; in patients with anemia of chronic disease, an elevated serum soluble transferrin receptor level favors the associated presence of iron deficiency. Determination of marrow iron stores on bone marrow aspiration or biopsy, the gold standard for determining iron stores, rarely is required for this purpose now. However, the diagnosis of myelodysplasia requires microscopic examination of bone marrow cell morphology, and diagnosis of sideroblastic anemia (Color Plate 6 E) also requires Prussian blue staining (for detection of iron) of normoblasts in the bone marrow (Table 159-6) . If there is mild microcytic anemia with significant numbers of target cells, thalassemia trait is the most likely diagnosis. beta-Thalassemia heterozygotes who have mild microcytic anemia can be diagnosed with hemoglobin electrophoresis, although more sophisticated tests, including direct sequencing of the beta-globin gene, may be needed to determine the specific type of beta-thalassemia. alpha-Thalassemia can be diagnosed definitively only with globin chain synthesis studies, Southern blotting, polymerase chain reaction, or alpha-globin gene sequencing; however, normal hemoglobin A2 and F levels in a patient with microcytosis, target cells, and no or mild anemia strongly suggest 1 or 2 gene deletion alpha-thalassemia trait. In real life, patients often have multiple potential causes of anemia. A patient with a rheumatologic or lymphoproliferative disease may have anemia of chronic disease but then may have a marked change in the severity of the anemia because of the development of autoimmune hemolysis. A patient with chronic hemolytic anemia such as sickle cell disease, thalassemia, or hereditary spherocytosis may develop folate deficiency or become infected with parvovirus B19, which prevents the bone marrow from continuing to overproduce erythrocytes and leads to a marked increase in the severity of the anemia. If the entire clinical picture cannot be explained by a single cause, the physician must search for secondary factors that may be important contributing components to the patient's anemia.

TABLE 159-6 -- SELECTED LABORATORY STUDIES THAT ARE USEFUL IN THE DIAGNOSIS OF ANEMIAS IF THIS IS CONSIDERED TO BE A THESE ARE POTENTIALLY USEFUL DIAGNOSTIC LABORATORY TESTS POSSIBLE CAUSE OF A PATIENT'S ANEMIA Hypoproliferative Anemias

Bone marrow aplasia/hypoplasia or myelophthisis

Platelet count, white blood cell count with differential, bone marrow aspirate and biopsy

Myelodysplasia

Bone marrow aspirate and biopsy (including Prussian blue stain of iron), karyotype analysis

Acute leukemia

Bone marrow aspirate and biopsy, flow cytometry, immunohistochemical staining, karyotype analysis

Myelofibrosis

Bone marrow biopsy with stains for collagen (trichrome stain) and reticulin (silver stain)

Iron deficiency

Serum iron, TIBC, ferritin, soluble transferrin receptor (± bone marrow iron stain)

Anemia of chronic disease/inflammation

Serum iron, TIBC, ferritin, soluble transferrin receptor (± bone marrow iron stain)

Folate deficiency

Red blood cell folate level, serum folate level, bone marrow aspirate

Vitamin B12 (cobalamin) deficiency

Serum vitamin B12 level, urine (± serum) methylmalonic acid level, bone marrow aspirate, Schilling tests

Hemolytic Anemias General measures of hemolysis (intravascular [T] and extravascular [E])

Reduction in serum haptoglobin (I > E), presence of urine hemoglobin (I) and/or urine hemosiderin (I), increased serum LDH (I > E), and serum unconjugated bilirubin (I > E)

Thalassemias

Hemoglobin electrophoresis, hemoglobin A2 and hemoglobin F levels, globin DNA analysis (Southern blotting, polymerase chain reaction, sequencing), globin chain synthesis ratios

Sickle cell disorders

Hemoglobin electrophoresis

Autoimmune hemolysis

Direct antiglobulin (Coombs) test, quantitation of red blood cell surface antibodies, cold agglutinin titer

Alloimmune hemolysis

Direct and indirect antiglobulin (Coombs) test with specificity analysis of eluted antibodies

Truamatic (microangiopathic or macroangiopathic) hemolysis

History and physical examination findings of hypertension, pregnancy, prosthetic heart valves or vascular grafts, systemic vasculitis, neurologic changes, fever; schistocytes, anemia, and destructive thrombocytopenia; BUN and creatinine; urinalysis; DIC panel

Hereditary spherocytosis, elliptocytosis, pyropoikilocytosis, and stomatocytosis

Primarily morphologic diagnoses; specific mutations detected by sequencing spectrin, ankyrin, band 3 or protein 4.1 DNA

Red blood cell enzymopathies

G6PD assay (1-2 months after acute hemolysis), Heinz body prep, specific enzyme assays

Unstable hemoglobins

Heat/isopropanol denaturation tests, hemoglobin electrophoresis

Paroxysmal nocturnal hemoglobinuria

Acid hemolysis (Ham) or sucrose hemolysis test, flow cytometry analysis of GPI-anchored cell surface proteins (e.g., CD55, 59)

TIBC = total iron-binding capacity; BUN = blood urea nitrogen; DIC = disseminated intravascular coagulation; G6PD = glucose-6-phosphate dehydrogenase; GPI = glycosylphosphatidylinosital.

Berliner N, Duffy TP, Abelson HT: Approach to the adult and child with anemia. In Hoffman R, Benz EJ Jr, Shattil SJ, et al (eds): Hematology: Basic Principles and Practice, 2nd ed. New York, Churchill Livingstone, 1995, p 468. Comprehensive review of the pathophysiology and evaluation of anemias. Erslev AJ: Clinical manifestations and classification of erythrocytic disorders. In Beutler E, Lichtman MA, Coller BS, Kipps TJ (eds): Williams Hematology, 5th ed. New York, McGraw-Hill, 1995, pp 441-447. Excellent review of the systemic manifestations of anemia. Hillman RS, Ault KA: Hematology in Clinical Practice. New York, McGraw-Hill, 1995. Excellent summaries of practical approaches to the evaluation and management of anemias. Hillman RS, Finch CA: Red Cell Manual, 7th ed. Philadelphia, FA Davis, 1996, pp 3-196. A definitive text on the production, function, and disorders of erythrocytes.

MD Consult L.L.C. http://www.mdconsult.com Bookmark URL: /das/book/view/882/162.html/top

Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

848

Chapter 160 - APLASTIC ANEMIA AND RELATED BONE MARROW FAILURE SYNDROMES Neal S. Young

Blood cell counts may be low because cells are prematurely removed from the peripheral circulation or are inadequately produced in the bone marrow. Bone marrow failure is often classified by other dominant clinical or morphologic features (e.g., the leukemias) or by specific etiology (e.g., pernicious anemia). The term bone marrow failure is vague and inclusive, and it awaits redefinition with more precise understanding of pathophysiologic processes. By default, therefore, the disorders of bone marrow failure are currently defined by their marrow pathology: the fatty bone marrow of aplastic anemia, the disordered hematopoiesis of the myelodysplasias, and the fibrosis of myelofibrosis. Making inferences about disease processes from the appearance of the bone marrow is as misleading as it is inevitable; what is understood must be distinguished from what is conjecture.

APLASTIC ANEMIA Definition (Table 160-1) APLASTIC ANEMIA.

Aplastic anemia is a disease of the young, with a median age at onset of about 25 years (excluding aplasia secondary to cancer chemotherapy). It is the most common cause of pancytopenia in the adolescent or young adult (Fig. 160-1) . The bone marrow usually can be aspirated easily but appears dilute on smear. The biopsy specimen (see Color Plate 5 C), often grossly TABLE 160-1 -- CLASSIFICATION OF APLASTIC ANEMIA AND SINGLE CYTOPENIAS APLASTIC ANEMIA

CYTOPENIAS

Acquired Radiation Drugs and chemicals Regular effects Idiosyncratic reactions Viruses Epstein-Barr virus (infectious mononucleosis) Hepatitis (non-A non-B non-C hepatitis) Human immunodeficiency virus (AIDS) Immune diseases Eosinophilic fasciitis Hypoimmunoglobulinemia Thymoma and thymic carcinoma Graft-versus-host disease in immunodeficiency Paroxysmal nocturnal hemoglobinuria Pregnancy Idiopathic--the most frequent diagnosis

Acquired Anemias Pure red cell aplasia (see Table 160-3) Transient erythroblastopenia of childhood Neutropenias Idiopathic Drugs, toxins Thrombocytopenias Drugs, toxins

Inherited Fanconi's anemia Dyskeratosis congenita Schwachman-Diamond syndrome Reticular dysgenesis Amegakaryocytic thrombocytopenia Familial aplastic anemias Preleukemia (e.g., monosomy 7) Non-hematologic syndromes (Down, Dubovitz's, Seckel's)

Inherited Anemias Congenital pure red cell aplasia Neutropenias Kostmann's syndrome Schwachman-Diamond syndrome Reticular dysgenesis Thrombocytopenias Thrombocytopenia with absence of radii Idiopathic amegakaryocytic thrombocytopenia

Figure 160-1 Diagnostic decisions in patients who have pancytopenia. PB = peripheral blood; BM = bone marrow; AA = aplastic anemia; MDS = myelodysplastic syndrome; AML = acute myeloid leukemia; AMM = agnogenic myeloid metaplasia; DEB = diepoxybutane; MMC = mitomycin-C; FA = Fanconi's anemia.

pale, shows mainly fat under the microscope; by definition, hematopoietic cells occupy less than 25% of the marrow space and, in the most serious cases, 0 to 5%. Prognosis is determined by the degree of blood cell count depression. The commonly accepted definition for severe disease is two of the following: (1) absolute neutrophil count (percentage of polymorphonuclear and band forms multiplied by the total white blood cell count) of less than 500/mm3 ; (2) platelets less than 20,000/mm3 ; and (3) anemia with a reticulocyte count (corrected for hematocrit) less than 1% (or an absolute reticulocyte count less than 40,000/mm3 ). A subset of very severe aplastic anemia, with the worst prognosis, is defined by more severe neutropenia (absolute neutrophil count less than 200/mm3 ). BICYTOPENIA AND SINGLE-LINEAGE FAILURE STATES.

Some patients have bone marrow hypocellularity and depression of only two of the three major blood lines; many such cases progress to typical aplastic anemia. Failure of a single lineage also occurs in pure red cell aplasia (rare), megakaryocytic thrombocytopenia (extremely rare), and agranulocytosis (not rare but usually an idiosyncratic drug reaction). These syndromes show the characteristic absence of a single set of recognizable precursor cells in otherwise cellular bone marrow, and in this way they are differentiated from the much more common causes of anemia (e.g., vitamin or iron deficiency and hemolysis) or thrombocytopenia (from peripheral destruction of platelets). The pathophysiology of the more restricted marrow failure states is probably similar to that of general bone marrow failure, but with a more mature target cell. CONSTITUTIONAL (FANCONI'S) ANEMIA.

Fanconi described children with inherited pancytopenia and hypocellular marrows and with associated anomalies of the skeletal and urogenital systems. Fanconi's anemia now is defined by specific chromosomal aberrations in cultured cells after clastogenic stress. Indeed, cytogenetic analysis of families of children with Fanconi's anemia has shown that the majority of patients lack associated anomalies and that the disease can manifest in the third and fourth decades or even later. Congenital pure red cell aplasia (Diamond-Blackfan syndrome) lacks a cytogenetic marker or associated physical abnormalities. Isolated neutropenia or thrombocytopenia occurs

in a number of pediatric syndromes. Etiology In the majority of patients, aplastic anemia is diagnosed as "idiopathic." There is little to distinguish these cases clinically from those with a presumed cause, such as exposure to a drug or chemical. 849

Even when clinical associations are established, they should not automatically be equated with etiology and pathophysiology. RADIATION (see Chapter 19) .

Marrow aplasia is a major acute sequela of radiation exposure. Radiant energy damages DNA; the bone marrow, which is a tissue dependent on active mitosis, is particularly susceptible to its effects. Nuclear accidents and radiation injury can involve not only power plant workers but also employees of hospitals, laboratories, and industry (e.g., food sterilization, metal radiography), as well as persons exposed to stolen, misplaced, or misused radiation sources. The radiation dose can be approximated from the rate and degree of decline in blood cell counts; dosimetry by reconstruction of the exposure can help to estimate the patient's prognosis and also to protect medical personnel from contact with radioactive tissue and excreta. Myelodysplasia and leukemia, but not aplastic anemia, are late effects of irradiation. CHEMICALS (Table 160-2) .

Benzene has been clearly linked to bone marrow failure, but the quality of the case reports, many from the early part of the century, usually does not allow accurate discrimination between aplasia and myelodysplasia (benzene exposure also increases the risk of acute leukemia). The occurrence of hematologic abnormalities is roughly correlated with cumulative exposure, but there must also be an important element of susceptibility, because only a minority of even heavily exposed workers develop evidence of myelotoxicity. A history of past employment is important, especially in "open" industries in which benzene is used for a secondary purpose (usually as a solvent) rather than in "closed" industries for chemical production. Benzene-related blood diseases have declined with regulation of industrial exposure, and benzene is not generally available as a household solvent. The benzene content of gasoline increased with the reduction of lead. The association of marrow failure with other organic chemicals is much less well substantiated. DRUGS.

Many of the common cancer chemotherapeutic drugs regularly and predictably suppress the bone marrow. A large and diverse group of other drugs have been linked to idiosyncratic aplastic anemia (see Table 26-5) , but some of these associations are based on case reports and are tenuous at best. For example, some incriminated drugs may have been used to treat the first symptoms of bone marrow failure (antibiotics for fever or the preceding viral illness) or may have provoked the first symptom of a pre-existing disease (petechiae produced by non-steroidal anti-inflammatory agents administered to a thrombocytopenic individual). In the context of total drug use, these idiosyncratic reactions, although individually devastating, are very rare events. Chloramphenicol, the most infamous culprit, reportedly produced aplasia in only about 1 of 60,000 therapeutic courses, and even this number is almost certainly an overestimate. Chloramphenicol also consistently causes dose-related, rather modest marrow depression, mainly reticulocytopenia and altered marrow morphology and iron kinetics. This effect of chloramphenicol use is mechanistically unrelated TABLE 160-2 -- SOME DRUGS AND CHEMICALS ASSOCIATED WITH APLASTIC ANEMIA Agents That Regularly Produce Marrow Depression as the Major Toxicity in Commonly Employed Doses or Normal Exposures Cytotoxic drugs used in cancer chemotherapy: alkylating agents, antimetabolites, antimitotics Some antibiotics Agents That Frequently But Not Inevitably Produce Marrow Aplasia Benzene (and benzene-containing chemicals like kerosene, carbon tetrachloride, Stoddard's solvent, chlorophenols) Agents Probably Associated With Aplastic Anemia But With Relatively Low Probability Insecticides Chloramphenicol Antiprotozoals: quinacrine and chloroquine, mepacrine Non-steroidal anti-inflammatory drugs (including phenylbutazone, indomethacin, ibuprofen, sulindac, aspirin) Anticonvulsants (hydantoins, carbamazepine, phenacemide) Heavy metals (gold, arsenic, bismuth, mercury) Sulfonamides: some antibiotics, antithyroid drugs (methimazole, methylthiouracil, propylthiouracil), antidiabetes drugs (tolbutamide, chlorpropamide), carbonic anhydrase inhibitors (acetazolamide and methazolamide) Antihistamines (cimetidine, chlorpheniramine) D-Penicillamine Estrogens (in pregnancy and in high doses in animals) to and clinically not predictive of the rare, severe reaction, which occurs 1 to 2 months or longer after its routine use. The introduction of chloramphenicol was thought to have produced a notable increase in the number of cases of aplastic anemia, but its diminished use has not been followed by reduced frequency of aplastic anemia. Chloramphenicol remains a popular antibiotic in less-developed countries. Recent epidemiologic studies in Thailand failed to show a relationship between chloramphenicol and aplastic anemia. Suspected drug reactions account for 15 to 25% of cases of aplastic anemia, whereas most agranulocytosis in adults is drug related. The drugs associated with agranulocytosis are similar, but not identical to, those related to generalized bone marrow failure. Myeloid cells may be uniquely susceptible because of their ability to metabolize drugs, often to toxic intermediate compounds. In contrast to drug-associated aplastic anemia, agranulocytosis should spontaneously resolve with removal of the drug, and the severely neutropenic patient should survive if infection is adequately treated. INFECTIONS.

Hepatitis, which is the most common infection preceding aplastic anemia, accounts for about 5% of cases in Western countries and perhaps twice that proportion in Asia. Typically, severe aplasia occurs in a young man who recovered from a mild bout of hepatitis 1 to 2 months earlier. The hepatitis is non-A, non-B, and non-C by serologic testing. Aplastic anemia can rarely follow infectious mononucleosis; and Epstein-Barr virus, with or without a suggestive preceding history, is found in the marrow of some patients with aplastic anemia. Parvovirus B19 has not convincingly been associated with permanent total bone marrow failure. Moderate marrow depression occurs commonly in the course of many viral and bacterial infections, but the primary disease is usually overt. IMMUNOLOGIC DISEASE.

Fatal aplasia can occur in immunodeficient children who receive unirradiated blood products and in other cases of transfusion-associated graft-versus-host disease. The syndrome eosinophilic fasciitis is associated with aplastic anemia. Pure red cell aplasia is associated with thymoma, and patients with red cell aplasia or pancytopenia may be hypoimmunoglobulinemic. OTHER ASSOCIATIONS.

Aplastic anemia may occur during pregnancy and sometimes resolves with delivery or with spontaneous or induced abortion. Pancytopenia occurs in about one third of

patients with paroxysmal nocturnal hemoglobinuria (see Chapter 165) , and patients with aplastic anemia may have a positive Ham test, often with hematopoietic recovery; a much larger proportion show evidence of absent cell surface membrane glycophosphoinositol proteins by flow cytometry of granulocytes. Pathophysiology TYPES OF INJURY.

Most bone marrow failure almost certainly results from damage to the hematopoietic stem cell compartment; little evidence exists of aplastic anemia due to defective stroma or from inadequate production of growth factors. In all patients with aplastic anemia, the numbers of both committed and primitive hematopoietic cells that can be assayed in vitro are markedly diminished, probably to about 1% of normal, by the time of clinical presentation with symptoms. Nevertheless, recovery of peripheral blood cell counts can occur despite low stem cell numbers and does not depend on repopulation of the stem cell compartment. Although aplastic anemia can result from direct damage to the bone marrow (e.g., due to high doses of physicochemical agents, irradiation, and cytotoxic drugs used to treat cancer), most community-acquired aplastic anemia is caused by immune system attack on the bone marrow and resulting destruction of hematopoietic stem and progenitor cells. The mechanism by which some drugs and chemicals or viruses provoke organ specific autoimmunity in aplastic anemia is unknown, as are the host factors that make only rare individuals susceptible to the idiosyncratic effects of commonly used agents. Specificity of the inciting agent is suggested by the incrimination of a non-A...E hepatitis virus in post-hepatitis aplastic anemia (the syndrome is not associated with other known hepatitis viruses [see Chapter 149]) and the involvement of certain types of drugs. On the host side, aplastic anemia has been linked to a few HLA antigens and occurs in association with other autoimmune diseases. Disease is likely the result of a combination 850

of genetically determined features of the immune response that convert a normal physiologic response to a sustained and abnormal pathologic process. METABOLIC DRUG INJURY.

Most drugs and chemicals, especially if they are polar and have limited water solubility, are metabolized to highly reactive electrophilic intermediates that bind to cellular macromolecules. Excessive generation of such toxic intermediates or failure to detoxify them may be genetically determined and apparent only on drug challenge. The complexity and specificity of the pathways implies multiple susceptible loci. For example, in one case of phenytoin-associated aplastic anemia, a defect in detoxification of that drug's metabolites was detected in the patient after recovery, and cells from the patient's mother were intermediately susceptible; cells from both individuals normally detoxified metabolites generated from drugs closely related to phenytoin. IMMUNE-MEDIATED INJURY.

The recovery of their own marrow function by some patients being prepared for bone marrow transplantation with immunosuppressive horse antilymphocyte globulin first suggested that aplastic anemia might be immune mediated. Blood and bone marrow of patients often suppress normal bone marrow growth in progenitor assays, and removal of T cells from the bone marrow of patients with aplastic anemia can improve colony formation in vitro. Patients with aplastic anemia may have increased numbers of activated cytotoxic lymphocytes (CD8+ cells bearing HLA-DR and interleukin-2 receptors) that overproduce lymphokines (particularly interferon-gamma and tumor necrosis factor). The interferon-gamma gene is overexpressed in the marrow of most aplastic anemia patients, and lymphocytes containing interferon can be detected by flow cytometric methods in the blood. Both interferon and tumor necrosis factor induce apoptosis in hematopoietic target cells through the Fas pathway; the result is a process of active cell destruction, not simply functional suppression of cell proliferation. The severe and fatal aplastic anemia that accompanies "runt" disease in animals and transfusion-acquired graft-versus-host disease in humans are evidence of the potency of immune cells to ablate bone marrow. Although immune system abnormalities improve when patients are treated with immunosuppressive therapies, they may not resolve completely even when blood cell counts have improved. The high rate of clinical relapse after discontinuation of immunosuppressive therapy and, conversely, the responsiveness, sometimes dependence, of blood cell counts on cyclosporine administration are further evidence of the pathogenic role of T cells in this disease. PURE RED CELL APLASIA (Table 160-3) .

Like aplastic anemia, pure red cell aplasia results from diverse causes. Immune mechanisms have been implicated when pure red cell aplasia is associated with thymoma, systemic lupus erythematosus, and chronic lymphocytic leukemia, but not in failed erythropoiesis secondary to myelodysplasia, myeloproliferative diseases, and distinct cytogenetic abnormalities. Antibodies to red blood cell precursors can be detected in the blood of some patients, but T-cell inhibition is probably the more common mechanism. Cytotoxic lymphocyte activity restricted by histocompatibility locus or specific for cells infected by human TABLE 160-3 -- CLASSIFICATION OF PURE RED BLOOD CELL APLASIA Self-limited Transient erythroblastopenia of childhood Transient aplastic crisis of hemolysis (parvovirus B19 infection) Fetal Red Blood Cell Aplasia Non-immune hydrops fetalis (in utero parvovirus infection) Hereditary Pure Red Cell Aplasia Congenital pure red cell aplasia (Diamond-Blackfan syndrome) Acquired Pure Red Cell Aplasia Thymoma and malignancy: thymoma, lymphoid malignancies (and more rarely other hematologic diseases), paraneoplastic to solid tumors Connective tissue disorders with immunologic abnormalities: systemic lupus erythematosus, juvenile rheumatoid arthritis, rheumatoid arthritis, multiple endocrine gland insufficiency Virus: especially persistent parvovirus B19, more rarely hepatitis, adult T-cell leukemia virus, Epstein-Barr virus Pregnancy Drugs: especially phenytoin, azathioprine, chloramphenicol, procainamide, isoniazid Idiopathic T-cell lymphotropic virus (HTLV-I) has been demonstrated in a particularly well-studied case. Parvovirus B19 represents the best example of the interaction of virus, host hematologic target cell, and immune response. This common virus causes fifth disease, a benign exanthem of childhood, and a polyarthralgia syndrome in adults. In persons with underlying hemolysis, parvovirus infection causes abrupt but temporary worsening of anemia resulting from failed erythropoiesis, a syndrome called transient aplastic crisis. Parvovirus B19 has extreme tropism for human erythroid progenitor cells, owing largely to its employment of red cell P antigen as a cellular receptor. Direct cytotoxicity of the virus causes anemia if demands on erythrocyte production are high. In normal individuals, the temporary cessation of red cell production is not clinically apparent and symptoms are entirely the result of immune complex deposition. In persons unable to mount an adequate antibody response, parvovirus B19 can persist in the bone marrow and cause chronic anemia that resembles pure red cell aplasia. The presence of giant pronormoblasts, the cytopathic sign of the infection, should suggest the diagnosis. Persistent parvovirus infection should be sought in anemic patients with congenital and acquired immunodeficiency syndromes as well as in patients iatrogenically immunosuppressed because it can be effectively treated with immunoglobulin infusions. Incidence and Epidemiology The incidence of aplastic anemia is approximately 2 per million in Europe and Israel, but the disease is more frequent in Asia, being 4 per million in Bangkok and higher in rural Thailand. Mortality statistics indicate an equal sex ratio and a preponderance of older persons, but at referral centers the median age is about 25 years. Agranulocytosis has an incidence of 3.4 per million in Europe. Pure red cell aplasia is a very rare disease, with only a few hundred reported cases, and

amegakaryocytic thrombocytopenia is rarer still, with only a few dozen cases reported in the literature. Clinical Description HISTORY.

Bleeding is the most common early symptom of aplastic anemia. Patients commonly report days to weeks of easy bruising, including oozing from the gums, nose bleeds, or heavy menstrual flow; sometimes petechiae will have been noticed. With thrombocytopenia, massive hemorrhage is unusual, but small amounts of bleeding in the central nervous system can result in serious symptoms and signs of intracranial or retinal hemorrhage. In cases of more gradual onset, symptoms of anemia are described: usually lassitude, weakness, shortness of breath, and a pounding sensation in the ears. Infection is unusual as a first symptom in aplastic anemia, in contrast to agranulocytosis, in which pharyngitis, anorectal infection, and frank sepsis may be presenting syndromes. A striking feature of aplastic anemia is the restriction of symptoms to the hematologic system. Patients often feel and look remarkably well despite drastically reduced blood cell counts; systemic complaints and weight loss should point to other causes of pancytopenia. Drug use, chemical exposure, and preceding viral illnesses should be sought with repeated questioning; prompt cessation of drug or chemical exposure is especially important in agranulocytosis, which is usually self-limited. PHYSICAL EXAMINATION.

Petechiae and ecchymoses are frequently present, and there may be retinal hemorrhages. Pelvic and rectal examinations should be performed infrequently and gently to avoid trauma; these examinations may show bleeding from the cervical os and blood in the stool. Pallor of the skin and mucous membranes is also common except in the most acute cases or in those patients who have received transfusions. Infection is uncommon on presentation; however, by the time the patient reaches a referral center, fever and signs of systemic or local infection may well be present. Lymphadenopathy and splenomegaly are very unusual in aplastic anemia. Cafe-au-lait spots and short stature point to Fanconi's anemia; peculiar nails suggest dyskeratosis congenita. Diagnosis and Differential Diagnosis The diagnosis of aplastic anemia is usually straightforward (Table 160-4) , based on the combination of pancytopenia with fatty bone marrow. Prompt arrival at the appropriate diagnosis is 851

TABLE 160-4 -- DIFFERENTIAL DIAGNOSIS OF PANCYTOPENIA Pancytopenia With Hypocellular Bone Marrow Acquired aplastic anemia Inherited aplastic anemia (Fanconi's anemia) Some myelodysplasia syndromes Rare aleukemic leukemia (acute myelogenous leukemia) Some acute lymphoblastic leukemias in childhood Some lymphomas of bone marrow Pancytopenia With Cellular Bone Marrow Primary Bone Marrow Diseases Myelodysplasia syndromes Paroxysmal nocturnal hemoglobinuria Myelofibrosis Some aleukemic leukemias Myelophthisis Bone marrow lymphoma Hairy cell leukemia Secondary to Systemic Diseases Systemic lupus erythematosus Hypersplenism Vitamin B12 or folate deficiency Overwhelming infection Acquired immunodeficiency syndrome Alcoholism Brucellosis Sarcoidosis Tuberculosis Hypocellular Bone Marrow ± Cytopenia Q fever Legionnaires' disease Anorexia nervosa, starvation Myocobacterial infection part of the effective management of the patient with aplastic anemia. BLOOD.

The smear typically shows large erythrocytes and a paucity of platelets and granulocytes. Macrocytosis, as determined by automated cell counting, is very common. Lymphocyte numbers may be normal or also reduced. The presence of immature myeloid forms should suggest leukemia or myelodysplasia; nucleated red cells suggest marrow fibrosis or invasion; and abnormal, or large, platelets suggest peripheral destruction, dysplasia, or fibrosis. BONE MARROW

(Fig. 160-1)

.

"Watery" marrow can almost always be obtained, and a "dry tap" occurs in fibrotic or myelophthisic disease. In severe aplasia, the smear of the aspirated specimen shows only residual lymphocytes and stromal cells; in milder cases, the remaining hematopoietic cells can show "megaloblastoid" erythropoiesis. Megakaryocytes are invariably greatly reduced and usually absent. The areas adjacent to the spicule should be searched for myeloblasts, which are not increased in aplastic anemia. Total cellularity is assessed by biopsy (see Color Plate 5 C) of a core more than 1 cm in length, which in the most severe cases is virtually 100% fat and in more moderate disease is less than 20% cellular. Nonetheless, the correlation between marrow cellularity and severity is imperfect: some patients with moderate disease according to blood cell counts have empty iliac crest biopsies, and there may be "hot spots" of hematopoiesis in severe cases. In single-lineage failure states, the bone marrow reflects the absence of a specific morphologic subtype, but in both pure red cell aplasia and agranulocytosis, early and mid-mature precursor cells may be present.

Granulomas may indicate an infectious cause of the marrow failure. ANCILLARY STUDIES.

Cytogenetic studies of peripheral blood should be performed on younger patients or if there is a suspicious family history or suggestive physical finding. Cytogenetic studies of bone marrow are almost always normal in aplastic anemia and frequently abnormal in myelodysplasia. Testing or abnormal sensitivity of erythrocytes to complement (Ham test) establishes paroxysmal nocturnal hemoglobinuria; flow microfluorometry of granulocytes is much more sensitive for the characteristically underexpressed proteins of this syndrome (see Chapter 165) . Serologic studies occasionally show evidence of viral infection, especially antibodies to human immunodeficiency virus or Epstein-Barr virus, but preceding hepatitis is usually indicated by abnormal liver enzymes rather than positive viral serologies. Parvovirus may be detected by DNA hybridization in chronic pure red cell aplasia. Hypoimmunoglobulinemia and thymoma are also associated with pure red blood cell aplasia; a thymoma should be sought by computed tomography, less because the hematologic disease remits with thymectomy (it often does not) than because a potentially malignant tumor must be removed. If the physical examination of the abdomen is suspicious or unsatisfactory, the size of the spleen should be determined by scanning. DIFFERENTIAL DIAGNOSIS.

Pancytopenia occurs in many diseases, but when secondary blood cell count depression rivals that of severe aplastic anemia, the primary diagnosis is usually obvious from either a history or the physical examination (e.g., the splenomegaly of alcoholic cirrhosis, a history of metastatic cancer or systemic lupus erythematosus, or obvious miliary tuberculosis on the chest radiograph). In practice, the distinction of aplasia from other hematologic diseases, especially hypocellular myelodysplasia, is more difficult. Treatment (Fig. 160-2) BONE MARROW TRANSPLANTATION (see

Chapter 182) .

This treatment offers the best therapy for a young patient with a fully histocompatible sibling donor. Survival of patients younger than about 20 years old after bone marrow transplantation is between 65% and 90%. Early consideration of the transplantation option in a child or adolescent can avoid unnecessary transfusions. Transfusions increase the risk of graft rejection, which is already high in patients with aplastic anemia, and graft rejection is a major determinant of successful clinical outcome. Graft-versus-host disease increases progressively with age and occurs in the majority of patients older than 30 years. In older persons, marrow transplantation also carries risks from infections and the effects of the conditioning regimen; as a result, it is usually not recommended for aplastic anemia in patients who are older than 45 to 50. Management of patients in the intermediate range, 20 to 45 years old, depends on their blood counts, especially the neutrophil number, and their general clinical condition. Use of alternative donors, unrelated histocompatible volunteers, or closely but not perfectly matched family members remains experimental; best results have been achieved in selected children employing intensive conditioning regimens, in which survival rates of 50% have been reported. IMMUNOSUPPRESSION.

Most patients with aplastic anemia lack a suitable marrow donor. Antithymocyte globulin (ATG) therapy leads to recovery of autologous bone marrow function in about 50% of patients, usually with independence from transfusion and a leukocyte count adequate to prevent infection. When therapy with ATG fails, about 50% of patients will respond to cyclosporine. For initial therapy for severe aplastic anemia, the combination of ATG and cyclosporine, which is superior to ATG alone, produces hematologic responses in about 70% of cases. Long-term survival rates among respondents are 80 to 90%. Improvement in granulocyte number is generally apparent within 2 months of treatment. In most patients who recover with this treatment, the blood cell counts remain somewhat depressed, the mean corpuscular volume continues to be high, and the bone marrow cellularity returns only very slowly toward normal, if at all. Relapse, meaning the need to treat again, is frequent but does not affect prognosis. Some patients may develop myelodysplasia, paroxysmal nocturnal hemoglobinuria, or acute leukemia years after successful immunosuppressive treatment of their aplastic anemia. Bone marrow examinations should therefore be performed annually or when there is an unfavorable change in blood cell counts, and a Ham test or, preferably, flow cytometry studies should be performed periodically. ATG can be given intravenously in a regimen of 40 mg/kg/day for 4 days. Anaphylaxis is a rare but occasionally fatal complication of ATG treatment; allergy should be evaluated by a prick test with an undiluted solution and immediate observation of the injected skin. ATG binds to peripheral blood cells, and therefore platelet and granulocyte numbers may fall further during active treatment. Serum sickness often develops about 10 days after initiation of treatment. Most patients receive methylprednisolone (1 mg/kg/day for 2 weeks) to ameliorate the immune consequences of heterologous protein infusion. Cyclosporine is administered orally at an initial dose of 12 mg/kg/day in adults and 15 mg/kg/day in children, with subsequent adjustment according to blood levels obtained every 2 weeks. Nephrotoxicity, hypertension, seizures, and 852

Figure 160-2 Therapeutic decisions in patients with aplastic anemia. HLA = human leukocyte antigen; BMT = bone marrow transplantation; ATG = antithymocyte globulin; CSA = cyclosporine; IS = immunosuppression; TX = transfusion.

opportunistic infections (especially Pneumocystis carinii pneumonia) are the most serious complications of cyclosporine treatment. Immunosuppression is also effective in pure red blood cell aplasia and probably in amegakaryocytic thrombocytopenia as well. Immunosuppressive agents include corticosteroids, azathioprine, cyclophosphamide, ATG, or cyclosporine. OTHER THERAPY.

Androgens have not been verified as effective in controlled trials, but occasional patients respond or even demonstrate blood cell count dependence on continued therapy. For patients with moderate disease or for those with severe pancytopenia in whom immunosuppression has failed, a 3-month trial is appropriate: nandrolone decanoate, 5 mg/kg/week given intramuscularly (with firm pressure at the injection site to prevent hemorrhage) or danazol, up to 800 mg/day by mouth. Cyclophosphamide given intravenously in very high doses, as used for conditioning in marrow transplant (45-50 mg/kg/day for 4 days), also offers effective immunosuppressive therapy and may have the advantage of avoiding the complications of relapse and the evolution of late clonal hematologic disease; because toxicity may be severe, this treatment is best given as part of a research protocol. Hematopoietic growth factors, granulocyte-macrophage and granulocyte colony-stimulating factors (GM-CSF and G-CSF) have not been shown to induce remissions in aplastic anemia, although they may increase the white blood cell count during the period of administration in some patients. PRINCIPLES OF SUPPORT.

Meticulous medical care is required so that the patient can survive to benefit from definitive therapy or, having experienced treatment failure, can maintain a reasonable quality of life in the presence of pancytopenia. First and most important, infection in the patient with severe neutropenia must be aggressively treated. Parenteral, broad-spectrum antibiotics should be started promptly: monotherapy with a late-generation cephalosporin is a reasonable regimen. Therapy is empirical and must not await results of culture, although specific foci of infection, like oropharyngeal or anorectal abscesses, pneumonia, sinusitis, and typhlitis should be sought on physical examination and with suitable radiographic studies. When indwelling plastic catheters become contaminated, vancomycin is added. Persistent or recrudescent fever implies fungal disease; candidiasis and aspergillosis are common, especially after several courses of antibacterial antibiotics, and a progressive course may be averted by timely initiation of amphotericin. Hand washing, the single most effective method of preventing the spread of infection in the hospital, remains a neglected practice. Non-absorbed antibiotics for gut decontamination may be helpful but are rarely used because of their gastrointestinal side effects. Total reverse isolation is difficult, expensive, psychologically debilitating, inhibitory of nursing and medical attention, and not clearly beneficial in reducing mortality from infections. Now that granulocytes can be efficiently mobilized from normal donors treated with G-CSF, their use in severely neutropenic patients with life-threatening infections will need to be reassessed. Platelet and erythrocyte levels can be maintained by transfusion. Candidates for bone marrow transplantation should be transfused sparingly and, of course, not with blood products from a family 853

member. Alloimmunization can limit the usefulness of prophylactic platelet transfusions, and single-donor platelets from which leukocytes have been removed by filtration are the best product. There are no direct studies of the value of prophylaxis versus demand platelet transfusions in chronic bone marrow failure. Any rational regimen of prophylaxis requires transfusions once or twice weekly to maintain the platelet count above 10,000/muL (oozing from the gut, and presumably also from other vascular beds, increases precipitously at values lower than 5000/muL). About one third of patients become refractory to platelet transfusions, sometimes to HLA-matched as well as to random-donor platelets. Inhibitors of fibrinolysis, such as aminocaproic acid, have been reported to be helpful in occasional patients but have not proven beneficial in controlled trials. Menstruation should be suppressed. Aspirin and other non-steroidal inflammatory agents that inhibit platelet function must be avoided. Red blood cells should be transfused to allow a normal level of activity, usually to a hemoglobin value of 7.0 g/dL (9.0 g/dL if there is underlying cardiac or pulmonary disease). A regimen of 2 units every 2 weeks replaces the normal loss of erythrocytes in a patient without a functioning bone marrow. In chronic anemia, the iron chelator deferoxamine should be considered at about the time the patient receives the 50th transfusion to avoid secondary hemochromatosis. Prognosis The natural course of untreated severe aplastic anemia is rapid deterioration and death resulting from infection or hemorrhage; historically, survival in patients with severe disease treated only with transfusions is poor, probably about 20% at 1 year. Fortunately, both transplantation of marrow from a matched sibling donor and intensive immunosuppressive therapies cure or ameliorate aplastic anemia in the great majority of patients. Recent retrospective comparisons from Europe suggest that results from both types of treatment are improving and about equivalent. The physician should inform the patient of the relative values of bone marrow transplantation, which cures the hematologic disease, but at great cost and often with significant morbidity, and immunosuppressive therapy, which is easier but often not completely effective. Pure red cell aplasia is compatible with long life. Patients with congenital anemias have survived for decades with a combination of transfusions and iron chelation. Probably more than half of patients with acquired red cell aplasia can be cured by immunosuppression.

MYELODYSPLASIA (see Chapter 175) Myelodysplasia describes a heterogeneous group of hematologic disorders that are defined only broadly by cytopenias associated with dysmorphic or abnormal-appearing bone marrow.

MYELOPHTHISIC ANEMIAS AND MYELOFIBROSIS Marrow fibrosis is usually accompanied by a characteristic blood smear presentation called leukoerythroblastosis; it can occur as a primary hematologic disease, called myelofibrosis or myeloid metaplasia (see Color Plate 6 D), or as a secondary process, called myelophthisis. Myelophthisis represents reaction to invading tumor cells, infectious agents such as mycobacteria or fungi, intracellular lipid deposition in Gaucher's disease, and the granulomas of sarcoidosis (Table 160-5) . In secondary fibrosis, the underlying infectious or malignant process is usually obvious. The pancytopenia of human immunodeficiency virus may be associated with moderate marrow fibrosis. Modest degrees of fibrosis can also be a feature of a variety of other hematologic syndromes, especially chronic myelogenous leukemia, poorly differentiated lymphomas, myeloma, and hairy cell leukemia. Marrow fibrosis also occurs in the bony proliferative disease of childhood called osteopetrosis. The pathophysiology of myelofibrosis has three distinct features: (1) proliferation of fibroblasts in the marrow space; (2) extension of hematopoiesis into the long bones and most peculiarly into extramedullary sites, usually the spleen, liver, and lymph nodes (myeloid metaplasia); and (3) ineffective erythropoiesis. The etiology of fibrosis is unknown but most likely involves dysregulated production TABLE 160-5 -- CAUSES OF MYELOPHTHISIS Neoplastic Infiltration of the Marrow Hematologic malignant diseases Leukemias--acute and chronic Lymphomas--Hodgkin's and non-Hodgkin's Plasma cell myeloma Hairy cell leukemia Nonhematologic malignant diseases Carcinomas--especially breast, prostate, lung, stomach Neuroblastoma Myelofibrosis Primary (idiopathic) Secondary--chronic myeloid leukemia, cancers, vasculitis (lupus, rheumatoid arthritis) Granulomatous Infections Tuberculosis Fungal infections Metabolic Abnormalities Lipid storage diseases (e.g., Gaucher's disease) Osteopetrosis of growth factors. Many cell types in the marrow produce growth factors for fibroblasts. Platelet-derived growth factor is one example, and profuse megakaryocytopoiesis and thrombocytosis are often seen early in the course of idiopathic myelofibrosis. Myelofibrosis is remarkable for pancytopenia despite extraordinarily large numbers of circulating hematopoietic progenitor cells. Idiopathic (or agnogenic) myelofibrosis is one of the myeloproliferative syndromes, a category that also includes polycythemia vera, essential thrombocythemia, and chronic myelogenous leukemia (see Chapter 174) . Anderson NS, Appelbaum FR: Myelodysplasia and myeloproliferative syndrome. Curr Opin Hematol 4:261, 1997. Most current review. Young NS, Barrett AJ: The treatment of severe acquired aplastic anemia. Blood 85:3367, 1995. Balanced review of transplantation and immunosuppression approaches. Young NS, Maciejewski JP: Pathophysiology of acquired aplastic anemia. N Engl J Med 336:1365, 1997. Stresses immune mechanisms.

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Chapter 161 - NORMOCHROMIC, NORMOCYTIC ANEMIAS Thomas P. Duffy

An optimal red blood cell (RBC) mass is maintained within the body via a feedback loop whereby the hormonal stimulus for RBC production, erythropoietin (EPO), is released in response to the hemoglobin needs of the body. EPO is a glycoprotein secreted by renal interstitial cells that respond to the oxidative state of hematin in RBCs perfusing the kidney. As anemia develops, this sensing device within the kidney causes increased EPO secretion, with overdrive of the erythroid component of the marrow. EPO causes amplification of erythroid precursors within the marrow, hastens their differentiation and release from the marrow, and inhibits apoptosis in the erythroid cell line. Under heightened EPO stimulation, normal marrow responds with erythroid hyperplasia and accelerated release of reticulocytes. These reticulocytes can be recognized by supravital staining of their residual polyribosomal reticulated network, which is the marker for these young RBCs in the peripheral blood. Under normal conditions, the marrow compensates for the 1 to 1.5% of the RBC mass that is lost each day through senescence by replacing it with reticulocytes. When anemia occurs, a physiologic "surge" in reticulocytes should follow if the marrow is capable of responding appropriately to EPO overdrive. This normal response is evidenced by an elevated reticulocyte count, significantly above the normal 1 to 1.5%. If an anemia has its origin within the marrow or is secondary to inadequate EPO stimulation, an appropriate reticulocytosis is not mounted to compensate for the anemia. This reticulocytopenic 854

response indicates that the anemia is due to problems in RBC production within the marrow rather than accelerated RBC loss or destruction in the periphery. Knowledge of this feedback EPO loop and the reticulocyte count permits a broad dissection of the cause(s) of the anemia (see Chapter 158) . Absence of an appropriate reticulocyte response in patients with anemia is the hallmark of hyporegenerative anemias. These conditions have myriad causes that include a lack of marrow precursors (stem cell or pure RBC aplasia), lack of necessary building blocks (iron, vitamin B12 , folate), and lack of adequate EPO stimulation, as well as abnormalities in proliferation and differentiation of RBCs (leukemia, myelodysplasias, infiltrative disorders of the marrow). The lesion in hyporegenerative anemias is within the marrow, and bone marrow aspiration and biopsy are the definitive procedures for investigation of such anemias if serum measurements (iron, iron-binding capacity, vitamin B12 , folate) do not provide an answer. The presence of an elevated reticulocyte count has the opposite implications regarding the cause of the anemia (Color Plate 5 B). Reticulocytosis indicates the presence of a hyperregenerative anemia in which the marrow is able to respond appropriately to the stimulus of anemia. This lesion has its locus in the periphery, with accelerated loss of RBCs from either premature RBC destruction secondary to hemolysis or excessive loss of blood secondary to bleeding. Measurement of the mean corpuscular volume (MCV) of RBCs, a value derived from the electronic Coulter counter, can further define anemias with a low reticulocyte count. Anemia with small, or microcytic, RBCs (MCV, 95 fL) is usually due to abnormalities in nucleic acid metabolism, with vitamin B12 or folate deficiency most commonly responsible (see Chapter 163) . Anemias with RBCs of normocytic size (MCV, 80 to 95 fL) have numerous causes from faulty production to infiltrative disorders; low EPO states also result in normocytic anemias. The early stages of most anemias are also normochromic/normocytic because of continued presence of the original, normal RBC population manufactured before the new pathologic lesion appeared.

BLOOD LOSS ANEMIA The hematologic manifestations of bleeding depend on the interval that separates the acute event from measurement of the hematocrit or hemoglobin concentration. Immediately following an acute bleed, the hematocrit is normal because hemodilution has not yet had time to occur and compensate for any reduction in blood volume. Early evidence of acute blood loss may be apparent only in postural changes in blood pressure and pulse rate. After about 24 hours, volume re-expansion corrects this defect by mobilization of extravascular fluid into the intravascular compartment; the result is a fall in hematocrit that parallels the degree of blood loss. After 3 to 5 days, the reticulocyte count rises to compensate for the anemia; this reticulocytosis may lead to confusion with hemolytic anemia--both acute blood loss and hemolytic anemia are normochromic, normocytic anemias with high reticulocyte counts. The MCV may actually be increased in both conditions because reticulocytes are polychromatophilic macrocytes that may elevate the MCV. The two anemias can be distinguished by the byproducts of accelerated RBC breakdown in hemolytic anemias, in which hyperbilirubinemia is frequently, but not always the marker of hemolysis. Evidence of bleeding is usually clear, but with bleeding into soft tissues or into a body cavity such as the retroperitoneum, resorption of blood may be associated with hyperbilirubinemia; the clinical picture may be confusing until the hematoma extends to the surface as an ecchymosis or a radiographic study identifies retroperitoneal bleeding. The normochromic, normocytic anemias of both hemolysis and acute post-hemorrhagic states are accompanied by leukocytosis and thrombocytosis; these responses represent cytokine stimulation of all cell lines within the marrow in response to the anemia.

OTHER NORMOCYTIC, NORMOCHROMIC ANEMIAS ANEMIA OF CHRONIC RENAL INSUFFICIENCY. Chronic renal failure leads to anemia because of the progressive absence of adequate EPO production in the feedback loop for maintenance of erythropoiesis (see Chapter 104) . No strict correlation exists between the degree of azotemia and the severity of this anemia, although anemia usually supervenes once the creatinine clearance falls below 35 to 45 mL/minute. Many other factors may also contribute to the development of anemia in renal failure. Bleeding may occur from angiomatous malformations that develop in the gastrointestinal tract in uremia, and the hemostatic platelet defect of renal failure may exaggerate this threat. Significant iron loss also occurs as a byproduct of hemodialysis, and folate stores may be compromised by loss of this dialyzable vitamin. Aluminum toxicity interferes with iron metabolism, and a microcytic anemia may develop in patients whose dialysate baths contain high concentrations of this metal. A microangiopathic process often develops with malignant hypertension, and this same RBC lesion is a hallmark of the hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura. A modest shortening of RBC survival occurs as a result of a metabolic lesion incurred from uremia. However, this abbreviated RBC survival is only a very minor contribution to anemia in these states because the uncomplicated anemia of renal disease can be reversed with the administration of EPO. EPO is usually administered three times weekly, either subcutaneously or intravenously, following dialysis treatments. Treatment is initiated with EPO doses of 150 U/kg three times weekly and reduced to 50 to 100 U/kg per dose once the desired response has been obtained. Weekly EPO administration is also effective but requires larger amounts (40,000 U) of the recombinant factor. With EPO therapy, the anemia of renal failure has been largely eliminated. ANEMIA OF LIVER DISEASE. After their release from marrow, RBCs' membranes are remodeled by splenic macrophages, and the lipid constituents of the membrane remain in dynamic equilibrium with plasma lipoproteins. Advanced stages of liver disease are complicated by progressive lipoprotein abnormalities that result in the sequential transformation of normochromic, normocytic RBCs into macrocytes, target cells, echinocytes, and at the final and most severe stage, acanthocytes. Acanthocytes, or spur cells, are converted into spherocytes by the spleen; their lifespan is significantly shortened because the lipid deposition in their membranes interferes with the normal plasticity or deformability of RBCs. In liver disease associated with portal hypertension, hypersplenism may shorten RBC survival even in the absence of any membrane lipid

abnormality. Anemia in liver disease may also have its origin in the several other insults that often accompany hepatic damage. Alcohol, with its effect on folate metabolism, may create a macrocytic, megaloblastic anemia; the same toxin may interfere with heme metabolism and produce a sideroblastic anemia. A metabolic product of alcohol, acetaldehyde is a direct inhibitor of erythropoiesis in vitro. Iron deficiency is also not uncommon in liver disease because of blood loss from varices, alcohol-induced gastritis, and the coagulopathy resulting from defective synthesis of coagulation factors. Wilson disease is associated with hemolytic anemia. ANEMIA OF ENDOCRINE DISORDERS. Dysfunction in hormonal regulation has systemic effects that include the production and survival of RBCs. An anemia, usually normocytic but sometimes macrocytic, accompanies hypothyroidism because of physiologic responses to decreased metabolic needs (see Chapter 239) . Menometrorrhagia occurs frequently in hypothyroidism and can lead to iron deficiency anemia. Erythrocytosis may be a feature of Cushing's disease because of androgen overdrive of the marrow; a reduction in RBC mass occurs in Addison's disease, but anemia is not usually evident because of a concomitant reduction in plasma volume caused by mineralocorticoid deficiency. Hypopituitary states are complicated by mild anemias; growth hormone has a growth-stimulating effect on RBCs. Anemia is not a feature of uncomplicated diabetes mellitus but usually occurs in the course of the disease as renal complications develop. Anemia occurs earlier in diabetic renal disease than in other azotemic states because a poorly documented metabolic lesion shortens RBC survival in uncontrolled diabetes. Severe hemolysis may occur in diabetic ketoacidosis if significant hypophosphatemia appears following insulin treatment. ANEMIA OF STEM CELL FAILURE. Deficiencies of stem cells, as occurs with aplastic/hypoplastic anemias, cause a normochromic, normocytic (sometimes slightly macrocytic) anemia that is usually part of a pancytopenia with attendant leukopenia and thrombocytopenia 855

(see Chapter 160) . Pure red cell aplasia, caused by parvovirus infection of RBC precursors or as a result of humoral or cellular immune mechanisms, may produce a normochromic, normocytic anemia without reticulocytes. Leukemias and lymphomas may replace and inhibit the marrow and cause normochromic, normocytic anemia. ANEMIA OF CHRONIC DISEASE. Most patients with the anemia of chronic disease have normochromic, normocytic RBC indices. The remainder have a mild hypochromic, microcytic anemia (see Chapter 162) . Bain BJ: Pathogenesis and pathophysiology of anemia in HIV infection. Curr Opin Hematol 6:89-93, 1999. Review of the multifactorial causes of anemia in HIV infection.

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Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 162 - MICROCYTIC AND HYPOCHROMIC ANEMIAS Thomas P. Duffy

Hemoglobin synthesis for the needs of normal red blood cell (RBC) production requires an adequate supply of iron and intact metabolic pathways for the generation of heme and globin molecules. Any deficiency in this triad of iron, heme, or globin may result in RBCs with a deficient mean corpuscular hemoglobin concentration. Such hemoglobin-deficient RBCs are usually microcytic with a reduced mean corpuscular volume that is attributable to additional divisions in the RBC maturation sequence in bone marrow in the setting of a low hemoglobin concentration. This combination of small and hypochromic RBCs can be detected on examination of the peripheral smear when the process is advanced and can be confirmed by indices generated from measurements of RBC size by electronic Coulter counters. An emerging population of microcytic RBCs at an early stage of iron deficiency anemia can be recognized by studying the red cell distribution width, in which any small cells constitute a peak separate from RBCs of normal size. Characterization of anemia as hypochromic and microcytic narrows the possible causes of the RBC deficiency to some abnormality in iron, heme, or globin metabolism. Low values for mean corpuscular volume and hemoglobin concentration generated by the electronic counter delimit a small number of possible lesions as the cause of this type of anemia.

IRON DEFICIENCY ANEMIA DEFINITION. Iron, as the core of the hemoglobin molecule responsible for the oxygen-carrying capabilities of blood, is the most precious element within the body; an efficient system of conservation and recycling of this valuable resource serves to guarantee the amount of iron necessary for daily hemoglobin synthesis. Storage depots of iron (as ferritin and hemosiderin) exist within the reticuloendothelial cells of the liver, spleen, and bone marrow and the parenchymal cells of the liver, and these stores are depleted before any restriction in hemoglobin synthesis occurs. Iron deficiency anemia therefore represents the final temporal development in the chronology of progressive iron deficiency within the body. Because this anemia does not supervene until iron stores are mobilized to maintain an optimal hemoglobin mass, absence of iron stores on examination of the marrow is specific confirmation that iron deficiency is contributing to any anemia that is present. PREVALENCE. Iron deficiency is the most common cause of anemia throughout the world and one of the most common medical problems that confronts the general physician. Its geographic distribution is determined by dietary deficiencies and intestinal parasitism, especially in Third World countries; hookworm infection has created the same lesion in the American South. The prevalence of iron deficiency is much higher in women than in men because of the toll of menstruation and pregnancy on the iron stores of women. The expansion of the blood pool that occurs during adolescence also leads to low iron stores that may be further depleted as a result of inadequate dietary intake. The latter factor contributes to the iron deficiency state in many women, even in affluent societies, as they embark on pregnancy. IRON METABOLISM. Mechanisms exist to ensure that the total-body iron content is maintained within a defined range. In specific contrast with other body constituents, control of iron content is imposed by limiting its entrance into the body rather than by increasing the excretion of any excess. Once iron has entered the plasma after absorption from the gastrointestinal tract or from the breakdown of transfused RBCs, it can be removed only by the withdrawal of blood or by the more laborious process of iron chelation therapy. The normal metabolism of iron is strictly weighted in favor of ensuring adequate iron reserves even at the cost of iron overload, which may result in hemochromatosis with organ damage created by the tissue accumulation of elemental iron. The major locus of iron within the body is the center of the hemoglobin molecule within RBCs and as part of the myoglobin molecule in muscle; a smaller fraction is a constituent of important tissue-based enzymes. Storage pools of iron in the form of ferritin and hemosiderin are present within the liver, spleen, and bone marrow. These reserves of approximately 1000 mg in males and 500 mg in females are derived from the breakdown of senescent RBCs within the reticuloendothelial system and from any surplus of absorbed iron beyond that needed for hemoglobin synthesis. The disparity in the size of these stores in men and women is attributable to the previously mentioned demands of menstruation and pregnancy in women. The tiniest compartment of iron within the body is transport iron (7 mg), in which iron travels while linked to the transport protein transferrin. Although transport iron is the smallest compartment, it is kinetically the most active and turns over several times a day as iron is transported to its various destinations within the body. Transferrin picks up iron from the gastrointestinal cells and delivers it primarily to cells engaging in hemoglobin synthesis. Transferrin also picks up iron from the storage depots in the daily recycling of iron stores. This system of conservation and recycling of iron serves to provide a constant supply of iron for the needs (30 to 35 mg) of daily hemoglobin synthesis. Only a tiny fraction of iron (1 mg) is lost each day via the pathway of sweating and epidermal shedding from the gut and urinary tract; this minuscule amount can easily be replaced from the food in a normal diet. The major source of iron for hemoglobin synthesis is derived from the breakdown of RBCs, which after survival for 90 to 120 days in peripheral blood, undergo phagocytosis by splenic macrophages; the iron released from these senescent RBCs is immediately available for the needs of hemoglobin synthesis, with the excess stored as ferritin and hemosiderin. The vector of iron transport is always in the direction of providing iron to fulfill the body's needs in maintaining an optimal RBC mass. ABSORPTION. The normal diet in the United States contains approximately 15 to 30 mg of iron each day, with every thousand calories in the diet containing about 6 mg of elemental iron. Iron is present in food as a portion of the heme ring in meats and in a less easily absorbable form as ferric hydroxide complexes in other foods. The acid environment of the stomach and its enzymatic secretions emulsify ingested food and liberate iron for absorption within the small intestine; pancreatic secretions counter this acidic pH and help control excessive absorption of iron. Iron must be in the reduced or ferrous form to be absorbed. Ingestion of reducing substances such as ascorbate or succinate enhances iron absorption because of their effect on iron valence. Other substances such as phytates in cereals, tannates in tea, antacids, and certain antibiotics (tetracycline) may complex with iron and thereby hinder its absorption. Maximal absorption of iron occurs in the duodenum and upper portions of the jejunum. Malabsorptive states or bypass of these areas by gastrojejunostomy may contribute to iron deficiency. Iron absorption can be adjusted over a broad range according to the body's needs. In normal health, the body must guard itself against iron overload by absorbing only one tenth of the iron available in the diet. The mechanism whereby such a limitation or "mucosal curtain" is imposed on iron absorption is still not defined; it appears to be regulated by some aspect of dynamic iron turnover 856

because hemolytic anemias, ineffective erythropoiesis, and hypoxemic states all have increased iron turnover and are all associated with increased iron absorption. The mucosal curtain is lowered by imposing a limit on the amount of iron that crosses the gastrointestinal membranes. Whatever iron is not needed by the body is diverted into storage molecules within gastrointestinal mucosal cells; this iron is lost from the body as these cells are exfoliated during the normal cycle of cell turnover. In the presence of iron deficiency, the body can increase its absorption efficiency at least five-fold to compensate easily and rapidly for any deficiency. In iron deficient states, in which iron needs are exaggerated, little iron is diverted to the storage form and the majority of the absorbed iron passes directly through the cells for plasma transport linked to transferrin. Failure to lower this mucosal curtain properly is thought to be the explanation for iron accumulation in primary hemochromatosis; such patients continue to absorb iron even in the face of total-body iron overload. Increased iron absorption also occurs with pancreatic insufficiency because of absence of the pH alteration contributed by normal pancreatic secretions; absence of this restraint on iron absorption explains in part the iron overload that often occurs in chronic alcoholic states. TRANSPORT. Transferrin, a glycoprotein with a molecular weight of approximately 80,000, is produced by liver parenchymal cells in inverse proportion to the iron stores within these cells. This matching of transferrin production to iron needs explains in part the elevated transferrin levels or iron-binding capacity that characterizes iron deficiency. Transferrin can bind one or two molecules of ferric iron, a process accompanied by the simultaneous attachment of an equal number of bicarbonate ions; the latter molecules facilitate the uncoupling of iron from the binding protein. Transferrin binding of iron protects the body against the toxicity of elemental iron and increases the solubility of this molecule within plasma. Transferrin receptors are present on the surface of developing RBCs in direct proportion to their potential for hemoglobin synthesis. Transferrin-bound iron links to these receptors, and the complex enters the RBC by endocytosis; dissociation of the complex occurs following a pH alteration in the vesicle. Iron is released to enter the cycle of heme synthesis, and transferrin leaves the cell to scavenge for other iron molecules. Transferrin is measured in the plasma by quantifying the amount of iron binding sites available, a measurement called the total iron-binding capacity of plasma. Under normal circumstances, total iron-binding capacity is only one third saturated, with the total amount of transferrin within the plasma being approximately 300 mg/dL. Iron levels vary diurnally, with the highest levels present in the morning; normal iron levels are usually within 60 to 180 mg/dL. A small amount of iron is also present in plasma in the form of the storage molecule ferritin, with the concentration of this molecule generally mirroring the stores of iron within the marrow. Iron also complexes with lactoferrin, which is an iron-binding protein liberated from neutrophilic granules and which is thought to play a role in defense against infection. Lactoferrin rapidly sequesters iron in reticuloendothelial cells, thereby depriving microorganisms of iron, which is an essential growth factor for most microorganisms. IRON KINETICS. Ferrokinetic measurements using radiolabeled iron-59 can quantify iron absorption, the marrow transit time of iron, and plasma and erythrocyte iron turnover. These studies permit in vivo localization of any defect in the uptake, transport, or delivery of iron; such measurements are now primarily investigative tools that are not used in routine clinical situations. PATHOGENESIS. Conservation and recycling of iron within the body provide an excellent buffer to fulfill the daily needs of iron for hemoglobin synthesis. Iron deficiency anemia occurs only after an extended period of negative iron balance, a period during which the storage pool is exhausted of its reserves. Although this depletion may result from decreased ingestion or absorption of iron, the most common causes of iron deficiency are blood loss from lesions in the gastrointestinal tract or from the demands of menstruation and pregnancy. DECREASED IRON UPTAKE.

To maintain iron balance within the body, the adult male needs to absorb only 1.0 to 1.5 mg of iron each day, whereas an adult female needs to absorb a larger amount (2 to 3 mg) because of the iron losses from menstruation. Each milliliter of blood contains approximately 0.4 mg of iron, so the monthly menstrual loss of approximately 60 mL creates the need for an additional 20 to 30 mg of iron absorption each month. Pregnancy, with its expansion of the maternal blood pool and additional needs for fetal hemoglobin synthesis, frequently overwhelms an already-marginal iron storage pool and requires supplemental iron as a prophylactic measure against the development of frank anemia. Because the iron-calorie ratio of the normal U.S. diet is 6 mg iron for every 1000 calories, males usually have no shortage of dietary iron; the restricted diets of some women may not provide a comparable surfeit and may give rise to an iron deficiency state without frank anemia. Diet-related iron deficiency may be aggravated by gastric achlorhydria, with its negative effect on iron absorption, but achlorhydria alone rarely causes iron deficiency anemia. Gastrojejunostomies and sprue may both result in iron deficiency as a result of loss of the necessary mucosal surface and/or increased intestinal transit time. The anemia seen with gastrojejunal bypass procedures has anastomotic mucosal lesions, with blood loss from these ulcerated sites as the principal cause of iron deficiency. The modern shift to non-iron-containing cooking utensils has eliminated this rich source of iron from the diet. The popularity of vegetarian diets may also lessen the amount of dietary iron. A vicious cycle may occur in which patients with iron deficiency acquire an appetite for bizarre foods. This phenomenon, pica, is the only known example of a compulsive appetite or behavior created by the lack of a normal body element. Its victims may ingest clay (geophagia), which in turn may potentiate the problem by chelating iron within the gut, ice (pagophagia), or starch (amylophagia). Iron replacement corrects the problem, which may or may not be accompanied by anemia. INCREASED IRON LOSS.

The most common cause of iron deficiency anemia in both men and women is blood loss; this loss most frequently has its source in gastrointestinal bleeding in the former and menstrual bleeding in the latter. The implication of the discovery of iron deficiency anemia in men and postmenopausal women is the same; the gastrointestinal tract harbors the causal lesion until proved otherwise (see Chapter 123) . Even in the absence of occult blood in the stool or a history of melena, it is still imperative to examine the gastrointestinal tract because of its frequent involvement when iron deficiency is present. Iron deficiency may be the initial manifestation of an otherwise occult carcinoma of the gut, with right-sided colon tumors not infrequently having this clinical picture. Multiple other gastrointestinal lesions, such as large hiatal hernias, ulcer disease, inflammatory bowel disease, or angiodysplasias, may all be characterized by iron deficiency. Ingestion of aspirin and non-steroidal anti-inflammatory agents, often in the treatment of arthritic conditions, may be complicated by gastrointestinal blood loss. Less common causes of excessive iron loss include urinary tract bleeding and renal filtration of hemoglobin released from the breakdown of RBCs; individuals with mechanical heart valves may have traumatic rupture of RBCs as they flow across the artificial surfaces of these valves. Pulmonary sequestration of iron also occurs following some pulmonary hemorrhagic states, with no mechanism available to the body to recapture this closeted iron. The stores of iron may also be depleted by frequent blood donations. CLINICAL MANIFESTATIONS. Iron deficiency anemia is characterized by a degree of fatigue that may be disproportionate to the apparent severity of the anemia, apparently because of depletion of essential tissue-based iron-containing enzymes with an attendant reduction in energy generation by muscle. Transfusion of RBCs to correct this anemia reverses the symptoms only in part; iron repletion is the definitive treatment for this fatigue. Iron deficiency has several characteristic clinical manifestations, but all of them are rare relative to the high incidence of this condition. A sore tongue (glossitis), atrophy of the lingual papillae, and erosions at the corners of the mouth (angular stomatitis) are oral manifestations of iron deficiency; atrophy of the gastric mucosa with achlorhydria is a further extension of the same process. An atrophic rhinitis with a foul nasal discharge (ozena) may progress to anosmia in iron-deficient individuals. A greenish hue to the complexion (chlorosis) is an accompaniment of the same deficiency, especially in adolescent girls in Victorian literature. Brittle, 857

fragile fingernails and spooning of the nails (koilonychia) are peripheral clues to the disorder.

Dysphagia, attributable to an esophageal web, occurs most frequently in elderly women with iron deficiency; this lesion, the Plummer-Vinson or Paterson-Kelly syndrome, may later be complicated by the development of esophageal carcinoma. The web may not disappear with iron replacement, and such patients may require dilatation for relief of symptoms. Splenomegaly has been described as an accompaniment of iron deficiency, although an independent or concomitant thalassemia trait may be the true cause of the enlargement. Pseudotumor cerebri has also been described as a very rare accompaniment of iron deficiency. LABORATORY FINDINGS. The laboratory findings in full-blown iron deficiency anemia include a reduction in all three parameters (mean corpuscular volume, hemoglobin, hemoglobin concentration) that are generated from the Coulter counter. In contrast, early iron deficiency anemia has normochromic, normocytic indices because the iron-deficient population of RBCs constitutes only a small percentage of the RBC mass. Only when the hematocrit falls below 31 to 32% do the RBC indices become microcytic; a normochromic, normocytic anemia is therefore the earliest form of anemia with iron deficiency. Coulter counter indices and an elevation of the automated platelet count have generally replaced examination of peripheral blood smears (Color Plate 5 D) in the recognition of hypochromia and microcytosis in iron deficiency. Serum iron and transferrin (total iron-binding capacity) levels help confirm the diagnosis of iron deficiency, with a low serum iron and an elevated transferrin level resulting in a transferrin saturation of less than 10 to 15%. Transferrin levels are increased in iron deficiency states because of increased hepatic synthesis of the protein and greater liberation of apotransferrin (the transport protein without iron) from hemoglobin-synthesizing sites. Serum transferrin receptor levels are also increased in iron-deficient states, and their measurement is a possible, but usually unnecessary means of making a diagnosis of iron deficiency. A low iron level is not in itself diagnostic of iron deficiency because many other systemic insults can alter the serum level of iron. Ferritin levels also permit recognition of iron deficiency, with a reduction in this serum protein to less than 10 ng/mL in uncomplicated iron deficiency. The final step in heme synthesis is the incorporation of iron into a protoporphyrin ring; deficient delivery of iron to red cells results in elevated levels of free erythrocyte protoporphyrin as an additional marker of iron-deficient erythropoiesis. Diagnosis of iron deficiency is usually possible by using the combination of RBC indices and serum measurement of transferrin saturation or ferritin levels. However, because both these levels are altered by perturbations as varied as infection, inflammation, malignancy, and starvation, bone marrow iron stores remain the final arbiter when any uncertainty exists regarding the presence of iron deficiency; the marrow is devoid of macrophage iron, and fewer than 10% of the RBC precursors contain siderotic granules. Absence of iron stores categorically confirms the presence of iron deficiency and serves as the gold standard for making the diagnosis. Serum transferrin receptor levels also help serve to discriminate iron deficiency from the anemias of chronic disease. TREATMENT. Recognition and treatment of iron deficiency anemia require the identification and reversal, if possible, of its cause; the anemia is a critical sign of an underlying lesion that may be as benign as aspirin ingestion or as threatening as an occult malignancy. Treating the anemia without identifying its cause may mean loss of the only opportunity to discover a malignancy at a potentially curable stage. Treatment of iron deficiency anemia is made somewhat difficult by the frequent induction of nausea, dyspepsia, constipation, and diarrhea by medicinal iron. These symptoms are usually proportional to the iron content of the prescribed oral iron preparation; the most commonly administered preparation is ferrous sulfate tablets, 300 mg, which contain 60 mg of elemental iron in each tablet. The drug is best absorbed on an empty stomach, but it is frequently prescribed with meals so that it is better tolerated. Most patients tolerate starting with once-daily dosing and escalating to a final dose of three times daily. Persistent intolerance can be addressed by switching to ferrous gluconate, but its lower elemental iron content requires a longer period of iron administration to correct the deficiency state; charting serum ferritin levels permits the ascertainment of adequate replacement with either preparation. Innumerable iron preparations are marketed, but there is little to recommend these preparations over the cost-effective ferrous sulfate pills. Although ascorbate and succinate enhance the absorption of iron, the addition of these agents to iron preparations is costly and unnecessary in light of the body's efficiency in iron absorption under normal circumstances. Enteric-coated iron tablets may actually be contraindicated because the coating may shield against absorption in the upper portions of the small intestine, where maximal iron absorption takes place. Liquid iron preparations may be better tolerated by some patients and better absorbed in patients with gastrojejunostomies or rapid intestinal transit times; because iron salts can stain the teeth, iron solutions should be ingested through a straw. At the time that iron therapy is initiated, a baseline reticulocyte count and ferritin level should be obtained. With iron replacement, the symptoms of fatigue and lassitude improve in the first week, but maximal reticulocytosis does not occur for 7 to 10 days. The hemoglobin level does not rise for 2 to 2.5 weeks, and it requires about 2 months of daily iron therapy for the hemoglobin level to return to normal. Measurement of ferritin levels determines when iron stores have been reconstituted and when iron therapy should be discontinued; return of ferritin levels to normal documents that iron stores have been restocked. In the rare patient who cannot tolerate or cannot absorb iron from the gastrointestinal tract and in individuals who require large iron boluses to compensate for chronic blood loss, parenteral iron is available as an iron-dextran complex; it should be used with restraint because of the threat of acute anaphylaxis and subacute (arthralgias, myalgias, and adenopathy) side effects. This parenteral preparation can be administered intramuscularly or intravenously, with the latter preferred because the total dose can be delivered in a single administration. No more than 2 mL of Imferon, which contains 50 mg iron per milliliter, can be administered at a single intramuscular site; staining of the skin may occur even though the recommended Z-track injection technique is used. A small test dose (0.25 mL) of the drug should be administered before intramuscular or intravenous injections to determine hypersensitivity to the agent. The dose to be infused for correction of iron deficiency can be calculated according to the following formula:

This total dose can be diluted in normal saline at a 1:20 dilution and infused slowly over several hours while watching for any side effects. PROGNOSIS. The prognosis in iron deficiency anemia is strictly related to the underlying cause of the anemia. Iron deficiency per se does not usually alter the prognosis because it is easily treated once recognized. The importance of the diagnosis is recognition of the need to identify the underlying cause of the condition and correct this lesion so that the anemia does not recur.

HYPOCHROMIC ANEMIAS NOT CAUSED BY IRON DEFICIENCY Because characterization of an anemia as hypochromic restricts its cause to some abnormality in iron, heme, or globin metabolism, the elimination of iron deficiency as its cause narrows the choices to these other components of hemoglobin metabolism. Abnormalities in globin chain synthesis, the thalassemias, are a more prominent consideration when hypochromic anemia occurs in the appropriate ethnic groups (see Chapter 167) . The sideroblastic anemias are iron-loading anemias caused by abnormalities in heme synthesis; a clue to their presence is nearly total saturation of serum transferrin levels, a striking departure from the findings in iron deficiency. Confirmation of the diagnosis requires bone marrow documentation of ringed sideroblasts, the pathognomonic lesion in this condition. THE ANEMIA OF CHRONIC DISEASE. Although iron deficiency is the most common anemia in general, anemia of chronic disease 858

is the most common anemia in hospitalized patients. This condition represents a shared hematologic response to systemic insults as varied as infection, inflammation, malignancy, and trauma. The anemia is moderate in degree, with the hematocrit usually in the range of 28 to 32%. The morphology is normochromic/normocytic in 60 to 70% of such patients, with the remainder having a mild hypochromic microcytic anemia. Hypoferremia is characteristic of anemia of chronic disease in the face of marrow iron overload. Confusion of anemia of chronic disease with iron deficiency anemia results from the overlapping of microcytosis and hypoferremia in both disorders. In anemia of chronic disease, the lesion includes deficient delivery of iron to developing RBCs, in addition to other derangements in RBC production.

ETIOLOGY AND PATHOGENESIS.

At least three different pathophysiologic mechanisms contribute to anemia of chronic disease, an anemia that develops within a few weeks of the onset of systemic disease and is independent of any marrow involvement or specific hematologic complication of the systemic disease. Accelerated RBC breakdown, abnormalities in iron mobilization and delivery, and cytokine inhibition of erythropoiesis have all been implicated to various degrees. A modest shortening of RBC survival is noted, probably resulting from extravascular sequestration by a stimulated reticuloendothelial system. The degree of hemolysis in anemia of chronic disease is modest, and failure of the host to mount an appropriate reticulocyte response to compensate for the anemia indicates that a hypoproliferative defect rather than hemolysis is the major lesion. Iron studies reveal low serum iron and transferrin levels in anemia of chronic disease, in contrast to the elevated transferrin levels in iron deficiency. Nevertheless, the transferrin saturation levels in anemia of chronic disease may overlap with those of iron deficiency, further adding to the confusion of these two entities. Anemia of chronic disease is a sideropenic anemia in the face of reticuloendothelial iron overload: both serum ferritin levels and bone marrow iron stores are increased in anemia of chronic disease. The cause of the hypoferremia in anemia of chronic disease is not strictly defined. The disproportionate incorporation of iron into ferritin in storage depots may explain ferritin elevation as an acute-phase reactant in all the conditions associated with anemia of chronic disease. Another explanation for the hypoferremia in this type of anemia is a form of nutritional deficiency because microorganisms and malignancies require iron for growth and proliferation. In the face of infection and malignancies, normal iron metabolism is subverted to bolster the body's defenses against these assaults; lactoferrin, the product of polymorphonuclear leukocytes, redirects the vector of iron delivery away from RBCs, which lack lactoferrin receptors, to cells of the reticuloendothelial system. Malignancies may themselves alter the vector of iron delivery because many tumors contain siderophores, which are molecules that can effectively extract iron from the surrounding plasma. This closeting of iron explains the fall in serum iron in anemia of chronic disease, although hypoferremia is unlikely to be the primary cause of the anemia. Administration of iron to such patients does not correct the anemia and is not indicated in its management. The hypoferremia is considered an advantage to the body in restraining bacterial or tumor cell growth; the anemia is the cost of the body's defense against invasion. Elevated ferritin production and lactoferrin linkage are not the only factors causing hypoferremia in patients with anemia of chronic disease; the low serum iron level is now thought to be only part of a more generalized response to infection, malignancy, or inflammation. These systemic threats to the body start a cascade of cytokines initiated by interleukin-1 release from macrophages. Anabolic and catabolic responses result, with an elevation in acute-phase reactants (C-reactive protein, haptoglobin, ceruloplasmin, fibrinogen, ferritin) and a reduction in serum iron and hematocrit levels. Playing an important role in the production of anemia is the liberation of tumor necrosis factor, or cachectin, a product of macrophages and part of the cytokine network. Injection of these substances creates the anorexia, debilitation, and weight loss of chronic disease and also inhibits the growth of erythroid precursor cells; anemia of chronic disease represents "cachexia" of the marrow, a sharing by marrow in the defense of the body against the threat of infection, malignancy, or inflammatory disorders. CLINICAL MANIFESTATIONS.

Anemia of chronic disease is not itself usually a cause of symptoms. The anemia is mild and well tolerated unless it is superimposed on other threatening conditions. The importance of recognizing anemia of chronic disease is in identifying its underlying cause. This type of anemia is not infrequently the initial evidence that otherwise occult disease is present. DIAGNOSIS.

Anemia of chronic disease is a moderate (hematocrit, 28 to 32%), normochromic, normocytic anemia that supervenes during the early course of disorders as diverse as malignancy, infection, inflammation, or trauma. Iron indices usually reveal hypoferremia and a reduced iron-binding capacity. Confusion occurs with iron deficiency anemia because microcytic anemia occurs in 30 to 40% of such cases and transferrin saturation may be reduced to levels seen in iron deficiency. Serum ferritin and serum transferrin receptor levels help distinguish iron deficiency from anemia of chronic disease. Iron deficiency states have elevated serum transferrin receptors relative to a marked lowering of ferritin levels; anemia of chronic disease is characterized by an elevation in ferritin levels, usually greater than 100 ng/mL. When both iron deficiency and anemia of chronic disease are present, as occurs in some patients with rheumatoid arthritis, elevated serum transferrin receptor levels permit recognition of iron deficiency that would otherwise be masked by the alterations in iron/transferrin levels in the anemia of chronic disease. Bone marrow iron stores also distinguish the two because of the presence of marrow iron in anemia of chronic disease; iron deficiency anemia is the only cause of hypochromic, microcytic RBCs in which iron stores are absent from the marrow. TREATMENT.

Anemia of chronic disease is a secondary manifestation of an underlying disorder, and its successful reversal requires recognition and correction of that disorder. Although hypoferremia is present, iron therapy does not correct the anemia and contributes to the usual iron overload in this condition. Blood transfusions are frequently not necessary because the anemia is modest and usually well tolerated. Because anemia of chronic disease results from a cytokine-induced hypoerythropoietin state, the defect can be overridden with erythropoietin administration; however, erythropoietin is commonly not appropriate because anemia of chronic disease is not usually severe. SIDEROBLASTIC ANEMIAS. Sideroblastic anemias, which are uncommon causes of hypochromic anemia, have their origins in altered production of the heme component of the hemoglobin molecule. The final step in heme synthesis involves the incorporation of iron into the protoporphyrin ring, which is synthesized in and around the mitochondria of developing RBCs. Any defect in the multistep generation of protoporphyrin creates a mismatch between iron delivery and iron incorporation into heme. This mismatch results in iron overloading of the mitochondria because heme, the feedback inhibitor of further RBC iron uptake, is deficient. Cells are designated "ringed" sideroblasts when the iron-laden mitochondria occupy a perinuclear distribution within the developing RBCs; Prussian blue staining of the RBCs within the marrow demonstrates these siderotic granules surrounding the nucleus (Color Plate 6 E). The siderotic granules of normal siderocytes are fewer in number and are distributed throughout the cytoplasm of the cell. Mitochondrial accumulation of iron is what distinguishes the sideroblastic anemias. A clue to the presence of these anemias is the paradoxical finding of hyperferremia and nearly total transferrin saturation in a patient with a hypochromic anemia. The hypochromia has its origin in deficient protoporphyrin ring synthesis, which leads to less hemoglobin in affected cells. PATHOGENESIS AND CLASSIFICATION.

Protoporphyrin ring synthesis is a multistep process that depends on several sequential enzymatic reactions occurring in and around the surface of cell mitochondria. A lesion at any stage in this sequence, whether caused by an enzymatic deficiency or an abnormality in mitochondrial structure or function, may result in faulty protoporphyrin synthesis. These lesions may occur as inherited or acquired defects in the pathway. The inherited forms have both mitochondrial and nuclear genetic mutations as their cause. As with disturbances in other metabolic pathways within the body, drugs and toxins are the major causes of acquired sideroblastic anemia; a less common form of acquired sideroblastic anemia exists as a clonal disorder that is a subgroup of the myelodysplasias. The primary lesion in sideroblastic anemia results in a mismatch between iron delivery and its incorporation into heme. The unincorporated 859

iron accumulates in the mitochondria and damages these critical organelles. Such iron loading of the mitochondria further contributes to ineffective erythropoiesis. In some patients, cautious phlebotomy may improve the anemia by unloading iron from the mitochondria and correcting this secondary lesion. The morphologic evidence for the sideroblastic process in peripheral blood is a population of hypochromic RBCs. Transferrin levels are saturated, and ferritin levels are increased, although not usually to the same degree as in hemochromatosis. Rare RBCs containing siderotic granules, or Pappenheimer bodies, may also circulate in the peripheral blood. The diagnosis of sideroblastic anemia is confirmed by the presence of ringed sideroblasts within marrow stained for iron: these forms are nucleated RBCs with a perinuclear collection of iron granules. ACQUIRED SIDEROBLASTIC ANEMIA.

Idiopathic Refractory Sideroblastic Anemia.

A hypochromic anemia, frequently with slightly macrocytic (rather than microcytic) indices, develops in elderly individuals as a predominantly erythroid manifestation of a myelodysplastic syndrome (see Chapter 175) The RBC population is often dimorphic, with a varying proportion of hypochromic and normochromic cells; the hypochromic cells have their origin in a clonal population of ringed sideroblasts within the marrow. The cause of the disorder is not known, although its occurrence following chemotherapy suggests that damage to the chromosomal material responsible for normal erythroid development creates this picture. The lesion is chronic and may remain restricted to the erythroid line with ineffective erythropoiesis in addition to the defect in heme synthesis. The lesion may also evolve into leukemia, but with no firm predictors of whether or when this transition will occur (see Chapter 177) . Common antecedents to leukemia transformation are an associated leukopenia, especially when accompanied by leukocyte developmental abnormalities (pseudo-Pelger-Huet anomaly) and alterations in platelet number (Color Plate 5 L). Treatment of the disorder remains experimental. Pharmacologic doses of pyridoxine, a vitamin necessary for the initial step in heme synthesis, usually have no benefit; androgens and erythropoietin are also rarely helpful. The process may be very chronic, with no need for RBC transfusion until late in its course, but prolonged support with RBC transfusions may lead to secondary hemochromatosis and require chelation therapy with deferoxamine. Sideroblastic anemia may be discovered in the setting of a large variety of medical conditions, including rheumatoid disease, malignancies, and endocrine disorders. The relation to these disorders is probably not causal because treatment or correction of the underlying disorder does not correct the anemia. It is more likely that the medical condition serves to unmask an otherwise undetected anemia. Sideroblastic Anemia Associated with Drugs or Toxins.

Consumption of large amounts of alcohol over a several-week period can induce sideroblastic anemia in the absence of any concomitant vitamin deficiency. The lesion is thought to have its origin in alcohol's interference with pyridoxine metabolism and its essential role as a coenzyme in the delta-aminolevulinic acid synthase step in porphyrin synthesis. Alcohol is also a mitochondrial toxin, and the anemia may be related to damage to mitochondrial function. In alcoholics with sideroblastic anemia, the marrow lesion persists for 7 to 10 days following the withdrawal of alcohol. Other insults to this metabolic pathway include lead, chloramphenicol, and several antituberculous drugs. All these agents interfere with the initial step in protoporphyrin ring synthesis, with lead also hindering a second site where heme synthetase catalyzes the incorporation of iron into the heme ring in the final step in this pathway. HEREDITARY SIDEROBLASTIC ANEMIAS.

Hereditary sideroblastic anemia is most commonly a moderate to severe hypochromic, normocytic anemia inherited in a sex-linked recessive fashion. A point mutation resulting in an amino acid change near the pyridoxal phosphate binding site of the erythrocytic delta-aminolevulinic acid synthase isoenzyme is the underlying defect in kindreds with this disorder. The anemia does not usually become evident until early adulthood and responds to varying doses of pyridoxine, which are usually much larger than the daily requirements for this vitamin. Mitochondrial cytopathies may also be responsible for congenital disorders when a sideroblastic anemia is linked to pancreatic, liver, and kidney dysfunction, as in Pearson's syndrome. These rare syndromes affect infants and are thought to be due to inherited mutations in mitochondrial DNA that result in defective oxidative phosphorylation in the involved organs. Fitzsimons EJ: The molecular basis of the sideroblastic anemias. Curr Opin Hematol 3:167, 1996. A comprehensive review. North M, Dallalio G, Donath AS, et al: Serum transferrin receptor levels in patients undergoing evaluation of iron stores: Correlation with other parameters and observed versus predicted results. Clin Lab Haematol 19:93, 1997. Documents the value of serum transferrin levels. Weiss G: Iron and anemia of chronic disease. Kidney Int Suppl 69:S12, 1999. Reviews role of cytokines and acute-phase reactants. Worwood M: The laboratory assessment of iron status--An update. Clin Chim Acta 259:3, 1997. An excellent review.

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Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 163 - MEGALOBLASTIC ANEMIAS Robert H. Allen

DEFINITION Megaloblastic anemias are caused by various defects in DNA synthesis that lead to a common set of hematologic abnormalities of bone marrow and peripheral blood. The term megaloblastic refers to a morphologic abnormality of cell nuclei that is readily recognizable but difficult to describe. The erythrocytic, granulocytic, and megakaryocytic cell lines are all involved, and pancytopenia may develop. Recognition of megaloblastic anemia is important because two of its most common causes, cobalamin (vitamin B12 ) deficiency and folate deficiency, are completely corrected with appropriate therapy. Recognition of cobalamin deficiency is of particular importance because it also causes a wide variety of neurologic and psychiatric abnormalities that are preventable or reversible if the diagnosis is made at an early stage.

ETIOLOGY Etiologic categories of megaloblastic anemia are cobalamin deficiency, folate deficiency, drugs, and miscellaneous causes, including rare enzyme deficiencies and unexplained disorders (Table 163-1) . The etiology of cobalamin deficiency can be subdivided into causes of decreased ingestion, impaired absorption, or impaired utilization of the vitamin. Folate deficiency can also be caused by decreased intake, impaired absorption, or impaired utilization or by a number of conditions with an increased requirement for folic acid or an increased loss of folic acid. Drugs causing megaloblastosis can be categorized as those that are purine or pyrimidine antagonists and those that inhibit some other aspect of DNA synthesis. The miscellaneous category includes enzyme defects and some cases of myelodysplastic syndrome and acute leukemia. It is important to determine the correct etiologic factor in megaloblastic anemia. For example, if a myelodysplastic syndrome is misdiagnosed in a cobalamin-deficient patient, chemotherapy might result in the early death of a patient who could have been completely cured with cobalamin therapy. Similarly, some causes of cobalamin and folate deficiency require therapy for the underlying disease, in addition to replacement therapy with the appropriate vitamin.

INCIDENCE AND PREVALENCE COBALAMIN DEFICIENCY. The term pernicious anemia, often used as a synonym for cobalamin deficiency, should be reserved for conditions in which a gastric mucosal defect results in insufficient intrinsic factor to facilitate the absorption of physiologic amounts of cobalamin. This lack of intrinsic factor, which is by far the most common cause of cobalamin deficiency in the Western hemisphere, occurs in individuals as early as their 20s and can develop in all ethnic groups. Chemically recognized pernicious anemia 860

CATEGORY

TABLE 163-1 -- ETIOLOGIC CLASSIFICATION OF THE MEGALOBLASTIC ANEMIAS ETIOLOGIC MECHANISMS

I. Cobalamin deficiency A. Decreased ingestion

Poor diet, lack of animal products, strict vegetarianism

B.Impaired absorption

1. Failure to release cobalamin from food protein Old age Gastrectomy (partial) 2. Intrinsic factor deficiency Pernicious anemia Gastrectomy (total) Destruction of gastric mucosa by caustics Congenital abnormal or absence of intrinsic factor molecule 3. Chronic pancreatic disease 4. Competitive parasites Bacteria in diverticula of bowel, blind loops Fish tapeworm infestations ( Diphyllobothrium latum) 5. Intrinsic intestinal disease Ileal resection, Crohn's disease, radiation ileitis Tropical sprue, celiac disease Infiltrative intestinal disease (e.g., lymphoma, scleroderma) Drug-induced malabsorption Congenital selective malabsorption (Imerslund-Graesback syndrome)

C.Impaired utilization

Congenital enzyme deficiencies Lack of transcobalamin II Nitrous oxide administration

II. Folate deficiency A. Decreased ingestion

Poor diet, lack of vegetables Alcoholism Infancy

B. Impaired absorption

Intestinal short circuits

Tropical sprue, celiac disease Anticonvulsants, sulfasalazine, other drugs Congenital malabsorption C. Impaired utilization

Folic acid antagonists: methotrexate, triamterene, trimethoprim, pyrimethamine, ethanol Congenital enzyme deficiencies

D. Increased requirement

Pregnancy, infancy Hyperthyroidism Chronic hemolytic disease Neoplastic disease, exfoliative skin disease

E. Increased loss III. Drugs-- metabolic inhibitors

Hemodialysis Purine synthesis: methotrexate, 6-mercaptopurine, 6-thioguanine, azathioprine Pyrimidine synthesis: methotrexate, 6-azauridine Thymidylate synthesis: methotrexate, 5-fluorouracil Deoxyribonucleotide synthesis: hydroxyurea, cytosine arabinoside

IV. Miscellaneous A. Inborn errors

Lesch-Nyhan syndrome Hereditary orotic aciduria Others

B. Unexplained disorders

Pyridoxine-responsive megaloblastic anemia Thiamine-responsive megaloblastic anemia Some cases of myelodysplastic syndrome Some cases of acute myelogenous leukemia

will develop in about 1.0% of individuals in the United States at some time during their lives. Approximately 10% of the U.S. population older than 70 years have low or low-normal serum cobalamin levels and metabolic evidence of cobalamin deficiency (elevated levels of serum methylmalonic acid and homocysteine that fall to normal with cobalamin therapy). The etiology and hematologic and neuropsychiatric significance of these findings are unknown at the present time, although there is increasing evidence of a strong correlation between serum homocysteine levels and all forms of vascular disease. FOLATE DEFICIENCY, DRUGS, AND OTHER CAUSES. The incidence of folate deficiency and drug-related megaloblastic anemia is less well established. Through its association with alcoholism, folate deficiency is far from a rare condition. The marked increase in the use of chemotherapeutic agents to treat malignant disease and immune disorders suggests that these drugs may now be the most common cause of megaloblastic anemia in the Western hemisphere.

PATHOGENESIS AND PATHOLOGY MECHANISM OF MEGALOBLASTOSIS. FOLATE DEFICIENCY.

Folate functions to transfer one-carbon units, such as methyl, methylene, and formyl groups, to various substrates in a variety of enzymatic reactions that are intimately related to the synthesis of DNA, RNA, and proteins. In folate deficiency, all forms of folate are reduced within cells, which impairs the growth and maturation of rapidly growing cells such as those in the bone marrow. For example, thymidylate synthase catalyzes the synthesis of thymidine from deoxyuridine and 5,10-methylenetetrahydrofolate. Inhibition of thymidylate synthase leads to increased intracellular concentrations of deoxyuridine triphosphate, which is incorporated into DNA in positions that normally arise from deoxythymidine triphosphate. Attempts to repair this abnormal DNA increase DNA fragmentation, which may play a major role in causing the abnormalities of cell growth and maturation that are present in folate deficiency. COBALAMIN DEFICIENCY.

Cobalamin functions as an essential cofactor for only two enzymes in human cells, methionine synthase and L-methylmalonyl coenzyme A (CoA) mutase (Figs. 163-1 and 163-2) . Methionine synthase catalyzes the recycling of homocysteine to methionine; this reaction requires 5-methylcobalamin as a coenzyme (see Fig. 163-1) . Methionine, an essential amino acid for protein synthesis, also serves in the form of S-adenosylmethionine as the major methyl donor in numerous important enzymatic reactions. In cobalamin deficiency, increasing amounts of intracellular folate are converted to 5-methyltetrahydrofolate in an attempt to prevent intracellular methionine deficiency. The "trapping" of intracellular 861

Figure 163-1 Reaction catalyzed by methionine synthase that requires methylcobalamin (Methyl-Cbl) and transfers the methyl group of 5-methyltetrahydrofolate (CH3-tetrahydrofolate) to homocysteine to form methionine and tetrahydrofolate. Homocysteine accumulates in cobalamin deficiency because of a lack of methylcobalamin and in folate deficiency because of a lack of 5-methyltetrahydrofolate.

folate as 5-methyltetrahydrofolate is augmented by the fact that this substance is the major component of plasma folate and is the form that enters cells and must be converted to tetrahydrofolate by methionine synthase before it can enter the folate pool. Thus cobalamin deficiency results in secondary intracellular deficiency of all forms of folate except 5-methyltetrahydrofolate. As a result, the activities of all of the enzymes using folate to transfer one-carbon moieties, including thymidylate synthase, are impaired. This concept of "methylfolate trapping" explains why cobalamin deficiency and folate deficiency produce indistinguishable hematologic abnormalities and why the hematologic abnormalities seen in cobalamin deficiency can be completely reversed by pharmacologic amounts of folic acid. The latter oxidized, non-physiologic form of folate can be directly reduced to tetrahydrofolate without initially being converted to 5-methyltetrahydrofolate. This concept also explains why the hematologic abnormalities caused by folate deficiency respond only slightly, if at all to large amounts of cobalamin. DRUGS AND OTHER CAUSES.

Drugs cause megaloblastic anemia by inhibiting a variety of enzymes involved in DNA synthesis. 5-Fluorouracil (5-FU) inhibits thymidylate synthase directly. The addition of 5-formyltetrahydrofolate (leucovorin) to 5-FU regimens actually increases the inhibition of thymidylate synthase because 5formyltetrahydrofolate is readily converted to 5,10-methylenetetrahydrofolate, which is involved in the formation of inhibitory ternary complexes between 5,10-methylenetetrahydrofolate, 5-FU, and thymidylate synthase. Why megaloblastic changes occur in some cases of the myelodysplastic syndrome and acute leukemias is unknown but is probably due to a variety of mutations that alter DNA synthesis. MECHANISM OF NEUROPSYCHIATRIC ABNORMALITIES IN COBALAMIN DEFICIENCY. A wide variety of neuropsychiatric abnormalities are seen in cobalamin deficiency and appear to be due to an undefined defect involving myelin synthesis. Because these abnormalities are not seen in folate deficiency, it has been tempting to ascribe them to deficient activity of the second cobalamin-dependent enzyme, L-methylmalonyl-CoA mutase, which is unrelated to any folate-dependent enzyme or pathway. This enzyme catalyzes the conversion of L-methylmalonyl-CoA to succinyl-CoA by using adenosylcobalamin as a required coenzyme (see Fig. 163-2) . Abnormal odd-carbon and branched-chain fatty acids are formed when the mutase is impaired. The neuropsychiatric abnormalities of cobalamin deficiency are not seen, however, in individuals with genetic defects of the mutase reaction caused either by primary defects in the enzyme itself or by defects in the formation of adenosylcobalamin. Impairment of methionine synthase has also been postulated as the cause of neuropsychiatric abnormalities in view of the importance of methionine and S-adenosylmethionine for the many methylation reactions occurring in the

nervous system. As noted, however, the neuropsychiatric abnormalities caused by cobalamin deficiency are not seen in folate deficiency, although methionine synthase appears to be equally impaired in both vitamin deficiencies (based on similar marked elevations in serum homocysteine concentrations). Genetic defects in which the synthesis of both adenosylcobalamin and methylcobalamin is impaired do lead

Figure 163-2 Reactions involved in the metabolism of D- and L-methylmalonyl coenzyme A(CoA). Methylmalonic acid accumulates in cobalamin deficiency because of a lack of adenosylcobalamin (Adenosyl-Cbl), which leads to an increase in L-methylmalonyl-CoA,

which is converted to D-methylmalonyl-CoA and hydrolyzed to methylmalonic acid.

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to neuropsychiatric abnormalities of the kind seen in cobalamin deficiency. These observations suggest that both cobalamin-dependent enzymes must be impaired for neuropsychiatric abnormalities to develop and that the two cobalamin-dependent enzymes or pathways are connected or interrelated in a way that is not yet understood. MECHANISMS OF COBALAMIN DEFICIENCY. Cobalamin is not present in plants; until recently, humans obtained their cobalamin exclusively from animal products. Cobalamin is synthesized only by certain microorganisms. During the last half of the 20th century, humans have received increasing amounts of dietary cobalamin from multivitamin supplements taken in the form of pills and as additives to many food preparations. Most cobalamin in animal products is tightly bound to proteins, i.e., the two cobalamin-dependent enzymes, and is released from them in the stomach by the concerted action of HCl and pepsin. The stomach is also the site of synthesis of intrinsic factor, which binds free cobalamin with high affinity and plays an essential role in cobalamin absorption. Gastric juice contains another cobalamin binding protein that originates in saliva and has a more rapid or "R"-type electrophoretic mobility than does intrinsic factor. R protein binds cobalamin with a higher affinity than does intrinsic factor, particularly at an acid pH. Thus under normal conditions of gastric acidity, dietary cobalamin enters the duodenum bound to R protein. Additional cobalamin bound to R protein enters the duodenum after secretion into bile by the liver (the only significant route by which cobalamin is lost from the body). Pancreatic proteases partially degrade salivary and biliary R protein-cobalamin complexes in the jejunum; cobalamin is bound to intrinsic factor only after this process occurs. The intrinsic factor-cobalamin complex remains intact until it reaches the distal end of the ileum, where it binds with high affinity to specific receptors located on ileal mucosal cells. Cobalamin then enters these cells and reaches the portal plasma, which contains three cobalamin binding proteins known as transcobalamin I, II, and III (Table 163-2) . Although it contains only about 10% of the plasma cobalamin, transcobalamin II is the important transport protein because of its rapid clearance and its ability to deliver cobalamin to all cells within the body. Transcobalamin II-cobalamin is taken up by cells by endocytosis during a process in which the transcobalamin II moiety is degraded and the cobalamin is reduced and eventually converted to its two coenzyme forms, methylcobalamin and adenosylcobalamin. Cobalamin is not stored intracellularly; the entire intracellular vitamin is bound to the aforementioned two enzymes, which are present in greater amounts than is cobalamin. A large number of acquired and genetic diseases affect the pathway of cobalamin absorption and transport and result in cobalamin deficiency. Strict vegetarians, who ingest neither meat nor other animal products such as milk, cheese, or eggs and who do not ingest multivitamin supplements, become cobalamin deficient on a dietary basis. Ten to 15 years is required for the development of clinical signs of dietary cobalamin deficiency because absorption of biliary cobalamin remains intact. The secretion of biliary cobalamin ranges from 5 to 10 mug/day, and approximately 90% is reabsorbed by strict vegetarians and other normal individuals. Thus only 0.5 to 1.0 mug of the 5 to 10 mug of cobalamin present in a normal diet must be absorbed each day to maintain the total-body content of cobalamin in the normal range of 2000 to 5000 mug. Achlorhydria and the loss of pepsin secretion are common in elderly subjects (>50% of individuals older than 70 years) and in those with partial gastrectomy. Cobalamin deficiency develops in these individuals because of an inability to liberate cobalamin from its protein-bound form in foods of animal origin. Secretion of intrinsic factor is reduced, but because it is normally formed in vast excess, sufficient intrinsic factor usually remains for the reabsorption of biliary R protein-cobalamin, which is not dependent on HCl and pepsin. The same time span of 10 to 15 years is required for these subjects to acquire clinical signs of cobalamin deficiency as for those who have deficient diets. Cobalamin deficiency never develops in many such subjects, apparently because of the availability of free, non-protein-bound cobalamin in multivitamin pills and supplements and because some natural animal products contain small amounts of free cobalamin. A complete lack of intrinsic factor occurs in individuals who have undergone total gastrectomy or who have pernicious anemia; these individuals have idiopathic and essentially complete atrophy of the gastric mucosa in association with autoantibodies to parietal cells and intrinsic factor. Only about 3 to 5 years is required for clinical signs of cobalamin deficiency to develop under these circumstances because such individuals demonstrate malabsorption of biliary as well as all forms of dietary cobalamin. Cobalamin malabsorption occurs commonly in severe pancreatic exocrine insufficiency because of an inability to degrade R protein-cobalamin complexes in the jejunum. Clinically evident cobalamin deficiency rarely occurs, however, probably because oral therapy with pancreatic extract is usually instituted in these patients during the 3 to 5 years necessary for the signs of cobalamin deficiency to develop. The abnormal presence of high concentrations of bacteria and certain parasites in the small intestine can result in cobalamin malabsorption inasmuch as these organisms can avidly take up and retain cobalamin. Diseases interfering with the integrity of the distal ileal mucosa can also result in cobalamin malabsorption, which occurs invariably after surgical removal of the distal 100 cm of ileum. A large number of genetic disorders involve the plasma transport of cobalamin, its intracellular conversion to its coenzyme forms, or its utilization by the two cobalamin-dependent enzymes. These disorders usually appear within the first few weeks of life. The general anesthetic nitrous oxide causes multiple defects in cobalamin utilization, including the following: (1) rapid (within minutes) inhibition of methionine synthase activity with slow (over several days) recovery when nitrous oxide administration is stopped, (2) displacement of cobalamin from methionine synthase, (3) decrease in the level of methylcobalamin, (4) irreversible conversion of cobalamin to inactive and inhibitory cobalamin analogues, (5) gradual (over many weeks) development of cobalamin deficiency, (6) an eventual decrease in L-methylmalonyl-CoA mutase activity, and (7) a further decrease in methionine synthase activity. General anesthesia with nitrous oxide can precipitate clinical signs of cobalamin deficiency in individuals whose cobalamin status is low or marginal. MECHANISMS OF FOLATE DEFICIENCY. Folate is widely distributed TABLE 163-2 -- DISTRIBUTION OF ENDOGENOUS COBALAMIN AMONG THE VARIOUS TRANSCOBALAMINS AND THEIR RELATIVE IMPORTANCE TO COBALAMIN TRANSPORT* COBALAMIN TRANSPORT ENDOGENOUS COBALAMIN T½ FOR COBALAMIN COBALAMIN CLEARANCE SITE OF SPECIFIC PROTEIN (pg/mL) CLEARANCE (hr) (pg/mL/24 hr) UPTAKE R proteins Transcobalamin I

425-450

Transcobalamin III

0-25

0.1

0-4000

50

0.1

8000

Transcobalamin II

240.0

30

None Hepatocytes All cells

*In a typical normal subject with a serum cobalamin level of 500 pg/mL. In congenital R-protein deficiency, the total serum cobalamin level is very low, but no hematologic abnormalities are present because R proteins do not transport cobalamin to rapidly dividing cells, such as those in the bone marrow. In congenital transcobalamin II deficiency, the total serum cobalamin level is well within the normal range, but severe megaloblastic anemia develops because only transcobalamin II transports cobalamin to rapidly dividing cells, such as those in the bone marrow.

863

in plants and in products of animal origin; green vegetables are particularly rich sources of folate. Excessive cooking will destroy or remove a high percentage of folate in foods. Folate is either missing or is present only in relatively small amounts ( 800 mug) in non-prescription multivitamin pills and supplements because of the concern that its presence in larger amounts might mask the diagnosis of cobalamin deficiency by correcting the associated hematologic abnormalities without having any beneficial effect on the neuropsychiatric abnormalities. Folates in natural foods are conjugated to chains of polyglutamic acid. Enzymes in the lumen of the small intestine convert the polyglutamate forms of folate to the monoglutamate and diglutamate forms, which are readily absorbed in the proximal portion of the jejunum. Absorption involves both active and passive transport. Most of the folate in plasma is present as 5-methyltetrahydrofolate in the monoglutamate form. The majority is loosely bound to albumin, from which it is readily taken up by the high-affinity folate receptors present on cells throughout the body. Once it enters the cell, 5-methyltetrahydrofolate must be converted to tetrahydrofolate by the cobalamin-dependent enzyme methionine synthase before it can be converted to the polyglutamate form and take part in the other folate-dependent enzymatic reactions. In addition to being secreted into bile and reabsorbed in the small intestine, folates are also degraded and excreted in the urine. Decreased intake is by far the most common cause of folate deficiency. Normal individuals have approximately 5000 to 20,000 mug of folate in body stores. Because folate is degraded within the body and is excreted in both bile and urine, 50 to 200 mug must be absorbed each day from the average Western diet, which contains about 200 to 500 mug of folate. The amount of dietary folate has increased approximately 100 mug/day in the United States because of the recent mandatory fortification of all grain products that was implemented to reduce the incidence of neural tube defects. Clinical signs of folate deficiency develop after approximately 4 months of decreased intake, as can readily occur in chronic alcoholism. Absorption of folate is impaired in a variety of diseases affecting the jejunal mucosa, including tropical sprue and celiac disease. Certain drugs such as anticonvulsants and sulfasalazine may impair folate absorption in some individuals. Ethanol and drugs such as triamterene impair the utilization of folate. Certain conditions associated with hypermetabolism or rapid cell growth lead to an increased requirement for folate that often cannot be met by a normal diet; these conditions include hyperthyroidism, pregnancy, chronic hemolysis, and various exfoliative skin diseases. Hemodialysis causes an increased loss of folate from the body.

CLINICAL MANIFESTATIONS OF MEGALOBLASTIC ANEMIA HEMATOLOGIC MANIFESTATIONS. All causes of megaloblastic anemia produce a common set of hematologic, laboratory, and other abnormalities (Table 163-3) . None of the abnormalities are specific for the various diseases that cause megaloblastic anemia, and each may also be present in any combination that may vary greatly from patient to patient. In addition, none of the abnormalities are always seen in conditions that cause megaloblastic anemia, and the absence of any one or more of them cannot be used to exclude any of the diseases that cause megaloblastic anemia in a given patient, including cobalamin or folate deficiency. Megaloblastic anemia typically develops over many months and may not cause symptoms until the hematocrit falls below 20%. The reticulocyte count is not elevated, in either absolute or relative (percentage) terms, even when the anemia is severe. The mean cell volume is often increased (normal, 80 to 100 fL), with values as high as 140 fL. A review of previous blood counts often reveals a steady increase in mean cell volume over several months or years. Neutropenia and thrombocytopenia occur less commonly than anemia and are not usually severe. On occasion, however, neutrophil counts of less than 1000 per microliter and platelet counts of less than 50,000 per microliter may be seen. A peripheral blood smear frequently shows neutrophil hypersegmentation (Fig. 163-3 and Color Plate 5 E), which may be documented by observing one or more of the following: (1) the presence of at least one neutrophil containing 6 or more lobes, (2) the presence of 5% or more of 5-lobe neutrophils, or (3) an increase above the normal neutrophil lobe average of fewer than 3.4 lobes per neutrophil. Erythrocytes TABLE 163-3 -- HEMATOLOGIC AND OTHER ABNORMALITIES THAT MAY BE DUE TO ANY OF THE VARIOUS CAUSES OF MEGALOBLASTIC ANEMIA* HEMATOLOGIC OTHER Anemia

Glossitis

Reticulocytopenia

Stomatitis

Macrocytosis (increased MCV)

Gastrointestinal symptoms

Neutropenia

Hyperpigmentation

Thrombocytopenia

Infertility

Peripheral blood smear

Orthostatic hypotension

Neutrophil hypersegmentation

Weight loss

Erythrocyte Variation in size Variation in shape Macro-ovalocytes Serum Elevated lactate dehydrogenase Elevated bilirubin Elevated iron Decreased haptoglobin Bone marrow Hypercellular Megaloblastic morphology Giant bands and metamyelocytes MCV = mean corpuscular volume. *These abnormalities may be present in any number or combination in a given patient. Absence of any one or more of them occurs commonly in individual patients with all causes of megaloblastic anemia, including cobalamin deficiency and folate deficiency.

often vary markedly in size and shape, and macro-ovalocytes (large, oval erythrocytes) are frequently present (Fig. 163-4) . When the hematocrit is low, nucleated red cells may be seen on the peripheral smear and permit detection of the megaloblastic morphology of the nuclei without the need to perform bone marrow aspiration or biopsy. Although the reticulocyte count may be normal or low, a number of serum abnormalities often suggest hemolytic anemia: elevated serum levels of lactate dehydrogenase, indirect bilirubin, and iron, as well as decreased levels of haptoglobin. These findings are consistent with the markedly increased red cell production and destruction seen in megaloblastic anemia but confined to the bone marrow and termed intramedullary hemolysis or ineffective erythropoiesis. The bone marrow is usually hypercellular with an increase in all cellular elements. Megaloblastic morphologic changes are often seen in all cells within the bone marrow but are usually more prominent in the erythroid series. All cells in the erythroid series are larger than their normal counterparts, their cytoplasm appears more mature than their nuclei (nuclear-cytoplasmic asynchrony),

Figure 163-3 A hypersegmented neutrophil on a peripheral blood smear from a patient with megaloblastic anemia.

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Figure 163-4 Peripheral blood smears from a patient with megaloblastic anemia (left) and from a normal subject (right), both at the same magnification. The smear from the patient shows variation in the size and shape of erythrocytes and the presence of macro-ovalocytes.

and the nuclear chromatin has a distinctive open and fine-grained texture (Fig. 163-5 and Color Plate 5 F). Similar abnormalities are seen in neutrophil precursors and are usually most striking at the metamyelocyte and band stages, in which "giant metamyelocytes" and "giant bands" are seen. All these features are much more prominent in a Wright-stained smear of bone marrow aspirate than in fixed sections from the bone marrow biopsy. Use of the latter alone can lead to disastrous clinical consequences because even the most experienced hematopathologist can, on the basis of fixed bone marrow sections only, experience difficulty in distinguishing the hypercellularity and abnormal morphology of megaloblastosis from the changes seen in the myelodysplastic syndromes and some cases of acute leukemia. Coexisting iron deficiency may also cause diagnostic problems inasmuch as all of the erythroid megaloblastic changes may be absent, even in Wright-stained smears of aspirated bone marrow. The diagnosis of megaloblastic anemia should never be excluded after bone marrow examination unless bone marrow aspirates have been examined and the presence of bone marrow iron has been established. Megaloblastic abnormalities may occur in other proliferating body cells, all of which share the underlying defect in DNA synthesis. Such changes have been documented in the epithelial cells

Figure 163-5 Erythroid precursors with marked megaloblastic features on a bone marrow smear from a patient with megaloblastic anemia.

of the buccal mucosa, stomach, intestine, and vagina and account for such phenomena as glossitis, stomatitis, and secondary malabsorption. Similar changes may account for the infertility that is sometimes seen. Few, if any patients with cobalamin or folate deficiency or other causes of megaloblastic anemia demonstrate all or even most of the classic hematologic or other abnormalities. Even anemia and increased mean cell volume are frequently absent in patients with otherwise severe deficiencies of cobalamin or folate. For example, in a prospective study of 86 consecutive patients with low serum cobalamin levels (38.5° C unless they appear toxic, have temperature > 40° C, are not receiving prophylactic penicillin, have previously documented S. pneumoniae bacteremia, or live in areas where antibiotic-resistant S. pneumoniae has evolved. In these situations, hospitalization is recommended with cultures of blood and cerebrospinal fluid and use of antibiotics likely to be effective against local strains of S. pneumoniae. Treatment of meningitis should cover S. pneumoniae and H. influenzae type b and be continued for at least 2 weeks. Antibiotic therapy for the acute chest syndrome should provide coverage for S. pneumoniae, H. influenzae type b, Mycoplasma pneumoniae, and Chlamydia pneumoniae. Cefuroxime and erythromycin combinations are recommended. The diagnosis of osteomyelitis is confirmed by culture of blood or infected bone, after which parenteral antibiotics that cover Salmonella spp. and S. aureus are administered. Antibiotic therapy is tailored by using culture and sensitivity results and continued for 2 to 6 weeks. Surgical drainage or sequestrectomy may be required. TRANSFUSION THERAPY. Patients with sickle cell disease have similar requirements for transfusion to other patients--oxygen carrying capacity and blood volume replacement (e.g., aplastic crisis, splenic sequestration). They also have indications unique to their disease--protection from imminent danger (e.g., acute chest syndrome, septicemia, metabolic acidosis) and improved rheologic properties of blood (e.g., prevention of recurrent CVA, priapism, pre-operatively). The routine acute painful crisis is not an indication for transfusion. Transfusion complications are alloimmunization, iron overload, and transmission of viral illness. Antibodies against the Rh (E, C), Kell (K), Duffy (Fya, Fyb), and Kidd (Jk) antigens present the greatest problem in transfusion of these patients. Transfusing extended-matched, phenotypically compatible blood has been documented to diminish alloimmunization rates. As sickle cell patients live longer and are transfused more, iron overload becomes a greater problem. Deferoxamine chelation should be considered for those with elevated total body iron level, i.e., serum ferritin levels that exceed 2000 ng/mL. This therapy is inconvenient, uncomfortable, and expensive. The anticipated availability of oral chelating agents will be a tremendous asset for the management of these patients. Transmission of human immunodeficiency virus (HIV), hepatitis B and C, and human T-lymphotropic virus 1 (HTLV-1) has diminished with improved screening, and it is anticipated that the use of leukocyte-depleted red cell transfusion will reduce this hazard further. Preoperative transfusion is recommended for patients with sickle cell anemia. Both simple transfusion to reduce HbS to 20%) in the blood or bone marrow, thrombocytopenia (90

FMC-7, CD22

Waldenstrom's macroglobulinemia

33

33

All B

Weak

Some

Many

CD38, PCA-1

Large granular lymphocytosis

10

10

All T

Absent

--

--

CD2, CD3, CD8

CD19--early pan B cell CD20--pan B cell FMC-7--PLL and hairy cell CD2--pan T cell CD3--pan mature T cell CD8--T cell (suppressor-cytotoxic) CD10--early B cell CD11C--hairy cell, activated T cell, NK cell CD38--activated B cell, thymocyte, plasma cell PCA-1--plasma cell CD25--low-affinity interleukin-2 (IL-2) receptor *CD5--pan T cell, B CLL

952

and its characteristics of massive splenomegaly, minimal lymphadenopathy, and WBC count commonly more than 100,00/muL, with 10 to 90% of the cells being prolymphocytes, distinguish this disease from typical B-cell CLL. Prolymphocytes are larger cells than typical CLL lymphocytes; they have a distinct nucleolus and are often FMC-7 positive. The male:female ratio is 4:1, and the median age at diagnosis is 70 years. Survival is shorter than in CLL (median, 3 years), and response is poor to therapies usually applied in CLL. A monoclonal spike, usually IgG or IgA, is present in one third of cases. The immunoglobulin on the surface of the cells is usually IgG or IgA, not IgM ± IgD, as in CLL. A specific karyotypic abnormality, t(6;12) (q15;13), has been reported in PLL. One fifth of the cases are of T-cell phenotype. The predominant clinical manifestation in Sezary's syndrome (a CD4+ T-cell malignant disorder related to mycosis fungoides) is chronic exfoliative erythroderma with a low number of circulating monoclonal T cells. The clinical and laboratory differential diagnosis from CLL is not difficult. Other T-cell malignant disorders with peripheral blood involvement are adult T-cell leukemia-lymphoma and large granular lymphocytosis (LGL), also referred to as "large granular lymphoproliferative disorder," "T-cell lymphocytosis with neutropenia," or "T-gamma lymphocytosis syndrome." Adult T-cell leukemia-lymphoma is associated with a retrovirus (human T-cell leukemia-lymphoma virus [HTLV-I]) and is common in Japan and the Caribbean. It is frequently manifested by lytic bone lesions and hypercalcemia. In T-LGL the absolute lymphocyte count is usually low (100,000/muL

>100,000/muL

100,000/muL or 50% from baseline

Hemoglobin

Not specified

>11 g/dL

>11 g/dL or >50% from baseline

Lymphocytes

50% decrease 4000/muL

Bone marrow Lymphocytes

Normal aspirate and biopsy *

N/A 1/3 the width of the mediastinum >10 cm maximal dimension of nodal mass E: Involvement of a single extranodal site, contiguous or proximal to a known nodal site CS: Clinical stage PS: Pathologic stage

972

TABLE 180-2 -- RECOMMENDED PROCEDURES IN STAGING HODGKIN'S DISEASE 1. Adequate surgical biopsy reviewed by an experienced pathologist 2. History and physical examination with particular attention to the pres ence and duration of B symptoms (see Table 180-1) and pruritus 3. Imaging studies Plain chest radiograph CT of thorax CT of abdomen and pelvis Gallium scan 4. Hematologic studies Complete blood cell count Erythrocyte sedimentation rate Bone marrow biopsy 5. Biochemical studies Liver function tests Renal function tests Lactate dehydrogenase, albumin, calcium 6. Under special circumstances Bipedal lymphography Magnetic resonance imaging Technetium bone scan Percutaneous or laparoscopic liver biopsy Staging laparotomy they are drenching and recurrent, and unexplained weight loss is significant only if at least 10% of body weight is lost within the preceding 6 months. Although pruritus is no longer considered a B symptom, the presence of generalized itching is considered by many to be an adverse prognostic symptom. Certain combinations of B symptoms have been found to be more prognostically significant than others. For example, the combination of fever and weight loss has a more adverse prognosis than night sweats alone. B symptoms probably reflect the end-product manifestation of cytokines produced by the tumor cells. The physical examination should carefully determine the location and size of all palpable lymph nodes. An inspection of Waldeyer's ring, detection of splenomegaly or hepatomegaly, and evaluation of the cardiac and respiratory status are important. LABORATORY STUDIES. The initial laboratory studies should include a complete blood cell count with white cell differential and platelet count, an erythrocyte sedimentation rate (ESR), tests for liver and renal function, and assays for serum alkaline phosphatase and lactate dehydrogenase. Mild to moderate anemia with normal indices of the type often found in patients with other malignancies or chronic disease may accompany Hodgkin's disease and does not necessarily indicate bone marrow involvement or hypersplenism. A moderate to marked leukemoid reaction and thrombocytosis are common, particularly in symptomatic patients, and usually disappear with treatment. Mild eosinophilia frequently exists, especially in patients with pruritus. Patients with advanced stage disease and those with HIV-related Hodgkin's disease may show absolute lymphopenia ( 40) attain better relapse-free survival rates with combined-modality therapy including chemotherapy (Table 180-3) than with radiation therapy alone. Two prospective randomized studies compared the efficacy of MOPP chemotherapy alone with radiation therapy alone in early-stage patients. Whereas a study from the National Cancer Institute (NCI) showed equivalent results for the two modalities, other analyses found a significantly lower survival rate among patients treated with MOPP than among those treated with standard radiation therapy. Although other drug combinations such as ABVD may be more effective and less toxic than MOPP, they have not been tested without radiation in early-stage Hodgkin's disease and should not be used alone outside a controlled clinical trial. RADIATION THERAPY. The cure of early-stage Hodgkin's disease with radiation alone became possible only after the recognition that all involved sites, as well as adjacent nodal areas, need to be treated with tumoricidal doses. Proper irradiation technique requires the use of linear accelerators that produce 6- to 10-MV photons. This degree of energy permits the exposure of large volumes to an adequate and homogeneous radiation dose with a modest degree of skin sparing. Treatment planning should be performed on a dedicated radiation CT-based simulator that duplicates the features of the treatment unit. The plan itself is based on detailed imaging information that has been obtained during the staging process and during the simulation. The radiation field is shaped to conform to the patient's anatomy and tumor configuration. Routine field verification (port films) is essential for controlling the proper delivery of treatment. Successful therapy with radiation alone requires treatment of all clinically involved lymph nodes and all nodal and extranodal regions at risk for subclinical involvement. Certain standard large radiation therapy fields (Fig. 180-3) have been designed for the treatment of Hodgkin's disease. The fields are shaped to include multiple adjacent lymph node sites while accounting for normal tissue tolerance and the technical constraints of field size. The mantle radiation field covers the lymph node areas above the diaphragm, including the submandibular, cervical, supraclavicular, infraclavicular, axillary, mediastinal, and hilar nodal areas. The para-aortic field includes the para-aortic lymph nodes from the diaphragm to the aortic bifurcation and the spleen or the splenic pedicle (after splenectomy). The pelvic field encompasses the iliac, inguinal, and femoral nodes. The inverted-Y field combines the para-aortic and pelvic fields. The term total lymphoid irradiation refers to treatment of all three fields. Subtotal lymphoid irradiation indicates treatment of the mantle and para-aortic fields only. To avoid excessive toxicity, the radiation fields are treated sequentially, the total dose is fractionated, and the radiated volumes are carefully tailored with individualized divergent blocks. When patients require separate treatment to adjacent regions, the calculation of field separation is particularly important to avoid overlap at the spinal cord. The dose required to eradicate Hodgkin's disease in demonstrably involved nodes is 40 to 45 Gy (1 Gy = 100 rad). A standard course of therapy with radiation alone includes treatment of the whole field to a total dose of 36 Gy (in 20 daily fractions of 1.8 Gy each, over a period of 4 weeks), with additional radiation restricted to the clinically apparent disease sites of 4 to 9 Gy. A lower dose of radiation, in the range of 24 to 36 Gy, is used when radiation is administered as adjuvant or consolidation treatment after chemotherapy. In such programs, the radiation port may be limited to the clinically involved sites. SIDE EFFECTS AND COMPLICATIONS OF RADIATION THERAPY. Early Effects.

These effects depend on the radiated volume, dose administered, and technique employed. They are also influenced by the extent and type of prior chemotherapy, if any, and by the patient's age. The acute side effects of mantle field radiation are usually mild and transient: they may include mouth dryness, change in taste,

Figure 180-3 Standard radiation fields for Hodgkin's disease.

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pharyngitis, nausea, dry cough, dermatitis, and fatigue. These side effects are managed symptomatically and subside gradually soon after the completion of radiation therapy. The main potential side effects of subdiaphragmatic radiation are loss of appetite, nausea, and increase in bowel movements. These reactions are usually mild and can be minimized with standard antiemetic medications. Irradiation of more than one field, particularly after chemotherapy, can cause myelosuppression, and treatment delays may be required during therapy. Six weeks to 3 months after completion of mantle therapy, approximately 15% of patients may develop Lhermitte's sign: patients note an electric shock sensation radiating down the backs of both legs when the head is flexed. Lhermitte's sign may be secondary to transient demyelinization of the cervical spinal cord; it resolves spontaneously after a few months and is not associated with late or permanent cord damage. During the same period, radiation pneumonitis and/or acute pericarditis may occur in less than 5% of patients, more often in those who had extensive mediastinal disease. Both inflammatory processes have become rare with modern radiation techniques. Patients with Hodgkin's disease, regardless of treatment type, have a propensity to develop herpes zoster infection within 2 years after the onset of therapy. Usually the infection is confined to a single dermatome and is self-limited. If the cutaneous eruption is identified promptly, treatment with systemic acyclovir limits the duration and intensity of the infection. Late Effects.

Mantle field radiation therapy can induce subclinical hypothyroidism, detected by elevation of the level of thyroid-stimulating hormone, in about one third of patients. Thyroid replacement with L-thyroxine is recommended, even for asymptomatic patients, to prevent the development of overt hypothyroidism and to decrease the risk of developing benign thyroid nodules. Radiation of the pelvic field may have deleterious effects on fertility; in most patients this effect can be avoided by appropriate

gonadal shielding. In females, the ovaries can be moved (oophoropexy) into a shielded area laterally or inferomedially near the uterine cervix. Irradiation of the mantle and para-aortic fields alone does not increase the risk of sterility. Hodgkin's disease patients who were cured with radiation therapy and/or chemotherapy have an increased risk of developing secondary solid tumors and non-Hodgkin's lymphoma 10 or more years after treatment. Unlike MOPP and similar chemotherapy combinations, radiation therapy for Hodgkin's disease is not leukemogenic. The most frequent solid tumors reported after radiation therapy or chemotherapy for Hodgkin's disease are lung cancer, breast cancer, stomach cancer, and melanoma. Patients who smoke should be strongly encouraged to stop because the increase in lung cancer after irradiation or chemotherapy has been detected mostly in smokers. The increase in breast cancer risk is inversely related to the age at Hodgkin's disease treatment; in women irradiated after the age of 30 years, no increase in the risk of breast cancer has been found. Breast cancer is curable in its early stages, and early detection significantly improves survival. Breast examination should be part of the routine follow-up program for women cured of Hodgkin's disease, and routine mammography should begin about 7 years after treatment of Hodgkin's disease. An increase in the risk of coronary artery disease has been reported for patients who have received mediastinal irradiation. To reduce this hazard, patients should be monitored and advised to avoid other established coronary disease risk factors such as smoking, hyperlipidemia, hypertension, and poor dietary and exercise habits. In children, high-dose radiation affects bone and muscle growth and may result in deformities. Current programs for pediatric Hodgkin's disease are chemotherapy based, and radiation therapy is limited to low doses. ADVANCED-STAGE DISEASE. The mainstay of treatment in advanced Hodgkin's disease (stages IIIB and IV) is combination chemotherapy. Before embarking on a therapeutic regimen, it is important to document carefully the diagnosis, clinical or pathologic stage, and possible medical contraindications to systemic therapy. The possible side effects of the treatment plan should be outlined given the reasonable expectation of a curative outcome. In selecting a combination chemotherapy regimen, it is important to evaluate the relative effectiveness, as well as potential acute and long-term side effects. Several combination chemotherapy regimens have been developed since their introduction in the 1960s and 1970s, but few studies have prospectively compared their efficacy. The most frequently used drug programs are MOPP, ABVD, MOPP-ABVD, and MOPP-ABV hybrid (see Table 180-3) . MOPP and ABVD are considered non-cross-resistant drug regimens; alternating and hybrid regimens have been developed to take advantage of this characteristic. In prospective, randomized studies, ABVD chemotherapy has been found to be at least as effective as MOPP and MOPP-ABVD; likewise, MOPP-ABV hybrid has been shown to be equivalent to MOPP-ABVD; and ABVD has been found equivalent to MOPP-ABV hybrid. Thus, ABVD is now considered the preferred drug combination in Hodgkin's disease treatment because it is at least equally effective and avoids exposure to the toxic drugs in MOPP or MOPP-containing regimens. In prospective comparisons, MOPP-containing regimens have had significantly greater risks of infection and late development of secondary myelodysplasia, leukemia, and solid tumors. Results of combination chemotherapy reveal a complete response rate of approximately 80%, a disease-free survival of complete responders of 50 to 60%, and an overall survival of 40 to 50%. Adverse prognostic factors include the presence of systemic symptoms, tumor bulk, multiple extranodal sites, age older than 40 years, and male gender. To increase the cure rate of advanced Hodgkin's disease, the most important strategy is to administer the planned drug regimen according to the dose and schedule of the empirically developed schema. Retrospective analyses have demonstrated that the relative dose intensity (amount of drug per unit time) of the drug regimen correlates with treatment outcome. Another approach, which is to add regional irradiation as a consolidative local therapy after chemotherapy induction, is routinely recommended when patients have bulky disease presentations (masses >10 cm) and often applied when residual masses remain after chemotherapy. Routine use of widefield consolidative radiation, either low dose or full dose, without these specific indications remains controversial, although retrospective studies and some prospective trials support this approach. Investigative strategies to increase the cure rate further include the use of intensive short-course combination chemotherapy with involved-field irradiation (e.g., BEACOPP or Stanford V) and consolidative autologous stem cell transplantation in first clinical remission, but these approaches have not yet proven to be superior to the standard drug regimens. When administering chemotherapy, the physician must pay attention to the rate of disease regression, remaining particularly alert to the rare situation in which response is sluggish (2 years after completion of standard-dose chemotherapy) may be salvaged with a second standard-dose combination chemotherapy, with or without involved-field irradiation. HD-ASCT is a cumbersome, toxic, and expensive process, making it important to identify proper candidates accurately. All should have histologic proof of active Hodgkin's disease at relapse because residual masses are common and may not represent active tumor. Consolidation HD-ASCT is not recommended in first

remission. At relapse, there is no standard reinduction chemotherapy, and it may include drugs used at initial therapy or new agents. The most commonly used HD-ASCT conditioning regimen is CBV (cyclophosphamide, BCNU [carmustine], and VP 16 [etoposide]). Other combinations also have demonstrated efficacy, and some programs also incorporate standard involved-field or intensive large-field radiation therapy. The autologous stem cell product may be provided from the patient's own bone marrow and/or peripheral blood with hematopoietic growth factor support. SPECIAL CIRCUMSTANCES. Pregnancy may complicate the management of initial or relapsed Hodgkin's disease. When the pregnancy is first diagnosed, it is important to stage the patient clinically by history and physical examination; posteroanterior chest radiograph; ultrasonography; MRI of the chest, abdomen, and pelvis (as indicated); and bone marrow biopsy. Before recommending medical management, it must be kept in mind that Hodgkin's disease is often an indolent tumor and may be clinically silent or asymptomatic for many months. For that reason, it may be possible to monitor a patient and defer treatment during the pregnancy. If treatment is indicated, options include involved-field radiation with shielding of the pregnant uterus, single-agent chemotherapy such as vinblastine, or even combination chemotherapy with ABVD. Treatment selection depends on disease sites at risk, age and size of the developing fetus, tumor bulk, the patient's symptoms, and predicted delivery date. Very rarely it may be necessary to consider therapeutic abortion if the diagnosis of advanced and/or symptomatic Hodgkin's disease is made early in the pregnancy. HIV-associated Hodgkin's disease is much less frequent than non-Hodgkin's lymphoma; the most important consideration is to establish an accurate diagnosis (see Chapter 416) . Clinical staging often reveals more advanced disease than in non-HIV patients, and extranodal involvement is more frequent. It is important to distinguish between Hodgkin's disease and infectious causes of apparent extranodal involvement (such as pulmonary nodules) before determining a final treatment plan. Staging laparotomy is generally not justified in HIV-affected patients. Primary radiation, based on clinical stage, with or without adjuvant chemotherapy is appropriate for early-stage presentations; chemotherapy alone, with or without consolidative radiation, is given in advanced disease. ABVD is a suitable combination regimen but may need to be modified to avoid bleomycin pulmonary toxicity. Pneumocystis carinii pneumonia prophylaxis should be instituted routinely. HIV antiviral therapy may be administered during chemotherapy as indicated and tolerated. Whenever possible, these patients should be approached with curative intent. Primary Hodgkin's disease regimens are not so immunosuppressive as to be contraindicated except in unusual circumstances. TREATMENT RECOMMENDATIONS. After an accurate histologic diagnosis and staging, the following general guidelines may be used in recommending therapy. For clinical stage I and IIA good-risk patients with a low likelihood of abdominal involvement, primary irradiation without staging laparotomy is appropriate. Combined-modality therapy (ABVD plus extended field radiation) is a less acceptable alternative because it exposes patients to the toxicities of both modalities in a low-risk setting. For clinical stage I and IIA or B, moderate-risk (see earlier) patients in whom the risk for abdominal involvement is greater than 10%, primary irradiation remains an appropriate therapy but requires staging laparotomy to confirm pathologic stage I or II disease. A frequently used alternative is combined modality therapy (ABVD plus involved-field or extended-field radiation), thus obviating the need for laparotomy. For all patients with clinical stage IIIA disease, combined modality therapy or ABVD alone are the acceptable options. Primary irradiation is not indicated in such patients, even when staging laparotomy reveals III1 A disease. TABLE 180-4 -- RECOMMENDED FOLLOW-UP IN TREATED HODGKIN'S DISEASE 1. End of therapy Repeat all studies initially positive for baseline values. If suspicious, consider biopsy. 2. 0 to 3 years after therapy Visits: Every 3 to 4 months Imaging: Chest radiography each visit, unless CT of chest obtained CT of chest every 6 months × 2, then yearly CT of abdomen and pelvis yearly Laboratory: With each visit: Complete blood cell count, platelets, eryth rocyte sedimentation rate Liver and renal function tests Lactate dehydrogenase Every 6 months: Thyroid-stimulating hormone 3. 3 to 5 years after therapy Visits: Every 6 months Imaging: Chest radiography each visit, unless CT of chest obtained CT of chest, abdomen, pelvis yearly Laboratory: As in 2 4. More than 5 years after therapy Visits: Yearly Imaging: Chest radiography; CT only as indicated Laboratory: As in 2 5. Other considerations, as indicated Mammography Lipid profile Pulmonary function studies Echocardiography Hormone replacement if menopausal

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For the bulky early-stage presentations, clinical stage IX or IIX disease, combined-modality therapy is essential. The choice of combination chemotherapy regimen is discussed earlier; usually this is ABVD. After successful induction of complete clinical remission, consolidative radiation should be administered. For advanced-stage disease (IIIB and IV), combination chemotherapy alone (ABVD) or combined with involved- or extended-field radiation is recommended. Follow-up studies for successfully treated patients are listed in Table 180-4 . Connors JM, Klimo P, Adams G, et al: Treatment of advanced Hodgkin's disease with chemotherapy--comparison of MOPP/ABV hybrid regimen with alternating courses of MOPP and ABVD: A report from the National Cancer Institute of Canada clinical trials group. J Clin Oncol 15:1638, 1997. A prospective randomized trial demonstrating the value of doxorubicin-containing regimens. Hancock SL, Hoppe RT: Long-term complications of treatment and causes of mortality after Hodgkin's disease. Semin Radiat Oncol 6:225, 1996. An outstanding review of long-term complications and their management. Loeffler M, Brosteanu O, Hasenclever D, et al: Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin's disease. J Clin Oncol 16:818, 1998. A meta-analysis of 1740 patients evaluating the role of chemotherapy with or without irradiation. Mauch P: What is the role for adjuvant radiation therapy in advanced Hodgkin's disease? J Clin Oncol 16:815, 1998. Companion editorial to previous article discussing

the merits of the meta-analysis. Nautiyal J, Weichselbaum RR, Vijayakumar S: Radiation therapy techniques in the treatment of Hodgkin's disease. Semin Radiat Oncol 6:131, 1996. An excellent review of radiation therapy for Hodgkin's disease. Yahalom J: Management of relapsed and refractory Hodgkin's disease. Semin Radiat Oncol 6:210, 1996. This review of relapse/refractory management discusses in detail autologous stem cell transplantation and the role of radiation therapy in salvage strategies.

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Chapter 181 - PLASMA CELL DISORDERS Robert A. Kyle

The plasma cell disorders are a group of neoplastic or potentially neoplastic diseases associated with proliferation of a single clone of immunoglobulin-secreting plasma cells derived from the B-cell series of immunocytes. This group of disorders has been referred to as monoclonal gammopathies, immunoglobulinopathies, paraproteinemias, and dysproteinemias. The plasma cell disorders are characterized by the secretion of electrophoretically and immunologically homogeneous (monoclonal) proteins. Each monoclonal protein (M-protein, myeloma protein, or paraprotein) consists of two heavy (H) polypeptide chains of the same class and subclass and two light (L) polypeptide chains of the same type (see Fig. 270-2) . The heavy polypeptide chains are designated by Greek letters: gamma in immunoglobulin G (IgG), alpha in immunoglobulin A (IgA), mu in immunoglobulin M (IgM), delta in immunoglobulin D (IgD), and epsilon in immunoglobulin E (IgE). The subclasses of IgG are IgG1, IgG2, IgG3, and IgG4. There are two subclasses of IgA--IgA1 and IgA2. No subclasses of IgM, IgD, or IgE have been recognized. The light-chain types are kappa (kappa) and lambda (lambda). Both heavy chains and light chains have "constant" and "variable" regions with respect to amino acid sequence. Class specificity of each immunoglobulin is defined by a series of antigenic determinants on the constant regions of the heavy chains (gamma, alpha, mu, delta, and epsilon) and the two major classes of light chains (kappa and lambda). The amino acid sequence in the variable regions of the immunoglobulin molecule corresponds to the active antigen-combining site of the antibody, whereas the constant regions convey other biologic properties (see Chapter 270) .

RECOGNITION OF MONOCLONAL PROTEINS High-resolution agarose gel electrophoresis is preferred for the detection of monoclonal proteins (M-proteins). Immunofixation should be used to confirm the presence of an M-protein and to distinguish the immunoglobulin class and its light-chain type. Note: Mayo Foundation retains copyright to Mayo copyrighted illustrations. Mayo Foundation is "author" for purposes of copyright ownership under the "work made for hire" provision of the copyright law. Analysis of Serum Serum protein electrophoresis should be done when multiple myeloma or Waldenstrom's macroglobulinemia is suspected because of unexplained weakness or fatigue, anemia, back pain, osteoporosis, osteolytic lesions or spontaneous fracture, elevation of the erythrocyte sedimentation rate, hypercalcemia, Bence Jones proteinuria, renal insufficiency, immunoglobulin deficiency, or recurrent infections. It should also be considered in adults with sensorimotor peripheral neuropathy, carpal tunnel syndrome, refractory heart failure, nephrotic syndrome, orthostatic hypotension, or malabsorption, because a spike or localized band is strongly suggestive of primary systemic amyloidosis (AL). An M-protein is usually seen as a narrow peak (like a church spire) in the densitometer tracing or as a dense, discrete band on agarose gel (Fig. 181-1) (Figure Not Available) . Although the immunoglobulins (IgG, IgA, IgM, IgD, and IgE) compose the gamma component, they are also found in the beta-gamma or beta region, and IgG may actually extend to the alpha2 -globulin area. Consequently, an IgG M-protein may range from the slow gamma (cathode) to the alpha2 -globulin region. In contrast, an excess of polyclonal immunoglobulins (having one or more heavy-chain types and both kappa and lambda light chains) produces a broad-based peak or broad band. It is usually limited to the gamma region (Fig. 181-2) (Figure Not Available) . It is important to differentiate between an M-protein and a polyclonal increase because the former is associated with a malignant process or a potentially neoplastic condition, whereas a polyclonal increase in immunoglobulins is associated with a reactive or inflammatory process. In 3% of sera with a monoclonal peak, there is an additional M-protein of a different immunoglobulin class. This condition is designated as a biclonal (double) gammopathy. The presence of an M-protein is most suggestive of monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma, primary amyloidosis, Waldenstrom's macroglobulinemia, or other lymphoproliferative disease (Table 181-1) . Rarely, other conditions may also simulate the presence of an M-protein in the serum (e.g., free hemoglobin-haptoglobin complexes resulting from hemolysis, large amounts of transferrin in patients with iron-deficiency anemia, or the presence of fibrinogen). On the other hand, an M-protein may appear as a rather broad band on agarose gel or as a broad peak in the densitometer tracing, owing to the complexing of an M-protein with other plasma components or aggregates of IgG, polymers of IgA, or dimers of IgM. An M-protein can be present when the total protein concentration, Figure 181-1 (Figure Not Available) A, Monoclonal pattern of serum protein as traced by densitometer after electrophoresis on agarose gel: tall, narrow-based peak of gamma mobility. B, Monoclonal pattern from electrophoresis of serum on agarose gel (anode on left): dense, localized band representing monoclonal protein of gamma mobility. (From Kyle RA, Katzmann JA: Immunochemical characterization of immunoglobulins. In Rose NR, Conway de Macario E, Folds JD, et al [eds]: Manual of Clinical Laboratory Immunology, 5th ed. Washington, DC, ASM Press, 1997, p 156, with permission of the American Society for Microbiology.)

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Figure 181-2 (Figure Not Available) A, Polyclonal pattern from densitometer tracing of agarose gel: broad-based peak of gamma mobility. B, Polyclonal pattern from electrophoresis of agarose gel (anode on left). Band at right is broad and extends throughout the gamma area. (From Kyle RA, Katzmann JA: Immunochemical characterization of immunoglobulins. In Rose NR, Conway de Macario E, Folds JD, et al [eds]: Manual of Clinical Laboratory Immunology, 5th ed. Washington, DC, ASM Press, 1997, p 156, with permission of the American Society for Microbiology.)

beta- and gamma-globulin levels, and quantitative immunoglobulin values are all within normal limits. A small M-protein may be concealed in the normal beta or gamma areas and may be overlooked. In addition, the presence of a monoclonal light chain (Bence Jones proteinemia) is rarely seen in the agarose gel. In the heavy chain diseases, the M-component is usually not apparent. Immunofixation, a useful technique for identifying an M-protein, should be performed when a peak or band is seen on protein electrophoresis or when multiple myeloma or related disorders are suspected despite a normal protein electrophoresis. Immunofixation is especially useful when one is searching for a small M-protein in primary amyloidosis, solitary plasmacytoma, or extramedullary plasmacytoma, or after successful treatment of multiple myeloma or macroglobulinemia. TABLE 181-1 -- CLASSIFICATION OF PLASMA CELL PROLIFERATIVE DISORDERS I. Monoclonal Gammopathies of Undetermined Significance (MGUS) A. Benign (IgG, IgA, IgD, IgM, and, rarely, free light chains) B. Associated neoplasms or other diseases not known to produce monoclonal proteins C. Biclonal gammopathies D. Idiopathic Bence Jones proteinuria II. Malignant Monoclonal Gammopathies A. Multiple myeloma (IgG, IgA, IgD, IgE, and free light chains) 1. Overt multiple myeloma

2. Smoldering multiple myeloma 3. Plasma cell leukemia 4. Non-secretory myeloma 5. IgD myeloma 6. Osteosclerotic myeloma (POEMS syndrome) 7. Solitary plasmacytoma of bone 8. Extramedullary plasmacytoma B. Waldenstrom's macroglobulinemia 1. Other lymphoproliferative diseases III. Heavy-Chain Diseases (HCDs) A. gamma HCD B. alpha HCD C. mu HCD IV. Cryoglobulinemia V. Primary Amyloidosis (AL) From Kyle RA: Classification and diagnosis of monoclonal gammopathies. In Rose NR, Friedman H, Fahey JL (eds): Manual of Clinical Laboratory Immunology, 3rd ed. Washington, DC, American Society for Microbiology, 1986, p 152.

Quantitation of Immunoglobulins This procedure is more useful than immunofixation for the detection of hypogammaglobulinemia. Rate nephelometry is the preferred method. Serum Viscometry Serum viscometry should be measured when the IgM monoclonal level is more than 4 g/dL, when the IgA or IgG value is more than 5 g/dL, or when the patient has oronasal bleeding, blurred vision, or other symptoms suggestive of a hyperviscosity syndrome. Analysis of Urine Dipstick tests are used in many laboratories to screen for protein, but unfortunately they are often insensitive to Bence Jones protein. Consequently, sulfosalicylic acid or Exton's reagent is best for the detection of protein. Screening tests for Bence Jones proteins (monoclonal light chain in the urine) that use their unique thermal properties are not recommended because of their serious shortcomings. Immunofixation of an adequately concentrated 24-hour urine specimen reliably detects Bence Jones protein. An M-protein appears as a dense, localized band on the agarose gel or a tall, narrow, homogeneous peak in the densitometer tracing, and its amount can be calculated on the basis of the size of the spike and the amount of total protein in the 24-hour specimen. It is not uncommon to have a negative reaction for protein and no obvious spike on electrophoresis and yet for immunofixation of a concentrated urine specimen to show a monoclonal light chain. Immunofixation should also be done on the urine of every adult older than age 40 who develops a nephrotic syndrome of unknown cause. The presence of a monoclonal light chain in nephrotic urine is strongly suggestive of primary amyloidosis or light chain deposition disease.

MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE The term monoclonal gammopathy of undetermined significance (benign monoclonal gammopathy) denotes the presence of an M-protein in persons without evidence of multiple myeloma, macroglobulinemia, amyloidosis, or other related diseases. The term benign monoclonal gammopathy is misleading because at diagnosis it is not known whether the process producing an M-protein will remain stable and benign or will develop into symptomatic multiple myeloma, macroglobulinemia, amyloidosis, or a related disorder. MGUS is characterized by a serum M-protein concentration less than 3 g/dL; fewer than 5% plasma cells in the bone marrow; no or only small amounts of M-protein in the urine; absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency; and, most important, the stability of the amount of the M-protein and the failure of other abnormalities to develop. Incidence More than 50% of patients with a serum M-protein will have an initial clinical diagnosis of MGUS (Fig. 181-3) . The prevalence of MGUS is 1% of patients older than 50 years and 3% of those older than 70 years. Because of this high prevalence, it is crucial to determine whether the M-protein will remain benign or will evolve to multiple myeloma, amyloidosis, macroglobulinemia, or another lymphoproliferative disease. Prognosis In one series of 241 patients followed long-term after a diagnosis of benign monoclonal gammopathy (i.e., patients in whom multiple myeloma, macroglobulinemia, amyloidosis, lymphoma, or related diseases were excluded), the median age of the patients was 64 years at the time when the M-protein was recognized. Of note was that about 75% of the patients had other conditions that brought them to medical attention but that were seemingly unrelated to the monoclonal gammopathy. In these patients, the M-protein level ranged from 0.3 to 3.2 g/dL (median, 1.7 g/dL) and consisted of IgG (73%), IgA (11%), and IgM (14%) or was biclonal (2%). An M-protein was found in the urine in only 9 patients, and bone marrow plasma cells ranged from 1 to 10% (median, 3.0%). Anemia, 979

Figure 181-3 A, Distribution of serum monoclonal proteins in 993 patients seen at the Mayo Clinic during 1996. B, Diagnoses in 1066 cases of monoclonal gammopathy seen at the Mayo Clinic during 1996. CLL = chronic lymphocytic leukemia; Macro = macroglobulinemia; MGUS = monoclonal gammopathy of undetermined significance; SMM = smoldering multiple myeloma. (From Kyle RA: Multiple myeloma, macroglobulinemia, and the monoclonal gammopathies. In Duffy T [ed]: Current Practice of Medicine, 2nd ed. Philadelphia, Current Science, in press, with permission of the publisher.)

leukopenia, leukocytosis, thrombocytopenia, renal insufficiency, and hypercalcemia, when present, were unrelated to the M-protein. At follow-up, 24 to 38 years later, the 241 patients could be divided into four groups. Approximately one tenth of the patients have remained stable and could be classified as having benign monoclonal gammopathy, although they must continue to be observed because serious disease may still develop. No initial laboratory measurements or clinical factors were predictive of which patients would remain in this stable or benign group. In 11% of the patients, the M-protein level increased to more than 3 g/dL, but they did not develop symptomatic multiple myeloma, macroglobulinemia, or related disorders; their condition remained clinically "benign," although with an M-protein level that causes concern. More than half of the patients died of seemingly unrelated causes without developing multiple myeloma, macroglobulinemia, or related disorders. Approximately one fourth of the patients (26%) developed multiple myeloma (18%), macroglobulinemia (3%), amyloidosis (3%), or related disorders (2%), with an actuarial rate of 16% at 10 years, 33% at 20 years, and 40% at 25 years (Fig. 181-4) . The interval from the time of recognition of the M-protein to the diagnosis of serious disease ranged from 2 to 29 years (median, 10 years). In seven patients, multiple myeloma was diagnosed more than 20 years after detection of the serum M-protein. Differentiation of MGUS from Multiple Myeloma and Macroglobulinemia Differentiation of the patient with benign monoclonal gammopathy from one in whom multiple myeloma, macroglobulinemia, or a related disorder eventually develops is very difficult when the M-protein is first recognized. The size of the M-protein is of some help--levels greater than 3 g/dL usually indicate overt multiple myeloma or macroglobulinemia, but some exceptions, such as smoldering multiple myeloma (SMM), exist. Levels of the immunoglobulin classes other than the M-protein (i.e., the

normal polyclonal or background immunoglobulins) are almost always reduced in multiple myeloma or Waldenstrom's macroglobulinemia, but a reduction may also occur in benign monoclonal gammopathy. The association of a monoclonal light chain (Bence Jones proteinuria) with a serum monoclonal gammopathy suggests multiple myeloma or macroglobulinemia, but many patients with small amounts of monoclonal light chain in the urine have stable M-protein levels in the serum for many years. The presence of more than 10% plasma cells in the bone marrow suggests multiple myeloma, but some patients with more plasma cells have remained stable for long periods. The presence of osteolytic lesions strongly suggests multiple myeloma, but metastatic carcinoma may produce lytic lesions

Figure 181-4 Incidence of multiple myeloma, macroglobulinemia, amyloidosis, or lymphoproliferative disease after recognition of monoclonal protein. (From Kyle RA: Multiple myeloma, macroglobulinemia, and the monoclonal gammopathies. In Duffy T [ed]: Current Practice of Medicine, 2nd ed. Philadelphia, Current Science, in press, with permission of the publisher.)

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as well as plasmacytosis and may be associated with an unrelated monoclonal gammopathy. Certain procedures show promise in differentiating the patient with MGUS or SMM from the patient with multiple myeloma. The plasma cell labeling index measures the synthesis of DNA; when elevated, it is good evidence that the patient has multiple myeloma or will soon have symptomatic disease. The presence of circulating plasma cells in the peripheral blood usually indicates active multiple myeloma. However, no single technique reliably differentiates a patient with a benign monoclonal gammopathy from one who will subsequently have symptomatic multiple myeloma or other malignant disease. The M-protein level in the serum and urine should be serially measured, together with periodic re-evaluation of clinical and other laboratory features, to determine whether multiple myeloma or another related disorder is present. In general, if the serum M-protein is less than 2.0 g/dL, electrophoresis should be repeated at 6 months; if it is stable, it should be checked annually. If the serum M-protein is 2.0 g/dL or more without evidence of myeloma or related disorders, electrophoresis should be repeated in 3 months; if it is stable, the test should be repeated annually. If an M-protein is present in the urine, the patient should be followed more closely by repeating serum and urine protein levels at 6-month intervals rather than annually. Association of Monoclonal Gammopathies with Other Diseases Monoclonal gammopathy frequently exists without other abnormalities. However, certain diseases are associated with it more often than expected by chance. LYMPHOPROLIFERATIVE DISORDERS.

An M-protein is found in 3 to 4% of patients with a diffuse lymphoproliferative process but in fewer than 1% of those with a nodular lymphoma. IgM monoclonal gammopathies are more common than IgG or IgA in lymphoproliferative diseases. In a large series of patients in whom a serum IgM monoclonal gammopathy was identified, more than half were originally considered to have MGUS (Table 181-2) . During follow-up, 17% of patients with MGUS of the IgM class developed a malignant lymphoid disease, most frequently Waldenstrom's macroglobulinemia. LEUKEMIA.

M-proteins occur in the sera of some patients with chronic lymphocytic leukemia but with no recognizable effect on the clinical course. M-proteins have also been recognized in hairy cell, adult T cell, chronic myelogenous, acute promyelocytic, and acute myelomonocytic leukemias, but without a documented increased prevalence over that in the normal population. M-proteins may also be found after liver, bone marrow, or kidney transplantation. NEUROLOGIC DISORDERS.

Approximately 5% of patients with sensorimotor peripheral neuropathy of unknown cause have an associated monoclonal gammopathy. In half of those with an IgM monoclonal gammopathy and peripheral neuropathy, the M-protein binds to myelin-associated glycoprotein (MAG). These patients have a slowly progressive sensorimotor neuropathy beginning in the distal extremities and extending proximally. Sensory involvement is more prominent than motor involvement. Cranial nerves and autonomic function are intact. The clinical and electrodiagnostic manifestations resemble those of chronic inflammatory demyelinating TABLE 181-2 CLASSIFICATION

PERCENTAGE OF PATIENTS

Monoclonal gammopathy of undetermined significance

56

Waldenstrom's macroglobulinemia

17

Lymphoma

7

Chronic lymphocytic leukemia

5

Primary amyloidosis (AL)

1

Lymphoproliferative disease

14

Total

100

From Kyle RA, Garton JP: The spectrum of IgM monoclonal gammopathy in 430 cases. Mayo Clin Proc 62:719, 1987, with permission of the Mayo Foundation, Rochester, MN. polyneuropathy. The relationship of the M-protein to the peripheral neuropathy is not clear. DERMATOLOGIC DISEASES.

Lichen myxedematosus (papular mucinosis, scleromyxedema) is characterized by papules, macules, and plaques infiltrating the skin and is associated with a cathodal IgG lambda protein. Pyoderma gangrenosum and necrobiotic xanthogranuloma have also been associated with an M-protein. Monoclonal Gammopathies with Antibody Activity In some patients with MGUS, myeloma, or macroglobulinemia, the M-protein has exhibited unusual specificity to one of various antigens. Examples include actin, dextran, anti-streptolysin O, antinuclear antibody, riboflavin, von Willebrand factor, thyroglobulin, insulin, double-stranded DNA, and apolipoprotein. The binding of calcium by an M-protein may produce hypercalcemia without symptomatic or pathologic consequences. Affected patients should not be treated for hypercalcemia. M-proteins have also been found to bind to copper and to phosphate.

BICLONAL GAMMOPATHIES Biclonal gammopathies occur in 2 to 3% of patients with monoclonal gammopathies. Biclonal gammopathy of undetermined significance accounts for about two thirds of patients. The remainder have multiple myeloma, macroglobulinemia, or other lymphoproliferative diseases. Triclonal gammopathies may also occur.

IDIOPATHIC BENCE JONES PROTEINURIA Bence Jones proteinuria is a recognized feature of multiple myeloma, primary amyloidosis, Waldenstrom's macroglobulinemia, and other malignant lymphoproliferative disorders. A benign Bence Jones proteinuria may also occur. Patients have been documented to have a stable serum level of M-protein and Bence Jones proteinuria for more than 15 years without developing multiple myeloma or related disorders.

MULTIPLE MYELOMA Multiple myeloma (myelomatosis, plasma cell myeloma, or Kahler's disease) is characterized by the neoplastic proliferation of a single clone of plasma cells engaged in the production of a monoclonal immunoglobulin. This clone of plasma cells proliferates in the bone marrow and frequently invades the adjacent bone, producing extensive skeletal destruction that results in bone pain and fractures. Anemia, hypercalcemia, and renal insufficiency are other important features. Etiology and Epidemiology The cause of multiple myeloma is unclear. Exposure to radiation, benzene and other organic solvents, herbicides, and insecticides may play a role. Multiple myeloma has been reported in familial clusters of two or more first-degree relatives and in identical twins. Multiple myeloma accounts for 1% of all malignant disease and slightly more than 10% of hematologic malignancies in the United States. The annual incidence of multiple myeloma is 4 per 100,000. An apparent increased incidence in recent years is probably related to increased availability and use of medical facilities, especially in older persons. Multiple myeloma occurs in all races and all geographic locations. Its incidence in blacks is almost twice that in whites. Multiple myeloma is slightly more common in men than in women. The median age of patients at the time of diagnosis is about 65 years; only 2% of patients are younger than 40. Biologic Aspects Multiple myeloma is a B-cell malignancy with mature plasma cell morphology. In most cases, the plasma cells are CIg+, CD38+, and PCA-1+, and only a minority express CD10, HLA-DR, and CD20. However, the nature of clonogenic cells in myeloma is still unknown. Circulating clonogenic pre-myeloma cells, by means of adhesion molecules, may home to the marrow, where they find an appropriate microenvironment (cytokine network) to differentiate and expand further. T cells may play an important role. In patients with multiple myeloma, CD4 T cells are often 981

reduced. Interleukin-6 (IL-6) is an important growth factor for myeloma cells. Elevated levels of IL-6 have been found in patients with progressive myeloma, in contrast to those with MGUS. Increased expression of c- myc, H- ras, and bcl-2 has been found in myeloma. Ras mutations as well as point mutations of the tumor suppressor gene p53 have been seen. Thus, c- myc, H- ras, and p53 genes may be involved in the pathogenesis of myeloma. Cytogenetic Abnormalities Flow cytometry studies have shown aneuploidy in about 80% of patients, hyperdiploidy in 70%, and hypodiploidy in the remaining 10%. Fluorescence in situ hybridization (FISH) using chromosome-specific probes reveals chromosome abnormalities in over 80% of patients with multiple myeloma. Structural changes of chromosomes 1, 11, and 14, monosomies and trisomies, and translocations have been detected, but no specific abnormality has been demonstrated. Clinical Manifestations SYMPTOMS (Table 181-3) .

Bone pain, particularly in the back or chest and less often in the extremities, is present at the time of diagnosis in more than two thirds of patients. The pain is usually induced by movement and does not occur at night except with change of position. The patient's height may be reduced by several inches because of vertebral collapse. Weakness and fatigue are common and often are associated with anemia. Fever is rare and, when present, is usually from an infection. The major symptoms may result from an acute infection, renal insufficiency, hypercalcemia, or amyloidosis. PHYSICAL FINDINGS.

Pallor is the most frequent physical finding. The liver is palpable in about 20% of patients and the spleen in 5%. Occasionally, extramedullary plasmacytomas may appear. Laboratory Findings A normocytic, normochromic anemia is present initially in two thirds of patients but eventually occurs in nearly every patient with multiple myeloma. The serum protein electrophoretic pattern shows a peak or localized band in 80% of patients, hypogammaglobulinemia in almost 10%, and no apparent abnormality in the remainder. IgG M-protein is found in 53%, IgA in 20%, light chain only (Bence Jones proteinemia) in 17%, IgD in 2%, and biclonal gammopathy in 1%, and 7% have no serum M-protein at diagnosis. Immunofixation of the urine reveals an M-protein in approximately 75% of patients. The kappa/lambda ratio is 2:1. Ninety-eight per cent of patients with multiple myeloma have an M-protein in the serum or urine at the time of diagnosis. In the bone marrow of patients with multiple myeloma, plasma cells usually account for 10% or more of all nucleated cells, but they may range from less than 5% to almost 100% (Fig. 181-5 ; Color Plate 6 J). Bone marrow involvement may be focal rather than diffuse, requiring repeated bone marrow examinations for diagnosis. Identification of a monoclonal immunoglobulin in the cytoplasm of plasma cells by immunoperoxidase staining is helpful for differentiating monoclonal plasma cell proliferation in multiple myeloma from reactive plasmacytosis due to connective tissue disease, metastatic carcinoma, liver disease, and infections. The immunoperoxidase technique is also useful in recognizing neoplastic plasma cells that have atypical features. TABLE 181-3 -- CLINICAL MANIFESTATIONS OF MULTIPLE MYELOMA Skeletal involvement: pain, reduced height, pathologic fractures, hypercalcemia Anemia: due mainly to decreased erythropoiesis; produces weakness and fatigue Renal insufficiency: mainly due to "myeloma kidney" from light chains or hypercalcemia; rarely from amyloidosis Recurrent infections: respiratory and urinary tract infections or septicemia due to gram-positive or gram-negative organisms Bleeding diathesis: from thrombocytopenia or coating of platelets with M-protein Amyloidosis: develops in 10 to 15% Extramedullary plasmacytomas: occur late in the disease Cryoglobulinemia type I: rarely symptomatic

Figure 181-5 Bone marrow aspirate containing increased numbers of abnormal plasma cells.

Radiologic Findings Conventional radiographs reveal abnormalities consisting of punched-out lytic lesions (Fig. 181-6) , osteoporosis, or fractures in 75% of patients. The vertebrae, skull, thoracic cage, pelvis, and proximal humeri and femora are the most frequent sites of involvement. Technetium-99m bone scanning is inferior to conventional radiography and should not be used. Computed tomography (CT) or magnetic resonance imaging (MRI) is helpful in patients who have skeletal pain but no abnormality on radiographs.

Diagnostic Criteria Minimal criteria for the diagnosis of multiple myeloma are a bone marrow containing more than 10% plasma cells or a plasmacytoma plus at least one of the following: (1) M-protein in the serum (usually greater than 3 g/dL), (2) M-protein in the urine, and (3) lytic bone lesions. These findings must not be from metastatic carcinoma, connective tissue diseases, chronic infection, or lymphoma. Patients with multiple myeloma must be differentiated from those with MGUS and smoldering multiple myeloma. Organ Involvement RENAL.

Bence Jones proteinuria detected by immunofixation is present in 75%. The serum creatinine value is increased initially in almost half of patients and is 2 mg/dL or more in one fourth. The two major causes of renal insufficiency are "myeloma kidney" and hypercalcemia. Myeloma kidney is characterized by the

Figure 181-6 Skull roentgenogram showing multiple lytic lesions.

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presence of large waxy laminated casts in the distal and collecting tubules. The casts are composed mainly of precipitated monoclonal light chains. The extent of cast formation correlates directly with the amount of free urinary light chain and with the severity of renal insufficiency. With dehydration, acute renal failure may occur. Hypercalcemia, which is present in 15 to 20% of patients initially, is a major and treatable cause of renal insufficiency. It results from destruction of bone. Hyperuricemia may contribute to renal failure. Amyloidosis occurs in 10 to 15% of patients and may produce nephrotic syndrome or renal insufficiency or both. Acquired Fanconi's syndrome, characterized by proximal tubular dysfunction, results in glycosuria, phosphaturia, and aminoaciduria. Deposition of monoclonal light chains in the renal glomerulus (light-chain deposition disease) may produce renal insufficiency and the nephrotic syndrome. NEUROLOGIC.

Radiculopathy, the single most frequent neurologic complication, is usually in the thoracic or lumbosacral area and results from compression of the nerve by the vertebral lesion or by the collapsed bone itself. Compression of the spinal cord occurs in up to 10% of patients. Peripheral neuropathy is uncommon in multiple myeloma and, when present, is usually caused by amyloidosis. Rarely, myeloma cells diffusely infiltrate the meninges. Intracranial plasmacytomas almost always represent extensions of myelomatous lesions of the skull. Other Systemic Involvement Hepatomegaly from plasma cell infiltration is uncommon. Ascites is rare. Plasmacytomas of the ribs are common and present either as expanding bone lesions or as soft tissue masses. The incidence of infections is increased in multiple myeloma. Streptococcus pneumoniae and Staphylococcus aureus organisms have been the most frequent pathogens, but gram-negative organisms now account for more than half of all infections. Propensity to infection results from impairment of antibody response, deficiency of normal immunoglobulins, and neutropenia. Bleeding from coating of the platelets by the M-protein may occur. Occasionally, a tendency to thrombosis is present. Treatment Not all patients who fulfill the minimal criteria for the diagnosis of multiple myeloma should be treated. Patients with MGUS or SMM should not be treated. The patient's symptoms, physical findings, and all laboratory data must be considered. An increasing level of the M-protein in the serum or urine suggests that therapy will be needed in the near future. Indications for therapy include the development of significant anemia, hypercalcemia, or renal insufficiency; the occurrence of lytic bone lesions; and the finding of extramedullary plasmacytomas. If there is doubt in the physician's mind, it is usually better to withhold therapy and to re-evaluate the patient in 2 or 3 months. RADIATION THERAPY.

Palliative radiation in a dose of 20 to 30 Gy should be limited to patients who have multiple myeloma with disabling pain and a well-defined focal process that has not responded to chemotherapy. Analgesics in combination with chemotherapy usually can control the pain. AUTOLOGOUS STEM CELL TRANSPLANTATION.

If the patient is younger than 70 years, the physician should discuss the possibility of autologous peripheral blood stem cell transplantation (see Chapter 182) , ideally as part of a prospective study. Peripheral blood stem cells are preferable to bone marrow transplantation because engraftment is more rapid and there is less contamination of the infused cells with tumor cells. Most investigators prefer vincristine, doxorubicin (Adriamycin), and dexamethasone, the VAD regimen, as the initial therapy because these drugs do not damage hematopoietic stem cells. The patient is treated initially with VAD or a similar program for 3 to 4 months to reduce the number of tumor cells in the bone marrow and peripheral blood. The patient is then given high-dose cyclophosphamide followed by granulocyte colony-stimulating factor, and the peripheral stem cells are collected. One can proceed with the transplantation, in which the patient is given high-dose melphalan and total-body irradiation or a similar preparative regimen followed by infusion of the peripheral blood stem cells. The alternative is to treat the patient with alkylating agents until a plateau state is reached and then maintain the patient with alpha2 -interferon or no therapy until early relapse. At that point, the patient is given high-dose melphalan and total-body irradiation, and the previously collected peripheral blood stem cells are infused. In a randomized prospective study comparing autologous bone marrow transplantation with conventional chemotherapy, the median survival was longer with transplantation than with chemotherapy. In a study of 496 patients enrolled in a non-randomized transplant program, complete response was obtained in 36% of patients, and the transplant-related mortality rate was 7%. The median duration of survival from the time of the first transplantation was 41 months. Autologous peripheral stem cell or bone marrow transplantation is applicable for up to 50% of patients with multiple myeloma. However, two major problems exist: (1) the multiple myeloma is not eradicated even with large doses of chemotherapy and total-body irradiation, and (2) infused peripheral blood stem cells or bone marrow cells are usually contaminated by myeloma cells or their precursors and may contribute to relapse. The complete remission rate is higher with high-dose chemotherapy, but the duration of response is relatively short, ranging from 1 to 3 years. Few, if any, patients are cured. Autologous transplantation should not be performed if the patient has received long-term chemotherapy and has refractory multiple myeloma. Purging of tumor cells or collection of CD34+ cells is of potential value. However, delayed engraftment may occur with stem cell selection because stem cells may be lost during collection. ALLOGENEIC BONE MARROW TRANSPLANTATION.

Ninety to 95 per cent of patients with multiple myeloma cannot have an allogeneic bone marrow transplantation because of their age, lack of an HLA-matched sibling donor, and inadequate renal, pulmonary, or cardiac function. Allogeneic transplantation has the advantage that the graft does not contain tumor cells, and it can produce a graft-versus-myeloma effect. Unfortunately, the mortality rate from the procedure is approximately 25% within the first 3 months and approaches 40% overall. Although complete response occurs in 40% of patients, most will relapse; and in long-term follow-up there is no apparent survival plateau. The use of T cell-depleted peripheral blood stem cells decreases the incidence of graft-versus-host disease and reduces transplant-related mortality. Donor lymphocyte infusions have produced significant benefit in up to one half of patients after allogeneic transplantation.

CHEMOTHERAPY.

Chemotherapy is the preferred initial treatment for overt, symptomatic multiple myeloma in patients older than 70 years or in younger patients in whom transplantation is not feasible. The oral administration of melphalan and prednisone produces objective response in 50 to 60% of patients. Melphalan can be given daily in a dosage of 0.15 mg/kg for 7 days (8-10 mg/day), with 20 mg of prednisone three times daily for the same 7 days. The melphalan must be given while the patient is fasting, because food reduces absorption. Leukocyte and platelet levels should be determined every 3 weeks after beginning each cycle of therapy, and the melphalan and prednisone treatment should be repeated every 6 weeks. The dosage of melphalan must be adjusted until mid-cycle cytopenia occurs. Unless the disease progresses rapidly, at least three courses of melphalan and prednisone should be given before therapy is discontinued. Because the natural course of multiple myeloma is to progress, alleviation of pain and stabilization of disease usually indicate some therapeutic benefit. An objective improvement may not be achieved for 6 to 12 months or longer in some patients. Because of the obvious shortcomings of melphalan and prednisone, various combinations of therapeutic agents have been tried. Generally, objective responses are higher, but no differences in survival have been reported in most studies. Chemotherapy should be continued for at least 1 year or until the patient is in a plateau state. At that point, interferon-alpha2 may be given; it prolongs the duration of the plateau state but does not generally produce significant survival benefit. If relapse occurs while in the plateau state, the initial chemotherapeutic regimen should be reinstituted. Most patients will respond, but the duration and quality of response are usually inferior to those of the initial response.

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Refractory Multiple Myeloma Almost all patients with multiple myeloma will eventually relapse. The highest response rates for patients resistant to alkylating agents have been with the VAD regimen. Dexamethasone is administered in a dosage of 40 mg/day on days 1-4, 9-12, and 17-20. The cycles are repeated every 28 days. Dexamethasone is usually given only on days 1-4 in even-numbered cycles because of toxicity. Most of the VAD activity is from the corticosteroid effects of dexamethasone. Methylprednisolone, 2 g three times weekly intravenously for a minimum of 4 weeks, is helpful for patients with pancytopenia and may have fewer side effects than from dexamethasone. If there is a response, methylprednisolone is reduced to once or twice weekly. VBAP (vincristine, carmustine [BCNU], and doxorubicin [Adriamycin]) on day 1 and prednisone daily for 5 days every 3 to 4 weeks benefits 30% of patients. It is well tolerated. If the patient's leukocyte and platelet levels are satisfactory, cyclophosphamide, 600 mg/m2 /day intravenously for 4 days (days 1-4), plus prednisone, 50 mg twice a day for the same 4-day period, followed by granulocyte colony-stimulating factor, has been helpful in patients with refractory advanced disease. The use of interferon as a single agent for these patients has been disappointing. The reversal of resistance to chemotherapeutic agents is an important area of research. The use of verapamil or quinine to reverse the resistance to doxorubicin has been disappointing. PSC-833, an analogue of cyclosporin A, is being investigated in an effort to reduce multidrug resistance to Vinca alkaloids and anthracyclines. Management of Complications HYPERCALCEMIA.

Hypercalcemia, present in 15 to 20% of patients at diagnosis, should be suspected in the presence of anorexia, nausea, vomiting, polyuria, polydipsia, increased constipation, weakness, confusion, or stupor. If hypercalcemia is untreated, renal insufficiency may develop. Hydration, preferably with isotonic saline plus prednisone (25 mg four times per day), relieves the hypercalcemia in most cases. The dosage of prednisone must be reduced and its use discontinued as soon as possible. If these measures fail, bisphosphonates such as pamidronate disodium or etidronate disodium are beneficial. Patients with myeloma should be encouraged to be as active as possible because prolonged bed rest contributes to hypercalcemia. RENAL INSUFFICIENCY.

This complication occurs in half of patients with multiple myeloma and may develop insidiously or rapidly (acute renal failure). Hydration and prednisone are necessary if there is accompanying hypercalcemia. Furosemide is helpful for maintaining a high urine flow rate (100 mL/hr). Hemodialysis is necessary in the event of symptomatic azotemia. Plasmapheresis may be helpful for regaining renal function, but patients with severe myeloma cast formation or other irreversible changes are unlikely to benefit from plasmapheresis. Allopurinol is necessary if hyperuricemia is present. Renal transplantation for myeloma kidney has been followed by prolonged survival. Maintenance of a high urine output (3 L/day) is important for preventing renal failure in patients with Bence Jones proteinuria. INFECTION.

Prompt, appropriate therapy for bacterial infections is necessary. Prophylactic penicillin often benefits patients with recurrent gram-positive infections. Intravenously administered gamma-globulin is helpful but expensive. Pneumococcal and influenza immunizations should be given to all patients. SKELETAL LESIONS.

Patients should be encouraged to be as active as possible but to avoid trauma. Fixation of fractures or impending fractures of long bones with an intramedullary rod and methyl methacrylate has produced good results. Patients in a prospective study receiving 90 mg of pamidronate every 4 weeks had fewer skeletal complications and improved quality of life; this medication is recommended for myeloma patients with skeletal involvement. MISCELLANEOUS COMPLICATIONS.

Symptomatic hyperviscosity should be treated with plasmapheresis. Hyperviscosity is usually manifested by oronasal bleeding, blurred vision, or heart failure. Serum viscosity levels do not correlate well with the symptoms or clinical findings. Plasmapheresis promptly relieves the symptoms and should be done regardless of the viscosity level, if the patient is symptomatic. Anemia during the plateau state often responds to erythropoietin. Spinal cord compression from an extramedullary plasmacytoma should be suspected in patients with severe back pain, the development of weakness or paresthesias of the lower extremities, or bladder or bowel dysfunction. MRI, CT, or myelography must be done immediately. Dexamethasone and radiation therapy are usually helpful. If the neurologic deficit increases, surgical decompression is necessary. Prognosis Multiple myeloma has a progressive course, and the median survival is approximately 3 years. The bone marrow plasma cell labeling index and beta2 -microglobulin level are the most important prognostic factors in previously untreated multiple myeloma. Cytogenetics contribute important and independent prognostic information: partial or complete deletion of chromosome 13, chromosome 11q abnormalities, and the presence of any translocation are predictors of a poor outcome. The level of C-reactive protein correlates with the serum IL-6 level and is a useful prognostic factor. An increased lactase dehydrogenase level is a predictor of poor prognosis. Advanced age, plasmablastic morphology, circulating myeloma cells in the peripheral blood, increased myeloma colony growth, and increased levels of IL-6 are all associated with more aggressive disease. Patients who respond rapidly to chemotherapy and who have an increased plasma cell labeling index have a shorter remission and survival. Twenty to 30 per cent of patients survive 5 or more years, but fewer than 5% survive longer than 10 years. In some patients, an acute or aggressive terminal phase is characterized by rapid tumor growth, pancytopenia, soft tissue subcutaneous masses, decreased M-protein levels, and fever; the survival in this subset is usually only a few months.

VARIANT FORMS OF MULTIPLE MYELOMA (See Table 181-1) Smoldering Multiple Myeloma The diagnosis of SMM depends on the presence of an M-protein level of more than 3 g/dL in the serum and more than 10% plasma cells in the bone marrow, but no anemia, renal insufficiency, or skeletal lesions. Often, a small amount of M-protein is found in the urine and the concentration of normal immunoglobulins in the serum

is decreased. The plasma cell labeling index is low. Biologically, patients with SMM have a benign monoclonal gammopathy (MGUS), but it is difficult to accept that diagnosis initially when the M-protein level is greater than 3 g/dL and the bone marrow contains more than 10% plasma cells. These patients must be observed over time because symptomatic multiple myeloma develops in many of them. However, SMM should be recognized because patients must not be treated unless progression occurs. Plasma Cell Leukemia Patients with plasma cell leukemia have greater than 20% plasma cells in the peripheral blood and an absolute plasma cell count of at least 2000/muL. Plasma cell leukemia is classified as primary when it is diagnosed in the leukemic phase (60%) or as secondary when there is leukemic transformation of a previously recognized multiple myeloma (40%). Patients with primary plasma cell leukemia are younger and have a greater incidence of hepatosplenomegaly and lymphadenopathy, a higher platelet count, fewer bone lesions, a smaller serum M-protein component, and a longer survival (median, 6.8 vs. 1.3 months) than patients with secondary plasma cell leukemia. Treatment of plasma cell leukemia is unsatisfactory, but partial responses occur with melphalan and prednisone or with a combination of alkylating agents. Autologous stem cell transplantation after myeloablative therapy is beneficial for some patients. Secondary plasma cell leukemia rarely responds to chemotherapy because the patients have already received chemotherapy and are resistant. Non-Secretory Myeloma Patients with non-secretory myeloma have no M-protein in either the serum or the urine and account for only 1 to 2% of those with myeloma. For certainty of diagnosis, an M-protein must be identified in the plasma cells by immunoperoxidase or immunofluorescence 984

methods. More than a dozen patients in whom no M-protein could be found within the myeloma cell have been described. Response to therapy and survival rate of patients with non-secretory myeloma are similar to those in patients with a serum or urinary M-component, but renal involvement is less. IgD Myeloma The M-protein is smaller than in IgG and IgA myelomas, and Bence Jones proteinuria of the lambda-type is more common. Amyloidosis and extramedullary plasmacytomas are more frequent with IgD myeloma. Survival is generally believed to be shorter than with other myeloma types, but IgD myeloma is often not diagnosed until later in its course. Osteosclerotic Myeloma (POEMS Syndrome) This syndrome is characterized by polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS). The major clinical features are a chronic inflammatory-demyelinating polyneuropathy with predominantly motor disability and sclerotic skeletal lesions. Except for the presence of papilledema, the cranial nerves are not involved. The autonomic nervous system is intact. Hepatomegaly occurs in almost one half of patients, but splenomegaly and lymphadenopathy occur in a minority. Hyperpigmentation and hypertrichosis are usually evident. Gynecomastia and atrophic testes as well as clubbing of the fingers and toes may be seen. In contrast to multiple myeloma, the hemoglobin level is usually normal or elevated and thrombocytosis is common. The bone marrow usually contains fewer than 5% plasma cells, and hypercalcemia and renal insufficiency rarely occur. Most patients have a lambda protein. Evidence of Castleman's disease may be found. Diagnosis is confirmed by the identification of monoclonal plasma cells obtained at biopsy of an osteosclerotic lesion. If the lesions are in a limited area, radiation therapy will produce substantial improvement of the neuropathy in more than half of the patients. If the patient has widespread osteosclerotic lesions, chemotherapy with melphalan and prednisone may be helpful. Solitary Plasmacytoma (Solitary Myeloma) of Bone Diagnosis of this disease is based on histologic evidence of a tumor consisting of monoclonal plasma cells identical to those seen in multiple myeloma. In addition, complete skeletal radiographs must show no other lesions of myeloma, the bone marrow aspirate must contain no evidence of multiple myeloma, immunofixation of the serum and concentrated urine should show no M-protein. Exceptions to the last-mentioned criterion occur, but therapy for the solitary lesion usually results in the disappearance of the M-protein. Almost 50% of patients with solitary plasmacytoma are alive at 10 years, and disease-free survival at 10 years ranges from 15 to 25%. Treatment consists of radiation in the range of 40 to 50 Gy. There is no evidence that chemotherapy affects the incidence of conversion to multiple myeloma. Progression usually occurs within 3 to 4 years, but the most uncertain criterion for diagnosis is the duration of observation necessary before deciding that the disease will not become generalized. Extramedullary Plasmacytoma Extramedullary plasmacytoma is a plasma cell tumor that arises outside the bone marrow. The tumor is found in the upper respiratory tract in approximately 80% of cases, especially in the nasal cavity and sinuses, nasopharynx, and larynx. Extramedullary plasmacytomas may also occur in the gastrointestinal tract, central nervous system, urinary bladder, thyroid, breast, testes, parotid gland, or lymph nodes. The diagnosis is based on the finding of a plasma cell tumor in an extramedullary site and the absence of multiple myeloma on bone marrow examination, radiography, and appropriate studies of blood and urine. Treatment consists of tumoricidal irradiation. The plasmacytoma may occur locally, metastasize to regional nodes, or, rarely, develop into multiple myeloma.

WALDENSTROM'S MACROGLOBULINEMIA (PRIMARY MACROGLOBULINEMIA) Macroglobulinemia is the result of an uncontrolled proliferation of lymphocytes and plasma cells in which a large IgM M-protein is produced. The cause is unknown, but it occurs more frequently in certain families. The median age of patients at the time of diagnosis is about 65 years, and about 60% are male. Clinical Presentations Weakness, fatigue, and bleeding (especially oozing from the oronasal area) are common presenting symptoms. Blurred or impaired vision, dyspnea, loss of weight, neurologic symptoms, recurrent infections, and heart failure may occur. In contrast to multiple myeloma, lytic bone lesions, renal insufficiency, and amyloidosis are rare. Physical findings include pallor, hepatosplenomegaly, and lymphadenopathy. Retinal hemorrhages, exudates, and venous congestion with vascular segmentation ("sausage" formation) may occur. Sensorimotor peripheral neuropathy is common. Pulmonary involvement is manifested by diffuse pulmonary infiltrates and isolated masses. Pleural effusion may occur. Diarrhea and steatorrhea are uncommon. Laboratory Evaluation Almost all patients have moderate to severe normocytic, normochromic anemia. Coombs-positive hemolytic anemia is uncommon. The serum cholesterol value is often low. The serum electrophoretic pattern is characterized by a tall, narrow peak or dense band and is usually of lambda mobility. Seventy-five per cent of the IgM proteins have a kappa light chain. Low-molecular-weight IgM (7S) is present and may account for a significant part of the elevated IgM level. A monoclonal light chain is present in the urine of 80% of patients. The amount of urinary protein is usually modest. The bone marrow aspirate is often hypocellular, but the biopsy is hypercellular and extensively infiltrated with lymphoid cells and plasma cells. The number of mast cells is frequently increased. Rouleaux formation is prominent, and the sedimentation rate is markedly increased unless gelation of the plasma occurs. About 10% of macroglobulins have cryoproperties. Diagnosis The combination of typical symptoms and physical findings, the presence of a large IgM M-protein (usually greater than 3 g/dL), and lymphoid-plasma cell infiltration of the bone marrow provide the diagnosis. Multiple myeloma, chronic lymphocytic leukemia, and MGUS of the IgM type must be excluded. Treatment Patients should not be treated unless they have anemia; constitutional symptoms such as weakness, fatigue, night sweats, or weight loss; hyperviscosity; or significant

hepatosplenomegaly or lymphadenopathy. Chlorambucil (Leukeran) is usually given orally in a dosage of 6 to 8 mg/day and is reduced when the leukocyte or platelet value decreases. Patients should be treated until the disease has reached a plateau state; the treatment can be discontinued and the patients observed closely. Chemotherapy should be reinstituted when the disease relapses. Combinations of alkylating agents, such as the M2 protocol (vincristine, BCNU, melphalan, cyclophosphamide, and prednisone), may be beneficial. alpha2 -Interferon may be of some use. Eighty per cent of previously untreated patients have been reported to respond to fludarabine or 2-chlorodeoxyadenosine. Autologous stem cell transplants have been performed in some cases, but series results have not been published. Transfusions of packed red blood cells should be given for symptomatic anemia. Spuriously low hemoglobin and hematocrit levels may occur because of the increased plasma volume from the large amount of M-protein. Consequently, transfusions should not be given solely on the basis of the hemoglobin or hematocrit value. Symptomatic hyperviscosity should be treated with plasmapheresis. The median survival in macroglobulinemia is 5 years.

HYPERVISCOSITY SYNDROME Chronic nasal bleeding and oozing from the gums are frequent, but postsurgical or gastrointestinal bleeding also may occur. Retinal hemorrhages are common, and papilledema may be seen. The patient occasionally complains of blurring or a loss of vision. Dizziness, headache, vertigo, nystagmus, decreased heating, ataxia, paresthesias, diplopia, somnolence, and coma may occur. Hyperviscosity can precipitate or aggravate heart failure. Most patients 985

have symptoms when the relative viscosity is greater than 4 centipoises (cP), but the relationship between serum viscosity and clinical manifestations is not precise. Patients with symptomatic hyperviscosity should be treated with plasmapheresis. Plasma exchange of 3 to 4 L should be performed daily until the patient is asymptomatic. The plasma should be replaced with albumin rather than plasma.

HEAVY CHAIN DISEASES The heavy chain diseases (HCDs) are characterized by the presence of an M-protein consisting of a portion of the immunoglobulin heavy chain in the serum or urine or both. These heavy chains are devoid of light chains and represent a lymphoplasma cell proliferative process. There are three major types: gamma-HCD, alpha-HCD, and mu-HCD. gamma-HCD The abnormal protein consists of gamma chain with significant deletions of amino acids, including the CH1 domain of the constant region. The median age of patients is approximately 60 years, although the condition has been noted in persons younger than 20. Patients with gamma-HCD often present with a lymphoma-like illness, but the clinical findings are diverse and range from an aggressive lymphoproliferative process to an asymptomatic state. Hepatosplenomegaly and lymphadenopathy occur in about 60% of patients. Anemia is found in about 80% initially and in nearly all eventually. A few patients have had a Coombs-positive hemolytic anemia. The electrophoretic pattern often shows a broad-based band more suggestive of a polyclonal increase than an M-protein. The urinary protein value ranges from a trace to 20 g/day, but it is usually less than 1 g/24 hours. Increased numbers of lymphocytes, plasma cells, or plasmacytoid lymphocytes are seen in the bone marrow and lymph nodes. The histologic pattern varies, usually including generalized or localized lymphoma or myeloma, but in some cases there is no evidence of a lymphoplasmacytic proliferative process. Treatment is indicated only for symptomatic patients. Many different drugs have been used, but the results have been inconsistent and generally disappointing. Therapy with cyclophosphamide, vincristine, and prednisone is a reasonable choice. If there is no response to this regimen, doxorubicin should be added. The prognosis of gamma-HCD is variable and ranges from a rapidly progressive downhill course of a few weeks' duration to the asymptomatic presence of a stable monoclonal heavy chain in the serum or urine. alpha-HCD This most common HCD occurs in patients from the Mediterranean region or Middle East, usually in the second or third decade of life. About 60% are men. Most commonly, the gastrointestinal tract is involved, resulting in severe malabsorption with diarrhea, steatorrhea, and loss of weight. Plasma cell infiltration of the jejunal mucosa is the most frequent pathologic feature. Immunoproliferative small intestinal disease is restricted to patients with small intestinal lesions who have the same pathologic features as those of alpha-HCD, but these patients do not synthesize alpha heavy chains. The serum protein electrophoretic pattern is normal in half the cases, and in the remainder an unimpressive broad band may appear in the alpha2 or beta regions. The diagnosis depends on the recognition of a monoclonal alpha heavy chain. The amount of alpha heavy chain in the urine is small, and Bence Jones proteinuria has never been reported. Most often, alpha-HCD is progressive and fatal, but it may respond to melphalan or to cyclophosphamide and prednisone. Antibiotics such as tetracyclines may also produce a remission. mu-HCD This disease is characterized by the demonstration of a monoclonal mu-chain fragment in the serum. The patient may present with chronic lymphocytic leukemia or lymphoma, but it is likely that the clinical spectrum will broaden when more cases are recognized. The serum protein electrophoretic pattern is usually normal except for hypogammaglobulinemia. Bence Jones proteinuria has been found in two thirds of cases. An increase in lymphocytes, plasma cells, and lymphoplasmacytoid cells is seen in the bone marrow. Vacuolization of the plasma cells is common and should suggest the possibility of HCD. The course of mu-HCD is variable, and survival ranges from a few months to many years. Treatment with corticosteroids and alkylating agents has produced some benefit.

CRYOGLOBULINEMIA Cryoglobulins are proteins that precipitate when cooled and dissolve when heated. They are designated as idiopathic or essential when they are not associated with any recognizable disease. Cryoglobulins are classified into three types: type I (monoclonal), type II (mixed), and type III (polyclonal). Type I (monoclonal) cryoglobulinemia is most commonly of the IgM or IgG class, but IgA and Bence Jones cryoglobulins have been reported. Most patients, even with large amounts of type I cryoglobulin, are completely asymptomatic from this source. Others with monoclonal cryoglobulins in the range of 1 to 2 g/dL may have pain, purpura, Raynaud's phenomenon, cyanosis, and even ulceration and sloughing of skin and subcutaneous tissue on exposure to the cold because their cryoglobulins precipitate at relatively high temperatures. Type I cryoglobulins are associated with macroglobulinemia, multiple myeloma, or MGUS. Type II (mixed) cryoglobulinemia typically consists of an IgM M-protein and polyclonal IgG, although monoclonal IgG or monoclonal IgA may also be seen with polyclonal IgM. Serum protein electrophoresis usually shows a normal pattern or a diffuse, polyclonal hypergammaglobulinemic pattern. The quantity of mixed cryoglobulin is usually less than 0.2 g/dL. Vasculitis, glomerulonephritis, lymphoproliferative disease, and chronic infectious processes are common. Purpura and polyarthralgias are frequently seen. Involvement of the joints is symmetric, but joint deformities rarely develop. Raynaud's phenomenon, necrosis of the skin, and neurologic involvement may be present. In almost 80% of renal biopsy specimens, glomerular damage can be identified. Nephrotic syndrome may result, but severe renal insufficiency is uncommon. Hepatic dysfunction and serologic evidence of infection with hepatitis C virus are common. Early administration of corticosteroids is the most frequent therapy. alpha2 -Interferon has been of benefit, but relapse is common after cessation of therapy. Cyclophosphamide, chlorambucil, or azathioprine should be used if there is no response. Plasmapheresis has been effective in some instances. Type III (polyclonal) cryoglobulinemia is not associated with a monoclonal component. Type III cryoglobulins are found in many patients with infections or inflammatory diseases and are of no clinical significance.

PRIMARY AMYLOIDOSIS (AL) Amyloid, stained with Congo red, produces an apple-green birefringence under polarized light. It is a fibrous protein that consists of rigid, linear, non-branching, aggregated fibrils of 7.5 to 10 nm width and of indefinite length. The type of amyloid cannot be differentiated by organ distribution or by electron microscopy. The amyloid fibrils in AL consist of the variable portion of a monoclonal light chain or, in some instances, the intact light chain (Table 181-4) . The light-chain class is more frequently lambda than kappa (2:1), with a predominance of the lambdaVI subclass. Patients with AL may have aberrant de novo synthesis or abnormal proteolytic processing of light chains. Rarely, the fibril consists of a monoclonal heavy chain. Amyloid P-component (AP) is a glycoprotein found in all types of amyloid, but its function is unknown. The catabolism, or breakdown, of amyloid fibrils is an important but poorly understood factor in pathogenesis. Clinical Features The median age at diagnosis is 64 years, and only 1% of patients are younger than 40. Two thirds are male. Weakness or fatigue and loss of weight are the most frequent symptoms. Dyspnea, pedal edema, paresthesias, light-headedness, and syncope are frequently seen in patients with heart failure or peripheral neuropathy. Hoarseness or change of voice as well as jaw claudication may occur. The liver is palpable in one fourth of patients, but splenomegaly 986

TABLE 181-4 -- CLINICAL CLASSIFICATION OF AMYLOIDOSIS CLASSIFICATION MAJOR PROTEIN COMPONENT

AMYLOID TYPE AL

Primary

kappa or lambda light chain

AA

Secondary

Protein A

AL

Localized

kappa or lambda light chain

ATTR

Familial Neurologic

Transthyretin mutant (prealbumin)

Cardiopathic

Transthyretin mutant (prealbumin)

Nephropathic Familial Mediterranean fever Senile systemic amyloidosis Abeta2 M

Long-term dialysis

Protein A Normal transthyretin (prealbumin) beta2 -Microglobulin

occurs in only 5%. Macroglossia is present in 10%. Purpura often involves the neck, face, and eyes. Ankle edema is common. Almost one third of patients have nephrotic syndrome. Carpal tunnel syndrome, heart failure, peripheral neuropathy, and orthostatic hypotension are other major presenting syndromes (Fig. 181-7) . The presence of one of these syndromes and an M-protein in the serum or urine is a strong indication of amyloidosis, for which appropriate biopsy specimens must be taken for diagnosis. Laboratory Findings Anemia is not a prominent feature, but, when present, it is usually due to renal insufficiency, multiple myeloma, or gastrointestinal bleeding. Thrombocytosis occurs in 10% of patients. Proteinuria is present initially in 80% and renal insufficiency in almost 50% of patients. Elevation of the serum alkaline phosphatase value is not uncommon. Hyperbilirubinemia is infrequent, but, when present, it is an ominous sign. Hypoalbuminemia and elevation of the cholesterol and triglyceride values are common with the nephrotic syndrome. The Factor X level is decreased in more than 10% of patients but is rarely the cause of bleeding. The prothrombin time is increased in about 15% of patients, and the thrombin time is prolonged in 60%. A localized band or spike in the serum protein electrophoretic pattern is found in about half of patients, but it is modest in size (median, 1.4 g/dL). Hypogammaglobulinemia is present in about 20%. Immunofixation reveals an M-protein in the serum and in the urine of more than 70% of patients. An M-protein is found in the serum or urine in almost 90% of patients at diagnosis. Bone marrow plasma cells are usually only modestly increased, with a median value of 7%. Less than one fifth of patients have more than 20% plasma cells in the marrow. Radiographs of the bones are normal unless the patient has multiple myeloma.

Figure 181-7 Syndromes seen at diagnosis and during follow-up of patients with primary amyloidosis. Some patients had more than two syndromes at presentation. CHF = congestive heart failure; Ortho hypo = orthostatic hypotension. (From Kyle RA, Gertz MA: Primary systemic amyloidosis: Clinical and laboratory features in 474 cases. Semin Hematol 32:45, 1995.)

Organ System Involvement CARDIAC AND CIRCULATORY.

Heart failure is present in approximately 20% of patients at diagnosis and develops during the course of the disease in an additional 10%. The electrocardiogram frequently shows either low voltage in the limb leads or features consistent with an anteroseptal infarction (loss of anterior forces), but there is no evidence of myocardial infarction at autopsy. Atrial fibrillation, atrial or junctional tachycardia, ventricular premature complexes, and heart block are common electrocardiographic features. Echocardiography is valuable for evaluation of amyloid heart disease. Increased thickness of the ventricular wall and septum correlates with an increased prevalence of heart failure (see Chapter 64) . Early cardiac amyloidosis is characterized by abnormal relaxation, whereas advanced involvement is characterized by restrictive hemodynamics. Intermittent claudication of the lower extremities, the upper extremities, or the jaw may be a prominent feature. Orthostatic hypotension occurs in about 15%. OTHER ORGANS.

Nephrotic syndrome is present in more than one fourth of patients at the time of diagnosis. The degree of proteinuria does not correlate well with the extent of amyloid deposition in the kidney. Gross hematuria is rare. Other organ involvement includes the lungs and gastrointestinal tract, but it is asymptomatic in most instances. Sensorimotor peripheral neuropathy characterized by dysesthetic numbness involving the lower extremities occurs in one sixth of patients. Autonomic dysfunction may be a prominent feature and is usually manifested by orthostatic hypotension, diarrhea, or impotence. Amyloidosis can involve the periarticular structures and produce the shoulder pad syndrome. Rarely, osteolytic lesions from amyloid may occur. Pseudohypertrophy of skeletal muscles from amyloid deposition may be impressive. Petechiae, ecchymoses, papules, plaques, nodules, tumors, bullous lesions, thickening of the skin, and dystrophy of the nails may occur. The diagnosis of amyloidosis depends on histologic proof. The initial diagnostic procedure should be abdominal fat aspiration, which is positive in 80% of patients. A bone marrow aspiration and biopsy should be done to determine the degree of plasmacytosis, and results are positive for amyloid in more than one half of patients. The abdominal fat or bone marrow biopsy results are positive in 90%. If subcutaneous fat and bone marrow biopsies are negative, a rectal biopsy should be done, or tissue should be obtained from a suspected organ.

Specific antisera are helpful for identifying the type of systemic amyloidosis. Antiserum to AP reacts with all amyloid types and is useful in demonstrating the presence of amyloid. Prognosis Currently, the median survival of patients with AL amyloidosis is 13 months. Survival varies greatly, depending on the associated syndrome; it is 4 months after the onset of heart failure. Patients with only peripheral neuropathy have a median survival of 2 years. Treatment Therapy of AL amyloidosis is not satisfactory. In a prospective study of treatment with melphalan and prednisone compared with colchicine, no significant difference in survival was noted (25 and 18 months, respectively). When the survival of patients who received only one regimen was analyzed, or when survival was determined from the time of entry into the study to the time of death or progression of disease, significant differences favoring melphalan and prednisone therapy were evident. In a randomized trial, patients with AL received melphalan and prednisone, colchicine, or a combination of the three. Survival of those receiving the two melphalan/prednisone-containing regimens was superior to that of those with the colchicine schedule. Substantial clinical improvement has been observed with the administration of 4 -iodo-4 -deoxyrubicin (I-DOX) in patients with primary amyloidosis. This agent appears to bind to amyloid fibrils and thus to contribute to the resolution of amyloid deposits. Encouraging results have been reported with high-dose intravenous melphalan (200 mg/m2 ) followed by autologous peripheral stem cell rescue. However, because of the short-term follow-up, the impact of this approach is still unknown. The nephrotic syndrome should be managed with salt restriction and diuretic agents as needed. If symptomatic azotemia develops, chronic renal dialysis is necessary. Salt restriction and the judicious use of diuretic drugs are helpful for heart failure. Digitalis must be 987

avoided or used with great care because patients are unusually sensitive to the drug, and heart block and arrhythmias are common. Elastic stockings or leotards may be of benefit in patients with orthostatic hypotension; fludrocortisone may also be useful, but it leads to retention of fluids. Agnello V: The etiology and pathophysiology of mixed cryoglobulinemia secondary to hepatitis C virus infection. Springer Semin Immunopathol 19:111, 1997. This is a review of mixed cryoglobulinemia associated with hepatitis C virus infection. Attal M, Harousseau J-L: Standard therapy versus autologous transplantation in multiple myeloma. Hematol Oncol Clin North Am 11:133, 1997. This is an update of the first prospective study comparing autologous transplantation and chemotherapy for multiple myeloma. Bataille R, Harousseau J-L: Multiple myeloma. N Engl J Med 336:1657, 1997. This article reviews the highlights of the biology of multiple myeloma. Berenson JR, Lichtenstein A, Porter L, et al, for the Myeloma Aredia Study Group: Long-term pamidronate treatment of advanced multiple myeloma reduces skeletal events. J Clin Oncol 16:593, 1998. This prospective study indicates that pamidronate reduces the number of skeletal complications and improves the quality of life in patients with myeloma. Dimopoulos MA, Alexanian R: Waldenstrom's macroglobulinemia. Blood 83:1452, 1994. This review covers features of the disease, complications, and therapy. Falk RH, Comenzo RL, Skinner M: The systemic amyloidoses. N Engl J Med 337:898, 1997. This is an excellent review of amyloidoses. Frassica DA, Frassica FJ, Schray MF, et al: Solitary plasmacytoma of bone: Mayo Clinic experience. Int J Radiat Oncol Biol Phys 16:43, 1989. In 46 cases of solitary plasmacytoma of bone, the presence of an M-protein did not significantly alter the survival or duration of disease-free survival. Gertz MA, Kyle RA: Hyperviscosity syndromes. J Intensive Care Med 10:128, 1995. Comprehensively reviews the pathophysiology, clinical features, and treatment of hyperviscosity. Gillmore JD, Hawkins PN, Pepys MB: Amyloidosis: A review of recent diagnostic and therapeutic developments. Br J Haematol 99:245, 1997. This is an extensive review of amyloidosis. Jagannath S, Tricot G, Barlogie B: Autotransplants in multiple myeloma: Pushing the envelope. Hematol Oncol Clin North Am 11:363, 1997. This is an extensive and detailed report of autologous transplants in multiple myeloma. Kyle RA: "Benign" monoclonal gammopathy--after 20 to 35 years of follow-up. Mayo Clin Proc 68:26, 1993. 0f 241 patients with MGUS, 24% developed multiple myeloma, macroglobulinemia, amyloidosis, or related disorders. Kyle RA, Gertz MA: Primary systemic amyloidosis: Clinical and laboratory features in 474 cases. Semin Hematol 32:45, 1995. A review of the clinical and laboratory data on 474 primary amyloidosis patients seen at one institution from 1981- 1992 within 30 days of diagnosis. Kyle RA, Gertz MA, Greipp PR, et al: A trial of three regimens for primary amyloidosis: Colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med 336:1202, 1997. This is a prospective study demonstrating that melphalan-prednisone was superior to colchicine in 220 patients with primary amyloidosis. Schey S: Osteosclerotic myeloma and "POEMS" syndrome. Blood Rev 10:75, 1996. This is a well-written review of the POEMS syndrome (osteosclerotic myeloma). Susnerwala SS, Shanks, JH, Banerjee SS, et al: Extramedullary plasmacytoma of the head and neck region: Clinicopathological correlation in 25 cases. Br J Cancer 75:921, 1997. Only 2 of the 25 patients with extramedullary plasmacytomas had development of multiple myeloma.

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Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 182 - STEM CELL TRANSPLANTATION Malcolm K. Brenner

Hematopoietic stem cell transplantation derives its feasibility from the biologic properties of these cells. Even in small numbers (60 mL/kg/day) to reduce clot formation and by maintaining platelet counts above 50,000/mm3 . More severe manifestations require irrigation through an indwelling urinary catheter, along with analgesia and antispasmodics. Refractory severe hematuria requires cystoscopy and instillation of aluminum hydroxide, silver nitrate, or formalin and may also necessitate the placement of ureteric stents, nephrostomy, or even cystectomy. Hemorrhagic cystitis usually resolves, but it may leave the patient with a scarred and dysfunctional urinary tract. Gastrointestinal mucositis with painful oral ulceration, dysphagia, vomiting, and diarrhea occurs almost universally, and it may be exacerbated by GVHD regimens that contain methotrexate. Patients require good oral and perianal hygiene and adequate analgesia until the condition resolves in 10 to 21 days. Most patients also require intravenous hyperalimentation to maintain adequate nutrient intake.

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Pneumonitis and acute carditis represent less than 2% of the regimen-related toxicity and usually occur in patients who have received extensive prior treatment. The mortality is high. Other pulmonary problems such as capillary leak syndrome and pulmonary alveolar hemorrhage occur with greater frequency but have a lower mortality. Treatment is symptomatic. To avoid these major complications, recent efforts have attempted sub-ablative or "mini" transplants using lower doses of cytotoxic drugs and radiation together with immunosuppressive agents. The donor immune system is then able to engraft, to achieve the final hematopoietic ablation, and to allow the donor hematopoietic system to follow. CELL INFUSION. Once the preparative regimen is completed, fresh stem cell products are infused by the usual procedures for blood product infusion, but without in-line filters. Most patients tolerate infusion well, although care must be taken to avoid volume overload, particularly when peripheral stem cells are used. Cryopreserved products are usually thawed at the bedside immediately before infusion. The dimethyl sulfoxide used as a cryoprotectant may cause nausea and cardiovascular instability; because the agent is a mercaptan, which is excreted through the lungs, it causes a garlic-like odor for 24 to 72 hours. Recipients of cryopreserved products should be well hydrated because red cell degradation products can precipitate acute renal failure.

COMPLICATIONS AFTER TRANSPLANTATION

Complications post-transplantation are due either to hematopoietic and immune system aplasia or to alloreactivity. Because preparative regimens destroy the recipient's own immune and hematopoietic system, recovery is dependent on engraftment and proliferation of the infused stem cells. This process is lengthy, and post-transplant immunodeficiency is associated with a high incidence of infection and considerable morbidity and mortality. The degree of risk is greater in allogeneic than autologous transplantation and is also increased by the presence of GVHD. To reduce this risk, a variety of precautions are taken. Rigorous hand washing before entering patients' rooms is probably the most important single preventive measure, but most units also isolate patients in positive-pressure rooms in which particulate matter is reduced by air filtration with high-efficiency particulate air filters or laminar flow. A variety of prophylactic antibiotic and antifungal regimens have been used in addition to these physical methods of protection, but to date no consensus has been reached on their value. In the initial post-transplantation period when patients are neutropenic, the primary risk is bacterial and fungal infection. The problem is exacerbated by mucositis from the preparative regimen, and both gram-positive and gram-negative bacteria may produce overwhelming infections. Fungal disease, most commonly with Aspergillus or Candida species, also occurs at this time. Temperatures higher than 38° C will develop in more than 65% of patients during the period of neutropenia, a sign that is always assumed to indicate sepsis. Treatment with broad-spectrum antibiotics is critical, and many different regimens have been designed to offer broad and effective coverage. Amphotericin is added when cultures are negative but fever persists. Parenteral antibiotics are continued until myeloid engraftment is stable and the patient is afebrile; amphotericin may be required for several weeks longer if fungal lesions are documented. Intravenous administration of the granulocyte growth factors G-CSF or GM-CSF from the time of marrow infusion or at the time of initial engraftment accelerates the recovery of neutrophils, particularly after autologous transplantation. However, these cytokines have little impact on the period of absolute neutropenia when patients are most vulnerable to infection, nor can they reduce the period of thrombocytopenia. Overall, the use of growth factors after transplantation may abbreviate the hospital stay if discharge is triggered by the point at which patients reach a specific neutrophil count. It has been much harder to demonstrate that these agents substantially reduce patient morbidity or mortality, and their cost-effectiveness is controversial. The risk of bacterial infection (Table 182-2) decreases after neutrophil recovery, but because the immune system is much slower to recover, recipients of allografts remain at risk of infection with viruses and other opportunistic pathogens for some months. Many post-transplant infections result from reactivation of latent TABLE 182-2 -- INFECTIOUS COMPLICATIONS OF TRANSPLANTATION PATHOGEN

SUGGESTED TREATMENT

Pre-engraftment Fever of unknown origin

Broad-spectrum antibiotics, usually in combination, e.g., oxacillin and a cephalosporin

Gram-positive bacteria

Vancomycin

Gram-negative bacteria

Aminoglycoside or cephalosporin

Fungi

Amphotericin B

Herpes simplex virus

Acyclovir

Respiratory syncytial virus

Inhaled ribavirin

Post-engraftment Cytomegalovirus

Ganciclovir/IVIG

Epstein-Barr virus

? Interferon-alpha, ? anti-B-cell antibodies, ? donor T cells

Varicella zoster

Acyclovir

Pneumocystis

Co-trimoxazole or pentamidine

Adenovirus

? IV ribavirin

Fungi

Amphotericin B

Encapsulated bacteria

Penicillin/erythromycin

Hepatitis C

Interferon-alpha, lamivudine

IVIG = intravenous immunoglobulin. herpesviruses, including cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex, and herpes zoster. Until recently, CMV was the cause of death in 10 to 20% of allograft recipients, usually from reactivation of host or donor virus but occasionally secondary to primary infection from blood products. CMV reactivation can cause disease affecting the lungs, liver, marrow, and gut. CMV disease occurs in fewer than 3% of autograft recipients, but CMV pneumonitis (the most severe manifestation), which has been fatal in 80 to 90% of cases, will develop in about half of allograft recipients who have evidence of CMV reactivation/infection (see Chapter 386) . Two developments have reduced the magnitude of this problem. Primary infections in CMV-negative recipients of CMV-negative stem cells can be reduced to almost zero if they receive leukocyte-filtered blood or blood products from CMV-negative donors. For CMV-positive donor/recipients, prophylaxis with ganciclovir (10 mg/kg intravenously for 5 days weekly) and immunoglobulin (0.4 g/kg intravenously weekly) has proved highly effective. Treatment of established disease requires these same agents in therapeutic doses (ganciclovir, 10 mg/kg daily, or foscarnet, 180 mg/kg daily, and immunoglobulin, 0.5 g/kg for 3 days weekly). EBV infection has become more problematic with the wider use of matched unrelated donor grafts, particularly if these transplants are also depleted of T lymphocytes to prevent GVHD (see below). EBV reactivation in these immunocompromised patients may be associated with uncontrolled lymphoproliferation and the development of frank immunoblastic lymphoma in 3 to 25% of recipients. Treatment has been difficult: withdrawal of immunosuppression may be insufficient to restore immunocompetence, and antiviral agents such as interferon-alpha or acyclovir have been of limited value. At present, the most effective way of preventing or treating the complication is to infuse donor T lymphocytes, preferably in the form of EBV-specific T-cell lines. Herpes simplex may become reactivated in the first 2 to 3 months post-transplant. Herpes zoster reactivation may occur at a later date, and one third of allograft recipients will have an episode of shingles in the first year post-transplant. Acyclovir (1400 mg/m2 in divided doses daily for 10 to 14 days) is usually effective therapy for this complication. Many other viral infections, including respiratory syncytial virus, parainfluenza, and adenovirus, may cause significant morbidity and mortality after transplantation, particularly when they produce pneumonitis. No therapies have been established for these viruses, which are treated with supportive care. Hepatitis B and C may cause severe liver disease, either from reactivation in seropositive patients or following transmission by blood products. Liver biopsy is usually required to differentiate viral hepatitis from other causes of abnormal liver function after transplantation. Interferon-alpha has proved beneficial in patients with hepatitis B, and some data support the use of lamivudine for hepatitis C.

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Complications caused by alloreactivity are manifested as rejection (host dominant) or GVHD (donor dominant). The risk of rejection increases with increasing donor/recipient disparity, being least in syngeneic grafts between twins and greatest between mismatched unrelated donors. Rejection is also increased by graft manipulations intended to reduce the incidence of GVHD (such as T-lymphocyte depletion) and by alloimmunization of recipients from the prior administration of blood products. Rejection occurs in up to 20% of the most at-risk group. The complication may be manifested as primary failure to engraft (defined as failure to attain a count of >500 × 106 neutrophils per liter for 3 consecutive days) or failure to maintain this count once achieved. Previous efforts to treat rejection by the administration of hematopoietic growth factors or by reconditioning of the patient and retransplantation have worked poorly, so the complication had been associated with a high mortality. More promising results have been reported following a combination of immunosuppressive antibody therapy with infusion of donor PBSCs. GVHD occurs when the donor's CD4+ and CD8+ T lymphocytes recognize major or minor histocompatibility antigens on host tissues. Like rejection, the risks increase with greater donor-recipient genetic disparity, and the risk is also greater in male recipients of female (multiparous) donor stem cells. The major targets for attack are the skin, gut, and liver. GVHD of the skin is manifested as erythema that initially affects the face, hands, and feet and then progresses to diffuse erythema with bullae and desquamation. In the gut, the complication is characterized by watery diarrhea that may progressively increase in volume and become bloody. The diarrhea is associated with abdominal distention and cramps. In the liver, the disease is typically manifested by hyperbilirubinemia and an elevated alkaline phosphatase concentration. Aminotransferase levels may remain almost normal even in liver GVHD. The diagnosis is confirmed by histologic examination of clinically affected tissue. GVHD is graded from I to IV according to severity. Following conventional matched sibling transplants, GVHD greater than grade II develops in 30 to 50% of recipients, and 10 to 15% died of the disease or associated complications. Mortality is substantially higher when the donor and recipient are HLA mismatched or

unrelated. Fortunately, a number of recent advances in GVHD prophylaxis have helped reduce this toll. The combination of cyclosporine begun on day -1 (either a fixed dose of 5 mg/kg or targeted dosing to achieve plasma concentrations of 250 to 350 mug/L) with methotrexate (e.g., 10 mg/m2 on days 0, 3, 7, and 11) after transplantation has proved very effective. As a substitute for cyclosporine, the fungal-derived immunosuppressive tacrolimus has recently been used with apparent success. T-lymphocyte depletion of the donor graft by means of monoclonal antibodies, erythrocyte rosetting, or elutriation is an even more effective means of preventing GVHD. Complete prevention of GVHD by removal of all T cells may not be of unalloyed benefit inasmuch as antihost reactivity has a potentially important role to play. The residual host hematopoietic and immune system cells that have survived the preparative regimen are important targets of the incoming donor T lymphocytes. Destruction of these host cells appears essential to ensure complete host engraftment and may also represent a major component of the antitumor effect of allogenic transplantation. This activity, termed the graft-versus-leukemia effect, has been especially well documented in chronic myeloid leukemias. Hence the most effective methods of GVHD prevention are often associated with the highest risk of rejection and relapse. Once GVHD has occurred, intravenous methylprednisolone in doses between 1 and 10 mg/kg/day is given. If the condition worsens or persists, additional immunosuppressive agents are given, including antithymocyte globulin and monoclonal anti-T-cell antibodies. However, severe steroid-resistant GVHD continues to carry a poor prognosis, with a 60 to 90% death rate. Patients with severe GVHD die of either end-organ failure or the immunosuppression that accompanies the condition and its treatment. The acute form of GVHD may be followed by chronic GVHD, although this complication may arise de novo after day 40. Any organ may be affected and manifestations are protean, so chronic GVHD is graded by the extent and sites of organ involvement. Chronic diffuse GVHD is often manifested as a systemic sclerosis-like syndrome affecting the skin, eyes, gut, liver, and lungs. Although skin involvement limited to the more superficial layers may be successfully treated with psoralens and ultraviolet light, disseminated and progressive chronic GVHD is very disabling. Treatment with immunosuppressive drugs, including prednisolone, cyclosporine, mycophenolic acid, azathioprine, and thalidomide, are often of only modest benefit, and the condition has a high mortality from end-organ failure and infection. Although recurrence of malignant disease is not strictly a complication of transplantation, it remains a major cause of treatment failure. Relapse is more common after autologous transplantation because of the lack of a graft-versus-malignancy effect and perhaps also because the stem cell graft may be contaminated with malignant cells. Although disease relapse may be treated by further doses of chemotherapy and even by additional transplantation, these approaches are rarely curative and have high treatment-associated mortality. An alternative approach after allografting is to use the graft-versus-leukemia effect by infusing donor T cells; alloreactive T lymphocytes may then eradicate resurgent host hematopoietic malignancy. Although this approach is associated with a risk of inducing severe GVHD and even marrow aplasia (if host hematopoiesis has come to predominate), it can produce remission in up to 70% of patients with relapsed chronic myeloid leukemia. In combination with chemotherapy, the approach induces prolonged remission in 20% or more of patients with acute myeloid leukemia, and it may also be effective in patients with relapsed myeloma. To date, only anecdotal success has been reported in acute lymphocytic leukemia or lymphoma.

LONG-TERM COMPLICATIONS Most late effects of bone marrow transplantation are related either to chronic GVHD or to the toxicity of chemotherapy and radiotherapy conditioning regimens. Post-transplant hemolytic-uremic syndrome (also called radiation nephritis) is seen primarily in patients who have received extensive previous chemotherapy. It generally occurs about 6 months post-transplant, and clinical findings include renal insufficiency, hematuria, and anemia with evidence of microangiopathic hemolysis. In most recipients, the syndrome is self-limited and resolves with no specific therapy. Occasionally the course is progressive and renal failure develops. Hemorrhagic cystitis may also occur or recur as a late complication. The major causes of pulmonary complications during the later post-transplant period are infection and regimen-related toxicity. Bacterial, fungal, and viral infections occurring at this time are usually associated with continuing immune deficiency from chronic GVHD. Less commonly, chronic obstructive lung disease, usually directly associated with chronic GVHD, develops in long-term survivors. The pathologic abnormality is obliteration of the bronchioles. The syndrome responds poorly to therapy with steroids, tends to progress, and has a poor prognosis. Independent of GVHD, a restrictive defect caused by interstitial fibrosis develops in many patients, although this complication is usually asymptomatic and detected only on pulmonary function tests. The risk of endocrine dysfunction is greater in patients who receive total-body irradiation, and abnormal thyroid function test results will develop in about 50% of such patients. In most cases the abnormality is subclinical, with elevated thyroid-stimulating hormone levels and increased response to thyroid-releasing hormone, but about 10% will eventually require replacement therapy. Growth hormone deficiency may also occur, especially in pediatric patients who have received prior cranial irradiation. In women who receive a transplant post-puberty with total-body irradiation as part of the conditioning regimen, ovarian failure is evidenced by increased levels of follicle-stimulating hormone and luteinizing hormone in the presence of low estrogen. Even conditioning regimens that use chemotherapy alone produce ovarian failure, but some of these patients may recover, and a small number of pregnancies have been reported. Ovarian hormone replacement is generally used in premenopausal women to prevent menopausal symptoms. In men who receive transplants after puberty, testosterone levels remain normal but spermatogenesis rarely recovers. Cataracts occur in about 20% of patients who have received fractionated total-body irradiation and in almost 80% of patients who have received single-dosage regimens. Steroid therapy is another risk factor for this complication. Cataracts begin to develop 991

between 5 and 10 years post-transplant and respond well to excision. Aseptic osteonecrosis occurs in 10 to 20% of long-term transplant survivors; it primarily involves the hip joints and is exacerbated by steroid therapy for GVHD or by ovarian failure in females. Several studies have shown a higher incidence of a second malignancy in transplant recipients, particularly in those who received radiation as part of their conditioning. In one series of 2246 patients, the relative risk was 6.7 times that observed in the general population adjusted for age. Both lymphoid and myeloid acute leukemias are increased, and the most common post-transplant solid tumors are melanoma and glioblastoma.

OUTCOME Despite the daunting list of short- and long-term complications, the safety of stem cell transplantation has improved substantially over the past decade. This effect can most readily be seen in patients receiving unrelated donor allografts for hematopoietic malignancies. In the past, these patients had a mortality that was more than 50% higher than that of recipients of grafts from HLA-identical sibling donors treated for the same disease at an equivalent stage of development. As a result of advances in tissue typing, GVHD prophylaxis, and antiviral prophylaxis, the survival rates of these two groups of patients are now nearly identical; a residual excess of procedure-related mortality in the unrelated donor recipients is offset by a lower relapse risk, presumably because of increased graft-versus-leukemia effects. Disease-free survival rates approaching or exceeding 90% can now be expected for individuals with aplastic anemia, chronic myeloid leukemia in the first chronic phase, or thalassemia without liver damage. Conversely, survival rates for patients with advanced malignancy remain low; the combination of both severe regimen-related toxicities in these heavily pre-treated patients and a high relapse rate means that only 5 to 30% may survive 5 years.

FUTURE TRENDS In allografting, the safety and effectiveness of preparative regimens should continue to improve. The trend has been toward a reduction in the intensity of the preparative regimen, with a correspondingly increased reliance on the ability of the donor immune system to eradicate host hematopoietic and malignant cells. A combination of this approach with the introduction of monoclonal antibodies (coupled to radionuclides or toxins) that specifically target the hematopoietic system without damaging other host organs should reduce the incidence and severity of complications associated with current preparative regimens. "Graft engineering," in which the component cells in a graft are separated and functionally modified, will probably be of increasing importance. These modifications are intended to produce a graft that lacks the capacity to induce GVHD but retains activity against pathogens and residual malignancy. The availability of improved growth factors with activity on stem cells and on all hematopoietic lineages should enable rapid ex vivo and/or in vivo expansion of the donor hematopoietic cells, thereby accelerating engraftment and minimizing the consequence of marrow aplasia. Finally, it is likely that hematopoietic stem cells will increasingly be used as vehicles for gene transfer to allow autologous transplantation to be curative for a number of inherited and acquired disorders currently amenable only to allogeneic therapies. Armitage JO: Bone marrow transplantation. N Engl J Med 330:827, 1994. An excellent overview of the indications for marrow transplantation. Blazar BR, Korngold R, Vallera DA: Advances in graft-versus-host disease (GvHD) prevention. Immunol Rev 157:79, 1997. Reviews the biology and treatment of this complication. Brenner MK: Gene transfer to hematopoietic cells: N Engl J Med 335:337, 1996. Summarizes the potential and the problems of hematopoietic stem cell gene therapy. Gerson SL: Mesenchymal stem cells: No longer second class marrow citizens. Nature Med 5:262, 1999. A description of mesenchymal cells in marrow and their possible applications after transplantation. Giralt S, Estey E, Ibitar M, et al: Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy harnessing graft versus leukemia

without myeloablative chemotherapy. Blood 89:4531, 1997. How the immune system can help eradicate leukemia in the absence of ablative conditioning. Hansen JA, Petersdorf E, Martin PJ, et al: Hematopoietic stem cell transplants from unrelated donors. Immunol Rev 157:141, 1997. A review of unrelated donor transplants. Kolb HJ, Poetscher C: Late effects after allogeneic bone marrow transplantation. Curr Opin Hematol 4:401, 1997. A good discussion of the longer-term problems of the procedure and how they affect quality of life. Rubinstein P, Carrier C, Scaradavov A, et al: Outcomes among 562 recipients of placental blood transplants from unrelated donors. N Engl J Med 339:1565, 1998. A large-scale multicenter account of the use of cord blood transplantation, mainly in patients with malignant disease.

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Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 183 - APPROACH TO THE PATIENT WITH BLEEDING AND THROMBOSIS Andrew I. Schafer

MECHANISMS OF HEMOSTASIS AND THROMBOSIS The intimal surface of the vasculature throughout the circulatory tree is lined by a monolayer of endothelial cells. These cells constitutively express anticoagulant properties that promote blood fluidity under normal circumstances. At a site of vascular injury, however, endothelial cells are either "activated," and are thereby converted from an antithrombotic to a prothrombotic state, or become detached to expose circulating blood to thrombogenic constituents of the subendothelial vessel wall. These processes result in the rapid formation of a hemostatic plug that consists of platelets and fibrin. Activation of platelets and formation of fibrin occur essentially simultaneously and interdependently to effect hemostasis. Subsequently, vessel wall repair is accomplished by thrombolysis and recanalization of the occluded site. In the presence of intact endothelium, platelets are repelled from the vessel wall and circulate passively. Prostacyclin and nitric oxide are among the potent, locally active platelet inhibitors (and vasodilators) that are elaborated by normal endothelial cells to promote blood fluidity. At a site of vascular damage, these antiplatelet substances are lost, and platelets adhere to the de-endothelialized intimal surface. Platelet "adhesion" (platelet-vessel wall interaction) is mediated by von Willebrand factor, which anchors the platelets to the vessel wall by binding to its platelet receptors localized in membrane glycoprotein Ib (GPIb). Adherent platelets then undergo the "release reaction," during which they discharge constituents of their storage granules, including adenosine diphosphate (ADP), and synthesize thromboxane A2 (TXA2 ) from arachidonic acid by means of the aspirin-inhibitable cyclooxygenase reaction. ADP, TXA2 , and other components of the release reaction then act in concert to recruit and activate additional platelets from the circulation to the site of vascular injury. These activated platelets expose binding sites for fibrinogen by forming the surface membrane glycoprotein IIb-IIIa (GPIIb-IIIIa) complex. In the process of platelet "aggregation" (platelet-platelet interactions), fibrinogen (or von Willebrand factor under conditions of high shear stress) mediates the formation of an occlusive platelet plug. The fibrin, which anchors the hemostatic platelet plug, is formed from soluble plasma fibrinogen by the action of the potent protease enzyme thrombin (Fig. 183-1) (Figure Not Available) . The fibrin mesh is then stabilized by covalent crosslinking mediated by Factor XIII. Thrombin is formed from its inactive (zymogen) plasma precursor, prothrombin, by the action of activated Factor X (Xa) and its cofactor, Factor Va. This sequence of reactions has been classically referred to as the "common pathway" of coagulation. Factor X can be activated, in turn, by either the tissue factor ("extrinsic") pathway or the contact activation ("intrinsic") pathway of coagulation. The former is initiated by the complex of tissue factor and Factor VIIa. The latter involves a series (or cascade) of zymogen-protease reactions that are initiated by contact activation of Factor XII to XIIa. High-molecular-weight kininogen and prekallikrein are two other plasma protein components of the contact activation system that leads to the generation of Factor XIIa. Factor XIIa then converts Factor XI to XIa, followed by Factor XIa-mediated activation of Factor IX to IXa. Factor IXa then serves as the enzyme to convert Factor X to Xa, a reaction that requires Factor VIIIa as a cofactor. In the interpretation of screening in vitro laboratory tests of coagulation, it is still convenient to separate the "extrinsic" and "intrinsic" pathways of coagulation that converge as alternative 992

Figure 183-1 (Figure Not Available) The coagulation cascade. This scheme emphasizes recent understanding of (1) the importance of the tissue factor pathway in initiating clotting in vivo; (2) the interactions between pathways; and (3) the pivotal role of thrombin in sustaining the cascade by feedback activation of coagulation factors. HMWK = high-molecular-weight kininogen; PK = prekallikrein; PL = phospholipid; PT = prothrombin; TF = tissue factor; Th = thrombin. (From Schafer AI: Coagulation cascade: An overview. In Loscalzo J, Schafer AI [eds]: Thrombosis and Hemorrhage. Cambridge, MA, Blackwell Scientific Publications, 1994, pp 3-12.)

mechanisms to activate Factor X, leading to the "common" pathway that culminates in fibrin formation. However, it is now understood that this is an inaccurate oversimplification of the situation in vivo. For example, Factor IX (an intrinsic factor) can be activated by Factor VII (an extrinsic factor). Furthermore, the absence of any clinical bleeding problems in patients with inherited deficiencies of the contact activation factors (high-molecular-weight kininogen, prekallikrein, Factor XII) has cast doubt on the physiologic importance of the intrinsic pathway in hemostasis. Just as intact, normal endothelium promotes blood fluidity by inhibiting platelet activation, it likewise plays a critical role in naturally anticoagulating blood by preventing fibrin accumulation. Among the physiologic antithrombotic systems that produce this effect are (1) antithrombin III; (2) protein C and protein S; (3) tissue factor pathway inhibitor (TFPI); and (4) the fibrinolytic system. Antithrombin is the major protease inhibitor of the coagulation system: it inactivates thrombin, as well as other activated coagulation factors. Heparin functions as an anticoagulant by binding to antithrombin and thereby greatly accelerating its ability to inhibit the coagulation proteases. Heparin and heparin sulfate proteoglycans are naturally present on endothelial cells, so antithrombin inactivation of thrombin and other coagulation proteases most likely occurs physiologically on vascular surfaces rather than in fluid phase plasma. Activated protein C, with its cofactor, protein S, functions as a natural anticoagulant by destroying Factors Va and VIIIa, two essential cofactors of the coagulation cascade. Thrombin itself is the activator of protein C, and this reaction again occurs rapidly only on the surfaces of intact vascular endothelial cells where thrombin binds to the glycosaminoglycan thrombomodulin. Thus, in the presence of normal vessel wall intima, small amounts of thrombin that are generated in the circulation bind to endothelial cell thrombomodulin, thereby not only removing it from the circulation but also activating anticoagulant protein C, which inhibits its further production. TFPI is another plasma protease inhibitor that quenches tissue factor-induced coagulation. Although inherited deficiencies of antithrombin, protein C or protein S are associated with a lifelong thrombotic tendency (hypercoagulable state), TFPI deficiency has not yet been related to clinical problems. Finally, what little fibrin can be produced, despite these potent physiologic antithrombotic mechanisms, is rapidly digested by the endogenous fibrinolytic system, in which endothelium-derived tissue plasminogen activator (t-PA) converts the plasma zymogen, plasminogen, to the active fibrinolytic protease, plasmin. Thrombus formation occurs wherever vascular damage causes loss of the natural endothelium-dependent antiplatelet and anticoagulant mechanisms or in disorders in which one or more of these protective systems is deficient. Thrombi are composed of platelets and fibrin, although their relative contributions vary with the site of thrombosis: the former tend to predominate in the high-shear arterial circulation, whereas the latter predominate in the venous system. Regardless of the site of thrombus formation, platelet activation and fibrin production occur simultaneously and in an interdependent manner: thrombin generation occurs most efficiently on the surfaces of activated platelets, whereas thrombin itself is a potent stimulus for further platelet activation.

EVALUATION OF THE PATIENT WITH A POSSIBLE BLEEDING DISORDER There are three general clinical settings in which patients may be required to undergo evaluation for a possible bleeding disorder. First, patients may present with a history or physical signs of bleeding that provoke suspicion of a systemic coagulopathy. Second,

TYPE OF DISORDER

TABLE 183-1 -- CHARACTERISTIC PATTERNS OF BLEEDING IN SYSTEMIC DISORDERS OF HEMOSTASIS SITES OF BLEEDING ONSET OF CLINICAL EXAMPLES BLEEDING General Skin Mucous Membranes Others

Platelet-vascular disorders

Superficial surfaces

Petechiae, ecchymoses

Common: oral, nasal, gastrointestinal, genitourinary

Rare

Spontaneous or immediately after trauma

Thrombocytopenia, functional platelet disorder, vascular fragilityDisseminated intravascular coagulation, liver disease

Coagulation factor deficiency

Deep tissues

Hematomas

Rare

Common: joint, muscle, retroperitoneal

Delayed after trauma

Inherited coagulation factor deficiency, acquired inhibitor, anticoagulationDisseminated intravascular coagulation, liver disease

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asymptomatic patients may be incidentally discovered to have laboratory abnormalities that suggest a bleeding disorder. Third, patients may be asked to undergo routine testing for bleeding risk before surgery or an invasive procedure. A thorough history is of paramount importance in all three of these settings. Not only should the patient be asked about spontaneous bleeding episodes in the past, but the response to specific hemostatic challenges should also be recorded. A bleeding tendency may be suspected if a patient has experienced excessive hemorrhage after previous surgery or trauma, including commonly encountered events, such as circumcision, tonsillectomy, labor and delivery, menses, dental procedures, vaccinations, and injections. Conversely, the history of normal blood clotting after such challenges in the recent past is at least as important to note because it may provide a better test of systemic hemostasis than any laboratory measurement could provide. Evaluation of the Patient With a History of Bleeding In a patient with a history of excessive or unexplained bleeding, the initial problem is to determine whether the cause is a systemic coagulopathy or an anatomic or mechanical problem. This situation is most frequently encountered in postoperative patients with excessive bleeding. A history of prior bleeding suggests a coagulopathy, as does the finding of bleeding from multiple sites. However, even diffuse bleeding may arise from anatomic rather than hemostatic abnormalities (e.g., recurrent mucosal hemorrhage in patients with hereditary hemorrhagic telangiectasia). Conversely, a single episode of bleeding from an isolated site may be the initial manifestation of a systemic coagulopathy. The history must also include a survey of coexisting systemic diseases and drug ingestion that may affect hemostasis. For exam ple, renal failure and the myeloproliferative disorders are associated with impaired platelet-vessel wall interactions and qualitative platelet abnormalities, connective tissue disease and lymphomas are associated with thrombocytopenia, and liver disease causes a complex coagulopathy. Aspirin and other non-steroidal anti-inflammatory drugs cause platelet dysfunction: these drugs are often contained in over-the-counter preparations that patients may neglect to report without specific questioning. Other drugs, such as antibiotics, also may be associated with a bleeding tendency by causing abnormal platelet function or thrombocytopenia. Finally, it is important to elicit a family history of bleeding problems. Whereas a positive history provides a clue to a possible inherited coagulopathy, a negative history does not exclude a familial etiology; for example, up to 20% of patients with classic hemophilia have a completely negative family history of bleeding. Patterns of clinical bleeding, as revealed by the history and physical examination, may be characteristic of certain types of coagulopathy (Table 183-1) . In general, patients with thrombocytopenia or qualitative platelet and vascular disorders present with bleeding from superficial sites in the skin and mucus membranes; these may involve petechiae, which are pinpoint cutaneous hemorrhages that appear particularly over dependent extremities (characteristic of severe thrombocytopenia), ecchymoses (common bruises), purpura, gastrointestinal and genitourinary tract bleeding, epistaxis, and hemoptysis. In these disorders, bleeding from these sites tends to occur spontaneously or immediately after trauma. In contrast, patients with inherited or acquired coagulation factor deficiencies, such as hemophilia or therapeutic anticoagulation, tend to bleed from deeper tissue sites (e.g., hemarthroses, deep hematomas,retroperitoneal hemorrhage) and in a delayed manner after trauma.

Figure 183-2 Classic coagulation cascade, in which the prothrombin time (PT) measures the integrity of the extrinsic and common pathways, while the activated partial thromboplastin time (aPTT) measures the integrity of the intrinsic and common pathways. Note that Factor (F) XIII deficiency is not detected by the PT or aPTT. HMWK = high-molecular-weight kininogen; PK = prekallikrein.

994

Figure 183-3 An algorithm for diagnostic decisions in evaluating patients with a prolonged bleeding time. The scheme assumes that the platelet count is normal, because thrombocytopenia itself can prolong the bleeding time.

Figure 183-4 Approach to evaluating patients with prolonged prothrombin time (PT) and/or activated partial thromboplastin time (aPTT).

Four simple, rapid screening tests are generally used in the initial evaluation of patients with a suspected coagulopathy: (1) platelet count, (2) bleeding time, (3) prothrombin time (PT), and (4) activated partial thromboplastin time (aPTT). It is also from one or more of these tests that asymptomatic individuals may be incidentally found to have abnormalities that suggest a bleeding disorder and prompt further evaluation. Thrombocytopenia, routinely reported by electronic particle counting, should be verified by examination of the peripheral smear. "Pseudothrombocytopenia," a laboratory artifact of ex vivo platelet clumping, may be caused by the EDTA anticoagulant used in tubes for blood cell counts, other anticoagulants, or cold agglutinins acting at room temperature; it should be suspected whenever a very low platelet count is reported in a patient who does not exhibit any clinical bleeding, and it has no known pathologic correlates. Pseudothrombocytopenia is indicated by the finding of platelet clumps on the peripheral smear, and the diagnosis is supported by the finding of simultaneously normal platelet counts in blood samples obtained by fingerstick, in tubes containing other anticoagulants, or when the tube of blood is maintained at 37° C before platelet counting. Examination of the blood smear in patients with real thrombocytopenia can also reveal clues to the cause, such as fragmented red cells in thrombotic thrombocytopenic purpura. The bleeding time is the most widely used clinical screening test for disorders of platelet-vessel wall interactions. It measures the time to cessation of bleeding after a standardized incision over the volar aspect of the forearm, now most commonly performed by disposable automated devices. The bleeding time is prolonged in (1) thrombocytopenia, (2) qualitative platelet abnormalities, (3) defects in platelet-vessel wall interactions (e.g., von Willebrand's disease), or (4) primary vascular disorders. The bleeding time usually is not prolonged in patients with coagulation factor deficiencies. However, the test is prone to problems of reproducibility, sensitivity, and specificity. The PT measures the integrity of the extrinsic and common pathways of coagulation (Factors VII, X, V, prothrombin, and fibrinogen) (Fig. 183-2) . The aPTT measures the integrity of the intrinsic and common pathways of coagulation (high-molecular-weight kininogen; prekallikrein; Factors XII, XI, IX, VIII, X, and V; prothrombin; and fibrinogen). The sensitivity of the PT and aPTT in detecting coagulation factor deficiencies may vary with the reagents used to perform these tests, and therefore each laboratory must determine its own reference standards. With a few notable exceptions, as follows, normal results for all four of the screening tests of hemostasis essentially exclude any clinically significant systemic coagulopathy. Patients with Factor XIII deficiency may have a serious bleeding diathesis but have normal screening tests; specific tests for Factor XIII deficiency should be performed when this disease is suspected. The PT and aPTT detect only more severe deficiencies of coagulation factors, generally involving levels of less than 30% of normal; therefore, specific factor levels should be determined if a mild coagulation factor deficiency is suspected. Patients with von Willebrand's disease sometimes have normal bleeding times and usually do not have sufficiently reduced levels of Factor VIII to affect the aPTT. Rare disorders of fibrinolysis may also be associated with normal screening tests, necessitating more specialized tests when indicated. Abnormalities in the screening tests of hemostasis may be pursued by more specialized tests to establish a specific diagnosis (see Chapters 184 to 187) . A prolonged bleeding time in the absence of thrombocytopenia should initially be approached by determining if the patient is taking any drugs that might interfere with platelet function (e.g., aspirin, other non-steroidal anti-inflammatory drugs) or has coexisting diseases that might explain the finding (e.g., renal failure) (Fig. 183-3) . If these conditions are not found, or if the bleeding time fails to correct after discontinuing any potential offending drugs, further specialized testing may include platelet aggregation studies to identify specific qualitative abnormalities of platelet function and specific assays to exclude one of the types of von Willebrand's disease. The finding of a prolonged PT and/or aPTT indicates that there is either a deficiency of one or more coagulation factors or an inhibitor, usually an antibody, directed at one or more components of the coagulation system (Fig. 183-4) . These two possibilities can be readily distinguished by performing an inhibitor screen, which involves a 1:1 mix of patient and normal plasma. The premise of the test is that, even if a patient's plasma is completely deficient 995

TABLE 183-2 -- CLINICAL CHARACTERISTICS OF PATIENTS WITH INHERITED HYPERCOAGULABLE STATES Venous thromboembolism (>90% of cases) Deep vein thrombosis of lower limbs (common) Pulmonary embolism (common) Superficial thrombophlebitis Mesenteric vein thrombosis (rare but characteristic) Cerebral vein thrombosis (rare but characteristic) Frequent family history of thrombosis * First thrombosis usually at young age (24 g/day) Heparin Plasminogen activators (streptokinase, urokinase, tissue plasminogen activator) Drugs That Affect Coagulation Factors Induction of antibodies inhibiting function Lupus anticoagulant Phenothiazines Procainamide Factor VIII antibodies Penicillin Factor V antibodies Aminoglycosides Factor XIII antibodies Isoniazid Inhibitors of synthesis of vitamin K-dependent clotting factors (Factors II, VII, IX, X; proteins C and S) Coumarin compounds Moxalactam Inhibitor of fibrinogen synthesis L-Asparaginase

*The list is limited to drugs for which there are multiple reports and in vitro or in vivo evidence of antiplatelet antibodies. Does not cause bleeding. May cause thrombosis.

splenectomy, the platelet count may increase transiently to 106 per microliter. An estimate of platelet number in the peripheral blood film (normal, increased, decreased) is useful in detecting patients with abnormally low platelet counts. Normally, 3 to 10 platelets per high-power (oil immersion) field appear on peripheral smears. Platelets are counted directly by an automated particle counter. PLATELET FUNCTION. Platelets contain three types of secretory granules: lysosomes, alpha-granules, and dense bodies (electron-dense organelles) (Fig. 184-1) . alpha-Granules contain platelet-specific proteins: platelet factor 4, beta-thromboglobulin, and several growth factors, including platelet-derived growth factor, platelet-derived endothelial cell growth factor, and transforming growth factor beta. alpha-Granules also contain several hemostatic proteins, including fibrinogen, Factor V, and von Willebrand factor, which is synthesized by megakaryocytes. Dense bodies (delta-granules) contain adenosine triphosphate, adenose diphosphate (ADP), Ca2+ , and serotonin. In addition to release of potent vasoconstrictors from intracellular 997

Figure 184-1 Electron micrograph of an unstimulated platelet. alpha = alpha-granule; d = dense body (×24,000). (Courtesy of Dr. Dorothy Bainton, University of California, San Francisco.)

granules in response to a variety of substances and aggregation to form a plug at the site of vessel injury, platelets provide a surface for the activation of soluble coagulation factors (Fig. 184-2) . Activated platelets expose specific receptors that bind Factor Xa and Va and in this way increase their local concentration, thus accelerating prothrombin activation. Factor X is also activated by Factors IXa and VIII (antihemophilic factor) on the platelet surface. Platelets contain a membrane phospholipase C that, upon stimulation by activating agents, hydrolyzes endogenous phosphatidylinositol to form a diglyceride. The diglyceride, in turn, is converted to arachidonic acid by a diglyceride lipase. Arachidonic acid is a substrate for prostaglandin synthetase (cyclooxygenase), a reaction inhibited by aspirin and non-steroidal anti-inflammatory drugs, and is subsequently converted to prostaglandins. The prostaglandin endoperoxide PGG2 is required for ADP-induced aggregation and release; both PGG2 and thromboxane A2 are potent platelet-aggregating agents. PLATELET FUNCTION TESTS. BLEEDING TIME.

(See Chapter 183.) The bleeding time is prolonged when the platelet count falls below 90,000 per microliter or when a functional platelet abnormality exists. Von Willebrand disease prolongs the bleeding time not as a result of a platelet defect but rather because of the lack of a plasma factor important for normal platelet function. Although imperfect, the bleeding time is the only test of platelet function that correlates with susceptibility to bleeding. Even though patients with a prolonged bleeding time may be at risk for increased bleeding with surgery, not all have abnormal bleeding. PLATELET AGGREGOMETRY.

The response of platelets to a variety of aggregating agents can be quantitated in platelet-rich plasma or whole blood. The aggregometer measures temporal, semiquantitative, and qualitative parameters of in vitro aggregation. This technique is of greatest value in diagnosing congenital qualitative platelet disorders.

ABNORMALITIES IN PLATELET COUNT Thrombocytopenia Low platelet counts (thrombocytopenia) (Fig. 184-3) can be caused by disturbances in production, distribution, or destruction. The consequences are entirely

hemostatic. With normally functioning platelets, the following is expected: when the platelet count is 100,000 per microliter or greater, patients have no abnormal bleeding even with major surgery; with a platelet count of 50,000 to 100,000 per microliter, patients may bleed longer than normal with severe trauma; with a platelet count of 20,000 to 50,000 per microliter, bleeding occurs with minor trauma, but spontaneous bleeding is unusual; with a platelet count less than 20,000 per microliter, patients may have spontaneous bleeding; and when the platelet count is less than 10,000 per microliter, patients are at high risk for severe bleeding. Decreased Production of Platelets

Hypoplasia of hematopoietic stem cells may cause thrombocytopenia (Table 184-2) . Examination of the bone marrow reveals decreased numbers of megakaryocytes and either an overall decrease in cellularity or infiltration by abnormal cells. Decreased production of platelets may also be due to abnormal maturation of megakaryocytes. Deficiency of either vitamin B12 or folate can cause thrombocytopenia owing to ineffective thrombocytopoiesis (see Chapter 163) . Similarly, abnormal platelet production is common in hematopoietic dysplasias (see Chapter 175) . In both disorders, megakaryocytes are usually increased. In hematopoietic dysplasia, megakaryocytes may be abnormal in appearance, such as micromegakaryocytes occasionally with a single-lobed nucleus. Increased Peripheral Destruction of Platelets (see

Table 184-2)

IMMUNE DISORDERS.

Three types of immunologic reactions cause premature destruction of platelets: (1) development of autoantibodies against platelet-membrane antigens, (2) binding of immune complexes to platelet Fc receptors, and (3) lysis of platelets because of fixation of complement on their surface. IDIOPATHIC THROMBOCYTOPENIC PURPURA.

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune bleeding disorder characterized by the development of antibodies to one's own platelets, which are then destroyed by phagocytosis in the spleen and, to a lesser extent, the liver. The spleen is the principal reticuloendothelial site of platelet destruction, as well as the major site of synthesis of antibody production in ITP. Childhood ITP is usually acute and follows recovery from a viral infection. The incidence is equal in boys and girls. In adults, the onset is usually more gradual, without a preceding illness and with a chronic course. In a small percentage of adult cases, the disease has an acute onset. Ninety per cent of adults with ITP are younger than 40 years, and the ratio of women to men is 3 to 4:1. Some patients' sera contain antibodies against platelet glycoproteins IIb and IIIa. Petechiae, ecchymoses, and epistaxis develop in this patients. Menorrhagia may develop in women. The incidence of death, reported in older series to be about 5%, is likely to be significantly lower now. Adverse risk factors are severe thrombocytopenia (platelet count, 90%) exhibit a relapse of thrombocytopenia. Thus the primary benefit of prednisone is in the acute management of bleeding. Another effective approach to managing patients who are actively bleeding or for whom major surgery is necessary is the use of intravenous gamma-globulin. Intravenous immune globulin (IVIG) concentrates raise the platelet count within 3 to 5 days in most patients and is the most rapidly active agent. Unfortunately, the therapeutic effect is usually transient because the platelet count falls to baseline levels over the next month. In rare instances, repeated infusions of IVIG have led to sustained remissions after discontinuation of therapy. It is proposed that IVIG works by blocking Fc receptors on macrophages, thereby inhibiting phagocytosis. The dosage is 1 g/kg/day on 2 successive days. In 80% of patients, subsequent platelet counts rise above 50,000 per microliter. A less expensive alternative is RhoGAM, anti-Rh antibody. The principle is the same as that in IVIG, reticuloendothelial blockade. Owing to the lack of a sustained remission in most patients with severe thrombocytopenia treated with steroids or IVIG, a more definitive approach is necessary. Splenectomy improves the platelet count in 70% of patients with ITP and induces sustained remission in approximately 60%, but no test can reliably predict which patients will respond. The platelet count rises, usually within a few days or at most 1 to 2 weeks after splenectomy. A variety of other therapies can induce partial or complete remissions in chronic ITP when splenectomy has failed. Danazol, 200 mg three times per day, induces a remission in approximately 999

Figure 184-3 Evaluation of thrombocytopenia. Abn = abnormal; N = normal; PT = prothrombin time; aPTT = activated partial thromboplastin time; LDH = lactate dehydrogenase; BUN = blood urea nitrogen.

40% of cases of chronic ITP. Response is delayed and takes 4 to 6 weeks. The mechanism remains unknown. Intravenous vincristine and vinblastine also raise the platelet count in ITP, usually within 1 to 2 weeks. Responses are transient and remissions are not sustained. Immunosuppressive agents--cyclophosphamide and azathioprine--improve the platelet count in 20 to 30% of cases of chronic ITP. The potential benefit of these drugs must be weighed against the risks of toxicity. In one small series, 60% of patients with refractory ITP had complete remissions with combination chemotherapy. Pulsed, high-dose dexamethasone has also been reported to be effective therapy in patients with refractory ITP. Management of ITP in pregnancy is complicated by the additional risk to the fetus of thrombocytopenia secondary to maternal antibodies. Intraventricular hemorrhage, gastrointestinal bleeding, and death have been reported in newborns. Whether the mother had ITP before pregnancy is critical. When ITP initially develops in women

during pregnancy, the risk of serious bleeding in the newborn is negligible. Conversely, neonates born to women with a history of ITP preceding pregnancy have a 20% risk of severe thrombocytopenia. In addition to treating the underlying ITP, cesarean delivery is recommended to decrease the risk of intracranial bleeding in these newborns. PLATELET ANTIBODIES ASSOCIATED WITH SYSTEMIC DISORDERS.

Antibodies directed against platelets and causing thrombocytopenia occur in several types of disorders in which bone marrow 1000

TABLE 184-2 -- DISORDERS ASSOCIATED WITH THROMBOCYTOPENIA Hypoplasia of Hematopoietic Stem Cells Aplastic anemia Marrow damage from drugs, chemicals, ionizing radiation, alcohol, infection Congenital and hereditary thrombocytopenias Thrombocytopenia with absent radii syndrome Wiskott-Aldrich syndrome May-Hegglin anomaly Replacement of Normal Marrow Leukemias Metastatic tumor (prostate, breast, lymphoma) Myelofibrosis Ineffective Thrombocytopoiesis (Normal or Increased Numbers of Megakaryocytes) Cobalamin or folate deficiency Hematopoietic dysplastic syndromes Increased Destruction of Platelets Immune disorders Idiopathic thrombocytopenic purpura Secondary causes Cancer: chronic lymphocytic leukemia, lymphoma Systemic autoimmune disorders: systemic lupus erythematosus, polyarteritis nodosa Infectious diseases: infectious mononucleosis, cytomegalovirus, HIV Drugs: quinine/quinidine, heparin, sulfa compounds (see Table 184-1) Non-immune disorders Disseminated intravascular coagulation Cavernous hemangioma Thrombotic thrombocytopenic purpura Hemolytic-uremic syndrome Sepsis Malaria Paroxysmal nocturnal hemoglobinuria Congenital cyanotic heart disease Acute renal transplant rejection Disorders of Distribution Hypersplenism Dilutional Secondary to transfusion megakaryocytes are normal or increased in number. Antibody-mediated destruction of platelets occurs in lymphoproliferative disorders such as chronic lymphocytic leukemia and lymphoma. Generally, thrombocytopenia improves with treatment of the underlying malignancy. Immune thrombocytopenia has also been associated with non-hematologic tumors, but it is unclear whether these have been chance associations. The platelet count improves with immunosuppressive therapy such as prednisone. Immune thrombocytopenia is common in systemic lupus erythematosus (SLE) (see Chapter 289) . Whether this association is due to specific antiplatelet antibodies, to antibodies against common antigens also found on platelets, or to immune complexes is unclear. The platelet count is usually mildly to moderately decreased. Treatment is usually directed at SLE because other manifestations of the disease are present in most cases. Occasionally, immune thrombocytopenia occurs in patients who have serologic evidence of SLE but fail to meet all the criteria for the diagnosis. The decision to treat such patients with splenectomy is difficult because other manifestations of SLE may appear subsequently. If the platelet count is severely decreased (3000 both synthesized in baby hamster kidney cell lines Ultrapure Plasma-Derived Factor VIII

Immunoaffinity chromatography and pasteurization (60° C, 10 hr)

Monoclate P (Centeon)

>3000

Immunoaffinity chromatography, solvent detergent (TNBP/Triton X-100), and terminal heating (25° C, >10 hr)

Hemofil M (Baxter), Monarc M (Baxter, distributed by the American Red Cross, which also provides the donor plasma)

>3000

Intermediate-Purity and High-Purity Plasma-Derived Factor VIII Affinity chromatography, solvent detergent (TNBP/polysorbate Alphanate (Alpha Therapeutics) 80), and terminal heating (80° C, 72 hr) Solvent detergent (TNBP/polysorbate 80)

8-30 (>400 when corrected for von Willebrand factor protein content)

Koate-HP (Bayer) 9-22

Pasteurization (60° C, 10 hr)

Humate-P (Centeon-Pharma) 1-2 Ultrapure Recombinant Factor IX

Affinity chromatography and ultrafiltration (Chinese hamster ovary cell lines maintained in fetal calf serum-free medium)

BeneFix (Genetics Institute)

>200 (albumin free)

Very Highly Purified Plasma-Derived Factor IX Dual-affinity chromatography, solvent detergent (TNBP/polysorbate 80), and nanofiltration

AlphaNine SD (Alpha Therapeutics)

>200

Immunoaffinity chromatography, solvent detergent (sodium thiocyanate), and ultrafiltration

Mononine (Centeon)

>160 (albumin free)

Low-Purity Plasma-Derived Factor IX Complex Concentrates Solvent detergent (TNBP/polysorbate 80)

Profilnine SD (Alpha Therapeutics) 4.5

Vapor heat (10 hr 60° C, 1190 mbar pressure plus 1 hr, 80° C, Bebulin VH (Immuno, distributed by Baxter) 1375 mbar)

2

Activated Plasma-Derived Factor IX Complex Concentrates (Reserved Primarily for Inhibitor Patients)

Dry heat (68 °C, 144 hr)

Autoplex T (Baxter, distributed by NABI) 5

Vapor heat (10 hr, 60° C, 1190 mbar plus 1 hr, 80° C, 1375 mbar)

Feiba VH (Immuno, distributed by Baxter) 0.8

1008

Factor IX inhibitor patients appear to be susceptible to anaphylaxis and the development of nephrotic syndrome with subsequent exposure to sources of Factor IX. Autoantibody inhibitors occur spontaneously in individuals with previously normal hemostasis (non-hemophiliacs). Although approximately 50% have no obvious underlying etiology, the remainder are associated with autoimmune diseases, lymphoproliferative disorders, idiosyncratic drug associations, and pregnancy. Patients typically have massive hemorrhagic events, usually much more severe than those produced by alloantibodies; the laboratory expression of autoantibodies is similar to that of alloantibodies except that clotting factor activity is not completely neutralized. Residual clotting factor activities between 3 and 20% of normal are frequently observed in autoantibody patients. The same principles of replacement therapy for alloantibodies also apply to these inhibitors. Porcine Factor VIII concentrate is particularly useful in acquired hemophilia A because very little cross-reactivity usually occurs even with extremely high titers of antihuman Factor VIII antibodies. Immunosuppressive therapy with steroids and cytotoxic agents is a necessary component of the overall treatment to suppress the inhibitor. High-dose intravenous gamma-globulin may be a useful adjunctive therapy. Immune tolerance induction is rarely successful in eradicating autoantibody inhibitors and is not usually attempted. For hemorrhagic catastrophes related to either alloantibodies or autoantibodies, extracorporeal plasmapheresis over a staphylococcal protein A column may remove enough of the IgG to allow for replacement therapy with enough factor concentrates to achieve hemostasis. VON WILLEBRAND DISEASE. In 1926 Erik von Willebrand described an autosomal dominantly inherited hemorrhagic disease affecting both sexes that was subsequently recognized as a deficiency in vWF. It has emerged as the most common bleeding disorder, with a prevalence of 1 to 3% of the population without any ethnic predominance. Homozygous patients are rare and are the result of a recessive mutant gene. Normal vWF is a large multimeric glycoprotein with monomeric subunits of 220,000 daltons. Its total molecular weight may reach 20 million daltons, with its platelet agglutination properties mediated predominantly by the highest-molecular-weight multimers. The phenotypic classification of vWD recognizes three major types of the disease based on their multimeric structure and function of the vWF protein (Table 185-3) . Type 1 vWD accounts for up to 75 to 80% of patients and is inherited predominantly via an autosomal dominant mode; a qualitative defect is present in which the vWF structure is normal but vWF antigen and activity are concurrently reduced. Type 2 vWD includes approximately 20% of vWD patients, is inherited in either a dominant or recessive pattern, and is characterized by qualitative and quantitative abnormalities in the vWF protein. Further subclassification is based on multimeric structure and responses in the ristocetin-induced platelet aggregation assay. Up to 30 variants have been described, each with unique aberrations in vWF multimer structure. Type 2A is the most common variant, with loss of the largest and intermediate-sized multimers, and type 2B lacks the only the largest vWF multimers. The multimeric patterns in type 2A may result from defective synthesis of the vWF protein or increased susceptibility of vWF to proteolysis in vivo. In type 2B, the highest-molecular-weight multimers of vWF are adsorbed preferentially and with abnormally high affinity to the glycoprotein Ib receptor binding site on the platelet membrane surface. Alternatively, a structural defect in the glycoprotein Ib platelet receptor binding site for vWF can produce a multimeric pattern similar to that of type 2B by virtue of its preferential adsorption of the highest-molecular-weight multimers from normal vWF in the circulation. This latter variant is designated platelet-type

COAGULATION PROTEIN DEFICIENCY

TABLE 185-2 -- COAGULATION PROTEINS AND REPLACEMENT THERAPY INHERITANCE PREVALENCE MINIMUM HEMOSTATIC REPLACEMENT SOURCES PATTERN LEVEL

Factor I (fibrinogen)

100 mg/dL

Cryoprecipitate/fresh-frozen plasma, viral-treated Factor VIII concentrates (intermediate purity)

Afibrinogenemia

Autosomal recessive

Rare (300 variants)

Factor II (prothrombin)

Autosomal dominant or recessive

Rare ( 25 kindreds)

30% of normal

Fresh-frozen plasma, Factor IX complex concentrates

Factor V (labile factor)

Autosomal recessive

1 per million births

25% of normal

Fresh-frozen plasma

Factor VII

Autosomal recessive

1 per 500,000 births

25% of normal

Fresh-frozen plasma, Factor IX complex concentrates, or recombinant Factor VIIa

Factor VIII (antihemophilic factor)

X-linked recessive

1 per 5,000 male births

80-100% for Factor VIII concentrates (see Table 185-1) surgery/life-threatening bleeds, 50% for serious bleeds, 25-30% for minor bleeds

Von Willebrand disease

Usually autosomal 1% prevalence dominant

>50% vWF antigen and ristocetin cofactor activity

DDAVP for mild to moderate vWD (except 2B. Variable response to 2A); cryoprecipitate and fresh-frozen plasma (not preferred except in emergencies); Factor VIII concentrates, viral attenuated, intermediate purity (preferred for vWD unresponsive to DDAVP and for Type 3) (see Table 185-1)

Type 1 and 2 variants Type 3

Autosomal recessive

1 per million births

Factor IX (Christmas factor)

X-linked recessive

1 per 30,000 male births

25-50% of normal, depending on extent of bleeding and surgery

Factor IX concentrates; fresh-frozen plasma is not preferred except in dire emergencies (see Table 185-1)

Factor X (Stuart-Prower factor)

Autosomal recessive

1 per 500,000 births

10-25% of normal

Fresh-frozen plasma or Factor IX complex concentrates

Factor XI (hemophilia C)

Autosomal dominant: severe type is recessive

20-40% of normal

Fresh-frozen plasma or Factor XI concentrate

4% Ashkenazi Jews; 1 per million general population

Factor XII (Hageman factor), Autosomal prekallikrein, recessive high-molecular-weight kininogen

Not available

No treatment necessary

Factor XIII (fibrin stabilizing factor)

1 per 3 million births

5% of normal

Autosomal recessive

vWF = von Willebrand factor; DDAVP = desmopressin

Fresh-frozen plasma, cryoprecipitate, or viral-attenuated Factor XIII concentrate

1009

TYPE

TABLE 185-3 -- PATTERNS OF VON WILLEBRAND DISEASE VWF:Ag/vWF:RCoF RIPA RIPA- LOW DOSE

1 (classic)

±

Absent

/

MULTIMERIC PATTERN Uniform in all multimers

2 (Variant) 2A

Absent /

2B

2N (Normandy) Platelet type

3 (Homozygote or compound heterozygote)

in large and intermediate multimers

± /±

Normal Increased

Normal/normal

Normal

± /±

±

Absent/absent

Absent Absent

in large multimers Normal Increased in large multimers Absent

vWF:Ag = von Willebrand factor antigen; vWF:RCoF = Willebrand factor ristocetin cofactor activity; RIPA = ristocetin-induced platelet aggregation. pseudo-vWD. Type 2N (Normandy) is an unusual variant that resembles hemophilia A, although it is inherited in an autosomal dominant pattern. The defective vWF protein is normal from functional and multimeric perspectives but lacks an intact binding site for Factor VIII. Thus unbound Factor VIII is cleared from the circulation with a very rapid half-life. Finally, type 3 vWD, an exceedingly rare variant that occurs in 1 per 1 million individuals, is characterized by nearly complete absence of circulating vWF. Most patients with vWD have mild disease that may go undiagnosed until trauma or surgery. Symptomatic individuals manifest easy bruisability and mucosal surface bleeding, including epistaxis and gastrointestinal hemorrhage. Menorrhagia affects 50 to 75% of women and may be the initial symptom. These symptoms are consistent with platelet-based defects and reflect the critical role of vWF protein in mediating platelet-platelet and platelet-subendothelial matrix interactions in the process of vascular plug formation and primary hemostasis. The use of aspirin or non-steroidal anti-inflammatory drugs with anti-platelet aggregation effects may exacerbate the symptoms. Deep subcutaneous and intramuscular bleeds, hemarthroses, and intracranial hemorrhage are unusual in vWD, except in the rare type 3 variant. The Factor VIII deficiency is due to the absence of vWF protein, which normally complexes with Factor VIII, delivers it to sites of ongoing coagulation, and prevents its clearance from the circulation. Physical examination usually reveals non-specific evidence of easy bruising and bleeding. The bleeding time is variably prolonged in patients with vWD and may be influenced by the thrombocytopenia associated with vWD type 2B. The aPTT is also variably increased because of concurrent Factor VIII deficiency; however, a normal aPTT does not exclude the diagnosis of vWD. The vWF activity assay or ristocetin cofactor activity (vWF:RCoF) is the most specific test for vWF function but may be only slightly decreased in mild vWD. The vWF:Ag assay measures the immunologic expression of vWF and is usually performed via electroimmunoassay or enzyme-linked immunosorbent assay. It is slightly reduced in mild vWD and its variants and virtually absent in type 3. Because these assays are sensitive to the molecular mass of vWF, vWF:RCof activity is discordantly low as a result of a low-normal or slightly reduced vWF:Ag level in the type 2 variants of vWD. Furthermore, vWF:RCoF and vWF:Ag are acute phase reactants and are increased by exercise, stress, pregnancy, oral contraceptives, and liver disease and decreased with hypothyroidism and in the presence of blood group O. vWD subtypes can be analyzed by in vitro platelet aggregation assays in which the patient's platelet-rich plasma is activated by the addition of standard and low concentrations of ristocetin or cryoprecipitate. Types 1 and 3 vWF will show mild or marked hyporesponsiveness, respectively, to the standard concentration of ristocetin, whereas type 2B and the rare platelet-type pseudo-vWD will hyperaggregate with half-standard concentrations of ristocetin. Platelet-type pseudo-vWD can be differentiated from type 2B by observing spontaneous platelet agglutination following the addition of cryoprecipitate. With type 2B vWD, the defect responsible for the high-affinity vWF-platelet interaction is present in the vWF protein, whereas in the platelet type the defect resides in the platelet glycoprotein Ib/IX complex. Gene-based assays are the most specific for diagnosing vWF variants via restriction enzyme mapping of the vWF gene. Type 3 vWF has large deletions whereas the others are caused by variable point mutation defects. Type 2N has defects in the functional domain coding for vWF binding to Factor VIII. TREATMENT.

The goals of therapy for vWD consist of correcting the deficiencies in vWF protein activity to above 50% of normal and Factor VIII activity to levels appropriate for the clinical situation. Although cryoprecipitate is licensed by the FDA for prophylaxis or treatment of vWD-related bleeding complications, the lack of viral safety relegates its use exclusively to emergency circumstances when no other options are readily available. Replacement therapy with viral-attenuated, intermediate- or high-purity Factor VIII concentrates containing high-molecular-weight multimers of vWF, e.g., Humate-P or Alphanate, is preferred and should be reserved for patients with type 1 and 2A variants who are unresponsive to DDAVP and for patients with type 2B and type 3 disease. These products are also indicated for the 2N variant and provide a source of normal vWF to complex with the normal intrinsic Factor VIII. Dosing of Factor VIII concentrates for vWD is calculated according to Factor VIII activity increments, assuming that these materials have a 1:1 relationship between Factor VIII and vWF content. On-demand and continuous infusion regimens have been used successfully. An ultrahigh-purity plasma-derived vWF concentrate is available for clinical research protocols; however, this product will have little value for type 3 individuals, who require simultaneous sources of Factor VIII. All these plasma-derived concentrates may precipitate thrombotic complications or exacerbate the thrombocytopenia in platelet-type pseudo-vWD. These individuals should receive transfusions with normal platelets that possess glycoprotein Ib/IX complexes with normal vWF affinity. Otherwise, DDAVP (0.3 mug/kg in 50 mL normal saline infused over a 20-minute period or intranasally at 150 mug per nostril for adults) is the recommended treatment and eliminates potential exposure to blood-borne pathogens. The adjunctive use of antifibrinolytic agents such as epsilon-aminocaproic acid is useful following DDAVP therapy for bleeds. These agents should not be used for renal bleeds or menorrhagia. The following important caveats for vWD treatment should be considered: (1) A prolonged bleeding time does not need to be normalized to achieve adequate hemostasis following replacement therapy. Correction of vWF and Factor VIII activity will suffice and correlates closely with the clinical risk of bleeding. (2) DDAVP administration should be avoided in most individuals with type 2B variant vWD. Their thrombocytopenia may worsen inasmuch as DDAVP induces the release of abnormal vWF into the circulation with additional in vivo platelet agglutination/aggregation. (3) Individuals with variant type 2N may not manifest a sustained response to DDAVP because the vWF released cannot complex with the simultaneously released Factor VIII and prevent its clearance from the circulation. (4) Individuals who respond adequately to intravenously administered DDAVP may not respond adequately to the intranasal DDAVP preparation. Ideally, patients should be tested for their responses before needing it for surgery, etc. (5) Pregnant women with type 2B variant vWD may experience an exacerbation of their thrombocytopenia as pregnancy progresses. Levels of the abnormal vWF increase as estrogen levels increase. (6) Free water intake, whether intravenous or by mouth, should be severely restricted for 4 to 6 hours after DDAVP administration to minimize the risk of hyponatremia and seizures. (7) vWD is clinically associated with Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia), so gastrointestinal bleeding may occur. (8) Replacement 1010

therapy in type 3 vWD may occasionally precipitate the formation of alloantibody inhibitors that neutralize vWF activity. Acquired vWD is a rare condition and usually occurs as a complication of autoimmune, myeloproliferative, or lymphoproliferative disorders. The acquired vWD associated with neuroblastoma is secondary to proteolysis of vWF by tumor-secreted hyaluronidase. Abnormal vWF multimeric composition is a hallmark of these syndromes. Treatment is similar to that for congenital vWD, but responses are unpredictable.

FACTOR XI DEFICIENCY (HEMOPHILIA C). Factor XI deficiency occurs at a prevalence of 1 per million in the general population and 1 per 500 births in Ashkenazi Jewish families. Factor XI is the only component of the contact phase system of coagulation (Factor XII, pre-kallikrein, and high-molecular-weight kininogen) that is associated with excessive bleeding complications when a deficient state exists. Factor XI deficiency is diagnosed in the laboratory by a prolonged aPTT, normal PT, and decreased Factor XI activity ascertained in a specific quantitative clotting assay (normal range, 60 to 130%). The clinical bleeding tendencies in Factor XI deficiency are less severe than those seen with severe hemophilia A or B and are not necessarily correlated with the extent of the deficiency. Most individuals with Factor XI levels less than 20% of normal activity experience excessive bleeding following trauma or surgery; however, a small number will not bleed. In contrast, bleeding has been observed in approximately 35 to 50% of mildly affected patients with Factor XI levels between 20 and 50%. Spontaneous hemorrhagic episodes, hemarthroses, and intramuscular and intracerebral bleeds are very unusual; traumatic and surgical bleeds typically involve the mucous membranes. Patients undergoing tonsillectomies, prostatectomies, and dental extractions are at highest risk for bleeding unless replacement therapy is administered. Women may experience significant menorrhagia. GENETICS.

Factor XI deficiency is an autosomal disorder that can be inherited in both recessive and dominant patterns. The Factor XI gene is located on chromosome 4. In Ashkenazi Jewish individuals, two predominant gene mutations occur with equal frequency and are designated type II (a stop codon in exon 5) and type III (a single base defect in exon 9). The most severe clinical disease is observed in homozygous type II patients, who usually have less than 1% Factor XI activity. Homozygous type III individuals also manifest severe symptoms, typically less severe than those in individuals with type II, and have slightly higher Factor XI levels of about 10 to 20%. Compound heterozygotes, type II/III, make up the bulk of Factor XI-deficient patients and are clinically mild, with Factor XI levels between 30 and 50%. Genotypic identification of affected patients is determined practically by Factor XI levels rather than by defining their specific gene defect. TREATMENT.

Although Factor XI activity in plasma may not correlate with the severity of clinical bleeding, individuals with severe deficiencies, i.e., less than 20% of normal, are at particular risk of bleeding from surgery and trauma. Replacement therapy for prophylaxis and treatment of acute bleeding events should increase Factor XI levels to at least 40%. FFP is the traditional replacement product of choice because of its rapid effects; however, this approach is associated with potential transmission of blood-borne viruses because FFP is not viral attenuated. In older adults, the volume of FFP required to raise Factor XI activity to adequate hemostatic levels may precipitate heart failure. An emerging alternative to FFP is solvent detergent-treated frozen plasma (currently awaiting FDA approval), which is as efficacious as FFP with substantially decreased risks of viral transmission. Recently, clinical studies have evaluated a high heat-treated (80° C) viral-attenuated high-purity Factor XI concentrate available on a compassionate basis (Bio Products Laboratory, Elstree, United Kingdom). Although very effective clinically, its usefulness has been compromised somewhat by it potential thrombogenicity manifested by the onset of occasional fatal disseminated coagulation, myocardial infarction, and acute cerebrovascular accident. These complications have usually occurred postoperatively in older individuals with pre-existing hypercoagulable conditions such as malignancy. Factor XI concentrate should be avoided or administered judiciously with careful patient selection. Replacement dosing levels should never exceed 70% Factor XI activity. Repeat dosing with FFP or Factor XI concentrate should account for the very long 60- to 80-hour biologic half-life of Factor XI in vivo. The decision to treat heterozygotes with Factor XI at levels greater than 20% is somewhat empiric and should be based on the individual's prior history of bleeding after trauma or surgery. Alternatively, the family medical history of previous bleeding complications can be considered. For symptomatic patients, the preoperative or post-trauma use of FFP and pooled plasma products can be minimized or avoided by administering DDAVP, 0.3 mug/kg intravenously. Because hemorrhagic complications originate most commonly from mucosal membrane surfaces, antifibrinolytic agents such as epsilon-aminocaproic acid or tranexamic acid are frequently helpful as adjunctive therapy. The poor correlation between Factor XI levels and bleeding risk has prompted a search for concurrent defects in coagulation and platelet function. Preliminary data suggest that individuals with absent platelet Factor XI content are at risk. In addition, a significant association is seen between an increased bleeding tendency in patients with mild Factor XI deficiency and coincident mild vWD. CONTACT ACTIVATION FACTORS. Although Factor XI is important for activating Factor IX in the intrinsic pathway generation of thrombin, it is only one of the four components of the contact phase of coagulation. Deficiencies in any of the other three factors (Factor XII, pre-kallikrein, and high-molecular-weight kininogen) will produce in vitro laboratory abnormalities but no clinical bleeding and therefore require no replacement therapy. Deficiencies of each of these contact factors prolong the aPTT, which may normalize after prolonged incubation of the patient's plasma at 37° C with a negatively charged activator of the aPTT assay, e.g., kaolin or celite. Specific assays are also available to quantitate each of the contact factors. Counterintuitively, 8 to 10% of individuals with severe Factor XII deficiency (50 mg/dL more antigenic than functional) is observed; plasma-based clotting times with substitution of snake venom for thrombin, e.g., reptilase and ancrod, are variably prolonged. Abnormal fibrinogens are rare autosomally inherited proteins. Their characterization has provided valuable structure-function information and better understanding of wound healing and fibrinolysis. Over 50% of the dysfibrinogenemias are asymptomatic, 25% are associated with a mild hemorrhagic tendency (commonly caused by defective release of fibrinopeptide A), and 20% predispose individuals to thrombophilia (usually caused by impaired fibrinolysis). Concurrent bleeding and thrombosis may also occur. The prevalence of dysfibrinogenemia in patients with a history of thromboembolic episodes approaches 0.8%, typically occurring in late adolescence and early adulthood. Females experience a high incidence of pregnancy-related complications such as spontaneous abortions and postpartum thromboembolic events. Thrombin and reptilase times are not helpful in predicting whether an abnormal fibrinogen will be prothrombotic, prohemorrhagic, or asymptomatic, but clinical history, fibrinopeptide release studies,

and fibrin polymerization studies may be useful. Clinically insignificant dysfibrinogenemias may be acquired in association with hepatocellular carcinoma. In contrast to the hepatic synthesis of a qualitatively abnormal protein in dysfibrinogenemia, congenital afibrinogenemia, an autosomal recessive disorder, represents the markedly deficient production of a normal protein. Severe life-threatening hemorrhagic complications can occur at any site, beginning at birth with umbilical bleeding. Intracranial hemorrhage is a frequent cause of death. Poor wound healing is characteristic. All coagulation-based assays dependent on detection of a fibrin clot end point are markedly prolonged. Afibrinogenemia is usually detectable by either specific functional or immunologic assays. Platelet dysfunction may accompany afibrinogenemia and exacerbate bleeding. Deficiencies of fibrinogen may be corrected by the administration of fresh-frozen plasma (FFP) or cryoprecipitate; however, viral safety remains an issue. Intermediate-purity Factor VIII concentrates from FFP that have been viral attenuated and treated with solvent detergent (when licensed by the FDA) are preferable alternatives. The replacement goal is 100 mg/dL fibrinogen. With a circulating biologic half-life of at least 96 hours, treatment every 3 to 4 days is adequate. Primary prophylaxis regimens may be useful in afibrinogenemia; on-demand or prophylactic replacement for trauma or surgery is recommended for prohemorrhagic dysfibrinogenemias. Individuals with thrombophilic manifestations should receive anticoagulation indefinitely. FACTOR V (PROACCELERIN, LABILE FACTOR) DEFICIENCY. Factor V is a component of the prothrombinase complex that assembles Factors Va and Xa on the phospholipid membrane of the platelet for prothrombin (Factor II) activation to thrombin. Deficiency of Factor V is a very uncommon autosomal recessive disorder (1 per 1 million births). The severity of the plasma Factor V reduction correlates less well with the risk of clinical bleeding than does the platelet Factor V content in the alpha-granule. This observation illustrates the critical role of the platelet in promoting adequate hemostasis at bleeding sites and explains why transfusions of normal platelets may be preferred over FFP for the treatment of hemorrhagic episodes secondary to congenital or acquired Factor V deficiency. Thus hemostasis can be maintained without correcting plasma Factor V activity (>25% of normal). The Factor V Leiden protein, which is responsible for resistance to activated protein C and thrombophilia, does not affect Factor V coagulant activity (see Chapter 187) . Combined deficiencies of Factors V and VIII occur as an autosomal recessive disorder with a prevalence of 1 per 100,000 births in Jews of Sephardic origin. The severity of bleeding is determined by the levels of these factors, usually ranging from 5 to 30% of normal. Replacement therapy should be aimed at normalizing both clotting protein activities. Factors V and VIII are structurally homologous proteins. Acquired Factor V deficiency has been described in individuals exposed to bovine Factor V, which contaminates the thrombin preparations used topically to control bleeding during cardiovascular surgery. This abnormality probably represents the development of antibovine Factor V antibodies that cross-react with the human Factor V protein. Profuse bleeding accompanies this complication. DEFICIENCIES OF VITAMIN K-DEPENDENT COAGULATION FACTORS II, VII, AND X. Congenital deficiencies of Factors II, VII, and X are rare autosomally inherited disorders. Heterozygotes (with factor levels 20% of normal) are typically asymptomatic except in the immediate newborn period, when physiologic vitamin K deficiency exacerbates the underlying clotting factor deficiency. Homozygotes with clotting factor levels less than 10% of normal manifest variable symptoms. As with other coagulopathies, these deficiencies are usually suspected after the onset of neonatal umbilical stump bleeding. Thereafter, unless replacement or prophylactic therapy is provided, such patients are subject to mucosal bleeding from epistaxis, menorrhagia, and dental extractions; to hemarthroses and intramuscular hematomas; and to post-surgical/trauma bleeding. In the coagulation laboratory, Factor VII deficiency is associated with a prolonged PT and normal aPTT. This pattern localizes the deficiency to the extrinsic pathway. In contrast, deficiencies of Factors II and X prolong both the PT and aPTT, with the defects localized to the common pathway of coagulation. A Russell's viper venom-based clotting assay can differentiate between these two deficiencies because as a direct activator of Factor X, the Russell's viper venom assay will be prolonged with Factor X but not Factor II deficiency. Mixing patient plasma with normal plasma will demonstrate correction of these assays; specific clotting assays using plasma deficient in the coagulation protein to be studied confirm the diagnosis. Replacement therapy is indicated for acute symptomatic bleeds and for prophylaxis for surgery. In addition to FFP, which has the potential to transmit blood-borne viruses, Factor IX complex concentrates can be administered to achieve hemostatic levels of any of these vitamin K-dependent factors (>25 to 30% of normal). Additional issues that should be considered when a deficiency of these or other coagulation factors is confirmed include the following: 1. Acquired severe deficiency of Factor X, often accompanied by deficiencies of other vitamin K-dependent factors, occasionally occurs in individuals with systemic amyloidosis. Because amyloid fibrils in the reticuloendothelial system bind both endogenous and exogenous sources of Factor X, replacement therapy with FFP or Factor IX complex concentrates, even in large quantities, may not always be sufficient. Splenectomy may ameliorate or reverse the bleeding complications. 2. Acquired Factor IX deficiency has been associated with Gaucher's disease because Factor IX binds to glucocerebroside (see Chapter 208) . 3. Factor IX deficiency may accompany Noonan's syndrome, an autosomal dominant disease complex characterized by congenital heart disease, abnormal facies, and excessive bleeding or bruising. 4. The genetic Factor II variant resulting from a G to A mutation at nucleoside 20210 is associated with elevated prothrombin levels and an increased risk of venous and arterial thrombosis (see Chapter 187) . The PT and aPTT are not affected. 5. Bleeding complications caused by acquired IgG autoantibodies directed against any coagulation factor protein may be rapidly but temporarily reversed by extracorporeal immunoadsorption over a Sepharose-bound polyclonal antihuman IgG or staphylococcal A column with concomitant replacement therapy and initiation of immunosuppression. 6. Acquired Factor VII deficiency has been associated with Dubin-Johnson and Gilbert syndromes.

LUPUS ANTICOAGULANTS The lupus anticoagulant may be discovered incidentally when routine coagulation assays reveal prolongations in the PT and/or the aPTT, when young women experience recurrent spontaneous miscarriages and/or pregnancy-related thromboembolic events, when young women and elderly men are detected with cerebral arterial 1012

thromboses, when patients are affected by systemic lupus erythematosus (20 to 40%) or other autoimmune diseases or lymphoproliferative malignancies, and when patients have been receiving longterm therapy with psychotropic medications, e.g., chlorpromazine. Lupus anticoagulant can also occur with the active opportunistic infections and malignancies associated with AIDS. The lupus anticoagulant is an IgG or IgM antiphospholipid antibody directed against the phospholipids that function as templates for activation of the prothrombinase complex in vivo and in coagulation assays in vitro. Anticardiolipin antibodies, which are a subset of the antiphospholipid antibody family, can be purified with cardiolipin liposomes and demonstrate anticoagulant activity similar to that of lupus anticoagulants. Recent data suggest, however, that anticardiolipin antibody and lupus anticoagulant may represent separate types of antibodies with different specificities and binding kinetics to phospholipid. Occasionally, individuals may have discordant test results for lupus anticoagulant and the anticardiolipin and antiphospholipid antibodies, particularly during an acute thrombotic event. For practical purposes, one or a combination of these antibodies can be associated with thrombotic complications. These antibodies are diagnosed when mixing studies of patient and normal plasma reveal immediate inhibition of the aPTT or PT at baseline with no additional prolongation after a 2-hour incubation (in contrast to Factor VIII autoantibody). Confirmatory assays include the dilute Russell's viper venom time, tissue thromboplastin time, and platelet neutralization assay. The lupus anticoagulant precipitates bleeding complications in the presence of prothrombin (Factor II) deficiency, probably because of clearance of complexes from the circulation, and when the lupus anticoagulant targets platelet membranes and produces quantitative and/or qualitative platelet abnormalities. The pathologic mechanism for thrombotic complications is not clear; however, lupus anticoagulant may activate platelets and/or inhibit prostacyclin synthesis by endothelial cells or interfere with thrombomodulin function. beta2 -Glycoprotein 1, a serum protein that mediates binding of anticardiolipin antibodies to phospholipid, may be critical to the development of thrombotic complications. beta2 -Glycoprotein 1 functions as a natural anticoagulant and appears to inhibit thrombin generation. Induction of antiphospholipid antibodies may be stimulated by the exposure of new epitopes that form after beta2 -glycoprotein 1 binds to phospholipid/cardiolipin. It has been shown in vitro that these antibodies can cross-react with beta2 -glycoprotein 1 and neutralize its anticoagulant capacity and may therefore promote the development of thrombotic complications. The approach to the management of lupus anticoagulant or antiphospholipid antibody varies according to the severity of symptoms and the clinical circumstances. Although daily low-dose aspirin (81 mg) and/or corticosteroids had been considered an important cornerstone in the prevention of spontaneous miscarriage secondary to lupus anticoagulant or antiphospholipid antibody, a recent large randomized trial found this combination to be ineffective in promoting live births. When a miscarriage

has been associated with lupus anticoagulant or antiphospholipid antibody, the preponderance of evidence indicates that more aggressive anticoagulation with full-dose or minidose unfractionated heparin regimens alone or in combination with low-dose aspirin should be used to reduce subsequent spontaneous fetal losses and to protect the mother who has experienced a previous thrombotic event. Clinical trials with low-molecular-weight heparin (LMWH) preparations and immunosuppressive agents such as intravenous gamma-globulin are in progress. Non-pregnant individuals with thrombotic manifestations of lupus anticoagulant or antiphospholipid antibody have up to a 50% risk of experiencing recurrent events over a 5-year period. Typically, recurrent hypercoagulable episodes occur in a pattern consistent with the initial findings; i.e., venous recurrence follows an initial deep venous thrombosis. Conventional oral anticoagulation to maintain the International Normalized Ratio (INR) between 2.0 and 3.0 does not effectively prevent recurrent events; therefore, a more aggressive regimen intended to achieve an INR of 3.0 to 3.5 is recommended. The non-virilizing androgen preparations danazol and stanazol may be helpful in raising depressed Factor II levels into the hemostatic range. Asymptomatic individuals may benefit from prophylactic aspirin therapy, which has a favorable risk-to-benefit profile.

COAGULOPATHIES SECONDARY TO ANTICOAGULATION The most common acquired clinical coagulopathies are secondary to anticoagulation with warfarin and other coumarin analogues and to heparin. Vitamin K-dependent clotting Factors II, VII, IX, and X are functionally defective after warfarin because post-translational carboxylation of their gamma-glutamyl residues cannot be accomplished (see Chapter 186) . The risks for bleeding increase proportionally with the intensity of anticoagulation and rising INRs. Warfarin effects can be exaggerated by potentiating medications, excessive ethanol use, and simultaneous dietary vitamin K deficiency. Bleeding may be severe or occult and may unmask the presence of pathologic lesions such as carcinomas. For acute and profuse bleeding events caused by warfarin, vitamin K1 , 1 to 5 mg, should be administered subcutaneously or intravenously in conjunction with FFP (10 to 20 mL/kg) or small amounts of Factor IX complex concentrates (20 to 50 U/kg). Bleeding due to over-anticoagulation with warfarin has also been reversed successfully and efficiently by infusions of recombinant Factor VIIa concentrate. For minor bleeding or a markedly increased INR without bleeding, warfarin should be withheld for 1 to 2 days and vitamin K1 administered at 1 to 2 mg subcutaneously or intravenously. This approach allows for easy reinitiation of warfarin with appropriate dose adjustment. Warfarin effects on the PT can be reversed in vitro by mixing patient plasma with normal plasma. Although the PT is the first coagulation screening parameter that is prolonged after warfarin therapy, this prolongation simply reflects decreased Factor VII activity. Protein C activity has a circulating half-life that parallels that of Factor VII. Thus in early anticoagulation, a potential paradoxical thrombogenic state is produced despite an increased PT. Simultaneous heparin therapy with a 5-day overlap with warfarin will minimize these risks. Heparin anticoagulation can also induce life-threatening hemorrhagic complications. The aPTT and thrombin times will be prolonged even with minimal amounts of heparin in the circulation or contaminating indwelling catheters from which blood specimens are obtained. The reptilase time can be used to distinguish heparin from other causes of thrombin time prolongation, e.g., fibrin degradation products, or abnormal fibrinogens. The PT may be prolonged in the presence of large concentrations of heparin. Heparin functions as a circulating inhibitor, so mixing studies of patient plasma with normal plasma will not result in correction of the aPTT. LMWH preparations will not affect the aPTT but may affect the thrombin time, depending on the thrombin concentration used in the assay (see Chapter 188) . The anticoagulant properties of LMWHs can be monitored by the anti-Factor Xa assay. Acute and profuse bleeding episodes secondary to heparin can be reversed by administering protamine sulfate (1 mg/100 U of residual heparin). Overdosing with protamine sulfate can produce its own coagulopathy. Otherwise, the circulating half-life of standard heparin is short enough (2 to 4 hours) to allow the anticoagulant state to dissipate on its own. The half-life of LMWH is longer, but bleeding is uncommon. The anticoagulation effects of LMWH may be reversed with protamine sulfate, although the response may be marginal and unpredictable. Bolton-Maggs PHB: Factor XI deficiency. Baillieres Clin Haematol 9:355, 1996. A comprehensive discussion of genetic aspects and treatment. Brettler DB: Inhibitors of factor VIII and IX. Haemophilia 1(Suppl. 1):35, 1995. A good review of the detection and treatment of this significant complication. Cohen AJ, Kessler CM: Treatment of inherited coagulation disorders. Am J Med 99:675, 1995. A review of preferred products for replacement therapy for all congenital coagulopathies. Cohen AJ, Kessler CM: Acquired inhibitors. Baillieres Clin Haematol 9:331, 1996. Basic concepts in the diagnosis and treatment of acquired inhibitors to coagulation proteins. Di Bona E, Schiavoni M, Castaman G, et al: Acquired haemophilia: Experience of two Italian centres with 17 new cases. Haemophilia 3:183, 1997. Lee CA (ed): Haemophilia. Baillieres Clin Haematol 9:1, 1996. This volume contains a comprehensive review of all aspects of hemophilia A and B, including descriptions of molecular diagnostics, new therapeutic modalities, prospects for successful gene therapy, and complications and treatment of alloantibody inhibitors. Martinez J: Congenital dysfibrinogenemia. Curr Opin Hematol 4:357, 1997. An excellent overview of the structure-function relationships of abnormal fibrinogens and their clinical features. Perry DJ: Factor X and its deficiency states. Haemophilia 3:159, 1997. An excellent summary of a rare condition with application for all vitamin K- dependent clotting factor protein deficiencies. Sadler JE: A revised classification of von Willebrand disease. Thromb Haemost 71:520, 1994. A good reference for interpretation of clinical and laboratory data.

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Chapter 186 - HEMORRHAGIC DISORDERS: MIXED ABNORMALITIES Andrew I. Schafer

DISSEMINATED INTRAVASCULAR COAGULATION Disseminated intravascular coagulation (DIC), also referred to as consumptive coagulopathy or defibrination, is caused by a wide variety of serious disorders (Table 186-1) . In most patients, the underlying process dominates the clinical picture, but in some cases (e.g., occult malignancy, envenomation), DIC may be the initial manifestation of the disorder. PATHOPHYSIOLOGY. DIC is primarily a thrombotic process, even though its clinical manifestation may be widespread hemorrhage in acute, fulminant cases. The basic pathophysiology (Fig. 186-1) , irrespective of etiology, is entry into the circulation of procoagulant substances that trigger systemic activation of the coagulation system and platelets and thereby lead to the disseminated deposition of fibrin-platelet thrombi. In most cases, the procoagulant stimulus is tissue factor, a lipoprotein that is not normally exposed to blood. In DIC, tissue factor gains access to blood by tissue injury, its elaboration by malignant cells, or its expression on the surfaces of monocytes and endothelial cells by inflammatory mediators. Tissue factor then triggers generation of the coagulation protease thrombin, which induces fibrin formation and platelet activation. In some specific cases of DIC, procoagulants other than tissue factor (e.g., a cysteine protease or mucin in certain malignancies) and proteases other than thrombin (e.g., trypsin in pancreatitis, exogenous proteins in envenomation) provide the procoagulant stimulus. In acute, uncompensated DIC, coagulation factors are consumed at a rate in excess of the capacity of the liver to synthesize them, and platelets are consumed in excess of the capacity of bone marrow megakaryocytes to release them. The resulting laboratory manifestations are a prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), as well as thrombocytopenia. Increased fibrin formation in DIC stimulates the compensatory process of secondary fibrinolysis in which plasminogen activators generate plasmin to digest fibrin (and fibrinogen) into fibrin(ogen) TABLE 186-1 -- MAJOR CAUSES OF DISSEMINATED INTRAVASCULAR COAGULATION Infections Gram-negative bacterial sepsis Other bacteria, fungi, viruses, Rocky Mountain spotted fever, malaria Obstetric complications Amniotic fluid embolism Retained dead fetus Abruptio placentae Toxemia Septic abortion Malignancies Pancreatic carcinoma Adenocarcinomas Acute promyelocytic leukemia Other neoplasms Liver failure Acute pancreatitis Envenomation Transfusion reactions Respiratory distress syndrome Trauma, shock Brain injury Crush injury Burns Hypothermia/hyperthermia Fat embolism Hypoxia, ischemia Surgery Vascular disorders Giant hemangioma (Kasabach-Merritt syndrome) Vascular tumors degradation products (FDPs). FDPs are potent circulating anticoagulants that further contribute to the bleeding manifestations of DIC. Intravascular fibrin deposition can cause fragmentation of red cells and thereby lead to the appearance of schistocytes in blood smears; however, frank hemolytic anemia is unusual in DIC. Microvascular thrombosis in DIC can also cause tissue necrosis and end-organ damage. ETIOLOGY. DIC always has an underlying etiology, which must generally be identified and eliminated for successful treatment of the coagulopathy. Infection is the most common cause of DIC. The syndrome is particularly associated with gram-negative sepsis, although it can be triggered by a wide variety of bacterial, fungal, viral, rickettsial, and

protozoal microorganisms. The placenta and uterine contents are rich sources of tissue factor and other procoagulants that are normally excluded from the maternal circulation; a spectrum of clinical manifestations of DIC may therefore accompany obstetric complications, especially in the third trimester. These syndromes range from acute, fulminant, and often fatal DIC in amniotic fluid embolism to chronic or subacute DIC with a retained dead fetus. Other obstetric problems associated with DIC include abruptio placentae, toxemia, and septic abortion. Chronic forms of DIC accompany a variety of malignancies, particularly pancreatic cancer and mucin-secreting adenocarcinomas of the gastrointestinal tract, in which thrombotic manifestations predominate (see Chapter 197) , and acute promyelocytic leukemia, in which acute exacerbation of chronic DIC can be precipitated by cytotoxic chemotherapy. It is not known whether liver failure can actually cause DIC or whether its coexistence merely exacerbates intravascular coagulation because of impaired clearance of activated clotting factors, plasmin, and FDPs. Snake venom contains a variety of substances that can affect coagulation and endothelial permeability. Bites from rattlesnakes and other vipers can induce profound DIC by introducing these exogenous toxins, as well as by endogenous tissue factor released by tissue necrosis. The likelihood and degree of DIC caused by trauma, surgery, and shock are related to the extent of tissue damage and the organs involved; the brain is a particularly rich source of tissue factor, so traumatic brain injury can precipitate acute DIC. Aortic aneurysms, giant hemangiomas, and other vascular malformations can cause subclinical or clinical DIC that is initiated locally in the abnormal vasculature but can "spill" into the systemic circulation. CLINICAL MANIFESTATIONS. The clinical manifestations of DIC are determined by the nature, intensity, and duration of the underlying stimulus. The coexistence of liver disease enhances DIC of any etiology. Low-grade DIC is often asymptomatic and diagnosed only by laboratory abnormalities. Thrombotic complications of DIC occur most often with chronic underlying diseases, as exemplified by Trousseau's syndrome in cancer (see Chapter 197) . Gangrene of the digits or extremities, hemorrhagic necrosis of the skin, or purpura fulminans may also be manifestations of DIC. Bleeding is the most common clinical finding in acute, uncompensated DIC. Bleeding can be limited to sites of intervention or anatomic abnormalities, but it tends to be generalized in more severe cases, including widespread ecchymoses and diffuse oozing from mucosal surfaces and orifices. DIAGNOSIS. The laboratory diagnosis of severe, acute DIC is not usually difficult. Consumption and inhibition of the function of clotting factors cause prolongation of the PT, aPTT, and thrombin time. Consumption of platelets causes thrombocytopenia. Secondary fibrinolysis generates increased titers of FDPs, which can be measured by latex agglutination or D-dimer assays. Some schistocytes may be seen in the peripheral blood smear, but this finding is neither sensitive nor specific for DIC. Chronic or compensated forms of DIC are more difficult to diagnose, with highly variable patterns of abnormalities in "DIC screen" coagulation tests. Increased FDPs and prolonged PT are generally more sensitive measures than are abnormalities of the aPTT and platelet count. Overcompensated synthesis of consumed clotting factors and platelets in some chronic forms of DIC may actually cause shortening of the PT and aPTT and/or thrombocytosis, even while elevated levels of FDPs indicate secondary fibrinolysis in such cases. The most difficult differential diagnosis of DIC occurs in patients who have coexisting liver disease. The coagulopathy of liver failure is often indistinguishable from that of DIC, partly because advanced 1014

Figure 186-1 Pathophysiology of bleeding, thrombosis, and ischemic manifestations in disseminated intravascular coagulation.

hepatic dysfunction is necessarily accompanied by a state of DIC. In liver failure, the combination of decreased synthesis of clotting factors, impaired clearance of activated clotting factors, secondary fibrinolysis, and thrombocytopenia from portal hypertension and hypersplenism may make the coagulopathy practically impossible to differentiate from DIC. In thrombotic microangiopathies, including thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome, platelet consumption and thrombocytopenia are not accompanied by activation of clotting factors or secondary fibrinolysis; hence the PT, aPTT, thrombin time, and FDPs are generally normal in these disorders. Furthermore, schistocytes, often with frank hemolysis, are much more prominent in the peripheral smear in thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome than in DIC. "Primary fibrinolysis" is disputed as a distinct entity. However, some patients with a serious clinical bleeding diathesis have laboratory evidence of predominantly fibrinolysis, including very high levels of FDPs (D-dimers) and severe hypofibrinogenemia, with relatively little consumption of coagulation factors and normal or near-normal platelet counts. These unusual findings, which approximate those expected with fibrinolytic therapy, are occasionally encountered, particularly in patients with prostate cancer. TREATMENT. Successful treatment of DIC (Table 186-2) requires that the underlying cause be identified and eliminated. All other therapies, including hemodynamic support, coagulation factor and platelet replacement, and pharmacologic inhibitors of coagulation and fibrinolysis, are only temporizing measures. In many patients with asymptomatic, self-limited DIC who have only laboratory TABLE 186-2 -- TREATMENT OF DISSEMINATED INTRAVASCULAR COAGULATION Identify and eliminate the underlying cause No treatment if mild, asymptomatic, and self-limited Hemodynamic support, as indicated, in severe cases Blood component therapy Indications: Active bleeding or high risk of bleeding Fresh-frozen plasma Platelets In some cases, consider cryoprecipitate, antithrombin III Drug therapy Indications: Heparin for DIC manifested by thrombosis or acrocyanosis; antifibrinolytic agents generally contraindicated except with life-threatening bleeding and failure of blood component therapy Heparin Antifibrinolytic agents (generally contraindicated) manifestations of the coagulopathy, no treatment may be necessary. In patients with DIC who are actively bleeding or who are at high risk of bleeding, the blood component treatments of choice are transfusions of platelets to improve the thrombocytopenia and fresh-frozen plasma to replace all consumed coagulation factors and thereby correct the prolonged PT and aPTT. The theoretic concern that these blood products may "fuel the fire" and exacerbate the DIC has not been supported by clinical experience. In some patients who have particularly profound hypofibrinogenemia, the additional transfusion of cryoprecipitate, a plasma concentrate that is enriched in fibrinogen, may also be useful. Although not of proven efficacy in human forms of DIC, the infusion of antithrombin III concentrate may be considered as an adjunctive measure in selected cases. The use of pharmacologic inhibitors of coagulation and fibrinolysis in DIC is controversial. Heparin is of theoretic benefit because it blocks thrombin activity and thereby quenches intravascular coagulation and the resultant secondary fibrinolysis. However, in practice, heparin might exacerbate the bleeding tendency in acute DIC. Heparin is therefore usually reserved for special forms of DIC, including those manifested by thrombosis or acrocyanosis and those that accompany cancer, vascular malformations, retained dead fetus, and possibly acute promyelocytic leukemia. Antifibrinolytic agents, including epsilon-aminocaproic acid and tranexamic acid, are generally contraindicated in DIC. By blocking the secondary fibrinolytic response to DIC, these drugs will cause unopposed fibrin deposition and may therefore precipitate thrombosis. However, antifibrinolytic agents may be effective in decreasing life-threatening bleeding in DIC, particularly in extreme cases in which aggressive blood component replacement fails to control the hemorrhage; the simultaneous infusion of low doses of heparin may reduce the risk of thrombosis in such situations.

LIVER FAILURE Bleeding complications in patients with advanced liver disease can be very severe and even fatal and directly account for about 20% of the deaths associated with hepatic failure. The extent of the bleeding tendency depends on the severity and type of liver disease involved. About one third of deaths in patients undergoing liver transplantation are attributable to perioperative hemorrhage. PATHOPHYSIOLOGY. The pathophysiology of bleeding in liver failure is complex and multifactorial. Anatomic abnormalities are frequently the major cause of gastrointestinal bleeding in patients with liver disease. These changes usually result from portal hypertension. 1015

Upper gastrointestinal bleeding can be caused by esophageal varices or hemorrhagic gastritis (congestive gastropathy), whereas lower gastrointestinal bleeding, although seldom life-threatening, can be due to hemorrhoids. The complexity of the systemic coagulopathy of liver failure is not surprising inasmuch as the liver is the principal organ site for the synthesis of coagulation and fibrinolytic factors and their protein inhibitors (Table 186-3) . Hepatocytes produce all of the clotting factors except von Willebrand factor, and advanced parenchymal liver disease therefore results in impaired synthesis of these proteins. When superimposed on this quantitative synthetic defect, liver disease can also produce impairment in vitamin K-dependent gamma-carboxylation of the procoagulant Factors II, VII, IX, and X, as well as the anticoagulant factors protein C and protein S because of either an intrinsic enzymatic abnormality or vitamin K malabsorption and deficiency in cholestatic forms of liver disease. In addition to a quantitative deficiency of fibrinogen, functional abnormalities of this protein, termed dysfibrinogenemias, are frequently found in various forms of liver disease, particularly in hepatomas. Most forms of advanced liver disease are accompanied by some degree of DIC caused by impaired synthesis of inhibitors of blood coagulation and defective hepatocellular clearance of activated coagulation factors. DIC is an especially important potential complication of LeVeen shunts used for the treatment of intractable ascites because this procedure introduces procoagulant-rich ascitic fluid into the systemic circulation. In many such cases, shunt ligation is required to terminate the DIC. DIC and bleeding risk are exacerbated by the enhanced fibrinolytic activity of liver disease that is caused by increased levels of tissue plasminogen activator accompanied by decreased synthesis of inhibitors of both plasminogen activator and plasmin. Quantitative and qualitative abnormalities of platelets also contribute to the bleeding diathesis of liver failure. Congestive splenomegaly secondary to portal hypertension causes increased pooling of platelets in the spleen (hypersplenism). The resultant thrombocytopenia, the degree of which generally correlates with spleen size, rarely causes a reduction in the platelet count below 50,000/mm3 . In alcoholic patients, suppression of bone marrow thrombopoiesis by the acute toxic effects of alcohol or folate deficiency may contribute to the thrombocytopenia. Qualitative platelet abnormalities have also been described in patients with liver disease. Liver transplantation poses special problems to the coagulation system. During the anhepatic stage of surgery, which lasts about 2 hours, the complete cessation of synthesis of coagulation factors causes further prolongations in the PT and aPTT. Release of tissue plasminogen activator from the newly grafted liver then leads to increased fibrinolysis and transient exacerbation of bleeding risk in the postoperative period. CLINICAL MANIFESTATIONS. The most common hemorrhagic complication of liver disease is gastrointestinal bleeding, which is usually caused by anatomic abnormalities and exacerbated by the systemic coagulopathy of liver failure. Bleeding from other mucosal sites, extensive ecchymoses, or more serious hemorrhage into the retroperitoneum or central nervous system generally indicates more significant derangements of the coagulation system. DIAGNOSIS. Routine coagulation tests are usually sufficient to diagnose the coagulopathy of liver failure. Although both the PT and aPTT are often prolonged in advanced liver disease, the former tends to be a more sensitive assay early in the course; in fact, a disproportionate prolongation of the aPTT should raise suspicion of a coexisting coagulation abnormality, such as a lupus anticoagulant or clotting factor inhibitor. The prolonged PT is also a useful prognostic indicator of poor outcome in patients with cirrhosis, TABLE 186-3 -- COAGULATION ABNORMALITIES IN LIVER DISEASE Abnormalities of Coagulation Decreased synthesis of coagulation factors Impaired vitamin K-dependent gamma-carboxylation Dysfibrinogenemia Disseminated intravascular coagulation Increased fibrinolytic activity Abnormalities of platelets Thrombocytopenia (hypersplenism) Abnormal platelet function acute acetaminophen hepatotoxicity, and acute viral hepatitis; in the latter, it is a better index of prognosis than the serum albumin or transaminases. A disproportionate prolongation of the thrombin time should suggest the presence of dysfibrinogenemia. Hypersplenism, possibly associated with nutritional folate deficiency or the acute toxic effects of alcohol on bone marrow, often causes mild to moderate thrombocytopenia in patients with liver disease; however, consideration should be given to other coexisting causes of thrombocytopenia if the platelet count is much below 50,000/mm3 . The coagulopathy of liver failure is sometimes indistinguishable from that of DIC, in part because some degree of DIC is a necessary accompaniment of advanced liver disease. However, in general, patients with DIC have more marked decreases in levels of Factor VIII and increases in titers of FDPs, particularly D-dimers, than do those with liver failure. TREATMENT. Therapy for the coagulopathy of liver disease may be directed at preventing the hemorrhagic complications of invasive procedures or treating active bleeding. Bleeding risks of surgical procedures in patients with liver failure are poorly defined. However, it is usually recommended that attempts be made to correct PT prolongations of over 3 seconds and platelet counts below 70,000/mm3 before surgical interventions, including percutaneous liver biopsy. The most effective treatment is blood component therapy with fresh-frozen plasma (which contains all of the coagulation factors) and platelet transfusions. Some patients require large volumes of fresh-frozen plasma (15 to 20 mL/kg) to lower the prolonged PT; rarely, plasmapheresis with plasma exchange is required to avoid fluid overload in such situations. Because of the short half-lives of some clotting factors, fresh-frozen plasma may have to be administered as frequently as every 8 to 12 hours to maintain acceptable coagulation test parameters. In some patients, especially those with cholestasis, parenteral administration of vitamin K can at least partially reverse the coagulation abnormalities; however, in patients with advanced hepatocellular failure, vitamin K is largely ineffective. Prothrombin complex concentrates are relatively contraindicated in liver failure, as in DIC, because of the risk of thrombotic complications. Platelet transfusions are not as effective as in thrombocytopenias caused by decreased platelet production. Because of immediate pooling of transfused platelets in the enlarged spleens of patients with hypersplenism, a higher than calculated dose of platelet concentrates is usually required to raise the circulating platelet counts significantly. Desmopressin (DDAVP), which can shorten the bleeding time of patients with cirrhosis, may be used as ancillary therapy.

VITAMIN K DEFICIENCY Vitamin K is required for gamma-carboxylation of glutamic acid residues of the procoagulant Factors II (prothrombin), VII, IX, and X and the anticoagulant factors protein C and protein S. This post-translational modification normally renders these proteins functionally active in coagulation. Severe vitamin K deficiency can lead to a hemorrhagic diathesis that is characterized by prolongations of the PT and sometimes also the aPTT. The PT is more sensitive than the aPTT in detecting vitamin K

deficiency states because Factor VII, the only one of the vitamin K-dependent factors that is in the extrinsic pathway of coagulation, is the most labile of these proteins. The two major sources of vitamin K are dietary intake and synthesis by the bacterial flora of the intestine. Therefore, in the absence of malabsorption, nutritional deficiency alone rarely causes clinically significant vitamin K deficiency. However, such a condition can arise when eradication of gut flora is combined with inadequate dietary intake. This situation typically occurs in critically ill patients in intensive care units who have no oral intake and are receiving broad-spectrum antibiotics for prolonged periods. Vitamin K deficiency can also develop in patients receiving total parenteral nutrition unless the infusions are supplemented with vitamin K. Vitamin K is absorbed predominantly in the ileum and requires the presence of bile salts. Therefore, clinically significant vitamin K deficiency occurs with malabsorption of fat-soluble vitamins secondary to obstructive jaundice or with malabsorption caused by intrinsic small bowel diseases, including celiac sprue, short-bowel 1016

syndrome, and inflammatory bowel disease. Finally, warfarin acts as an anticoagulant by competitive antagonism of vitamin K. Correction of vitamin K deficiency, when clinically significant, can be achieved with oral supplementation, unless malabsorption is present. In the latter case, parenteral vitamin K (10 mg subcutaneously daily) should be administered. Emergency treatment of bleeding caused by vitamin K deficiency is transfusion of fresh-frozen plasma. Carey MJ, Rodgers GM: Disseminated intravascular coagulation: Clinical and laboratory aspects. Am J Hematol 59:65, 1998. Review of concepts of diagnosis and treatment of DIC, including discussion of novel approaches. Furie B, Bouchard BA, Furie BC: Vitamin K dependent biosynthesis of gamma-carboxyglutamic acid. Blood 93:1798, 1999. Comprehensive review of basic mechanisms of vitamin K metabolism. Staudinger T, Locker GJ, Frass M: Management of acquired coagulation disorders in emergency and intensive-care medicine. Semin Thromb Hemost 22:93, 1996. Emphasis on a practical clinical approach to the treatment of bleeding problems in DIC and liver failure.

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Chapter 187 - THROMBOTIC DISORDERS: HYPERCOAGULABLE STATES Andrew I. Schafer

The "hypercoagulable states" encompass a group of inherited or acquired disorders that cause a pathologic thrombotic tendency or risk of thrombosis. These conditions are also known as "pre-thrombotic" states. A hereditary tendency to thrombosis, irrespective of its cause, is sometimes referred to as "thrombophilia." The primary hypercoagulable states (see Chapter 183) are caused by quantitative or qualitative abnormalities of specific coagulation proteins that lead to a prothrombotic state. Most of these disorders involve inherited mutations in one of the physiologic antithrombotic factors (see Chapter 183) . Particularly when combined with other prothrombotic mutations (multigene interactions), these primary hypercoagulable states are associated with a lifelong predisposition to thrombosis. The trigger for a discrete, clinical thrombotic event is often the development of one of the acquired, secondary hypercoagulable states superimposed on an inherited state of hypercoagulability. The secondary hypercoagulable states, a diverse group of mostly acquired conditions (Fig. 187-1) , cause a thrombotic tendency by complex and often multifactorial mechanisms.

PRIMARY HYPERCOAGULABLE STATES MOLECULAR MECHANISMS AND FREQUENCY. ANTITHROMBIN III DEFICIENCY.

Inherited quantitative or qualitative deficiency of antithrombin III leads to increased fibrin accumulation and a lifelong propensity to thrombosis (see Chapter 183) . Antithrombin is the major physiologic inhibitor of thrombin and other activated coagulation factors, and its deficiency leads to unregulated protease activity and fibrin formation. Two basic phenotypes of inherited antithrombin deficiency are recognized. Patients with type I antithrombin deficiency have proportionately reduced plasma levels of antigenic and functional antithrombin that result from a quantitative deficiency of the normal protein. Impaired synthesis, defective secretion, or instability of antithrombin in type I antithrombin-deficient individuals is caused by major gene deletions, single nucleotide changes, or short insertions or deletions in the antithrombin gene. Patients with type II antithrombin deficiency have normal or nearly normal plasma antigen accompanied by low activity levels, thus indicating a functionally defective molecule. Type II antithrombin deficiency is further subdivided into subtypes in which abnormalities affect the reactive protease inhibitory activity, the heparin binding site, or both. Type II deficiency is usually caused by specific point mutations leading to single amino acid substitutions that produce a dysfunctional protein. Over 80 different mutations causing type I or type II antithrombin deficiency have been recognized to date. The pattern of inheritance of antithrombin deficiency is autosomal dominant. Most affected individuals are heterozygotes whose antithrombin levels are typically about 40 to 60% of normal but may have the full clinical manifestations of hypercoagulability. Rare homozygous antithrombin-deficient patients usually have type II deficiency with reduced heparin affinity, a variant that is associated with a low risk of thrombosis in its heterozygous form. The frequency of asymptomatic heterozygous antithrombin deficiency in the general population may be as high as 1 in 350. Most of these individuals have clinically silent mutations and will never have thrombotic manifestations. The frequency of symptomatic antithrombin deficiency in the general population has been estimated to be between 1:2000 and 1:5000. Among all patients seen with venous thromboembolism, antithrombin deficiency is detected in only about 1%, but it is found in about 2.5% of selected patients with recurrent thrombosis and/or thrombosis at a younger age (15%) in the CA 125 may be the first sign of disease progression or recurrence. However, as is the case with the use of other tumor markers, changes in treatment should not be considered on the basis of one measurement. Particularly given the increasing number of second-line treatments available for ovarian cancer and the better outlook for patients with low-volume disease, it seems likely that early detection of disease progression by CA 125 monitoring may be advantageous; however, this assumption has not yet been confirmed in clinical trials.

BREAST CANCER SCREENING. At present there is no evidence that the most commonly used tumor markers, CA 15-3 or CEA, have any role in screening patients for breast cancer. They are not usually abnormal in early-stage disease, nor are they specific for breast cancer.

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MONITORING RESPONSE TO THERAPY. As in the use of tumor markers for monitoring patients with colon and ovarian cancer, a rising level of CA 15-3 or CEA in patients with breast cancer is often the first sign of disease progression. Analogous to ovarian cancer, tumor markers play an even more important role in monitoring response to therapy in patients with disease that cannot be followed well by physical examination or with radiographic studies. For example, in patients with disease limited to bone, the bone scan may lag behind improvements in tumor marker levels by many months. Similarly, in patients with abdominal carcinomatosis, tumor marker measurements may substitute for more costly computed tomographies. An important caveat to the use of tumor markers in patients on hormonal therapy is that some patients will have a "flare" (worsening clinical disease and increase in tumor markers) weeks to months after beginning hormonal therapy. Because these patients predictably go on to have excellent responses, such patients should not have therapy changed prematurely.

PROSTATE CANCER SCREENING. In large cohorts of asymptomatic men, screening with prostate-specific antigen (PSA) consistently detects approximately a third more cancers than digital rectal examination. Nevertheless, because a variable number of cancers have been found by digital rectal examination alone, both tests are recommended by proponents of screening. However, the routine use of the PSA for the detection of organ-confined prostate carcinoma remains controversial. If a cutoff of 4.0 ng/mL is used to separate normal from abnormal, then 38 to 48% of patients with organ-confined cancer will be missed because they fall within the normal range. Conversely, a great number of patients who do not have prostate cancer will be subjected to biopsies, thus increasing the cost of health care without any benefit. Because the PSA normally increases with age, using an age-adjusted PSA rather than the usual cutoff of 4.0 ng/mL may increase the sensitivity (percentage of patients with cancer who have an abnormal test) of screening in younger patients and improve specificity (percentage of patients without cancer who have a normal value) in older patients. Thus, a PSA of 3.8 ng/mL is inappropriately high for a 52-year old and requires further investigation. Conversely, a PSA of 4.2 ng/mL is probably normal in a 72-year old and, in the absence of an abnormal digital rectal examination, should not result in more extensive evaluation. Unfortunately, there are important limitations of the age-adjusted PSA because the range may be slightly different in white, black, and Asian men. In addition, tolerating higher values in older men will decrease the sensitivity of PSA screening in the population at greatest risk for cancer. Recently, it has been observed that there are different forms of circulating PSA and that PSA produced by prostate carcinoma tends to be bound by plasma proteins whereas PSA produced by normal cells is more likely to be free in plasma. Thus, a high normal (2.5-4.0 ng/mL) or marginally increased (4.0-10.0) PSA is of more concern if the percent free PSA is relatively low. Conversely, a high percent free PSA might be able to eliminate the need for blind biopsies in patients with marginally increased PSA values. For example, in one study, a percent free PSA of less than or equal to 19 detected 90% of organ-confined cancers when the PSA was between 3.0 and 4.0 ng/mL. Conversely, when the total PSA was between 4.0 and 10.0 ng/mL, using a slightly higher percent free PSA was able to maintain the sensitivity of prostate cancer detection to between 90 and 95% and, at the same time, decrease the number of biopsies by 13 to 31%. The use of free percent PSA is undergoing testing in larger cohorts. DECISIONS REGARDING INITIAL THERAPY. Nearly 50% of prostate cancers resected with curative intent are not confined to the prostate at the time of surgery. Recently, based on preoperative data from a large cohort of patients, the PSA, Gleason grade, and clinical TNM stage have been combined to construct nomograms to indicate the chance of finding tumor extending outside the prostate gland (see Chapter 118) . These data can theoretically be used to counsel patients before attempted definitive therapy with the anticipated result that fewer patients would opt for surgery in the face of a high chance of extra-organ tumor extension. Nevertheless, the most appropriate therapy for patients with early-stage prostate cancer by clinical criteria but with a high likelihood of extra-organ extension has not been defined. ASSESSMENT OF THE ADEQUACY OF DEFINITIVE THERAPY. Because PSA is organ specific, patients with completely resected prostate cancer should have undetectable levels of PSA. Thus, patients with measurable levels of

PSA 6 to 8 weeks after surgery generally have persistent disease. Similarly, the re-emergence of detectable PSA after surgery is indicative of recurrent prostate cancer. Although some investigators have suggested that pelvic radiation is indicated in patients with late (>1 year after surgery) detection of PSA, at present there are not enough data to support this practice. Nevertheless, given the increasing number of radical prostatectomies being done, the appropriate management of persistently detectable PSA levels or late increases in PSA are an important area of clinical research. After potentially curative radiation, local or systemic spread of cancer is likely if the PSA does not drop below 1.0 ng/mL. However, similar to the situation after surgery, a consensus on appropriate salvage treatment has not been reached. MONITORING THE RESPONSE OF HORMONAL ABLATION THERAPY. Androgen ablation therapy is the most effective treatment for patients with metastatic prostate cancer. Although it is now clear that androgen ablation can reduce PSA independent of any antitumor effect, PSA remains an excellent tumor marker in patients receiving androgen ablation treatment. This finding is particularly important because patients with metastatic prostate cancer generally do not have easily measurable disease. Several studies also show that the rate and depth of fall of PSA after androgen ablation correlate with the duration of response. It is rare for patients to have progression of disease in the absence of an increasing PSA.

TESTICULAR CANCER SCREENING. Human chorionic gonadotropin (hCG) and alpha-fetoprotein (AFP) have no value in screening because they are detected in fewer than 20% of patients with stage I tumors. DIAGNOSIS. Although 15% of seminomatous germ cell tumors are associated with an increased hCG, high levels of hCG are often associated with a non-seminomatous tumor component; an increased level of AFP is diagnostic of the presence of non-seminomatous tumor. The importance of this distinction is that non-seminomatous germ cell tumors (NSGCT) are treated with chemotherapy, whereas non-bulky seminomas confined to the abdomen are treated with radiation. In patients with midline tumors (pineal, mediastinal, and retroperitoneum regions), markedly elevated germ cell markers are diagnostic of a testicular or extragonadal germ cell tumor and do not require biopsy for diagnosis. However, low-level elevation of hCG may be seen in patients with lung, breast, gastrointestinal, and ovarian tumors and, as a result, is not diagnostic of a germ-cell tumor. MONITORING RESPONSE TO THERAPY. Because either hCG or AFP is increased in 89% of patients with NSGCT, they are useful in monitoring response after chemotherapy or for detecting recurrence after the completion of treatment. Generally, during chemotherapy, the hCG should fall by at least 1 log after each treatment, and the AFP should fall by 50% approximately every 7 days. However, in view of the exquisite sensitivity of germ cell tumors to therapy, it is not unusual for patients to have a temporary rise in tumor markers early after chemotherapy, presumably owing to tumor cell necrosis, before a subsequent fall. If the tumor markers do not return to normal after chemotherapy, residual disease is almost invariably present. In patients with very high tumor markers at diagnosis, the tumor markers may not return to normal until 1 or 2 months after therapy is completed. However, nearly one third of patients with normal markers and residual masses will have residual disease. Thus, in patients with NSGCT with residual retroperitoneal or pulmonary masses and negative markers, surgical resection is advised.

HEPATOMA USING AFP SCREENING. For a screening test to be effective, the disease in question must be relatively common, and efforts to detect early-stage 1042

disease must be focused in high-risk patients. Thus, screening with AFP and liver ultrasound have been relatively successful and cost-effective in Asian countries where hepatoma is common and high-risk patients can be identified by hepatitis B and C serology tests (see Chapter 150) . In contrast, studies in Europe, where the prevalence of hepatoma is much lower and the majority of screened patients have cirrhosis unrelated to hepatitis infection, have not been particularly successful in detecting small and potentially resectable tumors. It has been suggested but not proved that more aggressive screening (AFP testing and ultrasonography every 3 to 6 months) as done in Japan will be more successful. Importantly, because of the lower prevalence of hepatoma and more expensive testing in the United States, it has been estimated that the cost of detecting one hepatoma is as high as $270,000 compared with $8,000 in Japan. Nevertheless, despite the absence of confirmatory data, many hepatologists perform surveillance testing with AFP and/or liver ultrasonography in all patients with end-stage liver disease. Increases in AFP are particularly difficult to interpret in patients with chronic hepatitis B; in one study, only 6 of 44 patients with increases in AFP had hepatocellular carcinoma.

MULTIPLE MYELOMA PROGNOSIS. Multiple myeloma is a malignant lymphoproliferative disorder that is inevitably fatal in a period ranging from a few months to several years (see Chapter 181) . Because of the extreme variability in the aggressiveness of disease even in patients who have the same clinical stage, it is helpful to identify patients with more aggressive disease who might benefit from experimental treatment, including bone marrow transplantation. Although a number of clinical and laboratory tests have been used to predict prognosis, at present the beta2 -microglobulin (beta2 -M) level is the most important (and generally available) prognostic factor in multiple myeloma. In a large cooperative group study, patients with a beta2 -M level less than 6 mug/mL had a median survival of 36 months compared with a median survival of 23 months in patients with a beta2 -M greater than 6 mug/mL. If serum albumin also was considered, patients could be divided into three prognostic groups. The median survival of younger patients (100 pg/mL, ectopic ACTH concentration should be considered, although some patients with pituitary Cushing's disease may have values in this range. In patients with a plasma ACTH concentration between 10 and 100 pg/mL, inferior petrosal sinus sampling (IPSS) for ACTH should be performed after peripheral CRH injection(Chapter 240) to separate a pituitary (high central/peripheral ACTH ratio) from an ectopic ACTH (low central/peripheral ACTH ratio) source. In patients with a low basal peripheral ACTH value (10 pg/mL. ACTH = corticotropin; CRH = corticotropin-releasing hormone.

mimic those of pituitary Cushing's disease (Figure 194-2) . Diagnosis requires a high index of suspicion, combined with either measurement of CRH in the blood or identification of a neoplasm outside the pituitary. Some neoplasms produce both ACTH and CRH. Tumors reported to produce CRH include medullary thyroid carcinoma, paragangliomas, prostate cancer, and islet cell neoplasms. Hypercorticism associated with ectopic ACTH syndrome may present with classic features of Cushing's syndrome such as easy bruisability, centripetal obesity, muscle wasting, hypertension, diabetes, and metabolic alkalosis. In other patients, particularly those with rapidly growing SCCL, the clinical picture may be dominated by profound hypokalemic metabolic alkalosis and hypertension without the other clinical findings of Cushing's syndrome. Several different approaches have evolved for evaluation of Cushing's syndrome (Chapter 240) . One approach (Figure 194-2) is based on the plasma ACTH measurement in a patient with clinical and laboratory features of Cushing's syndrome. The finding of a marked elevation of the plasma ACTH concentration (>100 pg/mL) should prompt a search for an ectopic source of ACTH. In a patient with a plasma ACTH value greater than 10 pg/mL but less than 100 pg/mL, a more detailed evaluation is appropriate. The differentiation between a pituitary and an ectopic source may require stimulation of ACTH secretion by CRH combined with measurement of ACTH in blood from the pituitary venous drainage (inferior petrosal sinus sampling). Lack of an increase in the inferior petrosal sinus ACTH concentration (more than three times the peripheral ACTH) following peripheral CRH stimulation should prompt a search for an ectopic source. In patients who have an increased (more than three times the peripheral level) inferior petrosal sinus ACTH following CRH, a pituitary source is likely. Ectopic CRH can yield confusing results and may not be diagnosed unless the clinician considers the possibility and measures a plasma CRH or looks for an ectopic source. Other approaches have also been applied to the diagnosis of ectopic ACTH syndrome. For example, ACTH production from an ectopic source is not generally suppressed by high-dose dexamethasone. In a patient with an ACTH >10 pg/mL, administration of a single 8-mg oral dose of dexamethasone at 11:00 P.M. followed by measurement of serum cortisol level at 8:00 A.M. can differentiate between a pituitary and an ectopic source. The serum cortisol level in pituitary Cushing's syndrome will generally be suppressed 50% after dexamethasone, whereas levels in ectopic ACTH generally are not suppressed. However, false-positive or false-negative results occur with each of these testing procedures, making the differential diagnosis of Cushing's syndrome among the most challenging in medicine. Hypercortisolism associated with ectopic ACTH can be managed by removal of the ACTH- or CRH-producing tumor or by inhibition of cortisol synthesis with metyrapone (1 to 4g/day orally), aminoglutethimide (250 mg orally [PO] four times/day with upward titration), or ketoconazole (200-400 mg twice a day orally). Replacement glucocorticoid therapy is needed to prevent adrenal insufficiency. If surgical removal of an ACTH- or CRH-producing tumor is not possible and inhibition of cortisol synthesis is inadequate, bilateral adrenalectomy (with replacement glucocorticoid therapy) may be required. In patients with a rapidly progressive SCCL and ectopic ACTH syndrome, the oncologic imperative to initiate immediate cytotoxic therapy must be counterbalanced by the desire to normalize cell-mediated immunity by normalizing cortisol secretion, hypokalemia, and metabolic alkalosis. Cytotoxic chemotherapy generally should be delayed, if possible, until the serum cortisol level is normalized, because of the high rate of infection in neutropenic patients with hypercortisolism.

HUMAN CHORIONIC GONADOTHROPIN PRODUCTION Two different genes encode the alpha- and beta-subunits of human chorionic gonadotropin (hCG). The alpha-subunit is common to all of 1050

the pituitary glycoprotein hormones (luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, and hCG), whereas each of these hormones has a specific beta-subunit gene. Production of the alpha-subunit occurs in a variety of pituitary and non-pituitary tumors and does not cause any discernible clinical syndrome. The beta-subunit confers biologic specificity. Production of intact hCG occurs commonly in trophoblastic tumors (choriocarcinomas, testicular embryonal carcinomas, and seminomas) and less commonly in other tumors such as lung and pancreas. Clinical syndromes associated with production of hCG include precocious puberty, gynecomastia, and hyperthyroidism. Hyperthyroidism results from the low-affinity interaction of hCG with the thyroid-stimulating hormone receptor when hCG is present at high concentrations. Therapy for precocious puberty and gynecomastia is directed toward removal or treatment of the underlying tumor. Hyperthyroidism is treated by inhibition of thyroid hormone synthesis, usually by thionamide therapy, followed by therapy for the underlying tumor. Treatment of hyperthyroidism by surgical removal of the thyroid gland or ablation with radioactive iodine is rarely required since the hyperthyroidism resolves rapidly after treatment of the underlying tumor.

HYPOGLYCEMIA ASSOCIATED WITH CANCER Tumor-associated hypoglycemia is a rare but important cause of morbidity for cancer patients. Three different clinical syndromes cause most cancer-related hypoglycemia. The first is production of insulin by an islet tumor. Although primary insulinomas are rare, dedifferentiation and bulky hepatic metastasis of an islet cell carcinoma may be associated with excessive insulin production (Chapter 243) . A second cause of hypoglycemia, insufficient gluconeogenesis to maintain the plasma glucose concentration in the fasting state, is caused by near-complete replacement of the liver by metastatic tumor. A third cause of hypoglycemia is increased concentrations of insulin-like growth factor II (IGF-II), a ligand that interacts with the insulin receptor in large abdominal tumors, most commonly fibrosarcomas, hemangiopericytomas, or hepatomas. This increase appears to be due to the failure to form normal IGF binding protein 3 (IGFBP-3) and the acid labile subunit (ALS) complex that normally binds IGF-II; the result is an increase in free IGF-II concentrations. In all three types of hypoglycemia, the patient is at greatest risk for symptoms during periods of fasting, most commonly during sleeping hours. Therapy should focus on surgical excision, where possible, or antineoplastic therapy directed at the tumor. Initial therapy of hypoglycemia is focused on frequent meals, and patients may

occasionally be maintained symptom-free if awakened for one or more snacks during sleeping hours. If there is progression of the tumor or the patient's caloric intake is inadequate, additional measures may be required. In patients in whom hepatic replacement by tumor is evident, a continuous infusion of 20% dextrose through a central line may be required, especially during sleeping hours. In patients with insulin-producing or large retroperitoneal tumors, glucagon infusion (0.5-2 mg/hour) stimulates hepatic gluconeogenesis and prevents hypoglycemia, although in rare patients the rash associated with glucagonoma may develop. A glucose response to a single injection of glucagon (1 mg) should be documented before initiating therapy. In patients with large retroperitoneal tumors, treatment with growth hormone (3-6 mug/kg SQ) or glucocorticoids (20-40 mg/day) may reverse hypoglycemia possibly by facilitating IGFBP-3/ALS complex formation, thereby reducing free serum IGF-II levels. Growth hormone doses as high as 2600 mug/day have been administered in this condition, although long-term treatment with this dose may cause acromegalic side effects. Somatostatin analogues (octreotide or lanreotide) are generally not effective for normalizing the plasma glucose level in patients with islet cell tumors; diazoxide (3-8 mg/kg/day in two or three divided doses) may be effective, but problems with fluid retention frequently preclude its long-term use.

SYNDROME OF INAPPROPRIATE ANTIDURETIC HORMONE Ectopic production of vasopressin by head and neck tumors (3%), SCCL (15%), and other lung carcinomas (1%) causes a clinical syndrome characterized by hyponatremia, hypo-osmolality, excessive urine sodium excretion, an inappropriately high urine osmolality for the low serum osmolality, and normal function of the kidneys, adrenal glands, and thyroid (Chapter 238) . Other malignant neoplasms (primary brain tumors, hematologic neoplasms, skin tumors, and gastrointestinal, gynecologic, breast, and prostate cancers, and sarcomas) are rare causes of this clinical syndrome. In most cases the hyponatremia is asymptomatic, although altered mental status and seizures may develop when the serum sodium concentration falls below 120 mEq/L; hyponatremic women of the reproductive age may experience profound cerebral degeneration. Fluid restriction may be effective for short-term management but is difficult to maintain over long periods. Treatment with 150-300 mg/day demeclocycline can block the effects of vasopressin on the kidney and is the most effective long-term therapy in patients with cancer. Vasopressin receptor antagonists are in clinical trials but are not currently available.

RARE ECTOPIC HORMONE SYNDROMES Oncogenic Osteomalacia A clinical syndrome characterized by profound hypophosphatemia, muscle weakness, and osteomalacia can be produced by mesenchymal tumors (osteoblastomas, giant cell osteosarcomas, hemangiocytomas, and rarely prostate and lung carcinoma). Therapy is directed toward correction of hypophosphatemia with either oral or intravenous supplementation and vitamin D treatment. Surgical removal of the tumor is curative.

HEMATOLOGIC SYNDROMES The kidney is the primary site of erythropoietin production, and, therefore, the relatively common erythropoietin production by benign or malignant renal tumors is not an "ectopic" hormone syndrome. Production of erythropoietin by cerebellar hemangioblastoma, uterine fibroids, pheochromocytomas, and ovarian and hepatic tumors is generally considered "ectopic." Patients with excessive erythropoietin production may or may not have polycythemia. Other ectopic syndromes, less well defined, include production of thrombopoietin, leukopoietin, or colony-stimulating factor by some tumors. These conditions are treated by removal of the tumor or by appropriate chemotherapy.

HYPERTENSION Renal (Wilms' tumor, renal cell carcinoma, or hemangiopericytoma), lung (SCCL, adenocarcinoma), hepatic, pancreatic, and ovarian carcinomas may produce renin. The clinical presentation in these patients can include hypertension, hypokalemia, and evidence of increased aldosterone production. Therapy with spironolactone (Aldactone) or angiotensin-converting enzyme inhibitors may be effective.

GROWTH HORMONE AND PROLACTIN PRODUCTION Rare examples of growth hormone (GH) production have been identified in lung and gastric adenocarcinoma. Ectopic production of GHRH has been documented for islet cell tumors, bronchogenic carcinoids, and SCCL. Increased prolactin production is a rare phenomenon associated with lung and renal carcinoma; it produces galactorrhea and amenorrhea in women and produces hypogonadism and gynecomastia in men. Berenson JR: Bisphosphonates in the treatment of malignant bone disease. Annu Rev Med 50:237, 1999. Review of the use of bisphosphonates in reducing skeletal complications in patients with bone metastases. Hoff AO, Vassilopoulou-Sellin R: The role of glucagon administration in the diagnosis and treatment of patients with tumor hypoglycemia. Cancer 82:1595, 1998. Excellent review of clinical management of hypoglycemia associated with cancer and the use of a glucagon stimulation test to determine response to glucagon infusion. Miller M: Inappropriate antidiuretic hormone secretion. Curr Ther Endocrinol Metab 6:206, 1997. Current review of status of diagnosis and management of SIADH. Mundy GR, Guise TA: Hypercalcemia of malignancy. Am J Med 103:134, 1997. An overview of several mechanisms of hypercalcemia. Winquist EW, Laskey J, Crump M, et al: Ketoconazole in the management of paraneoplastic Cushing's syndrome secondary to ectopic adrenocorticotropin production. J Clin Oncol 13:157, 1995. Approach to medical management of ectopic ACTH syndrome.

MD Consult L.L.C. http://www.mdconsult.com Bookmark URL: /das/book/view/882/197.html/top

Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

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Chapter 195 - NONMETASTATIC EFFECTS OF CANCER: THE NERVOUS SYSTEM Jerome B. Posner

When nervous system dysfunction develops in patients with cancer, metastasis is usually the cause, but cancer also can exert deleterious effects on the nervous system by mechanisms other than metastasis. Recognition of these non-metastatic neurologic complications can prevent inappropriate and perhaps harmful therapy directed at a non-existent metastasis. Sometimes the nervous system symptoms precede discovery of the cancer and can, if correctly interpreted, lead the physician to the diagnosis of an otherwise occult neoplasm. An almost bewildering variety of neurologic disorders have been ascribed to the effects of systemic cancer (Table 195-1) . Most patients with nervous system dysfunction not caused by metastases are eventually found to be suffering from infection, vascular or metabolic disorders, or neurotoxicity secondary to chemotherapy. However, two other types of nervous system damage related to cancer are paraneoplastic syndromes (Table 195-2) and radiation injury. Paraneoplastic syndromes, also called "remote effects of cancer on the nervous system," refer to neurologic dysfunction caused by cancer but not ascribable to such well-defined secondary effects of cancer as infection, coagulation abnormalities, nutritional and metabolic disorders, or side effects of therapy (see Table 195-1) . Similar clinical disorders occur in the absence of cancer, and thus in any given patient, the cancer must be identified to document that the neurologic disorder is paraneoplastic. If patients with mild peripheral neuropathy or myopathy possibly associated with cachexia are excluded, remote effects of cancer affect fewer than 1% of patients with cancer. Lung cancer accounts for more than 50% of cases; the incidence is greatest in patients with ovarian cancer, small cell lung cancer, and Hodgkin's disease. Because of its rarity, the diagnosis of paraneoplastic syndrome should never be accepted until a thorough evaluation has excluded metastatic or other non-metastatic causes of neurologic dysfunction. In particular, infiltration of nerve roots by tumor in the leptomeninges may mimic paraneoplastic peripheral neuropathy. An exception exists when the serum of a patient suspected to be suffering from a paraneoplastic syndrome is found to contain an antibody reacting with both the cancer and the nervous system (onconeuronal antigen). Increasing evidence suggests that the etiology of most or all remote effects is autoimmune. Patients with Lambert-Eaton myasthenic syndrome (see below) harbor an IgG antibody that reacts with P/Q voltage-gated calcium channels on the pre-synaptic neuromuscular junction. Complexing of these channels by the antibody prevents normal release of acetylcholine, which in turn causes the clinical symptoms of the disorder. About two thirds of patients with Lambert-Eaton myasthenic syndrome have small cell lung TABLE 195-1 -- NON-METASTATIC EFFECTS OF CANCER ON THE NERVOUS SYSTEM Paraneoplastic syndromes or remote effects of cancer (see Table 195-2) Side effects of therapy Chemotherapy Radiation therapy (see Table 195-3) Metabolic and nutritional abnormalities Destruction of vital organs (e.g., liver) Elaboration of hormonal substances by tumor (e.g., carcinoid) Competition between tumor and brain for essential substrates (e.g., glucose) Malnutrition Infections (usually associated with lymphomas) Parasites (e.g., toxoplasmosis) Fungi (e.g., cryptococcosis, aspergillosis, mucormycosis) Bacteria (e.g., Listeria monocytogenes) Viruses (e.g., herpes zoster) Vascular disease Intracranial hemorrhage Cerebral infarction

TABLE 195-2 -- PARANEOPLASTIC SYNDROMES OF THE NERVOUS SYSTEM Brain and Cranial Nerves Limbic encephalitis * Brain stem encephalitis Cerebellar degeneration * Opsoclonus-myoclonus * Paraneoplastic visual syndromes Cancer-associated retinopathy * Optic neuritis Spinal Cord Necrotizing myelopathy Myelitis Motor neuron syndrome Subacute motor neuronopathy Dorsal Root Ganglia Paraneoplastic sensory neuronopathy Peripheral Nerves

Autonomic neuropathy Acute sensorimotor neuropathy Polyradiculoneuropathy (Guillain-Barre syndrome) Brachial neuritis Chronic sensorimotor neuropathy Sensorimotor neuropathies associated with plasma cell dyscrasias Vasculitic neuropathy Neuromyotonia Neuromuscular Junction and Muscle Lambert-Eaton myasthenic syndrome * Myasthenia gravis Polymyositis/dermatomyositis Acute necrotizing myopathy Cachectic myopathy Carcinoid myopathy * Myotonia Multiple Levels of Involvement or Uncertain Site Encephalomyelitis Stiff-person syndrome Carcinomatous neuromyopathy * *In some groups of patients (e.g., children with opsoclonus, postmenopausal women with cerebellar dysfunction), the neurologic disorder is associated with a tumor in more than 50% of instances. Can include cerebellar symptoms, autonomic dysfunction, and sensory neuronopathy.

cancer cells that also express the P/Q calcium channel protein. Removal of anti-calcium channel IgG from the serum of a patient with Lambert-Eaton myasthenic syndrome ameliorates the neuromuscular symptoms, and injection of that IgG into experimental animals reproduces the neurologic disorder. High titers of antibodies against other onconeuronal antigens are found in several other paraneoplastic syndromes, thus suggesting a mechanism similar to that in Lambert-Eaton syndrome.

PARANEOPLASTIC SYNDROMES Paraneoplastic syndromes are usually classified by the anatomic site of neurologic disability (see Table 195-2) . However, it is common for more than one anatomic site to be involved, e.g., dementia and myelopathy or limbic encephalitis and sensory neuronopathy. Sometimes, two different syndromes develop together, e.g., Lambert-Eaton myasthenic syndrome and cerebellar degeneration. Brain CEREBRUM.

Loss of recent memory (limbic encephalitis) and affective alterations, either anxiety or depression, are the usual findings. Seizures are prominent in some patients; others have a fluctuating confusional state. When other abnormal neurologic signs are present, they usually point to the brain stem, cerebellum, or peripheral nerves (encephalomyelitis). Cerebrospinal fluid (CSF) usually contains 10 to 40 lymphocytes per cubic milliliter, with a slight elevation in protein concentration. Magnetic resonance imaging (MRI) is usually normal, but in some patients abnormalities can be found in the medial temporal areas. Limbic encephalitis can be associated with anti-Hu antibodies in some patients with small cell lung cancer, and anti-TC antibodies in some patients with testicular cancer. Pathologically, two main groups of cerebrum involvement can be 1052

differentiated. In some patients, no significant pathologic changes are found in the cerebrum despite clinical dementia. Other patients demonstrate widespread cerebral neuronal loss, gliosis, and perivascular collections of lymphocytes, particularly in the medial temporal lobes (limbic encephalitis) or the thalamus. In patients who have anti-Hu antibodies in blood and CSF, the same antibodies can also be identified in the brain. The differential diagnosis includes brain or leptomeningeal metastases; fungal, parasitic, or viral infections (including multifocal leukoencephalopathy); metabolic encephalopathy; and nutritional deficits (e.g., thiamine deficiency leading to the memory loss and brain stem dysfunction of Wernicke-Korsakoff syndrome). These other disorders are usually readily identified by appropriate imaging studies, CSF examination, and other laboratory tests. The rapid onset of dementia in middle age accompanied by cerebellar, brain stem, or peripheral nerve dysfunction but no other focal cerebral signs suggests paraneoplastic dementia as a remote effect of cancer. Paraneoplastic dementia may be confused with Creutzfeldt-Jakob disease, but other degenerative dementias such as Alzheimer's disease are usually slower in onset and have a more protracted course. No specific treatment is available for paraneoplastic dementias, but they occasionally improve spontaneously with successful treatment of the cancer. CEREBELLUM.

Cerebellar symptoms usually evolve over weeks, with bilateral and symmetrical ataxia of gait and the arms and legs. Severe dysarthria is usually present; vertigo and diplopia are common, but nystagmus may be absent. Some patients have neurologic signs pointing to disease outside the cerebellum (e.g., extensor plantar responses, diminished or exaggerated tendon reflexes, dementia). Early in the disorder, CSF pleocytosis is present, and an elevated CSF IgG content is common. In about half of patients, the neurologic findings precede discovery of the cancer, but the clinical picture is so characteristic that cancer should be suspected. Cerebellar atrophy may be seen on MRI. In a subset of patients with gynecologic cancers (ovarian, uterine, fallopian tube, breast), an antibody (anti-Yo) reacting with cerebellar Purkinje cells and with the underlying tumor allows a definitive diagnosis to be made before the tumor is discovered. Other antibodies associated with paraneoplastic cerebellar degeneration include anti-Tr (Hodgkin's disease), anti-Hu (small cell lung cancer), and anti-Ma (several different cancers). Pathologic changes consist of loss of cerebellar Purkinje cells with or without lymphocytic cuffing of blood vessels in the deep nuclei. Cerebellar dysfunction is also caused by cerebellar or leptomeningeal metastases and by Listeria meningitis or progressive multifocal leukoencephalopathy. These disorders can easily be identified by MRI and CSF examination. In alcohol-nutritional cerebellar degeneration, truncal and lower extremity ataxia is prominent, but nystagmus, dysarthria, and upper extremity ataxia are mild or absent. Sporadic or familial cerebellar degenerative disorders are much slower in onset. Cerebellar dysfunction associated with viral infections (varicella, infectious mononucleosis) or with chemotherapy (5-fluorouracil, cytosine arabinoside) may mimic paraneoplastic cerebellar degeneration. Paraneoplastic cerebellar degeneration usually runs a subacute course and then stabilizes or occasionally improves with successful treatment of the tumor. Cranial Nerves Two rare but striking paraneoplastic syndromes affect the eyes. Carcinoma-associated retinopathy is characterized by rapid onset of blindness caused by retinal degeneration, usually of photoreceptors, and is associated with antibodies that recognize the retinal antigen recoverin. Optic neuritis, which does not differ clinically in any way from the idiopathic disorder, has also been described in some patients with underlying neoplasms. Opsoclonus (saccadic conjugate involuntary movement of the eyes), also called "saccadomania," is often a paraneoplastic disorder. About 50% of infants and children with opsoclonus have underlying neuroblastoma. In adults, about 20% of patients with opsoclonus probably have an underlying cancer, usually gynecologic or lung cancer, that is sometimes associated with the anti-Ri antibody. Except when this autoantibody is present, paraneoplastic opsoclonus cannot be clinically distinguished from opsoclonus caused by metabolic or structural abnormalities of the brain stem or cerebellum.

Spinal Cord Several distinct myelopathies complicate cancer. Subacute motor neuronopathy affects anterior horn cells, usually in patients with Hodgkin's disease or other lymphomas. The course is subacute, with progressive painless asymmetrical lower motor neuron weakness of the legs and arms. Some patients complain of sensory symptoms, but sensory loss is mild or absent despite profound weakness. Examination may also demonstrate extensor plantar (Babinski) reflexes, indicating that corticospinal tracts are also involved. The major pathologic finding is degeneration of anterior horn cells. Sometimes the anterior horns and ventral nerve roots are inflamed, in addition to demyelination in the white matter of the spinal cord. The clinical course is different from most remote effects of cancer in that some patients improve spontaneously, independently of the course of the underlying lymphoma. The etiology is unknown, but a similar disorder in mice with lymphomas appears to be caused by a retrovirus. Typical amyotrophic lateral sclerosis is rarely paraneoplastic, but primary lateral sclerosis, which is a variant of motor neuron disease that affects only the corticospinal tracts and hence causes weakness and spasticity, may complicate breast cancer. In subacute necrotic myelopathy, both gray and white matter are affected equally. Clinically, rapidly ascending sensory and motor loss is present, usually to the mid-thoracic levels; the patient becomes paraplegic and incontinent within hours or days. The neurologic symptoms often precede discovery of the neoplasm, and the illness is clinically and pathologically indistinguishable from idiopathic subacute necrotic myelopathy. Because epidural or intramedullary spinal metastases and arteriovenous spinal cord anomalies may present similar clinical signs, an MRI scan is essential. The stiff-person syndrome is characterized by rigidity and spasms of muscles associated with antiamphiphysin antibodies and breast cancer. Most "stiff persons" do not have cancer, but they produce antibodies against glutamic acid decarboxylase that cause both diabetes and the neurologic disorder. Peripheral Nerves and Dorsal Root Ganglia Four clinical peripheral nerve disorders occur in association with cancer. Characteristic of carcinoma is subacute sensory neuronopathy marked by loss of sensation with relative preservation of motor power. The illness usually precedes appearance of the carcinoma and progresses over a few months, and the patient is left with moderate or severe disability. CSF pleocytosis and increased IgG content are common. Pathologically, destruction of posterior root ganglia with perivascular lymphocytic cuffing and wallerian degeneration of sensory nerves is noted. Many patients also have encephalomyelitis with inflammatory and degenerative changes in the brain and spinal cord. The disorder, when associated with small cell carcinoma, is characterized by anti-Hu antibodies. More common than sensory neuronopathy is a distal sensorimotor polyneuropathy characterized by motor weakness, sensory loss, and absence of distal reflexes in the extremities. The illness is pathologically characterized by either segmental demyelination or axonal degeneration (or both) of sensory and motor peripheral nerves. Pathologically and clinically, the sensorimotor neuropathy is indistinguishable from polyneuropathies not associated with cancer. Indeed, some have suggested that late or terminal polyneuropathy may be due to nutritional deprivation associated with cancer. Its etiology, however, is not clear, and it does not respond to treatment with vitamins or other nutritional supplements. A polyneuritis clinically and pathologically indistinguishable from acute post-infectious polyneuropathy (Guillain-Barre syndrome) also complicates cancers, particularly Hodgkin's disease. A few patients with neuropathy limited to the autonomic nervous system have been reported. Neuromuscular Junction and Muscles NEUROMUSCULAR JUNCTION.

Myasthenia gravis is associated with thymomas but not usually with other systemic tumors. The Lambert-Eaton myasthenic syndrome is characterized by weakness and fatigability of proximal muscles, particularly of the pelvic girdle and thighs. The cranial nerves and respiratory muscles are usually spared. Patients often complain of dryness of the mouth, impotence, pain in the thighs, and peripheral paresthesias. Proximal muscles are weak, but strength increases over several seconds of 1053

sustained contraction. Deep tendon reflexes are diminished or absent. The diagnosis is made by electromyographic studies in which repeated nerve stimulation at rates above 10 per second causes a progressive increase in the size of the muscle action potential (the opposite of myasthenia gravis). About two thirds of patients with this syndrome either have cancer or will develop cancer, usually small cell carcinoma of the lung. Most patients harbor P/Q-type voltage-gated calcium channel antibodies in their serum, an excellent diagnostic test. Plasmapheresis and immunosuppressant drugs usually relieve the symptoms, as may successful treatment of the neoplasm. The illness responds poorly to anticholinesterase drugs but does respond to 3,4-diaminopyridine in doses up to 100 mg/day. MUSCLE.

Typical dermatomyositis or polymyositis may occur as a remote effect of cancer (see Chapter 296) . Fewer than 10% of patients with this disorder have cancer, but the figure is higher in older patients. The clinical picture of polymyositis associated with cancer (i.e., subacute development of weakness, particularly weakness involving the proximal muscles and sometimes the bulbar muscles) is indistinguishable from dermatomyositis or polymyositis not associated with cancer. Pathologically, it is possible to differentiate two groups: one with the typical inflammatory lesions of polymyositis and one with little inflammation but severe muscle necrosis. The latter group may suffer an explosive clinical course. These patients respond less well to corticosteroid therapy than do those with dermatomyositis unaccompanied by cancer, although substantial improvement with steroid treatment sometimes occurs. Intravenous immunoglobulin may help. Some patients with cancer complain of weakness and fatigability that seem worse than can be accounted for by their cancer alone. Cachexia and weight loss alone do not usually cause measurable muscle weakness. The weakness is usually proximal and produces particular difficulty climbing stairs or getting out of low chairs. Ankle reflexes may be diminished or absent. Further neurologic evaluation does not yield findings diagnostic of one of the remote effects of cancer described above. Brain and colleagues have labeled this entity "neuromyopathy" because its exact anatomic locus is unclear, but others have suggested that it is a non-specific accompaniment of cachexia and systemic illness. Specific (type II) muscle fiber atrophy develops early in patients with systemic cancer. The cause and treatment of the weakness are unknown.

NERVOUS SYSTEM INJURY FROM THERAPEUTIC RADIATION Adverse effects of ionizing radiation on the nervous system (Table 195-3) are related to the total dose of radiation, the size of each fraction, the total duration over which the dose is received, and the volume of nervous system tissue irradiated. Other factors such as underlying nervous system disease (e.g., brain tumor, cerebral edema), previous surgery, concomitant use of chemotherapeutic agents, and individual susceptibility make it impossible to define precisely a safe dose of radiation therapy for a given individual. However, guidelines generally allow the radiation therapist to calculate safe nervous system doses. Adverse effects may involve any portion of the central or peripheral nervous system and may occur acutely or be delayed weeks to years following irradiation. CLINICAL MANIFESTATIONS. Acute encephalopathy may follow large radiation doses to the brains of patients with increased intracranial pressure, particularly in the absence of corticosteroid prophylaxis. Immediately following treatment, headache, nausea, vomiting, somnolence, fever, and occasionally worsening of neurologic signs develop in susceptible patients; rarely, the syndrome culminates in cerebral herniation and death. Acute encephalopathy usually follows the initial radiation fraction and becomes progressively less severe with each ensuing fraction. This disorder is believed to result from increased intracranial pressure or brain edema from radiation-induced alteration of the blood-brain barrier. It responds to corticosteroids. Early delayed reactions appear 6 to 16 weeks after therapy and persist for days to months. A transient, diffuse encephalopathy commonly follows prophylactic irradiation of the brain for leukemia in children and for small cell lung cancer in adults. The disorder is characterized by somnolence, often associated with headache, nausea, vomiting, and sometimes fever. Whole-brain irradiation for brain tumor sometimes causes lethargy and worsening of focal neurologic signs suggestive of progression of the brain tumor. MRI scans may also suggest worsening. Both disorders usually respond to steroids but resolve spontaneously even if untreated. Rarely, a brain stem disorder characterized by diplopia, ataxia, dysarthria, and dysphagia and associated with foci of demyelination resembling acute multiple sclerosis follows irradiation to the brain stem. Early delayed myelopathy follows radiation therapy to the neck or upper part of the thorax and is characterized by Lhermitte's sign (an electric shock-like sensation radiating into various parts of the body when the neck is flexed). The symptoms resolve spontaneously. Early delayed radiation syndromes are believed to result from

demyelination, possibly caused by radiation-induced damage to oligodendroglia. Late delayed radiation injury appears months to years after radiation therapy and may affect any part of the nervous system. In the brain, two clinical syndromes of late delayed radiation injury may occur. The first follows whole-brain irradiation either prophylactically or, in some patients, for primary and metastatic brain tumors. The disorder is characterized either by dementia alone or by dementia with gait abnormalities and incontinence. Cerebral atrophy may occur alone or with diffuse white matter hyperintensity on MRI scans. Ventricular shunting may improve symptoms in some patients. The second disorder, radionecrosis, affects patients who receive either focal brain irradiation during therapy for extracranial neoplasms or irradiation for intracranial neoplasms. Neurologic signs suggest a tumor and include headache, focal or generalized seizures, and hemiparesis. MRI reveals a hypointense mass, sometimes with contrast enhancement. Neuropathologic features include coagulative necrosis of white matter, telangiectasia, fibrinoid necrosis of blood vessels with thrombus formation, glial proliferation, and bizarre multinucleated astrocytes. The clinical and imaging findings cannot be distinguished from those of brain tumor, and the diagnosis can be made only by biopsy. Positron emission tomography with radiolabeled glucose usually shows decreased metabolism in areas of radiation damage, whereas most malignant tumors show increased metabolism. Corticosteroids sometimes ameliorate the symptoms. Improvement in symptoms may be sustained even after corticosteroid withdrawal; however, if symptoms recur, the treatment of radionecrosis, if focal, is surgical removal. Late delayed myelopathy is characterized by progressive paralysis, sensory changes, and sometimes pain. A Brown-Sequard syndrome (weakness and loss of proprioception in the extremities of TABLE 195-3 -- RADIATION INJURY TO THE NERVOUS SYSTEM TIME AFTER RADIATION THERAPY ORGAN AFFECTED CLINICAL FINDINGS Primary injury Immediate (minutes to hours)

Brain

Acute encephalopathy

Early delayed (6-16 wk)

Brain

Somnolence, focal signs

Spinal cord

Lhermitte's sign

Brain

Dementia, focal signs

Spinal cord

Transverse myelopathy

Peripheral nerves

Paralysis, sensory loss

Several

Brain, cranial and/or peripheral nerve sheath tumor

Arteries (atherosclerosis)

Cerebral infarction

Small vessel telangiectasia

Cerebral or spinal hemorrhage

Endocrine organs

Metabolic encephalopathy

Late delayed (months to years)

Secondary injury (years)

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one side accompanied by loss of pain and temperature sensation on the other) is often present at onset. Patients occasionally respond transiently to steroids, and the disorder may stop progressing; generally, however, patients become paraplegic or quadriplegic. Pathologic changes include necrosis of the spinal cord. Late delayed neuropathy may affect any cranial or peripheral nerve. Common disorders are blindness from optic neuropathy and paralysis of an upper extremity from brachial plexopathy after therapy for lung or breast cancer. The pathogenesis is probably fibrosis and ischemia of the plexus. No treatment is available. Radiation-induced tumors, including meningiomas, sarcomas, or less commonly, gliomas, may appear years to decades after cranial irradiation and may follow low-dose irradiation. Malignant or atypical nerve sheath tumors may follow irradiation of the brachial, cervical, and lumbar plexuses. The central nervous system may also be damaged when radiation alters extraneural structures. Radiation therapy accelerates atherosclerosis, and cerebral infarction associated with carotid artery occlusion in the neck may occur many years after neck irradiation. Endocrine (pituitary, thyroid, parathyroid) dysfunction from radiation may be associated with neurologic signs. Hypothyroidism is often manifested as a neurologic disorder, and hyperthyroidism or hyperparathyroidism from radiation may also cause an encephalopathy. Keime-Guibert F, Napolitano M, Delattre JY: Neurological complications of radiotherapy and chemotherapy. J Neurol 245(11): 695, 1998. A comprehensive review. Nathanson L, Hall TC: Paraneoplastic syndromes. Semin Oncol 24:265, 1997. An entire issue devoted to paraneoplastic syndromes, including those involving the nervous system. Peterson K, Rottenberg DA: Radiation damage to the brain. In Vecht CJ (ed): Handbook of Clinical Neurology, vol 67. Amsterdam, Elsevier, 1997, pp 325-352. Comprehensive review of nervous system radiation changes. Posner JB: Neurologic Complications of Cancer. Philadelphia, FA Davis, 1995. Comprehensive chapters on radiation damage to the central and peripheral nervous systems (Chapter 13) and paraneoplastic syndromes (Chapter 15) .

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Chapter 196 - NONMETASTATIC EFFECTS OF CANCER: THE SKIN Frank Parker

Cutaneous changes associated with internal malignant conditions are diverse. Some of these skin alterations are clear indicators of underlying malignant disease. Others, less specific, arise in either the presence or absence of malignancy, but occur with sufficient frequency to arouse suspicion and require a search for underlying carcinomas or lymphomas. These various skin findings may precede signs of the internal malignancy; they are therefore of crucial importance in early identification and cure of internal neoplasms. Skin manifestations of internal malignancy can be classified into two groups: (1) those in which malignant cells are found in the skin on biopsy (specific skin lesions) and (2) those in which malignant cells cannot be identified in a skin biopsy (non-specific skin lesions). The specific lesions are diagnostic of the internal neoplasm, whereas non-specific skin alterations may or may not be associated with a neoplasm. Some non-specific skin changes are clear indicators of underlying tumor. Others merely alert the physician to the possibility of serious internal problems.

SPECIFIC SKIN LESIONS ASSOCIATED WITH INTERNAL MALIGNANT DISEASE Carcinomas, leukemias, lymphomas, plasma cell dyscrasias, and sarcoma can affect the skin specifically in clinically identifiable patterns. A skin biopsy of the lesions is diagnostic because the tissue of origin of the primary underlying neoplasm can be identified.

NON-SPECIFIC SKIN LESIONS ASSOCIATED WITH INTERNAL MALIGNANT DISEASE Malignant cells are not seen in the skin in a wide variety of cutaneous associations of internal malignancy (Table 196-1) . The pathogenesis of these disparate skin reactions is obscure. Often the only evidence that malignancy and cutaneous changes are related is the observation that following removal of the tumor, the skin change subsides or resolves and may subsequently become exacerbated if the neoplasm recurs. Skin manifestations may coincide with, antedate, or follow the clinical diagnosis of internal malignant disease. Although non-specific skin reactions are suggestive of underlying malignancy, they are more frequently seen with non-malignant conditions. When these skin changes are observed, therefore, an internal neoplasm is only one of several possibilities in the differential diagnosis. Non-specific skin manifestations can be considered under two major categories: (1) skin changes common to many skin diseases, including internal malignancies, and (2) syndromes and entities commonly associated with internal neoplasia. Skin Changes Common to Many Skin Conditions, Including Internal Malignancy Pruritus, or itching, unassociated with skin changes except for secondary lesions such as excoriations or prurigo-like papules, may be an important clue to various internal malignant and pre-malignant diseases, especially lymphomatous conditions. Hodgkin's disease, lymphocytic leukemia, polycythemia vera (in which pruritus often occurs or intensifies after exposure to heat), myeloid metaplasia, carcinoid, and less commonly, carcinomas cause itching. In Hodgkin's disease, itching is usually continuous and may be localized to the feet and lower part of the body, only later to become centralized. Up to 30% of patients with Hodgkin's disease may itch. Pruritus occurring with carcinoma is generally not as severe or intolerable as it is with lymphomas. Carcinomas of the gastrointestinal tract, lung, ovary, and prostate may also be associated with itching that may precede recognition of the cancer by a year. TABLE 196-1 -- NON-SPECIFIC SKIN LESIONS ASSOCIATED WITH INTERNAL MALIGNANCIES Skin Lesions Common to Many Skin Conditions, Including Internal Malignancy Pruritus Erythroderma Figurate erythemas Urticarial-like lesions Herpes zoster Paraneoplastic pemphigus Syndromes and Entities Commonly Associated with Internal Malignancy Non-genetic syndromes High incidence of association with internal malignancy Paget's disease Stewart-Treves syndrome Acanthosis nigricans Dermatomyositis Leser-Trelat syndrome Bazex's syndrome Pulmonary osteoarthropathy Carcinoid syndrome Lymphomatoid papulosis Low incidence of association with malignancy Sweet's syndrome Amyloid Urticaria pigmentosa and mastocytosis syndrome Bowen's disease Genetic syndromes High incidence of association with malignancy Torres' syndrome Gardner's syndrome

Cowden syndrome Multiple endocrine neoplasia IIB Ataxia-telangiectasia Low incidence of association with malignancy Neurofibroma Peutz-Jeghers syndrome Basal cell carcinoma nevus syndrome Bloom's syndrome

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Although dry skin (xerosis) is the most common cause of pruritus (especially in the elderly as a result of winter weather and excessive bathing), other systemic causes in addition to malignant disease include drug reactions, cholestatic liver disease, uremia, diabetes, thyroid disease, and emotional problems. Erythroderma, or exfoliative dermatitis, is a cutaneous reaction with redness, edema, scaling, and lichenification. In 10% of cases it is associated with malignancy, especially lymphomas, leukemia, and mycosis fungoides. In clinical practice the usual cause of erythroderma is either a drug reaction or a generalized exacerbation of a pre-existing dermatosis such as atopic eczema, psoriasis, or contact dermatitis. When it is due to malignant disease, erythroderma is most pathognomonic of Hodgkin's disease, less frequently seen with lymphocytic leukemia, and rarely associated with underlying solid tumor (stomach, liver, lung, prostate, thyroid). Erythroderma may be the first sign of Hodgkin's disease or leukemia. It is to be stressed that skin biopsies in these instances do not reveal lymphomatous or leukemic infiltrates, although the patients appear clinically identical to those with Sezary syndrome (in which skin biopsies display diagnostic cutaneous T-cell lymphoma with Sezary cells). Lymphadenopathy and hepatosplenomegaly are more important clues to the underlying lymphoma or leukemia. Erythroderma and itching improve or resolve with treatment and remission of the lymphoma or leukemia. Figurate erythemas are red, persistent, gyrate, serpiginous, and annular bands with a fine trailing scale that take on a pattern of wood grain; they have been given descriptive names such as erythema gyratum repens and erythema annulare centrifugum. The lesions, which persist and expand over large areas of the skin, have been associated with breast, stomach, bladder, prostate, cervix, tongue, and uterine cancer. Dramatic to moderate improvement occurs when the cancer is successfully treated. Urticarial-like lesions, or flesh-colored to red pruritic papules, nodules, and wheal-like plaques, at times accompany leukemia and are called leukemids. They may precede the development of leukemia by many months, and biopsy of the lesions does not show malignant cells. Treatment and control of the leukemic process often result in resolution of the skin lesions. Herpes zoster occurs with considerable frequency, especially with lymphomas (Hodgkin's disease), chronic lymphocytic leukemia, and a variety of neoplasms that are being managed with chemotherapy. Zoster and carcinoma, primarily breast cancer, are also linked. The painful, unilateral, grouped, clear, and often hemorrhagic umbilicated vesicles develop in a dermatomal distribution. About 1 week after the initial dermatomal outbreak, widespread vesicles on a red base ("dew drops on a rose petal"--as seen in varicella) can disseminate widely throughout the body, especially in patients who are immunosuppressed because of an underlying malignancy or chemotherapy. As a result, patients with destructive varicella lesions, disseminated disease, and a prolonged course need to be investigated for underlying neoplasia. Paraneoplastic pemphigus is a recently recognized condition with persistent, painful erosions of the oropharynx, vermilion border of the lips, and conjunctivae, as well as cutaneous pemphigus-like superficial intraepidermal bullae and non-healing erosions. Target lesions suggestive of erythema multiforme are seen on the extremities. Biopsy shows lesions identical to pemphigus vulgaris: suprabasilar intraepidermal acantholysis and IgG deposition on the surface of the epidermal cells on direct immunofluorescence. Patients have circulating autoantibodies that not only react against the tumor tissue but also cross-react with similar antigens found in the epidermal cell junction of normal skin. Underlying neoplasms related to this syndrome are most commonly T-cell and B-cell lymphomas, benign and malignant thymomas, chronic lymphatic leukemia, sarcomas, and Waldenstrom's macroglobulinemia. A number of miscellaneous dermatoses have been associated with internal malignancies, but it is not entirely clear whether these associations are real or fortuitous. Table 196-2 lists some of these associations. Syndromes and Entities Involving the Skin and Internal Malignancies A number of unique cutaneous syndromes are associated with internal neoplasms with sufficient frequency to alert the clinician to look for these tumors when they are potentially curable. Some TABLE 196-2 -- DERMATOSES ASSOCIATED WITH INTERNAL MALIGNANT DISEASE DERMATOSES ASSOCIATED NEOPLASM Bullous lesions: pemphigus, pemphigoid, dermatitis herpetiformis

Rectal, breast, larynx, lymphoma

Tylosis: palmar hyperkeratoses

Esophagus

Acquired ichthyosis

Gastrointestinal leiomyosarcoma, lymphoma, multiple myeloma

Acquired hypertrichosis lanuginosa (malignant down)

Breast, uterine, pancreatic, lung, gastrointestinal cancers and lymphomas

Generalized hyperpigmentation

ACTH-secreting tumors--pancreas, ovary, colon, breast, thyroid

Gynecomastia

Bronchogenic carcinoma, hepatoma

Cutaneous-systemic angiitis

Lymphomas, leukemia, colon, breast, lung, prostate cancers

ACTH = adrenocorticotropic hormone. syndromes are non-genetic and others are genetic in origin. Certain skin lesions have a high prevalence of associated neoplasia, whereas in others the prevalence is low. Non-Genetic Syndromes and Entities with Skin Changes Associated with Internal Malignancy CUTANEOUS LESIONS ASSOCIATED WITH A HIGH PREVALENCE OF INTERNAL MALIGNANCY.

Paget's disease of the breast is characterized by erythematous scaling or weeping, sharply marginated, eczematous patches on the nipple extending to the areola. A breast mass may not be palpable or may not even be found with mammography, but in virtually every case an underlying cancer is found. The lesion mimics eczema, which improves with topical therapy; any eczematous lesion on the nipple that does not respond to topical steroids should undergo biopsy, which shows diagnostic pathologic changes. Paget's disease can also be found in the anogenital area (extramammary Paget's disease). In this disorder, eczematous, pruritic, crusted, lichenified, well-demarcated patches may involve the lower part of the abdomen, inguinal regions, genitalia, or perianal area. The color of the lesions varies from red to whitish gray. Patients are usually older than 50 years, and an underlying carcinoma of the rectum, prostate, urethra, other parts of the genitourinary tract, or apocrine glands is found in up to 50%. The most common sites of metastasis, when present, are regional inguinal and pelvic lymph nodes, bone, liver, lung, brain, and bladder. Biopsy samples taken from patients with mammary and extramammary Paget's disease show the same diagnostic features, namely, large, round cells with clear cytoplasm in the epidermis (Paget's cells). Stewart-Treves syndrome is the occasional occurrence of a lymphangiosarcoma as a complication of chronic lymphedema of the arm after radical mastectomy for carcinoma of the breast. Angiomatous, livid, or dusky red blobs and nodules may evolve 2 to 20 years following the onset of postoperative lymphedema. Angiosarcoma has also developed in congenital lymphedema, as well as in lymphedema of the legs following surgery for cervical cancer. Acanthosis nigricans (see color Plate 14 A) is characterized by soft, velvety, verrucous, brown hyperpigmentation with skin tags in the body folds, especially those of the neck, axilla, and groin. When it occurs in patients older than 40 years, it is often a sign of an underlying malignant tumor, usually adenocarcinoma (most often of the

stomach, gastrointestinal tract, and uterus; less commonly of the ovary, prostate, breast, and lung; and rarely lymphoma). Acanthosis nigricans involving the tongue and oral mucosa is highly suggestive of an underlying neoplasm. In 80% of cases, the cancer is abdominal; in 60% of cases, the cancer is found in the stomach. Special concern must be given to non-obese adults in whom pigmented verrucous areas have recently developed in the body folds; in 80 to 90%, an underlying gastric cancer is present. Of patients with acanthosis and malignancy, the skin abnormalities precede the appearance of the neoplasm in 20% of cases. The skin findings often regress following successful antitumor therapy and reappear with recurrence of the tumor, which suggests that the underlying tumor secretes an unidentified substance that is responsible 1056

for the verrucoid skin lesions. Acanthosis nigricans is more commonly found in individuals younger than 40 years, in whom it is not usually associated with malignancy but rather with obesity, a familial occurrence, or a variety of endocrinopathies (Cushing's disease, acromegaly, polycystic ovaries, hypothyroidism, hyperthyroidism, and insulin-resistant diabetes). Dermatomyositis (see Color Plate 14 B) is recognized by proximal muscle pain and weakness and a characteristic dermatitis that includes a heliotrope rash (edematous, violaceous, telangiectatic discoloration of the eyelids) along with a violaceous, erythematous, telangiectatic scaling rash on the cheeks, forehead, V of the neck, elbows, and knees. Gottron's papules, slightly elevated, red to violaceous plaques over the knuckles, are also an important finding. In individuals older than 40 years, the prevalence of internal carcinoma, primarily breast and lung tumors, is increased (see Chapter 296) . Not uncommonly, the dermatomyositis resolves on removal of the carcinoma, but it may recur if the tumor reappears. In some instances, the dermatomyositis precedes the cancer by several years. Neoplasm should be especially suspected if the dermatomyositis does not respond to conventional therapy, if the patient has a history of previous malignant disease, or if atypical symptoms of dermatomyositis are present. The Leser-Tre lat sign, or the sudden or eruptive appearance or increase in size of multiple seborrheic keratoses, occurs with underlying cancer in the elderly. This sign has been the subject of controversy because seborrheic keratoses are common in the elderly, as are cancers, so their simultaneous occurrence may not have any relationship. Nevertheless, several case reports have described new and enlarging keratoses in association with cancer of the lung, adenocarcinoma of the bowel, mycosis fungoides, and Sezary syndrome; in some of these patients, the keratoses regressed when the malignant tumor was treated. Lymphomatoid papulosis is an uncommon condition of cutaneous lymphoid infiltration clinically characterized by involuting and recurring purplish red papules, plaques, and nodules. In 10 to 20% of patients the condition develops or evolves into a cutaneous T-cell lymphoma or Hodgkin's disease. Based on histologic features, lymphomatoid papulosis has been divided in two types: type A lesions contain large anaplastic tumor cells, whereas type B lesions have cerebriform mononuclear cells and epidermotropism indistinguishable from the changes seen in mycosis fungoides. In some patients, both histologic types are seen even within the same lesions. The lesions may wax and wane, and lymphoma does not develop in most patients. Unfortunately, no single clinical or pathologic feature distinguishes lymphomatoid papulosis from lymphoma. At onset, however, the presence of skin lesions larger than 3 cm in diameter, persistence without spontaneous regression, lymphadenopathy, and systemic symptoms (fever, weight loss) are suggestive of lymphoma. Later in the disease course, multiple, rapidly growing lesions that fail to regress spontaneously or become resistant to therapy (such as psoralen plus ultraviolet A or low-dose methotrexate) usually signal transformation to lymphoma. Necrolytic migratory erythema associated with alpha-cell tumors of the pancreas and elevated glucagon levels evolves as enlarging erythematous patches with central, superficial blister formation progressing to central crusting and healing. Annular lesions result, with exudative, erosive areas most pronounced in the perineum, groin, and perioral areas. The legs, feet, and hands may be involved, and painful glossitis, angular cheilitis, anemia, weight loss, and diarrhea are often seen. The rash and glossitis resolve rapidly after the tumor is removed. Bazex's syndrome, or acrokeratosis paraneoplastica, is a unique marker of carcinomas of the upper respiratory tract, especially squamous cell carcinomas of the oral, pharyngeal, laryngeal, esophageal, and bronchial tissues, primarily in males. When the tumor is asymptomatic, red to violaceous, scaling, eczematous, and psoriasiform patches are found over the nose, fingers, toes, and margins of the ear helices. The nail folds are red, scaling, and tender, with grooving of the nails and onycholysis. Later, the acral lesions become more extensive and spread from the digits to the palms and soles, which in turn become red and scaling and form a honeycomb-like thickening. The fingers and toes become violaceous and bulbous. In a still later stage, if the tumor has not been treated, new scaling lesions resembling psoriasis spread over the face, trunk, knees, arms, and scalp, with extensive nail dystrophy. In the majority of cases, cutaneous lesions improve significantly if the underlying neoplasm is successfully treated. Clubbing of the fingers is a significant sign of underlying bronchogenic carcinoma, mesothelioma, metastatic carcinoma to the thorax (from the colon, larynx, breast, or ovary), and occasionally, Hodgkin's disease. Hypertrophic pulmonary osteoarthropathy is new bone formation along the shafts of the long bones of the extremities and digits. Joints of the ankles, knees, wrists, and hands are swollen and painful. In some patients, cutaneous thickening of the legs and forearms produces enlargement of the limbs; facial features may become coarse with deep facial furrows simulating acromegaly, and deep confluent skin wrinkles evolve over the forehead and scalp, a condition termed pachydermoperiostosis. Carcinoid (see Chapter 245) , a malignant tumor of the chromaffin cells of the gastrointestinal tract and bronchus, may be associated with intermittent scarlet to red flushing of the head, neck, and upper part of the trunk. Eventually, the erythema becomes permanent, and telangiectasis and tortuous veins evolve in the flushed areas. CUTANEOUS LESIONS ASSOCIATED WITH A LOW PREVALENCE OF MALIGNANCY.

Amyloid deposits may occur in the skin without obvious cause (cutaneous amyloidosis) as part of an inherited syndrome or secondary to plasma cell dyscrasias--either primary systemic amyloidoses or multiple myeloma (see Chapter 297) In plasma cell dyscrasias, unique, shiny, translucent, waxy, firm, purpuric papules and plaques occur around the mucocutaneous junctions of the eyes, nose, and mouth. Occasionally, infiltrated papules are not apparent, and only purpuric lesions evolve around the eyes (raccoon eyes). Macroglossia is also common. Urticaria pigmentosa consists of red-brown macules and papules on the trunk and extremities caused by the accumulation of mast cells in the dermis. Light stroking of the skin lesion causes urtication with edema and a red flare as a result of release of histamine from the mast cells infiltrating the skin (Darier's sign). Rarely, the skin lesions are found in association with systemic mastocytosis (mast cell infiltrates of the bone, liver, spleen, and lymph nodes--see Chapter 280) or, even less commonly, with mast cell leukemia or myeloproliferative disorders. Bowen's disease of the skin consists of multiple, superficial squamous cell cancers over the non-sun-exposed areas of the body, particularly in individuals with a history of chronic exposure to arsenicals (drinking well water, exposure to insecticides or industrial arsenicals). Bowen's lesions appear as discreet, scaling, red, flat to elevated patches that mimic eczematous or psoriatic patches. The skin lesions should be removed to prevent progression to invasive squamous cell carcinoma and the possibility of metastasis. The relation of these lesions to internal malignancy is controversial, but cancers of the larynx, lung, esophagus, liver, and bladder should be considered. Sweet's syndrome may be the harbinger of underlying myelogenous or lymphoblastic leukemia, hairy cell leukemia, lymphoma, and solid carcinoma (breast, stomach, lung, colon) in 25% of cases. The unique syndrome consists of painful, raised erythematous plaques with sterile vesicles or pustules studding the surface of the face, trunk, and extremities. Fever occurs in 80% of cases and is often accompanied by arthritis, leukocytosis, and an elevated sedimentation rate; however, no obvious underlying infection is apparent. Skin biopsy shows the same band-like infiltration with neutrophils in the upper dermis in patients with or without internal malignancy. Genetic Syndromes Associated with Internal Malignant Disease CUTANEOUS LESIONS ASSOCIATED WITH A HIGH PREVALENCE OF INTERNAL MALIGNANCY.

Gardner's syndrome consists of multiple epidermal and sebaceous cysts of the face and scalp, fibrous tissue tumors of the skin (desmoid tumors, fibromas, and fibrosarcomas), osteoma of the membranous bones of the face and head, and polyps of the gastrointestinal tract. Adenocarcinomas of the bowel develop in most patients by the seventh decade. Cowden's disease, a condition characterized by numerous hamartomas of the skin, mucous membranes, and internal organs, is associated with malignant neoplasms of the breast and thyroid in a high percentage of patients. The hamartomas occur on the skin as 1057

warty keratotic papules and nodules on the central part of the face (trichilemmomas) and on the hands and arms. Papular cobblestone lesions may appear on the gingiva, palate, tongue, nose, and larynx. Multiple lipomas and cavernous hemangiomas occur in half of the cases.

Torre's syndrome, another autosomal dominant condition, consists of multiple sebaceous gland tumors, sebaceous adenomas, sebaceous hyperplasia, and basal cell cancers with sebaceous differentiation. The skin lesions appear as yellow to red papules and nodules. Gastrointestinal and genitourinary carcinomas arise up to 30 years after the cutaneous lesions. In the majority of cases, the colon and rectum are the sites of internal malignancy, but other associated cancers are found in the esophagus, stomach, duodenum, ovary, kidney, bladder, prostate, testes, and ampulla of Vater. Multiple endocrine neoplasia type IIB (see Chapter 244) consists of medullary carcinoma of the thyroid and pheochromocytoma in association with a marfanoid habitus and multiple whitish to pink papular mucosal neuromas studding the lips, tip of the tongue, buccal mucosa, gingivae, palate, and pharynx. Neuromas also develop on the conjunctivae and corneas; thickened corneal nerves may be found by slit-lamp examination. Ataxia-telangiectasia, an autosomal recessive disorder associated with lymphomas, is recognized by telangiectases over the ears, eyelids, nose, butterfly area of the face, and conjunctivae in association with profound immunologic deficiency and sinopulmonary infections. Hodgkin's disease, non-Hodgkin's lymphoma, or leukemia develops in 10% of patients, with other neoplasms such as ovarian dysgerminomas, gliomas, medulloblastomas, and gastric adenocarcinomas occurring less frequently. Persons with Wiskott-Aldrich syndrome also display a propensity to lymphomas (79%) or leukemias (13%) by the age of 10 years, probably related to the immunologic abnormalities of both the humoral and cell-mediated systems found in this condition. The skin changes are similar to atopic dermatitis. CUTANEOUS LESIONS ASSOCIATED WITH A LOW PREVALENCE OF INTERNAL MALIGNANCY.

Some autosomal dominantly inherited conditions are associated with internal malignancy, but the relationship is not frequently found. Thus patients with neurofibromatosis (see Chapter 522) , who have cafe au lait spots, axillary freckles, and multiple neurofibromas, are prone to the development of pheochromocytomas (10% of the patients by the age of 60 years), acoustic neuromas, and neurofibrosarcomas. Patients with Peutz-Jeghers syndrome have numerous brown-black macules on the lips, perioral regions, hands, and feet in association with hamartomatous polyps of the small bowel, stomach, and less commonly, the colon (see Chapter 139) . Malignancy can occasionally develop in the polyps, pancreas, ovary, and testes. Nevoid basal cell carcinoma syndrome can be associated with medulloblastomas and fibrosarcoma of the jaw, in addition to multiple basal cell skin cancers. Bloom's syndrome (telangiectatic redness of the skin in photoexposed areas and stunted growth) and Che diak-Higashi syndrome (light coloration of the skin and hair) are autosomal recessive conditions associated with a propensity for leukemias and lymphomas. Anhatt AJ: Paraneoplastic pemphigus. In Janes WD (ed): Advances in Dermatology, vol 12. St. Louis, CV Mosby, 1998, pp 77-96. Excellent review and new information on a newly recognized condition. Braverman IM (ed): Skin Signs of Systemic Disease, 3rd ed. Philadelphia, WB Saunders, 1998. A remarkably comprehensive review of all skin signs of systemic disease, including those related to underlying malignancies; extensive bibliography and referencing.

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Chapter 197 - NONMETASTATIC EFFECTS OF CANCER: OTHER SYSTEMS Marc S. Ernstoff Kenneth R. Meehan

In contrast to the direct effects that both primary and metastatic foci of malignancies may have on the body, paraneoplastic syndromes TABLE 197-1 -- PARANEOPLASTIC SYNDROMES Endocrine

See Chapter 194

Neurologic

See Chapter 195

Dermatologic and arthritic

See Chapter 196

Renal

Glomerular abnormalities, miscellaneous: amyloidosis, myeloma, kidney. See Chapter 106

Hematologic

Erythrocytosis, thrombocytosis, leukemoid reaction, anemia (chronic disease, aplastic anemia, microangiopathic hemolytic anemia), granulocytopenia, thrombocytopenia

Coagulation

Disseminated intravascular coagulation, superficial venous thromboembolism, marantic endocarditis, thrombotic microangiopathy

Miscellaneous

Hepatopathy, cancer-related cachexia, pulmonary osteoarthropathy

(Table 197-1) , which constitute signs and symptoms resulting from distant effects of the tumor on various body systems, can affect a variety of organ systems in addition to the endocrine system (see Chapter 194) , the nervous system (see Chapter 195) , and the skin (see Chapter 196) . These indirect effects can be due to the tumor's production and release of growth factors, biologically active hormones, immune mechanisms (antigen-antibody reactions), or other unidentified substances. Many paraneoplastic syndromes are due to excessive production of hormones resulting in signs or symptoms indistinguishable from primary endocrine diseases. Successful treatment of the underlying malignancy is associated with dramatic improvement in the paraneoplastic syndrome. The general approach to paraneoplastic syndromes requires careful diagnosis and therapy (Table 197-2) . Diagnosing the presence of a paraneoplastic syndrome is critical because these syndromes generally parallel the course of the underlying malignancy. In some cases, signs and symptoms may precede the diagnosis of cancer or signal the recurrence of a prior malignancy. Paraneoplastic syndromes may cause signs and symptoms that can be confused with direct effects of the primary tumor or metastases, infection, toxicity of therapy, or co-morbid illnesses. Thus it is important that a correct diagnosis be made to permit the institution of appropriate cancer-directed treatment and symptomatic therapy. Most of these syndromes occur rarely ( lumbar > cervical). The physical examination determines the pace of evaluation and treatment (Fig. 199-1) . Patients who show signs of spinal cord compression require immediate treatment with dexamethasone (10 mg intravenously plus 4-6 mg every 6 hours) followed by emergent evaluation. About 60% to 80% of patients with spinal cord compression will have plain film spine radiographs showing erosion or loss of pedicles, partial or complete collapse of vertebral bodies, or a paraspinous mass. Therefore, the patient with no neurologic findings but with plain film evidence of spine metastases should be evaluated emergently. Patients with no neurologic findings and no plain film abnormalities usually may be expeditiously evaluated as outpatients; the exception is patients with lymphoma, who more frequently may have epidural tumor without plain film abnormalities. The evaluation of patients with neurologic abnormalities should proceed directly to magnetic resonance imaging (MRI) with gadolinium enhancement. MRI will delineate intramedullary, extramedullary, intradural, and extradural lesions as well as encroachment on the cord through the spinal foramina. Although MRI of the suspected site of compression is usually performed emergently, a screening MRI of the entire spine is preferable because malignancies (especially lung, breast, and prostate) often produce multiple noncontiguous bone metastases that should be included in any planned radiation therapy. Metrizamide myelography, previously considered the diagnostic test of choice in spinal cord compression, should be considered in patients who cannot tolerate an MRI or in whom an MRI is contraindicated. If, after a lumbar injection, a myelographic block is identified, a C1-2 puncture should be performed to visualize the extent of the block, as well as to define other rostral lesions (15%); computed tomography (CT) focused on the spinal block, can then be performed to delineate the lesion further. Although treatment should be individualized, palliative radiation therapy is the treatment of choice for patients who have slowly evolving neurologic symptoms, incomplete block, cauda equina involvement, or widely metastatic disease. A commonly used radiation regimen is 3000 cGy (30 Gy) delivered in 10 fractions of 300 cGy per fraction. Corticosteroid doses can be reduced judiciously as radiation therapy proceeds. Surgery is recommended for spinal cord compression in the non-terminal patient if a tissue diagnosis is needed; for rapidly developing neurologic signs; if neurologic dysfunction

Figure 199-1 Flow diagram for evaluation of spinal cord compression in the cancer patient.

1076

progresses despite radiation treatment; if there is recurrent spinal cord compression in an area of previous radiation therapy; or if there is spinal instability resulting from vertebral body collapse or bony protrusion into the spinal cord. Simple laminectomy is not usually effective and may lead to spinal instability. The surgical procedure is dictated by tumor location and surgical experience and expertise. If surgery is used, radiation therapy should be administered postoperatively. For chemosensitive malignancies, chemotherapy may be considered in addition to irradiation or surgery. For the majority of patients with solid tumors, spinal cord compression can be palliated, but curative therapy is not available (exceptions are patients with lymphoma or testicular cancer). The patient's prognosis is related to the tempo of the underlying cancer, the presence of other metastases, and other medical problems.

INTRACRANIAL METASTASES. Headache, altered mental status, seizures, or a focal neurologic examination in cancer patients may signal intracranial metastases (most commonly melanoma and cancers of the lung and breast). Brain metastases are amenable to treatment but are fatal if left untreated. The differential diagnosis in a cancer patient includes iatrogenic causes (chemotherapy agents, narcotic analgesics, hypnotics, and antiemetics), metabolic disorders (hypercalcemia, hyponatremia, hypoglycemia, hyperviscosity, hepatic encephalopathy), paraneoplastic syndromes (subacute cerebral degeneration, dementia, limbic encephalitis, optic neuritis, progressive multifocal leukoencephalopathy), strokes (coagulation abnormalities, Trousseau's syndrome), sepsis, and intracranial metastases. A careful history and physical examination and laboratory evaluation are critical and should guide decisions for further evaluation. In acutely ill cancer patients, cranial CT with contrast medium enhancement should be performed to define the presence and characteristics of the intracerebral lesion. MRI is more sensitive in defining metastatic lesions and differentiating between vascular and malignant lesions and should be considered as an alternative to CT or if there is a need to clarify CT findings. If no mass lesion is demonstrable, leptomeningeal carcinomatosis should be considered as the cause of neurologic signs and symptoms and sought by examination of cerebrospinal fluid. Patients who are deteriorating neurologically or who show signs of impending intracerebral herniation should be intubated and hyperventilated to maintain the P CO2 between 25 and 30 mm Hg. Mannitol, up to 1.5 g/kg, should be administered immediately and repeated every 6 hours. If signs of increased intracranial pressure exist with or without impending herniation, intravenous dexamethasone (16 mg every 6 hours) should be administered to lessen cerebral edema. Status epilepticus requires immediate-acting drugs, such as benzodiazepines, and close attention to respiratory status. Seizures, other than status epilepticus, caused by intracranial metastasis are managed by phenytoin (oral loading dose 1 g in divided doses followed by 300 mg/day). Drug levels should be monitored, especially because accompanying dexamethasone therapy can accelerate the metabolism of phenytoin. Other than for seizures, the routine use of prophylactic phenytoin is not recommended for patients with intracranial metastases. Radiation therapy for intracranial metastasis is usually palliative. A total dose of 3000 cGy is delivered in 10 fractions. For patients with controlled or no systemic disease and a solitary intracranial metastasis in a site not amenable to surgery, radiation to the site of disease at higher doses (4000-5000 cGy) is justified. By and large, a surgically accessible solitary lesion in a patient with controlled systemic disease merits surgical removal followed by postoperative radiation therapy. Patients with solid malignancies who present with brain metastases have limited life expectancies (median survival in the range of 6-12 months), but there is considerable variation among patients.

SUPERIOR VENA CAVA SYNDROME. Superior vena cava (SVC) syndrome is usually caused by extrinsic compression (90%), but it can also be due to fibrosis, thrombosis, or invasion of the SVC. The most common malignancies associated with SVC syndrome are lung cancer and lymphoma. Signs and symptoms can be subtle and evolve slowly (over a 2- to 5-week period). The spectrum of signs with the SVC syndrome includes cyanosis; edema; venous engorgement of the head, neck, arms, chest, and upper abdomen; varying degrees of airway obstruction; pleural and pericardial effusions; and tracheal edema. Non-pitting edema of the neck (Stokes' collar) can also be found. Symptoms, which frequently worsen when the patient lies down or leans forward, may include fullness or stuffiness in the ears or nose, visual disturbances, facial swelling, shortness of breath, cough, chest pain, voice changes (hoarseness), dysphagia, headache, stupor, seizures, and syncope. Back pain may herald simultaneous spinal cord compression by a contiguously extending tumor. Upper extremity venography complements either CT or MRI in defining the level of SVC obstruction. In the past, malignancy-associated SVC syndrome was considered an oncologic emergency that merited immediate radiation therapy to avoid death from respiratory arrest or intracranial hemorrhage. Immediate therapy is indicated for impending airway obstruction (stridor) or increased intracranial pressure (stupor, seizure), particularly in a thrombocytopenic patient. However, given the vast array of benign causes of SVC syndrome and the frequency of chemosensitive malignancies such as small cell lung cancer and lymphomas, its cause should be determined while the patient is closely observed and managed symptomatically. Sputum cytology, bone marrow, lymph node biopsy, thoracentesis, bronchoscopy, and thoracotomy may confirm the diagnosis. Once a neoplastic cause of SVC syndrome has been established, appropriate treatment should be initiated. In most cases, radiation therapy remains the primary

treatment, commonly using doses of 150 to 300 cGy per fraction to a total dose of 3000 to 5000 cGy. About 85% of patients improve within 3 weeks, but symptoms usually recur. If small cell lung cancer, testicular cancer, or lymphoma causes SVC obstruction, chemotherapy should be delivered through a lower extremity vein. Corticosteroids may improve cerebral or laryngeal edema. The increasing use of subclavian catheters to deliver chemotherapy has increased the frequency of SVC thromboses. Low-dose warfarin (1 to 2 mg/day) may prevent such thrombosis. Localized fibrinolytic therapy should be considered for patients with catheter-associated thrombosis who have recently developed SVC syndrome if there is not a high risk of bleeding. After successful fibrinolysis, heparinization and subsequent warfarin therapy should be instituted to prevent recurrent SVC syndrome and to maintain the indwelling catheter. The prognosis of the patient with SVC is related to the underlying malignancy. Patients with lymphomas and Hodgkin's disase may be cured with appropriate therapy.

CARDIAC TAMPONADE (SEE CHAPTER 65) . Cardiac tamponade in a cancer patient may have a non-cancerous cause, may be the first manifestation of malignancy, or may signify disease progression. Prompt diagnosis is necessary because tamponade is life threatening, but successful treatment improves survival. Tamponade may be caused by primary tumors of the pericardium (mesothelioma, sarcoma, and teratoma) or, more frequently, by metastatic disease from breast, lung, leukemia, lymphoma, melanoma, and epidemic or non-epidemic Kaposi's sarcoma. When fluid pressure within the pericardial sac approaches right atrial and ventricular diastolic pressure, cardiac tamponade occurs. As intrapericardial pressure increases, heart rate, myocardial contractility, and systemic resistance increases. If intrapericardial pressure increases rapidly, between 150 to 250 mL of fluid (normal volume 8). However, practical considerations would dictate that excretion of uric acid is of primary importance and high volume urinary output, even when alkaline, will dilute calcium phosphate in the urine and lessen the danger of phosphate crystalluria. Hypocalcemia will occasionally require therapy with intravenous calcium. Rarely, calcitriol replacement will be necessary to obviate persistent hypocalcemia caused by low calcitriol levels. Hemodialysis should be initiated when volume status, urinary output, acid-base status, and electrolyte changes signal its necessity.

HEMORRHAGIC CYSTITIS. Patients who have received or are receiving cyclophosphamide or ifosfamide may develop a life-threatening urologic emergency, hemorrhagic cystitis, caused by metabolites (chlorethylazeridine, chloroacetic acid, and acrolein) of either chemotherapy agent. Because metabolites are excreted by the kidneys, high concentrations can accumulate in the bladder. The bladder grossly appears hyperemic and edematous with areas of punctate hemorrhage; mucosal erosions and sloughing are common. The best management entails prevention by maintaining a high urinary output to decrease the concentration of metabolites in the bladder and by correcting any coagulation defect. Systemic use of sodium 2-mercaptoethanesulfonate (mesna) prevents mucosal irritation by detoxifying the metabolites within the bladder. Once hemorrhagic cystitis occurs, conservative management with care to ensure excellent urinary output is often adequate. Blood product replacement may be necessary. The use of a urethral catheter to perform saline lavage, remove blood clots, and remove metabolites may be considered. If conservative management is not effective, the bladder may be irrigated by N-acetylcysteine. If that fails, irrigation with 1.0% to 2.0% formalin solution by an experienced urologist frequently (85%) stops bleeding after one treatment. Other agents that may be efficacious include the intravesicular administration of 1% alum or prostaglandins E2 and F2 . If conservative measures fail to control hemorrhage, diversion of hypogastric arteries with ureteral diversion and cystectomy may be necessary.

HEMATOLOGIC EMERGENCIES. Thrombocytopenia is common in patients who are undergoing chemotherapy (see Chapters 183 and 184) . The platelet count threshold that should trigger the prophylactic administration of a platelet transfusion depends on the clinical circumstances. At many institutions, it is routine to administer platelets to patients whose platelet count is below 15,000 to 20,000/mm3 , but evidence suggests that a prophylactic platelet transfusion should be considered only if the platelet count is below 5,000 to 10,000/mm3 ). However, uremia, fever, or any evidence of bleeding should raise this threshold. The expected duration of thrombocytopenia is also an important consideration. If the platelet count is less than 50,000/mm3 , platelets should be transfused for active bleeding, before surgery, or before an invasive procedure. When the patient is symptomatic from an associated anemia or has a hemoglobin value less than 8.0 g/dL, red blood cells should also be administered. Thrombopoietin, a stimulator of platelet production, appears to speed the recovery of the platelet count in patients with chemotherapy-induced thrombocytopenia. Leukostasis may result when the white blood cell count exceeds 100,000/mm3 , most often in chronic myelogenous leukemia or acute myelogenous leukemia. An oncologic emergency is not defined by the degree of leukocytosis but rather by the symptoms associated with elevated white blood cell count. The ensuing clinical dysfunction results from the lack of deformability of white blood cell blasts, with subsequent plugging of small vessels. The leukostasis syndrome affects the central nervous system, causing stupor, dizziness, visual problems, ataxia, coma, intracranial hemorrhage, and sudden death. It also affects the lungs, producing pulmonary infiltrates and hypoxia that can progress to pulmonary failure with a clinical picture similar to the adult respiratory distress syndrome. Because extreme leukocytosis results in hyperviscosity, diuresis and volume depletion should be avoided. The primary goal of treatment is to reduce the white blood cell count by leukopheresis (decrease white blood count by 20 to 60% over 3 to 4 hours), followed by immediate effective therapy of the underlying leukemia. Because of the potential of leukemic cell lysis, measures should be instituted to prevent the tumor lysis syndrome. Chanock SJ, Pizzo PA: Fever in the neutropenic host. Infect Dis Clin North Am 10:777, 1996. A practical review of the approach to the patient with fever and neutropenia including the use of colony-stimulating factors. Loblaw DA, Laperriere NJ: Emergency treatment of malignant extradural spinal cord compression: An evidence-based guideline. J Clin Oncol 16:1613, 1998. A comprehensive review of the literature for malignant spinal cord compression including general treatment guidelines. Markman M: Diagnosis and management of superior vena cava syndrome. Cleve Clin J Med 66:59, 1999. A review of the malignant and benign causes of SVC syndrome with an emphasis on the practical aspects of management and treatment. Mundy GR, Guise TA: Hypercalcemia of malignancy. Am J Med 103:134, 1997. A scholarly, well-referenced review of the pathophysiology, natural history, and treatment of malignancy-associated hypercalcemia.

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Chapter 200 - APPROACH TO THE PATIENT WITH METASTATIC CANCER, PRIMARY SITE UNKNOWN Daniel C. Ihde

DEFINITION. Cancers may first become manifest with visceral or nodal metastases without an obvious primary lesion. Patients presenting in this fashion are said to have metastatic cancer, primary 1079

site unknown (MCPSU). Other terms used to denote this clinical entity include cancer (or carcinoma) of unknown primary site and metastases of unknown origin. There is no consensus regarding the extent of clinical evaluation required before the conclusion is reached that the site of origin of the primary tumor cannot be found; as a result, there is considerable heterogeneity in the frequency with which MCPSU is ultimately diagnosed and in the clinical features of patients deemed to have this syndrome. Most authorities agree that complete history and physical examination, blood cell counts, a chemistry screening panel, tests for occult blood in urine and stool, mammography in women, and routine histologic evaluation of the diagnostic pathologic specimen should be performed. Other major sources of heterogeneity include the differing degrees of certainty that individual pathologists require to make a more specific diagnosis, the differing numbers and types of pathologic studies employed before the diagnosis of MCPSU is made, and the extent of imaging studies ordered by clinicians in patients exhibiting this syndrome.

ETIOLOGY. The syndrome of MCPSU by definition results from an occult primary cancer that produces clinically documented metastases. The etiology of this process varies markedly depending on the organ of origin of the malignancy. In a minority of patients, the primary site is not apparent even at autopsy. In a large series of 302 patients with MCPSU who eventually had a postmortem examination, the primary tumor site was eventually identified in 27% of individuals during life and an additional 57% at autopsy; in a residual 16% of cases, even autopsy could not discover the primary neoplasm. When autopsy is not performed, the fraction of cases in which the origin of cancer is not discovered is as high as 70 to 80%.

INCIDENCE. Because there is no standard definition of the MCPSU syndrome, its incidence can only crudely be estimated. Various authors suggest that from 2 to 12% of all cancer patients present in this fashion, with the higher estimates usually based on series from tertiary care centers. Because 1,229,000 individuals in the United States will be diagnosed with cancer in 1998, approximately 86,000 of them (the median of 2-12%) will have MCPSU.

PATHOGENESIS AND PATHOLOGY. The primary pathogenesis of the MCPSU syndrome is the sequence of events that produced the occult primary cancer and its metastases. These events differ greatly, depending on the primary neoplasm. Why the primary cancer is not discovered by routine diagnostic evaluation is a question of major interest. The most common explanation is that the primary tumor is simply too small to be detected by physical examination and imaging studies. Other possibilities include prior surgical excision of the primary lesion, as can occasionally be established in malignant melanoma presenting as an MCPSU; hemorrhagic infarction with resulting necrosis and scarring, as is thought to occur in some testicular choriocarcinomas; and spontaneous regression, which occurs rarely in renal cancers and melanomas and may be mediated by immunologic mechanisms. Because pathologic confirmation of a malignant neoplasm must be obtained and a search for the primary cancer by routine evaluation must be unrewarding before a tentative diagnosis of MCPSU is made, careful scrutiny of the pathologic specimen assumes critical importance. Discussion between clinician and pathologist should always occur and may sometimes reveal that available pathologic material is inadequate for a more specific diagnosis because of the suboptimal amount of tissue or a poorly processed specimen. This situation occurs with pathologically undifferentiated neoplasms or when the diagnosis of malignancy rests solely on cytologic material obtained by fine-needle aspiration, which sometimes provides little information on tissue architecture and may be insufficient for detailed immunohistochemical or electron microscopic studies that sometimes elucidate the primary site of malignancy. When the pathologist believes examination of additional tissue could lead to a more definitive diagnosis, careful communication is essential to ensure that a repeat biopsy will yield sufficient, properly processed material. Once an adequate pathologic specimen is available, routine light microscopic examination will reveal adenocarcinoma in approximately 40% of MCPSU patients, undifferentiated carcinoma or malignant neoplasm in 40%, squamous carcinoma in 10%, and, in fewer than 5% each, melanoma, neuroblastoma, neuroendocrine tumor, or other cancers. The pathologist must determine that the presumed metastasis is not the primary tumor. Carcinoma occurring in a setting of epithelial dysplasia suggests a primary neoplasm, whereas certain types of cells not normally present at the biopsy site, such as epithelial acinar structures in lymph nodes, confirm that the tumor is metastatic. Light microscopic examination can sometimes reveal structural features that suggest the origin of the cancer. For example, papillary adenocarcinoma most often arises in the thyroid, ovary, or lung; and signet ring carcinoma arises in the gastrointestinal tract. Rosetting malignant cells are characteristic of neuroblastoma, and psammoma bodies, of thyroid or ovarian carcinoma. More specialized studies, particularly immunohistochemical techniques (Table 200-1) , may be useful in diagnosing undifferentiated carcinomas or malignant neoplasms, which usually prove to be poorly differentiated squamous or adenocarcinoma, lymphoma, amelanotic melanoma, germ cell carcinoma, or undifferentiated sarcoma, and may identify the organ in which some carcinomas arise. However, the clinical behavior and response to therapy of these malignancies, particularly of undifferentiated neoplasms diagnosed exclusively by immunohistochemical means, may not be identical to corresponding neoplasms diagnosed routinely by light microscopy. Although not used as often as immunohistochemistry, electron microscopic examination of certain tissue specimens may sometimes be useful, particularly in undifferentiated neoplasms. Ultrastructural demonstration of microvilli is characteristic of adenocarcinoma, desmosomes of squamous carcinoma, premelanosomes or melanosomes of malignant melanoma, and cytoplasmic dense-core granules of neuroendocrine carcinomas such as small cell lung cancer.

CLINICAL MANIFESTATIONS. The first clinical manifestation and site of initial pathologic diagnosis of cancer in patients with MCPSU most often occurs in the lung or pleural space, liver, bone, or lymph nodes. Less frequent presentations include cancer in the peritoneum or pelvis, brain, epidural space, and skin. The distribution of metastases is clearly different in patients with MCPSU as compared with tumors that have an obvious primary site. For example, bone metastases are uncommon in typical cases of pancreatic cancer but are frequent in pancreatic cancer presenting as MCPSU. Liver and lung metastases are uncommon in typical prostatic cancer but occur much more frequently in prostatic cancer with a clinically undetected primary site. The most common ultimately detected primary sites of cancer in MCPSU patients arise in the pancreas, lung, colon, and hepatobiliary organs. In MCPSU cases presenting above the diaphragm, the lung is the most common primary cancer that is eventually discovered. For infradiaphragmatic presentations, the pancreas is the most frequent primary site. The distribution of eventually proven sites of cancer origin in patients with MCPSU is also somewhat different from the frequency of various malignancies in the general

cancer population. Germ cell, adrenal, hepatobiliary, pancreatic, and renal cancers are relatively overrepresented among patients with the MCPSU syndrome, whereas malignancies of the breast, endometrium, cervix, lung, and prostate are relatively underrepresented because these latter tumors are more readily diagnosed by simple means such as physical examination and chest radiography.

STAGING EVALUATION. Staging of the extent of tumor dissemination is somewhat atypical in patients with MCPSU because the presence of metastatic cancer has already been documented. Attempting to discover the primary malignancy is most often a futile TABLE 200-1 -- IMMUNOHISTOCHEMICAL TECHNIQUES IN CANCER DIAGNOSIS ANTIBODY REACTIVITY LIKELY DIAGNOSIS Leukocyte common antigen

Lymphoma

S-100 antigen

Melanoma, sarcoma

Epithelial membrane antigen

Carcinoma

Cytokeratin

Carcinoma

Prostate-specific antigen

Prostate cancer

Thyroglobulin

Thyroid cancer

Human chorionic gonadotropin

Germ cell tumor

alpha-Fetoprotein

Germ cell tumor, hepatoma

Gross cystic disease protein

Breast cancer

1080

exercise because the great majority of these patients will prove to have advanced carcinoma refractory to therapy. Furthermore, performing extensive testing to identify the site of the tumor's origin can sometimes occupy a considerable fraction of the patient's usually short remaining life span. Discovery of the primary tumor will, however, be beneficial to a small minority of patients. Tumor confined to a single peripheral lymph node region may potentially be eradicated with surgery and/or radiation, making identification and control of the primary cancer in the area drained by affected lymph nodes a potentially curative procedure. A pertinent example is occult primary squamous carcinoma of the head and neck region presenting in cervical lymph nodes. Second, documenting that effective systemic treatment is available for the primary tumor (e.g., breast cancer) strongly supports a trial of such therapy. Finally, location of a primary tumor that is producing or is about to produce disabling symptoms may permit institution of specific palliative therapy. Identification of additional asymptomatic visceral metastatic sites of tumor is of no value in a patient with known visceral metastases. However, in patients whose MCPSU arises in a single peripheral lymph node region, discovery of visceral or distant nodal metastases may prevent unnecessarily radical local or regional therapy. There is virtually a universal agreement that radiographic barium studies of the upper gastrointestinal tract and colon and intravenous pyelography are of no value in the absence of symptoms or signs suggestive of an occult primary cancer in the region being imaged, because false-positive studies occur more frequently than do true-positive results. Computed tomographic (CT) scans of the abdomen and chest have a higher yield, but in most cases they will detect only a poorly treatable malignancy, such as pancreatic or non-small cell lung cancer. In all patients with MCPSU, any imaging studies that are suggested by the evaluation of the pathologic specimen and that might support the diagnosis of a treatable malignancy (e.g., prostatic ultrasonography in an adenocarcinoma reacting with antibodies to prostate-specific antigen or an abdominal CT scan to detect retroperitoneal lymphoma in an undifferentiated neoplasm reacting with leukocyte common antigen) should be performed. Imaging studies are often appropriate to evaluate symptoms because detection of a symptomatic metastatic tumor requiring palliative therapy (e.g., intestinal bypass for bowel obstruction) may be initiated. Serum biochemical studies that may help to diagnose a treatable neoplasm (e.g., human chorionic gonadotropin and/or alpha-fetoprotein in germ cell carcinoma and prostate-specific antigen in prostatic cancer) should be obtained in the appropriate clinical and pathologic setting. However, only markedly elevated levels of these biomarkers are specific for germ cell (or hepatocellular cancer in the case of alpha-fetoprotein), because benign conditions, such as liver disease and prostatic hypertrophy, can yield false-positive results. Moderate elevations do, however, support further evaluation for the specific treatable neoplasm in question. Estrogen receptors can be performed on an appropriately prepared tumor biopsy, but only markedly elevated values strongly support the diagnosis of hormonally responsive breast or endometrial cancer, because many types of carcinoma can exhibit modestly elevated receptor protein levels. The remainder of the staging evaluation in patients with MCPSU should be closely tailored to the specific clinical presentation. It is most useful to segregate patients into two groups, those with known tumor confined to lymph nodes and those with tumor in visceral site(s), with or without nodal involvement. MCPSU CONFINED TO LYMPH NODES. Malignant melanoma and lymphoma can present as isolated lymphadenopathy in any node-bearing region. If neither is excluded by pathologic evaluation, a primary cutaneous melanoma (and any previously excised skin lesions) should be re-reviewed and other sites of adenopathy should be sought. In patients with middle and upper cervical adenopathy in whom biopsy reveals squamous or poorly differentiated carcinoma, complete endoscopic examination with blind biopsies and CT scan to identify areas of submucosal thickening may disclose a primary cancer of the upper aerodigestive tract. Patients with supraclavicular adenopathy more often prove to have an adenocarcinoma that is likely to originate in the lung, breast, or (principally in the left fossa) the gastrointestinal tract. Adenocarcinoma presenting as isolated axillary adenopathy most likely originates in the breast in the female, with lung cancer another possibility in both sexes. Careful breast examination and mammography should always be performed in this setting. Even if there is no evidence of a mammary tumor after this evaluation, axillary dissection and either breast irradiation or surgery is often recommended. With pathologic diagnoses other than adenocarcinoma, lung and skin of the upper extremity should be considered as primary sites. Isolated inguinal adenopathy may be either squamous or adenocarcinoma; the primary cancer often originates in genitalia, skin of the lower extremities, and anorectal structures, all of which should be carefully examined. MCPSU IN VISCERAL SITES. Approximately 85% of MCPSU patients will present with visceral metastases; no effective systemic therapy is available for the great majority. The clinician should focus on identifying neoplasms for which effective systemic therapy exists, specifically chemotherapy-responsive breast and ovarian cancer, pulmonary and extrapulmonary small cell carcinoma, germ cell carcinoma, and lymphoma; hormonally responsive prostatic, breast, and endometrial carcinoma; and papillary carcinoma of the thyroid, which responds to administration of radioactive iodine. Unfortunately, no more than 10% of MCPSU patients with visceral metastases will be shown to have one of these diagnoses. In women, pelvic examination should be performed and mammography obtained if pathologic evaluation does not exclude breast cancer. Any suspicion of gynecologic neoplasm should lead to abdominal and pelvic CT or pelvic ultrasonography. Some women who present with malignant ascites revealing adenocarcinoma on cytologic examination and no evidence of metastases outside the peritoneal cavity have tumors with clinical behavior similar to ovarian carcinoma. They are candidates for exploratory laparotomy and should generally be treated as if they had ovarian cancer. In men, prostatic examination and ultrasonography should be performed, and blind prostatic biopsy may be appropriate if suspicion of cancer is high. A previously overlooked subareolar breast mass should be sought. The thyroid gland should be carefully examined for masses in both sexes.

TREATMENT. MCPSU CONFINED TO LYMPH NODES. In patients who, after the staging outlined earlier, have all known tumor confined to a single lymph node region the disease should be approached aggressively,

because a fraction of these patients will attain 5-year survival and even cure. Patients with melanoma should undergo radical lymphadenectomy; the expectation is a 5-year survival of 15 to 35%, depending on the number and volume of nodal metastases, an outcome similar to stage III melanoma managed with excision of the skin primary and radical lymphadenectomy. If malignant lymphoma is the suspected diagnosis, combination chemotherapy appropriate for these diseases should be administered, followed by radiation therapy to the initial area of involvement. Squamous and undifferentiated carcinoma in the middle to upper cervical nodes is often managed with radical neck dissection and irradiation, although irradiation alone may be sufficient for low-volume disease. The radiation field usually includes the nasopharynx, oropharynx, and laryngopharynx in order to treat the most likely sites where the primary tumor originated. Five-year survival of 25 to 40% can be anticipated, depending on tumor volume. The outlook for patients with adenocarcinoma in supraclavicular node metastases is much more problematic, with only occasional 5-year survivors. Isolated axillary adenopathy in women with biopsy-proven adenocarcinoma is usually treated as if it were breast cancer. Axillary node dissection and modified radical mastectomy are often advocated in this setting and yield 5-year survival rates of 30 to 70%, results at least as good as in overt stage II breast cancer. Only half of modified radical mastectomy specimens will reveal a primary tumor. More recently, similar survival rates have been reported in patients treated with axillary node dissection in conjunction with breast irradiation. Because a fraction of these patients clearly have breast cancer, systemic adjuvant therapy appropriate for stage II breast cancer, either chemotherapy, tamoxifen, or both modalities, should be administered. Men and women with squamous or undifferentiated carcinoma confined to axillary nodes should be considered for node dissection, 1081

because about 20% of such patients so treated will live 5 or more years after surgery. Although physical examination usually reveals the primary cancer in patients with inguinal nodes, surgical extirpation or irradiation alone yields 5-year survival of approximately 25% in cases without a documented primary site. In younger men with predominant midline nodal presentations and minimal visceral tumor, historical evidence of rapid tumor growth, or response to previous chemotherapy, the still incompletely characterized syndrome of "poorly differentiated carcinoma of unknown primary site" should be considered. This syndrome, although not yet well defined, is of importance because a fraction of patients with some or all of the above characteristics obtain complete remissions, sometimes durable, with cisplatin-based chemotherapy programs similar to those employed in men with testicular cancer. Originally, these cases were thought to represent germ cell carcinomas in which a definitive pathologic diagnosis could not be rendered. Recent retrospective reviews indicate that fewer than 5% of patients have initially unrecognized germ cell tumors. The pathogenesis of this syndrome remains obscure, and until clinical trials using strict eligibility criteria for patient entry and adherence to a uniform therapeutic regimen are completed, the fraction of patients who benefit from therapy will remain uncertain. MCPSU IN VISCERAL SITES. Palliative or supportive care is usually the major focus of management in MCPSU patients with visceral metastases, because most have widely disseminated cancer for which no effective systemic treatment is available. However, palliative irradiation, for example of bone metastases, is often effective in ameliorating associated pain. In rare instances, such as intestinal obstruction by tumor, surgical resection of symptomatic metastases may be indicated. Chemotherapy and, in some instances, hormonal therapy or radioactive iodine are the only maneuvers that address the problem of distant metastatic disease, but success is expected in few patients. In women with isolated malignant ascites, laparotomy with maximum feasible resection of tumor masses, provided they are confined to the peritoneal cavity, is often appropriate. Whether or not a primary ovarian tumor is identified, one study reports a relatively indolent course in these patients, with some complete responses to chemotherapy regimens utilized in ovarian cancer. Whenever detailed review of the pathologic material or the staging evaluation raises reasonable suspicion of a primary cancer that might be expected to respond to systemic treatment, a trial of appropriate therapy may be initiated, provided a favorable risk-benefit ratio is thought to exist in the individual patient. For the remaining patients with visceral MCPSU, there is no evidence that any treatment improves survival. Close observation with palliation of symptoms as they arise is an appropriate management strategy. For fully ambulatory patients who understand the limitation of chemotherapy but still desire it, investigational therapies or empirical chemotherapy regimens, for which responses have occasionally been reported, may be tried.

PROGNOSIS. The prognosis of the great majority of patients with MCPSU is poor. In several large series of patients accrued in single institutions, median survival is 5 to 6 months and 5-year survival is 3 to 7%. The most important prognostic features, as in most cancers, are ambulatory status, sites and volume of tumor involvement, and degree of weight loss. Five-year survival is reported to be 25 to 50% for patients whose tumor is confined to peripheral lymph nodes and less than 3% for all other patients. Abbruzzese JL, Abbruzzese MC, Hess HR, et al: Unknown primary carcinoma: Natural history and prognostic factors in 657 consecutive patients. J Clin Oncol 12:1272, 1994. A large institutional series of consecutive MCPSU patients emphasizing detailed information on prognostic factors. Daugaard G: Tumour review: Unknown primary tumours. Cancer Treat Rev 20:119, 1994. Work-up should concentrate on identifying the occasional tumor responsive to treatment. Lembersky BC, Thomas LC: Metastases of unknown primary site. Med Clin North Am 80:153, 1996. Effective therapy does not exist for most patients with metastases of unknown primary site, but modern pathologic techniques provide better diagnostic precision and can identify some patients with better prognosis.

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Part XV - METABOLIC DISEASES

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Chapter 201 - APPROACH TO THE PATIENT WITH METABOLIC DISEASE Louis J. Elsas II

In this chapter we approach the principles of screening, diagnosing, and treating inherited metabolic diseases, many of which are detailed in subsequent chapters. In Chapter 32 , inborn errors of metabolism are defined in terms of the function and location of proteins and the pathophysiologic consequences to the human organism when they are impaired. Here we invoke a genetic approach through the use of predictive genetic testing to identify and prevent irreversible damage from an inborn error of metabolism. The goal is to diagnose the disorder and intervene to prevent damage by a return to metabolic homeostasis before the disease is irreversible. Genetic screening of symptomatic and pre-symptomatic individuals is used to accomplish this objective. Once the disorder is diagnosed, if its pathophysiology is understood, intervention can restore metabolic homeostasis and prevent progressive disease. Genetic screening is a process by which a small population of individuals at high risk for a genetic disorder are selected from a much larger group. From this smaller population, a diagnosis, preferably pre-symptomatic, is made. Screening is performed in at least five categories of heritable risk, age, or reproductive condition. Non-selected screening of a pre-symptomatic population is performed to identify homozygous affected individuals and to prevent death, mental retardation, and other irreversible clinical manifestations. Certain principles are used to determine which diseases would be ethically, legally, and socially acceptable for such a universal public health activity (Table 201-1) . At present, universal screening is limited to newborns because of this population's accessibility, the rapidity of progression, and the lifelong burden of disease processes. Disorders currently being screened for in various combinations include phenylketonuria, maple syrup urine disease, galactosemia, homocystinuria, tyrosinemia, sickle cell disease, congenital adrenal hyperplasia, biotinidase deficiency, hypothyroidism, and cystic fibrosis. Selective screening of symptomatic newborns, children, and adults is performed to identify inherited disorders that may be preventable or ameliorated, not only in the patient but in extended family members at risk as well. The objectives of diagnosis are to provide treatment; determine the genetic component of the disorder; provide genetic counseling, including heterozygote detection and prenatal diagnosis, to patients, parents, and relatives; provide new information about the disorder's pathophysiology; and develop prevalence data. The laboratory diagnostic methods used in selective screening are different from those used in non-selective mass TABLE 201-1 -- PRINCIPLES FOR NON-SELECTIVE GENETIC SCREENING The disorder should produce a high burden to the affected individual yet be preventable. Methods for screening, retrieval, diagnosis, and management must be practical and available to the target population as a whole. The inheritance and pathogenesis of the disease should be understood and genetic counseling available. The benefit-to-cost ratio of the program should be greater than 1. Patients' rights should be protected (voluntariness, informed consent, confidentiality). Sensitivity and specificity should be high for the methods used. screening, and clinical judgment is the primary criterion for a given patient's entry into this type of genetic screening. The preventive aspects of genetic screening of a symptomatic patient are important, particularly in disorders in which the onset of irreversible manifestations requires time for full expression. Given a specific diagnosis, genetic counseling may alter reproductive or life-planning behavior. Examples of heritable disorders amenable to selective screening are various cancers (breast, colon, medullary thyroid), peroxisomal disorders, Wilson's disease, cystinuria, familial hypercholesterolemia, early-onset heart disease associated with hyperlipidemia or hyperhomocystinuria, cirrhosis, organic acidemias, mucopolysaccharidosis and other lysosomal disorders, cystinosis, Duchenne's muscular dystrophy, disorders of mitochondrial function, and disorders of connective tissue. Selective and non-selective genetic screening in pregnant women is achieved by fetal sonography, chorionic villus biopsy, or amniocentesis coupled with biochemical, chromosomal, or molecular analyses of cultured fetal cells. Maternal blood is commonly screened for alpha-fetoprotein, chorionic gonadotropin, and estradiol to detect the fetal disorders Down syndrome and spina bifida. If maternal blood concentrations of alpha-fetoprotein, chorionic gonadotropin, or estriol vary above or below the mean values of normal at a specific age of gestation, further fetal studies by sonography and amniocentesis are indicated. Considerable research is in progress to isolate fetal cells from maternal blood to avoid the invasion of the amniotic cavity currently required for prenatal screening. Screening selected populations at risk for environmental hazards is generally applied to the adult population. Pharmacogenetic disorders fall into this category and include screening plasma pseudocholinesterase concentrations preoperatively to detect pseudocholinesterase deficiency and prevent death from succinyldicholine and determining alpha1 -antitrypsin genotypes in individuals exposed to dust to prevent occupation-related, early-onset emphysema from alpha1 -antitrypsin deficiency. Screening for the HLA-H mutations causing hemochromatosis may prevent cirrhosis from iron overload. Screening for asymptomatic heterozygotes in a "high-risk" population is another preventive approach to inborn errors of metabolism. The objective is to detect reproductive couples who carry high-burden recessive genes and provide genetic counseling and reproductive alternatives in high-risk matings. An example is screening for Tay-Sachs disease carriers in the Ashkenazi Jewish population (see Chapter 31) and for cystic fibrosis carriers in white couples planning pregnancy. Screening for heterozygotes requires consideration and fulfillment of ethical issues, including patient autonomy, beneficience to the patient, and confidentiality to prevent discrimination by insurers and employers and stigmatization by society.

TREATMENT OF INHERITED DISEASE Because the metabolic diseases considered in this section have in common that they are inherited and caused by genes of large effect, a general approach to their treatment is appropriate. These approaches are outlined in Table 201-2 . The level at which therapy is rendered depends on the level of understanding of the pathophysiologic mechanisms producing disease and the interventional methods available. Genetic counseling is used for all inherited diseases, even those whose mechanisms are not yet understood and for which no clear beneficial treatment is available. Genetic counseling is a unique and fundamental aspect of management in inherited metabolic diseases. Patients and relatives usually ask the following questions: Why did this disease occur? Will this disease happen to me or my other children? Can it be cured or 1083

TABLE 201-2 -- GENETIC APPROACHES TO THERAPY Genetic Counseling: Prospective Therapy Diagnosis, risk assessment, informational transfer, support for resource allocation Reproductive alternatives: Contraception, abstinence, artificial insemination, in vitro fertilization, risk taking with or without prenatal monitoring Environmental Engineering Avoiding the offending agent Supplemental physical, speech, developmental therapy Nutritional management Limit toxic precursor Provide deficient product Detoxify through alternative metabolic route Provide feedback inhibitor Provide supraphysiologic amounts of vitamin precursor Induce protein (enzyme) production Chemoprevention Protein and Enzyme Replacement Infuse protected pure enzyme Provide clotting factors and peptide hormones Transplantation (prospective) Organ transplant Bone marrow transplant Genetic Engineering Somatic gene therapy Random insertion Homologous recombination (site specific) Germ line therapy prevented? Genetic counseling tries to answer these questions through processes involving several elements (see Chapter 37) . One cannot overemphasize the importance of an accurate clinical and genetic diagnosis and the availability of a genetic discriminant for other family members before entering into formal genetic counseling. Surgical intervention may be a useful adjunct for treating heritable disorders. For example, stabilizing hypoplastic cervical vertebrae may prevent quadriparesis or death in a variety of chondrodysplasias and mucopolysaccharidoses accompanied by hypoplasia of the odontoid process. In Marfan syndrome, careful monitoring of aortic root diameter with surgical removal of the aorta and prosthesis may prevent a lethal aortic dissection. Similarly, evaluation of polyps and early colectomy may prevent disseminated adenocarcinoma in families with the autosomal dominant forms of familial polyposis coli. Molecular diagnoses of mutations in the APL gene help identify at-risk family members. Preventing heritable cancer by early surgical excision is therapeutic for medullary thyroid carcinoma, Wilms' tumors, and neurofibromas of von Recklinghausen's disease. Other examples of the benefit of preventive surgery for inborn errors include splenectomy for hemolytic anemias associated with spherocytosis and pyloroplasty in pyloric stenosis. Environmental engineering is the most commonly used approach to preventing disease in patients affected by inherited metabolic disease. The environment (nutritional intake, exposure to toxins, sun, stress, climatic variation, and drug therapy) may produce a disease state in individuals who have inherited single genes or polygenic susceptibility to the environmental stress. Many inborn errors of metabolism detected by newborn screening identify infants susceptible to the stress of lactose or protein in human or cow's milk. Restriction and replacement of lactose with sucrose will save the lives of infants with galactosemia. Pharmacogenetic disorders exemplify the simple treatment of avoidance once the genetic susceptibility is identified. Health can then be viewed as a continual adaptation between the individual and the environment. Environmental engineering is a form of genetic therapy in which individual genetic susceptibility is identified and the environment is altered to provide optimal health for that individual's unique genetic constitution. The frequency of diseases caused by genetic susceptibility to the environment varies from rare to 100%. Scurvy develops in all humans unless ascorbate is provided in the diet because we are all unable to convert glucuronic acid to glucuronolactone and ascorbate. Humans and primates lost this anabolic pathway during evolution. By contrast, humans readily synthesize tetrahydrobiopterin, a cofactor in many hydroxylase reactions, including phenylalanine hydroxylase. In some rare diseases (about 1 in 500,000) of increased blood phenylalanine and severe neurodegeneration, biopterin is not synthesized. Biopterin replacement may treat defects in biosynthesis and exemplifies a group of metabolic disorders known as vitamin dependency disorders. Nutritional management and chemoprevention involve correction of the metabolic imbalance and return of the patient to homeostasis through diet manipulation and drug therapy. Many of the diseases listed in this section are amenable to this approach and use the pathophysiologic mechanisms listed in Table 201-2 . For example, in disorders of the urea cycle, protein intake is limited to reduce ammonia accumulation. Arginine is supplemented to provide deficient product of the blocked reaction, and alternative pathways are induced for nitrogen excretion. The latter therapy is made possible by a ubiquitous enzyme, N-glycine-acylase, that forms adducts with benzoic acid and glycine to produce hippuric acid, which is excreted, thus ridding the body of one nitrogen molecule. Orotic aciduria is caused by mutations in the bifunctional enzyme orotate phosphoribosyl transferase-orotidine-5 -monophosphate decarboxylase. The disease process, which includes severe anemia and immune deficiency, is caused by a deficient end product, uridine, and is treated by replacing 100 to 200 mg/kg/day of uridine (orally). Feedback inhibition of pituitary adrenocorticotropic hormone production is important in treating congenital adrenal hypertrophy with replacement doses of hydrocortisone to prevent virilization from testosterone overproduction. Glucose decreases overproduction of the precursors delta-aminolevulinic acid and porphobilinogen in acute intermittent porphyria caused by porphobilinogen deaminase deficiency. Using supraphysiologic amounts of a specific vitamin is important if it is the precursor of a coenzyme required for holoenzyme function. Many vitamin-dependent metabolic disorders are known and include pyridoxine (vitamin B6 )-dependent homocystinuria and vitamin C-dependent Ehlers-Danlos syndrome type VI. In vitamin B6 -dependent homocystinuria, mutant cystathionine synthase is stabilized to biologic degradation when saturated with pyridoxal phosphate. Others include vitamin B12 -dependent methylmalonic aciduria, thiamine-dependent maple syrup urine disease, and biotin-dependent multiple carboxylase deficiency. Some blocked metabolic reactions can be augmented by inducing transcription of their gene. For example, phenobarbital and several other drugs induce hepatic uridine diphosphate glucuronyl transferase gene expression and reduce the accumulation of unconjugated bilirubin in Gilbert's syndrome. On the horizon is chemoprevention of common diseases such as breast cancer. Trials with estrogen receptor inhibitors in pre-symptomatic, high-risk members of families with breast and ovarian cancer are promising. Similar trials to prevent colorectal cancer by preventing polyps in at-risk offspring of patients are also promising. If the specific protein or enzyme has been purified and engineered to function in its specified organ or subcellular organelle, it can be used to treat an inherited metabolic disease. One good example is glucocerebrosidase, which has been purified in large quantities from placenta and from recombinant mammalian cells. The secreted enzyme is biochemically engineered to contain the mannose recognition site for cellular uptake into lysosomal compartments. It has been used successfully to prevent and reverse the hypersplenism, pancytopenia, and bone disease of type 1 Gaucher's disease (see Chapter 208) . Many proteins are now made through recombinant techniques to treat metabolic disease and bypass the risks of acquired immune deficiency syndrome and hepatitis attendant on using human-derived biologicals. These agents include glucocerebrosidase, Factor VIII for hemophilia type A, and growth hormone for growth hormone deficiency. Several other engineered proteins used to treat inherited metabolic disease include 1-deamino-8- D-arginine vasopressin to treat X-linked recessive diabetes insipidus and recombinant alpha1 -antitrypsin made stable by inactivating methionine 385 in the treatment of alpha1 -antitrypsin deficiency. Some enzymes such as adenosine deaminase have been modified with polyethylene glycol to reduce immunogenicity and prolong their biologic half-life in blood. It is used to treat severe combined immunodeficiency. Chemoprevention is being developed for heritable disorders such as cancer. For BRCA1 mutation carriers, anti-estrogen receptor medications such as tamoxifen may become an alternative preventive therapy to mastectomy and oophorectomy. For metabolic disorders that are lethal and have no other available therapy, organ transplantation may be life saving. Transplantation with histocompatible organs is clinically available because of

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advances in immunology that not only allow for better tissue typing but also enable chronic immunosuppression with such drugs as cyclosporine, azathioprine, and prednisone to prevent rejection. Several principles are required for successful treatment of an inherited metabolic disorder by organ transplantation: (1) The normal enzyme, protein, or function must be provided by the transplanted organ. (2) Usually the affected organ must be removed. (3) The host must be immunologically tolerant to the gene product being introduced in addition to the transplanted organ itself. These principles are particularly relevant when displacement bone marrow transplantation is used. In the latter, normal donor stem cells differentiate and provide their enzymes to the recipient's reticuloendothelial system. Diseases associated with accumulation of products in the central nervous system are not yet ameliorated by bone marrow transplantation, although accumulation in bone, liver, and spleen is reduced. One group of metabolic diseases uses stem cell bone marrow transplantation to prevent leukemia caused by inherited syndromes that are associated with defective DNA repair, such as Fanconi's anemia, Bloom's syndrome, and ataxia-telangiectasia. Liver or kidney transplantation can reverse growth and developmental delay in type I glycogen storage disease, cystinosis, acute intermittent porphyria, type I tyrosinemia, Fabry's disease, oxalosis, and non-neuronotrophic lysosomal storage diseases. Lung transplantation has been successful in cystic fibrosis and alpha1 -antitrypsin deficiency, and prophylactic aortic transplantation has prevented aortic dissection in Marfan syndrome. In the past decade somatic cell gene therapy to treat patients afflicted with genetic disease has entered the arena of clinical research. Numerous laboratories throughout the world are actively designing strategies by which exogenous DNA can be incorporated into the genomic DNA of specific organs to provide a missing gene function. It is not overly optimistic to assume that some form of somatic gene therapy for a number of inherited metabolic diseases will become routinely available (see Chapter 33) . Elsas LJ: Newborn screening. In Rudolph AM (ed): Pediatrics, 20th ed. New York, Appleton-Century-Crofts, 1996, pp 282-291. Approaches to genetic screening. Elsas LJ, Acosta PB: Nutrition support of inherited metabolic diseases. In Shils ME, Olson JA, Shike M (eds): Modern Nutrition in Health and Disease, 9th ed. Philadelphia, Lea & Febiger, 1998. Complete discussion of how to manage metabolic disease by diet. NIH Consensus Statement: Genetic testing for cystic fibrosis. NIH Consens Statement 15(4):1, 1997. A summary of issues both medical and ethical pertaining to genetic screening of asymptomatic adults.

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Section - Disorders of Carbohydrate Metabolism

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Chapter 202 - GALACTOSEMIA Robert K. Naviaux William L. Nyhan

Galactosemia is an inborn error of carbohydrate metabolism in which the activity of galactose 1-phosphate uridyltransferase is deficient (Fig. 202-1) . Patients are unable to metabolize galactose, a component of the disaccharide lactose, whose source in the diet is milk or milk products. Two other disorders, galactokinase deficiency and uridine diphosphate (UDP) epimerase deficiency, also represent abnormalities in this pathway and lead to excretion of galactose in the urine (Table 202-1) . The treatment of each of these disorders is elimination of galactose from the diet.

ETIOLOGY. Classic galactosemia and the other disorders of galactose metabolism are all transmitted by autosomal recessive genes. The gene for uridyl transferase is located on chromosome 9p13. The gene has been cloned and a number of mutations identified (Table 202-2) . The most common missense mutation in galactosemia (G) is a change in the codon for glutamine at position 188 to arginine in exon 6. More than 60% of white patients are homozygous or heterozygous for this mutation. Another common abnormal uridyl transferase enzyme, the Duarte variant (D), results from an A-to-G mutation in exon 10 that changes asparagine 314 to aspartic acid. Heterozygous carriers for the galactosemia (G) variant display transferase activity about half that of normal individuals. Homozygotes for the Duarte (D) variant also have about 50% of normal activity, but heterozygotes for this variant have about 75% of normal activity. Study of parents or assessment of the mutation will distinguish individuals with the Duarte variant from G heterozygotes. This distinction can also be made electrophoretically.

PREVALENCE. In central Europe the prevalence of galactosemia

Figure 202-1 Galactose 1-phosphate uridyltransferase, the site of the enzyme defect in patients with classic galactosemia. Shown also are the galactokinase and the epimerase reactions.

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TABLE 202-1 -- DISORDERS OF GALACTOSE METABOLISM DEFECTIVE ENZYME Galactose 1-phosphate uridyltransferase

METABOLIC PATTERN Galactose 1-phosphate

CLINICAL MANIFESTATIONS Classic galactosemia

Galactose Galactokinase

Galactose

Cataracts; pseudotumor cerebri

UDPglucose 4-epimerase

Galactose 1-phosphate

May be asymptomatic; may have the classic galactosemic phenotype

UDPgalactose UDP = uridine diphosphate. (GG) is 1 in 55,000; data from neonatal screening programs in California and Massachusetts yielded figures of 1 in 86,000 and 1 in 62,000. Prevalence of the GD compound has ranged from 1 in 3000 to 1 in 38,000. Infants with the GD phenotype have transferase activity 10 to 25% that of control erythrocytes. In general, this activity is sufficient and treatment is not required. Galactokinase deficiency is quite rare, with a prevalence of 1 in 500,000 to 1 in 1 million births. Epimerase deficiency is even rarer. The benign type has mainly been described in Swiss and Japanese populations. Two patients have been detected with symptomatic epimerase deficiency.

PATHOGENESIS. Three distinct enzymes catalyze the conversion of galactose to glucose. They also create the activated UDPgalactose needed for glycoprotein and glycolipid synthesis (see Fig. 202-1) . In normal individuals, administered galactose disappears rapidly from the blood and leads to an increase in the concentration of glucose. The defective enzyme in galactosemia is galactose 1-phosphate uridyltransferase. In individuals with the classic (G) variant, this activity is virtually completely absent. The immediate consequence of defective activity is the accumulation of galactose 1-phosphate. Ingested galactose is found in the blood and excreted in the urine. When concentrations of galactose are increased, alternative pathways are called into play. In one of these pathways galactose is reduced at carbon 1 to form galactitol, a sugar alcohol. In another, galactose is oxidized to galactonic acid. Both of these metabolites are found in tissues and are excreted in considerable amounts in the urine. The pathogenesis of many of the acute clinical manifestations of classic galactosemia has been related to the accumulation of galactose 1-phosphate in tissues. Among the best evidence for this pathogenesis are the observations that therapeutic measures that result in a reduction in intracellular concentrations of galactose 1-phosphate lead to prevention or disappearance of the acute symptoms. At the same time, it should be recognized that although this association is clinically useful, the mechanism of pituitary, hepatic, renal, and cerebral damage is unknown. It is clear that these complications do not occur in galactokinase deficiency. Therefore, it is clear that they are not due to galactose itself. Cataracts are, on the other hand, found in patients with galactokinase deficiency, as well as uridyl transferase deficiency. Cataracts appear to result from the accumulation of galactitol in the lens, where it causes osmotic swelling, precipitation of protein, and disruption of fibers. Osmotic swelling resulting from galactitol also appears to be the mechanism of production of acute cerebral edema. Pseudotumor cerebri occurs in patients with galactokinase deficiency, as well as in those with uridyl transferase activity. The galactitol theory of the genesis of cataracts is strengthened by the prevention of cataracts in galactose-treated rats by sorbinil, an aldose reductase inhibitor that prevents the formation of galactitol. The pathogenesis of the late-appearing manifestations in the ovary, in speech development, and in the brain are not clear. One theory is that of autointoxication, in which galactose 1-phosphate is formed from UDPgalactose, which is made from uridine diphosphoglucose via the epimerase reaction and thus from dietary glucose in the absence of dietary galactose. Another is a deficiency of intracellular UDPgalactose. Epimerase maintains a steady-state ratio of uridine diphosphoglucose (UDP glucose) to UDPgalactose of 3:1, which might be required for the synthesis of cerebral galactolipids. Low levels of UDPgalactose in erythrocytes have been reported in some patients with galactosemia. Abnormally low galactosylation of fibroblast glycoproteins has also been observed.

CLINICAL MANIFESTATIONS.

Vomiting and jaundice usually develop in infants with galactosemia within days of the initiation of feedings containing milk. Vomiting may be so severe that pyloric stenosis is diagnosed and surgery performed. The infant feeds poorly and fails to thrive. Hepatomegaly is a regular finding, and the hepatic damage is progressive to typical Laennec's cirrhosis. Edema, ascites, hypoprothrombinemia, and bleeding may be present, and splenomegaly develops with increased portal pressure. In the presence of continued milk feedings, this clinical picture rapidly leads to death. Granulocyte function may be impaired by galactose or its metabolites. Infants may have sepsis, most commonly caused by Escherichia coli. Fulminant septicemia may cause an early demise or complications such as osteomyelitis, meningitis, and gangrene. Cataracts are characteristic features. They may occur in very young infants. Pseudotumor cerebri in patients with galactosemia may be recognized by bulging of the anterior fontanelle or TABLE 202-2 -- MUTATIONS* ASSOCIATED WITH GALACTOSEMIA CODON AND AMINO ACID SUBSTITUTION NUCLEOTIDE CHANGE PHENOTYPE PREVALENCE IN CLASSIC GALACTOSEMIA White

Hispanic

Q188R

CAG CGG

G

62%

S135L

TCG TTG

G

0%

V44M

GTG ATG

G

M142K

ATG AAG

G

R148W

CGG TGG

G

L195P

CTG CCG

G

R231H

CGT CAT

G

H319Q

CAC CAA

G

R333W

CGG TGG

G

N314D

AAC GAC

Duarte

*In the gene for galactose 1-phosphate uridyltransferase (

58%

Black 12% 48%

GALT).

Found in 5.9% of non-galactosemic controls.

1086

by computed tomography or magnetic resonance imaging (MRI), which reveals cerebral edema. The renal abnormality in galactosemia is a renal Fanconi syndrome, in which renal tubular glycosuria, generalized aminoaciduria, proteinuria, and systemic hyperchloremic acidosis are present. Some patients have polyuria. In most patients with galactokinase deficiency, lenticular cataracts are the only clinical manifestation. A few infants have been reported with pseudotumor cerebri. Most patients with epimerase deficiency are asymptomatic. A very few have had a clinical picture identical to that of classic galactosemia.

LONG-TERM COMPLICATIONS OF GALACTOSEMIA. Although dietary therapy for galactosemia has effectively eliminated the acute toxicity syndrome of classic galactosemia, long-term complications have become evident as significant problems, even under ideal conditions of management and patient compliance. Ovarian failure in female patients may be manifested as either primary or secondary amenorrhea with hypergonadotropic hypogonadism (primary ovarian failure, resistant ovary syndrome, premature menopause). This complication in seen in 75 to 96% of female patients before the age of 30. The incidence of ovarian failure is unrelated to the patient's age at diagnosis or the level of dietary control in sibling pairs. The mechanism of this ovarian failure remains enigmatic. Impaired oocyte maturation and accelerated atresia have both been reported. One patient had normal ovaries at laparoscopy at 7 years of age and streak ovaries 10 years later, thus suggesting a time-dependent effect. Pregnancies have occurred in female patients with classic galactosemia, although they are very rare. In one patient who successfully gave birth, ovarian failure later developed. The male gonad is not affected. The second major later complication of classic galactosemia is delayed speech and language. Most children with galactosemia have delayed language development associated with a verbal dyspraxia that is often overcome with time. This complication also appears to be unrelated to the time of diagnosis or the level of compliance as assessed by erythrocyte levels of galactose 1-phosphate. Mental retardation is the most important long-term consequence of the disease. It is most severe in patients in whom diagnosis and treatment occurred late. Prior to the advent of neonatal screening, 11 of 85 patients had IQ levels below 70. An average IQ of 84 was seen in 32 highly compliant patients and an IQ of 77 in 22 poorly compliant patients. Early information on the development of patients in whom galactosemia was diagnosed early and who were compliant with therapy was optimistic. By 1972, data from the largest experience in the United States suggested that such patients had normal levels of IQ, and it appeared that the earlier diagnosis, the higher the IQ. However, more recent experience has led to a much more pessimistic prognosis. The results of a retrospective questionnaire survey of 298 patients from the United States and Europe on whom IQ data were available indicated that 45% of those at least 6 years old were developmentally delayed. This survey provided the first evidence of a definite decline in IQ with age; furthermore, the decline in females was significantly greater than that in males. A more recent retrospective study of 134 galactosemic patients in Germany also provided evidence of a decline in IQ with age in that 4 of 34 patients younger than 6 years had IQs less than 85 whereas 10 of 18 between 7 and 12 years of age and 20 of 24 older than 12 years had such levels. A best-fit regression line suggested a mean loss in cognitive performance of 2 IQ points per year (40 points in 20 years). Of course, most of these patients, especially the older ones, antedated nationwide neonatal screening in Germany, and in the earlier international study 270 patients had clinical symptoms before diagnosis and treatment. Data were not specifically set out in either study for patients in whom the diagnosis was made while pre-symptomatic and who were managed carefully. Nevertheless, decline with age in the earlier study was even shown in individuals tested at different ages. In addition, patients in both studies had evidence of microcephaly and specific neurologic manifestations such as progressive ataxia and tremor. MRI of the brain has revealed a substantial number of patients with cerebral atrophy. White matter abnormalities occurred in 95% (52 of 55) older than 1 year. In addition, many patients, even those with normal IQs, have had problems with behavior and school performance.

DIAGNOSIS. The ideal approach to the diagnosis of galactosemia is through routine neonatal screening for the activity of galactose 1-phosphate uridyltransferase in dried blood on filter paper. A positive screening test is confirmed by quantification of activity in freshly obtained erythrocytes in the fluorometric assay for reduced nicotinamide-adenine dinucleotide phosphate formed along with glucose 6-phosphate from the glucose 1-phosphate product. In classic galactosemia the activity approximates zero. Variants with greater activity than this can be elucidated by electrophoresis or by mutational analysis. In populations in which neonatal screening for galactosemia is not available, the disease is usually initially recognized after the development of symptoms by means of a test for the presence of reducing substance in the urine. It is important to emphasize that testing of the urine with glucose oxidase (Clinistix, Tes-Tape) will not detect

galactose, which is a strong argument for continued use of the older methods for urinary sugar (Benedict's or Fehling's test; Clinitest). Galactosuria is also dependent on the dietary intake of lactose. A patient who is admitted to the hospital acutely ill and treated with parenteral fluid therapy may have a negative urine test because galactose has been absent from the diet for 24 to 48 hours. Characterization of the reducing substance found in a urine sample can be done in a number of ways, including paper chromatography, but sugar in an infant's urine that is positive for reducing substance and negative for glucose oxidase is galactose until proved otherwise. Confirmation is by assay of the enzyme. Galactokinase deficiency is usually detected by assay of the urine for reducing substance in an infant or child with cataracts. The diagnosis is confirmed by assay of the enzyme in erythrocytes or cultured fibroblasts. Epimerase deficiency is suspected in a patient with signs of galactosemia and normal transferase activity. The diagnosis is confirmed by assay of the erythrocyte activity of the epimerase.

TREATMENT. Treatment of galactosemia is exclusion of galactose from the diet, which involves the elimination of milk and its products. The mainstay of the diet for an infant is the substitution of casein hydrolysate for milk formulas. Soybean preparations may also be used. Some fruits and vegetables such as watermelons and tomatoes are avoided. Education of parents and children as they grow older on the galactose content of foods is important. Lists of foods are available that are useful in management. Determination of the galactose 1-phosphate content of erythrocytes is useful in monitoring adherence to the diet. An acceptable level has been set at 150 mumol/L (4 mg/dL).

PROGNOSIS. Abundant experience with early treatment supports the concept that effective treatment instituted in the initial weeks of life can prevent all of the acute clinical manifestations of the disease. At the other end of the scale, mental retardation, once established, is irreversible, and if the diagnosis is delayed, some damage to the brain is inevitable. Abnormalities of visual perception, behavior problems, or convulsions may be present. Cataracts are reversible if treatment is started within the initial 3 months of life. Hepatic and renal manifestations of the disease are reversible. Late manifestations such as ovarian failure, white matter abnormalities, and problems with speech development are not prevented by exemplary treatment. These complications will require new insight into pathogenesis for effective prevention.

PREVENTION. Prenatal diagnosis can be accomplished by assay of uridyl transferase in chorionic villus sampling or in cultured amniocytes or by quantification of galactitol in amniotic fluid by gas chromatography-mass spectrometry. Elsas LJ, Langley S, Paulk EM, et al: A molecular approach to galactosemia. Eur Int Pediatr 154(Suppl. 2):21, 1995. Mutational analysis of the human uridyl tranferase gene in the most common clinical phenotypes elucidates the frequency of mutations by demonstrating the high incidence of the arginine substitution for glutamine at position 188 (Q188R) in classic galactosemia and N314D in the Duarte variant. Nyhan WL, Ozand PT: Galactosemia. In Atlas of Metabolic Disease. London, Chapman & Hall, 1998, pp 322-329. An illustrated treatment of the clinical, molecular, and therapeutic aspects of the disease. Segal S, Berry G: Disorders of galactose metabolism. In Scriver CH, Beaudet AL, Sly WS, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York, McGraw-Hill, 1995. A monograph providing the molecular bases of all aspects of galactose metabolism, galactosemia, and the pathophysiology of galactose intoxication.

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1087

Chapter 203 - GLYCOGEN STORAGE DISEASES Harry L. Greene

Glycogen is the storage form of glucose and is present in varying amounts in virtually all cells, although the liver is the primary organ for storage and subsequent release of glucose into the circulation. Glycogen is synthesized from glucose and glucose hydrolyzed and released from glycogen; this highly regulated process helps maintain normal blood glucose concentrations during fasting. At least eight enzymes involved in glycogen synthesis and the hydrolysis to glucose are utilized in this control. Glycogen storage diseases are characterized by an abnormal tissue concentration (> 70 mg/g of liver or > 15 mg/g of muscle) and/or an abnormal structure of the glycogen molecule. During the past four decades, patients who have deficient activity in virtually every enzyme important in the normal synthesis or degradation of glycogen have been identified. More recently, identification of the genetic mutations have led to more specific molecular classifications. Clinical expression of the disease can usually be traced to either the liver or the muscle.

HEPATIC FORMS OF GLYCOGENESIS The various hepatic enzymatic deficiencies are expressed primarily as hypoglycemia and hepatomegaly, and three defects (branching enzyme, glycogen synthetase, and debranching enzyme) result in the accumulation of abnormally structured glycogen and may cause progressive hepatic cirrhosis and associated splenomegaly. Conversely, the accumulation of normally structured glycogen, as seen with deficiency of phosphorylase, phosphorylase b kinase, acid alpha-glucosidase, or glucose-6-phosphatase, is usually not associated with hepatic fibrosis and splenomegaly. Figure 203-1 summarizes the general location of enzymatic defects resulting in the hepatic forms of glycogenesis. With the exception of lysosomal acid glucosidase deficiency, hypoglycemia is a common presenting feature. Clinical and biochemical expressions of the various types of glycogen

Figure 203-1 Mechanism for abnormalities in lipid, purine, and carbohydrate metabolism in type I (glucose-6-phosphatase deficiency) glycogen storage disease. * = associated with hepatic cirrhosis. = associated with elevated serum uric acid, lactate, and lipid levels and with hepatic adenoma.

storage diseases are summarized in Table 203-1 , and the more commonly diagnosed types are discussed below. GLUCOSE-6-PHOSPHATASE DEFICIENCY (TYPE I GLYCOGEN STORAGE DISEASE, GSD-I). The incidence of GSD-I is 1:100,000 to 1:300,000 live births and has been subcategorized into types a, b, or c, with type a the most common; but all types have similar clinical features. As noted in Figure 203-1 , all other enzymatic defects directly affect the formation or degradation of glycogen, with the exception of glucose-6-phosphatase. Similarly, the clinical expression of this defect is distinctly different from that of the other forms of glycogenosis. For example, fasting-induced hypoglycemia may be extreme, and associated with lactic acidosis, hyperlipidemia, and hyperuricemia. The mechanism for the striking abnormalities in lipid and purine metabolism results primarily from overproduction of substrate in response to a decline in blood glucose, as indicated in Figure 203-1 . The documented reversal of these abnormalities by treatment that maintains the blood glucose level between 80 and 90 mg/dL supports this postulate. Therapeutic intervention aimed at maintenance of blood glucose concentrations within these physiologic ranges has resulted in favorable development of many patients with delivery of unaffected offspring. Late Complications.

As more patients have survived and developed into active, functioning adults, two subsequent, unexpected complications have become apparent: (1) single or multiple hepatic adenomas, developing between ages 16 and 22, and (2) progressive glomerulosclerosis with renal failure. Because adenomas may become malignant, annual monitoring by ultrasonography is recommended. Any rapidly expanding lesion should be considered potentially malignant and should undergo surgical biopsy because serum alpha-fetoprotein measurements have been an unreliable marker for malignant transformation. There has been some indication that the adenomas could be prevented or reduced in younger children by more stringent dietary control; however, this hypothesis has not been substantiated in older individuals. The development of progressive glomerulosclerosis, proteinuria, hypertension, and renal failure has been a recent observation and usually occurs in older patients (> 18 years) who are less well managed and exhibit recurrent hypoglycemic episodes, chronic hypertriglyceridemia, and lactic acidosis. The mechanism(s) causing the renal lesion is not defined, although some improvement in proteinuria has been seen after better glucose control and use of angiotensin-converting enzyme inhibitors. Identification of several gene mutations in patients with GSD-I has led to a better understanding of the variability in clinical expression of the disease. DEBRANCHING ENZYME DEFICIENCY (TYPE III GLYCOGEN STORAGE DISEASE). GSD-III has an incidence of about 1:100,000 live births. This disease most often affects only the liver but may affect muscle as well, although a single variant in North African Jews show both liver and muscle involvement with a prevalence of 1:5,400. Elevated serum creatine kinase concentrations indicate muscle involvement, but these concentrations may not become elevated until later childhood or adolescence. Hypoglycemia with fasting is less severe (usually 40 to 50 mg/dL) than in patients with GSD-I, although hepatic enlargement may be substantially greater. Serum aspartate aminotransferase and alanine aminotransaminase concentrations are commonly above 500 units/mL. Correspondingly, hepatic fibrosis of varying degrees is usually present during childhood and may be progressive. Adult patients may present with "cryptogenic cirrhosis." Treating patients with GSD-III has not been advocated because the natural course of the disease has been thought to be benign. However, because growth retardation and cirrhosis may be serious complications, several patients have been treated with frequent feedings and raw cornstarch to maintain blood glucose levels between 75 and 100 mg/dL. Treated patients often show a significant reduction in serum transaminase levels and improvements in growth, and they may demonstrate improved muscle strength, although serum creatine kinase activities remain elevated. Identification of specific gene mutations should provide better prognostic predictions. Clinical and laboratory features of the other, less common forms of hepatic glycogenesis are presented in Table 203-1 . 1088

TYPE

TABLE 203-1 -- CLASSIFICATION OF GLYCOGEN STORAGE DISEASES ENZYME AFFECTED PRIMARY ORGAN MANIFESTATIONS INVOLVED

O

Glycogen synthetase

Liver

Hypoglycemia, hyperketonia, FFT, early death

Ia

Glucose-6-phosphatase

Liver

Enlarged liver and kidney growth failure, fasting hypoglycemia, acidosis, thrombocyte dysfunction

Ib

Microsomal membrane G-6-P translocase

Liver

As in Ia; in addition, recurrent neutropenia, bacterial infections

Ic

Microsomal membrane P-transporter

Liver

As in Ia

II

Lysosomal acid glucosidase

Skeletal and cardiac Infantile form: early-onset, progressive muscle hypotonia, cardiac failure, death muscle before 2 years Juvenile form: late-onset myopathy and variable cardiac involvement Adult form: limb-girdle muscular dystrophy-like feature

III

Amylo-1,6-glucosidase (debrancher enzyme)

Liver, skeletal muscle, heart

Fasting hypoglycemia, hepatomegaly in infancy; some have myopathic features, rarely clinical cardiac features

IV

Amylo-1,4-1,6-transglucosidase (brancher enzyme)

Liver, muscle

Hepatosplenomegaly, cirrhosis; may have late-onset myopathy

V

Muscle phosphorylase

Skeletal muscle

Exercise-induced muscular pain, cramps, and progressive weakness, sometimes with myoglobinuria; symptoms usually begin during adolescence or early adulthood

VI

Liver phosphorylase

Liver

Hepatomegaly, mild hypoglycemia, good prognosis

VII

Phosphofructokinase

Muscle, red blood cells

As in V; in addition, mild hemolytic anemia

Phosphorylase b kinase

Liver, leukocytes, (?) muscle

As in VI; X-linked inheritance

Cyclic AMP-dependent kinase

Liver, muscle

Hepatomegaly, mild hypoglycemia

Formerly VIb, VIII, or IX X

MUSCULAR FORMS OF GLYCOGEN STORAGE ACID alpha-GLUCOSIDASE DEFICIENCY (POMPE'S DISEASE, TYPE II GLYCOGEN STORAGE DISEASE). In this condition, virtually all tissues have an increased glycogen content. However, presenting clinical manifestations of the illness are cardiac enlargement, myocardial failure, and generalized muscle hypotonia without muscle wasting. The classic infantile form manifests during the first months of life, and few infants survive past the first year. The juvenile variant presents in later infancy or early childhood and progresses more slowly, with death in the second or third decade. The adult type manifests as a slowly developing adult-onset myopathy. In each case, the diagnosis is dependent on finding deficient activity of acid alpha-1,4-glucosidase in muscle specimens or cultured fibroblasts. More recently, diagnosis is possible by identification of genetic mutations. No treatment, including bone marrow transplantation and systemic enzyme infusion, has proved to be of long-term benefit to these patients. The finding of chimerization in other tissues after liver transplant in two patients with GSD-IV may offer some encouragement for future treatment for GSD-II. MYOPHOSPHORYLASE DEFICIENCY (TYPE V GSD, MCARDLE'S DISEASE). Most of these patients are asymptomatic during early childhood and escape diagnosis until the second or third decade of life. A history of muscle pain and cramps after exercise, signs of myoglobinuria, and painful cramping on an ischemic exercise test are characteristic. The diagnosis is suggested by an elevation in serum muscle creatine kinase isoenzyme activity and by failure to elevate the serum lactate level with exercise. The diagnosis is established by documenting elevated muscle glycogen in the sarcolemmal regions and reduced muscle phosphorylase activity. Glucose or fructose ingestion before exercise is said to reduce the symptoms. MUSCLE PHOSPHOFRUCTOKINASE DEFICIENCY (MUSCLE PHOSPHOGLYCERATE MUTASE DEFICIENCY, LACTATE DEHYDROGENASE [LDH-M] SUBUNIT DEFICIENCY, TYPE VII GSD). These muscle glycogenoses are rare and clinically similar to myophosphorylase deficiency. Patients with phosphofructokinase deficiency may also show a mild hemolytic anemia. Diagnosis depends on muscle enzyme analysis or identification of the genetic mutations. Treatment is aimed at avoiding strenuous exercise.

DIAGNOSIS AND PRENATAL DIAGNOSIS OF GLYCOGEN STORAGE DISEASE Diagnostic enzyme or genetic analysis of fibroblasts or hepatic or muscle tissue for most types of glycogen storage diseases can usually be performed at Duke Medical Center, Division of Genetics (Dr Y. T. Chen). Dimauro S, Tsujino S, Shanske S, et al: Biochemistry and molecular genetics of human glycogenoses: An overview. Muscle Nerve 3:S10, 1995. This extensively referenced article provides information on the molecular and biochemical aspects of the glycogen storage diseases. Ding JH, deBarsy T, Brown B, et al: Immunoblot analyses of glycogen debranching enzyme in different subtypes of glycogen storage disease type III. J Pediatr 116:95, 1990. Provides newer insights into the molecular basis of type III glycogenoses. Ghishan FK, Greene HL: Inborn errors of metabolism that lead to permanent liver injury. In Zakim D, Boyer TD (eds): Hepatology: A Textbook of Liver Disease, 3rd ed. Philadelphia, WB Saunders, 1996. An extensively referenced review that focuses on the altered metabolism, treatment, and outcome of the hepatic forms of glycogenesis. Ke-Jian L, Shelly LL, Chi-Jiunn P, et al: Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a. Science 262:580, 1993. First identification of the molecular basis of this disease. Parker PH, Ballew M, Greene HL: Nutritional management of glycogen storage disease. Annu Rev Nutr 13:83, 1993. Combines the biochemical abnormalities of the glycogenoses and associated research findings with a practical guide to dietary management of children and adults.

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Chapter 204 - FRUCTOSE INTOLERANCE Harry L. Greene

Fructose, a normal dietary constituent of fruits, vegetables, honey, and the disaccharide sucrose (table sugar), is present at a level of 50 to 100 g/day in the average Western diet. At this level of intake, it is rapidly absorbed in the proximal small intestine by the facilitative hexose transporter, designated as GLUT5. Fructose is extracted on the first pass from the portal vein. Fructose malabsorption has been described in some individuals, but no deficiency in GLUT5 has been described. The relative tolerance of dietary fructose in normal children was evaluated by feeding 31 children 2 g of fructose per kilogram of body weight. Four children developed gastrointestinal symptoms and 71% developed abnormal breath hydrogen excretion, suggesting that a significant increase in dietary fructose can result in malabsorption in some individuals. Initial metabolism of fructose primarily involves three enzymes: fructokinase, aldolase B, and triokinase (Fig. 204-1) , although hexokinase phosphorylates some of the fructose. Five enzymatic defects involving fructose metabolism have been identified: (1) fructokinase deficiency, (2) aldolase A deficiency, (3) aldolase B 1089

Figure 204-1 The major pathway for fructose metabolism in the liver, showing the five defects discussed in the text. Aldolase deficiency consists primarily of defects in aldolase B (3). Aldolase A deficiency (2) is extremely rare and is expressed primarily during embryogenesis.

deficiency, (4) fructose-1,6-diphosphatase deficiency, and (5) D-glycerate kinase deficiency. The enzymatic defects in fructose metabolism are illustrated in Figure 204-1 and are discussed below.

FRUCTOKINASE DEFICIENCY Fructokinase deficiency (essential fructosuria) is a rare (about 1:130,000 live births), asymptomatic, autosomal-recessive condition caused by deficient activity of fructokinase, the first enzyme in fructose utilization. Because no pathologic condition results from this defect, the primary concern relates to the fact that fructose is a reducing sugar. Thus, a positive reaction with urinary Clinitest tablets may result in the erroneous suggestion of diabetes unless glucose oxidase is determined with a dipstick.

ALDOLASE DEFICIENCY Three aldolases (A, B, and C) are responsible for the conversion of fructose-1,6-diphosphate into glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. Embryonic tissue produces aldolase A; adult liver, kidney, and intestine express aldolase B; and nervous tissue expresses aldolase C. Although all three aldolases are tetramers of identical 40-kd subunits, each is coded for different genes on different chromosomes: aldolase A on chromosome 16,16q22-q24, aldolase B on chromosome 9,9q13-q32, and aldolase C on chromosome 17,17 cen-q 21. ALDOLASE A DEFICIENCY. Aldolase A deficiency may be detrimental because of its pivotal role in glycolysis. This is apparently of special relevance to the developing embryo, which expresses only aldolase A. Only a few patients with this deficit have been described, and not all symptoms are expressed to the same degree. Potential symptoms include mental retardation, short stature, hemolytic anemia, and abnormal facial appearance. Because aldolase B becomes normal at birth as aldolase A declines, newborns with hereditary fructose intolerance (HFI) do not show fructosuria, explaining why neonates with HFI are unaffected in utero. ALDOLASE B DEFICIENCY (HEREDITARY FRUCTOSE INTOLERANCE). Aldolase B deficiency (prevalence about 1:23,000 live births) is a potentially life-threatening autosomal-recessive disorder than can be effectively treated by eliminating dietary fructose. This disorder is due to deficiency of fructose-1-phosphate aldolase (aldolase B). Aldolase B is normally present in large amounts in the liver, intestine, and renal cortex; thus, excessive fructose intake by patients with HFI adversely affects each of these organs. Recent expression of the C134R mutation showed partial activity of the enzyme, explaining why gluconeogenesis/glycolysis is maintained in patients with HFI. Symptoms become manifested only when patients ingest fructose or sorbitol-containing foods. Because lactose is the carbohydrate source in mammalian milk, infants do not develop symptoms until the introduction of dietary fruits or other fructose-containing foods or medication (e.g., fruits, fruit juices, medicinal syrups, sucrose-containing infant formulas, or sorbitol-sweeteners). The primary presentation is vomiting and other features of hypoglycemia within 20 to 30 minutes after fructose ingestion. These acute manifestations may not be apparent after lower chronic intakes, for example with fructose-containing infant formulas or sorbitol-containing gum. In these instances, failure to thrive, hepatomegaly, and cirrhosis may represent the dominant presenting features. Concomitant laboratory findings include an acute decrease in serum glucose and phosphate concentrations and an elevated uric acid concentration. With continued exposure to fructose, hyperbilirubinemia, lactic acidosis, hepatosplenomegaly, and liver failure develop in conjunction with renal tubular dysfunction (bicarbonaturia, aminoaciduria, phosphaturia). At this stage, fatty infiltration of liver, cellular necrosis, and mild bile duct proliferation with fibrosis occur. If exposure to fructose continues, progressive fibrosis, cirrhosis, and death from liver failure follow. The brain may also show diminished neurons. The diagnosis is suggested by the presence of urinary reducing sugar detectable by Clinitest tablets and not by urinary dipstick, which measures glucose oxidase. Because similar clinical features may be present with galactosemia or tyrosinemia, diagnosis can be confirmed by genetic screen. An intravenous fructose tolerance test (0.2 to 0.3 g/kg in adults or 3 g/m2 in children) after restriction of dietary fructose for several weeks has been used to confirm the illness, but this procedure may cause hypoglycemia and is no longer recommended. At present, 21 mutations of HFI have been reported; 15 are single base substitutions, resulting in nine amino acid replacements, four nonsense codons, and two putative splicing defects. Two large deletions, two four-base deletions, a single-base deletion, and a seven-base deletion/one-base insertion have been found. Regions of the enzyme where mutations have been observed recurrently are encoded by exons 5 and 9. The three most common mutations are found in these exons, making screening methods more feasible. In spite of recurrent bouts of hypoglycemia and substantial liver disease, restriction of dietary fructose usually results in almost complete recovery during a 3- to 5-week period, and affected adults have normal intelligence. Older children and adults are protected from large dietary intakes of fructose by an aversion to sweets, 1090

although small amounts taken chronically may result in isolated, often reversible, somatic growth retardation.

FRUCTOSE-1,6-DIPHOSPHATASE DEFICIENCY

This rare disorder was first described in 1970. Patients usually present before age 6 months with fasting-induced lactic acidosis, hypoglycemia, and hepatomegaly. The reaction to glycerol is similar to that from fructose ingestion but is less severe than that of patients with HFI. The condition is due to a defect of hepatic fructose-1,6-diphosphatase, a gluconeogenic enzyme (see Fig. 204-1) . Thus, when hepatic glycogen stores are depleted, fasting hypoglycemia develops. During fasting, urinary organic acids are similar to those of tyrosinemia type I but with an absence of succinyl acetate. In addition, starvation leads to increased excretion of glycerol. The enzyme is a tetramer for identical 36 kd subunits. The diagnosis is suspected when, after 12 to 16 hours of fasting, the blood sugar concentration falls and is not restored when glucagon is administered, and acidosis (lactate) is present. Loading tests with fructose or glycerol may be dangerous because they lead to hypoglycemia and lactic acidosis. Diagnosis is confirmed by measuring the enzyme in hepatic biopsy material. Treatment consists of avoiding fasting and restricting dietary fructose and glycerol. D-GLYCERATE

KINASE DEFICIENCY ( D-GLYCERIC ACIDURIA)

This is a rare, clinically variable disorder resulting in either no symptoms, or metabolic acidosis and failure to thrive, and profound psychomotor retardation and seizures. The variable phenotypic expression has not been fully explained on the basis of the enzymatic defect, but all patients who show a substantial increase in D-glycerate excretion after fructose ingestion should avoid dietary fructose. Cox TM: Iatrogenic deaths in hereditary fructose intolerance. Arch Dis Child 69:413, 1993. This paper illustrates the need to restrict intravenous sorbitol as well as fructose in patients with HFI. Hommes FA: Inborn errors of fructose metabolism. Am J Clin Nutr 58(Suppl):788, 1993. A recent correlation between the genotype and phenotype of five common defects in fructose metabolism. Tolan DR: Molecular basis of hereditary fructose intolerance: Mutations and polymorphisms in the human aldolase B gene. Hum Mutat 6:210, 1995. An extensively referenced review that focuses on the new advances in genetic methods for identification and screening methods of HFI.

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Chapter 205 - PRIMARY HYPEROXALURIA Richard E. Hillman

Primary hyperoxaluria refers to two different peroxisomal enzyme deficiencies that are characterized by massive synthesis and urinary excretion of oxalic acid. Until recently, primary hyperoxaluria was considered a very rare disease. However, the ready availability of oxalate assays in the past few years has led to the description of milder cases, mostly type II, which are either asymptomatic or present only with water deprivation. Oxalate is also deposited in the heart, the eye, the skin, and other organs, leading to a variety of clinical pictures. Of particular interest, oxalate has led to cardiac conduction system block. Particularly in type I disease, the clinical manifestations present early in childhood with nephrolithiasis or nephrocalcinosis and lead to renal failure within the first decade of life. Both types are inherited as autosomal recessive traits and must be distinguished from secondary hyperoxalurias due to increased absorption of oxalate by the gut. These secondary causes include inflammatory bowel disease and fat malabsorption, which may tie up calcium and convert insoluble calcium oxalate to more absorbable salts. Although most adult patients with calcium oxalate nephrolithiasis excrete normal amounts of oxalate, it is now clear that hyperoxaluria must be considered in the differential diagnosis. Primary hyperoxaluria type I (glycolic aciduria) is caused by a defect in the peroxisomal enzyme alanine:glyoxylate aminotransferase. This enzyme normally converts glycolic acid to the amino acid glycine. In its absence, glycolic acid leaves the peroxisome and is converted to oxalic acid by lactic dehydrogenase. Both glycolic and oxalic acids are excreted in large amounts, usually more than 60 mg/1.73 m2 /24 hours. In most cases, this concentration exceeds the solubility of oxalic acid. This enzyme has been cloned, and multiple defects have been demonstrated. Primary hyperoxaluria type II (glyceric aciduria) is due to one of two defects. Until recently it was believed that the defect was in the enzyme D-glyceric dehydrogenase. This enzyme leads to the accumulation of hydroxypyruvic acid, which is reduced in the cytoplasm to L-glyceric acid. It had been unclear why this defect caused hyperoxaluria. Recently, it was suggested that this enzyme may be the same as glyoxalate reductase, which leads to accumulation of glyoxalate and production of oxalate by lactate dehydrogenase. Type II is a much milder disease in most cases than type I. Asymptomatic cases or cases with only a single attack of oxaluria have been reported. Two patients in recent cases developed symptoms only after experiencing severe water deprivation (one while sailing and one while running in hot weather). Some patients with type I disease respond to large doses of pyridoxine (20 to 200 mg/day). This vitamin is the cofactor for the enzyme. It appears to act by stabilizing the remaining activity and is effective only in patients with some enzyme, in general the milder cases. Dilute urine should be maintained by high fluid intake, and some reports suggest that diuretics may help. Attempts to form more soluble salts of oxalate, particularly with magnesium orthophosphate and citrate, have met with some success. The only "cure" for this disease has been a combined renal and liver transplant. Renal transplants alone have failed, owing to the accumulation of oxalate produced in the liver. Therapeutic outcomes in type II patients are very variable. Pyridoxine has no effect. Other measures that maintain a dilute urine seem to be enough in the milder cases. Danpure CJ, Purdue PE: Primary hyperoxaluria. In Scriver CR, Beaudet AL, Sly WS, et al (eds): The Metabolic Basis of Inherited Disease, 7th ed. New York, McGraw-Hill, 1995, p 2385. A general review of the biochemistry of primary oxalosis and related secondary disorders. Danpure CJ, Purdue PE, Fryer P, et al: Enzymological and mutational analysis of a complex primary hyperoxaluria type I phenotype. Am J Hum Genet 53:417, 1993. The latest data on type I enzyme deficiencies, including variability.

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Section - Disorders of Lipid Metabolism

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Chapter 206 - THE HYPERLIPOPROTEINEMIAS Joseph L. Witztum Daniel Steinberg

Hyperlipidemia, abnormal elevation of plasma cholesterol and/or triglyceride levels, is one of the most common clinical problemsthat confront the physician in daily practice. Much attention has been focused on these disorders because there is a strong association of hyperlipidemia--especially hypercholesterolemia--with development of atherosclerosis, and of hypertriglyceridemia with pancreatitis. Hyperlipidemia may occur because of a primary genetic disorder or as a result of environmental influences secondary to other medical conditions, or any combination of these factors. Because lipids are transported in plasma as components of lipoprotein complexes, understanding lipoprotein physiology is necessary for informed diagnosis and therapeutic planning. 1091

TABLE 206-1 -- APOLIPOPROTEIN CHARACTERISTICS APOPROTEIN

LIPOPROTEINS

FUNCTION

Apo B-100

VLDL, IDL, LDL

Secretion of VLDL from liver. Structural protein of VLDL, IDL, and LDL. Ligand for the LDL receptor

Apo B-48

Chylomicrons, remnants

Secretion of chylomicrons from intestine

Apo E

Chylomicrons, VLDL, IDL, HDL

Ligand for binding of IDL and remnants to LDL receptor and LRP

Apo A-I

HDL, chylomicrons

Structural protein of HDL Activator of LCAT

Apo A-II

HDL, chylomicrons

Unknown

Apo C-II

Chylomicrons, VLDL, IDL, HDL

Activator of LPL

Apo C-III

Chylomicrons, VLDL, IDL, HDL

Inhibitor of LPL activity

PHYSIOLOGY OF LIPOPROTEIN TRANSPORT Lipoproteins are complex macromolecules that transport nonpolar lipids through the aqueous environment of plasma. The more nonpolar lipids--triglycerides and cholesteryl esters--are carried almost exclusively in the central core of the spherical lipoprotein particles. The more polar lipids (such as phospholipids and free cholesterol), together with amphipathic apolipoproteins, form a surface monolayer that serves to "solubilize" the particles and allows them to remain in stable solution in the aqueous plasma. Each lipoprotein particle contains on its surface one or more apolipoproteins that have a variety of functional and structural roles. Some apolipoproteins provide structural stability to the lipoprotein, serve as ligands for cellular lipoprotein receptors that help determine the metabolic fate of individual particles, and act as cofactors for plasma enzymes involved in plasma lipid and lipoprotein metabolism. Other apolipoproteins play several roles; for example, apolipoprotein B (apo B) is the major structural apolipoprotein of the triglyceride-rich lipoproteins secreted by the liver (very low-density lipoproteins [VLDL]), but it also serves as the ligand for binding of low-density lipoproteins (LDL) (formed from VLDL) to cellular LDL receptors. Table 206-1 lists major apoproteins, lipoproteins on which they reside, and known or postulated functions. The most widely used classification of lipoproteins is based on their different densities, which determine their behavior during preparative equilibrium ultracentrifugation. The fact that lipoprotein particles exist as relatively discrete species when separated this way led to the currently used density classification system outlined in Table 206-2 . A second classification system originally proposed many years ago assigns priority to the apoprotein content of the lipoproteins. For example, in the high-density lipoprotein (HDL) density class there are lipoprotein particles that contain mainly apo A-I and others that contain both apo A-I and apo A-II; these are designated LpA-I and LpA-I, A-II, respectively. Current research suggests that it is primarily LpA-I that confers the anti-atherogenic properties of HDL. Thus, in the future, full evaluation may include this type of analysis, but for now more research is needed to determine its clinical value. An older classification system of the lipoproteins, based on their electrophoretic patterns (lipoprotein pattern typing), while important historically for the development of our understanding of lipid transport disorders, is not used commonly today. However, for the sake of completeness, the electrophoretic mobility of each lipoprotein class is also given in Table 206-2 . SYNTHESIS AND TRANSPORT OF ENDOGENOUS LIPIDS. The endogenous lipid transport system can be divided into two major classes: the apo B-100 lipoprotein system (VLDL, IDL [intermediate-density lipoproteins], and LDL) and the apo A-I lipoprotein system (HDL). METABOLISM OF VERY LOW-DENSITY LIPOPROTEINS.

Between meals, free fatty acids are mobilized from the adipose tissue and serve as a major source for hepatic triglyceride synthesis. Lipogenesis, the synthesis of fatty acids de novo from carbohydrate or protein, also can occur in the liver. Fatty acids can either enter mitochondria (where beta-oxidation occurs) or they can undergo esterification to form triglycerides in the cytosol. Control of triglyceride synthesis is a complex process that appears to be regulated in part by changes in insulin and glucagon that occur with feeding. Glucagon enhances fatty acid oxidation, whereas insulin prevents it. In addition, insulin may induce lipogenic enzymes in the liver. Triglycerides, together with cholesterol synthesized de novo in the liver or delivered to the liver by chylomicron remnants, are packaged together with apo B and phospholipids and form a nascent VLDL (Fig. 206-1) . The details of the packaging process are still being worked out, but it is known that a microsomal triglyceride transfer protein (MTP) is essential for normal VLDL assembly and secretion from the hepatocyte. When mutations in MTP occur, the newly synthesized apo B is not lipidated within the lumen of the endoplasmic reticulum (ER), and as a result the apo B is degraded, leading to abetalipoproteinemia, even though the apo B gene is normal. This results in a serious clinical syndrome in which patients lack any apo B-containing lipoproteins in their plasma. Plasma VLDL also contain other apolipoproteins, including the C apoproteins and apo E. Apo B is found as a full-length protein termed apo B-100 (or apo B), which is made by the liver, or as a shortened form termed apo B-48, which is made in humans only by the intestine. Apo B is an obligatory component for nascent VLDL assembly and secretion from the hepatocyte; other apoproteins are added to VLDL after their entry into plasma. The size of the VLDL particle released depends on the availability of triglycerides in the liver. Very large triglyceride-rich VLDL are secreted when excess hepatic triglyceride synthesis is occurring, as in obesity, non-insulin dependent diabetes, and excess alcohol consumption. In contrast, small VLDL are secreted when availability of triglyceride, but not cholesterol, is decreased. Each VLDL particle contains one molecule of apo B, yet under ordinary circumstances the rate of apo B synthesis is not rate limiting for VLDL secretion. Although enhanced triglyceride synthesis can lead to enhanced triglyceride output, the number of VLDL particles released is not necessarily increased. Instead, larger individual VLDL particles containing more triglyceride are released. Understanding the processes regulating VLDL assembly and release by the hepatocytes is necessary to understand

the etiology of clinically important disorders, such as familial combined hyperlipidemia or hyperapobetalipoproteinemia, which are characterized by increased rates of secretion of VLDL particles from the liver. Other lipoprotein disorders (familial hypertriglyceridemia) are caused by hepatic secretion of a normal number of VLDL particles but ones that are enriched with triglycerides. The half-life of VLDL in plasma is about 1 hour or less. The primary function of lipoprotein particles is to transport lipids from one site to another. Triglyceride-rich lipoproteins serve to transport endogenously synthesized triglyceride to adipose tissue TABLE 206-2 -- CHARACTERISTICS OF MAJOR LIPOPROTEIN CLASSES LIPOPROTEIN CLASS

DENSITY (g/mL)

DIAMETER (nm)

MAJOR LIPID

ELECTROPHORETIC MOBILITY

Chylomicron and remnants

50 mutant alleles known

Many mutations responsible for disease, including amino acid substitutions, gene rearrangements, mRNA splicing defects

Gaucher's

1q21

cDNA, functional and pseudogenomic sequences, 4 mutations (N370S, L444P, 84insG, IVS2+1 ) account for 90-95% of >35 mutant alleles known mutant alleles in Ashkenazi Jewish patients

11p15.1 to p15.4

cDNA, entire genomic sequence, >30 mutant alleles known

Niemann-Pick Types A and B Type C

18

--

3 mutations account for >90% of mutant alleles in Ashkenazi Jewish patients with type A disease Specific gene and nature of the cholesterol defect unknown

cDNA = complementary DNA; mRNA = messenger RNA. of the disease, casts, red cells, and lipid inclusions with characteristic birefringent "Maltese crosses" appear in the urinary sediment. Proteinuria, isothenuria, and gradual deterioration in renal function and the development of azotemia occur in the 2nd to 4th decades. Cardiovascular findings may include hypertension, left ventricular hypertrophy, anginal chest pain, myocardial ischemia or infarction, and congestive heart failure. Mitral insufficiency is the most common valvular lesion. Abnormal electrocardiographic and echocardiographic findings are common. Cerebrovascular manifestations result primarily from multifocal small vessel involvement. Other features may include obstructive airway disease that increases with age, lymphedema of the legs without hypoproteinemia, episodic diarrhea, osteoporosis, retarded growth, and delayed puberty. Death most often results from uremia or vascular disease of the heart or brain. Before the advent of hemodialysis and renal transplantation, the mean age at death for affected men was 41 years. Atypical male variants with residual alpha-galactosidase A activity who are asymptomatic or mildly affected have been described, and more recently, several patients with late-onset isolated cardiac or cardiopulmonary disease have been reported. These patients do not have the early classic manifestations. These "cardiac variants" have cardiomegaly, usually involving the left ventricular wall and interventricular septum, and electrocardiographic abnormalities consistent with cardiomyopathy. Others have had hypertrophic cardiomyopathy and/or myocardial infarction. DIAGNOSIS. The diagnosis in classically affected males is most readily made from a history of painful acroparesthesias, hypohidrosis, the presence of characteristic skin lesions, and observation of the characteristic corneal opacities and lenticular lesions. The disorder is often misdiagnosed as rheumatic fever, erythromelalgia, or neurosis. The skin lesions must be differentiated from benign angiokeratomas of the scrotum (Fordyce's disease) or from angiokeratoma circumscriptum. Angiokeratomas identical to those of Fabry's disease have been reported in fucosidosis, aspartylglycosaminuria, late-onset GM1 gangliosidosis, galactosialidosis, alpha-N-acetylgalactosaminidase deficiency, and sialidosis. Diagnosis of the mild cardiac variants should be considered in individuals with left ventricular hypertrophy and/or cardiomyopathy. The diagnosis of classic and variant cases is confirmed biochemically by markedly decreased alpha-galactosidase A activity in plasma, isolated leukocytes, or cultured fibroblasts or lymphoblasts. Heterozygous females may have corneal opacities, isolated skin lesions, and intermediate activities of alpha-galactosidase A in plasma or cell sources. Rare female heterozygotes may have manifestations as severe as those in affected males. However, in asymptomatic at-risk females in families affected by Fabry's disease, optimal diagnosis should be by direct analysis of their family's specific mutation. Prenatal detection of affected males can be accomplished by demonstrating deficient alpha-galactosidase A activity or by detecting the family's specific gene mutation in chorionic villi obtained in the 1st trimester of pregnancy or in cultured amniocytes obtained by amniocentesis in the 2nd trimester. TREATMENT. Phenytoin and carbamazepine have been shown to decrease the frequency and severity of the chronic acroparesthesias and the periodic crises of excruciating pain. Otherwise, treatment of the disease complications is supportive and non-specific: Renal transplantation and long-term hemodialysis have become life-saving procedures. Replacement therapy using partially purified human enzyme has proved to be biochemically effective in pilot trials. The recent availability of cDNA encoding human alpha-galactosidase A has permitted the expression of sufficient quantities of recombinantly produced, active enzyme for further trials of enzyme replacement therapy, which have recently been initiated. Desnick RJ, Ioannou YA, Eng CM: Fabry disease: alpha-Galactosidase deficiency and Schindler disease: alpha- N-acetylgalactosaminidase deficiency. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York, McGraw-Hill, 1995. Definitive chapter describing the clinical, pathologic, biochemical, and molecular manifestations of Fabry's disease with more than 400 references. Eng CM, Desnick RJ: Molecular basis of Fabry disease: Mutations and polymorphisms in the human alpha-galactosidase A gene. Hum Mutat 3:103, 1994. Description of mutations in classic and variant cases.

GAUCHER'S DISEASE DEFINITION. Gaucher's disease is a lipid storage disease characterized by the deposition of glucocerebroside in cells of the macrophage-monocyte system. Three clinical subtypes are delineated by the absence or presence and progression of neurologic involvement: type 1, or the adult, non-neuronopathic form; type 2, the infantile or acute neuronopathic form; and type 3, the juvenile or Norrbotten form. All three subtypes are inherited as autosomal recessive traits. Type 1 disease is the most common lysosomal storage disease and the most prevalent genetic disorder among Ashkenazi Jewish individuals, with an incidence of about 1 in 1000 and a carrier frequency of about 1 in 16 to 18. ETIOLOGY AND PATHOGENESIS. All three subtypes of Gaucher's disease result from deficient activity of a lysosomal hydrolase (see Table 208-1) . The molecular basis of Gaucher's disease has been identified for 90 to 95% of Ashkenazi Jewish patients (see Table 208-2) . Genotype/phenotype correlations have been noted for the different subtypes and may provide the molecular basis for the remarkable clinical variation in type 1 Gaucher's disease. Presumably, the amount of residual enzymatic activity determines disease subtype and severity. For example, type 1 patients homozygous for the milder N370S mutation tend to have a later onset and milder course than do patients with one N370S allele and another mutant allele. However, the wide variability in clinical finding among patients with Gaucher's disease cannot be fully explained by the underlying acid beta-glucosidase mutations. The lesions causing the severe type 2 (infantile) disease express little if any enzymatic activity in vitro. PATHOLOGY. The pathologic hallmark is the presence of the Gaucher cell in the macrophage-monocyte system, particularly in the bone marrow. These cells, which are 20 to 100 mum in diameter, have a characteristic wrinkled-paper appearance resulting from intracytoplasmic substrate deposition. These cells stain strongly positive with periodic acid-Schiff, and their presence in bone marrow and/or other tissues suggests the diagnosis (Fig. 208-1) . The accumulated glycolipid glucosylceramide is derived primarily from the phagocytosis and degradation of senescent leukocytes and to a lesser extent from erythrocyte membranes. Glycolipid storage results in organomegaly and pulmonary infiltration. Neuronal cell 1106

Figure 208-1 Typical Gaucher cell (A) and a foam cell seen in Niemann-Pick disease (B). Both are viewed under phase microscopy with unstained smears of aspirated bone marrow. Magnification can be estimated from adjacent red cells.

loss in patients with type 2 and 3 disease is presumably caused by accumulation of the cytotoxic glycolipid glucosphingosine in the brain as a result of the severe deficiency of acid beta-glucosidase activity. Glucosylceramide accumulation in the bone marrow, liver, spleen, lungs, and kidney leads to pancytopenia, massive hepatosplenomegaly, diffuse infiltrative pulmonary disease, and nephropathy or glomerulonephritis. The progressive infiltration of Gaucher cells in the bone marrow

causes thinning of the cortex, pathologic fractures, bone pain, bony infarcts, and osteopenia. Central nervous system involvement occurs only in patients with type 2 and 3 disease. CLINICAL MANIFESTATIONS. A broad spectrum of clinical expression is seen in patients with type 1 disease, in part because of a combination of different mutant alleles. The onset of clinical manifestations occurs from early childhood to late adulthood, with most seen by adolescence. At examination, patients may have easy bruisability because of thrombocytopenia, chronic fatigue secondary to anemia, hepatomegaly with or without elevated liver function test results, splenomegaly, and bone pain or pathologic fractures. Occasional patients have pulmonary involvement. Patients whose disease is diagnosed in the first 5 years of life are frequently non-Jewish and typically have a more malignant disease course. Patients with milder disease are discovered later in life during evaluations for hematologic or skeletal problems or are found to have splenomegaly on routine examination. In symptomatic patients, splenomegaly is progressive and can become massive. Clinically apparent bone involvement, which occurs in more than 20% of patients, can be manifested as bone pain or pathologic fractures. Most patients have radiologic evidence of skeletal involvement, including an Erlenmeyer flask deformity of the distal end of the femur, which is an early skeletal change. In patients with symptomatic bone disease, lytic lesions can develop in the long bones, ribs, and pelvis, and osteosclerosis may be evident at an early age. Bone crises with severe pain and swelling can occur. Bleeding secondary to thrombocytopenia may be manifested as epistaxis and bruising and is frequently overlooked until other symptoms become apparent. Children with massive splenomegaly are short of stature because of the energy expenditure required by the enlarged organ. Type 2 disease, which is rare and pan-ethnic in distribution, is characterized by a rapid neurodegenerative course with extensive visceral involvement and death within the first 2 years of life. The disease occurs in infancy and is associated with increased tone, strabismus, and organomegaly. Failure to thrive and stridor from laryngospasm are typical. The progressive psychomotor degeneration leads to death, usually secondary to respiratory compromise. Type 3 disease is noted in infancy or childhood. In addition to the organomegaly and bone involvement, neurologic involvement is present. A high frequency of type 3 disease is noted in Sweden (1 in 50,000) and has been traced to a common founder in the 17th century. Type 3 has been further classified as type 3a and 3b based on the extent of neurologic involvement and whether progressive myotonia and dementia (type 3a) or isolated supranuclear gaze palsy (type 3b) is present. DIAGNOSIS. Gaucher's disease should be considered in the differential diagnosis of patients with unexplained organomegaly, easy bruisability, and/or bone pain. Bone marrow examination usually reveals the presence of Gaucher cells; however, all suspected diagnoses should be confirmed by demonstrating deficient acid beta-glucosidase activity in isolated leukocytes or cultured fibroblasts. For possible genotype/phenotype correlations, the specific acid beta-glucosidase mutation may be determined, particularly in Ashkenazi Jewish patients. Carrier identification can be achieved by enzymatic assay confirmed with DNA testing in most Jewish families. Testing should be offered to all family members, but it should be kept in mind that heterogeneity even among members of the same kindred can be so great that cases may be diagnosed in asymptomatic affected individuals during such testing. Prenatal diagnosis is possible by determining enzymatic activity or specific mutations in chorionic villi or cultured amniotic fluid cells. TREATMENT. In the past, management of patients with type 1 disease was primarily symptomatic and included blood transfusions for anemia, partial or total splenectomy for severe mechanical cardiopulmonary compromise or hypersplenism, analgesics for bone pain, and orthopedic procedures for joint replacement. A small number of patients have also undergone bone marrow transplantation, which if successful is curative. However, a matched donor is required, and significant morbidity and mortality are associated with the procedure. No effective treatment is known for the neurologic involvement in type 2 and 3 disease. More recently the safety and efficacy of enzyme replacement with purified placental or recombinant acid beta-glucosidase have been demonstrated in type 1 disease. Clinical trials have demonstrated that most extraskeletal symptoms are reversed by initial debulking doses of enzyme (30 to 60 IU/kg) administered by intravenous infusion every other week. The effectiveness of enzyme replacement in reversing and preventing bone manifestations is still under study; however, early data indicate that it may be efficacious. However, it has been demonstrated that enzyme replacement is effective in normalizing linear growth in affected children. Efforts are also under way to develop gene therapy for type 1 disease. Beutler E, Grabowski G: Gaucher disease. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York, McGraw-Hill, 1995. Comprehensive review of the clinical, biochemical, and molecular features of Gaucher's disease. Pastores GM, Sibille AR, Grabowski GA: Enzyme therapy in Gaucher disease type 1: Dosage efficacy and adverse events in 33 patients treated for 6 to 24 months. Blood 82:408, 1991. Description of the initial experience with enzyme replacement therapy.

NIEMANN-PICK DISEASE DEFINITION. The four major subtypes of Niemann-Pick disease are characterized by an accumulation of sphingomyelin and cholesterol in the lysosomes of cells of the macrophage-monocyte system. Type A disease is a fatal disorder of infancy, whereas type B disease is a non-neuronopathic form in which most affected individuals live into adulthood and suffer primarily from hepatic and pulmonary involvement. Types C and D are neurodegenerative disorders with onset in early or late childhood. All four subtypes are inherited as autosomal recessive traits and display variable clinical features.

1107

ETIOLOGY AND PATHOGENESIS. Types A and B Niemann-Pick disease result from deficient activity of a lysosomal hydrolase (see Table 208-1) . In types C and D, the genetic defect(s) involve the defective transport of cholesterol from the lysosome to the cytosol. The gene encoding the defect in type C disease has been localized (see Table 208-2) , but the specific gene and nature of the cholesterol transport defect remain unknown. PATHOLOGY. The pathologic hallmark in types A and B Niemann-Pick disease is the histochemically characteristic lipid-laden foam cell, often referred to as the Niemann-Pick cell. These cells, which can be readily distinguished from Gaucher cells by their histologic and histochemical characteristics, are not pathognomonic for Niemann-Pick disease because histologically similar cells are found in patients with Wolman's disease, cholesterol ester storage disease, and lipoprotein lipase deficiency and in some patients with GM1 gangliosidosis type 2. Sphingomyelin is the major lipid that accumulates in the cells and tissues of patients with types A and B Niemann-Pick disease. In most normal tissues, sphingomyelin constitutes 5 to 20% of the total cellular phospholipid content; however, in patients with types A and B, sphingomyelin levels may be elevated up to 50-fold and thus constitute about 70% of the total phospholipid fraction. Lysosomal sphingomyelin accumulation in the brain, liver, kidney, and lungs has been documented in organs from patients with types A and B Niemann-Pick disease; they contain about the same amount of sphingomyelin, with the notable exception that patients with type B Niemann-Pick disease have little or no lipid storage in their central nervous system. In general, patients with type A disease have less than 5% of normal acid sphingomyelinase activity when determined in cultured fibroblasts and/or lymphocytes, whereas cells from type B patients typically have 10 to 20% of normal activity that presumably prevents the development of neurologic symptoms. CLINICAL MANIFESTATIONS. The clinical features and course of type A Niemann-Pick disease are relatively uniform and are characterized by normal appearance at birth, although the newborn period is sometimes complicated by prolonged jaundice. Hepatosplenomegaly, moderate lymphadenopathy, and psychomotor retardation are evident by 6 months of life and are followed by rapid neurodegeneration. The loss of motor function and deterioration in intellectual capabilities are progressive. In later stages, spasticity and rigidity are evident, with affected infants experiencing complete loss of contact with their environment. In contrast to the predictable natural history of the A phenotype, the clinical features and course in patients with type B disease are variable. Most cases are diagnosed in infancy or childhood, when enlargement of the liver and/or spleen is detected during routine physical examination. At diagnosis, type B patients also have evidence of mild pulmonary involvement, usually detected as a diffuse reticular or finely nodular infiltration on chest radiography. In most patients, hepatosplenomegaly is particularly prominent in childhood, but with increasing linear growth the abdominal protuberance decreases and becomes less conspicuous. In mildly affected patients

the splenomegaly may not be noted until adulthood, and disease manifestations may be minimal. In most patients with type B disease, decreased pulmonary diffusion secondary to alveolar infiltration becomes evident in childhood and progresses with age. Severely affected individuals may experience significant pulmonary compromise by age 15 to 20. Such patients have low P O2 values and dyspnea on exertion. Life-threatening bronchopneumonia may occur and cor pulmonale has been described. Severely affected patients may also have liver involvement leading to life-threatening cirrhosis, portal hypertension, and ascites. Clinically significant pancytopenia from secondary hypersplenism may necessitate partial or total splenectomy. However, removal of the spleen can lead to significant worsening of the pulmonary involvement. Typically, patients with type B disease do not have neurologic involvement and are intellectually intact. Patients with type C disease often have prolonged neonatal jaundice, appear normal for 1 to 2 years, and then experience a slowly progressive and variable neurodegenerative course. Their hepatosplenomegaly is less severe than in patients with type A or B disease, and they may survive into adulthood. Neurologic symptoms develop in patients with type D Niemann-Pick disease later in childhood, and these patients have a slower neurodegenerative course than do patients with type C. Most patients with type D disease share a common ancestry traceable to the Acadians from Yarmouth County, Nova Scotia. It appears that these patients also have an abnormality in cholesterol metabolism and that the defect may be allelic with that causing type C disease. DIAGNOSIS. Type A disease is diagnosed in the patient's first year of life by failure to thrive, organomegaly, and severe psychomotor retardation. In type B Niemann-Pick disease, splenomegaly is usually noted early in childhood; however, in very mild cases, the enlargement may be subtle and detection may be delayed until adolescence or adulthood. The presence of the characteristic Niemann-Pick cells in the bone marrow supports the diagnosis. However, patients with types C and D disease also have extensive infiltration of these cells in the bone marrow. Thus all suspected cases should be evaluated enzymatically to confirm the clinical diagnosis by measuring the sphingomyelinase activity level in peripheral leukocytes, cultured fibroblasts, and/or lymphoblasts. Patients with types A and B disease will have markedly decreased levels of enzymatic activity (1 to 10% of normal), whereas patients with types C and D disease may have slightly decreased sphingomyelinase activity (50 to 75% of normal) and patients with Gaucher's disease and other storage disorders characterized by hepatosplenomegaly and/or neurologic involvement will have normal or near-normal levels. Types C and D disease can be biochemically documented by demonstrating the cholesterol transport defect in cultured fibroblasts. The enzymatic identification of type A carriers and of type B carriers is problematic. However, in families in which the specific molecular lesion has been identified, family members can be accurately tested for heterozygote status by DNA analysis. Heterozygote identification for types C and D disease is unavailable. Prenatal diagnosis of types A and B disease may be reliably made by measuring acid sphingomyelinase activity in cultured amniocytes or chorionic villi. In families in which the specific molecular lesions are known, prenatal diagnosis can be made by DNA analysis of fetal cells. TREATMENT. At present, no specific treatment is available for any of the Niemann-Pick disease subtypes. Orthotopic liver transplantation in an infant with type A disease and amniotic cell transplantation in several patients with type B disease have been attempted with little or no success. Bone marrow transplantation in a type B patient was successful in reducing the spleen and liver volumes, the sphingomyelin content of the liver, the number of Niemann-Pick cells in the marrow, and radiologically detected infiltration of the lungs. However, no long-term information is available because this patient died 3 months after transplantation. To date, lung transplantation has not been performed in any severely compromised patient with type B disease. Future prospects for treatment of type B disease include enzyme replacement and gene therapy. Treatment of types A, C, and D disease is presently precluded by the severe neurologic involvement. Schuchman EH, Desnick RJ: Types A and B Niemann-Pick disease. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York, McGraw-Hill, 1995. The most up-to-date description of the clinical, metabolic, and molecular nature of Niemann-Pick disease types A and B.

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Section - Inborn Errors of Amino Acid Metabolism

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Chapter 209 - THE HYPERPHENYLALANINEMIAS AND ALKAPTONURIA Charles R. Scriver

THE HYPERPHENYLALANINEMIAS DEFINITIONS. A widely accepted medical model of disease attributes manifestations (signs and symptoms) to a deviant underlying process (pathogenesis) that has its origins in both proximate and ultimate causes. According to this model, phenylketonuria (MIM 261600), * the best known form of hyperphenylalaninemia (HPA), is no longer a disease, although it continues to be a risk factor, because its principal manifestations (mental retardation, pigment dilution, mousy odor, neurotransmitter deficiency) occur only in rare cases escaping early diagnosis and treatment. This satisfactory turn of events came about because pathogenesis from hyperphenylalaninemia (the risk factor) is offset by treatment (low phenylalanine diet). Genetic forms of hyperphenylalaninemia are described here; they are all autosomal recessive disorders. About 0.01% of live births are affected. Physicians for adult-age patients must be aware of maternal hyperphenylalaninemia and its consequences for the fetus (see later). PHENYLALANINE METABOLISM. Phenylalanine is an essential amino acid. The normal concentration in plasma is less than 125 mumol/L (0.125 mM) (1 mumol = 165 mug). Metabolic utilization is largely controlled by a hydroxylation reaction (Fig. 209-1 A) and impaired hydroxylation is the chief explanation for hyperphenylalaninemia. The reaction requires the apoenzyme phenylalanine hydroxylase (a monooxygenase), molecular oxygen, and tetrahydrobiopterin cofactor; the last-named is consumed in stoichiometric amounts to form tyrosine, the reaction product. The catalytic property of phenylalanine hydroxylase requires both moment-to-moment regeneration of tetrahydrobiopterin from 4alpha-carbinolamine and dihydrobiopterin, consecutive byproducts of the hydroxylating reaction, and long-term renewal of the tetrahydrobiopterin pool by synthesis from precursors. The former is achieved by the enzymes 4alpha-carbinolamine dehydratase and dihydropteridine reductase, the latter by a synthesis pathway in which several enzymes act in sequence. Accordingly, there are several ways to impair phenylalanine hydroxylation. Failure to recognize the biologic heterogeneity of hyperphenylalaninemia may lead to erroneous counseling and the wrong treatment; all of its forms require special management of women during the reproductive years. DISORDERS OF PHENYLALANINE HYDROXYLASE INTEGRITY. The phenylalanine hydroxylase enzyme is multimeric and homopolymeric. The polypeptide is encoded by a gene (symbol, PAH) on chromosome 12, region q24.1, which is expressed only in liver in humans. PAH mutations are "severe" and cause phenylketonuria (with plasma phenylalanine values > 1 mM on a normal diet) or "mild" and cause non-phenylketonuric hyperphenylalaninemia (values < 1 mM but > 0.125 mM). Phenylketonuria is typically associated with mental retardation in the untreated patient; the other form is not. The incidence and relative frequencies of the two forms (together about 1 per 10,000 births) vary widely among population. The hydroxylation reaction accounts for about three fourths of the moment-by-moment metabolic outflow of phenylalanine; incorporation

Figure 209-1 A, Intake of phenylalanine (an essential amino acid supplied only by diet) and its disposal by hydroxylation (1) (representing three fourths of normal runout), transamination (2), decarboxylation (3), and incorporation into proteins (4) (representing a fourth of runout). B, Interrelations between phenylalanine hydroxylase (PAH), dihydropteridine reductase (DHPR), and the tetrahydrobiopterin (BH4 ) biosynthesis pathway serving aromatic amino acid hydroxylation reactions. Mutations at the relevant chromosomal loci impair the hydroxylation reactions with effects on PAH activity only (1); DHPR activity (2); GTP-cyclohydrolase 1 (GTP-CH-1) activity (3a); 6-pyruvoyltetrahydropterin synthase activity (6-PTS) (3b); and 4alpha-carbinolamine dehydratase (4). Disorders 2, 3a, 3b, and 4 can impair function of three hydroxylases: PAH, tyrosine hydroxylase (TYH), and tryptophan hydroxylase (TRH). GTP = guanosine triphosphate; DHNP = dihydroneopterin triphosphate; 6-PT = 6-pyruvoyltetrahydropterin; KR = 2 -ketotetrahydropterin reductase; SR = sepiapterin reductase; qBH2 = quinonoid dihydrobiopterin.

*MIM: (Online) Mendelian Inheritance in Man (catalogues of Mendelian traits); the URL is http://www.ncbi.nlm.nih.gov/OMIM 1109

into protein is the other important route (see Fig. 209-1 A). If there is deficient hydroxylating activity, and dietary intake is not curtailed, free phenylalanine accumulates in body fluids. Overflow into the alternative pathways generates excessive amounts of metabolites derived from phenylalanine, such as the pyruvic (causing "phenylketonuria"), lactic, and acetic acid derivatives. Overburden of phenylalanine impairs brain development in ways still not fully understood. Phenylketonuria was first described as a clinical entity in 1934 by Asbjorn Folling, who surmised that the disorder was autosomal recessive and an "inborn error of metabolism." In the following three decades, phenylketonuria was seen as a paradigm for the biochemical basis of mental disease, of disease that could be prevented by deliberately restoring normal metabolism, and of chemical individuality that could be used as the basis for a screening test and early diagnosis. Newborn screening for hyperphenylalaninemia is now one of the most widely applied "genetic" tests. The incidence of the risk factor has not changed, but the frequency of the associated disease is now trivial in screened populations. The practical issues for non-specialist physicians are interpretation of a positive screening test result, referral of the patient for reliable treatment, and monitoring for maternal hyperphenylalaninemia (all discussed later). TETRAHYDROBIOPTERIN-DEFICIENT FORMS OF HYPERPHENYLALANINEMIA. Not every case of persistent hyperphenylalaninemia is explained by a primary hydroxylase deficiency. Tetrahydrobiopterin insufficiency impairs function of three hydroxylases (for phenylalanine, tryptophan, and tyrosine) and synthesis of their products, notably 5-hydroxytryptophan (the precursor of serotonin) and L-dopa (the precursor of catecholamines) (see Fig. 209-1 B). The products function as neurotransmitters in the brain, and a deficiency of them gives rise to central nervous system disease (including retarded psychomotor development, basal ganglion dysfunction, and unstable body temperature). Regeneration of tetrahydrobiopterin is necessary to maintain catalytic function of the three hydroxylases. Deficient activity of quininoid dihydropteridine reductase (gene symbol QDPR on chromosome 4, region p15.31) or of 4alpha-carbinolamine dehydratase (gene symbol DCOH, chromosome 10q22) impairs recycling of dihydrobiopterin. Deficient activity of quanosine triphosphate cyclohydrolase I (gene symbol GCH1, chromosome 14q21-q22.2) or 6-pyruvoyl tetrahydropterin synthase (gene symbol PTS, chromosome 11q22.3-q23.3) impairs synthesis of tetrahydrobiopterin. SCREENING AND DIAGNOSIS. Screening newborns for hyperphenylalaninemia is public policy. Capillary blood collected on filter paper from heel puncture is analyzed by the bacterial inhibition (Guthrie) assay, fluorimetric analysis, or other quantitative methods. Blood phenylalanine values greater than 2 mg/dL (125 muM) on the first day of life or thereafter are considered abnormal and require further investigation; false-negative results do occur, some for biologic reasons. Urine screening for "phenylketones" is not reliable. The HPA phenotype test is still the most efficient; DNA-based tests will detect over 400 mutations in the PAH gene and dozens in the genes controlling

tetrahydrobiopterin homeostasis, but none is common to every case of HPA. Every infant with persistent hyperphenylalaninemia is investigated to rule out disorders of tetrahydrobiopterin homeostasis. Urine pterin metabolites or blood cofactor levels are measured under special conditions; there are distinctive urine profiles as well as low blood levels in the disorders of tetrahydrobiopterin homeostasis. The tests are done at established centers and require experienced interpretation. Direct measures of phenylalanine hydroxylase and 4alpha-carbinolamine hydratase require liver biopsy and are not necessary. Deficiency of dihydropteridine reductase can be confirmed in blood spots, fibroblasts, and amniocytes; of cyclohydrolase in phytohemagglutinin-stimulated leukocytes; and of synthase in erythrocytes. After excluding disorders of tetrahydrobiopterin metabolism, hyperphenylalaninemia is classified as follows. About one half of cases with primary phenylalanine hydroxylase deficiency have phenylketonuria, a generic term for severe hyperphenylalaninemia (>1 mM), low phenylalanine tolerance ( 1000 mg/day), and high risk of mental retardation in the absence of treatment. The remainder have non-phenylketonuric hyperphenylalaninemia with lower blood phenylalanine values (500 mg/day), and much lower risk for mental retardation if not treated. There is a correlation between level of hepatic hydroxylase activity and clinical form; in broad terms, activity is less than 1% of normal in phenylketonuria and more than 1% of normal in non-phenylketonuric hyperphenylalaninemia. DNA analysis, which is increasingly available, identifies mutations, and interprets phenotypes by mutation analysis, is beginning to have clinical relevance. Prenatal diagnosis by analysis of DNA (for linked markers or mutations) in chorionic villus samples or amniocytes is now feasible for (>85%) couples at risk; these tissues do not express the enzyme. Mutation databases exist for phenylketonuria (http://www.mcgill.ca/pahdb) and for disorders of tetrahydrobiopterin homeostasis (http://www.unizh.ch/ blau/bh4.htmL). TREATMENT. The mainstay of treatment for primary phenylalanine hydroxylase deficiency is dietary restriction of the amino acid. There are several semisynthetic diet products ("orphan foods") for this purpose. Phenylketonuric patients can tolerate only 250 to 500 mg of phenylalanine per day (normal intake >1000 mg) to maintain the blood phenylalanine level well below 1 mM. Intake, blood levels of phenylalanine, and growth rate are monitored at frequent intervals to avoid undertreatment or overtreatment. Treatment into adult life is now recommended to maintain normal neuropsychologic function. Well-treated patients have normal or near-normal intellectual development. The tetrahydrobiopterin-deficient forms require continuous replacement therapy of cofactor alone or in combination with neurotransmitter precursors. Whether postnatal treatment of these disorders is fully effective remains to be seen. MATERNAL HYPERPHENYLALANINEMIA. This problem is relevant to all practitioners who counsel women about pregnancy. Intrauterine hyperphenylalaninemia places the fetus at risk of microcephaly, mental retardation, and organ malformations (notably cardiac). Accordingly, all females with hyperphenylalaninemia should be identified, followed (registries are appearing for this purpose, e.g., Metabolic Information Network, email: mizesg@ix,netcom.com), counseled about risk when they attain reproductive age, and treated with diet to maintain near-normal blood phenylalanine levels before conception and throughout the pregnancy. GENETICS. Mutant alleles (at all relevant loci) are recessive. Their aggregate frequency in the population is about 0.01, meaning that 2% of the population is heterozygous. Observed explanations for the high allelic frequency of this "rare" phenotype include founder effect and genetic drift in some populations and mutability at the PAH locus.

ALKAPTONURIA DEFINITION. Alkaptonuria (MIM 203500) is an autosomal recessive disorder in which homogentisic acid oxidase activity is missing. Homogentisic acid produced during the metabolism of phenylalanine and tyrosine accumulates and is excreted in the urine. It causes pigmentation of cartilage and other connective tissue (ochronosis) and in later years a degenerative arthritis of the spine and the larger peripheral joints. The disease has historical significance, for it was chiefly on the basis of his study of families with alkaptonuria that Sir Archibald Garrod developed the concept of the "inborn error of metabolism." The alkaptonuria gene (symbol AKU), encoding homogentisic acid oxidase, has been mapped to human chromosome 3q21-q23, cloned, and characterized; and mutations have been identified--a major advance in the alkaptonuria saga. INCIDENCE AND PREVALENCE. The trait is rare (< 1 per 250,000 births), but cases are still being reported (now > 600), including one in a 3500-year-old Egyptian mummy. PATHOGENESIS. The activity of homogentisic acid oxidase in the normal adult human liver is sufficient to metabolize over 1600 g of homogentisic acid per day. Normally, no homogentisic acid can be detected in plasma or urine. In alkaptonuric individuals there is no detectable activity of this enzyme in liver, kidney, or prostrate where it is normally abundant. Plasma levels of homogentisic acid rise to about 3 mg/dL, and the urinary excretion ranges from 4 to 8 g/day. Mammalian tissue also contains an enzyme 1110

called homogentisic acid polyphenoloxidase that catalyzes the oxidation of homogentisic acid to an ochronotic pigment, but pigment can also be produced non-enzymatically in the presence of oxygen and alkali, as, for example, in urine. The homogentisic acid polymer has a high affinity for cartilage and connective tissue macromolecules. The stained tissue is fragile and eventually may break down, leading to degenerative intervertebral disk or joint disease. Homogentisic acid may also have a direct effect on collagen synthesis through inhibition of lysyl hydroxylase. PATHOLOGY. In the adult alkaptonuric patient, costal, laryngeal, and tracheal cartilages are densely pigmented, sometimes appearing coal-black. Pigmentation is also present throughout the body in fibrous tissue, fibrocartilage, tendons, ligaments, epidermis, endocardium, and intima of larger vessels in various organs including kidney, lung, and prostrate. CLINICAL MANIFESTATIONS. Homogentisic acid is present in urine from birth. Urine is colorless when passed but darkens when alkaline or after long exposure to air. Generally, the earliest physical sign is a slight pigmentation of the sclerae or the ears, beginning at age 20 to 30 years. The cartilage of the ears may be slate blue or gray and feel irregular and thickened. Sometimes dusky discolorations of underlying tendons can be seen through the skin over the hands. Pigment in perspiration stains clothing in the axillary and genital regions. The arthritis causes limitation of motion of the hips, knee joints, or shoulders; and there may be periods of acute inflammation. Limitation of motion and ankylosis in the lumbosacral region is a late finding. In addition, alkaptonuric patients appear to have a high incidence of cardiovascular disease; at least one degenerated pigmented aortic valve has been replaced with a prosthesis. Other complications include ruptured intervertebral disks, prostatitis, and renal stones. RADIOGRAPHIC CHANGES. Almost pathognomonic, the changes affect vertebral bodies of the lumbar spine, which show degeneration of the intervertebral disks, narrowing of the space, dense calcification of remaining disk material, and variable fusion of vertebral bodies, but little osteophyte formation and minimal calcification of intervertebral ligaments. The degenerative changes of ochronotic arthritis are most severe in the hip, shoulder, and knee; and there may be calcific deposits in the tendons. The sacroiliac joints and

smaller joints of the extremities usually show little or no abnormality. Ear cartilage may be calcified. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS. The diagnosis is suggested by urine discoloration and presence of non-glucose reducing substance, pigmentation of sclerae or cartilage, arthritic episodes, and typical radiographic changes of the lumbar spine. Homogentisic acid in urine can be identified by chromatographic or enzymatic assays. The ochronotic changes of skin and cartilage, in the past, have been confused with an effect of prolonged use of quinacrine (Atabrine) or of carbolic acid dressings for chronic cutaneous ulcers. The arthritis must be differentiated from rheumatoid arthritis, osteoarthritis, and gout. TREATMENT. A low protein diet for life would be prudent. Dietary restriction of phenylalanine and tyrosine of the degree necessary to reduce homogentisic aciduria is impractical and potentially deleterious. Pharmacologic doses of ascorbic acid, early and continuously, might reduce polymerization and pigmentation because ascorbic acid inhibits the polyphenol oxidase. It does not alter the primary metabolic defect. NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-l,3-cyclohexanedione), the potent inhibitor of p-hydroxyphenylpyruvic acid oxidase, would prevent excess formation of homogentisic acid by blocking the pathway prior to the mutant step. Fernandez-Canon JM, Granadino B, Beltran-Valero de Bernabe D, et al: The molecular basis of alkaptonuria. Nat Genet 14:19, 1997. A modern classic describing cloning of the HGO (AKU) gene and proof that it is the AKU locus harboring mutations causing alkaptonuria; companion papers (Genomics 43:115, 1979; Am J Hum Genet 62:776, 1998) document HGO gene structure and multiple AKU mutations. La Du BN: Alkaptonuria. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York, McGraw-Hill, 1995, p 1371. A detailed discussion of the history, clinical features, and biochemical derangements of alkaptonuria and ochronosis. Levy HL: Maternal phenylketonuria. Prog Clin Biol 281:227, 1988. A good discussion of an important problem (maternal hyperphenylalaninemia). Scriver CR, Kaufman S, Eisensmith RC, Woo SLC: The hyperphenylalaninemias. In Scriver CR, Beaudet AL, Sly WS, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York, McGraw-Hill, 1995, p 1015. A reference covering most issues concerning the hyperphenylalaninemias; also see URL websites for mutation data: http://www.mcgill.ca/pahdb; http://www.unizh.ch/ blau/bh4.htmL.

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Chapter 210 - THE HYPERPROLINEMIAS AND HYDROXYPROLINEMIA James M. Phang

There are three autosomal recessive genetic disorders in the degradative pathways for proline and hydroxyproline. Although these rare disorders are generally benign, the resulting metabolic abnormalities, at least for one of the disorders, are associated with neurologic manifestations in childhood. The alpha-nitrogen of the imino acids proline and hydroxyproline is incorporated within a pyrrolidine ring. This feature confers structural and functional properties to proteins. Because of the ring structure, the metabolism of proline, including biosynthesis from glutamate and ornithine and degradation back to glutamate, is catalyzed by a specific set of enzymes. Both synthetic and degradative pathways share Delta1 -pyrroline-5-carboxylate as an intermediate. The cycling of proline may mediate the transfer of reducing-oxidizing potential that may be important under certain conditions. Studies suggest that proline oxidation is increased during apoptosis. Pre-formed hydroxyproline is not incorporated into proteins. Instead, hydroxyproline is formed from peptide-linked proline primarily in collagen.

HYPERPROLINEMIAS. The two genetic disorders in proline metabolism are characterized by hyperprolinemia and iminoglycinuria, but they are due to different enzyme deficiencies; type II hyperprolinemia can be diagnosed directly. This disorder is due to a deficiency of Delta1 -pyrroline-5-carboxylate dehydrogenase, which catalyzes the second step in the degradative pathway for proline (Fig. 210-1) ; the deficiency in enzyme activity can be determined in extracts of circulating leukocytes or cultured fibroblasts. Hyperprolinemia in type II is more marked than in type I, but the distinguishing

Figure 210-1 Schematic of the degradative pathway for proline. Reaction 1 is catalyzed by proline oxidase (EC number unassigned); reaction 2 is catalyzed by Delta1 -pyrroline-5-carboxylic acid dehydrogenase (EC 1.5.1.12); and reaction 3 is

spontaneous. Type I hyperprolinemia is due to blockade at reaction 1 (deficiency of proline oxidase), and type II hyperprolinemia is due to blockade at reaction 2 (deficiency of Delta1 -pyrroline-5-carboxylic acid dehydrogenase).

1111

feature of type II is the accumulation of Delta 1 -pyrroline5-carboxylate in plasma and its excretion in urine. The hyperprolinemia in type I is due to a deficiency of the first enzyme in the pathway, proline oxidase. Although plasma proline is generally lower than in type II, the diagnosis of type I is one of exclusion, that is, hyperprolinemia unaccompanied by Delta1 -pyrroline-5-carboxylate in urine or plasma. Clinical manifestations have been described with the hyperprolinemias, but the association may be due to chance because, in most cases, hyperprolinemia was identified fortuitously in patients presenting with clinical abnormalities (biased ascertainment). This is true especially for type I hyperprolinemia in which renal disease and mental retardation found in some pedigrees were shown to segregate independently of hyperprolinemia. For type II hyperprolinemia, however, clinical associations untainted by biased ascertainment have been identified. Screening a large pedigree in Ireland identified 14 new cases confirmed by elevated plasma Delta1 -pyrroline-5-carboxylate levels and undetectable enzyme activity in leukocytes. Nine of these 14 new subjects had a history of recurrent childhood febrile seizures requiring hospitalization and treatment with anticonvulsants. Thus, the association of type II hyperprolinemia with a predisposition to seizures appears convincing. Adults in this pedigree were fertile and otherwise normal. Although the mechanism for this association remains unclear, the identification of a high-affinity proline transporter in rat brain suggests that proline or its metabolites may have a neuromodulatory function.

HYDROXYPROLINEMIA. Hydroxyprolinemia with hydroxyprolinuria, but without hyperprolinemia or prolinuria, has been described in members of several families. Although the degradation of hydroxyproline parallels that of proline, the pathway enzymes are distinct except the second degradation step is catalyzed by a common enzyme that dehydrogenates both Delta1 -pyrroline-5-carboxylate (see earlier) and 3-OH-Delta1 -pyrroline-5-carboxylate. The first step in the degradation, however, is catalyzed by distinct oxidases. The absence of urinary Delta1 -pyrroline-5-carboxylate or its hydroxylated congener leads to the conclusion that this autosomal recessive disorder is due to a deficiency of hydroxyproline oxidase. In this disorder there are no clinical manifestations related to abnormalities in collagen metabolism or central nervous system function and therapy is not indicated. Flynn MP, Martin MC, Moore PT, et al: Type II hyperprolinaemia in a pedigree of Irish travellers (nomads). Arch Dis Child 64:1699-1707, 1989. Documents the association of type II hyperprolinemia with seizures. Fremeau RT Jr, Caron MG, Blakely RD: Molecular cloning and expression of a high affinity L-proline transporter expressed in putative glutamatergic pathways of rat brain. Neuron 8:915-926, 1992. First report of high affinity transporters in the central nervous system. Phang JM, Yeh GC, Scriver CR: Disorders of proline and hydroxyproline metabolism. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic and Molecular Basis of Inherited Disease, 7th ed. New York, McGraw-Hill, 1995, pp 1125-1146. Review of proline metabolism. Polyak K, Xia Y, Zweier JL, et al: A model for p53-induced apoptosis. Nature 389: 300-395, 1997. Report of proline oxidase induction with apoptosis.

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Chapter 211 - DISEASES OF THE UREA CYCLE Stephen D. Cederbaum

Ammonia is a highly toxic metabolic product, which, when present at levels no more than two times the upper limits of normal (10 to 25 muM), may cause symptoms. The urea cycle is a five-step metabolic pathway in which two ammonia molecules and one bicarbonate molecule are converted to the relatively easily excreted and non-toxic urea. It is the only major pathway to remove waste nitrogen derived from ingested protein or from normal or augmented protein turnover in the body. The urea cycle occurs predominantly or possibly exclusively in the liver. In children, the vast majority of cases of hyperammonemia are the result of inborn errors of metabolism, primarily of the urea cycle. In adults, a larger proportion of cases are due to liver failure and less frequently to toxic ingestion. Nevertheless, with the wider availability of blood ammonia tests, the increased recognition of urea cycle disorders, and more successful treatment modalities, the inherited disorders of ammonia metabolism are being recognized with greater frequency in adolescents and adults with acute or intermittent organic brain syndrome. Hyperammonemia appears to be better tolerated in infants and young children, in part because the cranium is more compliant. Ammonia levels that leave minimal residual damage in infants may be deadly in adults. Ammonia itself appears to be the metabolite toxic to the central nervous system; however, there is some speculation that the accumulation of glutamine, a compound in equilibrium with ammonia, may be involved as well. The primary toxic effect appears to be the uptake of fluid into astrocytes, causing cerebral edema. Death is caused acutely by herniation of the brain through the foramen magnum with consequent cerebral ischemia, but survivors may have various degrees of brain damage. The urea cycle is shown in Figure 211-1 . The five enzymes generally associated with it are carbamoylphosphate synthetase 1 (CPS-1) and ornithine transcarbamoylase (OTC), both found in the mitochondrion, and argininosuccinate synthetase (ASAS), argininosuccinate lyase (ASAL), and arginase 1 (ARG-1) found in the cytoplasm. N-Acetylglutamate synthetase catalyzes the synthesis of N-acetylglutamate, which activates CPS-1 and modulates urea cycle function, and the ornithine transporter recycles ornithine to the mitochondrion. Deficiency of these latter enzymes has been associated with symptomatic hyperammonia, the former only in infants. The normal urea cycle can increase its ureagenic capacity greatly in response to ammonia challenge. The genes for all five enzymes have been cloned and are available for defining mutations, prenatal diagnosis, and population studies. Disorders of the urea cycle are estimated to occur in 1 in 25,000 births. It is probable that 2 to 4% of the population is heterozygous for a urea cycle defect, although only women who are carriers of ornithine transcarbamoylase deficiency are known to be prone to disease. It is unclear whether patients receiving intensive chemotherapy for leukemia, in whom hyperammonemia occurs rarely, or patients receiving valproate anticonvulsant therapy, in whom it occurs more mildly, are heterozygotes for one or another of these enzyme deficiencies. Complete deficiency of any of the first four enzymes in the cycle usually leads to severe hyperammonemia in the first 2 to 4 days of life. The patients have irritability, lethargy, and poor feeding that progress rapidly to stupor, seizures, coma, respirator dependence, and death. The plasma ammonia level often exceeds 1000 muM, and urea levels are extremely low. Episodic hyperammonemia occurs in association with periods of endogenous protein catabolism and severely affects patients, such as those with severe OTC deficiency; they almost certainly die or suffer severe neurologic impairment during one of these episodes. Patients with partial deficiency of urea cycle enzymes or those who avoid hyperammonemia in the neonatal period may present at any time later in life, from infancy to adulthood. Older patients have irritability, vomiting, and disorientation, which may progress (as in the infants) to stupor, seizures, coma, and death. These episodes are often precipitated by severe infection, excessive protein intake, parturition, or rarely menstruation, or they may have no apparent cause. Some general genetic characteristics of defects in the urea cycle are presented in Table 211-1 .

ENZYME DEFICIENCIES DEFICIENCY OF CARBAMOYL PHOSPHATE SYNTHETASE. CPS-1, the first enzyme in the urea cycle, constitutes up to 25% of the mitochondrial matrix protein in liver, and ordinarily all of the carbamyl phosphate synthesized from ammonium and bicarbonate by CPS-1 is used to produce urea. Orotic acid and pyrimidine are products of carbamoylphosphate as well, which is synthesized by a second, independently regulated cytoplasmic enzyme. Patients with both the neonatal and later-onset forms have been described. Diagnosis may be inferred from hyperammonemia, low to absent levels of citrulline in the plasma amino acid profile, and normal or elevated bicarbonate levels. During acute hyperammonemia there is 1112

Figure 211-1 Abbreviated pathway for the urea cycle. NAGS = N-acetylglutamate synthetase; CPS-1 = carbamoylphosphate synthetase 1; OTC = ornithine transcarbamoylase; ASAS = argininosuccinate synthetase; ASAL = agininosuccinate lyase; ARG-1 = arginase 1. Enzymes within the bold line function within the mitochondrial matrix.

usually a generalized hyperaminoacidemia with particular prominence of glutamine. Liver transplantation alone offers definitive treatment. Restricting dietary protein, supplementing essential amino acids and citrulline, hospitalizing for "catabolic crises," hemodialysis or peritoneal dialysis, and administering phenylacetate (or phenylbutyrate) and benzoate to divert ammonia to phenylacetylglutamine and benzoylglycine (hippurate) are used to control symptoms and treat crises (Fig. 211-2) . Patients with this and other urea cycle defects are prone to develop severe hyperammonemia with valproate anticonvulsant therapy. DEFICIENCY OF ORNITHINE TRANSCARBAMOYLASE. This mitochondrial enzyme catalyzes the reaction of carbamyl phosphate with ornithine to form citrulline, which is then transported out of the mitochondrion for further metabolism. The acute form of this X-linked enzyme deficiency usually occurs in males. Uncommonly a newborn female may be severely affected, thought to be due to non-random, X-chromosome inactivation. Female carriers of this co-dominant trait usually escape obvious symptoms, but those who have them usually present later in life or at parturition with hyperammonemic crises, some of which may be severe enough to be fatal. A number of males with partial enzyme deficiency may present later as well. Patients with this "later-onset" form of the disease may suffer from severe and otherwise inexplicable protein intolerance. The amino and organic acid profiles resemble those of CPS-1 deficiency. OTC deficiency is distinguished by extraordinarily high levels of orotic acid in the urine, formed when the excess carbamoyl phosphate accumulating in the mitochondrion leaks into the cytoplasm and is channelled into the pyrimidine biosynthetic pathway (see Fig. 211-1) . Orotic acid levels may be normal when ammonia has been controlled. Because of this typical clinical biochemical picture, liver biopsy to confirm enzymes is less frequently undertaken than in CPS-1 deficiency. An allopurinol challenge may be necessary to detect carrier females, a test with less than 100% accuracy. The treatment is identical to that described for CPS-1 deficiency. DEFICIENCY OF ARGININOSUCCINATE SYNTHETASE (CITRULLINEMIA). This cytoplasmic enzyme condenses the citrulline synthesized by OTC with aspartate to form argininosuccinate in a reaction that introduces the second ammonia nitrogen for excretion as urea. ASAS deficiency leads to hyperammonemia, greatly increased blood citrulline levels, and excretion of excessive amounts of citrulline and orotic acid in the urine. Here, too, neonatal, later-onset, or symptomless deficiency of the enzyme has been reported. Genetic heterogeneity at the ASAS locus has

been demonstrated by residual enzyme activity or by study of the gene and its messenger RNA. Treatment is similar to that for CPS-1 and OTC deficiencies except that arginine is supplemented instead of citrulline. Citrulline excretion is more complete than that of ammonia, and managing this condition is somewhat easier than managing hyperammonemia. DEFICIENCY OF ARGININOSUCCINATE LYASE (ARGININOSUCCINIC ACIDURIA). ASA is cleaved into two smaller product molecules, arginine and fumarate, in a reaction catalyzed by ASA lyase. This enzyme deficiency results in massive accumulation and excretion of ASA. Variable onset or lack of symptoms characterizes this enzyme deficiency as well. ASA is actively secreted by the renal tubules, and its synthesis can be stimulated by stoichiometric amounts of arginine as a source of ornithine to drive the urea cycle. By this means, ammonia levels are rapidly reduced and can be controlled more reliably than in any other urea cycle disorder. DEFICIENCY OF ARGINASE 1 (HYPERARGININEMIA). Arginase, the final enzyme in the urea cycle, catalyzes the hydrolysis of arginine to urea and ornithine, the latter returned to the mitochondrion to participate in another cycle of ammonia detoxification (see Fig. 211-1) . Clinical symptoms of hyperargininemia, the rarest of the urea cycle defects, are of later onset, are more gradual and relentless in progression, and are less frequently or seriously punctuated by apparent episodes of acute hyperammonemia and organic brain syndrome. Rather typically, normal patients begin to develop gait abnormalities and spasticity at age 2 to 3, and cortical and pyramidal tract dysfunction progresses slowly. More than 80% of the reported patients are still alive, some at age 30 or older. The diagnosis is often suspected when arginine levels are found to be elevated in blood or urine. Excess arginine excretion in urine along with secondary cystinuria pattern is more variable and less reliable TABLE 211-1 -- GENETIC CHARACTERISTICS OF DISORDERS OF THE UREA CYCLE ENZYME DEFECT

INHERITANCE PATTERN

HETEROZYGOTE DETECTION

HETEROZYGOTE SYMPTOMS

PRENATAL DIAGNOSIS*

Carbamoyl phosphate synthetase

AR

No

No

Yes

Ornithine transcarbamoylase

X-linked

Yes, in most instances *

Yes

Yes

Argininosuccinate synthetase

AR

No

No

Yes

Argininosuccinate lyase

AR

Yes

No

Yes

Arginase 1

AR

Yes

No

Yes

AR = Autosomal recessive. *With varying degrees of ease. Heterozygotes for all disorders can be detected, if the specific base change in the gene has been ascertained. This is not practical at this time outside the research laboratory.

1113

Figure 211-2 Mechanisms of ammonia diversion from the urea cycle with administration of sodium phenylacetate and sodium benzoate.

as a screening method. Hyperammonemia is usually seen only during acute catabolic episodes. Although most patients have been moderately to severely retarded at detection, treatment by limiting protein and diverting ammonia reverses many of the most severe manifestations of the disease, and presymptomatic treatment has allowed two patients to reach the age of 20 or older without apparent clinical manifestations.

FUTURE TREATMENT Urea cycle defects, originally considered a pediatric problem, are moving into the realm of internal medicine. Internists must cast aside the lactulose used for hyperammonemia of liver failure and gastrointestinal bleeding in favor of diversion therapy and hemodialysis. Soon liver replacement, the artificial liver, and gene therapy will be more widely used. As breakthroughs in gene technology allow us to dissect the pathobiology of the acute catabolic process, efforts to control this process rather than control its consequences will become increasingly important. Brusilow SW, Horwich AL: Urea cycle enzymes. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York, McGraw-Hill, 1995. The definitive clinical and molecular discussion of these inborn errors. Elsas III LJ, Acosta PB: Nutritional support of inherited metabolic diseases. In Shils ME, Olson JA, Shike M (eds): Modern Nutrition in Health and Disease, 9th ed. Malvern, PA, Lea & Febiger, 1998, 1003-1056. A practical guide to the nutritional aspects of treating this and other metabolic disorders. Leonard JV: Urea cycle disorders. In Fernandes J, Saudubray J-M, Van Den Bergh G (eds): Inborn Metabolic Diseases. New York, Springer-Verlag, 1995, p 167. A practical clinical chapter on urea cycle disorders reflecting a transatlantic perspective.

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Chapter 212 - BRANCHED-CHAIN AMINOACIDURIAS Louis J. Elsas II

MAPLE SYRUP URINE DISEASE (MSUD). Maple syrup urine disease, also called branched-chain alpha-ketoaciduria, derives its name from the burnt-sugar smell of affected infants. MSUD is caused by impaired branched-chain alpha-ketoacid dehydrogenase, which catalyzes decarboxylation of the alpha-ketoacid derivatives of all three of the branched-chain amino acids: leucine, isoleucine, and valine. They are essential amino acids that share branching, aliphatic chains. Isovaleric acidemia affects the next step but only for products of leucine catabolism. Leucine is transaminated to alpha-ketoisocoproate, which is decarboxylated to isovaleric acid. Isovaleric acidemia is caused by defects in isovaleryl coenzyme A (CoA) dehydrogenase. Both disorders conform to autosomal recessive patterns of inheritance. The affected homozygote for maple syrup urine disease exhibits impaired activity in the branched-chain alpha-ketoacid dehydrogenase (BCKD) multienzyme complex. This enzyme catalyzes oxidative decarboxylation and transacylation of alpha-ketoisocaproate, alpha-keto-beta-methylvalerate, and alpha-ketoisovalerate, which are derived from deamination of leucine, isoleucine, and valine, respectively. The blocked reaction is

If impaired, branched-chain alpha-ketoacids and amino acids accumulate throughout the body and produce neurotoxicity mechanisms, which include competitive inhibition by branched-chain alpha-ketoacids of mitochondrial oxidative phosphorylation in the brain. The disease is caused by mutations in one of six genes, which code for the six different proteins that make up the branched-chain alpha-ketoacid dehydrogenase multienzyme complex. A wide range of mutations is defined, along with the severity of impaired enzyme and consequent clinical manifestations (Table 212-1) . These mitochondrial proteins are encoded in the nuclear genome. Once translated in the cytosol, they are guided to the mitochondria by their intrinsic amino terminal leader sequences and chaperone proteins. They then transmigrate through outer and inner mitochondria membranes and assemble in the mitochondrial matrix. The six proteins are (1) E1alpha, and (2) E1beta, which produce the dimeric branched-chain alpha-ketoacid decarboxylase; (3) a branched-chain dihydrolipoamide acyltransferase (E2); (4) lipoamide oxidoreductase (E3); (5) E1 alpha-kinase; and (6) E1 alpha-phosphatase. TABLE 212-1 -- GENES, PROTEINS, AND MUTATIONS IN THE HUMAN BRANCHED-CHAIN alpha-KETOACID DEHYDROGENASE COMPLEX NAME (FUNCTION) E1alpha (decarboxylase) E1beta (stabilizes decarboxylase)

CHROMOSOME LOCUS

GENE SIZE (kb)

19q13.1-q13.2 6p21-p22

MATURE PROTEIN (kd)

MUTATION

55

47

Y393N (Mennonite missense mutation)

100

37

11bp deletion (frameshift with premature STOP)

E2 (acyltransferase)

1p31

68

52

E163STOP F215C (exonic and intronic insertions, deletions, and transitions)

E3 (dehydrogenase)

7q31

20

55

Affects other substrate-specific dehydrogenases (alpha-ketoglutarate and pyruvate)

E1alpha kinase (inactivates)

?

?

43

?

E1alpha phosphatase (activates)

?

?

?

?

1114

Several cofactors are involved in the overall reaction, including thiamine pyrophosphate, TP P, lipoamide covalently bound to E2, coenzyme A, and nicotinamide adenine dinucleotide. Many patients respond to pharmacologic excesses of thiamine supplement (8 mg/kg/day). The presumed mechanism is that by saturating binding sites for thiamine pyrophosphate on E1alpha, the multienzyme complex is stabilized to biologic degradation. Small increases in enzyme function can provide dramatic improvement to the patient, who will continue to require reduced intake of leucine, isoleucine, and valine. DIAGNOSIS. In typical MSUD, feeding difficulties and apnea develop in a newborn who was normal at birth. Convulsions and decorticate rigidity may develop, and before newborn screening affected infants died or were severely damaged. With newborn screening, retrieval, diagnosis, and diet intervention before age 2 weeks, these children not only survive but have reached adulthood. In surveyed populations the frequency of MSUD varies from 1 in 760 (in Mennonites) to an average U.S. figure of 1 in 200,000 newborns. Atypical cases with less severe clinical manifestations may be missed in newborn screening and appear with intermittent ataxia in later childhood or early adulthood. The diagnosis should be suspected clinically when a patient has intermittent symptoms related to protein ingestion and sweet smell to the earwax. A positive dinitrophenylhydrazine reaction is seen in affected patients' urine, and the diagnosis is confirmed by the abnormal excesses of branched-chain amino acids and keto acids in blood and urine. The enzyme defect is demonstrable in leukocytes and fibroblasts, and prenatal monitoring has been accomplished both biochemically and through DNA analysis of specific mutations when known. TREATMENT. Treatment is aimed at limiting intake of branched-chain amino acids to prevent accumulation of neurotoxic branched-chain alpha-ketoacids and at maintaining an anabolic state through non-protein caloric intake. Branched-chain amino acids are essential and must be ingested in quantities sufficient to allow new protein synthesis and normal growth but below levels that result in accumulation of toxic precursors in the blocked reaction. Commercial formulas are necessary to accomplish this goal. In infancy and early childhood, anabolism is encouraged by providing excess calories and maintaining branched-chain amino acid-restricted protein intake at the recommended daily allowance. Treatment is monitored clinically in terms of growth and development and biochemically through analysis of plasma amino acid and urine organic acid concentrations. Because leucine residues are more frequent than isoleucine and valine in natural proteins, care must be taken not to overrestrict isoleucine and valine while attempting to lower blood concentrations of leucine by restricting natural dietary protein. Thiamine supplements allow increased natural protein intake in thiamine-responsive patients. Chronic acidosis may deplete carnitine, which should also be monitored in blood and supplemented if deficient.

ISOVALERIC ACIDEMIA. Isovaleryl CoA is the product formed from BCKD action on alpha-ketoisocaproate (leucine's derivative). Isovaleryl CoA is then converted to beta-methylcrotonyl CoA by isovaleryl CoA dehydrogenase. When isovaleryl dehydrogenase is impaired, isovaleric acid accumulates in blood and urine and produces a foul odor similar to that of rancid cheese or sweaty feet. Symptoms are severe in the first week of life and consist of vomiting, acidosis, hypoglycemia, tremors, coma, and death. Leukopenia, anemia, thrombocytopenia, and hyperammonemia may occur during acute attacks. Emergency therapy consists of eliminating dietary leucine and supplementing with intravenous, oral, and colonic infusion of glycine (300 mg/kg/day) to provide an alternate excretory pathway for the non-toxic adduct, isovaleryl glycine. Carnitine (100 mg/kg/day) may provide non-toxic adducts of isovaleryl carnitine. Both adducts are excreted in the urine. Emergency therapy also requires producing anabolism by using excess calories from carbohydrates, fat, and non-leucine-containing protein. As patients mature, they have less frequent attacks and are developmentally normal. "Attacks" are caused by excess leucine ingestion, starvation, infections, or other causes of catabolism. Chronic intermittent forms of this disorder have not been differentiated from acute infantile forms at the biochemical or molecular level of enzyme or gene analysis and may result from epigenetic phenomena. DIAGNOSIS. The diagnosis is suspected as a result of the clinical presentation and associated odor and is established by demonstrating excess isovaleric acid and its adducts in the urine by gas-liquid chromatography. The gene has been cloned and sequenced and some mutations have been defined. The gene is located on chromosome 15q13 and the coding sequence has homology to short- and medium-chain acyldehydrogenase. TREATMENT. Chronic therapy includes reduced intake of leucine. Unlike in MSUD, normally valine and isoleucine are catabolized and are required as essential nutrients in normal amounts in the diet. Supplements of glycine (90 to 100 mg/kg/day) and carnitine (10 mg/kg/day) are used as part of chronic dietary management. Outcome is excellent in both infantile and later-onset forms of isovaleric acidemia diseases if the acute, irreversible effects of the neonatal disease are prevented. Danner DJ, Elsas LJ: Disorders of branched chain amino and keto acid metabolism. In Scriver CR, Beaudet A, Sly W, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York, McGraw-Hill Book Co., 1995. Sophisticated discussion of clinical, biochemical, and pathophysiologic characteristics of these diseases (268 references). Elsas LJ, Acosta PB: Nutrition support of inherited metabolic disease. In Shils ME, Olson JE, Shike M (eds): Modern Nutrition in Health and Disease, 9th ed. Malvern, PA, Lea & Febiger, 1998. A complete approach to dietary therapy of these diseases.

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Chapter 213 - HOMOCYSTINURIA Bruce A. Barshop

DEFINITIONS. Homocysteine is a non-protein amino acid and an intermediate in methionine metabolism that arises when methionine (through S-adenosylmethionine) acts as a donor in methylation reactions (Fig. 213-1) . The fate of homocysteine is either remethylation to methionine or transulfuration (through cystathionine) of serine to cysteine. Homocystinuria results from defective disposal of homocysteine because of a defect in either transulfuration or remethylation. The classic finding of the disulfide homocystine in urine gives this class of disorders its common name. The free sulfhydryl form, homocysteine, is present in lower amounts in blood; total homocyst(e)ine is the term used to described the mix of sulfhydryl and disulfide. The defining finding in blood is hyperhomocyst(e)inemia, which is distributed about 10% as free homocysteine and 90% as protein-bound and soluble disulfides (homocystine, cysteine-SS-homocysteine, etc.).

ETIOLOGY. The classic form of homocystinuria is cystathionine beta-synthase deficiency, which results in decreased transulfuration and hypermethioninemic hyperhomocyst(e)inemia. Homocystinuria may also result from defective remethylation, as in a deficiency of methylenetetrahydrofolate reductase, or from a disorder of the delivery, generation, or utilization of the methylcobalamin cofactor of methionine synthase. Defects of remethylation give rise to hyperhomocyst(e)inemia with normal or low methionine. All these disorders are inherited in an autosomal recessive manner (Table 213-1) .

INCIDENCE AND PREVALENCE. Minimum estimates of the incidence of cystathionine beta-synthase deficiency by newborn screening programs have ranged from 1:300,000 to 1:60,000 live births, varying with the population and method. Estimates of its incidence in Europe have been in the range of 1:40,000, which corresponds to a carrier (heterozygote) frequency of about 1%. The incidence of severe homocysteine remethylation defects appears to be less than 1:500,000. On the other hand, partial remethylation deficiencies seem to have a much greater incidence, which may be clinically relevant in predisposing individuals to thrombotic disorders; evidence of deficiency has been reported in 15 to 30% of some series of patients presenting with vaso-occlusive disease.

PATHOGENESIS AND MECHANISMS. Homocysteine has effects on vascular endothelium, platelets, and coagulation factors that predispose to thrombosis. Modification of connective tissue proteins may cause the skeletal and ocular manifestations associated with homocystinuria. These effects are particularly likely in relation to fibrillin, which is a component of the matrix of periosteum and perichondrium, the major component of the zonular fibers of the 1115

Figure 213-1 Pathways of homocysteine metabolism. The systems of transmethylation, remethylation, and transulfuration are marked. Steps discussed are numbered: (1) cystathionine beta-synthase; (2) methylenetetrahydrofolate reductase; (3) methionine synthase and methyltransferase reductase; (4) systems of cobalamin absorption, distribution, and reduction. THF = tetrahydrofolate; MeCbl = methylcobalamin; B12 = cyanocobalamin/hydroxocobalamin; B6 = pyridoxine.

ocular lens, and a protein singularly rich in cysteine. Fibrillin structure may be affected either by cysteine limitation or by homocysteinylation; the result is features of homocystinuria that are also associated with fibrillin mutations (Marfan syndrome). The neurologic effects of homocysteine may be due predominantly to agonism of the N-methyl- D-aspartate receptor by homocysteic acid, although cerebral vascular effects may contribute as well.

CLINICAL MANIFESTATIONS. Cystathionine beta-synthase deficiency is pleiotropic, with effects in the eye, skeleton, and central nervous and vascular systems (Table 213-2) . Eye and skeletal system changes resemble those in Marfan syndrome. Non-traumatic dislocation of the ocular lens can be an initial finding. Some abnormality of the skeletal system develops in almost all untreated patients. Between one third and three fourths of untreated patients have mild or moderate mental retardation, and cerebrovascular thrombosis may play a role in the neurologic picture. Affected patients have a lifelong danger of thromboembolic phenomena, which are the major cause of mortality in untreated disease. Arterial and venous occlusion, in small or large vessels, may occur at any time in life, including infancy. Treatment with pyridoxine, the cofactor of the enzyme, may be effective in nearly half of these patients, particularly those with relatively high residual activity and spared amounts of immunologically detectable enzyme. Blood total homocyst(e)ine concentrations may be intermediately elevated in heterozygotes, particularly after a methionine load, and heterozygotes are at some increased risk for vaso-occlusive events. Although increased vascular complications have not been formally demonstrated in outcome studies of obligate heterozygotes, a considerable number of studies show a highly disproportionate fraction of patients with various vaso-occlusive complications who manifest either total blood homocyst(e)ine concentrations or fibroblast cystathionine beta-synthase activities that fall in the range observed for heterozygotes. Methylenetetrahydrofolate reductase deficiency has been described in a limited number of patients, with a spectrum of manifestations including neurologic symptoms, thromboses, and lens dislocation, but without conspicuous skeletal changes. Partial deficiencies and thermolabile variants have been observed in otherwise normal subjects who have premature vaso-occlusive disorders. Polymorphisms are also found in the methylenetetrahydrofolate reductase gene in association with spinal closure defects, a class of disease that has been known to be influenced by folate. Cobalamin metabolic disorders generally occur in early childhood and are characterized by neurologic symptoms, megaloblastic anemia, and in some cases, methylmalonic acidemia.

DIAGNOSIS. Qualitative detection using sodium nitroprusside led to the recognition of homocystinuria early in the history of biochemical genetics, but it is neither specific nor sensitive. Assay of plasma amino acids by routine methods may not reveal homocysteine because of the high degree of protein binding. Because of lower protein concentrations, routine amino acid analysis of urine is more successful, hence the common name homocystinuria. The preferred diagnostic method is total homocyst(e)ine, which is measured in plasma treated with a reducing agent to release bound homocysteine before deproteinization. Plasma amino acids will indicate a transulfuration or remethylation defect, depending on the presence or absence of hypermethioninemia (see Table 213-2) . The clinical diagnosis of remethylation defects is facilitated by detection of urine methylmalonate and blood B12 and folate. The normal range of total homocyst(e)ine in blood extends up to around 15 mumol/L and may be more than 50% higher 2 to 4 hours after an oral methionine load. A standard methionine load (100 mg/kg) may identify individuals with partial defects, which could increase the susceptibility to vascular disease.

TREATMENT. Cystathionine beta-synthase deficiency is responsive to the cofactor pyridoxine in about 50% of cases. Doses of 100 to TABLE 213-1 -- GENETIC DEFECTS ASSOCIATED WITH HOMOCYSTINURIA

FUNCTIONAL DEFECT

COMMON NAME

ENZYME DEFECT

CHROMOSOME LOCUS

Transulfuration

"Classic" homocystinuria

Cystathionine beta-synthase

22q22.3

Remethylation

Folate-dependent homocystinuria

Methylenetetrahydrofolate reductase

1p36.3

Cbl G

Methionine synthase (methyltransferase)

5p15.2-p15.3

Cbl E

Methyltransferase reductase

1q43

TC-II

Transcobalamin II

22q11-q13.1

Cbl F

Lysosomal B12 translocase

--

Cbl C, Cbl D

Unknown

--

Cobalamin transport Cobalamin reductase

1116

TABLE 213-2 -- CLINICAL FEATURES OF HOMOCYSTINURIA CLASS

BIOCHEMICAL FEATURES Hcys

met

Cystathionine beta-synthase deficiency

-

Methylenetetrahydrofolate reductase deficiency

Transcobalamin II deficiency

MMA

-

-/

-/

+/-

CLINICAL FEATURES System

Signs

Ocular

Ectopia lentis, myopia, glaucoma, optic atrophy, retinal detachment

Skeletal

Elongated and thinned bones, arachnodactyly, genu valgum, pectus malformation, scoliosis

Vascular

Thromboembolic events (arterial or venous)

Neurologic

Mental retardation often in untreated cases Cerebrovascular thromboses, seizures Psychiatric disorders, personality disorder

Ocular

Ectopia lentis

Vascular

Thromboses

Neurologic

Variable-psychiatric to severe neurologic

Hematologic Pancytopenia, macrocytosis Pansystemic MMA, ketoacidosis, stomatitis

Cbl F

-/

?

+/-

Pansystemic MMA, macrocytosis, stomatitis

Cbl C, Cbl D

-/

-/

+

Hematologic Pancytopenia

Cbl E, Cbl G

-/

-

Neurologic

Mental retardation

Vascular

Vaso-occlusive phenomena

Neurologic

Spasticity, dystonia

Hcys = homocyst(e)inemia/homocystinuria; met = plasma methionine; MMA = methylmalonic acidemia; Cbl = cobalamin. 500 mg/day have been used successfully. Higher doses of pyridoxine should be used cautiously because of the risk of peripheral neuropathy. Responsiveness is documented by the elimination of free homocysteine in blood and urine as pyridoxine is added, but measurement of total homocyst(e)ine demonstrates that the effect is generally far less than complete. Betaine ( N,N,N-trimethylglycine) has recently become available commercially, and it is effective in reducing homocysteine through an alternative remethylation step. Betaine is generally given at 6 g/day in divided doses, but considerably higher doses have been used. It is particularly important in pyridoxine-unresponsive cases but may also be used as an adjunct in responsive patients. In the absence of vitamin responsiveness, special diets are adopted to restrict methionine and supplement cysteine. Folic acid may be effective in remethylation defects, and it is also generally used as a supplement (10 to 20 mg/day) in all forms of homocystinuria. Vitamin B12 preparations may be life saving in disorders of cobalamin metabolism, although its effectiveness in the most common forms of cobalamin C or D defects is generally far from complete. Initial doses are usually 1000 mug/day, and hydroxocobalamin may be more effective than cyanocobalamin. It is prudent to adopt measures to decrease thrombosis, such as using low-dose aspirin or dipyridamole and avoiding smoking and birth control pills. Nitrous oxide may also be relatively contraindicated inasmuch as it can inhibit methionine synthase. Surgery poses serious risks but can be performed safely as long as attention is paid to hydration and coagulation status.

PROGNOSIS. In cystathionine beta-synthase deficiency, pyridoxine responsiveness generally correlates with higher residual activity, and the prognosis is significantly better than that for unresponsive cases, with or without treatment. Skeletal, ocular, vascular, and neurologic risks are all reduced with successful treatment. Without early institution of treatment, the median IQ in a large outcome study was 57 for unresponsive and 78 for responsive patients. With early treatment, pyridoxine-unresponsive patients have nearly normal median IQ. With treatment in responsive patients, the prognosis for intellectual development is very good, but significant increases in total homocyst(e)ine generally still persist and some increased risk of vascular complications probably does remain. Kraus JP: Molecular basis of phenotype expression in homocystinuria. J Inherit Metab Dis 17:383, 1994. Discussion of the early mutational analysis in cystathionine synthase, with interesting correlations. Mudd SH, Levy HL, Skovby F: Disorders of transulfuration. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease, vol 1. New York, McGraw-Hill, 1995, pp 1279-1327. A definitive review with extensive references; although a new edition is awaited, this reference is invaluable. Nygard O, Vollset SE, Refsum H, et al: Total plasma homocysteine and cardiovascular risk profile: The Hordaland study. JAMA 274:1526, 1995. A large population study regarding homocysteine in association with cardiovascular risk factors, with references to other studies treating it as an independent risk factor. Rozen R: Genetic predisposition to hyperhomocysteinemia: Deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb Haemost 78:523, 1997. A review of methylenetetrahydrofolate reductase in homocystinuria and multifactorial disease.

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Section - Inherited Disorders of Connective Tissue

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Chapter 214 - THE MUCOPOLYSACCHARIDOSES Hans C. Andersson Emmanuel Shapira

The mucopolysaccharidoses (MPSs) are a heterogeneous group of inherited lysosomal storage disorders. The common feature of these disorders is intracellular storage and urinary excretion of glycosaminoglycans (GAGs), previously termed acidic mucopolysaccharides. GAGs result from the proteolytic cleavage of large macromolecules--the proteoglycans. They are highly glycosylated and sulfated molecules that are normally degraded in a stepwise manner in the lysosome by specific enzymes that either cleave terminal sulfate or glycosyl groups or acetylate the GAG to facilitate further degradation. MPSs result from deficient activity of one of these lysosomal enzymes. This deficiency arrests further degradation of GAGs and leads to their storage in various tissues. Such storage causes progressive disruption of cellular function and leads to physical deformation of various tissues. The group of MPS disorders demonstrates two principles of 1117

MPS TYPE

EPONYM

TABLE 214-1 -- THE MUCOPOLYSACCHARIDOSES ENZYME DEFICIENCY URINARY CLINICAL FEATURES GAG

I I-H

Hurler

alpha- L-Iduronidase

DS HS

Onset 5 yr), similar to I-H but with normal intellect, milder skeletal involvement, and slower progression

II

Hunter

Iduronate sulfatase

DS HS

Onset 2 yr, rapidly progressive neurologic/intellectual regression; late mild visceral and skeletal involvement

Morquio

IVA

N-acetyl-galactosamine-6-sulfatase KS

Onset q26.3

Congenital erythropoietic porphyria (CEP)

Autosomal recessive

Uroporphyrin-ogen decarboxylase

1p34

Porphyria cutanea tarda (PCT)

Autosomal dominant

X

Hepatoerythropoietic porphyria (HEP)

Autosomal recessive

X

ALA synthase Erythroid

X-linked recessive

X

X X

X

X

Copropor-phyrinogen oxidase

3q12

Hereditary coproporphyria (HCP)

Autosomal dominant

X

X

X

Protoporphy-rinogen oxidase

1q22 or 23

Variegate porphyria (VP)

Autosomal dominant

X

X

X

Ferrochelatase

18q21.3 or 22

Erythropoietic protoporphyria (EPP)

Autosomal dominant

X

X

*The most precise classification is according to the specific enzyme deficiencies. Other classifications based on the major tissue site of overproduction of heme pathway intermediates (hepatic versus erythropoietic) or the type of major symptoms (acute neurovisceral versus cutaneous) are useful but not precise or mutually exclusive. This enzyme is also known as hydroxymethylbilane synthase and formerly as uroporphyrinogen I synthase. Inherited deficiency of uroporphyrinogen decarboxylase is partially responsible for the familial (type II) form.

to causes unrelated to porphyria. Hyponatremia may be due to hypothalamic involvement and inappropriate antidiuretic hormone secretion; vomiting, diarrhea, and poor intake; or excess renal sodium loss. After several days, an attack may resolve quite rapidly, with abdominal pain disappearing within a few hours and paresis within a few days. Attacks during the luteal phase of the menstrual cycle usually resolve with the onset of menses. Even advanced neuropathy is potentially reversible. Pain, depression, and other symptoms are sometimes chronic. Chronic hepatic abnormalities are common in AIP, and affected patients have an increased risk of hepatocellular carcinoma (apparently not associated with hepatitis B or C). AIP may predispose to chronic hypertension and be associated with impaired renal function. The mechanisms of these associations are unknown. PRECIPITATING FACTORS.

Recognition of precipitating factors is important in management. Endogenous steroid hormones are probably most important. AIP is characterized by rarity of symptoms and excess ALA and PBG before puberty, more frequent clinical expression in women, premenstrual attacks in some women, and exacerbations after the administration of sex steroid preparations. Some patients manifest increased proportions of 5beta-hydroxysteroid metabolites, which are potent inducers of hepatic ALA synthase. Recurrent cyclic attacks are troublesome in some women and occur when progesterone levels are highest. Progesterone and its metabolites are potent inducers of ALA synthase, whereas estrogens are not. Pregnancy is usually well tolerated despite high progesterone levels. Some women are more prone to attacks

during pregnancy, possibly partly because of hyperemesis gravidarum and reduced caloric intake. Drugs remain important as causes of AIP attacks. Published information is insufficient to allow most drugs to be classified as definitely harmful or safe. The major drugs known to be harmful or safe in the acute porphyrias are listed in Table 219-3 . Barbiturates and sulfonamides are the most notorious. Benzodiazepines are much less hazardous. Some drugs may exacerbate porphyria cutanea tarda (PCT) but not acute porphyrias (see below). Advice can be sought from a center with experience in porphyria with regard to the use of drugs. Reduced caloric intake, usually instituted in an effort to lose weight, is a common cause of attacks. Attacks are also provoked by intercurrent infections, major surgery, and other conditions. Cigarette smoke contains chemicals that can induce hepatic heme synthesis and may predispose to attacks. Attacks are almost always due to two or more factors acting in an additive fashion. Probably for this reason, (1) drugs may produce attacks in adults but are rarely reported to do so in children with PBG deaminase deficiency, (2) anticonvulsants do not produce attacks in some PBG deaminase-deficient subjects, and (3) barbiturate anesthetics more frequently exacerbate porphyria if symptoms are present before anesthetic exposure. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS.

AIP and other acute

DISORDER

TABLE 219-2 -- THREE MOST COMMON HUMAN PORPHYRIAS AND MAJOR DIFFERENTIATING FEATURES INITIAL SYMPTOMS EXACERBATING FACTORS MOST IMPORTANT SCREENING TESTS

TREATMENT

Acute intermittent porphyria

Neurovisceral (acute)

Drugs (mostly P-450 inducers), progesterone, dietary restriction

Urinary porphobilinogen

Heme, glucose

Porphyria cutanea tarda

Blistering skin lesions (chronic)

Iron, alcohol, estrogens, hepatitis C virus, halogenated hydrocarbons

Plasma (or urine) porphyrins

Phlebotomy, low-dose chloroquine

Erythropoietic protoporphyria

Painful skin and swelling (mostly acute)

Plasma (or erythrocyte) porphyrins

beta-Carotene

1126

TABLE 219-3 -- DRUGS CONSIDERED UNSAFE AND SAFE IN ACUTE INTERMITTENT AND VARIEGATE PORPHYRIA AND HEREDITARY COPROPORPHYRIA UNSAFE

SAFE

Barbiturates *

Narcotic analgesics

Sulfonamide antibiotics *

Aspirin

Meprobamate * (also mebutamate * , tybutamate * )

Acetaminophen

Carisoprodol *

Phenothiazines

Glutethimide *

Penicillin and derivatives

Methyprylon

Streptomycin

Ethchlorvynol *

Glucocorticoids

Phenytoin *

Bromides

Mephenytoin

Gabapentin

Succinimides (ethosuximide, methsuximide)

Insulin

Carbamazepine *

Atropine

Clonazepam

Cimetidine

Primidone *

Ranitidine

Valproic acid *

Erythropoietin *

Pyrazolones (aminopyrine, antipyrine)

? Estrogens *

Griseofulvin

*

*

Ergots Metoclopramide * Rifampin

*

Pyrazinamide * Diclofenac and possibly other NSAIDs * Progesterone and synthetic progestins * Danazol * Alcohol NSAIDs = non-steroidal anti-inflammatory drugs. *Porphyria is listed as a contraindication, warning, precaution, or adverse effect in U.S. labeling for these drugs. For drugs listed here as unsafe, absence of such cautionary statements in U.S. labeling does not imply lower risk. Although porphyria is listed as a precaution in U.S. labeling, these drugs are regarded as safe by other sources. There is little evidence that estrogens alone are harmful in acute porphyrias. They have been implicated as harmful mostly from experience with estrogen-progestin combinations and because they can exacerbate porphyria cutanea tarda.

porphyrias are uncommon, their symptoms are non-specific, and physical findings are minimal. Therefore, a high index of suspicion is necessary for diagnosis. The diagnosis is established by demonstrating a marked increase in urinary PBG by quantitative assay (see the later discussion of laboratory methods). During an acute attack, PBG excretion is generally in the range of 50 to 200 mg/day (reference range, 0 to 4 mg/day), and ALA excretion is 20 to 100 mg/day (reference range, 0 to 7 mg/day). Such increases virtually ensure a diagnosis of AIP, variegate porphyria (VP), or hereditary coproporphyria (HCP). ALA and PBG excretion generally decreases with clinical improvement. Such decreases are particularly dramatic (but transient) after heme therapy. After an attack it is distinctly unusual for ALA and PBG to decrease to persistently normal levels, except after prolonged periods of latency. In HCP and VP, urinary ALA and PBG may be less increased and decrease to normal levels more readily than in AIP. Fecal porphyrins are usually normal or minimally increased, which distinguishes AIP from HCP and VP. Urinary uroporphyrin and coproporphyrin and erythrocyte protoporphyrin may be increased, but these findings are not specific. Decreased PBG deaminase (most conveniently measured in erythrocytes) confirms a diagnosis of AIP. However, as already noted, some mutations of the PBG deaminase gene only reduce the non-erythroid enzyme. Furthermore, erythrocyte PBG deaminase has a wide normal range (up to three-fold) that somewhat overlaps the AIP range and is increased by inapparent concurrent conditions that stimulate erythropoiesis. The enzyme is not reduced in HCP and VP, which are also important to consider when acute porphyria is suspected. For these reasons, measurement of erythrocyte PBG deaminase is not useful in acutely ill patients. On the other hand, its measurement is highly useful for analysis of pedigrees of known AIP patients, if it is established that the propositus has a low value. In screening family members, urinary PBG should also be measured. Diagnosis of AIP in utero is possible but seldom indicated in view of the favorable outlook for most PBG deaminase-deficient

subjects. No single laboratory test fully excludes AIP, HCP, and VP. However, a normal result of a quantitative test for urinary PBG virtually excludes AIP and is strong evidence against HCP and VP as a cause of the current symptoms. Attempting to provoke increases in ALA and PBG for diagnostic purposes by glycine loading or administration of phenobarbital may be dangerous and is not definitive. TREATMENT.

Acute attacks usually require hospitalization for the treatment of severe pain, nausea, and vomiting and for the administration of intravenous glucose and heme. Hospitalization also facilitates observation for neurologic complications, electrolyte imbalances, and nutritional status, as well as investigation of precipitating factors. Symptomatic therapy includes narcotic analgesics, which are usually required for abdominal pain, and small to moderate doses of a phenothiazine for nausea, vomiting, anxiety, and restlessness. Chloral hydrate can be used for insomnia. Diazepam in low doses is probably safe if a minor tranquilizer is required. Bladder distention may require catheterization. After recovery, continued treatment with a phenothiazine is seldom indicated. Heme therapy and carbohydrate loading are specific therapies because they repress hepatic ALA synthase and overproduction of ALA and PBG. Heme therapy is most effective in this regard and should be initiated early, but only after the diagnosis of a porphyric attack is confirmed by a marked increase in urinary PBG. Diagnosis is more difficult after heme therapy, which can at least transiently normalize ALA and PBG. The standard regimen for heme therapy is 3-4 mg heme per kilogram body weight infused intravenously once daily for 4 days. A longer course of treatment is seldom necessary if treatment is started early. Efficacy is reduced and recovery less rapid when treatment is delayed and neuronal damage is more advanced. It is not effective for chronic symptoms of AIP. A lyophilized hematin (hydroxyheme) preparation is available in the United States. The manufacturer recommends reconstitution with sterile water. However, the product is unstable and degradation products adhere to endothelial cells, platelets, and coagulation factors and cause a transient anticoagulant effect and phlebitis at the site of infusion. Reconstitution with human albumin enhances the stability of hematin and prevents these side effects. Heme arginate, which is available in Europe and South Africa, is much more stable than hematin and also does not have these side effects. It is an investigational drug in the United States. Carbohydrate loading may suffice for mild attacks and can be given orally as sucrose, glucose polymers, or carbohydrate-rich foods. If oral intake is poorly tolerated or is contraindicated by distention and ileus, intravenous administration of glucose (at least 300 g daily) is usually indicated. A central venous line facilitates more complete parenteral nutrition support and avoids excess fluid volumes. Parenteral nutrition support may be indicated in some patients who require heme therapy. Treatment of seizures is problematic because almost all antiseizure drugs can exacerbate AIP. Bromides, gabapentin, and probably vigabatrin can be given safely. beta-Adrenergic blocking agents may control tachycardia and hypertension in acute attacks of porphyria, but they may be hazardous in patients with hypovolemia, in whom increased catecholamine secretion may be an important compensatory mechanism. Numerous other therapies have been tried in this disease but have not been consistently useful. PROGNOSIS.

In the past 20 years, attacks of porphyria have rarely been fatal. If acute attacks are treated appropriately, inciting factors are removed, and precautions are taken to prevent further attacks, the outlook for patients with AIP is usually excellent. Recurrent attacks of porphyria occur in some patients and can be disabling, but they do not occur throughout adult life. Occasionally, chronic pain and other symptoms develop, but they may improve in the long term. Chronic symptoms and depression increase the risk of suicide and thus require careful management. Symptoms never develop in the great majority of relatives with PBG deaminase deficiency, especially if they have normal urinary porphyrin precursors. Although such individuals are less sensitive to inducing drugs, etc., than are patients with prior porphyric symptoms, they should follow the same precautions as patients with AIP. Latent AIP should never be construed as a health risk that limits the availability of health insurance. PREVENTION.

Some specific measures are helpful in preventing clinical expression of AIP. (1) Family members should be screened 1127

to detect latent cases. (2) Harmful drugs should be avoided. (3) "Crash diets" for weight reduction and even brief periods of starvation (e.g., during postoperative periods or intercurrent illnesses) should be avoided. Diet regimens for obesity should provide for gradual weight loss during periods of clinical remission of porphyria. (4) Gonadotropin-releasing hormone analogues (for women with frequent cyclic attacks) or periodic heme infusions can prevent attacks. Oophorectomy is not an acceptable option for preventing cyclic attacks. Because suicide is a risk in AIP, a preventive approach is appropriate, especially in patients with chronic symptoms and depression. CONGENITAL ERYTHROPOIETIC PORPHYRIA. Congenital erythropoietic porphyria (CEP) is an autosomal recessive disorder that is due to a deficiency of uroporphyrinogen III cosynthase. Fewer than 200 cases have been reported. CEP occurs in several animal species (including all fox squirrels). ETIOLOGY AND PATHOGENESIS.

Many different mutations of the uroporphyrinogen III cosynthase gene have been identified in CEP. Most patients have unrelated parents and have inherited a different mutation from each parent. The severity of the disease is variable and relates to the degree of enzyme deficiency caused by the particular mutations. There is considerable accumulation of hydroxymethylbilane (the substrate of the deficient enzyme), which is converted non-enzymatically to uroporphyrinogen I. Uroporphyrin I and other porphyrins accumulate in bone marrow erythroid cells that are actively synthesizing hemoglobin and lead to intramedullary and intravascular hemolysis. Even in the most severe cases some residual cosynthase activity is noted, and heme production is actually increased in response to hemolysis. Excretion of type III porphyrin isomers is also increased. Splenomegaly can contribute to anemia and cause leukopenia and thrombocytopenia. Sunlight, other sources of ultraviolet light, and minor trauma to friable skin are other determinants of clinical expression. Drugs, steroids, and nutrition have little influence. CLINICAL MANIFESTATIONS.

Clinical expression is variable. In most cases, reddish urine and severe cutaneous photosensitivity are noted in early infancy. In a few very severe cases, CEP has been manifested as non-immune hydrops and intrauterine transfusions were administered. If CEP was not recognized, marked photosensitivity developed when phototherapy was initiated for neonatal jaundice. In some milder cases, symptoms begin in adult life. Cutaneous features resemble those in PCT but are usually more severe. Lesions on sun-exposed skin include bullae and vesicles, which are prone to rupture and become infected, hypopigmented or hyperpigmented areas, and hypertrichosis. Loss of digits and facial features and corneal scarring can be severe. Porphyrins are deposited in the teeth (producing a reddish brown color termed "erythrodontia") and in bone. Bone demineralization can be substantial. No neurologic manifestations are known, but hemolysis and splenomegaly are almost always present. Life expectancy is often shortened by infections or hematologic complications. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS.

In CEP, porphyrin excretion and porphyrin levels in red cells and plasma are generally much greater than in other forms of porphyria. Porphyrins in urine are primarily uroporphyrin and coproporphyrin, and in feces porphyrins mostly consist of coproporphyrin. ALA and PBG are normal. In most cases, uroporphyrin I predominates in erythrocytes. A predominance of protoporphyrin in red cells has been described in some cases and is characteristic of bovine CEP. CEP is readily distinguished from EPP clinically but may resemble HEP and homozygous cases of AIP, VP, and HCP. TREATMENT.

Protection of the skin from sunlight and minor trauma and prompt treatment of secondary bacterial infections help prevent scarring and mutilation. Improvement may occur after splenectomy. Oral charcoal may be helpful by increasing fecal excretion of porphyrins. Blood transfusions sufficient to suppress erythropoiesis and bone

marrow transplantation may be the most effective current therapies but entail significant risks. Gene therapy may eventually be possible. PREVENTION.

In affected families, heterozygotes with intermediate deficiencies of the cosynthase can be detected, and CEP can be diagnosed in utero. Therefore, options are available for preventing genetic transmission. PORPHYRIA CUTANEA TARDA. PCT is the most common and readily treated form of porphyria and is caused by a deficiency of uroporphyrinogen decarboxylase in the liver. It is most common in men but has become more frequent in women in association with alcohol and estrogen use. ETIOLOGY AND PATHOGENESIS.

Both acquired and inherited factors can play causative roles in PCT. Individual cases can be classified as "sporadic" (type I) or "familial" (type II). The majority of cases are type I, in which uroporphyrinogen decarboxylase mutations are not found and the enzyme is deficient in the liver but not in erythrocytes and other tissues. The amount of hepatic uroporphyrinogen decarboxylase protein, as measured immunochemically, is normal, thus suggesting that an acquired process has inactivated the enzyme. With treatment and remission of the disease, enzyme activity gradually increases to normal. Familial (type II) PCT is distinguished from type I by an inherited, approximately 50% deficiency of the decarboxylase in all tissues, including erythrocytes. This deficiency is an autosomal dominant trait and can result from a number of different mutations of the uroporphyrinogen decarboxylase gene. Apparently, type II PCT is not manifested clinically until the product of the normal allele is inactivated in the liver, as in type I PCT. A type III PCT has been described in which the enzyme is deficient in the liver but not in other tissues and more than one family member is affected. Types I to III are clinically similar and often difficult to distinguish, and they respond to the same therapies. Examples of toxic porphyria have resembled PCT. Most notably, an extensive outbreak of porphyria occurred in eastern Turkey in 1955-1958 after seed wheat containing the fungicide hexachlorobenzene was used for food. Dichlorophenols, trichlorophenols, and 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD, dioxin) have been implicated in smaller outbreaks and single cases in humans. When administered to animals, these chemicals decrease uroporphyrinogen decarboxylase (only in the liver) and induce a pattern of excess porphyrins resembling PCT. A history of exposure to such chemicals is seldom found in sporadic (type I) PCT. A notable feature of PCT is massive accumulation of porphyrins in the liver, which may develop over many months. This accumulation precedes the appearance of excess porphyrins in plasma and urine. Hepatic ALA synthase may be little increased because the amount of excess porphyrins produced in PCT is small relative to the rate of hepatic heme formation. By contrast, during attacks of the acute porphyrias, much larger amounts of intermediates are excreted (as porphyrin precursors) and ALA synthase is substantially induced. Worsening of PCT by factors (other than alcohol) that induce heme synthesis is seldom reported. The pattern of porphyrins that accumulate in PCT is complex and characteristic. The enzyme-catalyzed decarboxylation of uroporphyrinogen occurs in four sequential steps. Therefore, when the enzyme is markedly deficient, uroporphyrin and the heptacarboxyl, hexacarboxyl, and pentacarboxyl porphyrins (type I and III isomers and porphyrins derived from the corresponding porphyrinogens) accumulate. In addition, pentacarboxyl porphyrinogen can be metabolized by coproporphyrinogen oxidase to a series of tetracarboxyl porphyrins termed isocoproporphyrins. These substances are excreted primarily in bile and feces and are diagnostic of uroporphyrinogen decarboxylase deficiency. Multiple factors may contribute to the inactivation of hepatic uroporphyrinogen decarboxylase. (1) A normal or increased amount of hepatic iron seems essential in this disease. Patients with PCT are homozygous or heterozygous for the HFE gene mutation, which is associated with genetic hemochromatosis more commonly than expected by chance. Ferrous iron may directly inhibit uroporphyrinogen decarboxylase. Iron may catalyze the formation of free radicals that damage the enzyme protein or oxidize its porphyrinogen substrates to porphyrins. (2) Cytochrome P-450 enzymes may also be involved in the oxidation of porphyrinogen substrates. (3) Alcohol intake may promote iron absorption, stimulate hepatic heme and porphyrin synthesis, or generate free radicals that damage the decarboxylase. (4) Levels of antioxidant vitamins (C and E) may be decreased. (5) Estrogens but apparently not other steroids can exacerbate PCT, perhaps by an unknown oxidative mechanism. (6) The strong association with chronic hepatitis C virus infection suggests that the hepatocellular damage induced by this virus, which appears to be accentuated by iron, can involve specific cellular proteins, including uroporphyrinogen decarboxylase. Drugs may 1128

worsen PCT; those so indicated in U.S. labeling are several non-steroidal anti-inflammatory drugs, sulfonylureas, and busulfan. CLINICAL MANIFESTATIONS.

Most patients with PCT have a history of moderate or heavy alcohol intake. The disease may develop in men treated with estrogens for prostate cancer and in women taking oral contraceptives or replacement estrogens. Cutaneous photosensitivity is the major clinical feature. Vesicles and bullae develop on the face, dorsum of the hands and feet, forearms, and legs. Sun-exposed skin becomes friable, and minor trauma may precede the formation of bullae or cause denudation of the skin. Small white plaques ("milia") may precede or follow vesicle formation. Involved skin tends to heal slowly. Hypertrichosis and hyperpigmentation sometimes occur even in the absence of vesicles. Thickening, scarring, and calcification of affected skin ("pseudoscleroderma") may be striking. Neurologic effects are not observed. Liver histopathology is not usually diagnostic of alcoholic liver disease. Cirrhosis and hepatocellular carcinomas are most common in older patients and at autopsy. In some locations as many as 80% of patients with PCT are chronically infected with hepatitis C virus. This strong association may explain much of the chronic liver damage and many of the hepatocellular carcinomas that have been observed in patients with PCT. However, liver damage occurs in PCT in the absence of hepatitis C. Liver iron may be increased and HFE mutations present. The disease is also associated with systemic lupus erythematosus and acquired immune deficiency syndrome. PCT sometimes occurs in patients with advanced renal disease. Skin lesions may be more severe and plasma porphyrin levels much higher in this setting because urinary excretion of porphyrins is not possible and they are poorly dialyzed. Very rarely, hepatic tumors themselves contain and presumably produce excess porphyrins. Some of these cases have resembled PCT. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS.

Skin lesions in PCT, VP, and HCP are indistinguishable clinically and histologically. It is important to differentiate these conditions by laboratory testing before starting therapy. A predominance of uroporphyrin and heptacarboxyl porphyrin in urine and increased isocoproporphyrin in feces is diagnostic of PCT. In PCT, urinary ALA may be slightly increased, whereas PBG is normal. Total fecal porphyrins are usually less increased in PCT than in other types of porphyria with photosensitivity. Plasma porphyrins are virtually always increased in patients with skin lesions from any type of porphyria; the fluorescence spectrum of plasma can distinguish VP and EPP from PCT (see below). TREATMENT.

A course of phlebotomies is the preferred treatment and almost always produces a remission. Patients are also advised to discontinue the use of alcohol, estrogens, iron supplements, or other contributing factors. Because iron stores in PCT are seldom markedly increased and may be normal, removal of only 5 to 6 U of blood at 1to 2-week intervals is usually sufficient. Many more phlebotomies may be needed in patients who also have hemochromatosis. Plasma (or serum) ferritin and porphyrin levels should be monitored (Fig. 219-2) . Deferoxamine, an iron chelator, may be effective but is much less efficient. A course of low-dose chloroquine, 125 mg twice weekly, or hydroxychloroquine, 100 mg twice weekly for several months, is usually effective when repeated phlebotomies are contraindicated. The mechanism of their effects in PCT has not been established. One hypothesis is that chloroquine forms complexes with porphyrins and promotes their removal from the liver. If usual doses of these drugs are given to patients with PCT, marked increases in photosensitivity and porphyrin levels in plasma and urine are seen and may be accompanied by nausea, malaise, fever, and hepatocellular damage. Although these adverse effects are generally transient and are followed by complete remission, it is prudent to avoid them by using a low-dose regimen. Therapy is more difficult when PCT occurs with advanced renal disease because phlebotomy is usually contraindicated by anemia (usually because of erythropoietin deficiency). Recent studies indicate that genetic recombinant erythropoietin can mobilize excess iron, support phlebotomy, and lead to remission of PCT in these

patients.

Figure 219-2 Treatment of porphyria cutanea tarda by repeated phlebotomy. The patient was a 37-year-old woman with a history of excess alcohol intake and chronic hepatitis C. Each arrow indicates removal of 450 mL of whole blood. Phlebotomies are stopped when serum ferritin is near the lower limit of normal. Further iron depletion is of no additional benefit and may cause anemia and associated symptoms. Plasma porphyrins become normal and the appearance of new skin lesions ceases within several months. After remission, ferritin can return to normal without recurrence, in most cases. In some cases, relapses occur and respond to another course of phlebotomies. Modified from Anderson KE: The porphyrias. In Zakim D, Boyer T (eds): Hepatology. Philadelphia, WB Saunders, 1996, pp 417-463.)

HEPATOERYTHROPOIETIC PORPHYRIA. This rare autosomal recessive disease is clinically similar to CEP but is distinguished by excess isocoproporphyrin in feces and urine and decreased uroporphyrinogen decarboxylase activity in erythrocytes (and other tissues). Mild cases may resemble PCT. Mutations in the uroporphyrinogen decarboxylase gene are found in this disease and are associated with some residual enzyme activity. Increased erythrocyte protoporphyrin probably reflects an earlier accumulation of uroporphyrinogen in erythroblasts, which after completion of hemoglobin synthesis is metabolized to protoporphyrin. A similar explanation can account for increased erythrocyte protoporphyrin in other homozygous forms of porphyria. HEREDITARY COPROPORPHYRIA AND VARIEGATE PORPHYRIA. These autosomal dominant acute hepatic porphyrias are clinically similar to AIP but are much less common in most countries. Unlike AIP, these disorders can cause cutaneous photosensitivity. VP is quite prevalent in South Africa, where most cases have been traced to a couple who immigrated from Holland in the late 1600s. ETIOLOGY AND PATHOGENESIS.

HCP and VP are due to approximately 50% deficiencies of coproporphyrinogen oxidase and protoporphyrinogen oxidase, respectively. Many different mutations in the genes for these enzymes have been described. A specific mutation of the protoporphyrinogen oxidase gene is common in South Africa. ALA and PBG are increased during acute attacks, although the degree and duration of increases are less than in AIP. Increases in ALA and PBG occur when hepatic ALA synthase is induced by factors such as endogenous steroids, drugs, and nutritional alterations and because PBG deaminase activity is almost as low as ALA synthase activity even in normal liver. Coproporphyrinogen III may accumulate in VP because of a functional association between coproporphyrinogen oxidase and the deficient protoporphyrinogen oxidase in mitochondria. Furthermore, coproporphyrinogen is more readily lost from the liver than are other porphyrinogens, and its loss increases further when heme synthesis is stimulated. The excess porphyrinogens are auto-oxidized to the corresponding porphyrins. In one form of HCP termed harderoporphyria, a structurally altered coproporphyrinogen oxidase with reduced substrate affinity results in the accumulation of harderoporphyrin (tricarboxyl porphyrinogen) as well as coproporphyrin. A few homozygous cases of HCP and VP have been described. CLINICAL MANIFESTATIONS.

Drugs, steroids, and nutritional factors that are detrimental in AIP provoke exacerbations of HCP and VP. Neurologic manifestations are identical to those in AIP. Skin 1129

manifestations are similar to those of PCT and may occur apart from the neurovisceral symptoms. Impaired biliary excretion by concurrent liver diseases or drugs such as contraceptive steroids can cause porphyrin retention and worsen photosensitivity. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS.

Urinary ALA and PBG are commonly increased during acute attacks. With resolution of symptoms, ALA and PBG normalize more readily than in AIP. Increases in urinary porphyrins are more persistent. A marked, isolated increase in fecal coproporphyrin (especially isomer III) is distinctive for HCP. Fecal coproporphyrin and protoporphyrin are about equally increased in VP. The fluorescence spectrum of plasma porphyrins (at neutral pH) is characteristic and very useful for rapidly distinguishing VP from the other porphyrias. This test is probably the most sensitive porphyrin measurement for detecting VP, including latent cases, at least in adults. TREATMENT AND PROGNOSIS.

Acute attacks of VP are treated as in AIP. Phlebotomies and chloroquine are not effective. The striking decreases in attacks and deaths from VP in South Africa have been attributed to identification of latent cases, avoidance of harmful drugs, and better treatment during acute attacks. Measures that protect the skin from sunlight are helpful for photosensitivity. Cholestyramine may decrease the photosensitivity occurring with liver dysfunction. ERYTHROPOIETIC PROTOPORPHYRIA. EPP was not clearly described until 1961, perhaps because it seldom causes blistering of the skin and urine porphyrins are not increased. Now recognized as the third most common porphyria, EPP is due to a deficiency of ferrochelatase, with increased protoporphyrin in erythrocytes, plasma, bile, and feces. ETIOLOGY AND PATHOGENESIS.

Many different mutations in the ferrochelatase gene have been identified in various EPP families. Most of these mutant alleles express little or no ferrochelatase. The pattern of inheritance often appears to be autosomal dominant, but some obligate carriers have little or no increase in red cell protoporphyrin. Co-inheritance of a common ferrochelatase allele that expresses low levels of enzyme may explain an incompletely dominant trait, at least in some families. Ferrochelatase is deficient in all tissues in clinically expressed EPP but becomes rate limiting for protoporphyrin metabolism primarily in bone marrow reticulocytes, which are the primary source of the excess protoporphyrin. Circulating erythrocytes and the liver contribute smaller amounts. Protoporphyrin is increased in plasma and is excreted in bile and feces. Protoporphyrin in erythrocytes in patients with EPP is not complexed with zinc and, when compared with zinc protoporphyrin (found in lead poisoning, iron deficiency, and homozygous forms of porphyria), diffuses more readily into plasma. Zinc protoporphyrin dissociates less readily from hemoglobin binding sites and persists in the red cell as long as it circulates. Disposition of the excess protoporphyrin in EPP depends on hepatic uptake, biliary excretion, and the degree of enterohepatic circulation. These processes are impaired by liver damage. CLINICAL MANIFESTATIONS.

Cutaneous manifestations usually begin in childhood and are distinctly different from those of other porphyrias. Burning, itching, erythema, and swelling can occur within minutes of sun exposure. Diffuse edema of sun-exposed areas may resemble angioneurotic edema. Other characteristic skin changes include lichenification, leathery pseudovesicles, labial grooving, and nail changes. Scarring is rarely severe or deforming. Vesicles, pigment changes, friability, and hirsutism are unusual. No fluorescence of the teeth and (except with severe hepatic failure) no neuropathic manifestations are present. Drugs that exacerbate hepatic porphyrias are not known to worsen EPP, although they are generally avoided as a precaution. Hemolysis is uncommon or very mild in uncomplicated cases. Erythropoiesis and iron metabolism are generally normal. Mild anemia with hypochromia and microcytosis is noted in some cases and is unexplained. Gallstones containing protoporphyrin may develop in patients with EPP. Liver function is usually normal in EPP. In a minority of patients with EPP, liver disease with protoporphyrin deposition can develop and progress rapidly to death from liver failure. Liver complications may be more likely to develop in individuals who have inherited certain ferrochelatase mutations. Excess protoporphyrin itself may have cholestatic effects and damage hepatocytes. Intercurrent factors such as viral hepatitis, alcohol, iron deficiency, fasting, and oral contraceptive steroids have played a role in some patients. Marked photosensitivity with blistering and motor neuropathy have occurred in some patients with EPP and liver failure. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS.

Protoporphyrin is increased in bone marrow, erythrocytes, plasma, bile, and the feces of patients with EPP. Urinary porphyrins and porphyrin precursors are normal. Hepatic complications of EPP are often preceded by increasing levels of erythrocyte and plasma protoporphyrin, abnormal liver function tests, marked deposition of

protoporphyrin in liver cells and bile canaliculi, and increased photosensitivity. TREATMENT AND PROGNOSIS.

beta-Carotene (Lumitene, Tishcon) was developed primarily for treating EPP. Its clinical benefits have been substantiated in large series of patients. No side effects other than a mild and dose-related skin discoloration because of carotenemia have been noted. Its mechanism of action may involve quenching of singlet oxygen or free radicals. Cholestyramine may reduce protoporphyrin levels by interrupting its enterohepatic circulation. Iron deficiency, caloric restriction, and drugs or hormone preparations that impair hepatic excretory function should be avoided. Hepatic complications may resolve spontaneously if a reversible cause of liver dysfunction such as viral hepatitis or alcohol is contributing. Transfusions or heme therapy may suppress erythroid and hepatic protoporphyrin production. Splenectomy, correction of iron deficiency, and cholestyramine or activated charcoal may be beneficial. Liver transplantation is sometimes required. Operating room lights have produced severe skin and peritoneal burns in some patients. DUAL PORPHYRIA. Dual porphyria refers to patients with porphyria and deficiencies of more than one enzyme of the heme biosynthetic pathway. Examples include double heterozygotes with both VP and familial PCT, deficiencies of both PBG deaminase and uroporphyrinogen decarboxylase (with symptoms of AIP, PCT, or both), and deficiencies of both coproporphyrinogen oxidase and uroporphyrinogen III cosynthase.

LABORATORY DIAGNOSIS OF PORPHYRIAS Appropriate laboratory testing for these disorders is both specific and sensitive. An array of tests for porphyria are available, but some are subject to overuse and misinterpretation. Porphyrias can be readily detected and misdiagnoses avoided by relying primarily on a few first-line tests. The preferred approach for screening, as outlined in Table 219-4 , is to rely on measurement of urinary porphyrin precursors (ALA and PBG) and total porphyrins for patients with neurovisceral symptoms and a fluorometric measurement of plasma total porphyrins when it is suspected that skin photosensitivity might be due to porphyria. In acutely ill patients, it is important to identify or exclude acute porphyria promptly. Urinary PBG (and ALA) is virtually always markedly increased during acute attacks of AIP. ALA and PBG may be less increased in HCP and VP, but urinary total porphyrins are consistently markedly increased in symptomatic patients. Normal levels of ALA, PBG, and total porphyrins effectively exclude all acute porphyrias as potential causes of the current symptoms. Because increases are so striking during an attack, quantitation on a random urine sample is highly informative. Assays for PBG use Ehrlich's aldehyde ( p-dimethylaminobenzaldehyde), which forms reddish purple chromogens with PBG, urobilinogen, and other substances in urine. Qualitative methods (e.g., the Watson-Schwartz and Hoesch tests) are still widely used to screen for increased PBG. They are subject to misinterpretation and false-positive reports, do not quantitate PBG, and are less sensitive and only slightly more rapid than quantitative methods, which separate PBG from interfering substances by ion exchange chromatography. If a qualitative test for PBG is used for screening, positive samples should be retested by a quantitative method. Total plasma porphyrins are virtually always increased in patients with active skin lesions from porphyrias. Normal plasma porphyrin levels exclude porphyria as a cause of cutaneous symptoms, especially if the measurement is carried out by a simple and direct fluorometric method. Plasma porphyrins in VP are mostly covalently bound to plasma porphyrins and may not be detected by other methods. More extensive testing is required if an initial screening test for 1130

TABLE 219-4 -- FIRST-LINE LABORATORY TESTS FOR SCREENING FOR PORPHYRIAS AND SECOND-LINE TESTS FOR FURTHER EVALUATION WHEN INITIAL TESTING IS POSITIVE TESTING SYMPTOMS SUGGESTING PORPHYRIA Acute Neurovisceral Symptoms

Cutaneous Photosensitivity

First line

Urinary ALA, PBG, and total porphyrins (quantitative, random urine)

Total plasma porphyrins *

Second line

Urinary ALA, PBG, and total porphyrins (quantitative, 24-hr urine) Total fecal porphyrins

Erythrocyte porphyrins Urinary ALA, PBG, and total porphyrins (quantitative, 24-hr urine) Total fecal porphyrins

Erythrocyte PBG deaminase Total plasma porphyrins * ALA = delta-aminolevulinic acid; PBG = porphobilinogen. *The preferred method is by direct fluorescent spectrophotometry. Urinary and fecal porphyrins are fractionated only if the total is increased.

porphyria provides a positive result; such testing may also be necessary initially if subclinical porphyria is suspected. Interpretation of urine, fecal, and erythrocyte porphyrin levels is often problematic for the following reasons. (1) These measurements do not individually detect all cutaneous porphyrias. (2) Urine and erythrocyte porphyrins can be increased in many conditions other than porphyria, whereas an increased plasma porphyrin concentration is much more specific for porphyria. (3) Fecal porphyrin determinations are semiquantitative and subject to interference by diet and other factors. Laboratory testing of relatives is not usually appropriate until test results have firmly established a diagnosis of porphyria in the propositus. Results of testing the propositus guide the choice of tests for relatives. Cytosolic heme biosynthetic pathway enzymes (ALA dehydratase, PBG deaminase, uroporphyrinogen III cosynthase, and uroporphyrinogen decarboxylase) can be measured in erythrocytes. These assays are not recommended for the initial screening of patients with symptoms suggestive of porphyria. The other heme pathway enzymes are mitochondrial and are not reliably measured in erythrocytes. Demonstrating a specific mutation in a family greatly facilitates the detection of relatives who carry the same mutation. Consultation with a physician and a laboratory experienced in testing for porphyrias is helpful in these situations. Laboratory data that were the basis for an original diagnosis of porphyria should remain available for future reference. Incorrect diagnoses of porphyria are not uncommon in patients with symptoms from other diseases. Not very much evidence supports recent suggestions that porphyria is common in disorders such as multiple chemical sensitivity syndrome. Anderson KE: The porphyrias. In Zakim D, Boyer T (eds): Hepatology. Philadelphia, WB Saunders, 1996, pp 417-463. One of several recent and detailed reviews on the genetic, biochemical, and clinical aspects of the porphyrias. Mustajoki P, Nordmann Y: Early administration of heme arginate for acute porphyric attacks. Arch Intern Med 153:2004, 1993. A large series of patients treated with intravenous heme, with an emphasis on the importance of early treatment. Roberts AG, Whatley SD, Morgan RR, et al: Increased frequency of haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda. Lancet 349:321, 1997. Homozygotes for this mutation may be seen late in life with PCT rather than hemochromatosis. Schmid R (ed): The porphyrias. Semin Liver Dis 18:1, 1998. A collection of reviews emphasizing recent progress in the cellular and molecular biology of these diseases.

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Chapter 220 - WILSON DISEASE William A. Gahl

DEFINITION. Wilson disease (hepatolenticular degeneration) is a rare, potentially fatal disorder of copper toxicity characterized by progressive liver disease, neurologic deterioration, or both.

ETIOLOGY. The Wilson disease gene, ATP7B, is located on chromosome 13q14.3 and codes for a copper-transporting P-type adenosinetriphosphatase (ATPase). ATP7B has 60% identity with MNK, the gene involved in Menkes' disease, a neurologic disorder of copper enzyme deficiency. Both genes code for a transporter that has six copper-binding motifs, an adenosine triphosphate-binding domain, an aspartyl kinase domain, a phosphatase domain, and eight membrane-spanning regions. ATP7B has 21 exons and is expressed primarily in the liver and kidney, with a shorter, alternatively spliced form in the brain. The full-length gene product has been localized to the trans-Golgi, whereas the truncated product is found in the cell cytoplasm. By late 1997, at least 27 distinct mutations in 20 different exons had been reported; the most common, His1069Gln, was present in one third of patients of European ancestry with Wilson disease. Correlations between genotype and phenotype are weak.

PREVALENCE. An autosomal recessive disorder, Wilson disease occurs throughout the world; the prevalence in the United States approximates 1 in 40,000.

PATHOGENESIS. In normal adults, the intestines absorb 1 to 5 mg of copper each day; net balance is achieved by the regulated biliary excretion of copper in a non-resorbable form. Urinary excretion is minimal in the absence of copper overload or excessive wasting of certain amino acids to which copper binds. In Wilson disease, biliary excretion of copper is reduced to approximately 20% of normal, and copper progressively accumulates in the liver. Increased hepatic copper damages the liver and overflows to other tissues. These complications occur at extremely variable rates that are influenced by allelic differences, other genes, dietary copper intake, and viral infections. Acute, substantial liver damage, for any reason, releases copper for uptake by the brain, cornea, kidney, muscle, bones, and joints. Ceruloplasmin is an alpha2 -globulin glycoprotein that carries over 80% of the copper present in human plasma. It has amine oxidase activity, by which the holoenzyme can be assayed, and may play a role in copper transport from the liver to other tissues. Soon after delivery from the intestine to the liver, copper is incorporated into ceruloplasmin. This process appears to be impaired in Wilson disease; 95% of patients have reduced ceruloplasmin levels despite having normal amounts of other copper enzymes. The dual defects of reduced ceruloplasmin levels and impaired biliary copper excretion can be explained by a copper-transporting ATPase located in the Golgi that fails to incorporate copper into proteins destined for secretion. Presumably, one of these proteins is ceruloplasmin secreted into the circulation and another is a non-resorbable copper-binding protein (perhaps ceruloplasmin) secreted into the bile. Alternatively, the protein(s) may incorporate copper but fail to leave the hepatocyte. Animal models of Wilson disease such as the Long-Evans cinnamon rat and the toxic milk mouse may help elucidate the precise metabolic defect in Wilson disease.

PATHOLOGY. The liver in patients with Wilson disease shows non-specific changes, including piecemeal necrosis and lymphocytosis progressing to fibrosis and cirrhosis, usually micronodular. Copper staining with rhodanine can be patchy and variable. In the brain, the basal ganglia can be atrophic, and the cerebrum may also show involvement. Descemet's membrane in the cornea contains granular deposits of copper.

CLINICAL MANIFESTATIONS. In general, one third of patients with Wilson disease have liver disease, one third have neurologic impairment, and one third have both. Because copper initially accumulates in the liver, patients with hepatic symptoms are younger, as a rule, than those with extrahepatic symptoms. The liver damage associated with Wilson disease frequently resembles viral hepatitis 1131

and appears between 8 and 16 years of age with jaundice, anorexia, malaise, and increased serum liver enzymes. It sometimes follows a waxing and waning course, and portal hypertension is common. Hepatic coma and death may occur precipitously without the benefit of a diagnosis. Cirrhosis eventually develops in all untreated patients. Neurologic symptoms of Wilson disease occur rarely before adolescence but commonly in early adulthood. They include dysarthrias and loss of fine motor coordination, abnormal tone, dystonic posturing, unsteady gait, and uncontrolled, involuntary movements including chorea and wing-beating proximal tremors. Psychiatric, intellectual, emotional, and behavioral disturbances often occur, and decreased school performance can be an initial sign. Organic dementia is usually present in neurologically involved patients. Seizures are rare. A pseudobulbar palsy may develop at any time and can be fatal. Copper overflow to the cornea results in Kayser-Fleischer rings, characteristic yellow-brown deposits at the limbus of the cornea, especially apparent at the upper and lower poles. Early in the disease, slit-lamp examination is required to see the rings, but they are easily visible in later stages. Kayser-Fleischer rings are present in nearly all patients with neurologic symptoms, in most patients with liver disease (including children), and in some asymptomatic but affected siblings of confirmed patients. However, some patients with Wilson disease plus hepatic disease do not have Kayser-Fleischer rings, and the rings do occur in patients without Wilson disease but with severe liver disease and copper overload. As a heavy metal, copper is toxic to the kidney tubules. Hence Wilson disease is one of the known causes of renal tubular Fanconi syndrome and may involve glucosuria, aminoaciduria, poor growth, electrolyte wasting (with acidosis), phosphaturia (with occasional hypophosphatemic rickets), or hypercalciuria (with renal stone formation). Other complications of Wilson disease include acute hemolysis caused by rapid hepatic copper release as a result of infarction or viral infection. Copper can also settle in bones and joints and cause osteomalacia, osteoporosis, osteophytes, lax ligaments, and arthritis. The pancreas, heart, and parathyroid glands may be damaged by copper accumulation, and sunflower cataracts occur in a few patients. Heterozygotes for Wilson disease are clinically normal.

DIAGNOSIS. The diagnosis of Wilson disease involves the classic triad of clinical, biochemical, and molecular findings. Clinically, Wilson disease must be the primary consideration in children and young adults with chronic liver disease or any unusual hepatitis and should be part of the differential diagnosis in adolescents and adults with characteristic neurologic manifestations. Routine studies such as serum liver enzymes and urine glucose and electrolyte measurements, slit-lamp examination of the corneas, electroencephalograms, and computed tomography and magnetic resonance imaging of the brain may show abnormalities, but suspicion of Wilson disease should lead to more specific biochemical tests. In Wilson disease, serum ceruloplasmin is below normal (200 to 400 mg/L) in over 80% of patients, but this acute phase reactant rises with inflammation and pregnancy. In the serum, total copper is reduced (normal, 11 to 24 mumol/L). Elevated non-ceruloplasmin copper binds to amino acids in the circulation, and urinary copper excretion is 2.5- to 20-fold elevated (normal, approximately 40 mug/day). A 5-mg liver biopsy specimen will give copper values of 200 to 3000 mug/g dry weight (normal, 20 to 50); the preferred method of assay is graphite furnace atomic absorption spectrometry or neutron activation; copper staining of a liver specimen should not be relied upon. Every liver biopsy should be assayed for copper regardless of the putative diagnosis. Evaluation of tests for Wilson disease requires caution. Copper measurements can be spuriously high if the tubes for blood collection or the containers for liver biopsy are contaminated. Laboratory consistency between ceruloplasmin and serum copper levels can be checked by multiplying the ceruloplasmin (milligrams per liter) by 3, which equals its contribution to serum copper in micrograms per liter. Some young patients with Wilson disease have normal ceruloplasmin, and liver copper can be elevated above 300 mug/g dry weight in severe liver disease not caused by Wilson disease. In equivocal cases, injection of copper isotope (64 Cu) can make the diagnosis. In this test, isotope appears progressively in the circulation 4 to 48 hours after injection because of its incorporation into ceruloplasmin; patients with Wilson disease show no such rise in circulating isotope. The many different mutations causing Wilson disease militate against an easy molecular diagnosis. A specific mutation can be sought in at-risk relatives of a patient with molecularly diagnosed Wilson disease, and this approach is relevant to prenatal diagnosis as well. Full siblings of a patient in whom Wilson disease is diagnosed carry a 25% risk of having the disorder and should undergo biochemical or molecular testing for Wilson disease and prophylactic treatment if the disease is diagnosed.

TREATMENT. The era of efficacious therapy for Wilson disease began in 1956 with Walshe's use of penicillamine, a free thiol that chelates copper for urinary excretion. Adult doses of D-penicillamine are 1 g/day in two to four doses away from meals, although up to 3 g daily has been given; children receive 0.5 to 1 g/day. The dose is titrated every 1 or 2 months so that urinary copper losses are 2 mg/day in the first year or two of therapy and 1 mg/day thereafter. Pyridoxine (25 mg daily) is often given at the same time. Penicillamine therapy takes weeks to relieve the neurologic symptoms and months to improve liver function. In fact, mobilization of hepatic copper by D-penicillamine may exacerbate the neurologic symptoms in the first days of treatment, sometimes irreversibly. Patients with severe hepatic dysfunction engage in a race between liver regeneration and continued cell damage from copper release. This process can last 3 to 6 months, and sometimes only hemofiltration, peritoneal dialysis, or plasmapheresis can remove copper and provide time enough for the liver to recover. Hemodialysis is ineffective. In 10 to 30% of patients, D-penicillamine has significant but reversible side effects, including skin rashes, neutropenia and thrombocytopenia, nephrotic syndrome, arthritis, and connective tissue laxity. These problems disappear with cessation of therapy and may not recur on resumption of treatment if 40 mg of prednisone is given before restarting the D-penicillamine. The occurrence of aplastic anemia precludes future use, and elastosis perforans may be irreversible. A penicillamine embryopathy consisting of connective tissue abnormalities has been reported in patients treated for cystinuria and rheumatoid arthritis, but over 50 pregnancies in patients with Wilson disease treated with D-penicillamine have yielded normal infants. Interruption of decoppering therapy during pregnancy is not recommended. The adverse effects of D-penicillamine have prompted use of the chelators trientine (triethylenetetramine dihydrochloride, 400 to 800 mg three times daily) and ammonium tetrathiomolybdate. Trientine but has no serious reported side effects. Tetrathiomolybdate is an extremely potent copper chelator suitable for acute copper reduction in neurologically affected patients or if rapid copper loss is required to win the race for liver regeneration. It is not generally recommended for long-term use and has not been approved by the Food and Drug Administration. Oral zinc acetate (100 to 150 mg/day in three to four doses away from meals) induces gastrointestinal cell synthesis of the copper-binding protein metallothionein; subsequent sloughing of the mucosal cells rids the body of copper. Increased hepatic metallothionein synthesis also means that liver copper is complexed and rendered non-toxic; liver histologic status improves. Other advantages to zinc are its low toxicity and the fact that in treated patients, urinary copper accurately reflects the hepatic copper load. However, experience with long-term zinc treatment is less than with D-penicillamine therapy, and zinc is relatively slow in its decoppering activity. For irreversible liver disease, orthotopic liver transplantation has proved curative in over 50 patients with Wilson disease; the survival rate for the procedure approximates 70%. Dietary copper restriction can be helpful and consists of avoiding shellfish and liver. Neurologic symptoms may be improved by L-dopa.

PROGNOSIS. Therapy for Wilson disease can prevent further neurologic and hepatic damage and reverse most if not all the symptoms and signs, including the Kayser-Fleischer rings. However, if long-term chelating therapy is stopped, irreversible and often fatal liver damage will occur within 1 to 2 years. Brewer GJ, Yuzbasiyan-Gurkan V: Wilson disease. Medicine (Baltimore) 71:139, 1992. A practical review antedating elucidation of the Wilson disease gene and emphasizing zinc therapy. Cuthbert JA: Wilson's disease: A new gene and an animal model for an old disease. J Invest Med 43:323, 1995. This easy read summarizes all aspects of the disorder without giving excruciating detail. Danks DM: Disorders of copper transport. In Scriver CR, Beaudet AL, Sly WS, Valle 1132

D (eds): The Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York, McGraw-Hill, 1995, pp 2211-2235. This chapter, like the bible it resides in, has a strong biochemical and genetic bent; look for the 8th edition to include molecular studies.

MD Consult L.L.C. http://www.mdconsult.com Bookmark URL: /das/book/view/882/228.html/top

Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 221 - IRON OVERLOAD (HEMOCHROMATOSIS) Virgil F. Fairbanks David J. Brandhagen

DEFINITION Hemochromatosis is a state of iron overload that results in parenchymal tissue damage. In persons of European descent, the disorder is most often hereditary (primary) hemochromatosis. Secondary hemochromatosis occurs in a variety of chronic anemias caused by ineffective erythropoiesis, as in thalassemia major, or as the result of multiple transfusions or one of the less frequent conditions listed in Table 221-1 .

PREVALENCE, GENETICS, AND CAUSE Hereditary hemochromatosis, transmitted by an autosomal recessive trait, is the most common single-gene disorder of people of northern European origin, particularly among those whose forebears inhabited the littoral of the North Sea or North Atlantic. Approximately 3 to 5 persons/1000 are homozygous for the disease in the United States, Canada, France (particularly in Brittany), Iceland, the British Isles, the Netherlands, Germany, Denmark, Sweden, Norway, Australia, New Zealand, and South Africa. Approximately 10 to 15% of the white population of these countries are heterozygous for the major hemochromatosis gene. The hemochromatosis gene is less frequent in eastern and southern Europe, and of low frequency in North Africa and the Middle East. Black Americans have a lower prevalence of homozygous hemochromatosis, but it is thought to be about 0.3 to 0.5/1000. Hemochromatosis is rare in Asians. The paradoxical occurrence of hemochromatosis in successive generations of some kindreds is best explained by homozygotes marrying heterozygotes. This occurs in approximately 10% of hemochromatosis kindreds because of the high heterozygote frequency in whites. The hemochromatosis gene is in linkage disequilibrium with the human leukocyte antigen A (HLA-A) and HLA-B genes. Seventy percent of persons with hemochromatosis have HLA-A3 antigens, compared with 28% in the general population. They also possess increased frequencies of HLA-B7 and -B14 antigens. In the course of numerous generations, the effect of normal meiotic recombination should have rendered the HLA allele frequencies in hemochromatosis TABLE 221-1 -- DISORDERS ASSOCIATED WITH IRON OVERLOAD Hereditary hemochromatosis Chronic anemias Thalassemia major Sideroblastic anemia Hereditary sideroblastic anemia Refractory anemia with ringed sideroblasts Congenital dyserythropoietic anemia Exogenous iron overload Transfusion-dependent anemia Chronic oral iron ingestion (in absence of iron deficiency) African (Bantu) hemochromatosis Porphyria cutanea tarda Portacaval shunt Juvenile hemochromatosis Neonatal hemochromatosis Congenital atransferrinemia

Figure 221-1 The structure of the HFE protein as postulated from the nucleotide sequence. See text for explanation. (From Feder KM, Gnirke A, Thomas W, et al: A novel MHC class 1-like gene is mutated in patients with hereditary haemochromatosis. Nature Genetics 13:399-408, 1996, with permission.)

similar to those in the general population. The most likely explanation for the high frequencies of certain HLA alleles is that the mutation is relatively recent, although it occurred and became widely prevalent before Europeans colonized North America, Australia, New Zealand, and South Africa. The gene that is responsible for hemochromatosis is located 4 million nucleotide base pairs (4 Mb) telomeric to the major histocompatibility complex (MHC) on the short arm of chromosome 6. The corresponding HFE protein contains 343 amino acids (Figure 221-1) . It is similar to MHC class I molecules, including a signal sequence, a peptide-binding region, an immunoglobulin-like domain, a transmembrane region, and a small cytoplasmic portion. The extracellular portion of the molecule, as in other MHC class I proteins, has three domains, designated alpha1, alpha2, and alpha3. Each of these contains several beta-pleated sheets. The alpha3 domain is closely associated with beta2 -microglobulin, which is encoded by a gene on chromosome 15. The HFE protein is expressed in nearly all cell lines that have been tested. Its normal function appears to be the control of iron uptake by cells through its interaction with transferrin receptor. Two mutations of the HFE gene have been described that are responsible for 90% of the cases of hereditary hemochromatosis in people of northern European origin. The more important of these is a guanine to adenine (G A) mutation at codon 845 (therefore designated 845A) that causes a substitution of tyrosine (Y) for cysteine (C) at position 282 in the HFE protein (therefore designated C282Y). Among whites of North America and northern Europe, Australia, New Zealand, and South Africa, 10 to 15% are heterozygous for the 845A (C282Y) mutation, and 83% of cases of hereditary hemochromatosis are homozygous for this mutation. Another mutation at codon 187, of cytosine to guanine, or C G (therefore designated 187G), causes the substitution histidine (H) to aspartic acid (D) at amino acid position 63 in the HFE protein (therefore designated H63D). Among North Americans and Europeans, approximately 2 out of every 7 are heterozygous for this 187G (H63D) mutation, and 1 out of every 12 is homozygous. Heterozygotes for either HFE mutation alone have negligible risk of hemochromatosis. Compound heterozygotes, who have both mutations, have increased risk of hemochromatosis and constitute approximately 5% of cases of this disease in North America and Europe. Those who are homozygous for the 187G mutation are at slightly increased risk for hemochromatosis. Even for those who are homozygous for 845A (C282Y), the more severe mutation, the exact level of risk is still uncertain and is the subject of current investigations. Furthermore, 10% or more of patients with clinically severe hereditary hemochromatosis do not appear to have either mutation; other mutations still to be identified presumably are responsible. This fact limits the value of DNA tests for diagnostic purposes. Normal adult males must absorb approximately 1 mg/day of iron from the intestinal tract in order to balance iron loss. Normal women, during the reproductive years, must absorb approximately 2 mg/day of iron, the greater need reflecting menstrual iron loss.

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Persons homozygous for hereditary hemochromatosis absorb from their intestinal tracts only a few milligrams of iron each day in excess of need, and the excess accumulates particularly in the liver but also in other critical organs. Clinical manifestations usually appear after the fourth decade but may appear even before age 20, when there has been a total iron accumulation of 15 to 40 g. Not all homozygotes experience overt disease, however, because the development of clinical manifestations is influenced by age, sex, iron content of the diet, alcohol, and other unknown factors. For example, women regularly lose iron during menses and childbirth, and this iron loss delays the onset of tissue damage. Thus, despite an equal frequency of homozygosity, women express the disease much less frequently than males. Ethanol abuse and hepatitis accelerate the development of liver and pancreatic disease in hereditary hemochromatosis. Alcohol abuse characterizes as many as one third of patients with hemochromatosis. The frequency of serum antibodies to hepatitis C is higher in hemochromatosis patients than in the normal population; that observation suggests a contributory role of this virus.

METABOLIC AND TISSUE EFFECTS Iron accumulates over decades, as ferritin and hemosiderin, in nearly all cells of the body. Tissue damage that leads to morbidity occurs in the liver, thyroid, hypothalamus, heart, pancreas, gonads, and joints. This leads to cirrhosis of the liver, hypothyroidism, hypothalamic hypogonadotropic hypogonadism, cardiomyopathy, diabetes mellitus, arthralgias, and deforming arthritis. There is pigment deposition in skin, principally melanin. Cardiac deposition of ferritin and hemosiderin causes cardiac arrhythmias and impaired contractility of cardiac muscle. The liver is a target organ because iron that is absorbed from the intestinal tract enters the portal circulation and passes through the liver before it enters any other organ. Quantities of iron that exceed the binding capacity of transferrin are deposited in the liver. In hereditary hemochromatosis, excess iron is deposited initially as hemosiderin granules in hepatocytes, in a periportal pattern; i.e., the heaviest deposition is at the periphery of the lobule. There is also marked deposition of hemosiderin in the epithelial cells of the biliary canaliculi. As iron overloading progresses, some hemosiderin deposits in Kupffer cells. Signs of hepatocellular injury are also first apparent and most pronounced in the periphery of the lobule. These changes consist of cytoplasmic ballooning and fatty change. As the disease progresses, filaments of fibrous tissue begin to traverse the lobules. As fibrosis develops, it is predominantly periportal. The other changes of severe cirrhosis follow. Similar histologic changes occur in the pancreas, heart, and other organs. In secondary hemochromatosis, as in that which may follow numerous transfusions for chronic anemia, hemosiderin deposition is initially more marked in Kupffer cells. Ultimately, however, the histologic pattern becomes indistinguishable from that of hereditary hemochromatosis. Furthermore, other histologic changes may be indistinguishable between late-stage hemochromatosis and alcoholic cirrhosis, except for the marked hemosiderosis in the former.

CLINICAL MANIFESTATIONS Most people with hemochromatosis are asymptomatic. All homozygotes are at risk, however, for development of severe dysfunction of the heart, liver, pancreas, pituitary, gonads, or joints, as well as for fatal peritonitis or sepsis. Clinical manifestations are more common in males older than 20, and in post-menopausal women. Rare cases may involve adolescent children and young women. Table 221-2 lists the potential symptoms, signs, and abnormal laboratory findings of hemochromatosis. The most common symptoms are fatigue that may be overwhelming, arthralgias, abdominal discomfort, impotence, amenorrhea, and palpitations. Cardiac arrhythmia is a common presenting sign and may be either atrial or ventricular. Suntan-like hyperpigmentation of the skin can affect both exposed and non-exposed areas as well as scars. In advanced cases, the skin may be slate gray. Hepatosplenomegaly, ascites, pleural effusion, and arthritis can be a late development. The arthritis may affect any joint but most commonly involves the second and third metacarpophalangeal joints, knees, and hips. The affected joints may be deformed with or without inflammatory signs. Signs of hypothyroidism and testicular atrophy often appear along with loss of hair on body and extremities. Mild abdominal pain is common. Infrequently, there may be an abrupt onset of abdominal pain followed by prostration, shock, and death. Hemochromatosis, because of its associated asthenia, cardiac, hypogonadal, or multiple-organ abnormality, may cause patients initially to seek the attention of general physicians, cardiologists, pediatricians, urologists, endocrinologists, neurologists, or psychiatrists. Therefore, its features should be understood by all physicians because concentrating on a particular organ system--like one of "the Six Blind Men of Hindustan"--may preclude early diagnosis and preventive treatment, which critically influence prognosis.

LABORATORY ABNORMALITIES AND DIAGNOSIS The most useful laboratory test to ascertain hemochromatosis is measuring serum iron concentration, total iron binding capacity, and transferrin saturation. These should be done together. The transferrin saturation, as a percentage, is calculated from 100 times serum iron concentration divided by total iron binding capacity. Characteristically, the transferrin saturation is >60% and may approach 100% in hemochromatosis, whereas normally it is 20 to 50%. Other conditions may also elevate serum iron concentration and transferrin saturation, particularly the recent ingestion of medicinal iron or iron-fortified vitamin preparations, or oral contraceptives (Table 221-3) . Therefore, if the transferrin saturation is elevated, the test should be repeated after eliminating such confounding variables. If it is still elevated, serum ferritin assay should be performed. When there is marked iron overload, as in advanced hemochromatosis, the serum ferritin concentration commonly exceeds 500 mug/L and may be >5000 mug/L. Each 1 mug/L of serum ferritin concentration is roughly equivalent to 120 mug of iron stores/kg of body weight (with 95% confidence limits of about

SYMPTOMS

TABLE 221-2 -- CLINICAL AND LABORATORY MANIFESTATIONS OF HEMOCHROMATOSIS SIGNS ABNORMAL LABORATORY FINDINGS

None (common)

Alopecia

Increased serum iron concentration

Fatigue

Hyperpigmentation

Serum transferrin saturation >60%

Weakness

Tender, swollen joints

Increased serum ALT or AST transaminase level

Arthralgia

Cardiac arrhythmia

Increased blood glucose level

Abdominal pain

Cardiomegaly

Abnormal glucose tolerance

Impotence

Hepatomegaly

Low serum testosterone level

Amenorrhea

Splenomegaly

Low serum estrogen and progesterone levels

Dyspnea

Pleural effusion

Low FSH and LH levels

Abdominal swelling

Ascites

Low serum T4 , high TSH level

Weight loss

"Spider" telangiectases

Azoospermia

Signs of hypothyroidism

Thrombocytopenia

Testicular atrophy

Macrocytosis Electrocardiographic abnormalities Echocardiographic abnormalities Roentgenographic and imaging abnormalities

ALT = alanine aminotransferase; AST = aspartate aminotransferase. FSH = follicle-stimulating hormone; LH = Luteinizing hormone; T4 = thyroxine; TSH = thyrotropin.

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TABLE 221-3 -- PHENOMENA KNOWN TO AFFECT SERUM IRON CONCENTRATION, TOTAL IRON-BINDING CAPACITY, AND TRANSFERRIN SATURATION PHENOMENON EFFECT

Menstrual cycle

Pre-menstrually, elevated values (SI increased by 10-30%); at menstruation, low values (SI decreased by 10-30%)

Pregnancy

May elevate SI through increased progesterone; may lower SI through Fe deficiency

Ingestion of iron (including iron-fortified vitamins)

High values (SI may rise by 300+ mug/dL and transferrin saturation to 75%)

Iron contamination of tube (Vacutainer) or other glassware (phenomenon may be rare, sporadic, very difficult to prove)

High values (SI 200-300 mug/dL, transferrin saturation of 75-100%)

Iron dextran injection

Very high values (SI may be >500 mug/dL, transferrin saturation 100%, probably from circulating iron dextran; effect may persist for several weeks)

Hepatitis (including steatohepatitis)

Very high values (SI may exceed 1000 mug/dL through hyperferritinemia from hepatocyte injury)

Acute inflammation (respiratory infection), abscess, immunization, myocardial infarction

Low or normal SI; normal or low Tsat

Chronic inflammation or malignancy

Low or normal SI; normal or low Tsat

Iron deficiency

Low or normal SI; increased TIBC; low or normal Tsat

Iron overload (hemochromatosis)

High SI, high Tsat

Abbreviations: SI = serum iron; TIBC = total iron-binding capacity; Tsat = transferrin saturation (percentage). ±30%). A 70-kg person with a serum ferritin concentration of 3000 mug/g has approximately 17 to 33 g of storage iron in ferritin and hemosiderin. This contrasts with the normal iron stores of about 0.5 to 0.8 g in adult males or about 0 to 0.3 g in adult women. However, since serum ferritin is an acute-phase reactant, elevated values may result from chronic disease, such as inflammation (as in rheumatoid arthritis), or from malignancies. Liver injury from hepatitis or alcohol abuse also elevates both the serum iron and the serum ferritin concentrations. High values of serum ferritin may be observed in Gaucher's disease and in a rare familial disorder associated with congenital cataracts (the hyperferritinemia-cataract syndrome), without concomitant excess iron accumulation in the liver or other organs. Therefore, elevated values of serum ferritin concentration must be interpreted in the context of the presence or absence of these other conditions. Among other frequent abnormal laboratory findings are elevated blood glucose concentration, abnormal glucose tolerance test results, elevated serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) activity, low serum thyroxine level, elevated serum thyroid stimulating hormone level, low serum values for pituitary gonadotropins, and thrombocytopenia (reflecting liver disease). Hemoglobin concentration, hematocrit, erythrocyte count, erythrocyte indices, and leukocyte count and differential are usually normal, although chronic liver disease may be reflected in macrocytosis. Bone marrow examination with iron stain variably shows increase in hemosiderin, hence is not reliable for diagnosis of iron overload. Roentgenographic examinations of affected joints show soft tissue swelling, narrowing of joint spaces, irregular articular surfaces, osteoporosis, and subcapsular cysts. There may be chondrocalcinosis or calcification of periarticular ligaments. Synovial fluid often contains calcium pyrophosphate and apatite crystals. Distinction from either degenerative arthritis or rheumatoid arthritis may be difficult. Electrocardiography may reveal atrial or ventricular arrhythmia, low QRS amplitude, and repolarization abnormalities of ST segment and T waves. Echocardiography and cinecardiography may show dilated, or, less commonly restrictive, cardiomyopathy. There may be radiographic evidence of pulmonary vascular congestion or pleural effusion. Traditionally, diagnosis has required liver biopsy. This also permits evaluation of the severity of liver injury and thus the prognosis. In addition to hematoxylin and eosin stain, the biopsy specimen should be examined for iron by Perls' stain. In the absence of iron overload, the stainable iron is 0 to 1+. In heterozygotes or those with alcoholic cirrhosis it is 1 to 2+; in those with homozygous hemochromatosis it is 3 to 4+. These semiquantitative estimates from iron stain correlate with quantitative measurements of hepatic iron concentration. The hepatic iron concentration can be measured in the liver biopsy specimen. Normal hepatic iron concentrations are 12.5

2

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200 mg/dL) lose the capacity to respond to increases in circulating glucose. These observations suggest that a specific abnormality in recognition of glucose by the beta cell occurs in the earliest stages of type 2 diabetes and that this defect worsens as the disease progresses. Unfortunately the cause of beta cell failure is unknown. Studies in rodents suggest that the loss of glucose-stimulated insulin secretion is followed by decreased expression of GLUT 2, the beta cell glucose transporter. Loss of GLUT 2 during transition to the diabetic state could accelerate further loss in glucose-stimulated insulin secretion. Pathology studies of patients with long-standing

Figure 242-3 Elevations of circulating glucose initiate a vicious cycle in which hyperglycemia begets more severe hyperglycemia.

type 2 diabetes have demonstrated amyloid-like deposits within islets composed of islet amyloid polypeptide, or "amylin," a peptide synthesized in the beta cell and cosecreted with insulin. Chronic hypersecretion of islet amyloid polypeptide accompanying hyperinsulinemia may lead to precipitation of the peptide, which over time might contribute to impaired beta cell function. Recent experiments in gene knockout mice suggest a potential role for impaired insulin receptor signaling within the pancreatic beta cell in the development of impaired beta cell function. A link between insulin resistance and secretion is also suggested by data showing that accumulation of fat within the beta cell as a result of insulin resistance and increased fatty acid turnover over time reduces insulin secretion. The mechanism for beta cell dysfunction has, however, been defined in a subgroup of patients with a related, but distinct disorder, MODY type 2. These patients share a mutation in the gene encoding glucokinase, the key enzyme responsible for the phosphorylation of glucose within the beta cell and liver. A variety of glucokinase mutations have been identified in different families, each capable of interfering with transduction of the glucose signal to the beta cell. Other MODY families have no detectable glucokinase gene mutations but instead carry mutations of two different genes encoding HNF-1alpha (MODY type 3), HNF-1beta (MODY type 4), and HNF-4alpha (MODY type 1). Thus MODY appears to be a heterogeneous disorder much like the more common type 2 diabetes, which is not characterized by glucokinase or HNF gene mutations. INSULIN RESISTANCE.

With few exceptions (e.g., some black patients), type 2 diabetes is characterized by marked impairment in insulin action. The insulin dose-response curve for augmenting glucose uptake in peripheral tissues is shifted to the right (decreased sensitivity), and the maximal response is reduced, particularly with more severe hyperglycemia. Other insulin-stimulated processes such as inhibition of hepatic glucose production and lipolysis also show reduced sensitivity to insulin. The mechanisms responsible for insulin resistance remain poorly understood. Early studies focused on defects in insulin binding to its receptor. Mutations in insulin receptors result in the syndrome called leprechaunism, characterized by severe growth retardation and insulin resistance. Two other rare syndromes of extreme insulin resistance have been identified and are characterized by either a profound deficiency of insulin receptors (most often affecting young females with acanthosis nigricans, polycystic ovaries, and hirsutism) or the presence of anti-insulin receptor antibodies (associated with acanthosis nigricans and other autoimmune phenomena). Although insulin receptors may be reduced in some type 2 diabetic patients, defects in more distal or "post-receptor" events play the predominant role in insulin resistance. An important component of this defect is reduced capacity for translocation of GLUT 4 to the cell surface in muscle cells. A separate defect in glycogen synthesis is also likely to be present. Whether the defects uncovered are primary or secondary to the disturbance in glucose metabolism is uncertain. Possibly, a variety of genetic abnormalities in cellular transduction of the insulin signal may individually or in concert produce an identical clinical phenotype. No evidence has shown that the mechanisms of insulin resistance in non-obese patients differ from those of their obese diabetic counterparts, but the coexistence of obesity accentuates the severity of the resistant state. In particular, upper body or abdominal as compared with lower body or peripheral obesity is associated with insulin resistance and diabetes. It is now believed that intra-abdominal visceral fat (detected by computed tomography or magnetic resonance imaging) may be a key culprit.

Abdominal fat cells have a higher lipolytic rate and are more resistant to insulin than is fat derived from peripheral deposits. Cortisol hypersecretion and/or hereditary factors influence the distribution of body fat, the latter contributing an additional genetic influence on expression of the disease. The adverse effects of increased free fatty acid levels include accelerated hepatic gluconeogenesis and impaired muscle glucose metabolism and beta cell function ("lipotoxicity"). The release of tumor necrosis factor alpha by adipocytes may also interfere with insulin-stimulated glucose uptake by altering the pattern of phosphorylation of insulin-signaling molecules. GLUCOTOXICITY.

Hyperglycemia per se impairs the beta cell response to glucose and promotes insulin resistance (see Fig. 242-3) . The exact mechanism remains uncertain; however, glucosamine--a product of glucose metabolism via the hexosamine pathway--has 1269

Figure 242-4 A proposed sequence of events leading to the development of type 2 diabetes: insulin resistance resulting from genetic influences, central obesity, inactivity, or a combination of these factors leads over time to a progressive loss of the beta cell's capacity to compensate for this defect.

been implicated as a culprit. Glucosamine induces insulin resistance in animals by impairing insulin-induced GLUT 4 translocation to the cell membrane in isolated adipocytes and in skeletal muscles in vivo. Activation of protein kinase C may also be a contributing factor. Regardless of its molecular mechanism, reversal of glucotoxicity can disrupt the vicious cycle that perpetuates hyperglycemia, thereby facilitating therapeutic outcomes. WHAT IS THE PRIMARY DEFECT?

It remains uncertain whether insulin resistance or defective insulin secretion is the primary event leading to type 2 diabetes. Because it is difficult to resolve this issue once overt diabetes has developed, attention has focused on high-risk non-diabetic subjects. Studies in populations with high prevalence rates, such as Pima Indians and Mexican Americans, have found that insulin resistance is the initial predisposing defect. Similar results have been reported in non-diabetic 1st-degree relatives of type 2 diabetic patients and in healthy pre-diabetic offspring of two diabetic parents. Interestingly, hyperinsulinemia has been detected in pre-diabetic subjects one to two decades before the onset of diabetes, thus suggesting that development of the diabetic syndrome is exceedingly slow. Although these studies support the view that insulin resistance generally antedates insulin deficiency, its presence was insufficient to produce overt diabetes. The finding implies that for diabetes to become manifested, the additional factor of impaired insulin secretion is required (Fig. 242-4) . It is unclear whether the appearance of a secretory defect is a secondary phenomenon (e.g., "beta cell exhaustion," increased fatty acid delivery, or islet amyloid polypeptide hypersecretion) or the result of a second independent defect that becomes evident only upon chronic beta cell stimulation (e.g., a subtle genetic defect in beta cell signal transduction). This sequence of events, although common, does not occur in all patients. The demonstration of functional glucokinase gene mutations in some patients with MODY clearly indicates that primary beta cell defects are capable of producing a similar phenotype. Furthermore, some blacks with type 2 diabetes exhibit little or no insulin resistance, and diminished glucose-stimulated insulin secretion has been reported to be a feature of the subgroup of women with gestational diabetes in whom type 2 diabetes later developed. Thus it is unlikely that a single pathogenetic mechanism is responsible for type 2 diabetes.

RELATIONSHIP BETWEEN DIABETES CONTROL AND ITS COMPLICATIONS Whether the vascular and neuropathic complications of diabetes can be prevented or delayed by improved glycemic control was debated for more than a half century. To answer the question, the National Institutes of Health initiated the Diabetes Control and Complications Trial (DCCT), a 9-year multicenter study involving 1441 type 1 patients aged 13 to 39 years who were randomly assigned to either intensive insulin therapy or conventional care. Intensive care consisted of three or more insulin injections per day or an insulin pump, self-monitoring of blood glucose at least four times per day, and frequent contact with a diabetes health care team. Conventional care consisted of one or more, commonly two injections of insulin mixtures per day, less frequent monitoring, standard education, and less frequent visits. The target goals of therapy were markedly different. The intensive care group sought pre-meal blood levels of 70 to 120 mg/dL, postprandial blood levels of less than 180 mg/dL, and glycohemoglobin values as close to normal as possible. In the conventional care group the goal was clinical well-being. Patients were divided into two groups: (1) a primary prevention group with diabetes for 1 to 5 years and no detectable complications and (2) a secondary intervention group with diabetes for 1 to 15 years who had mild non-proliferative retinopathy. Remarkably, nearly 99% of the patients completed the trial. The DCCT achieved a clear separation of glucose levels between the groups over the entire study period. Glycohemoglobin (Hb A1c ) and mean glucose levels in the intensive care group were 1.5 to 2.0% and 60 to 80 mg/dL lower than those receiving conventional care. Although considerable variability was noted among individual patients, most of the intensive care group failed to achieve normal glucose levels (glycohemoglobin averaged 1.1% above normal, or a glucose level of about 155 mg/dL). Nevertheless, intensive care reduced the development of retinopathy by 76% in the primary prevention group and the progression of retinopathy by 54% in the secondary intervention group (Fig. 242-5) . The latter effect became apparent only after 4 years. In addition, intensive care reduced the

Figure 242-5 A summary of the results of the Diabetes Control and Complications Trial (DCCT).

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risk of microalbuminuria by 39%, frank proteinuria by 54%, and clinical neuropathy by 60% when compared with conventional care. The incidence of major cardiovascular events also tended to be lower, but the number of events was insufficient to provide statistical proof. At the least, intensive therapy did not pose a risk for macrovascular complications. The exponential relationship over time between the average blood glucose level as reflected by Hb A1C and the frequency with which retinopathy progressed in the intensive care group suggests that there may be no threshold level at which complications occur. The findings imply that any degree of improvement in glycemic control has benefit and that normalization is not required to slow the progression of complications. The DCCT found that the benefits of intensive control were not without risk. The frequency of severe hypoglycemia requiring help from another person increased three-fold. Also, severe hypoglycemia often occurred without classic warning symptoms (often while the patient was asleep). These complications are in keeping with data showing suppression of adrenergic responses to hypoglycemia (1) in subjects treated with intensive insulin regimens that provoke iatrogenic hypoglycemia and (2) during stage 3 or 4 sleep. Weight gain was also more common. These changes indicate that in some patients the risks of intensive therapy may outweigh the benefits. Included are patients with recurrent severe hypoglycemia and hypoglycemic unawareness, patients in whom the dangers of hypoglycemia are greater because of other coexisting medical conditions or their occupation, patients with far-advanced complications, young children, the elderly, and patients who are unable or unwilling to participate in their management (e.g., self-monitoring of blood glucose). Such individuals are likely to benefit from less aggressive therapy designed to lower glucose levels without provoking hypoglycemia. It is noteworthy that despite a higher rate of hypoglycemia, intensive care did not have any detectable long-term effect on cognitive functioning. Although the DCCT did not involve type 2 diabetic patients, a small study using a similar experimental design in lean Japanese patients with type 2 diabetes showed virtually identical results with intensified insulin therapy. More conclusive evidence that improved control of blood glucose is beneficial for type 2 diabetic patients derives from the recently completed United Kingdom Prospective Diabetes Study (UKPDS). The UKPDS recruited 5102 patients with newly diagnosed type 2 diabetes between 1977 and 1991. After 3 months of diet therapy, the 3,867 patients with fasting glucose levels between 6.1 and 15.0 mmol/L (110 to 270 mg/dL) were randomized to a more intensified regimen consisting of sulfonylurea and metformin (for obese patients only) or insulin or a conventional treatment regimen focused on symptom reduction. Patients were monitored for an average of 10 years. Although glycemic control gradually deteriorated in both groups, the intensified treatment group had lower mean Hb A1c than their conventional treatment counterparts (7.0% versus 7.9%). This modest improvement significantly reduced microvascular complications by 25% and all diabetes-related events by 12%. A continuous relationship was noted between glycemia and diabetic complications, much the same as was seen in the DCCT. No glycemic threshold for microvascular complications was evident. The intensified treatment group also had a 16% reduction in fatal and non-fatal myocardial infarction and sudden death that did not quite reach statistical significance ( P = .052). Serious adverse events were rare for each of the pharmacologic agents used in the UKPDS; only 1 death from hypoglycemia occurred in over 27,000 patient-years of intensive therapy. This result is accounted for by more severe insulin resistance and less severe defects in hormonal counterregulation in patients with type 2 diabetes. What conclusions can be drawn from the DCCT and the UKPDS? The primary message is that "control matters." In both type 1 and type 2 diabetic patients who are willing and able to actively participate in their management, the goal should be the best level of glycemic control possible without placing them at undue risk. A health care team should be in place and able to provide the resources, guidance, and support required to achieve treatment goals. A larger subgroup of type 2 patients may

not be ideal candidates for tight control, particularly elderly patients with a shorter life expectancy, such those with coexisting severe cardiovascular disease. The DCCT and the UKPDS demonstrate that nearly all patients can benefit from lowering glucose from levels over 200 to levels less than 150 mg/dL; for most type 2 patients, such changes can be achieved by diet, oral agents, or less complicated insulin regimens than are required in type 1 patients. The greatest challenge for the clinician is how to effectively apply the DCCT and UKPDS results in practice, a formidable task. The study group was highly motivated and more compliant than the average patient with diabetes. Management was supervised by an experienced health care team that was able to devote more time to patients than is commonly possible in most practices. Also, the immediate costs of intensive treatment are greater, although the long-term cost savings of having healthier, more productive patients is obvious. An important lesson from the DCCT experience was that successful treatment was largely accomplished by the efforts of the patients themselves, as well as nurse educators and dietitians. Thus it may be more practical to use physician-directed health care teams to translate the findings of the DCCT and UKPDS.

TREATMENT Treatment of diabetes mellitus involves changes in lifestyle and pharmacologic intervention with insulin or oral glucose-lowering drugs. In type 1 diabetes, the primary focus is to replace insulin secretion; lifestyle changes are required to facilitate insulin therapy and optimize health. For most patients with type 2 diabetes, changes in lifestyle are the cornerstone of treatment, particularly in the early stages of the disease. Pharmacologic intervention is a secondary treatment strategy. Although therapeutic strategies for the two forms of diabetes differ, the short-term and long-term goals of treatment are identical (Table 242-3) . Type 1 Diabetes INSULIN PREPARATIONS AND PHARMACOKINETICS.

A variety of highly purified insulin preparations are commercially available that differ mainly in their time of onset and duration of action (Table 242-4) . Pre-mixed preparations of insulin containing both intermediate- and rapid-acting insulin are available and may be a convenient form of therapy for some patients, particularly those with type 2 diabetes. Nearly all insulin preparations contain 100 U/mL (U-100), although a more concentrated regular insulin with a more prolonged action (500 U/mL or U-500) can be obtained for resistant patients. Pure insulin preparations result in fewer problems related to insulin antigenicity, such as insulin allergy, insulin resistance, and lipoatrophy. Human insulin is now the only form of insulin sold in North America and other industrialized countries. Human insulin is less antigenic than porcine and much less antigenic than bovine insulin. Because human insulin generates lower titers of insulin antibodies, it acts more rapidly after injection and the effects tend to persist for a shorter time. This combination allows for better synchrony between insulin peaks and meal absorption after injection of rapid-acting insulin with meals. The earlier peaks of intermediate-acting human insulin, however, fail to sustain its effects for a full 24-hour period, thereby necessitating twice-daily injections. It is noteworthy that the same insulin preparation may produce variable responses in a given patient because the peak and duration of action of most insulin preparations depend on (1) the route of administration, (2) the dose, and (3) the duration of the treatment with insulin. RAPID-ACTING INSULIN PREPARATIONS.

After subcutaneous injection, regular insulin begins to act in about 30 minutes and should therefore be given 20 to 30 minutes before a meal. Because it acts quickly, it is most effective in blunting elevations in glucose following meals and in allowing for rapid adjustments in insulin dosage based on measurements of blood glucose by the patient. TABLE 242-3 -- TREATMENT GOALS Short term Restore metabolic control to as close to normal as possible Improve sense of well-being Long term: Minimize risk of diabetic complications Accelerated atherosclerosis Microangiopathy (retinopathy, nephropathy) Neuropathy

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CLASS

TABLE 242-4 -- INSULIN PREPARATIONS: TIME COURSE OF ACTION AFTER SUBCUTANEOUS ADMINISTRATION PREPARATION ONSET OF EFFECT PEAK EFFECT (hr) DURATION OF ACTION (hr)

Rapid acting

Regular

30 min

2-4

5-8

Lispro

10-15 min

1-2

3-4

Intermediate acting

NPH or Lente

1-2 hr

6-10

16-24

Long acting

Ultralente

4-6 hr

8-20

24-28

This property is especially helpful in managing glucose elevations that occur during illness or with consumption of large meals. Regular insulin preparations are predominantly in hexameric form and must dissociate into monomers, which accounts for the delay in its absorption from subcutaneous injection sites. Recently, lispro (an insulin analogue with reversed order of the amino acids in positions 28 [lysine] and 29 [proline] on the B chain) was developed by recombinant DNA technology, which can more easily dissociate into its monomeric form. Because it is absorbed more rapidly, lispro can be given just before eating, a feature that simplifies meal planning. Because its effects wane more rapidly, the risk of hypoglycemia if the next meal is delayed may be reduced. Rapid-acting insulins afford much greater flexibility and have therefore assumed a greater role in intensive treatment regimens. INTERMEDIATE- AND LONG-ACTING INSULIN PREPARATIONS.

Other insulin preparations are modified to delay their absorption from injection sites so that their action is prolonged. Either protamine is added, yielding intermediate-acting NPH insulin, or the size of the zinc-insulin crystal is enlarged by adjusting the preparation process. The latter yields Lente (intermediate-acting) and Ultralente (long-acting) insulin. The intermediate-acting insulins (NPH and Lente) have a similar time course of action. They offer the compromise of some degree of coverage for meals coinciding with their peak actions and provision of basal levels of insulin when given twice per day. Longer-acting insulins (Ultralente), because they have less evident "peaks," offer some advantages for basal insulin replacement but generally still require twice-daily dosing. INSULIN REGIMENS.

Insulin treatment of diabetes is complex; no universal and predictable algorithm can be uniformly applied to all patients. In general, treatment regimens may be divided into conventional insulin treatment and intensive insulin treatment (e.g., multiple subcutaneous injections and continuous subcutaneous insulin infusion). CONVENTIONAL INSULIN THERAPY.

During the first few years of type 1 diabetes some degree of beta cell function typically persists, which allows many patients to achieve glycemic control with less intensive effort. Because intermediate-acting insulins are not generally sustained over a 24-hour period and insulin requirements tend to increase early in the morning, most patients should start with two daily injections of a mixture of intermediate-acting and rapid-acting human insulin before breakfast and dinner. Although Lente insulin has a theoretic advantage over NPH insulin in that it does not contain a foreign protein (protamine), this difference appears to have negligible clinical significance. Some advantage is gained by using NPH if regular insulin is mixed with it because if NPH is mixed with Lente, the excess zinc may cause regular insulin to precipitate out of solution and delay its absorption. Initially, the doses of intermediate-acting insulin are adjusted to optimize pre-dinner and fasting glucose levels. Once this adjustment is accomplished, the doses of rapid-acting insulin are varied to optimize postprandial glucose peaks as well as pre-lunch and bedtime glucose values. Patients should inject in the same region but at different locations at the same time each day, i.e., in the abdomen in the morning to optimize insulin delivery and in the leg or buttock at night to slow absorption. Some patients may experience a brief "honeymoon" period during which beta cell function partially recovers and insulin doses need to be reduced. This improvement should not be used as a signal to reduce efforts aimed at glycemic control; optimized insulin therapy helps

preserve residual beta cell function. MULTIPLE SUBCUTANEOUS INJECTIONS.

Several years after the onset of type 1 diabetes, residual insulin secretion typically ceases and twice-daily insulin injections no longer suffice despite control of diabetic symptoms. Optimal glycemic control requires that insulin delivery be directed toward more closely simulating the normal pattern of insulin secretion, namely, continuous "basal" insulin secretion throughout the day and night and brief increases in insulin levels coinciding with the ingestion of meals. The major problem with regimens relying on twice-daily injections is that the glucose-lowering effect of pre-dinner intermediate-acting insulin is greatest at the time when requirements are lowest (i.e., 2:00 to 3:00 A. M.) whereas when requirements are increasing early in the morning (i.e., 5:00 to 8:00 A. M.), insulin levels decline. The result is a tendency to nocturnal hypoglycemia and/or fasting hyperglycemia. Successful management begins with control of fasting glucose levels. Failure to do so commonly leads to perpetuation of hyperglycemia for the remainder of the day or attempts at corrective measures with supplemental insulin that miss the mark. The therapeutic obstacle imposed by fasting hyperglycemia is best appreciated in the context of its pathogenesis, namely, glucose overproduction. Once hepatic gluconeogenesis has been activated in the morning, it is not readily suppressed by subcutaneous injections of insulin, and hyperglycemia persists after breakfast. The key factors responsible for fasting hyperglycemia are inadequate overnight delivery of insulin and sleep-associated growth hormone release. The "dawn phenomenon" is most pronounced in patients with type 1 diabetes because of their inability to compensate by raising endogenous insulin secretion. The magnitude of the dawn phenomenon can be attenuated by designing insulin regimens to ensure that the effects of exogenous insulin do not peak in the middle of the night and become dissipated by morning. Several approaches can deal with the problem (Fig. 242-6) . The simplest is to use three injections, i.e., mixtures of intermediate- and short-acting insulin before breakfast, short-acting insulin before dinner, and intermediate-acting insulin at bedtime. The primary disadvantage of this approach is that meal schedules must be fixed rather rigidly. Alternative multidose regimens include (1) Ultralente (twice daily) to replace basal insulin secretion and short-acting insulin before each meal or (2) short-acting insulin before each meal and intermediate-acting insulin at bedtime. Pen injectors containing cartridges filled with insulin make multidose insulin regimens more convenient. CONTINUOUS SUBCUTANEOUS INSULIN INFUSION.

An alternative that provides greater flexibility in insulin dosing while minimizing variation in absorption is continuous subcutaneous insulin infusion. In this method, rapid-acting insulin is administered around the clock via a battery-powered, externally worn, computer-controlled infusion pump (see Fig. 242-6) . The pump delivers basal rates continuously and can be programmed to vary the flow rate automatically for set periods, such as reducing the flow rate at 1:00 to 4:00 A. M. and then increasing it to compensate for increased insulin requirements early in the morning (i.e., 5:00 to 8:00 A. M.). Boluses determined by self-monitoring of blood glucose are given before meals by manually activating the pump. Most pumps contain a syringe filled with insulin attached to an infusion set consisting of a catheter and a needle that is inserted subcutaneously, preferably in the abdomen, to optimize absorption. Unfortunately, the approach has problems that limit its use. The most obvious disadvantage is wearing the pump itself. Because continuous subcutaneous insulin infusion uses short-acting insulin, any interruption in flow (most commonly because of insulin precipitation within the catheter) leads to rapid deterioration in control. Local infections at the catheter site occasionally occur. Also, maintenance of the pump and appropriate infusion rates requires effort and sophistication. The intensive treatment regimens described above are not for everyone. In patients appropriate for such care, however, intensive insulin therapy should be strongly encouraged to reduce the risk of late complications. An absolute indication for intensive therapy is pregnancy. To eliminate the excess neonatal morbidity and mortality 1272

Figure 242-6 Several intensive insulin regimens commonly used in the treatment of diabetes. Each is designed to provide a continuous supply of insulin around the clock and to make extra insulin available at the time of meals, thereby simulating more closely the normal physiologic pattern of insulin secretion.

that in the past were associated with diabetic pregnancy requires maintaining glycemic control. Ideally, intensive insulin therapy should be instituted before conception to minimize the higher risk of fetal anomalies. After conception, blood glucose targets are more stringently applied than at other times, with the aim of restoring glucose levels to those found in non-diabetic pregnant individuals. LIFESTYLE CHANGES.

Management of diet and exercise contribute importantly to the care of patients with type 1 diabetes (Table 242-5) . The patient must be advised of the need for a careful balance between calorie intake and energy expenditure (exercise) while taking into account the availability of injected insulin. DIET.

The introduction of intensive insulin regimens has permitted TABLE 242-5 -- LIFESTYLE MODIFICATIONS FOR PATIENTS WITH DIABETES I. Diet prescription 1. Weight reduction, gain, or maintenance (as appropriate) 2. Carbohydrates: 45-60% (depending on the severity of diabetes and triglyceride levels) 3. Restriction of saturated fat (to K

12-14

Tolbutamide

500-3000

2-3

L>K

6-12

Glimepiride

1-8

1

L>K

24

Glyburide

1.25-20

1-2

L>K

Up to 24

Glyburide micronized

0.75-12

1-2

L>K

Up to 24

Glipizide

2.5-40

1-2

L>K

Up to 24

Glipizide GITS

5.0-20

1

L>K

24

500-2550

2-3

K

Up to 24

Troglitazone

400-600

1

L

24

Pioglitazone

15-45

1

L

24

Rosiglitazone

4-8

1-2

L

Up to 24

Acarbose

75-300

3

gut/k *

N/A

Miglitol

75-300

3

gut/k *

N/A

1-16

3

L>K

short

Sulfonylureas Second generation

Biguanide Metformin Thiazolidinedione

alpha -Glucosidase inhibitors

Benzoic acid derivatives Repaglinide *L = liver; K = kidney. Pending FDA approval. To be taken with meals. **The small fraction of the drug which is absorbed is eliminated via kidneys.

patients because the metabolic improvement produced by weight loss reverses the accelerated gluconeogenesis and futile cycling of substrates commonly seen in poorly controlled diabetes, both of which waste energy. Moreover, dieting reduces glycosuria and thus lessens urinary caloric loss. Success is best achieved by a combination of a supportive environment that emphasizes long-term goals (short-term weight changes mean little in the big picture), regular exercise to increase energy expenditure, and behavior modification. Even when weight loss is not successful, the meal plan can remain a valuable tool to reduce the risk of cardiovascular disease in patients with diabetes. This benefit is best achieved by reducing saturated fat and in turn raising the content of carbohydrate or monounsaturated fat in the diet. Although it was originally thought that carbohydrate intake should be restricted, it is now appreciated that a diet higher in carbohydrate (50 to 60%) may improve insulin action and glycemic control, particularly in patients with mild hyperglycemia. In patients with more severe fasting hyperglycemia or with triglyceride elevations that may be aggravated by high-carbohydrate diets, reduced carbohydrate intake (45% of the total calories) and greater reliance on monounsaturated fats are preferable. It has been assumed that carbohydrate intake should be focused on complex carbohydrates (starches). Little evidence supports this assumption; simple sugars raise glucose levels to about the same extent as complex carbohydrates do when consumed by diabetic patients. Thus the total amount of carbohydrate in the diet rather than the source of carbohydrate should be the primary consideration. The optimal source of carbohydrate may be foods containing water-soluble fiber (e.g., oats, gums, legumes, fruit pectin). Such fiber blunts the meal-induced rise in blood glucose by delaying gastric emptying and, in turn, the rate of meal absorption. Mild lowering of triglyceride and low-density lipoprotein (LDL) cholesterol levels may occur as well. It is commonly believed that sucrose leads to excessive glycemic excursions and must therefore be omitted. Such is not the case when modest amounts of sucrose are eaten within the context of mixed meals. Glucose excursions are not significantly different when equivalent amounts of sucrose and complex carbohydrates are added to meals, possibly because other foods (e.g., protein and fat) act to delay absorption and promote insulin secretion. Thus it is unnecessary to forbid the use of foods containing sucrose, provided that sucrose is consumed in moderation. Such restrictions can lead to poor adherence to the meal plan.

A key component of the diabetic meal plan is to reduce or change the composition of dietary fat. The typical diet of Western countries, high in saturated or animal fat, appears to contribute to the development of atherosclerosis in patients with diabetes. Although substituting monounsaturated fatty acids rather than carbohydrates for saturated fat in the diet has been advocated to reduce LDL cholesterol without raising triglyceride levels, the approach may be difficult to achieve inasmuch as the major sources of monounsaturated fatty acids are olive, canola, and peanut oils. EXERCISE.

Regular exercise is a useful adjunct in the treatment of diabetes (see Table 242-5) . It can improve insulin action and facilitate weight loss, but its major advantage is to lower cardiovascular risk. In support of this view, regular exercise produces a fall in very-low-density lipoprotein triglyceride and a rise in high-density lipoprotein (HDL) cholesterol and fibrinolytic activity in type 2 diabetes. Limitations may be imposed by pre-existing coronary or peripheral vascular disease, proliferative retinopathy, peripheral or autonomic neuropathy, and poor control.

Figure 242-7 Mechanism of action of oral glucose lowering agents.

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Pharmacologic Intervention ORAL GLUCOSE-LOWERING AGENTS.

Several new classes of oral glucose-lowering agents have recently become available for the treatment of type 2 diabetes (Table 242-6 , Fig. 242-7) . These drugs are generally effective in patients in whom diet and exercise fail to achieve treatment goals. Oral agents tend to be favored as first-line therapy if hyperglycemia is mild, the patient is older, and obesity is more pronounced. The response cannot be predicted with certainty from clinical characteristics, and few circumstances contraindicate their use (e.g., severe insulin deficiency, allergy, pregnancy). Patients with severe hyperglycemia generally require insulin to lower glucose levels in the initial phases of treatment. Once glucose levels have stabilized and the "toxic" effects of severe hyperglycemia on beta cell function and insulin action have been minimized, many such patients become responsive to oral agents. SULFONYLUREA.

Sulfonylurea drugs were the only class of oral agents available in the United States before 1995. They act by enhancing insulin secretion by virtue of their ability to bind to their receptors associated with ATP-dependent potassium channels on the surface of the beta cell, thereby facilitating cellular depolarization. The reduction in glucose that follows is accompanied by a decline in insulin levels toward baseline. Insulin resistance commonly diminishes as a result of reversal of glucotoxicity. Because of their mechanism of action, sulfonylureas are totally ineffective in type 1 diabetes. Although the sulfonylureas differ in relative potency, effective dosage, duration of action, metabolism, and side effects, from a clinical standpoint these differences have marginal practical significance (see Table 242-6) . Each drug has similar hypoglycemic effects when used in maximal doses. Drugs with a shorter duration of action that are metabolized by the liver have advantages in elderly patients with impaired renal function because such patients are more vulnerable to hypoglycemia, but they may be less effective because of problems with compliance with multiple dosing schedules. Longer-acting sulfonylureas require only once-per-day dosing but enhance the risk of hypoglycemia in patients who omit meals. Sulfonylureas with an intermediate duration of action may offer a reasonable compromise, although they still have a risk of producing severe hypoglycemia. These drugs may be given once per day, although twice-daily dosing may be required in patients with more severe hyperglycemia. After choosing an oral agent, treatment is initiated at low doses, with the dosage increased every 1 to 2 weeks until treatment goals or maximally effective doses are reached. Most patients initially respond with a lowering of glucose levels; however, about 15 to 20% of diabetic patients do not benefit (so-called primary failure). It is not uncommon to see loss of drug effect after years of therapy because of failure to sustain enthusiasm for diet and exercise, progression of beta cell failure, superimposition of other medical problems or drugs, or drug tolerance. The deteriorating glycemic control begets even poorer control as a result of glucotoxicity (see Fig. 242-4) . Secondary drug failure occurs at a rate of 5 to 10% per year. Early signs of secondary drug failure should provoke renewed attempts to enforce diet, as well as a prompt increase in drug dosage. The appearance of hyperglycemia despite maximal drug doses signals the need to add another class of oral glucose-lowering agent (e.g., biguanide, or glucosidase inhibitor, thiazolidinedione) or to institute insulin therapy. BENZOIC ACID DERIVATIVES.

Repaglinide, a non-sulfonylurea which interacts with a different portion of the sulfonylurea receptor to stimulate insulin secretion, has recently been approved by the Food and Drug Administration (FDA). Its major advantage is its rapid and relatively short duration of action, which could potentially reduce the risk of hypoglycemia. The drug requires frequent daily dosing and must be taken at the beginning of each meal. BIGUANIDES.

Metformin (the only biguanide approved for use in the United States), unlike sulfonylureas, acts mainly by reducing hepatic glucose production. The cellular mechanism for this effect is, however, uncertain. Because its effect is extrapancreatic, insulin levels fall, a potential advantage if the theory implicating hyperinsulinemia in the development of atherosclerosis proves correct. Because metformin (unlike other oral glucose-lowering agents) may induce mild weight loss, it is particularly suitable for obese patients either as monotherapy or as an additive drug when other oral glucose-lowering agents are ineffective alone. The drug does not produce hypoglycemia when used as monotherapy; however, it can rarely produce lactic acidosis (approximately 0.03 cases per 1000 patient-years) and should therefore not be given to patients with renal insufficiency, liver disease, a history of congestive heart failure or chronic hypoxia, or alcohol abuse. The major side effects are gastrointestinal, particularly anorexia and nausea, which may contribute to its effect on weight loss. Metformin has a relatively short half-life (it is eliminated exclusively by the kidney), which generally necessitates administration as two or three divided doses given with meals. THIAZOLIDINEDIONES.

Thiazolidinediones reduce insulin resistance, most likely through activation of the peroxisome proliferator-activated receptor gamma--a nuclear receptor that regulates the transcription of several insulin-responsive genes. Their biologic effect is mediated via stimulation of peripheral glucose metabolism. They have little effect on hepatic glucose production. Clinical studies demonstrate a reduction in both plasma glucose and insulin levels. Troglitazone was the first thiazolidinedione derivative approved for use in the United States. It is most effective when used in conjunction with insulin in type 2 diabetic patients who are not adequately controlled with insulin or in combination therapy with other oral hypoglycemic agents such as sulfonylureas. Troglitazone commonly requires 4 to 6 weeks for its glucose-lowering effect to be fully manifested. It has been reported to cause an increase in transaminases in about 2% of patients. Reports of cases of severe liver failure have led the FDA to recommend measuring liver enzymes at baseline every month for the first year of treatment and on a regular basis thereafter. Recently, the FDA approved two new thiozolidinediones, rosiglitazone and pioglitazone, which are effective glucose-lowering agents either as monotherapy or in combination with other drugs. Preliminary data suggest that both drugs have a much lower risk of hepatotoxicity and therefore are more appropriate for use as monotherapy. Nevertheless, none of the thiozolidinediones should be used in patients with liver function abnormalities, and they should be discontinued if liver enzymes (e.g., ALT) become elevated. Hypoglycemia is rare when thiozolidinediones are used as monotherapy, but may occur when these drugs are used in conjunction with insulin or sulfonylureas. Weight gain and/or edema may also complicate thiozolidinedione therapy. alpha-GLUCOSIDASE INHIBITORS.

Acarbose and miglitolare, reversible inhibitors of alpha-glucosidases (the intestinal enzymes that break down complex carbohydrates into monosaccharides), delay the absorption of carbohydrates such as starch, sucrose, and maltose. It does not affect the absorption of monosaccharides such as glucose. To be effective, this class of drugs must be taken at the beginning of each carbohydrate-containing meal. In controlled trials performed in patients with type 2 diabetes, alpha-glucosidase inhibitors alone or as an adjunctive therapy to reduce postprandial hyperglycemia resulted in a small, but clinically meaningful reduction in glycosylated hemoglobin levels. A major advantage is that alpha-glucosidase inhibitors do not have significant toxicity. The most common side effects are abdominal bloating, flatulence, and sometimes diarrhea. The adverse gastrointestinal effects are minimized by using a slowly escalating dose titration schedule in which treatment is initiated at the lowest dose.

INSULIN THERAPY.

Insulin is most commonly used as 1st-line therapy for non-obese, younger, or severely hyperglycemic type 2 diabetic patients and is temporarily required during severe stress (e.g., injury, infection, surgery) or in pregnancy. Insulin should not be used as 1st-line therapy in poorly compliant patients who are unwilling to self-monitor glucose levels or for patients with a high risk of hypoglycemia. In patients with severe obesity, profound insulin resistance often necessitates the use of large doses of insulin, which sometimes interferes with efforts to restrict caloric intake to achieve weight loss. In patients with newly diagnosed diabetes or those with relatively mild fasting hyperglycemia who continue to maintain endogenous insulin secretory capacity, relatively small doses of insulin (e.g., 0.3 to 0.4 U/kg of body weight per day) given once or twice per day may be sufficient to achieve target goals. Such patients retain some degree of meal-stimulated endogenous insulin secretion and may therefore require less rapid-acting insulin. Although it is common practice to administer a single dose of intermediate-acting insulin in the morning, frequently its glucose-lowering effect does not extend over a full 24-hour period. Because a key element of successful insulin treatment is to diminish 1275

Figure 242-8 Strategy for the treatment of type 2 diabetes.

accelerated rates of endogenous glucose production in the morning, it is generally more effective to split the dose and administer sufficient amounts of intermediate-acting insulin in the evening (before dinner or preferably at bedtime) to optimize control of the fasting glucose level. Alternatively, a single small dose of intermediate-acting insulin given at bedtime to control fasting hyperglycemia may be effective throughout the remainder of the day in patients who have retained the capacity to secrete insulin with meals. This approach has the advantage of greater simplicity and may be combined with oral glucose-lowering agents during the day to facilitate endogenous insulin release or action with meals. In practice, most insulin-treated patients are obese, have more severe hyperglycemia, and have already failed oral therapy. These patients are more insulin deficient and insulin resistant. As a result, they often require multiple-dose regimens involving mixtures of rapid- and intermediate-acting insulin to control hyperglycemia. As in type 1 patients, it is best to distribute their insulin as evenly as possible throughout the day and to provide sufficient insulin overnight to control fasting hyperglycemia. The complexity of the regimen must be individualized according to the total clinical context of the patient's disease, the level of diabetes education and ability to perform self-care, and most importantly, the patient's motivation . In some cases, combinations of insulin and oral hypoglycemic drugs (particularly thiozolidinediones) may reduce insulin dose requirements and at the same time improve glycemic control. It should be noted that in such patients requiring insulin, combination therapy may be no more effective than giving larger doses of insulin alone in controlling blood glucose. The potential benefit of reducing circulating insulin levels with combination therapy on the development of atherogenesis remains to be established. Experience with the use of intensified insulin treatment, including continuous subcutaneous insulin infusion pumps and multiple subcutaneous injection regimens, is limited in patients with type 2 diabetes. However, preliminary data suggest that they may be successfully applied in a select group of these patients. TREATMENT STRATEGIES FOR TYPE 2 DIABETES.

In contrast to type 1 diabetes, in which pharmacologic treatment is limited only to insulin, several pharmacologic options exist for the management of type 2 diabetes. In the UKPDS, the improved outcomes produced by intensified therapy were similar for patients given insulin or oral agents (sulfonylurea or metformin). However, the ability of the UKPDS to detect differences among the various pharmacologic agents used is limited because of drug crossovers and the common need for drug combinations as the study progressed. It should be noted that some discrepancies were noted in the results derived from the smaller subgroup of patients who received metformin. However, overall analysis of the results of the metformin-treated group suggests that intensified therapy with each pharmacologic agent was beneficial and that no specific therapy was superior. Thus regardless of whether type 2 patients are treated with insulin or oral hypoglycemics, the goals of therapy should be the same, namely, to lower blood glucose as close to normal as possible. Success at meeting target goals requires careful follow-up and rapid therapeutic responses to the continuously progressing dysfunction of glucose homeostasis. For most patients, glycemic control deteriorates over time, thus necessitating more intensive pharmacologic interventions. The decision regarding initial therapy for type 2 diabetes should be influenced by the severity of the fasting hyperglycemia, the presence of symptoms, and obesity. Other factors such as the patient's age, motivation, and coexistence of other diseases should be considered as well. To determine the effectiveness of the therapy selected, dosages should be adjusted over about a 3-month period based on glucose self-monitoring. Failure to meet established target glycemic goals within 3 months should prompt modification of treatment (e.g., combination therapy). In many cases, patients who were initially well controlled with only one drug will with time require combination therapy and may ultimately use insulin. Ultimately, if treatment glycemic targets are not met with oral agents, insulin remains an effective treatment option (Fig. 242-8) . Monitoring SELF-MONITORING OF BLOOD GLUCOSE.

Self-monitoring of blood glucose has revolutionized diabetes management. It actively involves patients in the treatment process, allows more rapid treatment adjustments, and reinforces diet therapy. Self-monitoring provides the patient with the tools necessary for crucial self-management and is especially useful in the care of patients receiving insulin or oral glucose-lowering agents during periods of stress and in patients susceptible to hypoglycemia. Urine glucose testing is unreliable and should be used only in patients who cannot or refuse to apply self-monitoring of blood glucose or in whom the treatment goal is only prevention of symptomatic hyperglycemia. The newer glucose meters are small, portable, and accurate, give a digital readout, and have computerized memory to facilitate record keeping. These factors make them preferable to visual estimates from test strips. Blood sampling is facilitated and made less painful by automated spring-operated lancet devices. Self-monitoring of blood glucose is of value only if the patient performs tests on a regular basis, can accurately measure glucose levels, and can make use of the results. The patient must become familiar with what a normal glucose value is, what the glucose targets are, and how they may vary with changes in diet, activity, and insulin absorption. Day-to-day adjustments in short-acting insulin based on pre-meal values and a "sliding scale" can be readily accomplished by most patients. The patient also needs to examine the effects of longer-acting insulin and make small adjustments if glucose levels (e.g., pre-breakfast and pre-dinner values) are not within the target range. At a minimum, patients need to be able to adjust to repetitive patterns of hypoglycemia or hyperglycemia, as well as periods of illness ("sick days"). In the latter circumstance, urine testing for ketones should be done as well. The success of insulin therapy depends on the frequency with which the patient performs self-monitoring. Patients with type 1 diabetes should be encouraged to monitor before each meal and at bedtime. Periodic checks 90 to 120 minutes after meals help control postprandial hyperglycemia, and patients may occasionally need to monitor blood levels in the middle of the night (e.g., 3 A. M.) to avoid nocturnal hypoglycemia. Currently, no clear guidelines have been established for the frequency of self-monitoring of blood glucose in type 2 diabetes. Type 2 patients who are treated with insulin should conduct self-monitoring daily, before breakfast and dinner and at bedtime. Here the aim is to meet target glycemic goals and reduce the risk of hypoglycemia. In patients taking oral agents, the frequency of blood glucose self-monitoring will depend on the duration of the therapy and the metabolic control achieved by it. Self-monitoring of blood glucose should be more frequent at the beginning of treatment and any time that deterioration in metabolic control is suspected. Type 2 patients maintained by diet therapy should, at the very least, learn self-monitoring of blood glucose to prevent metabolic decompensation. They often benefit from monitoring glucose levels periodically so that they can better appreciate how individual foods or deviations from the meal plan adversely affect their glycemic control. GLYCOHEMOGLOBIN.

Glycohemoglobin (or glycosylated hemoglobin) assays have emerged as the "gold standard" by which glycemic control is measured. The test does not rely on the patient's 1276

ability to monitor or accurately record blood glucose levels, and it is not influenced by acute changes in blood glucose or by the interval since the last meal. Glycohemoglobin is formed when glucose reacts non-enzymatically with the hemoglobin A molecule and is composed of several fractions, the major one being Hb A1c . Total glycohemoglobin (Hb A1 ) and Hb A1c (expressed as the percentage of total hemoglobin) vary in proportion to the average level of glucose over the lifespan of the red blood cell (RBC), thereby providing an index of glycemic control during the preceding 6 to 12 weeks. Several assay methods have been developed that vary in their

precision, yield different ranges for non-diabetic values, and lack common standardization procedures. Clinicians must therefore become familiar with the assays used in their own laboratory and use that specific assay when evaluating changes in glycemic control in individual patients. Although the ambient glucose level is the dominant factor influencing glycohemoglobin, other factors may confound interpretation of the test. For example, any condition that increases RBC turnover (e.g., pregnancy or hemolytic anemia) spuriously lowers glycohemoglobin, regardless of the assay used. Some assays yield spuriously low values in patients with hemoglobinopathies such as sickle cell disease or trait and hemoglobin C or D or spuriously high values when hemoglobin F is increased (e.g., thalassemia, myeloproliferative disorders) or large doses of aspirin are consumed. Thus for unexpectedly high or low values, factors that alter the specific test used should be excluded. In most cases, however, discrepancies between self-monitoring of blood glucose and glycohemoglobin results reflect problems with the former rather than the latter. Although glycohemoglobin provides the most accurate estimate of overall glycemic control, it is less valuable in determining what specific changes in therapy are indicated. Blood glucose measurements are essential to adjust the components of the regimen appropriately. MANAGEMENT PLAN/TREATMENT GOALS.

A management plan should take into consideration the life patterns, age, work and school schedules, psychosocial needs, educational level, and motivation of the individual patient. The plan should include medications, recommendations for lifestyle changes, a meal plan, monitoring instructions (including "sick day" management), and hypoglycemia prevention and treatment strategies. Each component of the plan must be understood and agreed upon by the patient. Active patient participation in problem solving plus ongoing, continued support from the health care team is critical for successful management. At each visit the management plan should be reviewed and an assessment made of the patient's progress in achieving target goals. If the goals are not met, the causes need to be identified and the plan modified accordingly. The history and physical examination should focus on early signs and symptoms of retinal, vascular, neurologic, and foot complications and reinforcement of the diet and exercise prescription. A complete ophthalmologic examination, an assessment of cardiovascular risk factors, and a timed urine collection for albumin should be obtained annually. Formulation of individual target glycemic goals must take into account the results of the DCCT (type 1) and the UKPDS (type 2 diabetes) in the context of the patient's capacity to implement the treatment plan, the risk for hypoglycemia, and other factors that would alter the risk-benefit ratio. Table 242-7 presents target glycemic guidelines for non-pregnant diabetic patients and targets for other factors that increase the potential for diabetic complications. Pancreas/Islet Transplantation

Intensive insulin treatment rarely, if ever restores glucose homeostasis to levels achieved in non-diabetic individuals. The search for more effective methods of treatment thus remains a long-term goal of diabetes research. Efforts focused on transplantation of insulin-producing tissue have resulted in substantial improvement in the outcome of such pancreas transplant surgery in recent years. In major centers, most patients emerge from the perioperative period with a functioning graft, and once insulin independence is established, the majority stabilize for many years. Unfortunately, because of the need for long-term immunosuppression, pancreas transplantation is at present an option for only a select group of patients, mainly for type 1 diabetics who will require immunosuppression for renal allografts. In such individuals, successful pancreas transplantation is more effective in preventing nephropathy in the grafted kidney. Application of islet transplantation to humans with diabetes has proved exceedingly difficult, in part because of difficulty in obtaining sufficient numbers of viable human islets. Thus far, only a small percentage of type 1 diabetic patients have become insulin independent. Interestingly, islet transplantation has been much more successful in patients with chronic pancreatitis who have undergone total pancreatectomy followed by intraportal injection of their own islets. The implication is that the use of immunosuppressive drugs, chronic low-grade rejection of the foreign islet grafts, and activation of an autoimmune response account for the high incidence of failure. If correct, the future of islet transplantation therapy may depend more on manipulation of the islet or the immune system than on technical surgical advances. Prevention of Diabetes

As the pathogenesis of both types of diabetes becomes better understood, the potential for prevention of these diseases is more realistic. Multicenter disease prevention trials are already under way in the United States. In the Diabetes Prevention Trial Type 1, relatives of type 1 diabetic subjects who are at high risk (based on antibody screening and HLA typing for the disease) are given insulin, a therapy used in rodent models of spontaneous autoimmune diabetes to prevent disease expression. The Diabetes Prevention Program is designed to determine whether type 2 can be prevented or delayed with early introduction of lifestyle changes or oral glucose-lowering agents (metformin) in persons with impaired glucose tolerance.

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Chapter 242a - DIABETES MELLITUS - Part II ACUTE METABOLIC COMPLICATIONS HYPERGLYCEMIC STATES. Metabolic decompensation in diabetes is manifested as severe hyperglycemia with or without ketoacidosis. Although diabetic ketoacidosis is generally seen in type 1 patients and non-ketotic hyperosmolar syndrome is generally seen in type 2 patients, exceptions occur. In both conditions mortality increases with age and is usually due to an associated catastrophic illness (e.g., myocardial infarction, cerebrovascular accident, sepsis) or acute complications (e.g., aspiration, arrhythmias, or cerebral edema). Thus treatment does not simply depend on insulin to reverse the metabolic abnormalities that dominate the picture; it also depends on detection and treatment of precipitating illnesses, as well as prompt attention to fluid and electrolyte disturbances. DIABETIC KETOACIDOSIS. Diabetic ketoacidosis may herald the onset of type 1 diabetes, but it most often (>80%) occurs in established diabetic patients as a result of an intercurrent illness (e.g., infection), an inappropriate reduction in insulin dosage, or TABLE 242a-7 -- THERAPEUTIC TARGETS FOR NON-PREGNANT DIABETIC PATIENTS PARAMETERS NORMAL GOAL SIGNALS POSSIBLE INTERVENTION* Premeal glucose (mg/dL)

3 mo, not relieved by rest 2. Pain and stiffness in the thoracic region 3. Limited motion of the lumbar spine 4. Limited chest expansion 5. History of iritis 6. Radiograhic evidence of bilateral sacroiliitis Diagnosis requires 4 of the 1st 5 criteria or sacroiliitis plus 1 of the clinical criteria

Peripheral arthritis >1 mo in association with urethritis and/or cervicitis Criteria for Psoriatic Arthritis Cutaneous evidence of psoriasis plus inflammatory peripheral arthritis or spondylitis 6 wk

ESSG Criteriafor Spondyloarthropathy (1992) Inflammatory spinal pain or peripheral synovitis (asymmetrical or lower limbs) Plus one or more of the following: Alternate buttock pain Sacroiliitis Enthesopathy Positive family history Psoriasis Inflammatory bowel disease Urethritis, cervicitis, or acute diarrhea occuring within 1 mo of the onset of arthritis

Criteria for Diagnosing Spondyloarthropathies by Amor et al. (1993) Lumbar pain at night or morning stiffness Asymmetrical oligoarthritis Buttock pain Alternating buttock pain Sausage-like toe or digit(s) Heel pain or enthesitis Iritis Non-gonococcal urethritis/cervicitis within 1 mo of onset Acute diarrhea within 1 mo of arthritis onset Psoriasis, balanitis, or inflammatory bowel disease Sacroiliitis (bilateral grade 2 or unilateral grade 3) HLA-B27+ or positive family history of a spondyloarthropathy Rapid (0.5 g/day or >3+ if quantitation not performed OR b. Cellular casts--may be red cell, hemoglobin, granular, tubular, or mixed

8. Neurologic disorder a. Seizures--in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance OR b. Psychosis in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance 9. Hematologic disorder

a. Hemolytic anemia with reticulocytosis OR b. Leukopenia 30 min

+

±

+*

±

Variable

Headache and/or scalp tenderness

0

+

0

0

Variable

Pain with active joint movement

+

0

+*

0

Inconstant

Tender joints

±

0

+*

0

Tender spots

Swollen joints

±

±

+

0

0

Muscle weakness

±

0

+*

+

0

Normochromic anemia

+

+

+

0

0

Elevated erythrocyte sedimentation rate

+

+

+

±

0

Elevated serum creatine kinase

0

0

0

+

0

Serum rheumatoid factor

0

0

70%

0

0

Distinct electromyographic abnormality

0

0

0

+

0

Response to non-steroidal anti-inflammatory drug

±

0

+

0

0

0 = absent; + = present; ± = present in minority of cases. *Associated with affected joints. Pain inhibits movement. Disuse atrophy may occur.

1534

TABLE 295-3 -- GIANT CELL ARTERITIS: CLINICAL FINDINGS IN 94 PATIENTS CLINICAL MANIFESTATION

FREQUENCY ( % )

Headache

77

Abnormal temporal artery

53

Jaw claudication

51

Scalp tenderness

47

Constitutional symptoms

48

Polymyalgia rheumatica

34

Fever

27

Respiratory symptoms

23

Facial pain

14

Diplopia/blurred vision

12

Transient vision loss

5

Blindness (partial or complete)

13

Hemoglobin 40 mm/hr

97

After Machado EBV, Michet CJ, Ballard DJ, et al: Trends in incidence and clinical presentation of temporal arteritis in Olmstead County, Minnesota, 1950-1985. Arthritis Rheum 31:745, 1988. clues to the presence of arteritis. In the absence of similar changes in the lower extremities, pulse changes or bruits over the axillary and brachial arteries are more likely to be caused by vasculitis than by arteriosclerosis. Temporal artery biopsy is recommended for all patients suspected of having giant cell arteritis. A biopsy should be performed on the most clinically abnormal artery segment. When the arteries appear normal on examination, a segment several centimeters long should be removed from one temporal artery, and histologic sections should be examined at multiple levels in an effort to find an involved area. In the author's experience, if the first temporal artery biopsy is normal, the second side will yield approximately 10 to 15% additional positive cases. Some patients with polymyalgia rheumatica may be monitored carefully without a temporal artery biopsy. If no signs or symptoms of vasculitis are present and the symptoms and laboratory test parameters respond completely to low-dose corticosteroids, biopsy may be deferred and the patient monitored closely. DIFFERENTIAL DIAGNOSIS. Conditions that have been confused with giant cell arteritis include systemic infections, amyloidosis with prominent vascular involvement, neoplasms, arteriosclerotic vascular disease in patients with an elevated erythrocyte sedimentation rate that is due to some other cause, arteriovenous fistulas, and other forms of vasculitis. Follow-up studies of patients who have had a negative temporal artery biopsy have shown that in only approximately 10% do findings of giant cell arteritis develop; these patients require long-term corticosteroid therapy.

MANAGEMENT Therapy for polymyalgia rheumatica is aimed at alleviating systemic symptoms and musculoskeletal discomfort. Corticosteroids are recommended for most patients, with an initial daily dose of 10 to 20 mg of prednisone (or the equivalent dose of another corticosteroid). Prednisone acts rapidly, and the patient should notice significant improvement within 24 hours. The corticosteroid dose can be reduced as tolerated after 1 month or earlier. Non-steroidal anti-inflammatory drugs may be added to control the mild discomfort that may occur while corticosteroids therapy is being withdrawn and discontinued. In giant cell arteritis, the recommended dosage of prednisone is 40 to 60 mg/day. Vascular complications seldom occur after corticosteroids have been started. If the response to the initial dose of prednisone is incomplete, the dosage should be increased by 20 to 30 mg/day. Usually, if symptoms subside and laboratory values return to normal with a given dose, the disease process is adequately suppressed. Prednisone for both conditions may be administered as a single morning dose or in two to three divided doses per day. The overall goal of therapy is to administer the lowest dose of corticosteroid that adequately controls the arteritis and prescribe it for the shortest necessary time. The dose needed to achieve control varies among patients and must be determined empirically. There is no evidence that corticosteroid therapy alters the natural course of the disease. In a small proportion of cases, the corticosteroid dose cannot be reduced without an exacerbation of the disease. Cyclophosphamide, azathioprine, dapsone, and methotrexate have been reported as steroid-sparing drugs in some instances. The average duration of both polymyalgia rheumatica and giant cell arteritis is about 2 years, during which time the intensity of the process may flare up at times but appears to resolve slowly. The course in individual patients, however, varies considerably, and some may continue with active symptoms for several years. Thoracic aortic aneurysm is a late complication of giant cell arteritis. Aiello PD, Trautmann JC, McPhee TJ, et al: Visual prognosis in giant cell arteritis. Ophthalmology 100:550, 1993. A study of the ocular effects and outcome of vision in giant cell arteritis. Salvarani C, Gabriel SE, O'Fallon WM, et al: The incidence of giant cell arteritis in Olmsted County, Minnesota: Apparent fluctuations in a cyclic pattern. Ann Intern Med 123:192, 1995. A cyclic occurrence of giant cell arteritis suggests a possible infectious link. Weyand CM, Tetzloff N, Bjornsson J, et al: Disease patterns and tissue cytokine profiles in giant cell arteritis. Arthritis Rheum 40: 19, 1997. Manifestations in giant cell arteritis correlated with cytokines found in temporal arteries.

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Chapter 296 - IDIOPATHIC INFLAMMATORY MYOPATHIES Robert L. Wortmann

DEFINITION. The term "idiopathic inflammatory myopathy" designates a group of rare diseases of unknown cause that are characterized by symmetrical proximal muscle weakness and non-suppurative inflammation of skeletal muscle. Specific diagnoses characterized by this term include polymyositis, dermatomyositis, cancer-associated myositis, myositis associated with another connective tissue disease (overlap syndromes), and inclusion body myositis. Patients with any idiopathic inflammatory myopathy generally fulfill the criteria used to define polymyositis originally proposed in 1975 by Bohan and Peter (Table 296-1) .

INCIDENCE. The idiopathic inflammatory myopathies are rare conditions, with an annual incidence ranging between 0.5 and 8.4 cases per 1 million population. The incidence is highest in blacks and lowest in Japanese. Women are generally more often affected than men, with female preponderance most pronounced between the ages of 15 and 44 and in persons having myositis associated with other connective tissue diseases. The gender ratio is equal in older age groups and in myositis associated with malignancy, but it is reversed in inclusion body myositis. Overall, the age of onset has a bimodal distribution, with peaks in children between 10 and 14 and in adults between 45 and 54. The mean age of onset for the subset of myositides with other connective tissue diseases is similar to that for the associated condition. Individuals with myositis associated TABLE 296-1 -- CRITERIA USED TO DEFINE IDIOPATHIC INFLAMMATORY MYOPATHY* 1. Symmetrical weakness of limb girdle muscles and anterior neck flexors with or without dysphagia 2. Elevation in serum of skeletal muscle enzymes, especially creatine phosphokinase 3. Electromyographic changes consistent with inflammatory myopathy: short, small polyphasic motor units; fibrillations; positive waves; and bizarre, high-frequency repetitive discharges 4. Muscle biopsy evidence of fiber necrosis, phagocytosis, and regeneration; variation in fiber size; and inflammatory exudate Note: Patients are classified as having definite disease with four, probable disease with three, and possible disease with two criteria. *These criteria were orginally proposed in 1975 by Bohan and Peter to define polymyositis. At that time the term "polymyositis" was used to represent a specific disease, as well as being a general term representing all the recognized forms of inflammatory myopathy.

1535

with malignancy or inclusion body myositis have a mean age older than 60 years.

PATHOLOGY AND PATHOGENESIS. Abnormalities in skeletal muscle indicative of an idiopathic inflammatory myopathy include muscle fiber degeneration, regeneration, necrosis, phagocytosis, and mononuclear cell infiltration. In polymyositis, necrosis of single muscle fibers is common, and some non-necrotic fibers are invaded by T cells and macrophages. Collections of lymphocytes, plasma cells, and histiocytes are found primarily in the endomysium. Inflammatory aggregates contain high percentages of T cells but few B cells. Over time, fiber diameter variation increases, and interstitial fibrosis develops. Dermatomyositis can be distinguished histologically by the presence of perifascicular atrophy. This characteristic feature results from degeneration of fibers at the periphery of the fascicles secondary to microvascular damage. Analysis of these areas reveals focal capillary depletion and deposition of IgG, IgM, C3, and the complement membrane complex in and around microvascular endothelium. The inflammatory cells are grouped in the perimysium with a perivascular distribution and contain a higher percentage of B cells. In inclusion body myositis, light microscopy reveals inflammatory changes similar to those in polymyositis but with the additional feature of characteristic intracellular vacuoles. The vacuoles are lined with basophilic granules on cryostat sections and eosinophilic material on paraffin sections. Intracytoplasmic or intranuclear tubulofilamentous inclusions are also seen with electron microscopy. These inclusions are straight and rigid and have periodic striations resembling paramyxovirus. Ubiquitin and beta-amyloid protein (two proteins that have been identified in the plaques in brains from patients with Alzheimer's disease) have been identified in the vacuoles and tubulofilamentous inclusions. The idiopathic inflammatory myopathies are believed to be immune-mediated processes triggered by environmental factors in genetically susceptible individuals. This concept is in part based on the prevalence of autoantibodies, inflammatory pathology, association with other autoimmune diseases, and response to corticosteroid therapy. Many patients with idiopathic inflammatory myopathies have circulating autoantibodies (Table 296-2) . Some are termed "myositis-specific autoantibodies" and are seen only in patients with polymyositis or dermatomyositis; others are those associated with other connective tissue diseases. Most myositis-specific autoantibodies are directed against cytoplasmic antigens and bind to evolutionarily conserved epitopes. The percentage of patients with polymyositis and dermatomyositis who have circulating myositis-specific autoantibodies is uncertain, but estimates range between 10 and 50%. Eight different myositis-specific autoantibodies have been described, but no more than one has been found in an individual TABLE 296-2 -- AUTOANTIBODIES FOUND IN PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOPATHY AUTOANTIBODY

CLINICAL ASSOCIATION

Myositis-Specific Autoantibodies Anti-tRNA synthetases Anti-Jo-1 Anti-PL-7 Anti-PL-12 Anti-OJ Anti-EJ

PM with interstitial lung disease, arthritis, and fever; less common in DM

Anti-SRP

PM with poor prognosis

Anti-MAS

PM after alcoholic rhabdomyolysis

Anti-Mi-2

DM

Antinuclear Antibodies Associated with Other Connective Tissue Diseases Anti-SM

SLE

Anti-RNP

SLE, MCTD

Anti-SSA (anti-Ro)

SLE, Sjogren's syndrome

Anti-SSB (anti-La)

SLE, Sjogren's syndrome

Anti-centromere

CREST syndrome

Anti-SCL70

Scleroderma

Anti-PM-1

Scleroderma

Anti-Ku

Scleroderma

Anti-PM-Scl

Scleroderma

Anti-SRP = anti-signal recognition particle; PM = polymyositis; DM = dermatomyositis: SLE = systemic lupus erythematosus; MCTD = mixed (undifferentiated) connective tissue disease; CREST = calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia. patient. The more common myositis-specific autoantibodies are directed against aminoacyl-tRNA (transfer RNA) synthetases and inhibit the activity of the respective antigenic enzyme protein in vitro. The most prevalent antisynthetase antibody is directed against histidyl-tRNA synthetase and is called "anti-Jo-1." Certain picornaviruses can substitute for tRNA and interact with aminoacyl-tRNA synthetase enzymes. Interestingly, amino acid sequences near the active site of histidyl-tRNA synthetase (Jo-1) have some homology with certain capsid proteins in encephalomyocarditis virus, a picornavirus that induces a mouse model of polymyositis. Thus antibodies initially directed against virus or a virus-enzyme complex could cross-react with homologous areas of host proteins or the enzyme itself. This process is termed "molecular mimicry" and could explain the autoantibody production. Several observations emphasize the importance of genetic factors in general and class II antigens in particular in the pathogenesis of inflammatory myopathy (see Chapter 278) . Almost 50% of patients with polymyositis, dermatomyositis, and inclusion body myositis have the HLA-DR3 phenotype. This phenotype is almost always linked with HLA-B8 and is most common in patients with anti-Jo-1 antibodies. HLA-DR52 is found in over 90% of patients who have myositis and anti-Jo-1 antibodies. Viruses, particularly picornaviruses, have been implicated as causes of myositis. Several viruses, especially Coxsackie A9, have been associated with myositis in individual cases; elevated titers to coxsackievirus have been found in childhood dermatomyositis; mumps virus antigen has been demonstrated in inclusions in inclusion body myositis; and certain viral infections can induce inflammatory myopathy in mice, with inflammation persisting long after virus can be detected. The pathologic changes in polymyositis and inclusion body myositis appear to result from cell-mediated, antigen-specific cytotoxicity. Cell adhesion molecules participate in target-effector cell interactions in cell-mediated cytotoxicity and leukodiapedesis. One of these molecules, intercellular adhesion molecule type 1 (I CAM-1), is strongly induced on the surface of non-necrotic muscle fibers. In these disorders, non-necrotic muscle fibers are surrounded by and invaded by CD8+ mononuclear cells, with cytotoxic cells outnumbering suppressor cells by a ratio of 4:1. About 50% of the CD8+ antoinvasive T-cells are HLA-DR positive and express the RD form of the leukocyte common antigen CD45, which suggests that they are activated memory cells. Different immune mechanisms are evident in dermatomyositis. Mononuclear cell invasion of non-necrotic fibers is rare, ICAM-1 is strongly expressed on endothelial cells of perimysial arterioles and venules and on some perifascicular capillaries, cellular infiltration is predominantly perivascular, B cells outnumber T cells, and the CD4/CD8 ratio is higher. These findings indicate that humoral mechanisms play a significant role in the pathogenesis of dermatomyositis. Loss of muscle fibers as a result of the immune response may contribute to muscle weakness in some patients with an idiopathic inflammatory myopathy. However, other factors must also be involved because weakness can occur in the absence of an inflammatory infiltrate or fiber necrosis. These observations suggest that abnormalities of the contractile process may underlie the muscle weakness. Energy (adenosine triphosphate [ATP]) is required for normal muscle contraction and relaxation, as well as the maintenance of membrane integrity. Altered muscle energy metabolism has been demonstrated in vitro in a coxsackievirus B1-induced mouse model of inflammatory myopathy. Muscles from these mice have increased glycolytic activity when compared with controls, as well as decreased activity of myophosphorylase and myoadenylate deaminase. A secondary deficiency of myoadenylate deaminase activity has been observed in muscle from some patients with polymyositis. In vivo 31 P magnetic resonance spectrographic studies of patients with polymyositis and dermatomyositis have shown lower levels of high-energy phosphate-containing compounds at rest, faster depletion of ATP with exercise, and slower recovery rates than seen in normal individuals. These abnormalities reverse as patients improve with therapy, particularly in dermatomyositis. Such studies support the hypothesis that metabolic changes contribute to the muscle weakness in the inflammatory myopathies.

CLINICAL MANIFESTATIONS. The onset of an idiopathic inflammatory myopathy is usually insidious, with no identified precipitating 1536

event. The cardinal feature of any inflammatory myopathy is symmetrical muscle weakness of the shoulder and pelvic girdles, at times accompanied by mild pain and tenderness. Weakness of proximal leg and arm muscles, neck flexors, and pharyngeal muscles may follow. Early symptoms include difficulty getting up from a chair, climbing stairs, and using one's hands above shoulder level. Dysphagia, dysphonia, and dysarthria may develop when the disease affects the pharynx. Morning stiffness, fatigue, and other systemic symptoms are common. Arthralgias are noted with active disease, but frank synovitis is quite rare. With progression, weakness can become so severe that patients cannot lift their extremities against gravity, involved muscles become atrophic, and contractures develop. An explosive onset with rhabdomyolysis, myoglobinuria, and renal failure is rare. Typically, the neurologic examination is normal except for the motor component. Deep tendon reflexes are normal or appear slightly decreased because of muscle weakness. Cranial nerve function is normal. Dysphagia is primarily due to weakness of striated musculature in the posterior of the pharynx and is often associated with a poor prognosis. Patients may have difficulty swallowing liquids, are prone to aspiration, and may have nasal speech. These symptoms may be accentuated by spasm or fibrosis of the cricopharyngeal muscles and may require surgical treatment. Esophageal dysfunction may occur but is often clinically insignificant. Pulmonary manifestations develop in some patients as a result of hypoventilation secondary to muscle weakness, swallowing abnormalities with aspiration, and infection. Interstitial lung disease develops in approximately 5 to 10%. Some patients with interstitial pneumonitis have no respiratory symptoms, but others experience non-productive cough and dyspnea, which may precede the onset of muscle weakness. The restrictive lung disease is associated with bibasilar fine crackles on chest auscultation and reduced diffusion capacity. Symptomatic cardiac problems are unusual, although conduction abnormalities and tachyarrhythmias may be seen on electrocardiograms. Congestive heart failure can result from hypoxemia, pulmonary hypertension, or cardiomyopathy. Raynaud's phenomenon is reported in a small percentage of patients. Periorbital edema may develop in patients with polymyositis. When other cutaneous manifestations are seen, the disease is termed "dermatomyositis." Typically, the rash is erythematous and appears on the face, neck, chest, and extensor surfaces of the extremities. The name "Gottron's patches" is given to raised, red to violet, scaly patches seen over the knuckles, elbows, and knees. A heliotrope rash on the upper eyelids is very characteristic. The term "mechanic's hands" is applied to the darkened or dirty-appearing horizontal lines that develop across the lateral and palmar aspects of the fingers (because of the similarity to changes seen in the hands of people who do manual labor). Capillary nail fold changes are present in some individuals, especially those with Raynaud's phenomenon. These changes include dilated or distorted capillary loops sometimes alternating with avascular areas. Dermatomyositis in children is sometimes referred to by the specific term "childhood dermatomyositis." Childhood dermatomyositis is similar to dermatomyositis in adults, except that vascular involvement is more prominent. Fever, weight loss, and subcutaneous calcifications are more common, and gastrointestinal tract hemorrhage or perforation may occur. When myositis occurs in association with another connective tissue or autoimmune disease, the associated conditions may dominate the clinical picture. The most frequently associated disease is systemic lupus erythematosus (SLE), but others include scleroderma, rheumatoid arthritis, polyarteritis nodosa, giant cell arteritis, autoimmune thyroid disease, insulin-dependent diabetes mellitus, dermatitis herpetiformis, myasthenia gravis, and primary biliary cirrhosis. Approximately 20% of adults with polymyositis or dermatomyositis also have cancer. Although this figure may seem higher than expected for the general population, there appears to be no significant difference in the frequency of malignancy when compared with appropriate age-matched control populations. Most often the myositis and malignancy are diagnosed within a year of each other. In general, the type of neoplasm is that expected for the patient's age. Overall, the most commonly associated tumors are of the breast and lung. Ovarian and stomach cancers occur more frequently than in the general population; rectal and colon cancers are less frequent. Neoplastic disease is less common in patients with interstitial lung disease or in those with an associated connective tissue disease. Inclusion body myositis occurs most commonly in older men and can differ from polymyositis by the additional features of distal muscle weakness, asymmetrical muscle involvement, and neuropathic findings on physical examination and electromyography (EMG).

CLINICAL COURSE AND PROGNOSIS. The overall 5-year survival rate is approximately 80%, with children having the best prognosis. About half of surviving patients with polymyositis or dermatomyositis essentially recover completely. Older patients, those with associated neoplasms, or those with significant pulmonary, cardiac, or gastrointestinal involvement have a poorer prognosis. Patients with antibodies to aminoacyl-tRNA synthetases (i.e., anti-Jo-1) have a very high prevalence of interstitial lung disease, arthritis, and fever and do not respond well to therapy. Those with circulating anti-SRP (signal recognition particle) antibodies have a high prevalence of Raynaud's phenomenon and the worst prognosis of any subset. Although most patients with inclusion body myositis do not improve with therapy, their survival rate appears to be good. Typically the weakness progresses very slowly and may become fixed in some cases.

LABORATORY DATA. Serum levels of muscle-derived enzymes are elevated at some time during the course of the disease in 99% of patients. Creatine phosphokinase (CPK) levels are the most sensitive, but levels of aldolase, aspartate and alanine aminotransferase, and lactate dehydrogenase are also useful. CPK levels can be used as an index of disease activity or therapeutic response in some but not all patients. When normal CPK values are encountered in the presence of active disease, possible explanations include circulating enzyme inhibitors, a possible associated malignancy, or long-standing disease with severe muscle atrophy. The MB isoenzyme of CPK may be increased in the absence of cardiac involvement because of expression of that isoform in regenerating skeletal muscle fibers. The erythrocyte sedimentation rate remains normal in over half the patients and, when elevated, does not correlate with the degree of weakness. Complete blood count, urinalysis, and other laboratory studies are usually normal unless an associated connective tissue disease or neoplasm is present. Circulating autoantibodies are common in patients with idiopathic inflammatory myopathies (see Table 296-2) . The most common myositis-specific autoantibody, anti-Jo-1, is found in polymyositis and less commonly in dermatomyositis. Certain antinuclear antibodies may herald an associated connective tissue disease: anti-SM and anti-double-stranded DNA for SLE; anti-SS-A and anti-SS-B for Sjogren's syndrome; anti-centromere for CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia); and anti-PM-1, anti-Ku, anti-PM-Sc1, and anti-SCL70 for scleroderma. The EMG is abnormal in 90% of patients. Classic changes include the triad of (1) small-amplitude, short-duration, polyphasic motor unit potentials; (2) fibrillation, positive waves, and increased insertional irritability; and (3) spontaneous, bizarre high-frequency discharges. The complete triad may be found in only 40% of patients, and in some patients changes are restricted to the paraspinal muscles.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS. Criteria are useful in establishing the diagnosis of an idiopathic inflammatory myopathy (see Table 296-1) . These criteria can be used only after other causes are excluded because no change or test is specific for the diagnosis. CPK elevation can occur in a wide number of conditions, as well as with blunt or sharp trauma, aerobic exercise, EMG studies, muscle biopsies, or drugs that retard the elimination of CPK from the serum such as barbiturates or narcotics. Normal blacks have higher levels of CPK than whites do, frequently with values above the normals established for large populations. The EMG changes seen in polymyositis are not specific. Even in the classic case, the change can only be considered myopathic and consistent with inflammation. The EMG is useful in identifying areas of abnormality to be biopsied, but biopsy should not include the actual site of EMG needle insertion. Because of the symmetrical nature of this disease, it is best to limit the EMG to one side of the body and perform biopsy on the other side. Magnetic resonance 1537

imaging may provide an effective, non-invasive means for identifying the site for biopsy and for monitoring the course of the disease, especially in dermatomyositis. Although the possibility of malignancy should be considered in each patient with myositis, extensive undirected testing is not advised. Clues to the coexistence of neoplastic disease are almost always apparent on the history, physical examination, or routine laboratory tests. Routine screening should be appropriate for the patient's age and sex. A variety of other diseases may cause muscle weakness (Table 296-3) , and patients with these conditions may fulfill some or all four criteria for polymyositis (see Table 296-1) ; thus these diagnoses must be excluded before the diagnosis of an idiopathic inflammatory myopathy can be made. A careful history and physical examination coupled with the judicious use of laboratory tests allow one to sort through the extensive differential list efficiently. For example, a careful review of medication use may reveal an agent that induces muscle injury such as alcohol, corticosteroids, cimetidine, colchicine, lovastatin, or zidovudine (AZT). On physical examination, asymmetrical weakness and distal extremity involvement, as well as abnormal reflexes, altered sensation, or cranial nerve abnormalities, should suggest a neurologic disease. Patients with inclusion body myositis may prove the exception because some have distal or . TABLE 296-3 -- DIFFERENTIAL DIAGNOSIS OF MUSCLE WEAKNESS Immunologic Polymyositis Dermatomyositis Inclusion body myositis Polymyalgia rheumatica Temporal arteritis Rheumatoid arthritis Systemic lupus erythematosus Polyarteritis nodosa Scleroderma Adult Still's disease Eosinophilic fasciitis Graft-versus-host disease Endocrine Hypothyroidism Hyperthyroidism Hyperparathyroidism Hypocalcemia Cushing's disease Addison's disease Aldosteronism Malabsorption Diabetic amyotrophy Infectious Influenza, Coxsackie, HIV, and other viruses Infectious mononucleosis Rickettsia Toxoplasmosis

Trichinella Schistosomiasis Bacterial toxins Staphylococcal Streptococcal Clostridial Toxic (Drug Related) Alcohol Chloroquine/hydroxychloroquine Clofibrate Cocaine Colchicine Cromolyn Cyclosporine Emetine Gemfibrozil L-Tryptophan

Lovastatin Penicillamine Zidovudine (AZT) Miscellaneous Hypereosinophilic syndromes Rhabdomyolysis Sarcoidosis Fibromyalgia Metabolic-Nutritional Neurologic Denervating disorders Amyotrophic lateral sclerosis Neuromuscular junction disorders Myasthenia gravis Eaton-Lambert syndrome Muscular dystrophies Limb-girdle Becker's syndrome Duchenne's syndrome Neuropathies Guillain-Barre syndrome Diabetes mellitus Porphyria Metabolic-Nutritional Uremia Hepatic failure Hypercalcemia Hypocalcemia Hyperkalemia Hypokalemia Hypernatremia Hyponatremia Hypomagnesemia Hypophosphatemia Periodic paralysis Vitamin D deficiency Vitamin E deficiency Carcinomatous Neuropathy Neuromyopathy Myositis Microembolization Eaton-Lambert syndrome Inherited Deficiency States Glycogen storage diseases McArdle's syndrome (myophosphorylase) Phosphofructokinase Debrancher enzyme Brancher enzyme Phosphoglycerate kinase Phosphoglycerate mutase Lactate dehydrogenase

Acid maltase Lipid disorders Carnitine (primary and secondary) Carnitine palmitoyltransferase Purine disorders Myoadenylate deaminase Mitochondrial myopathies Psychosomatic Hysterical (?)

TABLE 296-4 -- PROTOCOL FOR FOREARM ISCHEMIC EXERCISE TESTING Procedure Venous blood samples are drawn for ammonia and lactate levels from the non-dominant arm, preferably without a tourniquet. A sphygmomanometer is inflated around the upper part of the dominant arm to at least 20 mm Hg above systolic pressure. The subject then squeezes the dominant hand as vigorously as possible at a rate of one squeeze every 2 seconds for 2 minutes. After 2 minutes of exercise, the cuff is deflated. Two minutes after the cuff is deflated, venous samples are taken from the dominant arm for lactate and ammonia levels. Interpretation Normal individuals exercising with maximal effort increase lactate and ammonia levels at least three-fold over baseline values. Individuals with a glycogen storage disease elevate ammonia levels normally but cannot raise lactate levels. Myoadenylate deaminase-deficient individuals raise lactate levels, but ammonia levels remain at baseline values. Falsely abnormal results may be obtained if the subject does not exercise with sufficient intensity. Abnormal results must be supported by a muscle biopsy to confirm the putative diagnosis. Inclusion body myositis may be difficult to separate from some cases of muscular dystrophy. Serum electrolytes (sodium, potassium, calcium, phosphorus, and magnesium) should be measured. An abnormality in any electrolyte may interfere with normal functioning of muscle fibers and result in weakness or myalgias. Uncovering an electrolyte abnormality usually reveals a reversible myopathy, especially if the cause of the electrolyte disturbance is identified. Some inherited metabolic myopathies can mimic inflammatory myopathy. Individuals with glycogen storage diseases such as myophosphorylase deficiency (McArdle's disease) or phosphofructokinase deficiency, as well as some with carnitine deficiency or myoadenylate deaminase deficiency, have proximal muscle weakness, elevated CPK levels, and myopathic EMG abnormalities. A forearm ischemic exercise test can be used to screen for the glycogen storage diseases and myoadenylate deaminase deficiency (Table 296-4) .

TREATMENT. During the active stage of the disease, bed rest is essential, and physical therapy with passive range-of-motion exercises should be performed to maintain function and avoid contractures. Smoking is prohibited, and the head of the bed should be elevated in patients at risk for aspiration. Antacids or H2 antagonists may also be useful to raise the pH of gastric fluids. Treatment with corticosteroids is empirical but the standard. Initially, prednisone is used in single daily doses of 1 to 2 mg/kg. In responsive patients, muscle strength usually improves in 1 to 2 months, and the CPK normalizes in 3 months. Daily high-dose prednisone should be continued until strength has remained normal for 3 to 6 weeks. Once remission is attained, steroid use is tapered very gradually, a process that may require up to 2 years. Alternate-day use is recommended only when the disease is under excellent control. Steroid failures may be attributed to an inadequate initial dosage, tapering too quickly, inaccurate diagnosis, or an associated malignancy, refractory disease, or coincident steroid myopathy. Improvement in muscle strength when the steroid dose is raised indicates active disease; improved strength with a lower dose of steroid implicates steroid myopathy. Immunosuppressive agents are used in patients who do not respond adequately to corticosteroids. Daily oral azathioprine and weekly oral or parenteral methotrexate are the usual next choices. Cyclophosphamide, chlorambucil, cyclosporine, and intravenous immunoglobulin have been used in refractory cases. Only a small percentage of patients with inclusion body myositis achieve remission with steroid or other immunosuppressive therapy. Despite this poor prognosis, a therapeutic trial is indicated because remission occurs in some cases and progression may be delayed in others. However, if some benefit is not observed, drug therapy should be discontinued to avoid side effects and toxicity. Drake LA, Dinehart SM, Farmer ER, et al: Guidelines of care for dermatomyositis: American Academy of Dermatology. J Am Acad Dermatol 34:824, 1996. Recent recommendations for the management of dermatomyositis by a large consensus group. Oddis C: Idiopathic inflammatory myopathy. In Wortmann RL (ed): Diseases of Skeletal 1538

Muscle. Philadelphia, Lippincott-Williams & Wilkins, 1999. Recent comprehensive discussion that includes historical perspective. Targoff IN: Immune manifestations of inflammatory muscle disease. Rheum Dis Clin North Am 20:857, 1994. Detailed review of the myositis-specific antibodies as well as autoantibodies associated with other connective tissue diseases. Wortmann RL: Inflammatory diseases of muscle. In Kelley WN, Harris ED Jr, Ruddy S, et al (eds): Textbook of Rheumatology, 5th ed. Philadelphia, WB Saunders, 1997, p 1177. In-depth review of the inflammatory myopathies. Wortmann RL: Inflammatory muscle disease. In Weisman M, Weinblatt M (eds): Drug Therapy for the Rheumatic Diseases. Philadelphia, WB Saunders, 1994. Current status of treatments used.

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Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 297 - THE AMYLOID DISEASES Louis W. Heck

DEFINITION. Amyloidosis is not one clinical entity but a group of diverse, structurally driven protein deposition diseases. They are similar in that protein deposition occurs extracellularly and these deposits stain eosinophilic with standard tissue histologic stains, bind Congo red dye, and emit an apple-green birefringence when examined under polarized light microscopy; they also exhibit metachromasia with crystal violet and have an array of 75- to 100-A non-branching fibrils by electron microscopy and a twisted, beta-pleated sheet, antiparallel configuration by x-ray crystallography. They differ, however, in the biochemical nature of the proteinaceous deposits, the "etiology" of the associated diseases (neoplastic, inflammatory, degenerative, hereditary), the tropism of protein deposition, and the spectrum of disease manifestations. Thus amyloidosis is not a single disease but a variety of diseases ranging from asymptomatic conditions with focal deposits discovered as an incidental finding to generalized involvement with severe multiorgan failure. Before the early 1970s, all amyloid deposits were thought to be chemically identical despite the clinical observations that systemic amyloidosis occurred in certain patients with either plasma cell myeloma or diverse chronic inflammatory states such as tuberculosis, osteomyelitis, rheumatoid arthritis, ankylosing spondylitis, and Crohn's disease. The major breakthrough in the physicochemical characterization of amyloid proteins resulted from the discovery that many of the non-amyloid proteins in amyloid-laden tissue could be extracted with physiologic saline and the insoluble amyloid fibrils solubilized by using dilute aqueous solutions and/or chaotropic agents such as urea and guanidine, isolated by column chromatography, and biochemically defined by amino acid sequence analyis. By studying amyloid-laden tissues and using the aforementioned techniques, many different amyloid proteins and precursor proteins associated with clinical syndromes or specific diseases have been identified (Table 297-1) . All the monomeric amyloidogenic proteins have a beta-pleated sheet conformation in solution, and many have been demonstrated to form insoluble beta-pleated sheet fibrils in vitro. The known properties of tissue amyloid deposits such as binding to Congo red, resistance to proteolysis, and insolubility in physiologic solutions are directly attributed to the periodic beta-pleated sheet motif. The formation of beta-pleated sheets in vivo is an extremely complex process involving crucial ion concentrations and hydrogen bonding between many similar monomeric polypeptide chains at high focal concentrations, as well as molecular interactions with the myriad extracellular matrix components. Furthermore, most amyloid deposits contain P component, an acute-phase circulating serum protein. No clinical classification of the amyloidoses is satisfactory. One method is to consider three major systemic forms--AA, AL, and ATTR; two major localized forms--Abeta2 and Abeta; and several miscellaneous forms (see Table 297-1) . Each form has many clinical features.

PATHOGENESIS AND CLINICAL MANIFESTATIONS. PRIMARY (AL) AMYLOIDOSIS. AL amyloid was the first amyloid protein defined biochemically and shown to be identical to the variable region of immunoglobulin light chain (Bence Jones protein). AL amyloidosis is the most common of the systemic amyloidoses in the United States and is associated with plasma cell myeloma (20%) or plasma cell dyscrasias (80%), with involvement of skin and subcutaneous tissue, nerve, liver, spleen, heart, kidney, and lung. In a large retrospective series of patients with AL protein, approximately 50% had initial symptoms of fatigue and weight loss; less frequent symptoms included peripheral edema, dyspnea, paresthesias, lightheadedness, hoarseness, purpura, and bone pain (usually related to bone lesions in plasma cell myeloma). The initial physical findings revealed a palpable liver and peripheral edema in one third of the patients. Orthostatic hypotension, purpura, macroglossia, a palpable spleen, skin papules, ecchymoses, and lymphadenopathy were found less commonly. The signs and symptoms result from amyloid infiltration of organs and tissues with subsequent dysfunction. Examples of syndromes include those related to nerve tissue such as carpal tunnel syndrome, peripheral neuropathy with paresthesias of the fingers and toes, and sympathetic dysfunction manifested by orthostatic hypotension, impotence, sweating abnormalities, and gastrointestinal disturbances secondary to autonomic nerve involvement; other syndromes include those related to congestive heart failure and characterized by either TABLE 297-1 -- NOMENCLATURE AND CLASSIFICATION OF THE AMYLOIDOSES, 1990 AMYLOID PROTEIN Major systemic amyloidoses

1. AA

CLINICAL STATE(S) 1. Chronic inflammatory conditions a. Infectious: tuberculosis, osteomyelitis, etc.

MAJOR ORGAN/TISSUE INVOLVEMENT* K, L, S, GI, Sc H, unusual

b. Non-infectious: juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's N, rare disease, etc. 2. Familial Mediterranean fever 2. AL

Plasma cell dyscrasia 10% multiple myeloma/macroglobulemia

H, L, S, T N, GI, Sc

90% idiopathic; "primary" Major localized amyloidoses

3. ATTR

Various familial polyneuropathies and cardiomyopathies

N, H, K, E, GI, Sc

4. Abeta2 M

Chronic dialysis usually longer than 8 yr

B, Sy, Ts

5. Abeta

1. Alzheimer's disease 2. Down syndrome 3. Hereditary cerebral hemorrhage, Dutch

C, CV

4. Non-traumatic cerebral hemorrhage of the elderly Miscellaneous amyloidoses

6. A Apo AI

Familial polyneuropathy, Iowa

N, K

7. A Gel

Familial amyloidosis, Finnish

CN, E, skin

8. A Cys

Hereditary cerebral hemorrhage, Icelandic

C, CV

9. A Scr

Creutzfeldt-Jakob disease

C

10. A Cal

Medullary carcinoma of the thyroid

Th

11. AANF

Atrial amyloid

H

12. AIAPP

Diabetes mellitus, insulinomas

P

*B = bone; C = cerebrum; CN = cranial nerves; CV = cerebral vessels; E = eye; GI = gastrointestinal; H = heart; K = kidney; L = liver; N = nerve; P = pancreas; S = spleen; Sc = subcutaneous tissue; T = tongue; Th = thyroid; Ts = tenosynovium; Sy = synovium.

1539

predominantly right-sided failure with restrictive cardiomyopathy (see Chapter 64) secondary to stiff noncompliant ventricles and a thick intraventricular septum (multiple discrete 3- to 5-mm highly refractile echoes with a "speckled" pattern on two-dimensional echocardiography) or, rarely, a dilated cardiomyopathy with biventricular failure. Both forms may be associated with conduction disturbances. Renal involvement consisting of albuminuria, full expression of the nephrotic syndrome (see Chapter 106) , and slow progressive renal failure may be seen. Finally, ecchymoses and "pinch purpura" may result from minor skin trauma caused by increased fragility from amyloid infiltration of the small blood vessels. SECONDARY (AA) AMYLOIDOSIS. AA amyloidosis was the 2nd systemic type of amyloidosis shown to be due to protein deposition--in this case the precursor protein is a serum component (serum amyloid A) synthesized in the liver that may increase 100- to 200-fold following an inflammatory stimulus. Certain monocyte/macrophage cytokines such as interleukin-1 (IL-1), tumor necrosis factor, and IL-6 may up-regulate hepatic gene expression of this protein. Secondary amyloidosis usually involves the liver, spleen, and kidneys; heart involvement is less frequent than seen in primary amyloidosis, and nerve involvement is very infrequent. Some of the associated infectious diseases include osteomyelitis, tuberculosis, and bronchiectasis, and some of the non-infectious inflammatory states include rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, and familial Mediterranean fever. Curiously, the renal disease may be slow and indolent, with progressive proteinuria evolving into nephrotic syndrome and persisting for 5 to 10 years before end-stage renal disease. In Europe, renal amyloidosis has been reported as the major cause of death in patients with juvenile rheumatoid arthritis, but this associated complication has not been seen in the United States. Another interesting observation is that AA may be resorbed in vivo, as manifested by reduction of an enlarged liver or spleen or reduction in proteinuria without defined treatment of the underlying disorder. Finally, the successful use of colchicine to reduce the attacks and development of amyloidosis in patients with familial Mediterranean fever, decrease proteinuria, and improve renal function in some cases mandates that AA be considered carefully and ruled out in all amyloid patients. FAMILIAL (ATTR) AMYLOIDOSIS. ATTR amyloidosis was the 3rd systemic amyloidosis to be defined and shown to be associated with the presence of an abnormal plasma pre-albumin protein that normally functions to transport thyroxine and retinol-binding protein and was subsequently termed transthyretin. It was originally defined as an autosomal dominantly inherited peripheral neuropathy (see Chapter 500) occurring in middle to late life that was progressive over the next several decades with additional autonomic neuropathy and variable organ involvement, primarily in Portuguese patients. Subsequently, many clinical manifestations defining different kindreds in Europe and the United States have resulted from mutations (greater than 50) in the gene for transthyretin; amino acid substitutions in this transport molecule have been associated with variable amyloid infiltration in the heart, bowel, and kidney. A recent report has defined an increased prevalence of late-onset cardiac amyloidosis in elderly blacks with variant-sequence transthyretin (isoleucine l22). DIALYSIS-RELATED (beta2 -MICROGLOBULIN) AMYLOIDOSIS (Abeta2 M). This localized amyloidosis occurs in most patients undergoing maintenance hemodialysis or peritoneal dialysis for longer than 8 years and is due to the deposition of beta2 -microglobulin amyloid in periarticular, joint, bone, and carpal tunnel tissue. Some of the rheumatic complaints/findings include chronic shoulder pain with tenderness over the subacromial bursae, pain and swelling of the wrist and finger joints, proliferative tenosynovium over the wrist extensor tendons, and radiographic evidence of subchondral erosions of the carpal bones, femur, and humerus. Pathologic fractures of the humerus and femur have been described. beta2 -Microglobulin is the non-covalently associated chain of class I major histocompatibility complex molecules and is present on virtually all human nucleated cells. Catabolism of this small protein depends on normal kidney filtration and excretion. In dialysis patients and those with end-stage renal disease, plasma levels of beta2 -microglobulin are elevated. Efforts to effectively remove this protein with conventional dialysis membranes of cellulose acetate or cuprophane have not been successful because of poor protein clearance. Furthermore, these membranes induce complement activation and generation of IL-1, which may result in beta2 -microglobulin accumulation. beta-PROTEIN (ALZHEIMER'S DISEASE) AMYLOIDOSIS. Alzheimer's disease, the most common cause of dementia in elderly patients, afflicts 5 to 10% of the population older than 65 years (see Chapter 449) . In neuropathologic studies of the brains of patients with Alzheimer's disease, neurofibrillary tangles and neuritic plaques are frequently found in the amygdala, hippocampus, and frontal, temporal, and parietal lobes. In addition, acellular thickening of the small and medium-sized arteries of the leptomeninges and cerebral cortex have been seen in aged patients and those with Alzheimer's disease. By standard histologic techniques, the amorphous material in the walls of meningeal vessels and the central region of neuritic plaques has the characteristic staining property for amyloid. The chemical nature of both amyloid deposits has been identified as a novel 40-amino acid protein (beta-protein) that is generated by proteolysis of a much larger transmembrane glycoprotein termed "beta-amyloid precursor protein." In some forms of familial Alzheimer's disease, point mutations have resulted in single-amino acid substitutions in this precursor protein. Recent studies have reported that most patients with late-onset sporadic Alzheimer's disease have a strong association of ApoE4 alleles and Abeta deposits within the cerebrum and cerebral vessels, which suggests the possibility that bimolecular complexes between ApoE4 and Abeta may be important in the extracellular deposition and formation of cerebral amyloid. There is evidence that cerebrovascular deposition of beta-protein amyloid is an important etiology of non-traumatic/non-hypertensive brain hemorrhage in the elderly, usually manifested as cerebral lobe hemorrhage involving the cortex and subcortical white matter. In addition, a familial syndrome defined in a Dutch kindred in which certain family members died in their 40s or 50s of cerebral hemorrhage (hereditary cerebral hemorrhage with amyloidosis, Dutch type) has been shown to be due to an amino acid substitution in the protein.

CLINICAL MANIFESTATIONS. The signs and symptoms suggestive of the amyloidoses result directly from tissue/organ infiltration with subsequent dysfunction. As can be seen in Table 297-1 , multiple organ involvement is common but variable in degree, which necessitates formulating a list of differential diagnoses to exclude other localized or systemic diseases. For example, carpal tunnel syndrome is a common clinical entity that is seen very frequently in patients undergoing hemodialysis for longer than 8 to 10 years; it is due to Abeta2 M deposition in the tenosynovium of the carpal tunnel. Such deposition is also commonly found in the AL and ATTR forms and in non-amyloid diseases such as hypothyroidism, rheumatoid arthritis, and diabetes mellitus. Thus many disorders must be considered and subsequently excluded. The AA, AL, and ATTR forms may be associated with significant proteinuria or nephrotic syndrome, and many primary glomerular diseases must be excluded. The AL and ATTR forms may also be the cause of vexing unexplained congestive heart failure with cardiomyopathy in patients who have had repeated heart catheterization and coronary angiography without a clear answer. Clues to cardiac amyloidosis may be present on the standard 12-lead electrocardiogram and include decreased QRS voltage, first-degree atrioventricular block with intraventricular conduction defects, and Q waves in precordial leads V1 to V3 (pseudoinfarction); findings of a "speckled" pattern of intraventricular septum/myocardium on two-dimensional echocardiography also provide clues to cardiac amyloidosis. Peripheral neuropathies may be the initial and dominant expression primarily in the ATTR and other familial forms (see Table 297-1) . Generally, the onset of symptoms occurs in early middle age (30 to 40 years old) in the lower extremity, with progressive sensorimotor involvement including the proximal and truncal sensory nerves. Foot ulcers with secondary infections may occur. An autonomic neuropathy with orthostatic hypotension, impotence, and diminished peristalsis with pseudo-obstruction, diarrhea, or malabsorption may be present. Gastrointestinal bleeding and/or perforation may be associated with amyloid infiltration of the lamina propria and submucosal blood vessels. Often, many interacting variables come into play; for example, orthostatic hypotension in an amyloid patient may result from the combination of restrictive cardiomyopathy with 1540

diastolic dysfunction, diminished intravascular volume, and sympathetic dysfunction. Two uncommon syndromes may be easily confused with amyloidosis. The POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin findings) (see Chapter 244) is a plasma cell dyscrasia with a constellation of diverse features similar to the systemic/localized amyloid syndrome, but no amyloid deposits have been described in these patients. Immunotactoid glomerulopathy (fibrillary renal deposits) is characterized by progressive proteinuria,

microscopic hematuria, and hypertension. Renal biopsy tissue has variable glomerular deposits containing IgG, IgM, C3, C4, and lambda and kappa light chains (immunotactoid). On electron microscopy, fibrillary material is deposited within the mesangium and capillary walls and can be differentiated from typical amyloid fibrils in that the fibrils are thicker and do not stain with Congo red.

DIAGNOSIS. The diagnosis is made by detecting amyloid deposits in tissue preparations stained with Congo red; polarized light microscopy discloses an apple-green birefringence. If a patient is suspected of having one of the systemic amyloidoses (AL, AA, ATTR), aspiration and staining of abdominal subcutaneous fat tissue should be performed and can be done rapidly and safely at the bedside. Fat tissue is obtained with a 16-gauge needle fixed to a 20- to 30-mL syringe--repeated movement of the needle with gentle pulling of the syringe barrel to produce negative pressure is done to obtain fragments of the fatty tissue. The fatty fluid and fragments are placed on alcohol-cleaned glass slides, air-dried, and submitted for Congo red staining. Because variable false-negative results have been reported, repeat biopsy of the subcutaneous tissue or an alternative site such as the rectal mucosa is warranted. The redundant mucosal folds (valves of Houston) may be visualized directly and tissue (including the vascular submucosa) obtained by pincer forceps with bleeding controlled by cautery. Other biopsy sites include carpal tunnel tissue, kidney, sural nerve, heart (endomyocardial biopsy of the right ventricle), bone, and synovium. Staining of amyloid deposits in the synovial fluid of patients with the AL and Abeta2 M forms has been described. In general, biopsy of the liver should be avoided because of the risk of bleeding. Attempts to define the chemical amyloid type should be made. For example, specific antisera to lambda and kappa light chains, serum amyloid A, beta2 -microglobulin, and transthyretin are commercially available to stain the tissue via immunofluorescent or immunoperoxidase methods. In patients with suspected AL amyloidosis with or without myeloma, agarose gel electrophoresis of serum and concentrated urine may be done easily. The monoclonal paraprotein is separated from other serum components by electrophoresis; interacted with separate antisera to lambda and kappa light chains, IgM, IgA, and IgG (immunofixation); and identified by protein staining. Bone marrow aspiration and biopsy are usually done to quantify the number of plasma cells, which can be stained for amyloid. Scintigraphy using radiolabeled P component, which binds to all amyloid types, remains experimental and cannot be justified as a screening or routine test.

TREATMENT. AL amyloidosis is treated with chemotherapy as a plasma cell neoplasm, even though only 10 to 20% of patients have plasma cell myeloma. Some have used a treatment protocol of melphalan, 0.15 mg/kg/day in two divided doses, and prednisone, 0.8 mg/kg/day in four divided doses. The duration of each treatment is 7 days, with repeated cycles every 6 weeks. Diuretics may be necessary to treat fluid retention. Every patient with AL amyloidosis should be given a trial with this regimen, even though the response rate is disappointingly low at approximately 20%. However, dramatic resolution of multiorgan dysfunction/amyloid infiltration with cyclic prednisone and melphalan treatment has been reported. Newer treatments involving dose-intensive melphalan therapy with either allogeneic bone marrow transplantation or autologous growth factor-mobilized blood stem cells have been performed in a few patients with AL amyloid; complete remission of the plasma cell dyscrasia and organ-specific disease was noted after a 1-year follow-up. Clearly, further long-term studies need to be done to assess efficacy. Successful prevention and treatment of the amyloidosis of familial Mediterranean fever with low-dose colchicine, 0.6 mg once or twice daily, have been dramatic developments in the treatment of AA amyloidosis. If the amyloidosis is related to an infectious process such as tuberculosis, it must be defined and treated aggressively. Likewise, any non-infectious inflammatory condition should be treated and patients given colchicine concomitantly. Since 1993, several hundred patients have received liver transplants for the treatment of ATTR amyloidosis; the abnormal transthyretin protein in the blood disappeared, and the severity of neuropathy improved in some patients. However, guidelines for hepatic transplatation have not been defined and results of long-term outcome have not been published. Abeta2 M is a very common localized amyloidosis that is thought to result from poor clearance of beta2 -microglobulin by conventional dialysis membranes, with subsequently high levels of this protein in serum and tissues enhancing fibril formation. A new group of synthetic high-flux, highly permeable dialysis membranes (polycarbonate, polymethylmethacrylate, polyacrylonitrile) are currently available but very expensive. Long-term studies are necessary to determine whether these new synthetic membranes will prevent dialysis-related Abeta2 M amyloidosis. No preventive therapy for Alzheimer's disease is currently available. Research is currently being performed to understand the the role of ApoE-Abeta complexes in the formation of neuritic plaques. Benson MD: Amyloidosis: In Beaudet AL, Scriver CR, Sly WS (eds): The Metabolic Basis of Inherited Disease. New York, McGraw-Hill, 1994. A superb review of amyloidosis focusing primarily on the ATTR forms. Falk RH, Comenzo RL, Skinner M: The systemic amyloidoses. N Engl J Med 337:898, 1997. A review of the clinical features of AL, AA, and ATTR amyloid and recent progress in pathogenesis and new treatments of these disorders. Jacobson DR, Pastore RD, et al: Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med 336:466, 1997. A newly described senile cardiac amyloidosis primarily in older blacks that is underrecognized.

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Chapter 298 - BEHCET'S DISEASE Eugene V. Ball

Behcet's disease is idiopathic and multisystemic and can closely resemble sarcoidosis. Its symptoms appear insidiously, one by one, or dramatically and involve several organs. They commonly wax and wane. Although no invariable symptom of Behcet's disease can be found, certain symptoms occur often enough to define the syndrome and serve as the basis for diagnostic criteria. One set of criteria in common use requires the presence of recurrent oral ulcers and any two of the following: genital ulcers, uveitis, cutaneous or large vessel inflammation, arthritis, and meningoencephalitis. An "incomplete" form has been defined as recurrent aphthous ulcers and any one of the other features. Although oral ulcers are the linchpin of diagnostic criteria, a diagnosis of probable Behcet's disease is tenable when several of these symptoms occur together in the absence of aphthous ulcers and when other known causes can be excluded. Diagnosis has been possible in some patients only after as many as 20 years of minor symptoms. No laboratory tests are diagnostic.

CLINICAL MANIFESTATIONS. Table 298-1 lists manifestations of the disease in one group of 60 patients. Constitutional signs such as fever and weight loss were noted in 63%. At least 24 patients from Mediterranean areas have had both Behcet's disease and secondary (AA) amyloidosis. Painful oral ulcers are round or oval and usually multiple. Recurrent

MANIFESTATION

TABLE 298-1 -- MAJOR MANIFESTATIONS OF BEHCHET'S DISEASE PREVALENCE (% )

Mouth ulcers

97

Genital ulcers

83

Uveitis

48

Joint pain

48

Phlebitis

17

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oral ulcers may be the only sign of Behcet's disease; for example, of 67 patients with recurrent ulcers only who were monitored in a Behcet's disease clinic in Korea, other signs of the disease eventually developed in 52%. On the other hand, isolated genital ulcers are seldom indicative of Behcet's disease. Ulcers occur elsewhere on the skin, and an assortment of non-ulcerative skin lesions can be found such as erythema, erythema nodosum, photosensitivity, and spontaneous pustules. The pustular reaction of the skin to intradermal needle prick (sometimes referred to as "pathergy") was once thought to be pathognomonic of Behcet's disease, but this reaction occurs in no more than 70% of patients, usually in those with extensive disease. In a group of 85 Saudi patients, the pathergy test was positive in only 15 (17.6%). Furthermore, it is non-specific in that it was positive in 7% of one group of healthy control subjects. Eye involvement is common: 10 to 15% of cases of acquired blindness among Japanese are thought to be due to the uveoretinitis of Behcet's disease, which is characterized by waves of repeated attacks and spontaneous improvement. Decreased visual acuity results from retinal veno-occlusive disease, inflammation with secondary glaucoma, cataracts, or vitreous hemorrhage; retinal vein thrombosis leading to sudden blindness is not rare. As many as a quarter of all patients will have phlebitis or arteritis predisposing to thrombosis and aneurysms; for example, 10% of a group of 450 Tunisians had arterial aneurysms, large artery occlusions, or both. Thromboses occur in almost any vessel, including the superior vena cava, and Behcet's disease was found in 7 of 44 patients with cavernous transformation of the portal vein. Aneurysms are particularly common in pulmonary arteries and are most often single, but as many as 14 have occurred in 1 patient in less than 1 year. Pulmonary arteritis produces dyspnea, chest pain, cough or hemoptysis and is a significant cause of death. Its radiographic signs include scattered infiltrates and pleural effusions. The arthritis of Behcet's disease is usually intermittent, self-limited, and localized to the knees and ankles; however, bone erosions have been observed in hip, heel, wrist, knee, ankle, and foot radiographs. Aseptic meningitis and transverse myelitis are common in neurologic Behcet's disease; other manifestations include encephalopathy, seizures, bulbar palsy, ataxia, transient ischemic attacks, strokes, and pseudotumor cerebri. These complications may be acute or gradual in onset and cause persistent neuropathies or death, or they may resolve completely. Focal intracranial abnormalities are detected by imaging studies. Small and large ulcers in the gut produce symptoms of inflammatory bowel disease and perforation and are more common in Japanese than in Turkish patients.

PREVALENCE. Behcet's disease is rare in the Americas and Europe. It is more prevalent--and more virulent--in Turkey and the Middle and Far East. Evidence of Behcet's disease was found in 19 of 1531 persons aged 10 or older in a field survey conducted in rural Turkey. On Hokkaido, Japan, its estimated prevalence was 1 in 1000 persons, but Behcet's disease is less common in ethnic Japanese living in Hawaii. Its prevalence was estimated at 1 in 25,000 in Olmsted County, Minnesota.

GENETICS AND PATHOLOGY. Although not considered hereditary, Behcet's disease was present in members of four HLA-B51-positive families. HLA-B51, a split antigen of HLA-B5, has been detected in 51% of patients with Behcet's disease versus 16% of control subjects in Japan and in 62% with the disease versus 29% of control subjects in Iraq. The HLA-B5101 allele of B51 was found in all 46 HLA-B51-positive Japanese patients with Behcet's disease; 80% of 31 Greek patients were also B5101 positive. The histopathologic characteristics of Behcet's disease are non-specific. Despite its classification as a vasculitis, fibrinoid necrosis of vessels is not usually apparent. Mononuclear cells, found in the epidermis and around small vessels in early lesions, are later replaced by neutrophils and plasma cells. Arteritis, which may be catastrophic, is due to inflammation of the vasa vasorum. Many of the attributes of autoimmune disease are missing, and abnormalities of the immune system have been found inconsistently, thus providing few clues to the cause and pathogenesis of Behcet's disease. Experiments showing the induction of uveitis in Lewis rats by heat shock protein T-cell peptide epitopes specific for T lymphocytes from subjects with Behcet's disease offer some support for the view that peptide T-cell determinants may be involved in neutrophil hyperfunction and the pathogenesis of Behcet's disease.

TREATMENT.

Treatment is based on symptoms, and the spontaneous ebb and flow of these make treatment evaluation difficult. For example, pentoxifylline has been advocated as treatment of uveitis, but improvement in the few reported patients may have been spontaneous. More conventional treatment of eye disease has included colchicine, corticosteroids, azathioprine, cyclosporine, and laser photocoagulation. Corticosteroids are given for life-threatening complications, although in general the response to these drugs is disappointing. Allowing for proscriptions against its use in women of childbearing age, thalidomide appears to be particularly useful in the treatment of mucocutaneous ulcers. Interferon-alpha and -gamma have been advocated for arthritis and mucocutaneous lesions, and, on the assumption that streptococcal antigens may play a role in pathogenesis, benzathine penicillin has been used for the latter. Thromboses are treated with anticoagulants, and arterial aneurysms may require surgical treatment or embolization. Specialty sources should be consulted for details of treatment. Akman-Demir G, Baykan-Kurt B, Serdaroglu P, et al: Seven year follow-up of neurologic involvement in Behcet syndrome. Arch Neurol 53:691, 1996. Fifteen patients with neuro-Behc ets were re-evaluated 7 years after the appearance of neurologic signs; the course was stationary in 7 and progressive in 8. The 3 deaths emphasize the investigators' conclusions that neuro-Behc ets is less favorable than had been thought. Hamurydan V, Mat C, Saip S, et al: Thalidomide in the treatment of the mucocutaneous lesions of the Behcet syndrome. Ann Intern Med 128:443, 1998. Thalidomide was moderately effective in suppressing ulcers, follicular lesions, and erythema nodosum; however, polyneuropathy was detected in 6.3% of treated patients. Mizuki N, Inoko H, Ando H, et al: Behcet's disease associated with one of the HLA-B51 subantigens, HLA-B*5101. Am J Ophthalmol 116:406, 1993. Of three HLA-B51 alleles, only B05101 was found in 46 HLA-B51- positive Behc et's patients. Nussenblatt RB: Uveitis in Behcet's disease. Int J Immunol 14:67, 1997. An authoritative review of the manifestations of uveitis and its treatment.

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Chapter 299 - GOUT AND URIC ACID METABOLISM Michael S. Hershfield

Gout refers to the inflammatory arthritis induced by microscopic crystals of monosodium urate monohydrate and to the pathognomonic deposition of aggregated monosodium urate crystals ( tophi) in various tissues and some organs. Chronic hyperuricemia is necessary for the development of gout, although not sufficient. Urolithiasis (renal stones composed of uric acid) may accompany gout or occur independently when renal urate excretion is excessive. Gout is chiefly a disease of adult men. It is mostly idiopathic and multifactorial in etiology. A few rare, inherited metabolic disorders markedly enhance urate production, with urolithiasis and gout as primary manifestations. Other genetic and acquired disorders and some drugs cause secondary hyperuricemia and gout by impairing renal urate excretion or by indirectly increasing urate production (Table 299-1) . If untreated, gout can lead to painful, destructive arthropathy, and urolithiasis can lead to renal failure. Correcting hyperuricemia and hyperuricosuria prevents these consequences and is achievable in most cases. However, because neither gout nor renal insufficiency will develop in most hyperuricemic individuals and because therapy is not without risk and expense, asymptomatic hyperuricemia per se generally does not require therapy; observation and in some cases a search for a contributing, treatable disease are warranted.

PREVALENCE AND INCIDENCE. Surveys made in the 1960s estimated the prevalence of gout at about 0.5 to 0.7% for men and about 0.1% for women. The prevalence has been increasing over the past two decades. Gout is the most common inflammatory arthritis in men older than 40 years in the United States. A 1986 U.S. Health Interview Survey estimated 2.2 million cases of self-reported gout, about twice the physician-reported prevalence. 1542

TYPE

TABLE 299-1 -- CLASSIFICATION OF HYPERURICEMIA AND GOUT DISTURBANCE IN URIC ACID, PURINE METABOLISM

INHERITANCE

Primary I. Idiopathic (>99% of primary gout) A. Normal urinary excretion (80-90% of primary gout)

Decreased renal clearance ± overproduction of urate

Polygenic

B. Increased urinary excretion (10-20% of primary gout)

Overproduction ± decreased renal clearance of urate

Polygenic

Increased de novo purine synthesis

X-linked

II. Due to specific inherited metabolic defects (>1% of primary gout) A. PP-ribose-P synthase overactivity

B. Hypoxanthine-guanine phosphoribosyltransferase deficiency Impaired purine salvage + increased de novo purine synthesis

X-linked

Secondary I. Glucose-6-phosphatase deficiency II. Chronic hemolysis; erythroid, myeloid, and lymphoid proliferative disorders

Increased catabolism of adenine nucleotides + secondary increase in purine Autosomal synthesis de novo recessive Increased cell and nucleic acid turnover

--

A. Familial progressive renal insufficiency

Reduced renal functional mass and various defects in renal tubular function

Variable

B. Acquired chronic renal insufficiency

Reduced renal functional mass

--

C. Drugs (diuretics, cyclosporine, toxins, including lead)

Inhibited urate secretion or enhanced reabsorption

--

Inhibited urate secretion

--

III. Renal mechanisms

D. Endogenous metabolic products (lactate, ketoacids, beta-hydroxybutyrate) PP-ribose-P = phosphoribosylpyrosphosphate.

As Hippocrates observed, gout rarely occurs before puberty in males and seldom before menopause in females. Serum urate values are consistent with this pattern. In normal children of both sexes, serum urate averages 3.6 mg/dL. Levels rise at puberty, more so in males than in females. In the United States, the central 95% segment of the serum urate distribution ranges from 2.2 to 7.5 mg/dL in adult men and from 2.1 to 6.6 mg/dL in adult premenopausal women. Serum urate values increase with age; after menopause, mean values in women approach levels in men. Epidemiologic surveys have noted a trend toward increasing serum urate values in the United States in recent decades and significant variations among population groups, which is a reflection of genetic and environmental factors. Obesity, alcohol consumption, and diuretic use are associated with hyperuricemia. The incidence of gout increases with the degree and duration of hyperuricemia; age, obesity, hypertension, and alcohol intake show much weaker relationships when serum urate is factored out. Although lower levels are occasionally found during an attack, serum urate exceeds 7 mg/dL at some time in virtually all patients with gout. Nevertheless, the risk of gout is modest, even at higher serum urate levels. Among about 2000 initially healthy white males monitored over a 15-year period, annual incidence rates for gout were 0.1% at less than 7 mg/dL, 0.5% at 7.0 to 8.9 mg/dL, and 4.9% at 9 mg/dL. At levels over 9 mg/dL (the highest 1.8% of values observed), the cumulative incidence of gout after 5 years was 22%. Incidence rates were about three-fold higher for hypertensive men than for normotensive men in all age groups because of the hyperuricemic effect of diuretics. The incidence of gout was about two-fold greater among black than white male physicians monitored for 26 to 34 years after graduation from medical school; this difference was partly explained by a greater incidence of hypertension among the blacks.

PATHOGENESIS AND PATHOLOGY. Serum urate levels are low and gout is nonexistent in species that possess urate oxidase ( uricase), which converts urate to allantoin, a more soluble and efficiently excreted compound. Mutational inactivation of the uricase gene occurred during evolution of Homo sapiens and several hominoid species. From this perspective, hyperuricemia in humans is due to an inborn error of urate catabolism. Urate (in solution) may be of benefit as a scavenger of reactive oxygen species, including peroxynitrite derived from nitric oxide and superoxide. Because gout is caused by urate crystals rather than urate in solution, "hyperuricemia" is defined by the solubility of urate in body fluids, not by statistical distributions of urate levels. Producing more urate than can be disposed of or maintained in solution over time leads to extracellular deposition of monosodium urate crystals. Urate solubility is much lower at the temperature of peripheral joints (about 32° C in the knee and 29° C in the ankle). Gout ensues when an inflammatory response is triggered.

URATE PRODUCTION AND ELIMINATION. The total-body urate pool, with which sodium urate in plasma is miscible, is determined by rates of uric acid production and disposal and is expanded in patients with gout (Table 299-2 A). Urate arises from the action of xanthine oxidase on its substrates, the purine bases hypoxanthine

A. URATE KINETICS

TABLE 299-2 -- URIC ACID PRODUCTION AND ELIMINATION MILLIGRAMS (mmol)

Total miscible pool

1200 (7.2)

Daily turnover

600-900 (3.6-5.4)

Daily production

750 (4.5)

Daily intestinal uricolysis

100-365 (0.6-2.2)

Daily urinary excretion

500-1000 (3-6) on normal diet 420 ± 75 (2.5 ± 0.5) on a purine-restricted diet B. RENAL CLEARANCE (FOUR-COMPONENT, BIDIRECTIONAL TRANSPORT MODEL)

RELATIVE AMOUNT

1. Glomerular filtration Complete By diuretics, renal failure 2. Tubular reabsorption Active, linked to Na+ reabsorption Inhibited by uricosuric drugs: probenecid, sulfinpyrazone, benzbromarone, high-dose aspirin (>2 g/d) 3. Tubular secretion Active process Inhibited by agents that cause hyperuricemia: pyrazinamide, low-dose aspirin, lactate, beta-hydroxybutyrate, branched-chain keto acids 4. Post-secretory reabsorption

6-10

Net clearance

Note. Gouty individuals have shown enlarged urate pools and in some cases increased urate turnover. Daily urinary excretion of uric acid is an index of urate production, provided that renal function is normal. About 10% of patients with idiopathic gout are "urate overexcretors," defined as a daily urinary excretion exceeding the normal mean + 2 SD (i.e., >600 mg on a purine-restricted diet or >800 mg on an ordinary diet).

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and xanthine (Fig. 299-1) . Dietary purines are largely degraded to urate by catabolic enzymes located in the intestinal epithelium, including xanthine oxidase. Purine restriction can modestly reduce serum urate by 0.6 to 1.8 mg/dL, but variation in absorption has not been implicated as a cause of hyperuricemia. Most urate is produced by hepatic xanthine oxidase acting on hypoxanthine and xanthine derived from nucleic acids of senescent cells and from the metabolic turnover of cellular purine nucleotides. The latter arise from two biosynthetic pathways termed "de novo" and "salvage" (or "reutilization") (see Fig. 299-1) . Most urate is eliminated by renal excretion (see Table 299-2 B). About one third is degraded by bacteria in the gut, but bacterial degradation of urate increases substantially in renal insufficiency. Uricosuric agents act by blocking urate reabsorption, whereas other drugs and weak organic acids raise serum urate levels by blocking renal urate secretion (see Table 299-2 B). The latter mechanism contributes to the hyperuricemia associated with fasting, alcohol metabolism, and ketoacidosis. MECHANISMS OF HYPERURICEMIA. About 10% of patients with gout show evidence of urate overproduction, as indicated by urinary excretion of uric acid exceeding the normal mean plus 2 SD (>600 mg per 24 hours on a purine-restricted diet, >800 mg on an ordinary diet). The highest overproduction occurs in patients with either of two rare inherited defects in the regulation of purine nucleotide synthesis, deficiency of the salvage enzyme hypoxanthine-guanine phosphoribosyltransferase and overactivity of phosphoribosylpyrophosphate synthetase (see Fig. 299-1) . In the majority of patients with idiopathic gout, renal function is normal, but reduced clearance of filtered urate results in hyperuricemia. No specific renal abnormality has been identified to account for this action. Urate excretion diminishes with the onset of renal insufficiency, but in general, gout is uncommon in patients with chronic renal failure. Several kindreds have been reported in which early-onset hyperuricemia, gout, and progressive renal failure (with or without hypertension) are linked (see Table 299-1) . Chronic lead nephropathy, alcohol abuse, diuretics, and certain other drugs have been implicated in causing hyperuricemia and gout through renal mechanisms (see Tables 299-1 and 299-2 B). In renal and

Figure 299-1 Intracellular purine metabolism and the basis for "metabolic" hyperuricemia. In the "de novo" pathway, the purine ring (hypoxanthine) of inosinic acid (IMP) is constructed from precursors on a ribose-5 -phosphate backbone derived from phosphoribosylpyrophosphate (PP-ribose-P). At IMP the pathway branches and gives rise to adenosine monophosphate (AMP) and guanosine monophosphate (GMP) and their derivatives. In the "salvage" pathway, the pre-formed purine bases hypoxanthine, guanine, and adenine, derived from turnover of IMP, GMP, and AMP, are directly condensed with PP-ribose-P by hypoxine-guanine phosphoribosyltransferase (HPRT) and adenine phosphoribosyltransferase (APRT) to regenerate these ribonucleotides. Some of the hypoxanthine formed by nucleotide turnover is divereted to the liver and catabolized by xanthine oxidase (XO) to uric acid; the remainder is salvaged by HPRT.Operation of the salvage pathway (the more economical in terms of energy required) reduces de novo activity because (1) HPRT and APRT have greater affinity for PP-ribose-P than amidophosphoribosyltransferase does AmidoPRT, the first committed enzyme of the de novo pathway, (2) base salvage lowers the concentration of PP-ribose-P and AmidoPRT is converted to an inactive form, and (3) the nucleotide and products of the HPRT and APRT reactions directly inhibit AmidoPRT. Allopurinol, by blocking XO, enhances salvage of hpoxanthine, further inhibiting de novo activity; this action reduces purine excretion more than expected from inhibition of uric acid formation alone.Deficiency of HPRT causes an obligatory loss of all hypoxanthine and guanine as urate and also allows a compensatory increase in de novo pathway activity because of reduced formation of inhibitory nucleotides and increased concentration and availability of PP-ribose-P for the AmidoPRT reaction. In individuals with inherited "overactive" variants of PP-ribose-P synthase, increased formation of PP-ribose-P stimulates AmidoPRT and thereby markedly enhances de novo purine synthesis. The excess IMP formed is degraded to urate.Increased nucleotide breakdown can cause hyperuricemia by increasing the production of XO substrates and by releasing inhibition of AmidoPRT. This mechanism has been implicated in the hyperuricemia and gout associated with glucose-6-phosphatase deficiency (glycogen storage disease type I): Glucose-6-phosphate accumulates at the expense of hepatic adenosine triphosphate (ATP), with degradation of AMP to urate. Hyperuricemia may occur acutely in various conditions that result in nucleotide catabolism: hypoxia, metabolism of some sugars, vigorous exercise in normal individuals, and moderate exercise in patients with metabolic myopathies. (5 NT = 5 -nucleotidase; PNP = purine nucleoside phosphorylase; ADA = adenosine deaminase; AK = adenosine kinase.)

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cardiac transplant patients, the use of cyclosporine has been associated with severe hyperuricemia and accelerated development of gout. Hyperuricemia and idiopathic gout are associated with both obesity and hypertriglyceridemia. In some gouty patients, weight reduction and abstinence from alcohol reverse the hypertriglyceridemia, hyperuricemia, and evidence of both overproduction and impaired renal clearance of urate. MECHANISM OF THE ACUTE GOUTY ATTACK. The neutrophil is an essential mediator of acute inflammation in gout (Fig. 299-2) . Ingestion of monosodium urate crystals causes neutrophils to release leukotrienes, interleukin-1, and the glycoprotein "crystal chemotactic factor"; these substances further amplify neutrophil infiltration into the involved joint. Activated neutrophils also

produce superoxide and release lysosomal enzymes as a result of crystal-induced rupture of lysosomal membranes and cell lysis. The resulting cleavage of complement peptides and kinins from precursors induces pain, vasodilation, and vascular permeability. Released lysosomal and cytoplasmic enzymes, as well as collagenase and prostaglandins produced by joint mesenchymal cells, contribute to chronic articular destruction and tissue necrosis. Extracellular urate crystals are often found in asymptomatic joints of gouty individuals. Attacks may be initiated and terminated by plasma proteins that selectively adsorb to crystals and modify their interaction with neutrophils. Early in an attack, IgG antibody, possibly induced by monosodium urate crystals acting as antigens, may serve as a nucleating agent that promotes monosodium urate crystallization and increases phagocytosis of these crystals by neutrophils, thereby enhancing the release of lysosomal enzymes. Late in an attack, lipoproteins containing apoprotein B enter the inflamed joint from plasma and coat the monosodium urate crystals; this action inhibits phagocytosis, neutrophil oxidative metabolism, superoxide production, and cytolysis. Qualitative and quantitative differences in protein modulators may account for the variable inflammatory response to urate crystals in gouty and non-gouty individuals. TOPHI. A tophus is a deposit of fine, needle-shaped monosodium urate crystals surrounded by a chronic mononuclear cell reaction and a foreign body granuloma of epithelial and giant cells, which may be multinucleate (see Fig. 299-2) . Tophi are commonly found in articular and other cartilage, synovia, tendon sheaths, bursae and other periarticular structures, epiphyseal bone, subcutaneous tissues, and the kidney interstitium. When compared with an acute gouty attack, tophi evoke little inflammatory response and generally develop silently. In some gouty individuals, tophi may be detected radiographically in bone and articular cartilage but may be absent in subcutaneous tissues. In the joint, tophi gradually enlarge and cause degeneration of cartilage and subchondral bone, proliferation of synovium and marginal bone, and sometimes fibrous or bony ankylosis. The punched-out lesions of bone commonly seen on radiographs represent marrow tophi, which may communicate with the urate crust on the articular surface through defects in cartilage. In vertebral bodies, urate deposits involve the marrow spaces adjacent to the intervertebral disks. THE GOUTY KIDNEY. Interstitial deposits of monosodium urate crystals in the medulla or pyramids, with surrounding mononuclear and giant cell reaction, are found commonly in gouty patients at autopsy and have been referred to as "urate nephropathy." Crystalline deposits of uric acid (not urate) within distal tubules and collecting ducts may occur and lead to dilatation and atrophy of the more proximal tubules. Renal disease is common in gout but generally mild and slowly progressive. Interstitial nephropathy may be due to urate deposits but can also be present in their absence. Other possible causes include nephrosclerosis secondary to hypertension, uric acid stone disease, infection, aging, and lead toxicity. URIC ACID NEPHROLITHIASIS. About 10 to 25% of gouty patients experience renal stones, an incidence over 200-fold higher than in the general population. The incidence of stones exceeds 20% when daily uric acid excretion is greater than 700 mg (see Table 299-2 A), and it is about 50% at 1100 mg. The prevalence of stones is also related to hyperuricemia and reaches 50% at serum urate levels greater than 12 mg/dL. Over 80% of the stones are uric acid (not sodium urate); the remainder are mixtures of uric acid and calcium oxalate or calcium oxalate or phosphate alone. For reasons that are unclear, both gouty and non-gouty uric acid stone formers exhibit persistently low urinary pH, which favors uric acid stone formation. At pH 5 and 37° C, free uric acid has a

Figure 299-2 Inflammatory responses to monosodium urate crystals.

1545

solubility of only 15 mg/dL. Thus supersaturation is required to excrete an average uric acid load in a normal urine volume. The solubility increases more than 10-fold at pH 7 and more than 100-fold at pH 8.

CLINICAL MANIFESTATIONS. The peak age of onset of gout is about 45 years in men, by which time the average gouty male has been exposed to 20 or 30 years of asymptomatic hyperuricemia and to varying degrees of tissue urate deposition. In predisposed women, gout usually occurs some years after menopause, when they become hyperuricemic. ACUTE GOUTY ARTHRITIS. Gout is usually initially manifested as a fulminating arthritic attack affecting the lower extremity. Over 75% of initial attacks are monarticular; at least half involve the metatarsophalangeal joint of the great toe (podagra). Next in order are the instep, ankle, heel, knee, wrist, finger, and elbow. Tenosynovitis, bursitis, or cellulitis may also occur. Minor episodes of "ankle sprain" or twinges of pain in the great toe may precede the first attack, sometimes by several years. More often the attack occurs explosively during apparent good health, often at night. Within minutes to hours the affected joint becomes hot, dusky red, and exquisitely tender and painful. Very severe attacks may be manifested as fever, leukocytosis, and an increased erythrocyte sedimentation rate, suggestive of infection. The course of an untreated attack is variable, with resolution in hours or a few days when mild and lasting many days to several weeks when severe. As the attack subsides, desquamation of inflamed skin over the affected joint may occur. Once the attack has broken, recovery is generally rapid and complete. The patient then re-enters an asymptomatic phase, often termed "intercritical" or "interval" gout. The subsequent course is variable, but commonly a pattern of recurrences develops. Attacks often follow a precipitating event such as a long walk, trauma, surgery, alcohol or dietary overindulgence, starvation, infection, or the start of hypouricemic drug therapy. In an untreated patient, attacks often increase in frequency, and they may become more severe, last longer, and are more often polyarticular. Later attacks may involve the shoulder or hip or rarely the sacroiliac, sternoclavicular, or mandibular joints or even the spine. The more distal the site, the more typical the attack. Eventually, attacks may be refractory to usually effective measures; they resolve incompletely, and disability may become permanent. CHRONIC TOPHACEOUS GOUT. Progressive inability to dispose of urate results insidiously in tophaceous crystal deposition in and around joints. Tophi may first appear as superficial yellowish white infiltrates on the fingertips, palms, and soles and later as irregular, asymmetrical enlargement of joints, fusiform or nodular enlargements of the Achilles tendon, or saccular distentions of the olecranon bursa (Fig. 299-3) . A classic, although relatively infrequent, site of tophi is the helix or anthelix of the external ear. Visible tophi develop in 10 to 25% of gouty patients and in over 50% of those who are non-compliant; the time of appearance after the initial attack is correlated with the degree and duration of hyperuricemia and with renal insufficiency. In rare patients, often those with gout secondary to a myeloproliferative disease or in organ transplant recipients receiving cyclosporine, tophi are present at the time of the initial attack. Although tophi themselves are relatively painless, they often result in stiffness and persistent aching that limit the use of affected joints. Destruction of cartilage and bone by tophi leads to radiolucent "punched-out" lesions and to cortical erosions with characteristic "overhanging margins" (see Fig. 299-3) . Eventually, extensive destruction of joints may be disabling, and large subcutaneous tophi may cause grotesque deformities. The stretched, thin skin over tophi may ulcerate and extrude white chalky or pasty "milk of urate" composed of a myriad of fine, needle-like crystals. The olecranon bursa may be massively distended with this material, which may be mistaken for pus if not examined by polarized light microscopy. Rarely, tophi may involve the tongue, larynx, corpus cavernosum and prepuce of the penis, aortic or mitral valves, and cardiac conducting system and cause rhythm disturbances. They do not involve the liver, spleen, lungs, or central nervous system. GOUTY NEPHROPATHY. Progressive renal failure secondary to urate nephropathy may occur in patients with inherited metabolic disorders that cause extreme urate overproduction and possibly in rare forms of inherited renal disease and chronic lead poisoning. Isosthenuria and mild intermittent proteinuria occur in about one third of patients with idiopathic gout. The decline in renal function correlates with aging, hypertension, renal calculi, pyelonephritis, or independently occurring nephropathy. Hyperuricemia

per se is not a risk factor for renal insufficiency. Acute oliguric renal failure can result from bilateral tubular obstruction by uric acid crystals. This disorder occurs in several clinical settings, including untreated leukemia and lymphoma or during chemotherapy for these disorders (tumor lysis syndrome), and in the presence of severe dehydration and acidosis. This condition is preventable by maintaining a high urine volume, with alkalinization, and by pre-treating with allopurinol. Daily infusions of fungal urate oxidase have also been effective (this drug has not been approved by the Food and Drug Administration at the time of publication).

DIAGNOSIS. The sudden onset of severe inflammatory arthritis in a peripheral joint, especially a joint of the lower extremity, suggests gout. A history of discrete attacks separated by completely asymptomatic periods is helpful for diagnosis. The diagnosis is established by demonstrating brilliant, negatively birefringent, needle-shaped monosodium urate crystals by polarized light microscopy in the leukocytes of synovial fluid (see Chapter 285) (Fig. 299-4 ; Color Plate 7 G). The synovial fluid leukocyte count ranges from 5000 to over 50,000 per cubic millimeter, depending on the acuteness of inflammation. A Gram stain and culture of synovial fluid should always be obtained to evaluate infection, which may coexist. Determining the 24-hour urinary excretion of uric acid can be informative, particularly in a young, markedly hyperuricemic patient in whom a metabolic etiology may be suspected. The sample should be collected after 3 days of moderate purine restriction, during an intercritical period. Values greater than 600 mg/1.72 m2 /day under these conditions suggest overproduction, and those over 800 mg/day warrant additional studies for a specific subtype of primary gout, such as hypoxanthine-guanine phosphoribosyltransferase deficiency or phosphoribosylpyrophosphate synthetase overactivity, or for a subtype of secondary gout, such as a myeloproliferative disorder. Elevated urinary uric acid excretion also predicts a higher risk for renal stones and is an indication for allopurinol rather than uricosuric drug therapy for gout.

DIFFERENTIAL DIAGNOSIS. Acute gout must be differentiated from pseudogout, acute rheumatic fever, rheumatoid arthritis, traumatic arthritis, osteoarthritis, pyogenic arthritis, sarcoid arthritis, cellulitis, bursitis, tendinitis, and thrombophlebitis. Gout can coexist with most of these conditions. Podagra, the most common initial manifestation of gout, can be mimicked by trauma, degenerative arthritis, acute sarcoidosis, psoriatic arthritis, pseudogout, Reiter's syndrome, and infection, and in the immediate postoperative period following parathyroidectomy, podagra can be caused by hydroxyapatite crystals. Pseudogout (see Chapter 300) , which is manifested by acute attacks of arthritis of the knees and other joints, is often accompanied by calcification of joint cartilage; the synovial fluid contains non-urate crystals of calcium pyrophosphate. When gout and pseudogout coexist, both types of crystals will be found in synovial leukocytes.

TREATMENT. Understanding of the rationale for treatment by both the physician and patient is essential for long-term success. One aspect is aimed at terminating the acute inflammatory gouty attack, and the other is aimed at correcting the underlying metabolic problem (Table 299-3) . ACUTE ATTACK. The affected joint(s) should be kept at rest and therapy begun promptly with full doses of an oral non-steroidal anti-inflammatory drug (NSAID). Salicylates should not be used because of their effects on urate excretion (see Table 299-2) . The typical monarticular acute attack responds within 24 hours and resolves in 48 to 72 hours; established or polyarticular attacks may require longer treatment. Once the attack subsides, the NSAID dose is tapered over several days and treatment discontinued. Hypouricemic therapy should not be initiated during an acute attack because it is ineffective in relieving inflammatory symptoms and in some patients (estimated at 10 to 24%) may induce a recurrent attack by mobilizing urate from tissues. Oral colchicine is effective therapy for acute gout but has a low therapeutic index; relief of pain often coincides with gastrointestinal toxicity. If an attack does not respond in 48 hours, alternative therapy should be used. If oral medication is precluded, intravenous colchicine may be used with caution. Colchicine is a microtubule 1546

Figure 299-3 Tophaceous gout. A to C, Chronic gouty arthritis with tophaceous destruction of bone and joints ( A and B ) and improvement after 3 years of treatment with allopurinol, prophylactic colchicine, and a moderately low purine diet ( C). D, Tophaceous deposits in the digital pad of a 28-year-old man with systemic lupus erythematosus under treatment with diuretics. A single attack of gout had occurred 2 years earlier. E , Tophaceous enlargement of the great toe in a 44-year-old man with a 4-year history of recurrent gouty arthritis.

poison; it is retained in cells (half-life, about 30 hours) and is not dialyzable. Dose-related toxicity includes alopecia, bone marrow suppression, and hepatocellular damage. Deaths from overdosage have been reported. Blood counts should be monitored during intravenous use of colchicine and periodically during long-term oral therapy. The dosage should be reduced in the presence of renal or hepatic disease, and it should not be used in patients with advanced disease. Reversible myopathy has occurred in elderly patients undergoing daily colchicine prophylaxis who have been treated with larger doses for an acute attack. In patients with peptic ulcer disease or renal insufficiency, in whom NSAIDs and colchicine may be contraindicated, various steroid preparations such as intramuscular injection of triamcinolone acetonide can be effective in treating the acute attack. INTERVAL PHASE. Patients should be warned that acute attacks may still occur, particularly in the first 6 months or so after beginning hypouricemic therapy. Oral colchicine is effective prophylaxis to prevent recurrent attacks, but an NSAID should be taken at the initial sign of prodromal symptoms, if recognizable. Although hypouricemic therapy is not usually initiated during an acute attack, once begun, it should not be interrupted during subsequent attacks. Hypertension should be treated vigorously; if hyperuricemia worsens, antihyperuricemic drug therapy can be initiated or appropriately increased. LONG-TERM MANAGEMENT. Use of a drug to lower the serum uric acid level to less than 6 mg/dL is indicated in all patients with visible tophi or radiographic evidence of urate deposits or in patients with a history of two or more major attacks of gouty arthritis per year. Allopurinol is preferred unless the patient is already well managed with a uricosuric agent. With either type of agent, the number of acute attacks may increase during the initial few months (this situation may be prevented with prophylactic colchicine); after 12 to 18 months, the frequency of attacks should decline. Allopurinol reduces urate production by inhibiting xanthine oxidase, with secondary reduction of de novo purine synthesis (see Fig. 299-1) . Its major active metabolite, oxypurinol, has a long half-life (about 28 hours) and is primarily responsible for these effects during maintenance. In contrast to uricosuric agents, allopurinol 1547

Figure 299-4 Sodium urate monohydrate crystals phagocytosed by a leukocyte in synovial fluid from acute gouty arthritis, examined by polarized light.

reduces urinary uric acid excretion and is effective in renal failure and in controlling urolithiasis, and its action is not blocked by salicylate. In the presence of renal insufficiency, the maintenance dose of allopurinol should be reduced because the half-life of oxypurinol is prolonged. Allopurinol-induced xanthinuria has resulted in

xanthine renal stones on rare occasion in patients with hypoxanthine-guanine phosphoribosyltransferase deficiency and during chemotherapy for leukemias. Allopurinol is well tolerated but may cause gastric irritation, diarrhea, or skin rash in about 3% of patients. In about 0.4%, allopurinol causes a serious hypersensitivity syndrome, with worsening renal function, hepatitis, and severe dermatologic injury (epidermal necrolysis, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome), often with fever, leukocytosis, and eosinophilia. Patients with renal insufficiency are at higher risk, particularly if the dosage has not been appropriately reduced. Allopurinol interferes with the metabolism and increases the half-life of azathioprine and 6-mercaptopurine used to treat leukemia and to prevent allograft rejection, conditions in which significant hyperuricemia and gout may be associated with renal insufficiency. If the serum urate level can be maintained at less than 6 mg/dL, some tophi resolve and bone erosions may be reduced. In selected patients, surgical treatment of chronically draining tophi or removal of large extra-articular urate deposits may be advisable. Effective treatment of severe gout is difficult in certain situations, particularly in patients with renal failure and allopurinol hypersensitivity and if allopurinol may interfere with drug therapy necessary for allograft rejection or malignancy. Desensitization to allopurinol has been used in some patients with mild allergic reactions but is considered dangerous in those who have had severe hypersensitivity reactions. ASYMPTOMATIC HYPERURICEMIA. Asymptomatic hyperuricemia is frequent in family members of patients with gout and in the general population. In fewer than a fifth of hyperuricemic individuals does gout ever develop, and effective therapy can be begun when attacks do occur. In patients with a strong family history of tophaceous diseases or gout and renal problems, treatment with allopurinol should be begun before articular or renal complications develop.

ACUTE GOUT

TABLE 299-3 -- TREATMENT OF GOUT INTERVAL GOUT

LONG-TERM TREATMENT

Therapeutic goal: Terminate acute inflammatory attack.

Therapeutic goal: Prevent recurrent attacks.

Therapeutic goals: Prevent attacks, resolve tophi, maintain serum urate at 6 mg/dL.

NSAIDs ( preferred): Indomethacin, 50 mg qid, or ibuprofen, 800 mg tid (or other NSAIDs in full doses) ( lower dose in renal insufficiency; contraindicated with peptic ulcer disease).

Colchicine, oral: 0.6-1.2 mg daily as prophylaxis against recurrent attacks.

Colchicine, oral: 0.6-1.2 mg daily for 1-2 weeks before initiating hypouricemic therapy and for several months afterward to prevent recurrent attacks during initial period of hypouricemic therapy (see text for discussion of colchicine toxicity).

Hypouricemic agent: Start only if indicated by frequent attacks, severe hyperuricemia, presence of tophi, urolithiasis, or urate overexcretion.

Allopurinol: Dose variable; usually 300 mg once daily, but up to 900 mg may be needed in occasional patient; dose should be reduced to 100 mg daily or every other day in patients with renal insufficiency (see text for discussion of allopurinol hypersensitivity).

OR Colchicine, oral ( used infrequently): 0.6-1.2 mg (1-2 tablets), then 0.6 mg (1 tablet) q1-2h until attack subsides or until nausea, diarrhea, or GI cramping develops. Maximum total dose, 4-6 mg. If ineffective in 48 hr, do not repeat (see text for discussion of colchicine toxicity).

OR Colchicine, IV ( only if oral medication is precluded): 1-2 mg in 20 mL 0.9% saline infused slowly ( extravasation causes tissue necrosis); dose may be repeated once in 6 hr. Few GI symptoms with IV use. Maximum total dose, 4 mg per attack. Monitor blood counts.

Other: Diet--moderate protein, low fat; avoid excessive alcohol. Treat hypertension if present. High fluid intake to promote uric acid excretion in a dilute urine (for uric acid overexcretors).

Steroids ( if NSAIDs or colchicine is contraindicated or if oral medication is precluded, e.g., postoperatively): Triamcinolone acetonide, 60 mg IM, or ACTH, 40 U IM or 25 U by slow IV infusion, or prednisone, 20-40 mg daily. Intra-articular steroids may be used to treat a single inflamed joint: triamcinolone hexacetonide, 5-20 mg, or dexamethasone phosphate, 1-6 mg.

Uricosuric agent ( reduced efficacy if creatinine clearance < 80 mL; ineffective if < 30 mL): Probenecid, 0.5-1 g bid, or sulfinpyrazone, 100 mg tid or qid; usually well tolerated, but may cause headache, GI upset, rash.

Other: Diet--moderate protein, low fat; avoid excessive alcohol. Treat hypertension if present. For uric acid overexcretors or when initiating uricosuric agent: high fluid intake, particularly at night, to promote uric acid excretion in a dilute urine. Acetazolamide, 250 mg at bedtime, may be used to keep urine pH >6.

Hypouricemic agents: Of no benefit for inflammatory attack and may initiate recurrent attack. Should not be started until attack has resolved, but ongoing use should not be interrupted during an attack. NSAIDs = non-steroidal anti-inflammatory drugs; qid = four times daily; tid = three times daily; q1-2h = every 1 to 2 hours; IV = intravenously; GI = gastrointestinal; bid = twice daily; ACTH = adrenocorticotropic hormone; IM = intramuscularly.

Arellano F, Sacristan JA: Allopurinol hypersensitivity syndrome: A review. Ann Pharmacother 27:337, 1993. Reviews over 100 reports of a serious potential complication of allopurinol therapy. Hochberg MC, Thomas J, Thomas DJ, et al: Racial differences in the incidence of 1548

gout. The role of hypertension. Arthritis Rheum 38:628, 1995. Analyzes the incidence of gout in cohorts of black and white male physicians. Hooper DC, Spitsin S, Kean RB, et al: Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis. Proc Natl Acad Sci U S A 95:675, 1998. Intriguing study suggesting that multiple sclerosis and gout are mutually exclusive diseases because hyperuricemia protects against free radical injury. Pui C-H, Relling MV, Lascombes F, et al: Urate oxidase in prevention and treatment of hyperuricemia associated with lymphoid malignancies. Leukemia 11:1813, 1997. A fungal urate oxidase infused daily for 6 days was effective in preventing hyperuricemia caused by tumor lysis syndrome. Rosenthal AK, Ryan LM: Treatment of refractory crystal-associated arthritis. Rheum Dis Clin North Am 21:151, 1995. A helpful discussion of the management of gout in difficult situations.

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Chapter 300 - CRYSTAL DEPOSITION ARTHROPATHIES H. Ralph Schumacher Jr.

Introduction At least three different calcium-containing crystals are now known to be deposited in joints and are associated with a variety of patterns of arthritis, in much the same way as urate crystals cause the various features of gouty arthritis. Calcium pyrophosphate and occasionally calcium oxalate produce linear or punctate calcifications in menisci and articular cartilage that can be readily seen on radiographs (Fig. 300-1) . These calcifications are termed "chondrocalcinosis." Both these crystals and calcium apatite can also be deposited diffusely in synovium and periarticular tissues and produce a soft tissue pattern on radiographs. Moreover, radiographs may not show obvious calcifications when crystals are relatively few. Definitive diagnosis is made only by aspiration of synovial fluid for identification of crystal type. In addition to the crystals discussed below, others of various implications may be seen in joint fluid (Table 300-1) . Schumacher HR, Reginato AJ: Atlas of Synovial Fluid Analysis and Crystal Identification. Philadelphia, Lea & Febiger, 1991. An extensively illustrated compendium of all joint fluid findings, including less common crystals and artifacts.

CALCIUM PYROPHOSPHATE DIHYDRATE CRYSTAL DEPOSITION DISEASE (PSEUDOGOUT SYNDROME) Calcium pyrophosphate dihydrate (CPPD) crystals are rod- or rhomboid-shaped, 2- to 20-mum-long weakly birefringent crystals

Figure 300-1 Chondrocalcinosis (arrow) at the elbow joint of a patient with calcium pyrophosphate dihydrate deposition disease.

with positive elongation. CPPD crystals can be present without symptoms or can cause several patterns of arthritis. They are most frequent in the elderly. Up to 27% of nursing home patients in their 80s have radiographic evidence of chondrocalcinosis. Familial cases have been described in populations of various ethnic origins. Both genders are affected. The cause of CPPD crystal deposition is not established, but local overproduction of pyrophosphate related to excessive activity of nucleoside triphosphate pyrophosphohydrolase, deficiency of phosphatases, and local changes in matrix proteoglycans and collagen are probably important. CPPD crystals are deposited only in joints and adjacent tendons or bursae, where they produce hematoxyphilic clumps replacing the normal tissue. Virtually any joint can be involved, but the knees, wrists, and second and third metacarpophalangeal joints are most common, so chronic cases can be confused with rheumatoid arthritis. Acute bouts of crystal-induced arthritis at one or more joints can mimic gout and lead to "pseudogout." Fever with bouts of arthritis can mimic infection. Recent reports have emphasized occurrence of symptomatic CPPD disease at rare sites such as the spine, temporomandubular joint, and sacroiliac joints. CPPD crystal deposition often complicates osteoarthritis; this association is more prominent at the knees than the hips. Whether crystals contribute to cartilage degeneration in osteoarthritis or are purely an epiphenomenon is not yet clear. Occasional severe arthritis mimics the destruction seen in neuropathic joints. Radiographic evidence of calcification can be present in some cases TABLE 300-1 -- DIFFERENTIAL DIAGNOSTIC FEATURES FOR SOME OF THE CRYSTAL-ASSOCIATED ARTHROPATHIES CRYSTAL SIZE CRYSTAL CRYSTAL BIREFRINGENCE AND OTHER POINTS X-RAY FINDINGS (mum ) SHAPE ELONGATION Calcium pyrophosphate

2-20

Rods, rhomboids

Weak positive

Elderly and consider associated metabolic diseases

Chondrocalcinosis, bony sclerosis

Apatite

2-25

Chunks or globules *

Non-birefringement

Clumps stained with alizarin red S

Soft tissue calcification

Oxalate

2-15

Rods, bipyramids

Positive

Renal failure

Chondrocalcinosis or soft tissue calcification

Monosodium urate

2-20

Rods, needles

Bright negative

Middle-aged men and elderly women

Cysts and erosions; tophi may calcify

Liquid lipid crystals

2-12

Maltese crosses

Positive

Unexplained acute arthritis

Cholesterol

10-80

Notched rectangles

Positive or negative

May complicate RA and OA

Depot corticosteroids

4-15

Irregular or rods

Bright positive or negative

Can cause iatrogenic inflammation

Immunoglobins, other proteins

3-60

Rods or irregular

Positive or negative

Cryoglobulinemia

Charcot-Leyden

10-25

Spindles

Positive or negative

Eosinophilic synovitis

RA = rheumatoid arthritis; OA = osteoarthritis. *Aggregates are seen by light microscopy. Individual needle-shaped crystals are seen only by electron microscopy.

1549

TABLE 300-2 -- SYSTEMIC CONDITIONS ASSOCIATED WITH CALCIUM PYROPHOSPHATE DIHYDRATE DEPOSITION DISEASE Hyperparathyroidism Hemochromatosis Hypophosphatasia Hypomagnesemia Myxedematous hypothyroidism Ochronosis

for years without inducing any symptoms. Others may have crystals in joint fluid with osteoarthritis-like radiographic changes but no visible chondrocalcinosis. Synovial effusions may have leukocyte counts up to 100,000 per cubic millimeter and with 80 to 90% neutrophils during acute attacks. Between attacks or in osteoarthritis, crystals can be seen in clear, non-inflammatory joint effusions. CPPD crystal deposition can be an important clue to a number of associated diseases, many of which have specific treatments that can control systemic features if not the arthropathy. Some clearly associated diseases are shown in Table 300-2 . CPPD crystal deposition is increased in knees after meniscectomy and may complicate advanced arthritides. Treatment of inflammatory episodes with thorough aspiration and use of non-steroidal anti-inflammatory drugs (NSAIDs) is generally successful. Intra-articular steroid injections may provide relief in refractory involvement of individual joints. Intravenous colchicine may also be helpful. Chronic therapy with 0.6 to 1.2 mg of colchicine per day can decrease the frequency of acute attacks but may be accompanied by neuropathy or myopathy if patients have liver or kidney disease. Hydroxychloroquine or methotrexate can be tried in the presence of chronic synovitis. Otherwise the prognosis is for slow progression. Joint replacement has been successful when needed. Rahman MU, Shenberger KN, Schumacher HR: Initially unrecognized calcium pyrophosphate dihydrate deposition disease as a cause of fever. Am J Med 89:115, 1990. Even mild crystal-induced joint findings can cause potentially confusing fever. Roane DW, Harris MD, Carpenter MT: Prospective use of intramuscular triamcinolone acetonide in pseudogout. J Rheumatol 24:1168, 1997. In polyarticular disease, systemic steroids may occasionally be needed as in gout to control attacks.

APATITE CRYSTAL DEPOSITION DISEASE Individual apatite crystals can be seen only by electron microscopy, but clumps of these crystals appear as 2- to 25-mum shiny (but not generally birefringent) globules that can suggest the diagnosis. Apatite crystal deposition and crystal-induced inflammation are common factors in bursitis and periarthritis. Apatite crystals also occur in some cases of otherwise unexplained acute arthritis and in osteoarthritic joint effusions. Most joints or bursae can be involved, with more common sites including the shoulders, hips, knees, and digits (including the first metatarsophalangeal joint). Joint or periarticular inflammation can be acute or chronic. An extremely destructive arthritis has been noted especially at the shoulders ("Milwaukee shoulder"), hips, and knees in elderly patients. Radiographs can show soft tissue calcifications with or without bone erosions. Definitive diagnosis of the crystal type is only possible by electron microscopy with electron probe elemental analysis, x-ray diffraction, or infrared spectroscopy. Other calcium phosphates, such as octacalcium phosphate, can be seen along with the apatite; the significance of amounts of other associated calcium phosphates is not known. Synovial or bursal effusions can have many or few leukocytes. Serum studies are generally normal except that phosphate levels are often elevated in renal dialysis patients, who are at high risk of apatite deposition, and in tumoral calcinosis caused by renal retention of phosphate. Apatite deposition can also be associated with scleroderma and other connective tissue diseases, repeated depot corticosteroid injections, central nervous system injury, and high-dose vitamin D therapy. In most instances, the cause of soft tissue apatite deposition is not known. Treatment of acute arthritis or periarthritis is with NSAIDs or colchicine. Aspiration of crystals and local injection with depot corticosteroids can also be effective. Diltiazam has recently been suggested to be able to slowly resorb the chronic calcinosis seen with collagen disease. Paul H, Reginato AJ, Schumacher HR: Alizarin red S staining as a screening test to detect calcium compounds in synovial fluid. Arthritis Rheum 26:191, 1983. This article describes a simple office screening test for apatite and other calcium-containing crystals. Pinals RS, Short CL: Calcific periarthritis involving multiple sites. Arthritis Rheum 9:566, 1966. This recurrent calcific periarthritis is related to apatite crystals. Zakraouil, Schumacher HR, Rothfuss S: Idiopathic destructive arthropathies: Clinical, light and electron microscopic studies. J Clin Rheumatol 219, 1996. The very destructive osteoarthritis at large joints of the elderly is invariably associated with apatite or CPPD crystals and must be distinguished from joint infections.

OXALATE CRYSTAL DEPOSITION DISEASE Calcium oxalate deposition can occur in joints along with other tissues of patients with renal failure who are maintained on chronic hemodialysis or peritoneal dialysis and can produce radiographic evidence of soft tissue calcification or chondrocalcinosis. Acute or chronic joint effusions with intracellular crystals can be seen. Oxalate deposits in vessels can mimic vasculitis. Masses of vertebral oxalates can cause spinal cord compression. The diagnosis is made by identification of typical bipyramidal crystals in joint fluid or biopsy specimens. When less characteristic crystals are seen, other techniques as described under apatite deposition can be used. Vitamin C may potentiate oxalate deposition, so it might be avoided. Hoffman EC, Schumacher HR, Paul H, et al. Calcium oxalate microcrystalline-associated arthritis in end stage renal disease. Ann Intern Med 97:36, 1982. Three cases with oxalosis and arthritis are described. Methods to identify oxalate crystals are included. Reginato AJ, Kurnik BRC: Calcium oxalate and other crystals associated with kidney disease and arthritis. Semin Arthritis Rheum 18:198, 1989. Extensive oxalosis can involve the skin, bursae, tendon sheaths, vessel walls, and joints, as well as the kidneys and various viscera.

GOUT Monosodium urate crystal deposition (see Color Plate 7 G) in joints and other connective tissue accounts for the most frequent clinical manifestations of gout. The complex genetic, metabolic, and renal factors that interact to produce hyperuricemia and eventually gout are described in detail in Chapter 299 . Gouty arthropathy and the gross tophaceous deposits in chronic gout are also described in Chapter 299 but are summarized here because gout is the most common and prototypic of the crystal deposition diseases. Monosodium urate crystals are rods or needles up to 15 to 20 mum in length and are brightly birefringent with negative elongation when viewed with compensated polarized light. Those from visible tophi or synovial microtophi tend to be more often needle-like, whereas some in acute arthritis can be very short. At least some crystals are intracellular during gouty arthritis. Leukocyte counts during attacks usually range from 10,000 to 50,000 per cubic millimeter, with 80 to 90% neutrophils. Gout is most common in middle-aged men but is increasingly seen in women after menopause. It is very rare in premenopausal women but may occur with chronic renal failure. A variety of lower extremity joints are commonly involved, in addition to the classic first metatarsophalangeal joint, but any joint or bursa, including those in the upper extremities, can be affected by either acute or chronic arthritis. Chronic or recurrent acute gout can be polyarticular, can mimic rheumatoid arthritis, and may be misdiagnosed, especially if the typical dramatic early short-lived attacks are not appreciated and synovial fluid is not examined. Tophaceous gout can slowly destroy joints. Crystals are often present in joint fluid even between attacks and may contribute to low-grade inflammation and joint damage. Radiographs show only soft tissue swelling early in gout but can later reveal cystic erosions with thin, overhanging edges of bone suggestive of gout. Soft tissue tophi are common around joints, in bursae, in Achilles tendons, and at the extensor surface of the forearm. Gout should be recognized as a syndrome resulting from the many possible causes noted in Chapter 299 . Cyclosporine causes an especially rapidly progressive form of gout in transplant patients. Treatment of acute gouty arthritis can be with NSAIDs (although relatively high doses are needed), oral or intravenous colchicine, adrenocorticotropic hormone, or prednisone. The latter two agents may be needed in complicated patients with renal failure, liver disease, or gastrointestinal disease. Colchicine is most effective early in attacks (see also Chapter 299) . Joint aspiration with instillation of depot corticosteroids may also be used if a single joint is involved and infection is excluded. If recurrent attacks develop, 1550

chronic low doses of NSAIDs or colchicine can suppress inflammation, but crystal accumulation will probably continue. Thus with more frequent attacks or visible tophi, patients should be considered for long-term lowering of urate levels with a uricosuric agent such as probenecid (if renal function is good and the patient is not overexcreting uric acid) or, in other cases, allopurinol, a xanthine oxidase inhibitor. Either urate-lowering agent must be given in sufficient dosage to lower serum uric acid levels below 6.0 mg/dL, a level at which tophi can dissolve and attacks eventually cease. Moreland LM, Ball GV: Colchicine and gout. Arthritis Rheum 34:782, 1991. Some of the complex situations involved in colchicine use for acute and chronic gout are

reviewed. There are risks both from disease progression and from drug toxicities. Colchicine, NSAIDs, and allopurinol all require care in appropriate use.

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Chapter 301 - RELAPSING POLYCHONDRITIS H. Ralph Schumacher Jr.

The uncommon disease relapsing polychondritis is characterized by recurrent inflammation and destruction of cartilaginous and other connective tissue structures. Frequently involved cartilagenous structures are the pinnae of the ears, nasal cartilage, and tracheal rings. Polychondritis occurs nearly equally in both genders and at any age, but with a peak in onset between the ages of 40 and 60. The pathologic lesion seen by light microscopy consists of loss of matrix staining, predominantly superficial infiltration with polymorphonuclear neutrophils or lymphocytes, and eventual destruction of normal structures followed by fibrosis. Electron microscopy in addition shows alterations of superficial chondrocytes, matrix, and elastic fibers. The cause of polychondritis is unknown, but the location of lesions and frequency of associated systemic diseases suggest the importance of systemic factors. Antibodies to types II, IX, and X collagen and the presence of cell-mediated immunity to proteoglycan and type II collagen are evidence of immunologic aberrations. An association with HLA-DR4 has been noted. Inflammation of the cartilaginous structures of the ears is the most common initial finding (see Color Plate 8 C). An acute onset of pain and tenderness may be seen along with erythema and swelling of one or both helices. The lobe is spared. Inner and middle ear involvement can occur and cause hearing loss or vertigo. Hearing loss can also result from edema of the external canal. Nasal cartilage involvement can produce a saddle nose. Laryngeal and tracheal disease can cause hoarseness or life-threatening upper respiratory obstruction. Ocular manifestations are common and include conjunctivitis, episcleritis, iridocyclitis, proptosis, and, rarely, other problems such as optic neuritis. Cardiac involvement, especially involvement of the aortic root with aortic insufficiency, is seen in up to one fourth of cases. Aortic aneurysms, arrhythmias, and mitral regurgitation may also be present. Arthritis is reported in about three fourths of cases but is generally non-destructive. Fever, rashes, oral or genital ulcers, and renal disease can occur. Renal involvement can include glomerulonephritis and IgA nephropathy. Aseptic meningitis has been reported. No laboratory tests are diagnostic, although the erythrocyte sedimentation rate is often elevated. Antineutrophil cytoplasmic antibodies have been reported. Anemia and leukocytosis may be present. Radiographs can detect advanced tracheal narrowing. Computed tomographic scans or magnetic resonance imaging and pulmonary function tests can detect more subtle airway obstruction. Relapsing polychondritis is associated with other diseases in one third or more of cases, including rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, thyroid disease, inflammatory bowel disease, psoriasis, spondyloarthropathies, Behcet's disease, vasculitis of various types, cryoglobulinemia, diabetes mellitus, biliary cirrhosis, panniculitis, malignancies, myelodysplastic syndromes, sinusitis, and mastoiditis. Wegener's granulomatosis and infections can cause potentially confusing chondritis. In mild cases, non-steroidal anti-inflammatory agents can be used for symptomatic treatment, although adrenocorticosteroids in the range of 30 to 60 mg of prednisone per day are generally needed for acute inflammatory episodes and severe respiratory involvement. Methotrexate can be steroid sparing. Other immunosuppressives and cyclosporine have also been used with apparent benefit. Dapsone has been used with variable results. Tracheostomy or stents may be life saving if tracheal collapse occurs. The course is unpredictable, with about 55% of subjects surviving for 10 years. Infection and systemic vasculitis caused more deaths than did airway obstruction in a recent series. Remissions do occur. Aortic valve disease has required surgery. Chang-Miller A, Okamura M, Torres VE, et al: Renal involvement in relapsing polychondritis. Medicine (Baltimore) 66:202, 1987. Glomerulonephritis often responds to corticosteroids or cytotoxic agents. Michet CJ, McKenna Ch, Luthra HS, et al: Relapsing polychondritis. Survival and predictive role of early disease manifestations. Ann Intern Med 104:74, 1986. Anemia, saddle nose deformity, and vasculitis appear to be poor prognostic signs. Park J, Gowin KM, Schumacher HR: Steroid-sparing effect of methotrexate in relapsing polychondritis. J Rheumatol 23:937, 1996. Methotrexate may be the easiest to use and safest steroid-sparing agent. Yang CL, Brinkmann J, Rui HF, et al: Autoantibodies to cartilage collagens in relapsing polychondritis. Arch Dermatol Res 285:245, 1993. Immune mechanisms appear to be important. Zeuner M, Straub RH, Rauh G, et al: Relapsing polychondritis: Clinical and immunogenetic analysis of 62 patients J Rheumatol 24:96, 1987. HLA-DR4 and other autoimmune diseases are frequently associated with polychondritis.

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Chapter 302 - OSTEOARTHRITIS (DEGENERATIVE JOINT DISEASE) Thomas J. Schnitzer

Osteoarthritis is a disorder of diarthrodial joints characterized clinically by pain and functional limitations, radiographically by osteophytes and joint space narrowing, and histopathologically by alterations in cartilage integrity. The most common of all joint diseases, its importance derives from its economic impact, in terms of both productivity (single greatest cause of days lost from work) and cost of treatment (chronic use of analgesics and anti-inflammatory drugs). Although the etiology of the disorder is still not clearly understood, osteoarthritis has been shown to be a family of disorders with cartilage as a target organ in which biomechanical factors play a central role and with risk factors such as age, weight, and occupation also of major importance. Because no treatment can currently prevent or ameliorate the basic disease process, medical treatment is aimed primarily at relieving pain, with orthopedic intervention largely reserved for situations that cannot be controlled with more conservative therapy.

EPIDEMIOLOGY. Osteoarthritis is by far the most common joint disorder, one of the most common chronic diseases in the elderly, and a leading cause of disability. Because osteoarthritis can be defined both radiographically and clinically and because there is little correlation between the two, the prevalence of this condition has been variously estimated in epidemiologic studies. If radiographic criteria are used, the prevalence of joint findings steadily increases from less than 2% in women younger than 45 years to 30% in those aged 45 to 64 and to 68% in those older than 65. Its prevalence in men is slightly higher in the younger age groups (younger than 45), whereas women are affected more commonly at ages older than 55, except for disease of the hip. The pattern of joint involvement in osteoarthritis is strikingly affected by age, gender, and previous occupational history. Before age 55, little difference in joint pattern is noted between men and women. In older men, hip osteoarthritis is more common, whereas older women tend to have more involvement of the proximal interphalangeal (PIP) joints and the base of the thumb. Joints subjected to repeated trauma or overuse demonstrate a higher prevalence of osteoarthritis. Cotton and mill workers have increased osteoarthritis of the hand and involved fingers, miners demonstrate increased knee and spine involvement, and pneumatic drill workers experience increased elbow and wrist disease. Racial and genetic factors are also important in the prevalence 1551

and pattern of osteoarthritis. Chinese, Jamaican blacks, South African blacks, and Asian Indians have been shown to have a lower incidence of osteoarthritis of the hip than do whites, whereas Japanese have an increased incidence, apparently related to the more frequent occurrence of congenital hip dysplasia. Black American women have a higher prevalence of knee osteoarthritis than do white women, but a lower prevalence of involvement of the distal interphalangeal (DIP) joints of the hand (Heberden's nodes). Involvement of the DIP joints of the hands is particularly common in women and is often found to have a familial pattern of inheritance, with the female relatives of the proband having similar joint findings with a two- to five-fold increased prevalence. Modifiable risk factors for osteoarthritis have also been identified in recent studies. Weight demonstrates by far the strongest association with osteoarthritis, and importantly, weight reduction has been shown to correlate with a reduction in the risk of later osteoarthritis. Certain types of repetitive activities have been correlated with increased osteoarthritis in the stressed joint (see above), whereas, interestingly, others have not. In particular, marathon runners appear to have no increased prevalence of knee osteoarthritis, but this observation may be due to a self-selection process, with those experiencing knee pain unable to continue the activity. Smoking and osteoporosis have both been shown to be negatively associated with osteoarthritis, but the explanation for this association is unknown.

PATHOLOGY. The hallmarks of osteoarthritis on gross or arthroscopic examination are focal ulcerated areas of cartilage exposing underlying eburnated (ivory-appearing) bone that occur at the load-bearing areas of the joint surface, as well as juxta-articular osteophytes growing at the joint margins. It is important to understand that these states represent the end stage of a continuum and that osteoarthritis is a pathologic process. At its earliest stage, it appears as a softening of the cartilage surface that progresses to fibrillation of the surface layers, loss of cartilage thickness, development of clefts into the depth of the cartilage, and eventual loss of cartilage integrity with release of shards of cartilage. Bone participates in this process as well, with reactive changes (bony sclerosis) underlying the areas of cartilage loss, development of subchondral bone cysts that may communicate with the joint space and expand into geodes, and marginal osteophytes (new cartilage and bone growth) at non-weight-bearing areas. The earliest histologic changes reveal loss of extracellular cartilage matrix, loss of chondrocytes in the surface layers of articular cartilage, and reactive changes in the deeper chondrocytes manifested by cellular division and "cloning" in an apparent attempt at repair. Later, progressive loss of chondrocytes is seen at all levels, with marked thinning of the cartilage matrix and, in some instances, development of fibrocartilage in place of lost hyaline cartilage. The surrounding synovium is largely unaffected, although in later disease cartilage fragments may incite focal inflammatory lesions without the progressive and destructive pannus seen in typical inflammatory arthropathies.

PATHOGENESIS. Articular cartilage serves two major functions: (1) to permit nearly frictionless joint motion and (2) to act as a "shock absorber" and transmit loads across joint surfaces to the surrounding tissue. The requisite properties of elasticity and high tensile strength are imparted by proteoglycans and collagen in the extracellular matrix, which account for over 90% of the cartilage macromolecules. The proteoglycan elements of the matrix are actively being metabolized and turned over with a half-life of weeks. The highly negatively charged sulfated glycosaminoglycan components of the proteoglycans impart the elastic properties to cartilage. The collagen component is characterized by a unique structure (type II collagen), provides the tensile strength, and tightly constrains the proteoglycan molecules in a three-dimensional framework. The collagen fibers are covalently linked by other matrix molecules believed to provide the "glue" to hold the matrix intact. Collagen itself is extremely slowly metabolized (half-life of many years) in the normal state. Osteoarthritis begins with an initial phase in which chondrocytic metabolic activity is up-regulated (enhanced proteoglycan synthesis), followed by eventual chondrocytic loss (apoptosis). The reason for failure of repair is unclear but may relate to the inability to re-form, once disrupted, the three-dimensional architecture of cartilage in mature individuals. The processes responsible for degrading collagen and proteoglycans in osteoarthritis are driven by proteolytic enzymes being synthesized and released from the chondrocytes themselves. Subsequent activation of these potent enzymes overwhelms the natural matrix defenses and ultimately results in collagen breakdown and proteoglycan cleavage. Fragments from these molecules are then released into the synovial fluid and enter the circulation, where they provide "markers" that can be used as a means to detect and measure the degradative process. The factors responsible for activating chondrocytes to degrade matrix in osteoarthritis are not known. However, certain conditions causing biomechanical alteration of cartilage are known to lead to osteoarthritis: joint injury, abnormal joint loading because of neuropathic changes (Charcot joint) or ligamentous damage (anterior cruciate ligament or meniscus injuries), altered joint surface congruity as in dysplasias, and muscle atrophy in the elderly. A number of metabolic conditions are known to predispose to the early onset of osteoarthritis; e.g., ochronosis with the deposition of homogentisic acid and hemochromatosis with the deposition of iron. Gene

defects affecting matrix structures would be expected to possibly lead to osteoarthritis, but thus far genetic factors have played a role only in the development of dysplasias with secondary osteoarthritic changes. The pathogenetic mechanisms and feedback loops associated with altered cartilage structure and biomechanics are demonstrated in Figure 302-1 .

CLINICAL FEATURES. The initial stages of the osteoarthritic process are clinically silent, which explains the high prevalence of radiographic and pathologic signs of osteoarthritis in clinically asymptomatic patients. Even in the later stages of osteoarthritis, clinical symptoms and alterations in cartilage and bone integrity, defined arthroscopically or by indirect imaging techniques (radiography, magnetic resonance imaging [MRI]), are poorly correlated. The factors or events that make the osteoarthritic process clinically apparent are unknown but are likely to be heterogeneous in nature and invoke processes within the synovium, bone, and surrounding supporting structures (muscle, ligaments) that produce pain rather than involve cartilage itself, a completely aneural tissue. Pain is the predominant symptom that prompts the diagnosis of osteoarthritis and initially often involves only one joint, with others becoming painful subsequently. The pain is most often described as a deep ache frequently accompanied by joint stiffness that follows periods of inactivity (upon arising in the morning, after sitting). Pain is aggravated by using the involved joints, may radiate or be referred to surrounding structures, and in the early stages of the disease is commonly relieved by rest. With more severe disease, pain may be persistent and interfere with normal function. and prevent sleep, even with medical management. Even in severe disease, systemic manifestations such as fever, weight loss, anemia,

Figure 302-1 Pathogenetic pathways in osteoarthritis. IL-1 = interleukin-1; MRI = magnetic resonance imaging.

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and an elevated erythrocyte sedimentation rate (ESR) are not present. The joints most commonly involved in osteoarthritis are the metatarsophalangeal joint of the great toe (hallux valgus or "bunion"), the PIP and DIP joints of the fingers, the carpometacarpal joint of the thumb, and the hips, knees, and both the lumbar and cervical spine. Interestingly, other joints, even major weight-bearing joints such as the ankle, are regularly spared unless involved in secondary forms of osteoarthritis (Table 302-1) . On physical examination the joints may demonstrate tenderness, crepitus, and limited range of motion. Joint swelling may be due to an accompanying synovial effusion or bony enlargement and osteophytes. Joint instability is seen only in severe disease or after internal derangement of the knee with disruption of one or more of the major supporting structures (e.g., anterior cruciate ligament, medial collateral ligament). Patients with far-advanced disease exhibit gross deformity with subluxation of the involved joints. Although osteoarthritis is thought to be a uniformly progressive disease that invariably leads to joint replacement, such is not the case. The disease appears to stabilize in many patients with no worsening of signs or symptoms and actual improvement in some.

SPECIFIC JOINT INVOLVEMENT. HAND. Firm, slowly progressive bony enlargements of the DIP joints are called Heberden's nodes and represent marginal osteophytic spurs. Occasionally, the onset of symptoms is acute with sudden redness and tenderness in the involved joint. These changes can lead to deformity at these joints with lateral and flexor deviation. A related disorder, erosive osteoarthritis, is associated with repetitive episodes of acute symptoms and is differentiated by the additional finding of erosive changes on radiographs of the involved joints and a tendency to bony ankylosis. A genetic basis for Heberden's nodes appears to exist, the condition demonstrating a distinct female-dominant familial tendency (women are affected 10 times more commonly than men) (Fig. 302-2) . Changes similar to those in the DIP joints occur in the PIP joints and are termed Bouchard's nodes. The only other joint to be commonly involved is the carpometacarpal joint of the thumb, often eliciting complaints of pain on use (wringing out TABLE 302-1 -- ETIOLOGIC CLASSIFICATION OF OSTEOARTHRITIS Idiopathic (Primary) Localized Hands: Heberden's nodes, erosive interphalangeal arthropathy Feet: hallux valgus, hammer toes; talonavicular osteoarthritis Knees: medial, lateral, patellofemoral compartments Hips: sites of cartilage loss--eccentric (superior), concentric (axial, medial), diffuse Spine: zygapophyseal joints, osteophytes, intervertebral disks (spondylosis); ligaments, e.g., disseminated idiopathic skeletal hyperostosis Other single sites: shoulder, temporomandibular and carpometacarpal joints Generalized--includes three or more areas listed above Mineral deposition diseases Calcium pyrophosphate deposition disease Hydroxyapatite arthropathy Destructive disease (e.g., Milwaukee shoulder) Secondary Post-traumatic Congenital or developmental Legg-Calve-Perthes hip dislocation Epiphyseal dysplasias Articular cartilage disorders associated with a gene deficiency (e.g., association with type II procollagen gene mutation) Disturbed local tissue structure by primary disease, e.g., ischemic necrosis, tophaceous gout, hyperparathyroid cysts, Paget's disease, rheumatoid arthritis, osteopetrosis, osteochondritis Miscellaneous additional diseases Endocrine: diabetes mellitus, acromegaly, hypothyroidism Metabolic: hemochromatosis, ochronosis, Gaucher's disease Neuropathic arthropathies Miscellaneous: frostbite, Kashin-Bek disease, caisson disease Mechanical: obesity, unequal lower extremity length; valgus/varus deformities, ligamentous laxity (including associations with type I procollagen gene mutations of Ehlers-Danlos syndrome) Compiled in part by the Osteoarthritis Diagnostic Criteria Committee, American Rheumatism Association, 1983.

Figure 302-2 Typical hand deformities in osteoarthritis. A, Typical Heberden's and Bouchard's nodes represent hypertrophic bony enlargement of the distal and proximal interphalangeal joints, respectively. B, Prominent Bouchard's nodes and minor

subluxations may cause a misdiagnosis of rheumatoid arthritis.

clothes [washerwoman's hands] and grasping objects such as screwdrivers and doorknobs) and leading to a squared appearance of the base of the hand. KNEE. Idiopathic knee osteoarthritis is a leading cause of painful ambulation and its prevalence has a direct relationship to weight; it is more common in women than in men. The medial compartment of the femorotibial joint space is more frequently affected and results in varus deformity (bowlegs). Lateral compartment disease may lead to valgus (knock-knee) deformity. Patellofemoral disease has recently been shown to be common and may represent a substantial portion of knee pathology in patients with knee pain. It is important to exclude other causes of knee pain such as internal derangements of the knee (which may lead to secondary knee osteoarthritis), soft tissue sprains, bursal inflammation, and Baker's cysts (which may coexist with knee osteoarthritis). In young women, the possibility of chondromalacia patellae should always be considered. Its cause is not known, but it is almost always self-limited and is not thought to lead to osteoarthritis. In idiopathic knee osteoarthritis, physical examination of the involved joint often elicits crepitus, pain, and decreased range of motion. Effusions are not infrequently present but are often small and may be difficult to appreciate. HIP. Although congenital (Legg-Calve-Perthes disease) and developmental (slipped femoral capital epiphysis) abnormalities have long been implicated in secondary hip osteoarthritis, the majority of primary hip osteoarthritis is now believed to be the consequence of mild dysplasia of the femoral head and/or acetabulum resulting in incongruity of the articulating surfaces. Use of the joint leads to progressive cartilage degeneration and secondary bony productive changes typical of osteoarthritis. Pain is typically referred to the groin, with anterior thigh and knee symptoms occasionally predominant. The majority of patients with pain in their "hip" are suffering from osteoarthritis of the lumbar spine. The earliest physical finding 1553

in hip osteoarthritis is loss of internal rotation; with progressive disease, range of motion is limited further in all directions, and significant functional limitation occurs, often necessitating surgery. FOOT. The 1st metatarsophalangeal joint is the primary joint involved with associated bony swelling and deformity (bunion). Significantly more common in women than in men, these changes have been attributed to abnormal stresses imposed on the joint by footwear. In extreme cases, the joint space may be destroyed and result in a condition known as "hallux rigidus," which may interfere with normal ambulation and necessitate surgical correction. SPINE. Technically, osteoarthritis of the spine relates strictly to changes in synovial-lined joints (apophyseal and uncovertebral joints) that can lead to localized pain as well as irritation of adjacent nerve roots with referred pain in the form of radiculopathy. Nerve root compression resulting from apophyseal joint subluxation, prolapse of an intervertebral disk, or osteophytic spurring may occur and be manifest as muscle weakness, hyporeflexia, and paresthesia or hypoesthesia. In the cervical region, spinal involvement can lead to cord impingement with long tract signs or may affect the vertebral artery and produce posterior circulation insufficiency with associated symptoms. Osteoarthritis of the spine should be differentiated from diffuse skeletal hyperostosis, which is characterized by marked calcification of the paraspinous ligaments and sparing of the arthrodial spinal joints. PRIMARY GENERALIZED OSTEOARTHRITIS. The pattern of involvement of three or more joints or joint groups with osteoarthritis has been given the name primary generalized osteoarthritis and is seen most commonly in older women. Typically, the DIP and PIP joints of the hand, the knees, and the spine are involved. Whether this pattern represents a distinct subset of osteoarthritis is not known but has been suggested.

LABORATORY FINDINGS. Osteoarthritis involves a pathologic process that appears to be largely limited to cartilage and surrounding tissues with no evidence of systemic involvement. Typically, the ESR is normal, and levels of acute-phase reactants are not elevated. The hemoglobin and leukocyte counts remain within normal limits. The synovial fluid itself demonstrates no evidence of an inflammatory reaction, with few leukocytes (typically less than 3000 per cubic millimeter) and good viscosity. Occasionally, fragments of cartilage and crystals of calcium hydroxyapatite or calcium pyrophosphate dihydrate are seen. Rheumatoid factor is absent in the majority affected, but a significant number of older individuals will exhibit low-titer elevations that are not diagnostic of rheumatoid arthritis but are a common accompaniment of aging. Cartilage matrix components unique to the joints have been identified, and sensitive assays have been developed to detect these "markers" in synovial fluid, serum, and urine. Further clinical correlations will need to be performed to determine the relationship of these markers to the disease process, activity, and state and their utility for earlier diagnosis and management of osteoarthritis.

RADIOLOGY AND IMAGING TECHNIQUES. Pathognomonic findings on plain radiography of involved joints include the presence of osteophytes at the margins of involved joints, associated joint space narrowing representing areas of cartilage thinning or loss, and evidence of bony reaction marked by subchondral sclerosis and bone cysts in more progressive disease. Some patients may lack one or more of these findings. Radiography has been shown to be very insensitive to the pathologic processes occurring in the cartilage, with many patients having normal radiographs but destructive cartilage changes documented by arthroscopy. Other techniques have therefore been developed with greater potential sensitivity to detect cartilage change. In particular, MRI has the advantage of demonstrating cartilage as a positive image and has been widely used to document major cartilage injury such as meniscal tears. Further refinement of this technology will enhance the resolution possible, as well as increase the sensitivity to detect changes in hydration, which mark the earliest changes in osteoarthritis. It is anticipated that such technology will be important in assessing disease progression in the future. Other technologies being developed to evaluate osteoarthritic joints include scintigraphy and ultrasound.

TREATMENT. People with osteoarthritis seek pain relief and improvement in physical functioning. Because no therapy in humans is known to affect the basic disease process (inhibit cartilage degradation or enhance synthesis), medical therapy has focused on providing symptomatic relief. Largely because of ease of administration and acceptance by patients, unwarranted reliance has been placed on pharmacologic intervention, particularly non-steroidal anti-inflammatory drugs (NSAIDs), as initial therapy at the expense of physical measures that have less morbidity and may provide longer-term benefit. The American College of Rheumatology has recently formulated evidence-based guidelines for progressive, step-wise treatment of patients with knee and hip osteoarthritis that incorporates this approach. PHYSICAL MEASURES. Although often overlooked, physical therapy and exercise programs provide important benefit and should be prescribed as baseline therapy for all patients with osteoarthritis. Muscle atrophy commonly accompanies osteoarthritis. Because muscles serve to reduce load on cartilage, maintaining muscle function is crucial for cartilage integrity and can reduce pain. Both muscle strength and range of motion can be improved with appropriate physical therapy. Isometric exercises are preferred to isotonic ones because they place less stress on the involved joint. Heat and cold are both used with varying effectiveness to provide symptomatic relief to patients and as an important adjunct to physical therapy regimens. The use of transcutaneous nerve stimulation, particularly to relieve back pain, is effective in some patients and provides an attractive alternative to pharmacologic intervention. Periods of rest throughout the day may be an important adjunct in the routine of patients with osteoarthritis. Reduction in joint loading, either by resting or appropriately

using a cane, will often permit increased periods of activity with reduced pain. Using cushioned shoes (commercial running or walking shoes) may also help lower extremity joint symptoms. Back pain may be reduced by muscle-strengthening exercises, as well as a well-fitted brace. PHARMACOLOGIC THERAPY. Symptomatic relief of pain in patients with osteoarthritis is best achieved with simple analgesic agents such as acetaminophen. The effectiveness of NSAIDs is due primarily to their analgesic rather than their anti-inflammatory properties. Recent controlled studies have demonstrated that acetaminophen is as effective as NSAIDs and has considerably fewer serious side effects. Particularly in the elderly, with decreased renal reserve and an increased risk of upper gastrointestinal bleeding, acetaminophen and other simple analgesics should be the drugs of initial choice. If inflammation is present (erosive osteoarthritis) or symptoms are not well controlled with simple analgesics, low (analgesic) doses of NSAIDs may prove effective. A new class of NSAIDs (COX-2 inhibitors) that inhibit inflammatory-mediated production of prostaglandins (cyclooxygenase 2 mediated) but permit constitutive prostaglandin production (cyclooxygenase 1 mediated) are now available. If the gastrointestinal and overall safety of these agents is adequately demonstrated, their use will be preferred to nonselective NSAIDs, particularly in patients at high risk of GI side effects. Intra-articular injection of both various steroid and hyaluronan preparations can also control joint symptoms. Controlled studies of intra-articular steroid injections have demonstrated only short-term relief of symptoms. Intra-articular injections of steroids should not be repeated more than three to four times per year in any given joint because of the possibility of the steroids potentiating cartilage breakdown. Systemic use of steroids has no place in the treatment of osteoarthritis. In knee osteoarthritis, intra-articular hyaluronan has been shown to produce modest clinical benefit that may persist for months. Other approaches to therapy are under investigation. Topical treatment with capsaicin, a substance P inhibitor, has been shown to relieve localized pain in some patients with osteoarthritis. The development of agents that can stimulate cartilage synthesis or prevent degradation is actively being pursued and should provide the next generation of agents to treat this condition. ORTHOPEDIC SURGERY. Joint replacement surgery has been the single biggest advance in the treatment of osteoarthritis in the past half century. Patients in whom optimal medical management has failed and who continue to have pain that interferes with sleep or activity or have significant limitations of joint function are candidates for an operation. Some individuals, those with altered limb alignment and early osteoarthritis of a hip or knee, may benefit from osteotomy. Most patients have more advanced disease and 1554

require total joint replacement. Ideal candidates for total joint arthroplasty have well-maintained muscle strength and should be older than 60 years. Younger patients are discouraged from undergoing joint replacement because of the small but real incidence of long-term failure of joint implants, mainly from loosening. Revision arthroplasty is possible but has a higher failure rate and can be avoided by delaying the initial arthroplasty as long as possible and putting less load on the replaced joint. Arthroscopic surgery is useful for removing loose bodies and repairing intrinsic defects of the knee, as well as for shoulder (rotator cuff) and ankle pathology. Arthroscopic lavage (flushing of saline to remove cartilage debris) in patients with knee osteoarthritis may provide pain relief. Abrasion arthroplasty (chondroplasty) has been widely used in patients with knee osteoarthritis, but no data have demonstrated its efficacy, and it cannot currently be recommended. Koopman WJ: Arthritis and Allied Conditions: A Textbook of Rheumatology. Baltimore, Williams & Wilkins, 1996. Comprehensive overview of all aspects with illustrations. Kuettner K, Goldberg V (eds): Osteoarthritis Disorders. Rosemont, IL, American Academy of Orthopedic Surgeons, 1995. Current understanding of cartilage biology and the pathogenesis of osteoarthritis. Moskowitz W, Howell DS, Goldberg VM, et al: Osteoarthritis: Diagnosis and Medical/Surgical Management. Philadelphia, WB Saunders, 1992. In-depth coverage of all aspects of osteoarthritis. Silman AJ, Hockberg MC (eds): Epidemiology of the Rheumatic Diseases. New York, Oxford Press, 1993. A comprehensive review of the definition, incidence, and prevalence of rheumatic disease.

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Chapter 303 - THE PAINFUL SHOULDER Dennis W. Boulware

Shoulder pain can originate from many anatomic sites, including the structures comprising the glenohumeral joint and the periarticular soft tissue structures, or be referred from the cervical spine, the thorax, the diaphragm, and the upper abdominal cavity. Although non-musculoskeletal causes of shoulder pain are important, the focus in this chapter is on the musculoskeletal causes of isolated shoulder pain. The more common causes of shoulder pain are due to disorders of the surrounding periarticular soft tissue structures: the biceps and rotator cuff tendons, the subacromial and subdeltoid bursae, and the

Figure 303-1 Anterior aspect of the shoulder joint showing palpable landmarks and their relationship to the subacromial bursa. (From Polley HF, Hunder GG [eds]: Rheumatologic Interviewing and Physical Examination of the Joints, 2nd ed. Philadelphia, WB Saunders, 1978, p 63.)

articular capsule (Fig. 303-1) . Infrequently, diseases of the bone and the glenohumeral joint can be responsible for isolated shoulder pain. With a fundamental knowledge of the anatomy of the shoulder joint and the physical examination of these specific structures, a proper diagnosis can be made. Once a proper diagnosis is made, appropriate treatment can be prescribed, ensuring greater success for improvement.

TENDONS. In general, tendon lesions are painful only during active use. A bicipital tendinitis will elicit anterior shoulder pain during active flexion of the elbow or forward flexion of the shoulder, and a rotator cuff lesion will cause more diffuse pain on active abduction of the shoulder. On examination, active testing of the myotendinous unit results in more tenderness than passive range of motion. Isometric loading of the tendon by active resistance without joint motion will often pinpoint a tendinous cause of pain rather than an articular cause. Passive range of motion is preserved in isolated tendinitis. THE ROTATOR CUFF. All lesions of the rotator cuff will precipitate pain on active abduction of the shoulder, particularly the initial 90 degrees of motion. This pain is usually focused over the lateral aspect of the shoulder and frequently a problem during sleep. On examination of the shoulder, active abduction will elicit more tenderness than passive abduction done by the examiner. A "drop

Figure 303-2 Calcific tendinitis. A , Two distinct deposits of calcium are present on the internal rotation view. B , External rotation projects the supraspinatus calcification above the greater tuberosity and superimposes the larger collection (within the infraspinatus tendon) over the humeral head. (From Forrester DM, Brown JC: The Radiology of Joint Disease, vol 2. Philadelphia, WB Saunders, 1987, p 364.)

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sign" is helpful in identifying the rotator cuff as the source of pain and can be accomplished by passively placing the patient's arm at full abduction. The patient will experience severe pain when the arm is slowly adducted from 120 to 60 degrees and the arm will reflexively "drop." Rotator cuff tendinitis is the most common cause of shoulder pain and is usually due to unaccustomed overuse of the arm in overhead activities. This abducted position impinges the cuff between the acromion and the humeral head, resulting in injury. An acute impingement can also occur during a fall on the arm or shoulder, trapping the cuff between the humeral head and the acromion. Occasionally, this injury can lead to a partial or complete tear. Chronic impingements also can occur from inferior osteophytes of the acromioclavicular joint encroaching into the acromiohumeral space. With time, chronic impingements can result in attenuation of the rotator cuff and an eventual tear. Injury, overuse, or degenerative processes can lead to rotator cuff tears in the shoulder. The tear can exist as a complete rupture of the rotator cuff or as incomplete tears. Similar to tendinitis, the pain is worse with active abduction of the shoulder, particularly the initial 90 degrees. A complete tear of the cuff will make abduction of the initial 90 degrees impossible when the patient is upright. Differentiating tendinitis from a tear requires diagnostic imaging, but this should be reserved for suspected complete tears because the initial treatment of incomplete tears and tendinitis is similar. The diagnosis of calcific tendinitis is made in the clinical setting of a rotator cuff tendinitis coupled with the radiographic appearance of calcification of the rotator cuff, usually the supraspinatus tendon near its insertion on the humerus (Fig. 303-2) . Diagnostic plain radiography is helpful in chronic rotator cuff lesions. Chronic impingements with tendinitis will reveal degenerative sclerotic and cystic changes of the humeral greater tuberosity. Significant attrition or complete tears of the cuff will be demonstrated as narrowing or obliteration of the acromiohumeral space. Magnetic resonance imaging and ultrasonography are useful but expensive and difficult to interpret except by experienced musculoskeletal radiologists. Arthrography is the best study to document complete ruptures and often can detect incomplete tears (Fig. 303-3) . The diagnosis of a rotator cuff lesion often can be made by instilling an intralesional local anesthetic agent. When 2 to 4 mL of a local anesthetic is properly placed inferolaterally to the acromial process in the subacromial bursa, the patient should experience significant relief of pain and be capable of active, painless abduction. The exception will be the complete rupture of the rotator cuff, which will have pain relief but still be incapable of unassisted abduction. The treatment of lesions of the rotator cuff is similar for all types of problems except a complete tear, which will require a surgical referral. Initial management with heat, physical therapy, and non-steroidal anti-inflammatory drugs (NSAIDs) is more effective when prescribed early. If this therapy is ineffective, intralesional corticosteroid agents placed in the subacromial bursa may be required. Recalcitrant cases of impingement may eventually require surgery in the form of acromioplasty. Job modification is essential for individuals with chronic impingement from occupational overuse. BICIPITAL TENDON. In bicipital tendinitis, the tendon of the long head of the biceps becomes inflamed as it traverses the bicipital groove of the humerus. Clinically, the patient experiences pain in the anterior aspect of the shoulder, especially on actively using the biceps. Clinical examination can confirm the presence of bicipital tendinitis by one of several techniques. Tenderness elicited by directly palpating the tendon within the bicipital groove is a very helpful sign. Further confirmation of bicipital tendinitis can be demonstrated by Yergason's sign. The examiner should place the shoulder in the initial position of full adduction, the elbow in full flexion, and the wrist in supination. Then the patient is asked to resist an attempt to suddenly extend the elbow and pronate the wrist. Tenderness in the anterior shoulder would be indicative of bicipital

tendinitis. Chronic problems can cause attrition of the tendon and eventual rupture. Complete rupture will cause mild weakness of the biceps and a prominent bulge of the muscle belly. Integrity of the rotator cuff should be assessed in chronic bicipital tendinitis, because the two entities frequently occur concomitantly. Treatment of bicipital tendinitis is initially conservative with rest and NSAIDs. Physical therapy and intralesional corticosteroids are reserved for refractory cases. Successful treatment is more likely when initiated early. Surgery is essential for complete rupture and may be required for intractable cases of tendinitis.

BURSAE. The subacromial or subdeltoid bursa is the largest and most frequently inflamed bursa of the shoulder. Located between the acromion process and the rotator cuff, and extending beneath the deltoid muscle, subacromial or subdeltoid bursitis will cause pain in the lateral aspect of the shoulder similar to that caused by rotator cuff tendinitis. It differs from a rotator cuff tendinitis by the presence of tenderness on direct palpation beneath the acromion

Figure 303-3 A , Arthrogram of normal shoulder. The extent of the joint capsule is delineated by contrast material. A prominent subscapular extension of the capsule is seen projecting toward the axilla. Filling of the subacromial bursa may occasionally occur normally. Extension of the capsule as a pouch around the long head of the biceps demarcates the intertubercular groove. B , Rotator cuff tear. Filling of (1) the subacromial bursa superiorly and (2) the subcoracoid bursa inferiorly indicates tear of the rotator cuff. The normal hyaline articular cartilage is seen as a radiolucent crescent over the head of the humerus. (From Forrester DM, Brown JC: The Radiology of Joint Disease, vol 2. Philadelphia, WB Saunders, 1987, pp 362, 363.)

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Figure 303-4 Calcific bursitis. A large amorphous collection of calcium lies within the subacromial bursa. In addition, a small fleck of calcium just above the greater tuberosity represents supraspinatus tendinitis. (From Forrester DM, Brown JC: The Radiology of Joint Disease, vol 2. Philadelphia, WB Saunders, 1987, p 369.)

process. Similar to tendinitis, isolated bursitis will have full passive range of motion. Plain radiography is typically not helpful but sometimes can demonstrate calcification in chronic subacromial bursitis (Fig. 303-4) . Treatment of subacromial or subdeltoid bursitis is conservative, with rest, physical therapy, and NSAIDs. Patients whose cases are refractory to initial conservative management can receive intralesional corticosteroids given directly into the subacromial bursa, which are quite effective.

ARTICULAR CAPSULE. Disorders of the articular capsule often cause diffuse shoulder pain radiating into the brachium. It will be evident by the limitation of range of motion by both active and passive abduction. Adhesive capsulitis, also known as "frozen shoulder," is a common entity that can occur in association with diabetes mellitus, tuberculosis, cervical spine disease, upper extremity injuries, coronary artery disease, and chronic pulmonary disease. Initially a painful condition, it will proceed through an adhesive phase characterized by the painless progressive loss of both passive and active range of motion in all directions, but usually starting with a loss of external rotation and abduction. Eventually, the shoulder "thaws," with the return of range of motion after several years. The diagnosis is best confirmed by arthrography, which reveals a contracture of the articular volume and loss of the axillary pouch. Pain is best managed by physical therapy, NSAIDs, and judicious use of intra-articular corticosteroids. Early restoration of range of motion has been uniformly unsuccessful even when attempted by physical therapy, closed manipulation under general anesthesia, and hydraulic distention using large-volume intra-articular injections. Reflex sympathetic dystrophy syndrome is similar to adhesive capsulitis except for more diffuse involvement with pain and vasomotor instability of the hand, wrist, and arm. More common after trauma of the upper extremity, it occurs in association with some clinical situations similar to adhesive capsulitis. This condition can occur bilaterally and responds more favorably to early therapy. Treatment should include aggressive physical therapy to maintain range of motion, non-narcotic analgesia for pain management, and a short, rapidly tapering course of corticosteroids. Best results have occurred when corticosteroids are started at 40 to 60 mg of prednisone per day and tapered over a 3-week period. Stellate ganglion blocks and intra-articular corticosteroids are sometimes helpful, but with less uniform improvement.

BONE. Primary diseases of the bone can manifest themselves as shoulder pain. Avascular necrosis of bone can affect the humeral head, although it is not as common as avascular necrosis of the femoral head. If avascular necrosis of bone is suspected, early diagnosis is best made by magnetic resonance imaging. Plain radiographic changes occur late in the disease process and should not be required to confirm the diagnosis. GLENOHUMERAL JOINT. Arthritis of the glenohumeral joint is common and like adhesive capsulitis has diffuse shoulder pain often radiating into the upper arm. Glenohumeral arthritis is easily detected on physical examination by the presence of tenderness on passive rotation of the fully adducted shoulder. Soft tissue swelling is not easily perceived on routine examination, and tenderness on active rotation will not discriminate glenohumeral arthritis from lesions of the rotator cuff. Although painful for the patient, passive range of motion should be determined because it will be near normal in acute arthritis but not in adhesive capsulitis. Because the glenohumeral joint is a common site of involvement for many forms of the polyarthritides, most episodes of glenohumeral arthritis are part of a polyarthritis. Alternatively, an isolated severe destructive degenerative glenohumeral arthritis seen in the elderly should make the clinician suspect Milwaukee shoulder. Predisposing factors for this condition include chronic renal failure, local calcium pyrophosphate dihydrate deposition, chronic joint overuse, and large tears of the rotator cuff. The long-term disruption of the rotator cuff and chronic shoulder instability seem to be the key factors in allowing this problem to occur. Biundo JJ, Torres-Ramos FM: Common shoulder problems. Primary Care Rheumatol 4:1, 1991. A practical approach to examination of the shoulder and diagnosing common problems. Boublik M, Hawkins RJ: Clinical examination of the shoulder complex. J Orthop Sports Phys Ther 18:379, 1993. A comprehensive approach to the examination of the shoulder. Kozin F: Painful shoulder and the reflex sympathetic dystrophy syndrome. In Koopman WJ (ed): Arthritis and Allied Conditions, 13th ed. Baltimore, Williams & Wilkins, 1997, pp 1887-1922. A detailed and comprehensive resource of etiology, diagnosis, and treatment with 315 references. Thornhill TS: Shoulder pain. In Kelley WN, Harris ED, Ruddy S, et al (eds): Textbook of Rheumatology, 5th ed. Philadelphia, WB Saunders, 1997, pp 413-438. A detailed and comprehensive resource of etiology, diagnosis, and treatment with 157 references.

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Chapter 304 - SYSTEMIC DISEASES IN WHICH ARTHRITIS IS A FEATURE Eugene V. Ball

Eleven per cent of adult Americans interviewed in a national health survey claimed to have had one or more episodes of joint pain over a period of 6 weeks. Much of this pain was probably due to fibromyalgia and soft tissue syndromes, or to common rheumatic diseases such as osteoarthritis and rheumatoid arthritis, that are defined by their own attributes and not by associated symptoms. The arthralgias of a fraction of these persons might have represented early symptoms of systemic diseases that could be diagnosed only by the appearance of other clinical signs or by laboratory testing. Table 304-1 is a list of selected general medical laboratory tests of value in the evaluation of non-specific joint symptoms. The tests afford significant diagnostic clues for certain systemic diseases in which arthralgias can be the earliest and only symptoms. Brief descriptions of musculoskeletal manifestations of a few systemic disorders follow.

PRIMARY BILIARY CIRRHOSIS (see Chapter 153) . More than half of women with primary biliary cirrhosis may have rheumatoid factors and antinuclear antibodies, in addition to antimitochondrial antibodies. A large percentage of these have joint pains or outright rheumatic disease, mainly rheumatoid arthritis, Sjogren's syndrome, or limited scleroderma. An asymmetrical, non-deforming arthritis has been described in as many as 30% of patients. Other defined 1557

TABLE 304-1 -- LABORATOORY TESTS IN THE EVALUATION OF NON-SPECIFIC JOINT SYMPTOMS TEST

DISEASE

Liver function tests

Primary biliary cirrhosis; hepatitis B and C; chronic active hepatitis

Calcium and phosphorus

Hyperparathyroidism

Serum protein electrophoresis

Hypogammaglobulinemic arthritis; primary amyloidosis; hyperimmunoglobulin D

Serum iron and total iron-binding capacity; ferritin

Hemochromatosis

Lipase or amylase

Pancreatic-arthritis syndrome

Thyroid-stimulating hormone; thyroxine

Thyroid myopathy or arthritis

Complete blood cell count

Leukemia; sickle cell disease

Lipid analysis

Hyperlipidemia-associated arthritis

Partial thromboplastin time; rapid plasma reagin (RPR) or VDRL

Hemophilia Syphilis

Anti-human immunodeficiency virus (HIV)

HIV arthritis

Antiparvovirus antibody

Parvovirus arthritis

causes for bone or joint pains in primary biliary cirrhosis include osteomalacia and hypertrophic osteoarthropathy.

HEMOCHROMATOSIS (see Chapter 221) . Arthritis is frequently the first sign of hemochromatosis and eventually develops in as many as half of all persons with the disease. Typically occurring between the ages of 40 and 50, the arthritis of hemochromatosis has been reported in persons younger than age 30 and is easily overlooked or confused with primary osteoarthritis, even though their distributions often differ. It also may be dismissed as idiopathic tendinitis or bursitis. Pain and stiffness frequently appear first in the metacarpophalangeal joints; other joints that are involved frequently include wrists, hips, and knees. Signs of inflammation are negligible except during episodes of pseudogout. Chondrocalcinosis is common on radiographs, as are subchondral cysts, sclerosis, and joint space narrowing. The arthritis is not altered by phlebotomy; treatment is symptomatic and may necessitate arthroplasties, particularly in the hips.

SICKLE CELL DISEASE AND OTHER HEMOGLOBINOPATHIES (see Chapter 169) . Almost all persons with sickle cell disease experience musculoskeletal symptoms. Large joint arthritis lasting a few days to a few weeks results from small vessel occlusion caused by local sickling. Osteonecrosis occurs in both SS and SC disease, often in the head of the femur; however, multiple areas may be infarcted. Osteomyelitis is much more common in persons with sickle cell disease than in normal persons and is often caused by Salmonella. Hyperuricemia attributable to SS disease has culminated in gout in older patients. Pain due to microfractures in the lower leg, ankle, or foot, lasting up to 1 to 2 years, has been described in almost one half of a group of 50 patients with beta-thalassemia.

HYPOGAMMAGLOBULINEMIA (see Chapters 272 and 305) . Arthritis as a complication of hypogammaglobulinemia is most typical of the X-linked variety (Bruton's disease) in children; however, it also occurs in other types of primary hypogammaglobulinemia. Septic arthritis is caused by common pathogens or by mycoplasmal organisms such as Ureaplasma urealyticum. Non-erosive oligoarthritis, without evidence of infection or other demonstrable cause, often resolves after institution of immunoglobulin therapy. Its resolution with treatment does not necessarily constitute a priori evidence of an infectious etiology. Intravenous gamma globulin treatment might suppress arthritis through its complex modulating effect on the immune system.

WHIPPLE'S DISEASE (see Chapters 134 and 136) . The arthritis of Whipple's disease mimics that of rheumatic fever in some respects. It is painful, and there is often warmth, redness, and swelling; it favors large joints, and subcutaneous nodules have been noted in a few patients. Recurrences are common, and the disease can be migratory. Less often, small joints of the hands and feet are inflamed, and the arthritis becomes chronic and resembles rheumatoid arthritis. The synovial fluid white blood cell count is sometimes elevated to 50,000/mm3 , and rod-shaped bacilli (Tropheryma whippelii) have been identified, usually by electron microscopy, in synovial biopsy specimens. These organisms are also seen attached to circulating erythrocytes. Diagnosis is facilitated by polymerase chain reaction analysis of tissue or blood. The arthritis may antedate gastrointestinal and other symptoms by years. Rheumatoid factors and antinuclear antibody are not features of Whipple's disease.

HYPERLIPOPROTEINEMIA (see Chapter 206) .

An association exists between type II familial hypercholesterolemia (both homozygous and heterozygous forms) and musculoskeletal symptoms such as Achilles tendinitis, oligoarthritis, and polyarthritis. Transient pain in the Achilles tendon appears to be more common than frank inflammatory tendinitis, which can last a few days and recur two or three times a year. A few patients have acute painful monoarthritis or pauciarthritis of the knees, ankles, or small joints that lasts a week or more and recurs frequently. Less common is an incapacitating polyarthritis resembling rheumatic fever, persisting a month or more. In one study, 40% of 73 heterozygous patients were symptomatic; articular manifestations appeared at times before the xanthomas that are the major diagnostic sign of familial hypercholesterolemia.

ENDOCRINE DISORDERS (see Chapters 237 , 239 , and 264) . Aches and stiffness simulating fibromyalgia may appear early in hypothyroidism; if untreated, this may progress to proximal myopathy with elevated creatine kinase levels, simulating polymyositis, or to a syndrome of synovial thickening and joint effusions, simulating rheumatoid arthritis. Carpal tunnel syndrome is a recognized manifestation of hypothyroidism, and there appears to be an association with calcium pyrophosphate deposition disease. Hyperthyroidism can cause myopathy without elevations of the creatine kinase level but with muscle wasting, which can be severe. Thyroid acropachy, seen rarely in association with pretibial myxedema and Graves' disease, is characterized by diffuse swelling of the fingers and clubbing. Hyperparathyroidism is a rare cause of diffuse, vague musculoskeletal pains resembling those of fibrositis. The other musculoskeletal complications of hyperparathyroidism include back pain due to vertebral body fractures, an erosive arthritis predominantly in the hands and wrists, and chondrocalcinosis (with pseudogout occurring most often after parathyroidectomy). Carpal tunnel syndrome has been reported in almost one half of persons with acromegaly. Raynaud's phenomenon is rare. The arthritis of acromegaly is clinically indistinguishable from osteoarthritis.

SARCOIDOSIS (see Chapter 81) . Joint or juxta-articular pains are experienced by as many as one third of patients with acute sarcoidosis and may be the only symptom of the disease; however, erythema nodosum often accompanies the arthritis and, together with hilar adenopathy, suggests the diagnosis (one should be aware that arthritis may accompany erythema nodosum of any cause). Arthritis often begins in the ankles and spreads symmetrically. The distal interphalangeal joints are typically spared, but any of the other peripheral joints, as well as the heels, may be painful out of proportion to signs of inflammation, which are meager. Episodes last a few days to a few months, and the arthritis usually resolves completely. The erythrocyte sedimentation rate is often elevated; antinuclear antibodies and rheumatoid factors may be present in high titer. Treatment with salicylates, non-steroidal anti-inflammatory drugs (NSAIDs), or prednisone is based on the severity of the arthritis. Progressive, deforming arthritis is a feature of chronic sarcoidosis, as are bone lesions, both lytic and sclerotic. Clinically significant sarcoid myopathy is rare.

FAMILIAL MEDITERRANEAN FEVER (see Chapters 171 and 297) . Serositis, fever, and arthritis are the major signs of familial Mediterranean fever. Arthritis occurs in as many as one half of patients; it is usually monoarticular and confined to large joints in the lower extremities. Although the arthritis usually lasts less than 1 week, it has been reported to persist for several months. Synovial fluid contains large numbers of granulocytes, and there is intense infiltration of granulocytes and hyperemia in synovial tissue. Diagnosis is suggested by demographic and other clinical features of the disease; criteria for diagnosis have been proposed and are based on the clinical features. In the absence of these, familial Mediterranean 1558

fever is easily confused with juvenile rheumatoid arthritis. Colchicine often prevents arthritis as well as amyloidosis. Livneh A, Langevitz P, Zemer D, et al: Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 40:1879, 1997. The authors propose diagnostic criteria based on the major clinical manifestations of pleuritis, pericarditis, peritonitis, fever, and arthritis. Totemchokchyakarn K, Ball G: Sarcoid arthropathy. Bull Rheum Dis 46:3, 1997. A review of the various rheumatologic manifestations of sarcoidosis.

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Chapter 305 - MISCELLANEOUS FORMS OF ARTHRITIS Eugene V. Ball

NEUROPATHIC JOINT DISEASE (CHARCOT'S JOINTS). Recognition of neuropathic joint disease and its association with syphilis preceded reports of its association with diabetes mellitus by 64 years, but syphilis has been surpassed by the latter as the leading cause of this disorder. In syphilis, subacute combined degeneration of the spinal cord, paraplegia, and Charcot-Marie-Tooth disease, weakness, decreased pain sensation, and impaired position sense contribute to the massive destruction of the knee (or less often the hip, ankle, or spine) that typifies the disorder. In syringomyelia, the shoulder or upper limb is most often involved. Neuropathic disease of the knee or ankle is suggested by effusions, crepitus, enlargement, and relatively little pain, although pain may become worrisome late in the disease. Neuropathic joint disease in diabetes mellitus (Fig. 305-1) causes painless swelling of one or both feet in patients with long-standing disease and sensory neuropathy. For mechanical reasons, the tarsometatarsal and the metatarsophalangeal joints are most frequently involved. Destruction also occurs in the talus, the calcaneus, the ankle joints, and the distal tibia. Radiographs characteristically show loss of joint space, sclerosis, multiple irregular bodies representing chip fractures, and new bone formation; comparable changes are seen in osteomyelitis. Differentiation

Figure 305-1 Diabetes mellitus and neuropathic arthritis. Note lateral displacement of metatarsals (left) and fragmentation and osseous debris (right).

of these two disorders can be difficult; magnetic resonance imaging may help identify them. (Less severe, but similar, changes have been reported in calcium pyrophosphate deposition disease.) It is thought that excess osteoclast activity is responsible for early bone changes in diabetes. Treatment of acute arthropathy requires prompt reduction in weight bearing. Attempts at stabilizing the involved joint with various orthotic devices are often unsatisfactory, and surgical fusion is difficult. Total knee or hip arthroplasty may be useful.

HEMARTHROSIS. Although trauma accounts for most hemarthrosis, hemophilia A and B (see Chapter 185) are its major medical cause. The severity of hemarthrosis in hemophilia is related to the levels of clotting factors. For example, infants with factor VIII or IX levels less than 1% often experience hemarthrosis before the age of 1. By age 15, virtually all persons with severe, inadequately treated factor deficiencies have some form of chronic joint impairment. Acute bleeding into a joint (most often the knees, elbows, or ankles) or muscle is frequently signified by stiffness or discomfort, followed by pain, swelling, and redness. The joint should be immobilized, and adequate factor replacement should be started as early as possible, preferably during the prodromal phase. The joint changes stimulated by repeated intra-articular bleeding resemble those of rheumatoid arthritis. Hyperplastic synovium appears to be the source of proteases and other enzymes that destroy cartilage and bone, culminating in the absence of articular cartilage, joint disorganization, and fibrous contractures. Education of the patient and family, as well as home treatment, prevents or attenuates chronic, destructive arthritis. Joint replacements have been done successfully to relieve pain and restore function. Bleeding into a muscle, which also should be treated with replacement factor, can lead to necrosis and fibrotic scarring. Pseudotumors are cystic bone swellings resulting from intraosseous bleeding and necrosis. Von Willebrand's disease can produce hemarthrosis and joint destruction comparable to that of hemophilia. Painful but non-destructive intra-articular bleeding is a common feature of scurvy, and intra-articular tumors such as pigmented villonodular synovitis frequently cause monoarticular bleeding. MULTICENTRIC RETICULOHISTIOCYTOSIS. The chief manifestations of multicentric reticulohistiocytosis are arthritis and red to purple skin nodules varying in size from 1 to 10 mm. The nodules are found in any part of the skin but tend to concentrate on the face and hands and uncommonly coalesce. The arthritis is most often symmetrical and polyarticular. Unlike adult rheumatoid arthritis, it does not spare the distal interphalangeal joints. It can be severely destructive, and in one third of cases it progresses to arthritis multilans. Systemic signs include fever and weight loss; less often, pericarditis and myositis are present, and it is frequently associated with malignancy. The disorder also has been termed lipoid dermatoarthritis because of the glycolipids contained within the histiocytes and granulomas that constitute the basic lesion. In the absence of a serum or lesional lipid abnormality, lipid deposition is now thought to be non-specific. Improvement, which may be spontaneous, has been reported more consistently with alkylating agents and methotrexate than with prednisone.

HYPERTROPHIC OSTEOARTHROPATHY AND CARCINOMA POLYARTHRITIS. Hypertrophic osteoarthropathy is a systemic disorder distinguished by clubbing of the digits as a result of edema and collagen deposition and by periostitis of the distal ends of tubular bones. The lesions presumably begin with increased blood flow and periosteal edema and with fibroblast proliferation, followed by new bone formation. Radionuclide bone scans are positive at an early stage, often preceding radiographic evidence of periosteal new bone. Hypertrophic osteoarthropathy frequently involves the tibiae, ulnae, radii, femora, metatarsals, and metacarpals. Painful articular swelling appears in approximately 30% of patients and may be debilitating; other variable features of the syndrome include gynecomastia and thickening and furrowing of the facial skin. Intrathoracic malignancies, especially squamous cell carcinoma, have supplanted pulmonary infections as the most common cause. Pleural and diaphragmatic neoplasms and nasopharyngeal carcinomas are strongly associated with hypertrophic osteoarthropathy. Less common causes include chronic liver disease, inflammatory bowel disease, and cyanotic heart disease. There is also a hereditary form termed pachydermoperiostosis, with strong male 1559

predominance and a curious bimodal distribution of disease onset during the first year of life or the midteens. No satisfactory unifying theory of pathogenesis exists, although there is some evidence that platelet activation of endothelial cells, and excess platelet-derived growth factor and fibroblast growth factors, may cause the changes seen clinically. Successful treatment of the underlying disorder results in regression of the disorder. In fact, thoracotomy for cancer-causing pulmonary hypertrophic osteoarthropathy may result in a marked decrease in pain and swelling within 24 hours. Pamidronate and subcutaneous octreotide have been reported to reduce pain, which can be severe. The "sudden" onset of polyarthritis resembling rheumatoid arthritis in an older adult should prompt suspicion of an associated malignancy. Carcinoma polyarthritis may appear months before, or after, detection of malignancy of many types, particularly lung and breast. Its incidence is unknown; in one small series it was almost as common as carcinomatous hypertrophic osteoarthropathy and more common than cancer-related dermatomyositis. Palmar fasciitis has been noted in association with

ovarian cancer. Holmes GB, Hill N: Fractures and dislocations of the foot and ankle in diabetics associated with Charcot joint changes. Foot Ankle Int 15:182-185, 1994. A report of foot and ankle fractures and their management in 18 patients with diabetes mellitus. Hoyer LW: Hemophilia A. N Engl J Med 330:38, 1994. A review of the structure and function of factor VIII, the molecular genetics of hemophilia A, its clinical manifestations, and treatment. Speden D, Nicklason F, Ward FHJ: The use of pamidronate in hypertrophic pulmonary osteoarthropathy (HPOA) Aust NZ J Med 27:307-310, 1997. Pain was relieved in three patients given pamidronate.

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Chapter 306 - NON-ARTICULAR RHEUMATISM Eugene V. Ball

FIBROMYALGIA (FIBROSITIS). Primary fibromyalgia (FM) has been defined as chronic, widespread musculoskeletal pain and tenderness at multiple sites (e.g., at 11 of 18 specific sites in the criteria of the American College of Rheumatology). (The tender point count has been referred to as a "sedimentation rate" for distress.) Implicit in this definition is the absence of signs of connective tissue or other musculoskeletal disease. Because of its subjective nature and its frequent association with disturbed sleep, chronic fatigue, headaches, and irritable bowel syndrome, the validity of classifying FM as a disease rather than a "syndrome of being out of sorts" has been challenged. Patients often appear anxious and depressed, and studies have shown that they may feel dissatisfied with all aspects of their lives and it is claimed there is strong evidence for an association between FM and major depressive disorder. Nevertheless, the specific characteristics of anxiety and depression have not been identified consistently on psychological testing, and it has been suggested that chronic pain and fatigue of any cause can engender anxiety and depression. Despite their subjectivity, symptoms of FM tend to be constant over many years; exceptionally, FM has been found to be premonitory of psychosis or hypothyroidism. Decreased threshold to pain on pressure over certain sites and increased skin fold tenderness have led to numerous attempts to demonstrate localized peripheral abnormalities and to speculation that FM is a disorder of pain modulation. There have been no irrefutable biochemical, immunologic, or anatomic abnormalities detected in FM; however, studies of biopsied muscle samples have found decreased levels of adenosine triphosphate and phosphocreatine. These findings have been confirmed by magnetic resonance spectroscopy in a small number of patients. Other findings such as decreased regional cerebral blood flow have been cited as evidence for functional dysregulation of central pain pathways. Functional disability in FM may exceed that of rheumatoid arthritis; and in 1989, FM was the most frequent single reason for disability pensions among women in Norway, accounting for 7.2% of new pensions. (The prevalence in Norway has been estimated to be as high as 10% in women.) Patients whose FM begins acutely after a specific traumatic event are more likely to be disabled than those in whom the disorder evolves insidiously. FM is significantly less common in men than in women and is either underreported or uncommon in developing countries. Treatment is often frustrating for both patient and physician. It should emphasize the non-destructive nature of FM, and the physician should be wary of overusing drugs to allay anxiety or induce sleep. Low-dose amitriptyline and fluoxetine are valuable for decreasing pain and improving sleep in some patients. It has been the author's experience that patients are often either intolerant of medications or they have a short-lived response to any intervention.

BURSITIS. Bursae are small, synovial-lined, fluid-filled sacs located between tendons and bones which serve to reduce friction between opposing muscles or tendons. Most bursae are present from birth; however, others form in response to repeated pressure. Of the approximately 80 bursae located on each side of the body, only a few are common sources of pain. The subdeltoid is the largest of the bursae around the shoulder (see Chapter 303) ; it is located between the deltoid muscle and the shoulder capsule and extends under the acromion. Acute inflammation of this or nearby bursae and tendons may be exceedingly painful, resulting in restricted shoulder movement and tenderness over the rotator cuff. Intrabursal injection of lidocaine is diagnostic and often curative; however, recurrences are common. Bursal calcification predisposes to more frequent attacks. Infection is most common in the olecranon bursa. Trochanteric bursitis is believed to occur as a result of chronic strain on weak quadricep muscles or overuse of hip and thigh muscles. Pain is often perceived to be in the lateral aspect of the thigh and the low back and is aggravated by abducting the affected leg and by lying on the affected side. Tenderness is present at the edge of the greater trochanter. Injections of lidocaine and depot corticosteroids often abolish the pain.

TENDINOUS LESIONS. Tendinous lesions include tenosynovitis, a lesion of the gliding surfaces of a tendon and its sheath; tendinitis, painful scarring within a tendon; and trigger lesions, which are localized enlargements of the tendon that engage a constricted part of the sheath (as in "trigger finger"). Flexor digital tenosynovitis may cause pain in the metacarpophalangeal or proximal interphalangeal joints. Tendinous lesions are common, occurring in many areas of the musculoskeletal system. An example is de Quervain's disease, which is stenosing tenosynovitis of the abductor pollicis longus and extensor pollicis brevis at the medial styloid. Pain can localize or radiate into the hand or back to the shoulder. This and carpal tunnel syndrome occur frequently during pregnancy.

CARPAL TUNNEL SYNDROME. The symptoms of carpal tunnel syndrome are paresthesias and pain in the palmar side of the first three fingers and at times the radial half of the fourth finger; the pain may radiate proximally to the shoulder, creating confusion with a cervical disk syndrome. Physical findings include sensory loss, weakness on abduction and opposition of the thumb, and atrophy of the thenar eminence. Carpal tunnel syndrome is caused by an array of conditions that result in pressure on the median nerve as it passes through the bony flexor compartment of the wrist. Some of these are listed in Table 306-1 . Patients with fibromyalgia often have symptoms of carpal tunnel syndrome. Diagnosis is confirmed by electrophysiologic nerve tests. (The clinical tests commonly used are of questionable value.) Magnetic resonance imaging may be useful in defining the cause and thus directing treatment, which might include splinting of the wrist, corticosteroid injections, and surgical release of the transverse carpal ligament.

TENNIS ELBOW. "Tennis elbow" refers to a lesion of the wrist extensor muscles causing pain at the outer elbow, along the back of the forearm, or, less commonly, into the shoulder. The burning or TABLE 306-1 -- CONDITIONS CAUSING CARPAL TUNNEL SYNDROME Trauma Occupation Infections (e.g., Lyme disease and rubella) Rheumatoid arthritis and gout Pregnancy Hypothyroidism and acromegaly Amyloidosis Median artery aneurysm Ganglion cyst, increased fat, hypertrophy of abductor pollicis muscle

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aching pain is produced by resisted extension of the wrist, as in grasping and lifting, and rarely is felt as sudden, searing twinges of intensity sufficient to cause momentary grip paralysis. Tennis elbow usually results from repeated forceful extension of the wrist. A tear or area of degeneration most often occurs at the origin of the common extensor tendon from the lateral humoral epicondyle; much less frequently, the tear is in the muscle belly. Treatment includes exercise of wrist extensor muscles, injection of triamcinolone into the painful scar, manipulation, or partial tenotomy. Like tennis elbow, "golfer's elbow" is a misnomer in that both conditions occur frequently in people who do not play either sport. Golfer's elbow is less painful than tennis elbow; it represents a lesion of the common flexor tendon at the medial epicondyle. Pain is usually localized to the inner side of the elbow and is produced by resisted flexion of the wrist. Treatment includes triamcinolone injection and massage.

TIETZE'S SYNDROME. Tietze's syndrome is an uncommon cause of chest pain that can be mistaken for visceral pain. There is tender, most often unilateral, swelling at one or more costosternal junctions. Biopsy samples of involved areas have revealed chronic inflammatory fibrosis. The syndrome may result from prolonged coughing or hyperventilation, but it is often idiopathic. Injections into the painful area with triamcinolone are sometimes curative. Tietze's syndrome may be differentiated from the more common costochondritis, in which there are no signs of inflammation. Chest wall pain and tenderness are common in patients with fibromyalgia. Aaron LA, Bradley LA, Alarcon GS, et al: Perceived physical and emotional trauma as precipitating events in fibromyalgia: Associations with health care seeking and disability status but not pain severity. Arthritis Rheum 40:453-460, 1997. Kennedy M, Felson DT: A prospective long-term study of fibromyalgia syndrome. Arthritis Rheum 39:682-685, 1996. Park JH, Phothimat P, Oates CT, et al: Use of P-31 magnetic resonance spectroscopy to detect metabolic abnormalities in muscles of patients with fibromyalgia. Arthritis Rheum 41:406-413, 1998.

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Chapter 307 - ARTICULAR TUMORS Eugene V. Ball

Articular tumors can be classified as those that arise within the synovium; those that arise from cartilage, bone, or contiguous structures; and neoplasms that are non-articular in origin but that metastasize to joints or develop in multiple areas, including joints. Benign tumors include lipomas, neuromas, fibromas, and hemangiomas. The most common of these are probably synovial chondromas, which develop as cartilaginous synovial plaques that sometimes calcify. These plaques cause episodic pain or swelling in a single knee, hip, elbow, or shoulder and osteoarthritis. The joint may lock if the plaques become detached, forming loose bodies. Radiographs reveal multiple opacities if ossification has occurred; arthroscopy may be useful for both diagnosis and treatment, which is surgical. Pigmented villonodular synovitis (PVNS) is a non-malignant proliferative disorder of unknown cause that usually affects the entire synovium of a single joint. This condition occurs most often in early middle age and in the knee in 80% of cases. Uncommonly, two or more joints are involved; similar lesions occur in tendons and bursae. Pain and swelling are characteristic, as is serosanguineous synovial fluid. Radiographic signs include soft tissue swelling, osteolysis, subchondral cysts (particularly in the hip), and pressure erosions. One of two major cell types exhibit features associated with osteoclasts. Treatment is synovectomy. Hemangiomas, lipomas, and xanthomas may simulate PVNS. Synovial sarcomas (synoviomas) are rare, aggressive tumors of young adults. They usually originate in the extremities adjacent to, but not within, a joint. Primary tumors histologically identical to synoviomas have been found in the head and neck, abdominal wall, retroperitoneum, heart, and mediastinum, supporting the view that the tumor originates from mesenchyme rather than synovium. An SYT-SSX fusion gene is detectable in almost all synovial sarcomas. These tumors are usually discovered as deep swellings within a tendon sheath, a bursa, or a joint capsule. A few have been described with extensive osteoid and bone formation, simulating the radiographic appearance of benign lesions. Pain and tenderness are variable, as are effusions. These tumors metastasize early to lungs, bone, and lymph nodes. Tumor size more than 4 cm, a high mitotic rate, and local recurrence after excision convey a poor prognosis. Metastatic synovial sarcomas appear to be sensitive to multiagent chemotherapy. Chondrosarcomas and fibrosarcomas are other malignancies arising within or near joints, and intrasynovial myeloma and lymphoma are rare causes of a swollen or painful joint. Thorough investigation is required for unexplained pain or swelling within or adjacent to a single joint. Kawai A, Woodruff J, Healey JH, et al: SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. N Engl J Med 338:153-160, 1998. The authors found that SYT-SSX fusion transcripts are a diagnostic marker, and have prognostic implications, for synovial sarcomas. Neale SD, Kristelly R, Gundle R, et al: Giant cells in pigmented villonodular synovitis express an osteoclast phenotype. J Clin Pathol 50:605-608, 1997. The authors found evidence in one patient that the multinucleated giant cells of PVNS were phenotypically similar to osteoclasts, including their ability to cause bone resorption.

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Chapter 308 - ERYTHROMELALGIA Eugene V. Ball

Erythromelalgia (erythermalgia) is a syndrome of episodic burning pain and redness in the extremities. Attacks may be confined to feet or, if severe and prolonged, may spread to hands, or they may begin simultaneously in hands and feet. They are often provoked by increasing ambient temperatures, although a few persons experience attacks only with febrile illnesses. The combination of increasing warmth and exercise often induces symptoms. To avoid attacks, some persons maintain environmental temperatures at levels that are uncomfortably low for themselves, as well as others. Relief may require immersing the feet in ice water. The feet appear normal between attacks, except in those persons who habitually walk barefoot because their attacks are provoked by wearing shoes. Some clinicians use the terms erythromelalgia and erythermalgia for the symptom-complex, which they classify into primary erythromelalgia, erythromelalgia associated with thrombocythemia, and secondary erythromelalgia associated with a potpourri of unrelated medications and disorders. The primary form is sometimes familial. In one paradigmatic kindred, the disorder is autosomal dominant, and it has afflicted 29 members. Most often beginning between ages 2 and 8, it has been responsible for severe adjustment problems in youth, engendered in part by an inability to sit comfortably in a heated classroom or to participate in physical activities. In this kindred, the disorder has been frequently misdiagnosed as arthritis, reflex sympathetic dystrophy, or Raynaud's phenomenon. Its pathogenesis is unknown, but it is not related to thrombocythemia. The most common recognized cause of non-familial erythromelalgia is thrombocythemia, which is usually a feature of a myeloproliferative disorder. In essential thrombocythemia, erythromelalgia has been noted with platelet counts as low as 400-500 × 109 /L. It can be prevented by aspirin but not by oral anticoagulant or heparin therapy. Arteriolar inflammation and thrombotic occlusions are found on skin punch biopsy samples. Erythromelalgia disappears for 3 or 4 days after a single dose of aspirin, which is the duration of its inhibition of platelet aggregation; and studies by van Genderen and associates confirm that the erythromelalgia is caused by intravascular activation and aggregation of platelets, leading to endothelial cell damage. Other reported associations with erythromelalgia include diabetes mellitus, pregnancy, neurologic disorders, and gout and connective tissue diseases. Nifedipine and bromocriptine can cause an erythromelalgia-like disorder. In the absence of thrombocythemia, aspirin is ineffective for treating or preventing erythromelalgia. Although there is no proven treatment, examples of those agents for which effectiveness has been claimed for non-thrombocythemic erythromelalgia 1561

include intravenous nitroprusside, cyproheptadine, and, counterintuitively, capsaicin ointment. Finley WH, Lindsey Jr, Fine J-D, et al: Autosomal dominant erythromelalgia. Am J Med Genet 42:310, 1992. Clinical description of erythromelalgia in a large kindred. Millard FE, Hunter CS, Anderson M, et al: Clinical manifestations of essential thrombocythemia in young adults. Am J Hematol 33:27, 1990. Essential thrombocythemia was identified in 13 patients whose median age was 26. Erythromelalgia was the most common complication, occurring in 7 of the 13, of whom 7 were males. Van Genderen PJJ, Lucas IS, van Strik V, et al: Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation. Thromb Haemost 76:333, 1996. Studies show that the generation of thrombin is not essential for formation of platelet thrombi in this condition and that aspirin-induced remission was accompanied by a significant decrease in beta -thromboglobulin and thrombomodulin.

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Chapter 309 - MULTIFOCAL FIBROSCLEROSIS H. Ralph Schumacher Jr.

Introduction In rare instances, the delicate fibrous areolar tissue in a certain anatomic region becomes the site of a chronic low-grade inflammatory process leading to deposition of dense sclerotic plaques that may obstruct or limit the movement of adjacent viscera. When the process is in the active phase, characteristic findings of chronic or granulomatous inflammation are present and featured by mononuclear cell infiltration, plasma cells, some eosinophils, and occasional giant cells. In the end stages the pathologic lesion is simply that of scar tissue, so by the time that this process causes clinical manifestations, little evidence of the initial inflammatory reaction may remain. At least some cases have an accompanying vasculitis. As a general rule, the process tends to originate in the midline, around the great vessels, and to then spread laterally. In most cases a clue to the inciting mechanism is lacking. Syndromes that have been considered as manifestations of multifocal fibrosclerosis include retroperitoneal fibrosis, mediastinal fibrosis, sclerosing cholangitis (see Chapter 157) , Riedel's thyroiditis (see Chapter 239) , pseudotumor of the orbit, Peyronie's disease (sclerotic induration of the corpora cavernosa of the penis), pachymeningitis, and sclerosing peritonitis. Other sites of a similar fibrosis, such as the testes and vagina, have also been reported. Pulmonary and myocardial fibrosis syndromes have not generally been seen as being related to multifocal fibrosclerosis, although pleural fibrosis along with retroperitoneal fibrosis can be seen with ergotamine use. Although most of these syndromes have been described as separate entities, several anatomic areas may become affected in one person. For example, retroperitoneal fibrosis and sclerosing mediastinitis may be present at the same time along with varying combinations of sclerosing cholangitis, Riedel's thyroiditis, and pseudotumor of the orbit. A possible genetic predisposition is suggested by familial cases and by an association between fibrosing syndromes and alpha1 -antitrypsin deficiency. Familial mediastinal or retroperitoneal fibrosis may also be associated with HLA-B27 and seronegative spondyloarthrophaties. Comings DE, Skubi KB, Van Eyes J, et al: Familial multifocal sclerosis. Ann Intern Med 66:884, 1967. Description of multiple sites of fibrosis in two brothers. Goldbach P, Mohsenifar Z, Salick Al: Familial mediastinal fibrosis associated with seronegative spondyloarthropathy. Arthritis Rheum 26:221, 1983. Two siblings with both diseases.

RETROPERITONEAL FIBROSIS. In retroperitoneal fibrosis, the process usually begins over the promontory of the sacrum and extends laterally across the ureters and as high as the 2nd or 3rd lumbar vertebra. Less commonly, the lesion develops in other extraperitoneal areas, e.g., contiguous with the kidneys, duodenum, descending colon, or urinary bladder. Some cases have an associated vasculitis in the skin and subcutaneous tissue manifested by the formation of nodules, erythematous discoloration, and ulceration. Similarly, inflammatory changes in small vessels at the sites of the sclerosis have been noted. Glomerulonephritis has been seen in a few patients. The occurrence of retroperitoneal fibrosis in patients taking methysergide for migraine has been reported with greater frequency than could be due to chance. Occasional cases have been reported after the use of other drugs such as ergotamine, pergolide, various beta-adrenergic blocking agents, hydralazine, and methyldopa. Associated diseases in patients with retroperitoneal fibrosis have included systemic lupus erythematosus; vasculitis with one patient positive for cytoplasmic antineutrophil cytoplasmic antibody; scleroderma; eosinophilic fasciitis; biliary cirrhosis; juvenile and rubella-associated arthritis; renal, uterine, and other cancers; and carcinoid. Trauma, surgery, and, occasionally, ruptured echinococcal cysts have been reported as apparent causes. One patient with associated periarticular fibrosis had elevated plasma levels of a platelet-derived growth factor. The disorder is about twice as common in males as in females, and the peak incidence is in the 5th and 6th decades. Cases have been reported in children. The manifestations are variable, depending on the anatomic location of the process. Pain is the most common symptom; it tends to be located in the low back region and may be accompanied by symptoms referable to the gastrointestinal tract. The patient is likely to lose weight and have low-grade fever. Some anemia and an elevated erythrocyte sedimentation rate may be present. Although the ureter is the structure most often affected, symptoms referable to the urinary tract are uncommon until obstructive uropathy has led to azotemia and other clinical manifestations of renal insufficiency. The fibrosing process may surround the inferior vena cava, but obstruction of that vessel is uncommon. Thromboembolism and hypertension can be complications. Arterial invasion has been described, and portal hypertension or bile duct obstruction with pseudotumor of the pancreas may occur. Retroperitoneal fibrosis occasionally develops in association with definable abdominal aortic aneurysm or aortitis and is considered in some cases to begin as a periaortitis. A possible element of reaction to atheromatous components has been described. The diagnosis of retroperitoneal fibrosis has been most often suggested by findings at intravenous pyelography: displacement of the ureters toward the midline and evidence of obstruction, usually at the level of the pelvic brim. One or both ureters may be affected. In rare instances a mass can be palpated in the pelvis or on the posterior abdominal wall. Ultrasonography, computed tomographic scanning, and magnetic resonance imaging can also identify the fibrosing masses. Gallium scintigraphy may help assess activity of inflammation. Once a mass has been disclosed, the main problem in the differential diagnosis lies in distinguishing retroperitoneal fibrosis from retroperitoneal tumor. Multiple deep biopsies should be made at the time of laparotomy. Fine-needle aspiration biopsy may be suggestive if laparoscopy or laparotomy are not possible. Surgical treatment, if performed before severe renal damage, is often highly successful. Inasmuch as the fibrosing process is seldom invasive, the constricted organ can usually be freed by blunt dissection so that normal movement or flow is restored. Relief of ureteral obstruction is usually achieved by bringing the ureter out on the anterior surface of the sclerotic mass. Occasionally, however, the obstruction recurs months or years after such treatment. Some surgeons wrap the ureters in omentum to decrease recurrent obstruction. Steroid therapy may be helpful in the rare case detected early or may be used as an adjunct to surgical measures. Azathioprine or cyclophosphamide has been used successfully in a few cases. Progesterone and tamoxifen have been reported to produce regression of fibrosis. When the inferior vena cava is obstructed, surgical relief is technically difficult and risky; here it may be preferable to temporize in the hope that development of collateral pathways may alleviate the circulatory block. The long-term outlook is fairly good if the disease is recognized and its obstructive consequences can be treated by surgical means. The disease often tends to run its course and subside. Most deaths have been caused by renal failure. Bonnet C, Arnavel M, Bertin P, et al: Idiopathic retroperitoneal fibrosis with systemic manifestations. J Rheumatol 21:360, 1994 Panniculitis occurred along with mesenteric, pulmonary, and perhaps periarticular fibrosis. Cohle SD, Leil JT: Inflammatory aneurysm of the aorta, aortic note and coronary arteritis. Arch Pathol Lab Med 112:1121, 1988. Inflammatory aneurysms of the aorta and other vasculitis may be associated with retroperitoneal fibrosis. Owens LV, Cance WG, Huth JF: Retroperitoneal fibrosis treated with tamoxifen. Am Surg 61:842, 1985. Tamoxifen is an increasingly reported therapeutic choice.

MEDIASTINAL FIBROSIS. Taut bundles of collagenous tissue form in the superior and anterior mediastinum, with impingement

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on the aorta, trachea, bronchi, esophagus, and pericardium. Patients may have thoracic pain, but the predominant manifestations are those caused by obstruction of the superior vena cava: puffy, suffused appearance of the face and conjunctivae; non-pitting edema of the face, neck, and upper extremities: and distended veins in the neck and upper extremities. Rarely, the principal vessels affected are the pulmonary arteries, with subsequent pulmonary hypertension. More frequently, the pulmonary veins are involved, and here severe hemoptysis may be the most prominent manifestation. Pericardial fibrosis can lead to constrictive pericarditis. The main task in the differential diagnosis is to distinguish this relatively benign condition from obstruction caused by tumor. Radiographic examination of the chest may reveal little or no abnormality or some pleural thickening. Angiographic studies show obstruction of the affected vessels. Thoracotomy may be required for histologic diagnosis. Histoplasmosis and possibly tuberculosis may cause some mediastinal fibrosis. Mediastinal hemorrhage can lead to fibrosis, and cases have been associated with methysergide use. An interesting recent association has been with the SAPHO syndrome ( synovitis, acne, pustulosis, 0 hyperostosis, and osteomyelitis). Some patients with this syndrome have shown gradual improvement over months or years, presumably because of the development of collateral circulation. Successful superior vena cava bypass surgery has been described. Corticosteroid therapy was ineffective in some reported cases. Cunningham T, Farrell J, Veale D, et al: Anterior mediastinal fibrosis with superior vena caval obstruction complicating the synovitis-acne-pustulosis-hyperostosis-osteomyelitis syndrome. Br J Rheumatol 32:408, 1993. This idiopathic sterile inflammatory reaction most often involves the anterior chest wall. Mathiesen DJ, Grillo HC: Clinical manifestation of mediastinal fibrosis and histoplasmosis. Ann Thorac Surg 54:1053, 1992. Histoplasma was still stainable in some resected specimens. Papandreou L, Panagou P, Bouros D: Mediastinal fibrosis and radiofrequency radiation exposure: Is there an association? Respiration 59:181, 1992. Hemoptysis can be an initial symptom. This and other reports raise the question of radiation as a cause.

SCLEROSING PERITONITIS. A fibrotic syndrome has been observed in patients treated for prolonged periods with the now withdrawn beta-adrenergic blocking drug practolol and very rarely with other beta-blockers. Some cases developed years after cessation of therapy. The peritonitis consists of thick fibrous encasement of the small intestine, and symptoms include abdominal fullness, back pain, ascites, weight loss, and signs of subacute intestinal obstruction. Surgery may be needed to peel away the fibrous tissue. Sclerosing peritonitis with many similarities has also been seen in idiopathic forms in association with systemic conditions, including drug abuse, sarcoidosis, and sicca syndrome, and now most importantly in patients treated with continuous ambulatory peritoneal dialysis and in women with ovarian tumors, most often luteinized thecomas. A variety of factors used in dialysis have been suggested to contribute. Hemoperitoneum and peritoneal calcification have been reported along with intestinal obstruction and ultrafiltration failure. Ultrasound findings can suggest the diagnosis. Some recent cases have responded to immunosuppresive or corticosteroid therapy. Lo WK, Chan KT, Leung AC, et al: Sclerosing peritonitis complicating prolonged use of chlorhexidine in alcohol in the connection procedure for continuous ambulatory peritoneal dialysis. Peritoneal Dialysis Int 11:166, 1991. A mechanism is suggested and improvement noted with continued chronic ambulatory peritoneal dialysis without the chlorhexidine. Mori Y, Matsco S, Sutch IT et al: A case of a dialysis patient with sclerosing peritonitis successfully treated with corticosteroid therapy alone. Am J Kidney Dis 30:275, 1997. Surgery may be avoided in some cases.

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Part XXII - INFECTIOUS DISEASES

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Chapter 310 - INTRODUCTION TO MICROBIAL DISEASE Gerald L. Mandell

Infectious diseases have profoundly influenced the course of human history. The black plague (caused by Yersinia pestis) changed the social structure of medieval Europe. The outcomes of military campaigns have been altered by outbreaks of diseases such as dysentery and typhus. Malaria influenced the geographic and racial pattern of distribution of hemoglobins and erythrocyte antigens. The development of Plasmodium falciparum is inhibited by the presence of hemoglobin S, and Duffy blood group-negative erythrocytes are resistant to infection with Plasmodium vivax. Thus, populations with these erythrocyte factors are found in areas where malaria is common. Infections are the major cause of morbidity and mortality in the developing world. The acquired immunodeficiency syndrome (AIDS) threatens to disrupt the social fabric in some countries of Africa and is severely stressing the health care system in the United States and other parts of the world. Infection may be defined as multiplication of microbes (viruses, bacteria, fungi, protozoa, or multicellular parasites) in the tissues of the host. The host may or may not be symptomatic. For example, infection with the human immunodeficiency virus (HIV) may cause no overt signs or symptoms of illness for years. The definition of infection also should include instances of multiplication of microbes on the surface or in a lumen of the host, causing signs and symptoms of illness or disease. Toxin-producing strains of Escherichia coli may multiply in the gut and cause a diarrheal illness without invading tissues. Microbes can cause diseases without actually coming in contact with the host by virtue of toxin production. Clostridium botulinum may grow in certain improperly processed foods and produce a toxin that can be lethal on ingestion. A relatively trivial infection such as that caused by Clostridium tetani in a small puncture wound can cause devastating illness because of a toxin released from the organism growing in the tissues. We live in a virtual sea of microorganisms, and all our body surfaces have an indigenous bacterial flora. This normal flora actually protects us from infection. Reduction of gut colonization increases susceptibility to infection by pathogens such as Salmonella typhimurium. The normal florae are thought to exert their protective effect by several mechanisms: (1) utilizing nutrients and occupying an ecologic niche, thus competing with pathogens; (2) producing antibacterial substances that inhibit the growth of pathogens; and (3) inducing host immunity that is cross-reactive and effective against pathogens. In addition to the normal flora, transient colonization may be seen with known or potential pathogens. This may be a special problem in hospitalized patients (see Chapter 315) . Only a very small proportion of microbial species may be considered to be primary or professional pathogens, and even among these species only a relatively small number of clones have been shown to cause disease. This supports the concept that pathogenic organisms are highly adapted to the pathogenic state and have developed characteristics that enable them to be transmitted, to attach to surfaces, to invade tissue, to avoid host defenses, and thus to cause disease. In contrast, opportunistic pathogens cause disease principally in impaired hosts. Organisms that may be harmless members of the normal flora in healthy persons may act as virulent invaders in patients with severe defects in host defense mechanisms. Pathogenic organisms may be acquired by several routes. Direct contact has been implicated in the acquisition of staphylococcal disease. Airborne spread, usually by droplet nuclei, occurs in respiratory diseases such as influenza. Contaminated water is the usual vehicle in Giardia infection and typhoid fever. Food-borne toxin illnesses may be caused by extracellular toxins produced by Clostridium perfringens and Staphylococcus aureus. Blood and blood products may be vectors for transmitting hepatitis B virus and HIV. Sexual transmission is also important for these latter two agents and for a variety of pathogens, including Treponema pallidum (syphilis), Neisseria gonorrhoeae (gonorrhea), and Chlamydia trachomatis (non-specific urethritis). The fetus may be infected in utero, and this may be devastating if the infective agent is rubella virus or cytomegalovirus. Arthropod vectors may be important, as illustrated by mosquitoes for malaria, ticks for Lyme disease, and lice for typhus. Pathogens are able to cause disease because of a finely tuned array of adaptations. These include the ability to attach to appropriate cells, often mediated by specialized structures such as the pili on gram-negative rods. Microbes such as Shigella species have the ability to invade cells and cause damage in that way. Toxins may act at a distance or may intoxicate only infected cells. Pathogens have the ability to thwart host defenses by a variety of ingenious maneuvers. The antiphagocytic capsular coat of the pneumococcus is an example. Organisms may change their surface antigen display so as to outmaneuver the host immune system. This can be seen with influenza virus and trypanosomes. Certain pathogens have the ability to inhibit the respiratory burst of phagocytes (Toxoplasma gondii), and others can destroy phagocytic cells that have engulfed them (Streptococcus pyogenes). The environment plays an important role in infection, both in transmission and in the ability of the host to combat the invader. The humidity and temperature of air may affect the infectivity of airborne pathogens. The sanitary state of food and water is an important factor for the acquisition of enteric pathogens. The "bad air" of swamps associated with malaria turned out to be due to the mosquitoes, but the environmental association was appropriate. The nutritional status of the host clearly is a significant factor in certain infectious diseases. The establishment of infection is a complicated interplay of factors involving the microbe, the host, and the environment. Host reaction to infection may result in illness. For example, recent data suggest that prior infection with Campylobacter jejuni is responsible for about 40% of cases of Guillain-Barre syndrome. The mechanism is thought to be production of antibodies against C. jejuni lipopolysaccharides that cross react with gangliosides in peripheral nerves. With rare exceptions, infections are treatable and often curable diseases. Thus, it is important to make an accurate etiologic diagnosis and promptly institute appropriate therapy. In acute infections such as pneumonia, meningitis, or gram-negative sepsis, rapid institution of therapy may be lifesaving, and thus a presumptive etiologic diagnosis should be established before a definitive diagnosis. This presumptive diagnosis can be based on the history, physical examination, epidemiology of illness in the community, and rapid techniques such as microscopic examination of appropriate gram-stained specimens. Antimicrobial therapy can then be instituted for the presumptive etiologic agents but must be re-evaluated as more definitive diagnostic information becomes available (see Chapters 318 and 374) .

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Chapter 311 - THE FEBRILE PATIENT David C. Dale

Fever, or "pyrexia," is an elevation of body temperature to a level above normal, i.e., to greater than 37.5° C (99.5° F), caused by resetting of the thermoregulatory center in the medulla. To detect fever, oral, rectal, tympanic membrane, and pulmonary artery measurements are more reliable than axillary temperatures. Fever is a useful marker of inflammation; usually the height of the fever reflects the severity of the inflammatory process. Anorexia, malaise, myalgias, headache, and other constitutional symptoms often occur concomitantly. When the body temperature changes rapidly, chills and sweats are also observed. Fever with night sweats is a feature of many chronic inflammatory conditions. Hyperthermia is a term for fever caused by a disturbance in thermal regulatory control: excessive heat production (e.g., with vigorous exercise or as a reaction to some anesthetics), decreased dissipation (e.g., with dehydration), or loss of regulation (e.g., from injury to the hypothalamic regulatory center). Most febrile patients have pain, tenderness, redness, and swelling at the site of inflammation, and the cause of the fever is readily identified. In a general medical practice, the most common causes of fever are upper respiratory illnesses, urinary tract infections, cellulitis, superficial abscesses, and pneumonia. In otherwise healthy individuals, fever alone is not a cause for hospitalization unless it is quite high (>39° C or 102° F) or accompanied by shaking, chills, hypotension, a change in sensorium, or other symptoms suggesting bacteremia. However, in immunosuppressed individuals, the elderly, and patients with recent surgery, greater caution is indicated.

FEVER OF UNEXPLAINED ORIGIN. A unexplained fever is usually defined in adults as an illness lasting more than 3 weeks with temperatures greater than 101° F (38.3° C) in which a diagnosis has not been made despite a good hospital or office evaluation. Ordinarily, by this time the work-up has included a history, physical examination, routine blood and urine tests and cultures, radiographs, and some specialized serologic tests. With careful further evaluation a diagnosis can be made in 70 to 90% of these cases. Diagnoses for unexplained fevers fall into six general categories: infections, non-infectious inflammatory conditions, neoplastic diseases, drug fevers, factitious illnesses, and a group of less common causes (Table 311-1) . The pattern of fever is only occasionally helpful in pointing to a specific diagnosis, e.g., the alternate-day fever in established Plasmodium vivax infections, the sustained fever in untreated Salmonella typhi infections and other continuous bacteremias, and the relapsing (Pel-Ebstein) fever in Hodgkin's disease and other lymphomas.

EVALUATION OF THE PATIENTS WITH UNEXPLAINED FEVER. In patients with persisting fever, it is important initially to review carefully the medical history and repeat the physical examination. New clues may be found in the social, occupational, travel, and medication history. On physical examination, special attention should be given to the skin, lymph nodes (including epitrochlear, post-auricular, axillary), mucous membranes (including the conjunctivae), and abdominal region (masses, tenderness, and size of the liver and spleen). Usually the basic laboratory tests--complete blood count, differential, sedimentation rate, urinalysis, liver function tests, skin tests for delayed hypersensitivity (e.g., purified protein derivative, mumps), and stool for occult blood--should be repeated. Most patients with active inflammation are anemic, and the leukocyte differential can provide valuable clues. Neutrophilia suggests an occult bacterial infection. Monocytosis suggests tuberculosis, brucellosis, inflammatory bowel disease, or other chronic inflammatory conditions. Severe lymphopenia suggests immunodeficiency or a malignancy. A very elevated sedimentation rate suggests giant cell/temporal arteritis, polymyalgia rheumatica, Still's disease, bacterial endocarditis, or other occult infections, and a normal test rarely occurs with any of these illnesses. If the alkaline phosphatase level is elevated, obstructive or infiltrative disease of the liver is the most likely cause, although non-specific elevation is TABLE 311-1 -- CAUSES OF FEVER OF UNKNOWN ORIGIN Infections Abscesses--hepatic, subhepatic, gallbladder, subphrenic, splenic, periappendiceal, perinephric, pelvic, and other sites Granulomatous--extrapulmonary and miliary tuberculosis, atypical mycobacterial infection, fungal infection Intravascular--catheter-related endocarditis, meningococcemia, gonococcemia, Listeria, Brucella, rat-bite fever, relapsing fever Viral, rickettsial, and chlamydial--infectious mononucleosis, cytomegalovirus, human immunodeficiency virus, hepatitis, Q fever, psittacosis Parasitic--extraintestinal amebiasis, malaria, toxoplasmosis Non-infectious Inflammatory Disorders Collagen vascular diseases--rheumatic fever, systemic lupus erythematosus, rheumatoid arthritis (particularly Still's disease), vasculitis (all types) Granulomatous--sarcoidosis, granulomatous hepatitis, Crohn's disease Tissue injury--pulmonary emboli, sickle cell disease, hemolytic anemia Neoplastic Diseases Lymphoma/leukemia--Hodgkin's and non-Hodgkin's lymphoma, acute leukemia, myelodysplastic syndrome Carcinoma--kidney, pancreas, liver, gastrointestinal tract, lung, especially when metastatic Atrial myxomas Central nervous system tumors Drug Fevers Sulfonamides, penicillins, thiouracils, barbiturates, quinidine, laxatives (especially with phenolphthalein) Factitious Illnesses Injections of toxic material, manipulation or exchange of thermometers Other Causes Familial Mediterranean fever, Fabry's disease, cyclic neutropenia not uncommon. Other tests, e.g., antinuclear antibodies, febrile agglutinins, complement assays, may be positive but are rarely helpful in evaluation of unexplained fever. A definitive diagnosis is usually made through a combination of imaging studies, microbiologic tests, and/or biopsies. Previous radiographs should be carefully reviewed for evidence of sinusitis, apical inflammation or small nodules in the lungs, hilar adenopathy, or an intra-abdominal mass. Abdominal ultrasonography, gallium and radioisotopically labeled leukocyte scans, computed tomography, and magnetic resonance imaging are very helpful to examine the liver, gallbladder, spleen, and

pelvic areas for tumors and abscesses. These tests have reduced, but not completely eliminated, the need for exploratory laparotomies. Cultures of blood (including for Myobacterium avium in human immunodeficiency virus-infected patients), urine (including mycobacterial cultures if tuberculosis is suspected), and other body fluids (e.g., cerebrospinal, peritoneal, pleural) should be obtained if at all suggested by the clinical examination. It is useful to perform anaerobic cultures of material from suspected abscess cavities and to examine blood cultures for fastidious bacteria, yeast, and fungi in difficult cases. A tissue diagnosis can often be made from a biopsy of abnormal skin or lymph nodes or the bone marrow. Biopsy or needle aspiration of liver, lung, bone, or other deep tissue sites is also valuable when abscesses or tumors are suspected.

THERAPY. Therapeutic trials with antibiotics, corticosteroids, or antipyretics before the diagnosis is clear can confuse the evaluation. In some instances, a trial may be justified but should be time limited, i.e., about 2 weeks. In patients with deep tissue abscesses, fever usually persists despite antibiotics. In patients with non-infectious inflammatory diseases, e.g., sarcoidosis, Still's disease, or vasculitis, a good clinical diagnosis can usually be made before such therapies are begun. In patients with malignancies, rational therapy depends on a tissue diagnosis. Patients with factitious illness often have serious underlying psychiatric disorders. Care in confrontation is essential to prevent desperate acts, including suicide. Extensive work-ups of unexplained fevers can be very expensive. In every patient the need for hospital care and testing should be continually reassessed. When the patient is not severely ill, it is frequently worthwhile to use observation alone as a diagnostic tool. Sometimes even a short period of observation allows an obscure diagnosis to become obvious. In other cases, the fever disappears without the necessity for further diagnostic tests. Arnow PM, Flaherty JP: Fever of unknown origin. Lancet 350:575, 1997. A succinct summary of the causes of unexplained fever category by category.

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de Kleijn EM, van Lier HJ, van der Meer JW: Fever of unknown origin (FUO). II. Diagnostic procedures in a prospective multicenter study of 167 patients. The Netherlands FUO Study Group. Medicine (Baltimore) 76:401, 1997. A report on the value of diagnostic tests and procedures in a series of 167 patients recently evaluated for unexplained fever. Sullivan, M, Fineberg, J, Bartlett, JG: Fever in patients with HIV infection. Infect Dis Clinic North Am 10:149, 1996. A good summary of the causes of fever in patients with HIV infection. This issue also contains a series of other excellent articles on evaluating patients with fever.

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Chapter 312 - THE PATHOGENESIS OF FEVER Bruce Beutler Steven M. Beutler

DEFINITION. Fever (pyrexia) is defined as an elevation of core body temperature above the level normally maintained by the individual. Under normal circumstances, core body temperature (the temperature of blood in the right atrium) is tightly regulated, with circadian variations over a range that usually does not exceed 1° F (0.6° C) and a mean value of 98.6° F (37° C) (the normal "set-point"). An array of thermoregulatory mechanisms, described in detail below, ensure that this temperature is maintained. During episodes of fever, the thermoregulatory set-point is shifted such that the same thermoregulatory mechanisms are used to maintain an abnormally elevated temperature. It is important to realize that fever is not equivalent to an elevated core temperature but to an elevated set-point. Under many circumstances ranging from intense physical exertion to immersion in hot liquids, core temperature may be elevated yet fever does not exist because the body is attempting to cope with the departure from homeostasis. Failure of thermoregulation may also be associated with elevated core temperature; this problem too (which occurs in malignant hyperthermia) is distinct from fever. THERMOREGULATORY MECHANISMS. Core body temperature is determined by two opposing processes, each of which is regulated by the central nervous system. On the one hand, energy in the form of heat is generated by living tissues ("thermogenesis"). Energy may be passively absorbed from the environment as well. On the other hand, energy is inevitably lost to the environment, chiefly through the emission of infrared radiation and through transfer of energy to the surrounding medium. The temperature at which tissues are maintained is related to heat capacity (e.g., to the amount of energy required to elevate temperature by a defined increment) and to the quantity of energy lost or gained by the system. Metabolic reactions proceed more rapidly at an elevated temperature. Therefore, the passive warming effect of a febrile state leads to accelerated energy production in the form of heat: for each temperature increment of 1° F (0.6° C), the basal metabolic rate increases by approximately 10%. This increase may at times be quite significant from a nutritional point of view. Muscle is a particularly flexible transducer of chemical energy. "Shivering thermogenesis" refers to the unconscious process whereby muscles are recruited to produce energy through the exercise of activity. Such induction of energy leads to enhanced metabolic demand, which is one mechanism responsible for the rise in body temperature in fever. Hence a sharp "chill" often heralds the onset of fever. Conservation of energy is effected through piloerection in mammals other than humans. In humans, "gooseflesh" is the equivalent response. "Flushing" represents a redistribution of circulation to dermal vessels and facilitates heat loss; a blanched appearance of the skin indicates an attempt to conserve heat. INITIATION OF FEVER. The neural pathways responsible for thermoregulation originate in the hypothalamus. A local sensing mechanism exists wherein the temperature of blood is coupled to the development of autonomic discharge. Elevation of body temperature depends primarily on sympathetic outflow and leads to shivering thermogenesis and dermal vasoconstriction, whereas cooling mechanisms (sweating and dermal vasodilation) involve a mixture of sympathetic and parasympathetic pathways. Certain neurotropic drugs can disrupt the hypothalamic thermosensory mechanism--or blunt the hypothalamic response--and thus may interfere with the development of fever. Among these drugs phenothiazines are the best known for their "poikilothermic" effect. These agents are not specifically active in febrile states; rather, they act to disable thermoregulatory mechanisms.

CLINICAL MANIFESTATIONS. Although fever patterns tend to be non-specific, they may sometimes provide diagnostic clues (Table 312-1) . Intermittent fevers are seen in many conditions and are therefore of little help in discriminating between various disorders. Intermittent fever may also occur when a continuous fever is interrupted with antipyretics or cooling measures; such interventions must be taken into account in analysis of a temperature curve. In addition to considering patterns of pyrexia, it is worthwhile to note the relationship between core temperature and other vital signs. For example, dissociation between the temperature and pulse is sometimes seen in cases of typhoid fever, Legionnaires' disease, psittacosis, and brucellosis. Factitious fever is also accompanied by an inappropriately low pulse. In addition, the respiratory rate may remain unchanged and normal, superimposed diurnal variations in temperature may be absent in factitious fever. Drug fever may occur in association with nearly any medication. No fever pattern is characteristic. Fevers caused by drug allergy tend to be well tolerated and may be accompanied by other allergic phenomena such as rash, nephritis, or neutropenia in 20 to 60% of patients. Extreme pyrexia (characterized by a core temperature higher than 106° F) often indicates failure of a distal mechanism of thermoregulation occurring alone or in combination with infection. Examples of non-infectious causes of such extreme pyrexia include heat stroke (see Chapter 97) , neuroleptic malignant syndrome (see Chapter 451) , and malignant hyperthermia associated with succinylcholine. CYTOKINES AND FEVER. Hypothalamic dysregulation and fever are triggered by proteins released from cells of the immune system (Fig. 312-1) . This communication between the immune system and the nervous system is perhaps the most thoroughly studied "neuroimmunoendocrine" link. In response to invasive stimuli, including components of various microorganisms (e.g., lipoteichoic acid, lipopolysaccharides, and other constituents collectively termed "exogenous pyrogen") or certain chemical agents (e.g., amphotericin and perhaps other drugs), cells of the immune system (principally macrophages and, to a lesser extent, lymphocytes) produce proteins that behave as "endogenous pyrogens." These proteins are designated "monokines" and "lymphokines," respectively, and are often denoted under the more general heading of "cytokines." During the past decade, several of the cytokines active in the pathogenesis of fever have been isolated, and their structures have been determined by molecular cloning. As of this writing, 11 proteins with pyrogenic activity have been identified (Table 312-2) ; it is likely that many others exist. Although mononuclear phagocytes are the principal source of pyrogenic cytokines, the same proteins may sometimes originate from non-immune cells of neoplastic tissue through autonomous production and secretion. The pyrogenic cytokines are structurally diverse proteins with well-established effects in hematopoiesis, inflammation, and regulation of cell metabolism. Individual agents are often markedly pleiotropic in their actions. In addition to their involvement in mediating fever, cytokines mediate the "acutephase-response" (see Chapter 313) , which is characterized by increased production of "acute-phase reactants" in the liver (fibrinogen, C-reactive protein, complement

TABLE 312-1 -- FEVER PATTERNS AS DIAGNOSTIC CLUES FEVER PATTERN

CAUSE

Alternate-day fever

Plasmodium vivax, P. ovale

Fever every 3rd day

P. malariae

Relapsing fever: daily for 3-6 d; fever-free interval for about 1 wk supervenes

Borrelia spp., rat-bite fever (Streptobacillus moniliformis; Spirillum minus)

Continuous "undulating fever"

Brucellosis; typhoid

Periodic pyrexia (Pel-Ebstein phenomenon) with variable cycles

Hodgkin's disease

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Figure 312-1 Production of endogenous pyrogens by macrophages and T lymphocytes. A variety of microbial pathogens produce molecules that function as exogenous pyrogens and trigger the release of endogenous pyrogens from mononuclear cells. ACTH = adrenocorticotropic hormone: CRF = corticotropin-releasing factor; PGE2 = prostaglandin E2 ; other abbreviations are defined in the text and Table 312-2 .

proteins B, C3, C4, alpha2 -acid glycoprotein, serum amyloid A, and a variety of proteinase inhibitors among them), decreased production of albumin and transferrin, hypoferremia, hypertriglyceridemia, and other metabolic changes. Pyrogenic cytokines are presumed to bind to receptors present on vascular endothelial cells that lie within the hypothalamus. They act to reset the hypothalamic thermoregulatory center by prompting an elevation in core body temperature. The resetting is believed to depend largely on endothelial cells producing prostaglandins (PGE2 and perhaps PGF2alpha ). Thromboxanes and lipooxygenase products may also affect the set-point. Cytokines can also interact directly with neural tissues; some evidence suggests that the release of corticotropin-releasing factor may trigger thermogenesis in response to at least one cytokine (interleukin-1 beta [IL-1beta]). Although no single cytokine is capable of provoking fever of a magnitude equivalent to that elicited by endotoxin, it is probable TABLE 312-2 -- PROTEINS WITH PYROGENIC ACTIVITY ENDOGENOUS PYROGEN

OTHER NAMES/ABBREVIATIONS

PRINCIPAL SOURCE

INDUCED BY

PRINCIPAL EFFECTS IN ADDITION TO PYROGENESIS

PHYSICAL CHARACTERISTICS

Cachectin/tumor necrosis factor alpha

TNF-alpha

Macrophages

Lipopolysaccharide Fever, shock, anorexia, wasting, Homotrimer; 17 kd (LPS), other microbial tumor necrosis, bone resorption, subunit size products adipocyte lipoprotein lipase, (non-glycosylated) neutrophil activation, endothelial cell 26% identity adhesiveness/procoagulant effect

Lymphotoxin/tumor necrosis factor beta

TNF-beta; LT

Lymphocytes (T & B)

Antigenic/mitogenic stimulation

Interleukin-1alpha (IL-1alpha)

Leukocyte activity factor (LAF), Macrophages and many leukocyte endogenous mediator other cell types (LEM), mononuclear cell factor (MCF), endogenous pyrogen (EP)

LPS, other microbial products, TNF

Homotrimer; 20-25 kd subunit size (glycosylated) Fever, IL-2 production, bone resorption, pannus formation, neutrophil activation, endothelial cell adhesiveness/procoagulant effect

Interleukin-1beta (IL-1beta) Interferon-alpha

Monomer; 17 kd (glycosylated) 26% identity

Monomer; 17 kd (glycosylated) IFN-alpha; leukocyte interferon

Leukocytes (esp. monocyte-macrophages)

Induction of antiviral state

22 kd (glycosylated) 23% identity

Interferon-beta

IFN-beta; fibroblast interferon

Fibroblasts

Interferon-gamma

IFN-gamma; immune interferon; type 2 interferon

T lymphocytes

LPS, viral infection, double-stranded RNA

22 kd (glycosylated) Macrophage activation

20-25 kd (glycosylated)

Up-regulation of class I and class II MHC molecules Interleukin-6 (IL-6)

Interferon-beta2 , hepatocyte-stimulating factor (HSF), B-cell stimulating factor-2 (BSF-2), B-cell differentiation factor (BCDF)

Many cell types

LPS, TNF

21-26 kd (glycosylated) Synthesis of acute-phase reactants Weak antiviral effect Terminal differentiation of B cells; T-cell activation

Macrophage MIP-1alpha inflammatory protein 1alpha

7.9 kd (non-glycosylated) LPS 57% identity

Macrophage MIP-1beta inflammatory protein 1beta Interleukin-8 (IL-8)

Macrophages

Monocyte-derived neutrophil chemotactic factor (MDNCF)

Neutrophil chemotaxis

LPS, TNF, IL-1

7.8 kd (non-glycosylated) 8.0 kd (non-glycosylated)

that the combined production of several cytokines is sufficient to explain most fevers. One monokine known as tumor necrosis factor alpha (TNF-alpha) seems capable of reproducing many of the physiologic derangements observed in septic shock and thus appears to mediate most of the deleterious effects of bacterial endotoxin, including fever. A lymphokine known as lymphotoxin (also referred to as tumor necrosis factor beta) is homologous to TNF-alpha, binds to the same receptor as TNF-alpha, and elicits many of the same effects. Two other cytokines (IL-1alpha and IL-1beta), although incapable of causing shock by themselves, produce many effects similar to those of TNF-alpha, and in some instances, synergistic responses have been noted. Many of the cytokines are mutually inducing, and the concept of a "cytokine cascade" has been offered to describe the production of several factors occurring in response to the elaboration of one member of the group. The temporal sequence of induction may be reflected in the course of fever in vivo. For example, injecting a bolus of TNF-alpha into a rabbit will immediately raise body temperature and cause a delayed rise, apparently related to secondary production of IL-1. MECHANISMS OF ANTIPYRESIS. Non-steroidal antipyretic agents inhibit fever by blocking the synthesis of prostaglandins (see Chapter 29) within the endothelium of the hypothalamic vasculature, which is accomplished through inhibition of cyclooxygenase. However, they do not diminish the elaboration of endogenous pyrogens and may actually increase the

production of some of these proteins (notably TNF-alpha). Non-steroidal antipyretics do not produce poikilothermic effects; they can reduce fever but cannot lower body temperature beneath its normal set-point. It may reasonably be inferred from this observation that prostaglandins do not normally act to maintain core body temperature. Glucocorticoid hormones directly impede the production of endogenous pyrogens by mononuclear phagocytic cells. Cytokine synthesis is inhibited at more than one level and has been studied most thoroughly in the case of TNF-alpha biosynthesis. Both transcription of the TNF-alpha gene and translation of TNF-alpha mRNA are down-regulated by glucocorticoid agonists. The cyclic (often circadian) course followed in many febrile illnesses has not been fully explained. In some instances (e.g., in malaria), a clear relationship to the life cycle of the pathogen has been demonstrated. Cyclicity may, in other cases, follow from the fact that cells constituting the chief source of endogenous pyrogens are rendered refractory by continued exposure to the stimulatory agent and must recover or be replaced.

TREATMENT. In the absence of specific knowledge concerning the benefits of fever, a conservative approach to the treatment of fever is advisable. Core temperatures beneath 105° F are well tolerated by most individuals. Moreover, when its source has been defined, fever often serves as an important indicator of therapeutic effect. Under certain circumstances, aggressive treatment of fever is warranted. Patients with myocardial ischemia, patients predisposed to seizures, and pregnant women may require treatment with antipyretics because elevation of core temperature increases cardiac output and myocardial oxygen demand, increases the likelihood of seizures, and may exert a teratogenic effect. Acetaminophen or non-steroidal anti-inflammatory agents prove adequate for this purpose in the majority of cases. Physical methods for increasing heat dissipation may also be used. Temperatures that exceed 106° F are life threatening and must be lowered immediately. Antipyretics are often ineffective in such instances because pyrexia of this degree does not result from an aberrant hypothalamic set-point. It is advisable, in such cases, to lower the temperature by any means possible; the most effective action to be taken is to immerse the patient in ice water while monitoring core temperature to be certain that a state of hypothermia is not induced. Moltz H: Fever: Causes and consequences. Neurosci Biobehav Rev 17:237, 1993. An excellent review analyzing the neurochemistry and neuroanatomy of fever. Rothwell NJ: CNS regulation of thermogenesis. Crit Rev Neurobiol 8:1, 1994. A current appraisal of the pyrogenicity of various cytokines.

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Chapter 313 - THE ACUTE-PHASE RESPONSE Charles A. Dinarello

ACUTE-PHASE CHANGES. Infections, trauma, inflammatory processes, and some malignant diseases induce a constellation of host responses collectively referred to as the "acute-phase response." The response is associated with characteristic metabolic changes in liver protein synthesis, but on closer examination, changes also occur in several other systems and are responsible for various hematologic, endocrinologic, and immunologic dysfunctions. These changes are called "acute" because most are observed within hours or days following the onset of infection or injury, although some acute-phase changes also indicate chronic disease. The full spectrum of the response includes dramatic increases in the synthesis of several unique hepatic proteins that are not produced in health. One of these, C-reactive protein, is a marker of the acute-phase response and can be used to indicate disease. The increased plasma concentrations of acute-phase hepatic proteins, glycoproteins, and globulins are responsible for elevated erythrocyte sedimentation rates. Although the liver is producing increasing amounts of a variety of proteins, hepatic albumin synthesis is decreased. Increases in gluconeogenesis, energy expenditure, and muscle proteolysis occur and contribute to weight loss. However, anorexia is often present and 1568

may account for most of the weight loss. Fever may be present, and increased sleep and lethargy are frequent clinical complaints. Leukocytosis with increased numbers of circulating immature neutrophils is common, and serum iron and zinc levels are depressed, whereas increased ceruloplasmin levels result in elevated serum copper. Thyroid dysfunction can be present, and glucose tolerance and lipid metabolism are often abnormal. In addition, anemia develops despite adequate stores of iron, and hypergammaglobulinemia often occurs. Although the most florid manifestation of the acute-phase response is observed in patients with bacterial infections, burns, or multiple injuries, clinicians also encounter acute-phase changes in patients with occult infections or chronic illnesses such as rheumatoid arthritis, Crohn's disease, and several autoimmune diseases. The presence of acute-phase changes can also serve as an indicator of silent disease and some cancers, particularly renal cell carcinoma and Hodgkin's disease. The acute-phase response has the outstanding characteristic of being a generalized host reaction irrespective of the localized or systemic nature of the inciting disease. The various components of the response are remarkably consistent despite the considerable variety of pathologic processes that induce it. For example, plasma levels of several acute-phase proteins are elevated following myocardial infarction, fracture of a bone, or bacterial pneumonia.

INDUCTION OF ACUTE-PHASE CHANGES. How are infections, injuries, and immunologic and inflammatory reactions able to elicit acute-phase changes in the host? Initiation of the acute-phase response is linked to the production of hormone-like polypeptide mediators, now called cytokines. Several cytokines induce acute-phase changes: interleukin 1 (IL-1), tumor necrosis factor, interferon-gamma, IL-6, leukemia inhibitory factor, ciliary neurotropic factor, oncostatin M, and 1L-11. These last five cytokines induce hepatic acute-phase protein synthesis via glycoprotein cell receptor 130. The ability of microbial and inflammatory substances to stimulate the production of these mediators in strategically located, specialized cells appears to be part of local pathologic changes in many diseases, as well as the systemic characteristics of the acute-phase response. Interferon-alpha is produced primarily during viral infections. Although it shares with IL-1 and tumor necrosis factor the ability to produce fever, sleep, and lethargy, interferon-alpha does not induce certain other acute-phase changes, and hence elevated erythrocyte sedimentation rates and neutrophilia are not commonly observed during viral infections. A patient with a localized bacterial infection represents an excellent example of development of the acute-phase response. At the onset of the infection, blood monocytes and tissue macrophages become activated either by phagocytosis of the invading microbe or by exposure to its products or toxins; the process results in the synthesis and release of various cytokines within 1 to 2 hours. These mediators enter the circulation and reach the brain, where they initiate fever. Whereas fever is clearly one of the most obvious signs of the acute-phase response, other components of the response can be present without apparent clinical manifestations. One of the most sensitive measures of the acute-phase response is an increase in the number and immaturity of circulating neutrophils. In human subjects injected with small doses of IL-1 or related cytokines, neutrophilia can be measured in the absence of fever. Although not routinely measured, serum zinc and iron levels are depressed. Low serum iron associated with anemia in the face of adequate iron stores is characteristic of the acute-phase response. Within 8 to 12 hours after the onset of infection or trauma, the liver increases the synthetic rate of the so-called acute-phase proteins. The response includes increases in proteins normally found in health, as well as the appearance of new proteins that serve as markers of a pathologic event. Several normal plasma proteins increase several-fold during the acute-phase response, including haptoglobin, certain protease inhibitors, complement components, ceruloplasmin, and fibrinogen. However, true acute-phase reactants increase several hundred-fold. These reactants include serum amyloid A protein, a precursor of the amyloid fibril in secondary amyloidosis, and C-reactive protein. C-reactive protein was named for its ability to interact with the C polysaccharide of pneumococci and was the first acute-phase protein described. Table 313-1 lists TABLE 313-1 -- PLASMA PROTEINS THAT INCREASE DURING THE ACUTE-PHASE RESPONSE C-reactive protein Serum amyloid A protein alpha1 -Glycoprotein Ceruloplasmin alpha-Macroglobulins Complement components (C1-C4, factor B, C9, C11) alpha1 -Antitrypsin alpha1 -Antichymotrypsin Fibrinogen Prothrombin Factor VIII Plasminogen Haptoglobin Ferritin Immunoglobulins Lipoproteins

the characteristic pattern of increased plasma proteins observed during the acute-phase response. Note one exception: The plasma concentration of albumin is decreased. Of all the acute-phase proteins, C-reactive protein is clinically the most important because its presence serves as an indicator of disease. C-reactive protein is particularly useful as a marker of the hepatic acute-phase protein response and can be measured easily in most hospital clinical laboratories. Despite the anabolic processes of the liver, the acute-phase response is accompanied by pronounced catabolism of muscle protein associated with loss of body weight and overall negative nitrogen balance. Fever increases oxygen and caloric demands (usually 7% per degree F), and most of the negative nitrogen balance results from the oxidation of amino acids from skeletal muscle, which contributes to wasting. These amino acids are largely used for gluconeogenesis. Although the metabolic demands of elevated temperature contribute to the increased need for energy substrates, the host also requires a large supply of amino acids to synthesize new protein at a time when food intake may be impaired or appetite reduced. Amino acids are required for immunologic and reparative processes such as the clonal expansion of lymphocytes and the proliferation of fibroblasts. Also, they are needed for synthesis of hepatic acute-phase proteins, immunoglobulins, and collagen. The mechanism of providing ample amino acids for these cellular functions seems to be well orchestrated during the acute-phase response. The catabolism during infection and inflammation differs from that of starvation. Unlike starvation, in which large amounts of ketones are spilled into the urine, an individual with an infectious or inflammatory disease excretes protein with small amounts of ketones. IL-1, tumor necrosis factor, and IL-6, the primary mediators of acute-phase changes, inhibit lipoprotein lipase and suppress appetite. In addition, these cytokines and interferons directly stimulate hepatic lipogenesis, thereby contributing to the hypertriglyceridemia observed in patients with either acute or chronic disease.

MEASUREMENT OF ACUTE-PHASE CHANGES IN CLINICAL MEDICINE. The acute-phase response is non-specific. However, the presence of certain acute-phase changes in an otherwise healthy individual can alert the physician to hidden disease. Increased peripheral neutrophils and erythrocyte sedimentation rate are often used to detect an acute-phase response. Measurement of C-reactive protein can help the physician determine the presence of disease in patients with vague constitutional complaints. C-reactive protein levels are usually less than 100 mug/L but increase within hours 10- to 1000-fold. In severe bacterial infections, the serum level can rise from undetectable to over 100 mg/L in 48 hours. The presence of elevated levels of C-reactive protein or serum amyloid A protein, even in the absence of fever or neutrophilia, may indicate occult infection or malignant change. Increases in C-reactive protein and serum amyloid A protein occur in patients of any age and also in immunocompromised patients with opportunistic infections. Not all inflammatory diseases are associated with elevated C-reactive protein. A refractory state can develop in certain diseases such as scleroderma, ulcerative colitis, and lupus erythematosus. Failure of hepatic protein changes and the neutrophilia of the acute-phase response to develop seems to be related to the presence of 1569

circulating inhibitors of cytokines, e.g., the IL-1 receptor antagonist.

TREATMENT OF ACUTE-PHASE RESPONSES. Measurements of fever, acute-phase plasma proteins, and peripheral leukocyte numbers are well-established procedures for monitoring many disease states. Although non-steroidal anti-inflammatory agents are used to treat the fever and associated myalgias of acute-phase responses, these drugs do not affect other acute-phase changes in the liver, various endocrinologic parameters, or the bone marrow response. Antipyretic blood levels of aspirin and therapeutic concentrations of drugs such as indomethacin or ibuprofen do not reduce the production of cytokines. On the other hand, corticosteroids are highly effective in reducing cytokine synthesis, as well as the effect of these mediators on various tissue targets. Patients receiving therapeutic doses of corticosteroids have blunted acute-phase responses with ongoing infections, inflammatory processes, or immunologic reactions. The role of acute-phase proteins in host defense and repair is not entirely clear. Studies suggest that the major role of C-reactive protein is to bind serum lipids or opsonize pneumococci, whereas serum amyloid A is thought to be immunosuppressive. Ceruloplasmin scavenges toxic free oxygen radicals that are injurious to many tissues. What is clear, however, is that the production and physical structure of these acute-phase proteins have been conserved through 400 million years of evolution, and therefore they have presumably been useful to the host. The Limulus crab and fish make C-reactive protein that is nearly identical to human C-reactive protein, which argues that the acute-phase response plays a role in survival. Beisel WR: Magnitude of the host nutritional responses to infection. Am J Clin Nutr 30:1236, 1977. Discussion of the metabolic imbalances seen in patients with infection and injury. Dinarello CA, Wolff SM: The role of interleukin-1 in disease. N Engl J Med 328:106, 1993. Clinical role for IL-1 and IL-1 receptor antagonist in disease. Feingold KR, Soued M, Serio MK: Multiple cytokines stimulate hepatic lipid synthesis in vivo. Endocrinology 125:267, 1989. Evidence that IL-1, tumor necrosis factor, and interferon may account for the hyperlipidemias observed in patients with acute or chronic inflammatory disease. Kushner I, Gewurz H, Benson MD: C-reactive protein and the acute-phase response. J Lab Clin Med 97:739, 1981. A brief discussion of the usefulness of measuring C-reactive protein levels in clinical practice. Pepys MB, Baltz ML: Acute phase proteins with special reference to C-reactive protein and related proteins (pentaxins) and serum amyloid A protein. In Dixon FJ, Kunkel HG (eds): Advances in Immunology, vol 34. New York, Academic Press, 1983, pp 141-211. A comprehensive discussion of the hepatic acute-phase protein pattern observed during the acute-phase response, with special attention to various autoimmune diseases.

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Chapter 314 - THE COMPROMISED HOST Philip A. Pizzo

"Compromised host" is used to describe patients who have an increased risk for infectious complications as a consequence of a congenital or acquired qualitative or quantitative abnormality in one or more components of the host defense matrix (Table 314-1) . Until the early 1980s, this term was largely restricted to patients with congential immunodeficiencies (see Chapter 272) those who became immunocompromised as a consequence of cancer or its treatment, bone marrow failure, or treatment with immunosuppressive therapy. The advent of acquired immune deficiency syndrome (AIDS) has given the term "compromised host" a new meaning and relevance. The compromised host with AIDS is discussed in detail in Part XXIII. In this chapter the focus is on non-AIDS patients with altered immune defenses. However, many of the complications and approaches to diagnosis and management are generic.

PHYSICAL DEFENSE BARRIERS The skin and mucosal surfaces represent the primary defense against both endogenous and exogenous sources of infection. Disruption of skin and mucosa may result from trauma, tumor invasion, the cytotoxic effects of chemotherapy or radiotherapy, the use of invasive diagnostic or therapeutic procedures (e.g., intravenous catheters), and effects of locally destructive infections such as oral herpes simplex. Such mucosal alterations provide a nidus for microbial colonization, a focus for localized infection, and a portal of entry for systemic invasion. The skin and various mucosal surfaces are normally colonized by aerobic and anaerobic bacteria. However, in patients who have been hospitalized, who are neutropenic, or who have received prior broad-spectrum antibiotics, the normal gram-positive flora of the skin can be replaced by other gram-positive organisms such as Centers For Disease Control and Prevention (CDC) group JK Corynebacterium or Bacillus species or by gram-negative organisms (e.g., pseudomonads, enteric gram-negative rods), fungi (e.g., Candida albicans or Aspergillus species), and atypical Mycobacterium species such as M. chelonei or M. fortuitum. Similarly, the gastrointestinal tract is normally colonized by an array of aerobic and anaerobic bacteria, as well as some fungi, and disruption of its mucosa may lead to infection by a variety of pathogens, including polymicrobial infections. A common cause of disruption of gastrointestinal mucosal integrity is cytotoxic chemotherapy to patients with malignancy, particularly cytarabine, the anthracyclines (daunorubicin and doxorubicin), methotrexate, 6-mercaptopurine, and 5-fluorouracil. Although stomatitis is usually the most clinically recognizable manifestation of gastrointestinal toxicity, diffuse gastrointestinal involvement is also likely. Frequently the differentiation between chemotherapy-induced stomatotoxicity and localized infection (e.g., necrotizing gingivitis from anaerobic bacteria or mucosal lesions from herpes simplex virus [HSV]) can be difficult, particularly in neutropenic patients. In addition to mucosal breakdown, mechanical obstruction of body passages can also increase the risk of serious localized infection as a result of stasis of local body fluids and resultant overgrowth of potentially pathogenic colonizing organisms. Common sites of secondary infection resulting from obstruction include the lung, urinary tract, biliary tract, and eustachian tube. One should consider an obstructive process when infection at any of these sites fails to respond to appropriate antibiotics. Anatomic changes can also contribute to the risk of infection. For example, in patients with sickle cell disease, macrophage and splenic dysfunction predispose to the development of certain bacteremias, especially by Streptococcus pneumoniae and Salmonella species. Anatomic abnormalities of bones and joints as a result of vaso-occlusive crises caused by infarction of bone marrow, bony cortex, or synovium in patients with sickle cell disease can also predispose to the development of infections caused by these organisms such as osteomyelitis or arthritis.

PHAGOCYTE DEFECTS The polymorphonuclear leukocyte (PMN) and the monocyte are the two most important components of cellular host defense that protect against invasive bacteria and fungi. Both quantitative and qualitative defects affecting PMNs and monocytes may occur in compromised patients. Quantitative Abnormalities of Phagocytes Granulocytopenia is among the most important risk factors for serious infection in a compromised host. However, it is important to keep in mind that except for congenital neutropenias, other alterations of the host defense matrix often occur in concert with granulocytopenia and can further alter the risk for infection, as well as the types of infectious complications that occur. Granulocytopenia is most commonly associated with malignant disease and its treatment with cytotoxic therapy. This category includes patients with hematologic malignancies and lymphomas, as well as the increasing number of patients with solid tumors who receive cytotoxic chemotherapy. Patients with primary or secondary bone marrow failure also have neutropenia as their predominant risk for infection. In addition to the neutropenia per se, the patterns of infection are also influenced by the other disease- or treatment-related immune abnormalities. For example, despite equivalent degrees of granulocytopenia, a patient with acute myelogenous leukemia may have a different pattern of infection than a patient with aplastic anemia. Disruption of a mucosal defense barrier in a patient 1570

TABLE 314-1 -- PREDOMINANT PATHOGENS IN COMPROMISED PATIENTS; ASSOCIATION WITH SELECTED DEFECTS IN HOST DEFENSE HOST DEFENSE BACTERIA FUNGI VIRUSES OTHER IMPAIRMENT/PHAGOCYTIC DYSFUNCTION Neutropenia

Gram-negative Enteric organisms

Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Citrobacter spp. Pseudomonas aeruginosa Gram-positive Staphylococci Coagulase-negative, coagulase-positive

Candida species C. albicans > C. tropicalis > other species Aspergillus species

A. fumigatus, A. flavus Other opportunistic fungi Mucor, Trichosporon

Streptococci, including viridans enterococci Anaerobes Anaerobic streptococci, Clostridium spp., Bacteroides spp. Abnormal cell-mediated immunity

Immunoglobulin abnor malities

Legionella

Cryptococcus neoformans

Varicella-zoster virus

Pneumocystis carinii

Nocardia asteroides

Histoplasma capsulatum

Herpes simplex virus

Toxoplasma gondii

Salmonella spp.

Coccidioides immitis

Cytomegalovirus

Cryptosporidium

Mycobacteria

Candida

Epstein-Barr virus

Strongyloides stercoralis

M. tuberculosis and atypical mycobacteria

Herpesvirus 6

Disseminated infection from live bacteria vaccine (BCG)

Disseminated infection from live virus vaccines (vaccinia, measles, rubella, mumps, yellow fever, live polio)

Gram-positive

Enteroviruses

Streptococcus pneumoniae, Staphylococcus aureus

Disseminated infection from live virus vaccines (vaccinia, measles, rubella, mumps, yellow fever, polio)

Giardia lamblia

Gram-negative Haemophilus influenzae Neisseria spp., enteric organisms Complement abnormalities C3, C5

Gram-positive S. pneumoniae, staphylococci Gram-negative H. influenzae, Neisseria spp., Enteric organisms

C5-C9

Neisseria species N. gonorrhoeae, N. meningitidis

Anatomic disruption Oral cavity

alpha-Hemolytic streptococci, oral anaerobes Peptococcus, Peptostreptococcus

Candida

Herpes simplex virus

Esophagus

Staphylococci, other colonizing organisms

Candida

Herpes simplex virus Cytomegalovirus

Lower gastrointestinaltract

Gram-positive

Candida

S. stercoralis

Enterococci Gram-negative Enteric organisms Anaerobes (Bacteroides fragilis, Clostridium perfringens) Skin (IV catheter)

Gram-positive Staphylococci, streptococci

Candida Aspergillus

Corynebacterium, Bacillus spp. Gram-negative P. aeruginosa, enteric organisms Mycobacteria M. fortuitum, M. chelonei Urinary tract

Gram-positive

Candida

Enterococci Gram-negative Enteric organisms P. aeruginosa Splenectomy

Gram-positive

Babesia

S. pneumoniae Gram-negative Capnocytophaga H. influenzae Salmonella (sickle cell disease) BCG = bacille Calmette-Guerin. From Rubin M, Walsh TJ, Pizzo PA: Clinical approach to the compromised host. In Hoffman R, Benz EJ Jr, Shattil SJ, et al (eds): Hematology: Basic Principles and Practices, 2nd ed. New York, Churchill Livingstone, 1994.

1571

with acute myelogenous leukemia who is receiving cytotoxic therapy appears to increase the risk for infection with enteric gram-negative bacteria, alpha-hemolytic streptococci, or anaerobes. In contrast, a patient with aplastic anemia who does not have impaired mucosal integrity may be able to sustain longer periods of granulocytopenia without a systemic bacterial infection developing. On the other hand, if a patient with aplastic anemia is treated with steroids or cyclosporine, the risk for viral or fungal infection may be increased. Regardless of these modifying factors, the relationship between granulocytopenia and serious infection has been unequivocally established by the classic study of Bodey and colleagues (Table 314-2) . This study demonstrated that the risk of infection begins to increase significantly when granulocyte counts fall below 1000 per

microliter and is most marked when the counts are 100 per microliter or lower. In addition to the absolute granulocyte count, the duration of granulocytopenia is also directly related to the direction of granulocytopenia as well as whether the counts are rising or falling. For practical purposes, granulocytopenia is usually defined as a count of 500 or fewer PMNs and band forms per microliter. However, a patient with an absolute granulocyte count of 500 to 1000 per microliter that is rapidly falling is probably at greater risk for infection than a patient with a count of 200 per microliter that is rising. Thus the absolute granulocyte count, the duration of granulocytopenia, and whether the neutrophil count is falling or rising must all be considered when assessing the risk to any individual patient. Some clinicians also include the monocyte count in this equation to generate an absolute phagocyte index. Granulocytopenia primarily predisposes patients to bacterial and fungal infection and does not of itself appear to increase the incidence or severity of viral and parasitic infections. In the 1950s and 1960s, when cytotoxic therapy was initially being developed, gram-positive bacteria (especially Staphylococcus aureus) predominated. In the early 1970s, with the availability of antibiotics to control gram-positive bacteria (e.g., methicillin), gram-negative organisms (e.g., Escherichia coli, Klebsiella, Pseudomonas aeruginosa) emerged as the predominant pathogens in neutropenic patients, perhaps because of the increasing use of more aggressive chemotherapy regimens and the use of broader-spectrum antibiotics. During the 1980s, gram-positive organisms re-emerged as common bacterial isolates, and at many centers they now represent the most frequently encountered organisms. In addition to these changes in the pattern of infection, institutional and geographic variations in the causes of infection and the antibiotic sensitivity patterns of isolates cannot be overemphasized, and it is imperative that physicians have a working knowledge of the specific isolates encountered at their own clinical setting. The gram-negative organisms encountered most commonly in granulocytopenic patients are E. coli, Klebsiella pneumoniae, and P. aeruginosa. Together, these organisms have generally accounted for approximately 90% of the gram-negative isolates at most centers. A precise source for gram-negative bacteremia is identified in only a minority of cases, but the gastrointestinal tract, respiratory tract, soft tissue, and urinary tract are the most probable sources for infection. Of these three organisms, P. aeruginosa is often the most virulent in neutropenic hosts, although in most developed countries the incidence of infection by Pseudomonas declined in neutropenic patients during the 1980s. As a general rule, however, virtually any organism can be pathogenic if host defenses are severely impaired. Enterobacter species, Citrobacter species, and Serratia marcescens are less frequently encountered but are notable because they rapidly become resistant to beta-lactam antibiotics through the induction of chromosomally mediated beta-lactamases. Of concern, an increase in Enterobacter sepsis has been observed at a number of treatment centers. Other less common gram-negative isolates include Acinetobacter species, Haemophilus species (usually non-typable H. influenzae), and nonaeruginosa pseudomonads (often catheter related and antibiotic resistant). The gram-positive organisms most frequently encountered are the coagulase-negative staphylococci (most commonly S. epidermidis), coagulase-positive staphylococci ( S. aureus), enterococci, and alpha-hemolytic streptococci (e.g., S. mutans or viridans group streptococci). Both coagulase-positive and coagulase-negative staphylococci are most commonly isolated from the blood, often from patients with indwelling intravenous catheters or from those with foreign bodies such as prosthetic heart valves or orthopedic implants. S. aureus tends to be significantly more virulent, and its sensitivity to beta-lactam antibiotics (e.g., methicillin, oxacillin, or nafcillin) can vary from center to center, thus making it imperative for physicians to be aware of the frequency of methicillin-resistant S. aureus at their institutions. In contrast, coagulase-negative staphylococci tend to be relatively indolent. During the last decade, coagulase-negative staphylococci have become increasingly resistant to beta-lactam antibiotics, and the majority (50 to 80%) are methicillin resistant and generally require treatment with vancomycin. Notable are the recent reports of alpha-hemolytic viridans streptococci that have been associated with septic shock and adult respiratory distress syndrome in patients who are receiving high-dose cytosine arabinoside and in whom oral mucosal disruption occurs. Other gram-positive bacteria that may be encountered in neutropenic patients include Bacillus species (often catheter related), and group CDC-JK Corynebacterium (often catheter related and relatively antibiotic resistant). Enterococcus has emerged as a cause of serious infection in some centers and is particularly important because of the increased resistance to vancomycin (e.g., E. faecium). Infections caused solely by anaerobic bacteria are less common and usually associated with a concomitant abnormality in gastrointestinal mucosal integrity. Although Bacteroides fragilis and Clostridium perfringens are the most common organisms, other Bacteroides species, as well as other Clostridium species (e.g., C. tertium, C. septicum), which are often clindamycin resistant, can be clinically important. Anaerobes are frequent components of intra-abdominal infections, including peritonitis, intra-abdominal abscesses, and perirectal cellulitis or abscesses. Clostridium difficile is a common cause of colitis in neutropenic patients treated with antibiotics or cytotoxic agents. Although infections by Mycobacterium tuberculosis have not been significantly increased in non-AIDS immunocompromised hosts, the increases in the incidence of tuberculosis (especially with multidrug-resistant strains) in homeless persons and people with AIDS raises serious concern that these infections will occur in other immunocompromised hosts. Patients with hairy cell leukemia, who have profound monocytopenia in addition to neutropenia, appear to have an increased risk for atypical mycobacterial infection (e.g., M. kansasii, M. fortuitum, M. chelonei, and M. avium-intracellulare complex). Rapidly growing mycobacteria ( M. fortuitum and M. chelonei) may also cause exit site infections in patients with indwelling intravenous catheters or wound infections following surgery. In contrast to bacterial infections, which are often associated TABLE 314-2 -- ASSOCIATION OF GRANULOCYTE LEVEL AND CHANCE OF SIGNIFICANT INFECTION DEVELOPING PERCENTAGE OF SERIOUS INFECTIONS (DURATION OF GRANULOCYTE LEVEL (per mm3 ) GRANULOCYTOPENIA IN WEEKS) Initial

Change

1

Any level

Any fall

12

Any level

Fall to 2000

2

Any level

Fall to 1500

5

Any level

Fall to 1000

10

Any level

Fall to 500

19

Any level

Fall to 2) AIDS (40)

Immune suppressive therapy for solid organ transplantation (>2) Chronic heart or lung disease (>1) Renal failure requiring dialysis (20) Lung or hematologic cancer (especially hairy cell leukemia) (7-20) Increased Chance of Exposure to Environmental Legionella Bacteria Recent travel away from home (2) Use of domestic well water (2) Recent plumbing work in home or at work (2) Exposure to poorly maintained hot tub spas Recent surgical procedure *Numbers in parentheses represent the approximate relative risk of acquiring legionnaires' disease over that for someone without the risk, where known.

disease about twice as often as females, although this difference does not hold true for several epidemics of legionnaires' disease. No good evidence exists for person-to-person spread of legionnaires' disease. Legionnaires' disease may occur in epidemics originating in a single building or area. Outbreaks of the disease have occurred among hotel guests, hospital inpatients and outpatients, office building workers, and factory workers. People with occupational water exposure appear to have little, if any increased risk of disease acquisition. About 80% of cases of legionnaires' disease are non-epidemic. Of these, perhaps 10% may be acquired in the home and the remainder through other exposure. It is estimated that from 1 to 5% of all pneumonias requiring hospitalization in adults are due to legionnaires' disease, which represents about 10,000 cases of legionnaires' disease per year in the United States. In some geographic regions, community-acquired legionnaires' disease is more common, such as in western Pennsylvania and Ohio. When the disease occurs in endemic or epidemic nosocomial form, 1% to as many as 20% of hospitalized patients with pneumonia have this disease. Pontiac fever has been recognized primarily as an epidemic illness, with attack rates in excess of 90%. It has been noted to occur in office and factory workers and in recreational bathers using spa or whirlpool-type baths. The disease very likely has a sporadic form, but the lack of specific diagnostic tests makes diagnosis of this form very difficult.

PATHOLOGY. Specific pathologic changes are found only in the lung in the vast majority of fatal cases of legionnaires' disease. Intense inflammation is present in alveoli, alveolar ducts, respiratory bronchioles, and alveolar septa. The inflammatory process consists of bacteria, polymorphonuclear leukocytes, and macrophages. On occasion, pleuritis, pleural empyema, pericarditis, and cavitary lung disease are found. Very rarely, abscess formation occurs outside the chest cavity.

CLINICAL FEATURES. Legionnaires' disease is manifested as a febrile systemic illness with pneumonia. Several prospective and retrospective studies of patients with different types of pneumonia have shown that legionnaires' disease has few, if any characteristic clinical features and that it cannot be clinically distinguished from pneumococcal pneumonia. However, clinical observations during epidemics of legionnaires' disease have often documented characteristic clinical findings. It is probable that the spectrum of clinical findings is wide, ranging from a "typical" form of legionnaires' disease to one indistinguishable from other causes of pneumonia. This chapter describes the "typical" form of legionnaires' disease, which in reality may be present in the minority of patients. A prodromal illness consisting of malaise, low-grade fever, and anorexia may develop several days before the onset of more severe symptoms. Myalgia, extreme fatigue, and high fever then develop. Gastrointestinal complaints are common, such as generalized or localized abdominal pain, nausea, vomiting, and diarrhea; the diarrhea is generally watery and not dehydrating. Recurrent rigors and prostration may occur. Symptoms referable to the respiratory tract 1618

may not develop until later. It is this paucity of respiratory tract symptoms, despite evidence of a systemic febrile illness, that can either be a clue to diagnosis or mislead clinicians. When the patient is pressed for details regarding symptoms, a history of a non-productive cough or one productive of non-purulent, sometimes bloody secretions is usually obtained. Production of large amounts of grossly purulent sputum is unusual. Pleuritic chest pain, sometimes in concert with hemoptysis, may occur and can mislead the clinician into considering pulmonary infarction. Mental confusion is commonly reported in some series; obtundation, seizures, and focal neurologic findings may also occur less frequently. Fever is almost uniformly present in cases of legionnaires' disease, although short (days) afebrile periods have been reported in some immunosuppressed patients with L. micdadei pneumonia. Chest examination early in the disease may reveal only scattered rales or evidence of pleural effusion. However, later in the course, most patients have classic findings of consolidating pneumonia. Abdominal examination may reveal generalized or local tenderness and, in rare cases, evidence of peritonitis. Splenomegaly is uncommon. Findings of pericarditis, myocarditis, and focal abscesses are rare. No rash is associated with this disease, except that caused by other factors such as drug therapy. The fatality rate of untreated legionnaires' disease is about 3 to 30% in non-immunosuppressed patients and up to 80% in immunocompromised ones. The majority of previously healthy people recover from untreated legionnaires' disease after 7 to 10 days of severe illness; those who do not recover die of progressive respiratory and multisystem failure. Clinically significant extrapulmonary infection in patients with legionnaires' disease is quite rare (Table 323-2) . Pontiac fever is a non-fatal influenza-like disease, with symptoms of myalgia, fever, headache, and malaise occurring in 60 to 90% of patients. Arthralgia occurs with variable frequency, as do cough, anorexia, and abdominal pain. The illness is generally not severe enough or long enough in duration to cause most patients to seek medical attention. Not much is known about its physical findings early in the disease; findings after 3 to 5 days of illness are generally normal except for fever and possibly tachypnea. Pneumonia does not occur. The illness lasts about 3 to 5 days, although some patients may have persistent fatigue or non-focal neurologic complaints for weeks to months afterward.

CHEST RADIOGRAPHIC FINDINGS. Legionnaires' disease causes alveolar-filling infiltrates that usually eventuate in consolidation. Interstitial infiltrates are rare, although they may occur early in the course of disease and then progress to consolidating infiltrates. The infiltrates may be unilateral or bilateral and can spread very quickly to involve the entire lung. Pleural effusion, usually small in volume, occurs commonly and may be the sole abnormal radiographic finding in early disease.

DIAGNOSIS. The results of multiple non-specific laboratory tests may be abnormal in patients with legionnaires' disease. These abnormal findings include proteinuria, pyuria, hematuria, leukocytosis, leukopenia, and thrombocytopenia. Disseminated intravascular coagulation may be seen in patients with respiratory failure caused by TABLE 323-2 -- EXTRAPULMONARY INFECTIONS CAUSED BY LEGIONELLA Dialysis shunt infection Sinusitis Pericarditis

Prosthetic valve endocarditis Peritonitis Abscesses Skin Brain Bowel Rectum Kidney Myocardium legionnaires' disease. Hyponatremia, hypophosphatemia, hyperbilirubinemia, and elevated serum alanine transminase, serum aspartate transaminase, and alkaline phosphatase concentrations may also be found. Elevation of creatine kinase (MM isoenzyme) is common, and myoglobinuria and renal failure develop in some patients. Cerebrospinal fluid is usually normal, although rare patients may have 25 to 100 white blood cells per microliter of cerebrospinal fluid. Legionnaires' disease can be diagnosed by using specific laboratory tests (Table 323-3) . The most sensitive and specific test is culture of respiratory tract secretions, such as sputum. Sputum culture for Legionella should be performed on every patient suspected of having this disease. Serologic testing is more useful to epidemiologists than to clinicians because of cross-reactions with antibodies to unrelated organisms. No laboratory test currently available is 100% accurate for the diagnosis of legionnaires' disease. Thus empirical therapy must be considered in appropriate clinical settings. The diagnosis of Pontiac fever is based on demonstration of legionellae in water to which the patient was exposed, significant increases in antibody to the isolated Legionella species, and a clinical course compatible with this diagnosis. To be certain about the diagnosis of Pontiac fever, it is almost always necessary to perform extensive studies of unaffected people and their environments because recovery of legionnellae from water and the elevation of antibodies to Legionella are relatively common events. Thus it is nearly impossible to diagnose non-epidemic cases of Pontiac fever specifically. The differential diagnosis of legionnaires' disease is broad because the disease is usually manifested as a non-specific pneumonia. Mycoplasmal pneumonia is generally much less severe and causes significant respiratory system complaints. Pneumococcal pneumonia, in contrast to legionnaires' disease, is usually penicillin responsive. Psittacosis and Q fever can have clinical features quite similar to those of legionnaires' disease.

THERAPY. Erythromycin (Table 323-4) is considered the drug of choice for this disease on the basis of retrospective studies, which show that the case fatality rate is lowered about two-fold by prompt administration of erythromycin. Intravenous drug therapy should be given until clinical improvement is seen, which usually occurs in 2 to 4 days. Afterward, oral drug therapy is continued.

TYPE

TABLE 323-3 -- SPECIFIC DIAGNOSTIC TESTS FOR LEGIONELLA SUITABLE SPECIMENS SENSITIVITY* SPECIFICITY (% ) (% )

NOTES

Culture

Sputum, lung, pleural fluid, -blood, abscess contents

100

Use of special and selective media required; 3 to 5 d required for growth

Immunofluorescent microscopy

Sputum, lung, pleural fluid, 25-75 abscess contents

95-99.9

Species-specific monoclonal antibody available; not helpful for diagnosis of all species; highest specificity for L. pneumophila; relatively low specificity for other species; 2 to 3 hr required for testing

Urine antigen detection Urine

90-95

99.9

Useful only for detection of L. pneumophila serogroup 1, the most common cause of legionnaires' disease; 2 to 3 hr required for testing; may be positive despite antimicrobial therapy

Antibody

60-70

90-99

Requires testing of paired specimens; seroconversion may not occur until 2 to 3 mo after infection; most specific for L. pneumophila serogroup 1; cross-reactions with antibodies to many other bacteria

Serum

*Sensitivity versus culture. Culture is the most sensitive diagnostic technique, but its absolute sensitivity is unknown; reasonable estimates are 80 to 90%.

1619

PATIENT TYPE Normal host

DISEASE SEVERITY* Mild to moderate

TABLE 323-4 -- ANTIMICROBIAL DRUG THERAPY FOR LEGIONNAIRES' DISEASE FIRST DOSAGE ALTERNATIVES CHOICES Erythromycin

500 mg to 1 g IV, 500 mg orally each four times daily; 14-21 d

or

Severe Immunosuppressed Any type

Levofloxacin

DOSAGE 500 mg IV or orally once daily; 7-10 d

or

Doxycycline

200 mg IV or orally once daily; 14-21 d

Azithromycin

500 mg IV or orally once daily; 3 d

Levofloxacin

500 mg IV or orally once daily; 7-10 d

Azithromycin

Same dosage as above; 5 d

Levofloxacin

Same as above

Azithromycin

Same dosage as above; 5 d

*Severe disease is that causing respiratory failure, bilateral pneumonia, or rapidly worsening pulmonary infiltrates, or the presence of at least two of the following three: blood urea nitrogen 30 mg/dL (11 mmol/L); diastolic blood pressure 30/min. Approved by the Food and Drug Administration for the treatment of legionnaires' disease. Acceptable alternatives include trovafloxacin, 200 mg once daily IV or orally and ofloxacin, 500 mg twice daily IV or orally, both for 7 to 10 days.

Mild cases of legionnaires' disease can be treated with oral therapy exclusively. Quinolone antimicrobials (especially levofloxacin, trovafloxacin, and sparfloxacin) and the newer macrolide antimicrobials (clarithromycin and especially azithromycin) are more effective than erythromycin or doxycycline in experimental laboratory studies. The more active quinolone drugs (levofloxacin, trovafloxacin, and sparfloxacin) are preferred for organ transplant patients because of their very high activity in experimental legionnaires' disease and lack of interference with cyclosporine levels. In addition, most immunocompromised patients and most patients with severe legionnaires' disease should receive one of the more active quinolone antimicrobials or perhaps azithromycin rather than erythromycin. Because of its potent activity in experimental legionnaires' disease, many clinicians add rifampin to an erythromycin or doxycycline regimen for treatment of severe cases of legionnaires' disease. No clinical data have indicated the superiority of such combination therapy. The availability of newer and more active drugs makes such combination therapy less desirable. Penicillins, cephalosporins (first, second, and third generation), and aminoglycosides are ineffective for the treatment of legionnaires' disease. In fact, failure of pneumonia to respond to these agents should prompt consideration of legionnaires' disease and perhaps initiation of specific anti- Legionella therapy. No effective

therapy for Pontiac fever is known. Most patients with legionnaires' disease respond within 1 to 4 days to specific antimicrobial therapy. The symptoms clearing most rapidly are rigors, mental confusion, myalgia, anorexia, fatigue, and abdominal complaints. Fever may persist for a week after the initiation of therapy but starts a downward trend within a few days. Despite this clinical evidence of improvement, other findings may falsely imply disease progression, such as evidence of increased pulmonary consolidation on physical examination and on radiography. Weeks to months are required for the resolution of pulmonary infiltrates. Patients with respiratory failure have a relatively poor prognosis and tend to have a much slower response to therapy. Edelstein PH: Antimicrobial chemotherapy for legionnaires' disease: A review. Clin Infect Dis 21 (Suppl.):265, 1995. Detailed review of antimicrobial therapy. Fang GD, Fine M, Orloff J, et al: New and emerging etiologies for community-acquired pneumonia with implications for therapy: A prospective multicenter study of 359 cases. Medicine (Baltimore) 69:307, 1990. Excellent survey of community-acquired pneumonia, including legionnaires' disease. Stout JE, Yu VL: Legionellosis. N Engl J Med 337:682, 1997. Good recent clinical review.

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Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 324 - STREPTOCOCCAL INFECTIONS Dennis L. Stevens

CLASSIFICATION AND IDENTIFICATION OF STREPTOCOCCI Streptococci are gram-positive globular or coccoid bacteria that grow in chains. Streptococci colonize the skin and mucous membranes of animals, produce catalase, and may be aerobic, anaerobic, or facultative. Streptococci require complex media containing blood products for optimal growth. On blood agar plates, streptococci may cause complete (beta), incomplete (alpha) or no hemolysis (gamma). The exhaustive work of Rebecca Lancefield has allowed hemolytic streptococci to be classified into types A through O based on acid-extractable carbohydrate antigens of cell wall material. The availability of rapid latex agglutination kits provides even small clinical laboratories with the means to identify streptococci according to Lancefield group. Bacitracin susceptibility, bile esculin hydrolysis, and the CAMP (Christie-Atkins-Munch-Peterson) test (flame-type synergistic hemolysis on a Staphylococcus aureus blood agar streak) are useful presumptive tests for classifying groups A, D, or B streptococci, respectively. Modern schemes of classification of hemolytic and non-hemolytic streptococci use complex biochemical and genetic techniques. GROUP A STREPTOCOCCAL INFECTIONS EPIDEMIOLOGY. HOST RANGE.

The concept of group A streptococcus as a pure human pathogen is supported by the observations that (1) natural group A streptococcus infection in animals is rare; (2) laboratory animals are not useful models of streptococcal pharyngitis, scarlet fever, erysipelas, rheumatic fever, or post-streptococcal glomerulonephritis; (3) the inoculum needed to cause infection in laboratory animals is orders of magnitude greater than that estimated to cause infection in humans; and (4) streptococci have developed highly sophisticated defensive molecules that bind, inactivate, or destroy human immune response molecules (e.g., IgG antibody and complement [C5a]). AGE-RELATED ATTACK RATES.

All group A streptococcal infections have the highest incidence in children younger than 10 years. The asymptomatic prevalence is also higher (15 to 20%) in children than in adults (5%). Diabetes may be an additional risk factor for Salmonella infection. Most cases of Salmonella infection occurring in the United States are sporadic rather than related to outbreaks. However, when an infection occurs in a family, other members of the household also tend to have positive stool cultures. About 40,000 cases of culture-confirmed Salmonella infection have been reported annually to the Centers for Disease Control and Prevention in recent years, a marked increase over the past 30 years. However, this undoubtedly represents only a fraction of actual cases. It has been estimated that 2 to 4 million cases actually occur each year. A disproportionate number of infections occur in July through October, probably related to the warm weather. Salmonella infections are most common in infants and in children younger than 5 years of age. Salmonellae have become increasingly resistant to antibiotics, usually by acquiring resistance transfer factors. It is believed that much of the resistance has been related to widespread use of antimicrobial agents in farm animals. A multidrug-resistant strain of 1684

S. typhimurium (definitive type 104 [DT 104]) has emerged as an important cause of infection in the United Kingdom, with very recent outbreaks reported in the United States.

PATHOGENESIS. After ingestion of organisms, the determinants of whether or not infection results, as well as the severity of infection, are the dose and virulence of the Salmonella strain and the status of host defense mechanisms. Large inocula such as 107 bacteria are usually required to produce clinical infection in the normal host. Smaller inocula are more likely to result in no infection or to produce a transient intestinal carrier state. Gastric acid serves as a host defense mechanism by killing many of the ingested organisms, and intestinal motility is also probably a host defense mechanism. In the absence or decrease of gastric acidity (as in the elderly, after gastrectomy,

vagotomy, or gastroenterostomy, with H2 -receptor antagonists, and with antacids) and with decreased intestinal motility (as with antimotility drugs), much smaller inocula can produce infection and the infection tends to be more severe. Administration of antimicrobial agents before ingestion of salmonellae can markedly reduce the size of inoculum needed to produce infection, presumably by reducing the protective bowel flora. Although any Salmonella serotype can produce any of the Salmonella syndromes (transient asymptomatic carrier state, enterocolitis, bacteremia, enteric fever, and chronic carrier state), each serotype tends to produce certain syndromes much more often than others. For example, S. anatum usually causes asymptomatic intestinal infection, whereas S. typhimurium usually causes enterocolitis. S. choleraesuis is more likely to produce bacteremia (often with metastatic infection) than asymptomatic infection or enterocolitis, and some serotypes such as S. typhi are most likely to cause enteric fever as well as the chronic carrier state. Fortunately, most Salmonella serotypes are of relatively low pathogenicity for humans; and, therefore, although food products are commonly contaminated, large outbreaks occur only when more virulent serotypes are involved. To produce infection, invasion must occur across the mucosa of the intestine. When the organisms reach the lamina propria, an influx of polymorphonuclear leukocytes serves as a defense mechanism to prevent invasion of lymphatics. Certain serotypes seem more able than others to invade lymphatics and subsequently produce bacteremia. For example, S. dublin, which has been isolated from unpasteurized milk, commonly produces bacteremia after intestinal infection. Both the small intestine and colon are involved in the inflammatory process. The diarrhea in Salmonella enterocolitis results from the inflammation. In addition, watery stools may occur, apparently the result of secretion of water and electrolytes by small intestinal epithelial cells in response to an enterotoxin secreted by some of the Salmonella strains or in response to tissue mediators of inflammation. Patients with diseases that impair host defense mechanisms seem to have an increased frequency of severe Salmonella infection. For many years, a striking association has been recognized between diseases producing hemolysis and Salmonella bacteremia. Specifically, Salmonella bacteremia is common in patients with sickle cell disorders, malaria, and bartonellosis. In fact, because of the frequency of Salmonella bacteremia in sickle cell diseases and the underlying bone disease in these patients to which salmonellae localize, these organisms are the most common cause of osteomyelitis in patients with sickle cell disorders. Prolonged Salmonella bacteremia occurs in patients with hepatosplenic schistosomiasis, probably related to localization on and in the intravascular schistosomes. Patients with lymphoma and leukemia also are more prone to develop Salmonella bacteremia. Prolonged and recurrent refractory Salmonella bacteremia has been observed in patients with the acquired immunodeficiency syndrome (AIDS).

CLINICAL SYNDROMES. Asymptomatic Intestinal Carrier State. The asymptomatic intestinal carrier state may result from inapparent infection, which is the most common form of Salmonella infection, or may follow clinical disease (convalescent carrier). The carrier state is usually self-limited to several weeks to months, with the incidence of positive stool cultures rapidly decreasing. By 1 year, far less than 1% still have positive stools. The major exception is with S. typhi: about 3% of those infected excrete the organism for life. A patient who has had Salmonella in the stool for 1 year (chronic carrier) is likely to become a lifelong carrier. Patients with Schistosoma haematobium infections are predisposed to become chronic urinary carriers of Salmonella. Enterocolitis. After an incubation period, which is usually 12 to 48 hours, the illness starts suddenly with crampy abdominal pain and diarrhea. A chill is common. Although occasional patients have nausea and vomit once or twice, vomiting is not persistent. The diarrhea may be watery and of large volume or small volume. The stools may contain mucus and occasionally blood. Polymorphonuclear leukocytes are present in the stool. Diarrhea may be mild or may be severe with up to 20 to 30 stools a day. Fever is present in most patients, whose temperature may reach 40° C (104° F) or higher. The abdomen is tender to palpation. Transient bacteremia may occur and is most likely in infants, the elderly, and patients with impaired host defense mechanisms. Symptoms usually improve over a period of days, with fever lasting no more than 2 to 3 days and diarrhea no more than 5 to 7 days. However, these symptoms may occasionally persist for up to 14 days. More severe disease is seen with malnutrition, inflammatory bowel disease, and AIDS. Reactive arthritis may follow enterocolitis in up to 7% of cases. It is especially frequent in those with the HLA-B27 phenotype. Enteric Fever. Paratyphoid fever is an enteric fever syndrome identical to typhoid fever but produced by a serotype other than S. typhi (most often S. paratyphi A, S. schottmuelleri, or S. hirschfeldii). On occasion, it may immediately follow classic enterocolitis caused by the same organism. The syndrome, characterized by prolonged sustained fever, relative bradycardia, splenomegaly, rose spots, and leukopenia, is described in Chapter 340 . Enteric fever produced by serotypes of Salmonella other than S. typhi is usually milder than typhoid fever, and the chronic carrier state follows less commonly than after typhoid fever. Bacteremia. Patients with the syndrome of Salmonella bacteremia usually complain of fever and chills for a period of days to weeks. Gastrointestinal symptoms are unusual, but in some patients the syndrome of Salmonella bacteremia follows classic enterocolitis. Other symptoms are non-specific, such as malaise, anorexia, and weight loss. Metastatic infection of bones, joints, mycotic aneurysm (particularly of the abdominal aorta), meninges (mainly in infants), pericardium, pleural space, lungs, heart valves, cysts, uterine myomas, malignancies, and other sites is common, and symptoms may be related to the site of metastatic infection. Stool cultures are usually negative for Salmonella, but blood cultures are positive. Although any Salmonella serotype can produce the syndrome of bacteremia, S. choleraesuis is most likely to cause this syndrome; over 50% of S. choleraesuis infections are bacteremic. Salmonella bacteremia occurs with increased frequency in infants and the elderly and in patients with diseases associated with hemolysis (such as sickle cell diseases, malaria, and bartonellosis), with lymphoma, with leukemia, and perhaps with systemic lupus erythematosus. Localization to bone is common in patients with sickle cell diseases. Prolonged Salmonella bacteremia lasting for months occurs in patients with hepatosplenic schistosomiasis. Patients with AIDS develop recurrent, relapsing Salmonella bacteremia that is difficult to cure with antibiotics.

DIAGNOSIS. The diagnosis of Salmonella infection is made by isolating the organism from the stool in enterocolitis, from the blood in bacteremia, from blood and stool in enteric fever, and from the local site in localized infection. Serologic studies are of little clinical value in Salmonella infections other than typhoid fever, but they may be of use in epidemiologic studies. A stained smear of the stool usually demonstrates polymorphonuclear leukocytes in patients with Salmonella enterocolitis. The differential diagnosis of Salmonella enterocolitis includes all causes of acute diarrhea, including invasive bacteria such as Campylobacter jejuni, Shigella species, invasive Escherichia coli, Yersinia enterocolitica, and Vibrio parahaemolyticus; toxigenic bacteria such as V. cholerae, enterotoxigenic E. coli, E. coli 0157:H7, S. aureus, Bacillus cereus, Clostridium perfringens, and C. difficile; viruses; and protozoa such as Entamoeba histolytica, Giardia lamblia, and Cryptosporidium species. Invasive bacterial causes of diarrhea, E. coli 0157:H7, and C. difficile infection are also associated with polymorphonuclear leukocytes in the stool, whereas bacterial toxigenic causes (other than C. difficile and E. coli 0157:H7), viruses, and protozoa generally are not. The bacterial toxigenic 1685

causes of diarrhea other than C. difficile and E. coli 0157:H7 do not produce fever. Stool culture is definitive for the diagnosis of Salmonella enterocolitis; but by the time the results of the stool culture are available, most patients are recovering.

The differential diagnosis of Salmonella bacteremia includes all acute infectious and non-infectious causes of fever, including bacteremia caused by other organisms. The differential diagnosis of enteric fever is the same as discussed in Chapter 340 .

TREATMENT. Enterocolitis. The primary approach to treatment of Salmonella enterocolitis is fluid and electrolyte replacement. Drugs with antiperistaltic effects such as loperamide or diphenoxylate with atropine can relieve cramps but should be used sparingly because they can prolong the diarrhea. Salmonella enterocolitis is self-limited. Furthermore, there has been a reluctance to treat Salmonella enterocolitis because antibiotic therapy has been reported to have no effect on the clinical course and, in some studies, to prolong the period of time salmonellae are excreted in the stool. In addition, most patients are improving by the time that salmonellae or other bacterial pathogens are isolated from the stool. However, infants, the elderly, and those with sickle cell disease, lymphoma, leukemia, or other serious underlying diseases who are severely ill and may have bacteremia may benefit from antimicrobial therapy. The fluoroquinolones are active against virtually all bacterial pathogens that cause diarrhea except for C. difficile, and it is reasonable to use them empirically in the early therapy of adults with severe diarrhea of presumed bacterial etiology. It is also reasonable to use them for patients with known Salmonella enterocolitis who are suspected of being bacteremic. Ciprofloxacin, 500 mg every 12 hours orally or 400 mg every 12 hours intravenously for 3 to 5 days, has been widely used. Other agents, such as amoxicillin (1 g every 6 hours orally), ampicillin (1 to 2 g IV every 6 hours), trimethoprim-sulfamethoxazole (one double-strength tablet every 12 hours orally), and trimethoprim-sulfamethoxazole (10 mg/kg/day IV of the trimethoprim component) have also been widely used in severely ill adults. However, many strains of Salmonella are now resistant to these agents. Bacteremia and Enteric Fever. The agents of choice to treat these disorders are the third-generation cephalosporins, such as ceftriaxone, cefotaxime, and ceftizoxime, or the fluoroquinolones, such as ciprofloxacin and ofloxacin. Typical doses are ceftriaxone, 1 g every 12 hours intramuscularly or intravenously, and ciprofloxacin, 400 mg every 12 hours intravenously. After response, therapy can be changed to oral ciprofloxacin, 500 mg every 12 hours, or oral cefixime, 400 mg every 12 hours. When the salmonellae are known to be susceptible, ampicillin or trimethoprim-sulfamethoxazole can be used in the doses described in the section on enterocolitis. Chloramphenicol, 50 mg/kg/day in four equally divided doses orally or intravenously, is an alternative regimen. Therapy is continued for 7 to 14 days for enteric fever and bacteremia without localization of organisms and for much longer periods of time with localization to bone, aneurysms, heart valves, and various other sites. Surgical drainage or removal of foreign bodies or resection of an aneurysm is often necessary to cure localized infection. Curing schistosomiasis in patients with Salmonella bacteremia may cure the bacteremia. Patients with AIDS tend to relapse repeatedly after treatment courses for Salmonella bacteremia. Long-term suppressive therapy has been recommended by some. Carriers. Chronic carriers (i.e., over 1 year) of salmonellae other than S. typhi are rare. Stools of convalescent carriers spontaneously become negative over a period of weeks to months, and no therapy should be given. The rare chronic carrier of non- S. typhi serotypes (usually infected with S. paratyphi A, S. schottmuelleri, or S. hirschfeldii) may be treated with 4 to 6 g of ampicillin plus 2 g of probenecid orally each day in four divided doses for 6 weeks. The fluoroquinolones are probably equally effective. Patients who experience relapse usually have gallbladder disease (most often calculi) and will not be cured with antimicrobial therapy. Cholecystectomy plus antimicrobial therapy may cure these patients, but it is doubtful that the carrier state per se is a sufficient indication for cholecystectomy.

PROGNOSIS. Mortality in Salmonella enterocolitis is rare; infants and the elderly are at greatest risk, with death occurring from dehydration and electrolyte imbalance. Mortality from Salmonella bacteremia or enteric fever is not uncommon and is most likely to occur in the very young and the very old. S. choleraesuis bacteremia has the highest mortality rate of any Salmonella serotype, as high as 20 to 30% if untreated.

PREVENTION. Salmonella infection is best prevented by properly managing the water supply and sewage disposal, cooking and refrigerating foods made from animal products, pasteurizing milk and milk products, and hand washing before preparing foods and after handling animals and uncooked animal products. Despite these precautions, because of the widespread presence of salmonellae in the animal kingdom, it is unlikely that the frequency of Salmonella infections will be significantly diminished. There is no vaccine for any infection with salmonellae other than that for infection with S. typhi. Centers for Disease Control and Prevention: Multidrug-resistant Salmonella serotype typhimurium--United States, 1996. MMWR Morbid Mortal Wkly Rep 46:308-310, 1997. A report of an outbreak of multidrug-resistant Salmonella typhimurium infection in the United States caused by definitive type 104 (DT104), a strain that has been an increasing cause of infection in the United Kingdom. Centers for Disease Control and Prevention: Outbreaks of Salmonella serotype enteritidis infection associated with consumption of raw shell eggs--United States, 1994-1995. MMWR Morbid Mortal Wkly Rep 45:737-742, 1996. A description of the increasing importance of Salmonella enteritidis as a cause of infection associated with consumption of eggs. Gruenewald R, Blum S, Chan J: Relationship between human immunodeficiency virus infection and salmonellosis in 20- to 59-year-old residents of New York City. Clin Infect Dis 18:358-363, 1994. A report of the strong association between Salmonella infection and AIDS. Hennessy TW, Hedberg CW, Slutsker L, et al: A national outbreak of salmonella enteritidis infections from ice cream. N Engl J Med 334:1281-1286, 1996. A description of a major outbreak of Salmonella enteritidis infection from ice cream caused by transport of pasteurized ice cream base in containers previously used for transport of non-pasteurized liquid eggs. Mahon BE, Ponka A, Hall WN, et al: An international outbreak of Salmonella infections caused by alfalfa sprouts grown from contaminated seeds. J Infect Dis 175:876-882, 1997. A description of a Salmonella outbreak caused by alfalfa sprouts grown from contaminated seeds. Torok TJ, Tauxe RV, Wise RP, et al: A large community outbreak of salmonellosis caused by intentional contamination of restaurant salad bars. JAMA 278:389-395, 1997. A description of a large outbreak of Salmonella infection related to intentional contamination of restaurant salad bars.

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Chapter 342 - SHIGELLOSIS Thomas Butler

DEFINITION. Shigellosis is an acute bacterial infection caused by the genus Shigella resulting in colitis affecting predominantly the rectosigmoid colon. "Bacillary dysentery" is synonymous with shigellosis. The disease is characterized by diarrhea, dysentery, fever, abdominal pain, and tenesmus. Shigellosis is usually limited to a few days. Early treatment with antimicrobial drugs results in more rapid recovery.

ETIOLOGY. Shigellae are non-motile gram-negative bacilli belonging to the family Enterobacteriaceae. Four species of shigellae are recognized on the basis of antigenic and biochemical properties: S. dysenteriae (group A), S. flexneri (group B), S. boydii (group C), and S. sonnei (group D). Among these species there are over 40 serotypes, each of which is designated by the species name followed by a specific Arabic number. S. dysenteriae 1 is called the "Shiga bacillus" and causes epidemics with higher mortality than other serotypes. With the exception of S. flexneri 6, they do not ferment lactose. Serotypes are determined by the O polysaccharide side chain of the lipopolysaccharide (endotoxin) in the cell wall. Endotoxin is detectable in the blood of severely ill patients and may be responsible for the complication of the hemolytic-uremic syndrome. To be virulent, shigellae must be able to invade epithelial cells, as tested in the laboratory by keratoconjunctivitis in the guinea pig (Sereney test) or HeLa cell invasion. Bacterial invasion of cells is genetically governed by three chromosomal regions and a 140-Md plasmid. 1686

Shiga toxin is produced by S. dysenteriae 1 and in lesser amounts by other serotypes. It inhibits protein synthesis and has enterotoxic activity in animal models, but its role in human disease is uncertain.

INCIDENCE AND PREVALENCE. In the United States there were more than 14,000 cases reported in 1996 with species distribution of 73% S. sonnei, 19% S. flexneri, 2% S. boydii, and 1% S. dysenteriae. Most cases were in young children, women of child-bearing age, and low-income minority residents; and a large proportion occurred in population groups living in homes for the mentally ill or in nursing homes. A large outbreak in 1987 in Tennessee affected more than 1000 persons camping under unsanitary conditions at a mass gathering. Worldwide, most cases of shigellosis occur in children of developing countries, where S. flexneri is the predominant species. In 1994, an epidemic in Rwandan refugees caused an estimated 30,000 deaths.

EPIDEMIOLOGY. Shigellosis is transmitted by the fecal-oral route. Crowded living conditions, low standards of personal hygiene, poor water supply, and inadequate sewage facilities all contribute to an increased risk of infection. Transmission most often occurs by close person-to-person contact through contaminated hands. During clinical illness and for up to 6 weeks after recovery, organisms are excreted in the feces. Although the organisms are sensitive to desiccation, they may survive several months in food or water, which are occasional vehicles of transmission. Children between 1 and 4 years old have the greatest risk of developing shigellosis. Inhabitants of custodial institutions, such as homes for retarded children, are at highest risk. Intrafamilial spread follows often when the initial case has occurred in a preschool child. In young adults, the incidence is higher in women than in men, which probably reflects closer contact of women with children. The male homosexual population in the United States is at increased risk for shigellosis, which is one of the causes of the "gay bowel syndrome." Humans and higher primates are the only known natural reservoirs of shigellosis. Transmission shows variable seasonal patterns in different regions. In the United States, the peak incidence is in late summer and early autumn.

PATHOGENESIS AND PATHOLOGY. Because the microorganisms are relatively resistant to acid, shigellae pass the gastric barrier more readily than other enteric pathogens. In volunteer studies, as few as 200 ingested bacilli regularly initiate disease in 25% of healthy adults. This contrasts strikingly to the much larger numbers of typhoid or cholera bacilli required to produce disease in normal individuals. During the incubation period (usually 12 to 72 hours), the organisms traverse the small bowel, penetrate colonic epithelial cells, and multiply intracellularly. An acute inflammatory response ensues in the colonic mucosa attended by prodromal symptoms (Table 342-1) . Epithelial cells containing bacteria are lysed, resulting in superficial ulcerations and shedding of shigella organisms into stools. The mucosa is friable and covered with a layer of polymorphonuclear leukocytes. Biopsy specimens show ulcers and crypt abscesses. Initially, the inflammation is confined to the rectosigmoid colon but after about 4 days of illness may advance to involve the proximal colon and sometimes even the terminal ileum; a pseudomembranous type of colitis may develop. Levels of proinflammatory cytokines are elevated in stool and plasma and correlate with disease severity. Diarrhea results because of impaired absorption of water and electrolytes by the inflamed colon. Although the colonic inflammation is superficial, bacteremia occurs occasionally, especially in S. dysenteriae 1 infections. Susceptibility of organisms to serum complement-mediated bacteriolysis may explain the infrequency of bacteremia and disseminated infection. Colonic perforation is a rare complication during toxic megacolon. Children with severe colitis due to S. dysenteriae 1 are prone to develop the hemolytic-uremic syndrome. In this complication, fibrin thrombi are deposited in the renal glomeruli, causing cortical necrosis and fragmentation of red cells.

CLINICAL MANIFESTATIONS. Most patients with shigellosis begin their illness with a non-specific prodrome (see Table 342-1) . The height of the temperature varies, and children may have febrile convulsions. The initial intestinal symptoms soon follow as cramps, loose stools, and watery diarrhea, which usually precede the onset of dysentery by 1 or more days. The average fecal output is about 600 g/day for adults. The dysentery consists typically of flecks and small clots of bright red blood and mucus in stools that are small in volume. Frequency of passage is often as high as 20 to 40 times a day, with excruciating rectal pain and tenesmus during defecation. Some patients develop rectal prolapse during severe straining. The amount of blood in stools varies widely but usually is small because of the superficial colonic ulcerations. Abdominal tenderness is often most marked in the left lower quadrant over the sigmoid colon but also may be generalized. The fever is likely to abate after a few days of dysentery, making afebrile bloody diarrhea an occasional clinical presentation. After 1 to 2 weeks of untreated disease, spontaneous improvement occurs in most patients. Some patients with mild disease develop only watery diarrhea without dysentery.

Complications include dehydration, which can cause death, especially in children and the elderly. Shigella septicemia occurs mainly in malnourished children with S. dysenteriae 1 infections. The leukemoid reaction and hemolytic-uremic syndrome may develop in children late in the course after antimicrobial treatment when the dysentery has started to improve. Neurologic manifestations can be striking and include delirium, seizures, and nuchal rigidity. The important postdysenteric syndromes are arthritis and Reiter's triad of arthritis, urethritis, and conjunctivitis (see Chapter 287) . These are non-suppurative phenomena that occur in the absence of viable Shigella organisms 1 to 3 weeks after resolution of dysentery.

DIAGNOSIS. Shigellosis should be considered in any patient with acute onset of fever and diarrhea. Examination of the stool is essential. Blood and pus are grossly apparent in severe bacillary dysentery; even in milder forms of the disease, microscopic examination of the stool often reveals numerous leukocytes and erythrocytes. The fecal leukocyte examination should be performed with a portion of liquid stool, preferably containing mucus. A drop of stool is placed on a microscopic slide, mixed thoroughly with two drops of methylene blue, and overlaid with a coverslip. The presence of abundant polymorphonuclear leukocytes helps distinguish shigellosis from diarrheal syndromes caused by viruses and enterotoxigenic bacteria. The fecal leukocyte examination is not helpful in distinguishing shigellosis from diarrheal illnesses caused by

STAGE

TABLE 342-1 -- EVOLUTION OF CLINICAL SYNDROMES IN SHIGELLOSIS TIME OF APPEARANCE AFTER SYMPTOMS AND SIGNS ONSET OF ILLNESS

PATHOLOGY

Prodrome

Earliest

Fever, chills, myalgias, anorexia, nausea, vomiting

None or early colitis

Non-specific diarrhea

0-3 days

Abdominal cramps, loose stools, watery diarrhea

Rectosigmoid colitis with superficial ulceration, fecal leukocytes

Dysentery

1-8 days

Frequent passage of blood and mucus, tenesmus, rectal prolapse, abdominal tenderness

Colitis extending sometimes to proximal colon, crypt abscesses, inflammation in lamina propria

Complications

3-10 days

Dehydration, seizures, septicemia, leukemoid reaction, hemolytic-uremic syndrome, ileus, peritonitis

Severe colitis, terminal ileitis, endotoxemia, intravascular coagulation, toxic megacolon, colonic perforation

Postdysenteric syndromes

1-3 weeks

Arthritis, Reiter's syndrome

Reactive inflammation in HLA-B27 haplotype

1687

other invasive enteric pathogens (non-typhoidal Salmonella, Campylobacter, and Yersinia). Amebic dysentery is excluded by the absence of trophozoites on a microscopic examination of fresh stool under a coverslip. The peripheral white cell count is of little diagnostic value, because it may range from less than 3000 to more than 30,000/mm3 . Sigmoidoscopic examination reveals diffuse erythema with a mucopurulent layer and friable areas of mucosa with shallow ulcers 3 to 7 mm in diameter. Definitive diagnosis depends on isolating shigellae by selective media. A rectal swab, a swab of a colonic ulcer obtained by sigmoidoscopic examination, or a freshly passed stool specimen should be inoculated immediately on culture plates or into carrying media. Because isolation rates of shigellae from freshly passed stools of patients with shigellosis may be as low as 67%, culturing for 3 successive days is recommended. Stool cultures are generally positive within 24 hours after onset of symptoms and may remain positive for several weeks in the absence of antimicrobial therapy. Appropriate culture media include blood, desoxycholate, and Salmonella-Shigella (S-S) agars. Selected colonies should be diagnosed by agglutination with polyvalent Shigella antisera. S-S agar is inhibitory for S. dysenteriae 1. Definitive bacteriologic diagnosis becomes critically important for distinguishing the more severe and prolonged cases of shigellosis from ulcerative colitis, with which it may be confused both clinically and on sigmoidoscopic examination. Patients with shigellosis have been subjected to colectomy because of a mistaken diagnosis of ulcerative colitis; a positive culture should prevent such a misadventure.

TREATMENT. Appropriate antimicrobial therapy instituted early may decrease the duration of symptoms by 50% and decrease the duration of excretion of shigellae (an important epidemiologic factor) by a far greater percentage. Because of the increasing frequency of plasmid-mediated antimicrobial resistance to Shigella infections, surveillance of drug susceptibility in an endemic area is important. In adults, ciprofloxacin given orally in a dose of 500 mg twice daily for 5 days or 1 g as a single dose is the treatment of choice when the susceptibility of a strain is unknown. In children, treatment should be trimethoprim-sulfamethoxazole, ampicillin, or azithromycin, depending on susceptibilities of Shigella in a given location. Fluid losses in shigellosis are qualitatively similar to those in other infectious diarrheal diseases, and the patient should be treated with appropriate intravenous or oral electrolyte repletion fluids in quantities adequate to correct clinical signs of saline depletion. The requirement for fluids is generally small, but fluid repletion is lifesaving in exceptional cases. Agents that decrease intestinal motility should not be used. Such preparations as diphenoxylate and paregoric may exacerbate symptoms, presumably by retarding intestinal clearance of the microorganisms. There is no convincing evidence that pectin- or bismuth-containing preparations are helpful.

PROGNOSIS. The mortality rate in untreated shigellosis depends on the infectious strain and ranges from 10 to 30% in certain outbreaks caused by S. dysenteriae 1 to less than 1% in most S. sonnei infections. Even with infection caused by S. dysenteriae 1, mortality rates should approach zero if appropriate fluid replacement and antimicrobial therapy are initiated early. About 2% of patients may develop arthritis or Reiter's syndrome weeks or months after recovery from shigellosis.

PREVENTION. Individuals excreting shigellae should be excluded from all phases of food handling until negative cultures have been obtained from three successive stool specimens collected after completion of antimicrobial therapy. In institutional outbreaks, strict and early isolation of infected individuals is mandatory. Targeted antimicrobial chemoprophylaxis has been disappointing. The most important control measure is rigorous hand washing with soap and water by all individuals involved in handling of food or changing diapers. Reporting of shigellosis cases to health authorities should be mandatory. For the traveler to countries with major Shigella problems, no chemoprophylactic agent is an adequate substitute for good personal hygiene and avoiding contaminated food and water. A variety of vaccines has been developed and tested, but no vaccine is now commercially available. Bogaerts J, Verhaegen J, Munyabikali JP, et al: Antimicrobial resistance and serotypes of Shigella isolates in Kigali, Rwanda (1983-1993): Increasing frequency of multiple resistance. Diagn Microbiol Infect Dis 28:165, 1997. Emergence of multidrug resistance, including resistance to nalidixic acid in S. dysenteriae 1, in infected refugees posed threats to effective therapy. Khan WA, Seas C, Dhar U, et al: Treatment of shigellosis: V. Comparison of azithromycin and ciprofloxacin. Ann Intern Med 126:697, 1997. Azithromycin and ciprofloxacin were equally effective against multiresistant infections in Bangladesh. Kolavic SA, Kimura A, Simons SL, et al: An outbreak of Shigella dysenteriae type 2 among laboratory workers due to intentional food contamination. JAMA 278:396, 1997. In Texas, 12 laboratory personnel became ill after ingesting muffins and doughnuts that had been deliberately contaminated by an unusual laboratory stocked

strain. Pulsed-field gel electrophoresis of isolated strains confirmed the likely source of the outbreak. Raqib R, Wretlind B, Andersson J, et al: Cytokine secretion in acute shigellosis is correlated to disease activity and directed more to stool than to plasma. J Infect Dis 171:376, 1995. Proinflammatory cytokine levels were elevated in stool and plasma during acute disease, whereas interferon-gamma was below normal levels. Tauxe RV, Puhr ND, Wells JG, et al: Antimicrobial resistance of Shigella isolates in the USA: The importance to international travelers. J Infect Dis 162:1107, 1990. In the United States, resistance of Shigella isolates to trimethoprim-sulfamethoxazole occurred in 4% of domestically acquired cases and 20% of travel-related cases. Wharton M, Spiegel RA, Horan JM, et al: A large outbreak of antibiotic-resistant shigellosis at a mass gathering. J Infect Dis 162:1324, 1990. Poor sanitation at a camp site in Tennessee led to an attack rate of more than 50% in several thousand attendees; disease was caused by multiresistant S. sonnei.

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Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 343 - CAMPYLOBACTER ENTERITIS Richard L. Guerrant

Enteric infection with a member of the genus Campylobacter usually results in an inflammatory, occasionally bloody diarrhea or dysentery syndrome in industrialized, temperate areas. Campylobacter jejuni is often the most commonly recognized cause of community-acquired inflammatory enteritis. The diarrhea also may be watery, especially in developing, tropical areas. An enterocolitis or protocolitis syndrome similar to that seen with C. jejuni is also seen in homosexual males with several " Campylobacter-like organisms," that are now being classified as Helicobacter species such as H. cinaedi, H. fennelliae and others. Like C. jejuni, these Campylobacter-like organisms may cause life-threatening bacteremic infections in patients with the acquired immunodeficiency syndrome. The other major Campylobacter species that infects humans is C. fetus, a relatively uncommon cause of bacteremia and occasional intravascular infection in immunocompromised hosts. Helicobacter pylori (the cause of gastritis and peptic ulcers) was once called Campylobacter pylori, but is now reclassified.

ETIOLOGY. Campylobacter (meaning "curved rod") is a curved or spiral, motile, non-spore-forming, gram-negative rod measuring 1.5 by 3.5 mum that is distinguished from Enterobacteriaceae by its inability to ferment or oxidize carbohydrates. It was once called a "vibrio," but is now recognized as a separate genus on the basis of its distinctive DNA content. It is both oxidase and catalase positive and is a microaerophilic organism that requires reduced oxygen (5 to 10%) and increased carbon dioxide (3 to 10%). The organism does not grow at either aerobic or strictly anaerobic conditions. Perhaps reflecting its avian reservoir, C. jejuni also requires an increased temperature to 42° C for optimal growth. C. jejuni is distinguished from C. fetus by its higher growth temperatures, cephalothin resistance, and nalidixic acid sensitivity. As shown in Table 343-1 , the additional Campylobacter species that infect humans include C. lari, a thermophilic organism commonly found in healthy sea gulls that has been reported in children with mild recurrent diarrhea and in an elderly patient with sepsis and terminal multiple myeloma. The weak or non-catalase-producing C. upsaliensis may cause diarrhea or bacteremia, and C. hyointestinalis, like C. fetus, causes occasional bacteremia in compromised hosts. These organisms are also inhibited by cephalothin that is in some selective culture media. Like C. fetus, the Campylobacter-like organisms ( H. cinaedi, H. fennelliae, others) do not grow at 42° C or in the presence of cephalosporin antibiotics (present in some selective media for C. jejuni) and may require several days to grow on microaerophilic subcultures on blood agar. C. jejuni is further subdivided into over 90 serotypes on the basis of heat-stable somatic 1688

SPECIES

TABLE 343-1 -- HUMAN CAMPYLOBACTER INFECTIONS GROWTH RESERVOIR TEMPERATURE

CLINICAL MANIFESTATIONS

C. jejuni/coli

37-42° C

Poultry, mammals

Common cause of dysentery/diarrhea

C. fetus (sub. sp. fetus, old sub sp. intestinalis)

25-37° C

Cattle, sheep

Uncommon, bacteremia; intravascular infections in debilitated hosts

C. laridis

30-42° C

Sea gulls

Uncommon, childhood diarrhea, one case of sepsis

C. upsaliensis

37-42° C

Dogs

Occasional diarrhea

C. hyointestinalis

37° C

Swine

Occasional bacteremia in compromised hosts

" Campylobacter-like organisms": (including Helicobacter cinaedi, H. fennelliae)

37° C

?

Proctocolitis, rarely sepsis, in homosexual males

lipopolysaccharide O antigens or some 112 heat-labile flagellar and cellular antigens or even additional subtypes based on phage restriction DNA or ribosomal RNA digests, all markers that are helpful in tracing the epidemiology of this common enteric pathogen.

EPIDEMIOLOGY. Although the frequency of other Campylobacter infections is either low or unclear. C. jejuni infections are extremely common throughout the world. In many studies, the frequency of Campylobacter enteritis exceeds that of Salmonella or Shigella infections, and it has been estimated that as many as 2 million Campylobacter enteritis cases occur annually in the United States. The reservoirs of C. jejuni/coli include a wide range of mammalian species. Between 30 and 100% of chickens, turkeys, and water fowl may be infected asymptomatically in their intestinal tracts, and commercially prepared poultry in supermarkets can often be shown to be culture positive. In addition, swine, cattle, sheep, horses, and even household pets and rodents may carry C. jejuni, C. coli, or C. fetus. Dogs and cats are more likely to be infected with C. upsaliensis. Enteric symptoms may be found, particularly in puppies, kittens, calves, or lambs, which may have diarrhea when infected. Furthermore, the organisms survive days to weeks in fresh or salt water and in milk and are killed most effectively by pasteurization, chlorination, drying, or freezing. The transmission of Campylobacter infections is likely via the fecal-oral route. Fecal-oral spread may occur by contact among animals, those practicing oral-anal sex, and those in day-care centers. Secondary transmission is relatively infrequent, and the infectious dose appears to vary from 500 to over 1 million organisms. The majority of infections are probably acquired by ingesting contaminated food, water, or milk vehicles. Many cases and outbreaks are associated with ingesting inadequately cooked poultry, unpasteurized milk, inadequately treated water, and even cake icing, salads, beef, and clams. The majority of those infected in well-described outbreaks are symptomatic. Asymptomatic infection appears to be relatively infrequent in temperate climates and in adults. An exception is among young children in certain tropical developing areas such as Bangladesh, where as many as 39% of children younger than age 2 years may be infected asymptomatically (Table 343-2) . These frequent asymptomatic infections in tropical areas raise important questions about possible strain differences in virulence, host susceptibility, and protective immunity against disease that might be acquired very early in developing areas. Throughout the world, Campylobacter infections appear to predominate during the warmer or wet season. As with diarrheal illnesses in general, the highest age-specific attack rate is in young TABLE 343-2 -- CLINICAL PRESENTATIONS OF CAMPYLOBACTER JEJUNI INFECTION INDUSTRIALIZED COUNTRIES DEVELOPING COUNTRIES Percent of all diarrhea with C. jejuni

5-13

2-35

Fecal polymorphonuclear leukocytes

78-93

22-46

Blood in stool

60-65

5-17

100

Adenovirus 33 Influenza

3 (type A subtypes change)

Echovirus

31

Coxsackievirus Group A

23

Group B

6

From Hendley JO: Immunology of viral colds. In Veldman JE, McCabe BF, Huizing EH, Mygind N (eds.): Immunobiology, Autoimmunity, Transplantation in Otorhinolaryngology. Amsterdam, Kugler Publications, 1985, pp 257-260.

1791

Figure 375-1 Schematic diagram of the incidence of colds and frequency of the causative viruses.

months. Influenza viruses appear later in winter, then rhinovirus has a resurgence in spring. Summer colds are usually caused by rhinovirus or one of the enteroviruses. The wave of each virus moving through is not sharp, and many times two or three viruses may be overlapping. Adenovirus and parainfluenza virus type 3 contribute to the burden of illness throughout the epidemic. Determinants of this yearly epidemic of colds are not established but certainly include human behavior, with more virus transmitted by higher indoor contact in colder months. Another determinant might be attributes of the viruses. Enveloped viruses, including RSV, parainfluenza virus, influenza virus, and coronavirus, may survive outside the host for longer periods in winter when the relative humidity of indoor (but not outdoor) air is very low. Transmission of viruses causing colds could occur by one or more of three mechanisms: (1) small-particle (10 mu in diameter) airborne droplets that travel less than 1 m and infect by landing on a mucosal surface such as conjunctiva or nasal mucosa, and (3) direct transfer of virus in secretions via hand contact from a person with a cold to a well person, who inoculates the virus onto his or her own conjunctival or nasal mucosa. Oral inoculation of rhinovirus or RSV does not result in infection, presumably because the

stratified squamous epithelium of the mouth and oropharynx is not susceptible. The transmission route under natural conditions in the home has not been definitely established for any of the viruses. However, the importance of spread of colds in the home favors direct contact and/or large-droplet spread as being most likely. Influenza virus clearly can be transmitted by small-particle aerosol in some circumstances.

PATHOGENESIS. It had been assumed until recently that the symptoms of colds were produced by a viral cytopathic effect destroying the nasal mucosa. However, one recent study found that the histologic appearance of the nasal mucosa in biopsy specimens taken during natural colds could not be distinguished from that of biopsy specimens taken 2 weeks after illness except for an increased number of polymorphonuclear leukocytes (PMNs) during illness. The unexpected infiltration of PMNs in the nose in uncomplicated colds was confirmed in another study; the number of PMNs in nasal secretions increased coincidently when symptoms appeared in experimentally induced rhinovirus colds. Rhinovirus and coronavirus, in contrast to influenza virus and adenovirus, were not found to be destructive of nasal epithelium in organ cultures in vitro. Because mucosal damage by the virus during colds does not adequately explain the symptoms, the hypothesis that the viral infection of the nose triggers a cascade of inflammatory mediators that results in the symptoms is being explored. Initial support for this hypothesis was provided in volunteers with experimentally induced rhinovirus colds. Kinins (primarily bradykinin) and PMNs appeared in nasal secretions of infected volunteers at the time that they became ill, and their presence paralleled cold symptoms. More recent work has suggested that viral infection of individual epithelial cells in the mucosa of the nose and nasopharynx can lead to elaboration of cytokines that effect the symptomatic illness and influx of PMNs. Infected cells have been shown to elaborate interleukin (IL)-8, which is a chemoattractant for PMNs. Increased levels of IL-1beta, IL-6, and IL-8 have been detected in nasal secretions during colds. Whether the release of proinflammatory cytokines from the host cells induced by the viral infection can be interrupted has not been ascertained. However, the concept that it might be possible to ablate cold symptoms by blocking the mediators of the host response without having to kill the virus is exciting.

CLINICAL MANIFESTATIONS. The clinical manifestations of colds, which are familiar to all, are predominately subjective. In adults, rhinorrhea, nasal obstruction, and scratchy/sore throat are usually noted. The rhinorrhea is usually clear early in illness and may become white or yellow-green. Some malaise and non-productive cough are common; sneezing is noted in some colds. Other common symptoms include sinus fullness and a "nasal" quality to the voice. Hoarseness is sometimes present. Objective findings in an adult with a cold are usually minimal. The nasal mucosa may be red but not to a degree that differs from normal. Mild erythema of the pharynx and redness around the external nares from nose blowing may be noted. Fever (>38° C) is uncommon in a cold in an adult; the presence of fever would suggest influenza or a bacterial complication of the cold. The symptoms of the cold usually abate in 5 to 7 days. Colds in infants and children may be associated with more objective signs than in adults. In addition to rhinorrhea and nasal obstruction, moderate enlargement of the anterior cervical lymph nodes is frequent. Fever during the first 2 to 3 days of a cold in young children is not unusual, even when the child's parent or older sibling does not have an elevated temperature during the cold due to the same virus. In contrast to in adults, the usual duration of cold symptoms in children is 10 to 14 days.

DIAGNOSIS. Self-diagnosis of a cold by the patient is usually accurate. Laboratory tests including white blood cell count and differential are not helpful. Sloughed ciliated cells may be present, and PMNs would be expected in nasal secretions during viral colds. The differential diagnosis of a cold includes an intranasal foreign body in a child and allergic or vasomotor rhinitis in adults and children. Examination of the nose should exclude a foreign body; the chronicity of symptoms with allergic or vasomotor rhinitis should differentiate these conditions from an acute cold. Etiologic (virologic) diagnosis of a cold can be attempted by inoculation of a sample of nasal secretions into tissue cell cultures, but this is rarely needed or useful. Rhinovirus can be grown in human embryonic lung fibroblast cultures. Coronavirus infections have been diagnosed by serologic titer rise because coronaviruses cannot be detected accurately in cell culture. Assays using polymerase chain reaction for detection of rhinovirus and coronavirus have been developed that will facilitate diagnosis of these infections. Influenza and parainfluenza viruses can be grown in primary rhesus monkey kidney cell culture, and adenoviruses will grow in human embryonic kidney cells. RSV antigen in nasal secretions can be reliably detected with commercially available rapid tests. In addition, a new test for detection of the nucleoprotein of influenza virus A appears to be useful as a rapid screen for this virus.

TREATMENT. Given the self-limited nature of colds, any treatment should be completely safe. Antibiotics have no place in therapy for uncomplicated colds, because they neither hasten nor delay recovery from the cold, nor do they reduce the frequency of bacterial complications. 1792

Figure 375-2 Sinus CT scan of adult during symptomatic cold (left panel) and 2 weeks later (right panel). Arrow in the left panel denotes an infraorbital air cell (Haller cell). Bilateral abnormalities were observed in the ethmoid and maxillary sinuses during the cold, with an air-fluid interface in the right maxillary sinus. Two weeks later, all abnormalities had cleared except for a residual density in the right maxillary sinus. The infundibulum (two arrows) draining the maxillary antrum was now open. (Courtesy of Dr. Jack M. Gwaltney, Jr., Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia).

Because the subjective symptoms of a cold disappear in 7 days without intervention, a variety of actually ineffective treatments have been reported to be effective due to inadequate blinding of placebo recipients. One example of this phenomenon was a study of large doses of vitamin C to prevent colds, in which many placebo recipients dropped out of the study because they could tell by tasting the medication that they were not receiving the vitamin C. Another example was the use of zinc gluconate lozenges as an antiviral treatment for colds. In the blinded trial, the only appropriate placebo that could be found to match the noxious taste of the zinc was denatonium benzoate, which is so bitter that it has been painted on the thumbs of children to discourage them from thumb-sucking. No antiviral agents are currently available for treating colds. Individual symptoms may be treated. Malaise may be relieved by analgesics (e.g., aspirin, acetaminophen, ibuprofen). Nasal congestion may be relieved by decongestants by mouth (pseudoephedrine, 60 mg, three times a day) or by topical application (oxymetazoline 0.05%, two sprays to each nostril twice daily). Oral first-generation antihistamines (e.g., brompheniramine, chlorpheniramine, clemastine) may provide modest relief of sneezing and rhinorrhea in colds.

COMPLICATIONS. Secondary bacterial infection may complicate viral colds. The most common is bacterial suppurative otitis media, which occurs in some 5% of colds in preschool-aged children. Otitis media may be heralded by a secondary fever with associated ear pain. Bacterial sinusitis is estimated to occur in 0.5% of colds, primarily in adults. Sinusitis would be suggested by the presence of fever and/or facial pain (see Chapter 515) . Bacterial pneumonia is thought to complicate colds, but it is very uncommon. Clinical differentiation between primary viral and secondary bacterial infection of the respiratory tract is a challenge, because respiratory viruses may involve the middle ear or paranasal sinuses in the absence of bacterial infection. Tympanocentesis or maxillary sinus puncture provides definitive information on viral versus bacterial infection, but these are too invasive for routine use. Coronal computed tomography (CT) is an accurate non-invasive method for imaging the paranasal sinuses. Recent work using CT has demonstrated that abnormalities in the sinuses may occur in colds not complicated by secondary bacterial infection. Coronal CT in 27 (87%) of 31 young adults during uncomplicated colds had abnormalities in one or more sinuses (Fig. 375-2) . In 11 (79%) of the 14 subjects who had repeat scans 2 weeks later, the abnormalities had cleared or were markedly improved without antibiotic therapy. An important complication of viral colds occurs in adults and children with underlying reactive airways disease or asthma. Wheezing occurs in 30 to 50% of episodes of viral colds in prospective studies of patients with asthma. Colds in these patients produce a large burden of illness, because up to 50% of asthma exacerbations in children and up to 20% of exacerbations in adults have been associated with an identified virus.

PREVENTION. Vaccine(s) to prevent common colds are unlikely to be useful given the multiplicity of immunotypes of some of the viruses and the lack of solid immunity to reinfection with the other viruses (see Table 375-1) . Prophylaxis with topical interferon applied intranasally for 5 days after one family member appears with a cold has been shown to be moderately effective in preventing other family members from acquiring a cold, particularly colds due to rhinovirus. The practicality of this preventive

approach may be argued, particularly in view of the fact that prolonged use of intranasal interferon is complicated by alteration or damage of the nasal mucosa. Probably the only practical, albeit imperfect, means of preventing colds available is to prevent virus from reaching the nasal or conjunctival mucosa by way of one's own hands. If transmission occurs by inhalation of airborne small particles or by adherence of large droplets to a mucosal surface, infection is inevitable for those who enjoy contact with other humans. However, if transmission occurs by self-inoculation with virus on contaminated fingertips, the simple measure of ridding the fingers of viable virus before touching one's eye or nose might be helpful. The virus can be removed physically by rinsing the hands. Applying a virucide to the hands might be another approach. Arruda E, Pitkaranta A, Witek TJ Jr, et al: Frequency and natural history of rhinovirus infections in adults during autumn. J Clin Microbiol 35:2864, 1997. Use of PCR in addition to cell culture demonstrated that 80% of colds in the fall were caused by rhinovirus. Gwaltney JM Jr, Phillips CD, Miller RD, et al: Computed tomographic study of the common cold. N Engl J Med 330:25, 1994. Sinus CT during naturally acquired common colds demonstrated that one or more of the sinuses was abnormal in more than 80% of subjects. Most abnormalities had cleared on repeat scan after the cold was over. Hendley JO: Epidemiology, pathogenesis, and treatment of the common cold. Semin Pediatr Infect Dis 9:50, 1998. Review of differences in colds in children versus adults and of recent work on pathogenesis of symptoms. Pattemore PK, Johnston SL, Bardin PG: Viruses as precipitants of asthma symptoms: I. Epidemiology. Clin Exp Allergy 22:325, 1992. Review of evidence incriminating viral respiratory infections as common precipitants of wheezing. Rhinovirus and RSV were most commonly associated with episodes of wheezing, but all respiratory viruses have been found. Winther B. Gwaltney JM, Hendley JO: Respiratory virus infection of monolayer 1793

cultures of human nasal epithelial cells. Am Rev Respir Dis 141:839, 1990. Growth of rhinovirus and coronavirus in nasal epithelial cells produced no visible destruction of the epithelial layer, whereas influenza and adenovirus produced obvious disruption.

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Chapter 376 - VIRAL PHARYNGITIS, LARYNGITIS, CROUP, AND BRONCHITIS Maurice A. Mufson

DEFINITION. Viral infections that localize to the upper and middle respiratory passages produce an acute inflammatory response and, depending on the anatomic site involved, evoke the clinical manifestations of pharyngitis, laryngitis, croup (laryngotracheobronchitis), and bronchitis. These infections do not ordinarily involve the pulmonary alveoli. Pharyngitis, laryngitis, and bronchitis can occur in persons of any age. Croup occurs exclusively in children and mainly during the second year of life. Usually these illnesses begin abruptly with predominant upper respiratory tract signs and symptoms and limited systemic findings. Mainly uncomplicated illnesses, they abate after 5 to 10 days.

ETIOLOGY. The viral pathogens of the respiratory tract that cause pharyngitis, laryngitis, croup, and bronchitis include members of the myxoviruses (influenza, parainfluenza, and respiratory syncytial viruses), adenoviruses, coronaviruses, picornaviruses (rhinoviruses and enteroviruses), and herpesviruses (Table 376-1) . However, they differ in their propensity to cause these illnesses (Table 376-2) . An etiologic diagnosis requires either isolation of virus or detection of viral antigen or demonstration of a rise in antibody during convalescence. Such diagnostic studies infrequently need to be done in advance of beginning treatment. Pharyngitis also can occur as part of systemic viral illnesses associated with Epstein-Barr virus (see Chapter 387) or cytomegalovirus (see Chapter 386) infection, and laryngitis and bronchitis can occur in measles virus infection (see Chapter 381) . When coryza represents the main feature of an upper respiratory infection, the term common cold (see Chapter 375) prevails. When influenza virus is the infecting virus, the designation influenza describes an acute respiratory tract infection with fever and systemic features (see Chapter 379) .

INCIDENCE AND PREVALENCE. Most children and adults experience three to five viral infections of the upper respiratory tract each year. In infants and children, croup is a serious illness that peaks in the second year of life, as high as 47 cases per 1000 children per year, and by age 4 to 5 it declines to under 15 cases per 1000 children per year.

EPIDEMIOLOGY. Viral pharyngitis, laryngitis croup, and bronchitis occur during all months of the year, in parallel with the occurrence of individual viruses. Respiratory syncytial virus, influenza A and B viruses, and parainfluenza virus type 1 occur in epidemics, mainly in the late fall, winter, and spring (see Table 376-3) . The other viral pathogens occur endemically or sporadically. Virus infections of the respiratory tract spread mainly by

VIRUS

TABLE 376-1 -- VIRUSES THAT CAUSE PHARYNGITIS, LARYNGITIS, CROUP, AND BRONCHITIS SEROTYPE

Influenza

Types A, B,

Parainfluenza

Types 1, 2, 3

Respiratory syncytial

Subgroups A, B1, B2

Adenovirus

Types 1, 2, 3, 4, 5, 6, 7 (also others)

Coronavirus

Types 229E, OC43 (also others)

Rhinovirus

Most or all of more than 100 serotypes

Enterovirus

At least some of more than 75 serotypes

Herpes simplex

Type 1

TABLE 376-2 -- RELATIVE IMPORTANCE OF VIRUSES CAUSING PHARYNGITIS, LARYNGITIS, CROUP, AND BRONCHITIS VIRUS OCCURRENCE IN INDICATED ILLNESS* Pharyngitis Laryngitis Croup Bronchitis Influenza A

++++

++++

++

++

++

++

++++

++

2

+

+

+++

+

3

++

++

++++

++

+

+++

B Parainfluenza 1

Respiratory syncytial

+

+

++++ ++

Adenovirus

++++

++

++

Coronavirus

+

+

+++

Rhinovirus

+

+

+

Enterovirus

+

Herpes simplex

+

*Graded from minimal (+) to major (++++) importance; blank means unlikely occurrence; and ± means rare occurrence.

direct person-to-person contact, and less commonly by infectious aerosols and fomites.

CLINICAL MANIFESTATIONS. VIRAL PHARYNGITIS.

+

+

Acute viral pharyngitis is characterized by a scratchy and sore throat, but pain on swallowing is not a prominent or constant feature. Dysphagia occurs infrequently in viral pharyngitis. Cough is not a feature of acute viral pharyngitis. Pharyngeal erythema and enlarged tender lymph nodes may be the only physical findings. Fever and malaise often accompany influenza and adenovirus infections; they infrequently occur with the other respiratory virus infections. Adenovirus pharyngitis may be associated with conjunctivitis. Exudative tonsillitis occurs in adenovirus infections, infectious mononucleosis associated with Epstein-Barr virus infection, herpetic pharyngitis (with or without vesicles or small ulcers), as well as streptococcal pharyngitis. Bronchospasm occurs as a feature of herpes tracheobronchitis in elderly persons. VIRAL LARYNGITIS. In acute viral laryngitis, hoarseness predominates, associated with difficulty in talking, pain on clearing respiratory secretions, and often fever, depending on the infecting virus. Cough and pharyngitis may be present. The larynx appears erythematous and edematous, and the regional lymph nodes show slight enlargement and tenderness. Wheezes may be audible on auscultation. VIRAL CROUP. The clinical picture of croup characteristically includes inspiratory stridor, hoarseness, and a brassy cough. This distinctive triad of symptoms reflects the acute and intense edema and mucoid exudative secretions of the larynx and associated obstruction of the subglottic portion of the upper airway. These symptoms develop acutely, accompanied by fever, cough, tachypnea, and wheezing. Retractions of the chest wall occur. Hemoptysis does not occur. Rhonchi, rales, or wheezes, alone or in combination, may be audible on auscultation of the lungs. Radiographic examination of the neck can demonstrate subglottic narrowing, and views of the chest can show hyperinflation of the lungs. In the uncomplicated case, the findings resolve in several days, but some children develop respiratory failure and pneumonia. Children who experience multiple episodes of croup may as an adolescent or adult manifest bronchial hyperreactivity and peripheral airways obstruction. TABLE 376-3 -- EPIDEMIOLOGY OF VIRUSES THAT CAUSE PHARYNGITIS, LARYNGITIS, CROUP, AND BRONCHITIS EPIDEMIC ENDEMIC SPORADIC Parainfluenza 1 *

Parainfluenza 3

Parainfluenza 2

Influenza A

Adenovirus

Herpes simplex

Influenza B

Coronavirus

Respiratory syncytial

Rhinovirus Enterovirus

*Alternate years, usually. Epidemic and pandemic. Annual epidemics.

1794

TABLE 376-4 -- ANTIVIRAL DRUG THERAPY OF VIRUSES THAT CAUSE PHARYNGITIS, LARYNGITIS, CROUP, AND BRONCHITIS VIRUS DRUG DOSE (DURATION) Influenza A

ROUTE

Amantadine * 200 mg daily (7-10 days)

Oral

Rimantidine

200 mg daily (7-10 days)

Oral

*

Respiratory syncytial

Ribavirin

20 mg/mL solution (administered over 12-18 hours for 3-7 days)

Aerosol

Herpes simplex

Acyclovir

8 mg/kg q8h (7-10 days)

IV

*More commonly used for prophylaxis at same daily dose over longer periods of time until the virus leaves the community. In patients with hepatic dysfunction or renal failure and elderly nursing home residents, the dose for treatment and for prophylaxis is 100 mg/day. Herpes simplex tracheobronchitis treated with intravenous acyclovir.

VIRAL BRONCHITIS. In acute viral bronchitis, cough, with or without sputum production, and fever are the main features. The sputum is slightly mucoid or watery and white. Other symptoms and signs include hoarseness, non-pleuritic substernal chest pain, malaise, rhonchi, and rales. The chest roentgenogram may show increased intensity of the vascular pattern, but not pulmonary infiltrates. Acute bronchitis associated with influenza or coronavirus infection occurs often as an exacerbation of chronic bronchitis. Persons with chronic respiratory disease suffer more severe exacerbations.

TREATMENT AND PROGNOSIS. Viral pharyngitis, laryngitis, and bronchitis are self-limited illnesses and not severe, except for herpes tracheobronchitis infections. The symptoms of these illnesses should be treated with analgesics, fluids, and rest. Persistent cough can be treated with suppressant preparations. Antibiotics are not indicated. Secondary bacterial infection complicates mainly influenza virus infection; it should be treated with antibiotics. In pharyngitis, pharyngeal pain or dysphagia should be treated with analgesics and fluids. Less serious cases of croup can be managed by having the child rest in bed at home and use a room vaporizer. Children with severe croup require hospitalization, supportive treatment, and constant monitoring for the development of respiratory distress. If hypoxemia develops, oxygen therapy is essential; hypoxemia requiring oxygen can develop even before cyanosis becomes evident. Subglottic edema may be reduced by the administration of racemic epinephrine. Some children with moderately severe croup may show reduced severity of their illness within 24 hours after a single intramuscular injection of dexamethasone (0.6 mg/kg). Antiviral drug therapy is available for influenza A, respiratory syncytial, and herpes simplex viruses (Table 376-4) . Ribavirin lessens the severity of serious respiratory syncytial virus infection in the infant and child. Herpes tracheobronchitis responds to treatment with acyclovir. Influenza virus vaccine must be administered to persons in high-risk groups (unless contraindicated) to diminish the chance of infection. Cruz MN, Stewart G, Rosenberg N: Use of dexamethasone in the outpatient management of acute laryngotracheitis. Pediatrics 96:220, 1995. In most children with moderately severe croup, a single intramuscular injection of dexamethasone reduces severity within 24 hours. Mancao MY, Sindel LJ, Richardson PH, Silver FM: Herpetic croup: Two case reports and a review of the literature. Acta Paediatr 85:118, 1996. Herpesvirus is an infrequent cause of croup. Marx A, Torok TJ, Holman RC, et al: Pediatric hospitalizations for croup (laryngotracheobronchitis): Biennial increases associated with human parainfluenza virus 1 epidemics. J Infect Dis 176:1423, 1997. Major epidemics of parainfluenza 1 virus occur in alternate (odd-numbered) years and are associated with croup illnesses. Mufson MA. Akerlind-Stopner B, Orvell C, et al: A single season epidemic with respiratory syncytial virus subgroup B2 during 10 epidemic years, 1978 to 1988. J Clin

Microbiol 29:162, 1991. Annual winter-spring epidemics of respiratory syncytial virus. Subgroup A predominated. One third to one half of infections were limited to the upper respiratory tract. Wiselka MJ, Kent J, Cookson JB, Nicholson KG: Impact of respiratory virus infection in patients with chronic chest disease. Epidemiol Infect 111:337, 1993. Adults with chronic chest disease suffer worse symptoms due to virus infections of the respiratory tract.

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Chapter 377 - RESPIRATORY SYNCYTIAL VIRUS Edward E. Walsh

DEFINITION. Respiratory syncytial virus (RSV) causes yearly outbreaks of illness during the fall, winter, and early spring. Since its discovery in 1957, RSV has been found to be the single most important cause of bronchiolitis and pneumonia in young infants and is a common cause of upper respiratory illness in older children and young adults. In addition, RSV is a cause of serious respiratory infection in the elderly, adults with underlying cardiopulmonary disease, and those who are severely immunocompromised.

ETIOLOGY. RSV is an enveloped virus of the family Paramyxoviridae, genus Pneumovirus. The single-stranded negative-polarity RNA encodes 10 proteins, of which 8 are found in purified virions. Three transmembrane glycoproteins (G, attachment protein; F, fusion protein; SH protein) protrude from a lipid bilayer encompassing three nucleocapsid proteins (N, P, polymerase) complexed with the genome. Two additional proteins (M, M2) are associated with the viral envelope. Neutralizing antibodies are directed at F and G glycoproteins, whereas F, N, and M2 are targets for cytotoxic T cells. Two major virus groups (A and B), each with four to five subgroups, are distinguishable by antigenically divergent G proteins.

EPIDEMIOLOGY. Similar to influenza, worldwide RSV outbreaks occur annually. In the United States, epidemics generally begin in the southern states in late fall, move steadily north, and peak in February and March in colder climates. RSV causes approximately 90,000 hospitalizations and accounts for 60% of bronchiolitis and 25% of pneumonia cases in infants in the United States. In the first year of life, over half of all infants become infected, with the remainder infected the following year. Family studies suggest that schoolchildren introduce RSV into the home with subsequent spread to parents and younger siblings, with infection rates of 43% and 62%, respectively. Like rhinovirus (see Chapter 375) , RSV is transmitted principally by direct contact with large-particle fomites from respiratory secretions, in contrast to the primary mode of spread of influenza virus, aerosolization. Approximately 0.5% of infected infants require hospitalization, but underlying prematurity, congenital cardiac abnormalities, bronchopulmonary dysplasia, and immunosuppression significantly increase the risk of serious disease. Hospitalization is most frequent between the ages of 1 to 6 months, with a median age of 2 months. Maternally derived antibody appears to protect in the first month of life when serious lower respiratory symptoms are infrequent, but this benefit is rather brief. Reinfection occurs frequently throughout life, although illness is less severe and hospitalization infrequent, except for those with underlying cardiac or pulmonary conditions. Although often not considered in adults, RSV infection in certain populations may be severe. RSV has been identified as a relatively common cause of community-acquired pneumonia in adults, ranking third behind pneumococcus and influenza in one large study. Elderly persons appear to be at highest risk, and nosocomial outbreaks in nursing homes are common. In addition, RSV infection has been associated with about 10% of hospitalizations for cardiopulmonary deterioration in the winter among community-dwelling elderly. RSV infection in severely immunocompromised adults, such as bone marrow transplant recipients and those with acute leukemia undergoing cytotoxic chemotherapy, often results in very high morbidity and mortality. Both RSV groups usually co-circulate during outbreaks, although group A strains usually dominate and are associated with more severe disease in hospitalized infants. Evidence suggests that strain variation alone does not solely account for reinfections. Partial immunity to RSV develops over time, as indicated by the resistance to both infection and illness. Experimental studies suggest that immunopathologic mechanisms, principally mediated by T helper cells, and their cytokines, contribute to disease manifestations.

CLINICAL MANIFESTATIONS. After an incubation period of 3 days, previously uninfected infants develop upper respiratory symptoms. Conjunctival injection, mucopurulent nasal discharge, cough, 1795

and low-grade fever (38° C) are typical and indistinguishable from other respiratory infections. Otitis media occurs commonly, generally in association with bacteria. After several days, lower respiratory tract symptoms develop in 25 to 50% of infants. Cough, wheezing, increased respiratory rate, accessory muscle use, intercostal retractions, and cyanosis are seen as the disease progresses. Expiratory wheezes, rhonchi, and fine rales are the most common findings on lung examination. Sudden apnea may develop in the youngest infants. Mortality for otherwise healthy children is about 1% in hospitalized infants but can reach 37% in infants with cardiac disorders. Hyperinflation and diffuse interstitial pneumonitis are the most frequent radiographic findings. Infiltrates are usually diffuse, but consolidation is seen in up to one fourth. Virus is shed from respiratory secretions for 7 to 10 days, although immunocompromised infants (i.e., those with human immunodeficiency virus infection) may excrete virus for a month or longer. Interestingly, clinical symptoms may not correlate with prolonged shedding. Co-infection with other respiratoy viruses is not uncommon but is not clinically discernible. Should bacterial superinfection develop, with Streptococcus pneumoniae and Haemophilus influenzae the most frequent organisms isolated, treatment with antibiotics is indicated. Long-term sequelae of lower respiratory tract infection include development of childhood asthma, although the precise contributions of RSV infection and allergic predisposition are unknown. Normal adults typically manifest nasal discharge, pharyngitis, and low-grade fever, and virus is shed for an average of 3 days. Elderly persons with RSV infection may develop cough, dyspnea, fever, wheezing, and, in some cases, respiratory failure. Adults most at risk of severe infection are the frail elderly, those with underlying chronic obstructive pulmonary disease or congestive heart failure, and those with severe immunocompromise. Attack rates are variable in nosocomial outbreaks in nursing homes, averaging 10 to 15%. Rales and wheezes are evident in one third of patients, and radiographically confirmed pneumonia is noted in approximately 10%. Symptoms are similar among community-dwelling elderly, and infection can lead to exacerbation of underlying congestive heart failure or chronic bronchitis. RSV infection has been documented in up to 10% of bone marrow transplant recipients and those with acute leukemia during the winter months. The illness begins with upper respiratory symptoms but frequently spreads to the lower respiratory tract. If RSV infection occurs before marrow engraftment, pneumonia will develop in half with an attendant mortality of 90%. Notably, this is somewhat higher than the mortality with influenza virus pneumonia in this population. Chest radiographs demonstrate diffuse interstitial and alveolar infiltrates. A useful clinical clue to the presence of RSV is the almost universal presence of radiographically proven sinusitis. The presence of upper respiratory tract symptoms distinguishes this illness from cytomegalovirus pneumonia.

DIAGNOSIS. In the pediatric setting, a presumptive diagnosis is suggested by typical symptoms occurring during the epidemic season. In adults, the diagnosis is often never considered. Because the clinical picture of RSV is indistinguishable from illness caused by other infectious agents of respiratory disease, laboratory confirmation of RSV infection is required, especially if antiviral therapy is contemplated. In infants, RSV is readily grown from respiratory secretions on HEp-2, human diploid fibroblast,

and HELA cell lines. The sensitivity of viral culture is about 75%. Rapid diagnostic tests rely on detecting viral antigen or RNA in respiratory secretions. Immunofluorescence (IF) is a widely used test and has a sensitivity of about 80%, whereas commercial enzyme immunoassay (EIA) is less sensitive and less specific than IF. Serologic diagnosis can be made but is not useful in immediate management. Reverse transcription-polymerase chain reaction (RT-PCR) is more sensitive than culture but is not comercially available. In normal adults, diagnostic tests, with the exception of serology, are significantly less sensitive: approximately 50% for virus culture and 10% or less for IF and EIA antigen detection. In immunocompromised adults, detection of RSV antigen in throat swabs by EIA is only 15% sensitive, but it is 90% sensitive when bronchoalveolar lavage specimens are used.

THERAPY AND PREVENTION. Therapy for hospitalized infants includes hydration, oxygen, bronchodilators, and specific antiviral medication. Severely ill infants are commonly dehydrated and require intravenous fluid. Supplemental oxygen, administered as a humidified mist, should be given to all infants with hypoxia. The value of bronchodilators for the treatment of wheezing is controversial, because most studies have not demonstrated clear benefit, but a trial of inhaled bronchodilators is probably indicated. Specific antiviral therapy is currently limited to inhaled ribavirin (1-beta- D-ribafuranosyl-1,2,4-triazole-3-carboxamide), a nucleoside analogue with activity against several RNA viruses. Ribavirin is administered via aerosol, typically for 4 hours three times a day for 3 to 5 days, although longer therapy has been used. High-dose, short-duration (2 hours three times daily) treatment is considered equivalent. Some placebo-controlled clinical trials demonstrate more rapid resolution of respiratory symptoms and hypoxia. The majority of infants do not require therapy, but ribavirin treatment may be indicated for infants at high risk of serious disease and those who are severely ill. Although short- or long-term toxicity of ribavirin has not been recognized, hospital personnel and family members of patients should minimize exposure to the drug and pregnant health care workers should avoid exposure altogether. Inhaled ribavirin has also been used in treatment of immunocompromised adults with RSV pneumonia. Although results from controlled trials are not available, anecdotal data suggest benefit, but only if therapy is begun before respiratory failure develops. Finally, intravenous high-titer RSV immunoglobulin or humanized monoclonal antibody has demonstrated benefit when administered prophylactically to high-risk infants with underlying cardiopulmonary disease or prematurity. Immunoglobulin, in combination with inhaled ribavirin, has been used in treatment of RSV pneumonia in immunosuppressed adults. Adherance to standard infection-control principles (e.g., gloves, gowns, and frequent hand washing) can substantially reduce nosocomial spread. A vaccine for prevention of RSV is not available, although both inactivated purified subunit and live attenuated vaccines are in clinical trials. Committee on Infectious Diseases: Reassessment of the indications for ribavirin therapy in respiratory syncytial virus infections. Pediatrics 97:137-140, 1996. Recommendations by clinical virology experts on appropriate use of aerosolized ribavirin in infants. Dowell SF, Anderson LJ, Gary HE, et al: Respiratory syncytial virus is an important cause of community-acquired lower respiratory infection among hospitalized adults. J Infect Dis 174:456-462, 1996. Clinical epidemiology of RSV as a cause of community-acquired pneumonia in adults. Englund JA, Piedra, PA, Whimbey E: Prevention and treatment of respiratory syncytial virus and parainfluenza viruses in immunocompromised patients. Am J Med 104:61-70, 1997. Review of studies describing RSV infection and treatment in immunocompromised adults. Falsey AR, Cunningham CK, Barker WH, et al: Respiratory syncytial virus and influenza A infections in the hospitalized edlerly. J Infect Dis 172:389-394, 1995. Prospective description of RSV and influenza virus infection in elderly hospitalized with cardiopulmonary deterioration. Falsey AR, Treanor JJ, Betts RF, Walsh EE: Viral respiratory infection in the institutionalized elderly: Clinical and epidemiologic findings. J Am Geriatr Soc 40:115, 1992. This prospective study of respiratory illness in a long-term care facility describes clinical features of RSV infection in the elderly with comparison with other viral pathogens.

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Chapter 378 - PARAINFLUENZA VIRAL DISEASE Edward E. Walsh

DEFINITION. Parainfluenza viruses are important causes of a wide spectrum of respiratory illness in infants and young children, producing syndromes ranging from the common cold and otitis media to severe croup, bronchiolitis, and pneumonia. In older children and adults, illness is usually limited to the upper respiratory tract, although immunocompromised individuals may develop fatal respiratory failure.

ETIOLOGY. The parainfluenza viruses are enveloped single-stranded non-segmented RNA viruses and belong to the family Paramyxoviridae, which also includes measles, mumps, and respiratory syncytial viruses (RSV). The genome encodes for six structural proteins, of which the hemagglutinin-neuraminidase (HN) and fusion proteins (F) are exposed on the bilayered lipid envelope that 1796

TYPE

TABLE 378-1 -- PARAINFLUENZA PATTERNS SEASON

MANIFESTATION

COMMENTS

1

Epidemic croup

Fall of odd-number years

Since 1970

2

Epidemic croup

Fall or early winter

Less predictable than type 1; less widespread

3

Epidemic bronchitis and pneumonia

Late winter, early spring

Recently epidemic; often following influenza season; low levels of virus year-round

4

Unknown

?

Mild illness; frequently unrecognized

surrounds a helical nucleocapsid-RNA complex. The two surface proteins, which mediate attachment and penetration of the virus into susceptible mammalian cells, have retained antigenic stability for more than 30 years. There are four serotypes of human parainfluenza viruses, types 1 through 4, with two subgroups (A and B) of type 4 virus. In addition, numerous animal strains of parainfluenza viruses exist, including shipping fever virus of cattle and Newcastle disease virus of chickens, important causes of lost income for the livestock industry. These viruses do not cause human illness.

EPIDEMIOLOGY. The parainfluenza viruses are ubiquitous and have worldwide geographic distribution. Spread principally by large-particle fomites and close person-to-person contact, each of the four serotypes displays somewhat different epidemiologic features. Over the years, parainfluenza virus activity has displayed both endemic and epidemic patterns (Table 378-1) . Primary infection with parainfluenza viruses begins soon after birth, with each serotype favoring different age groups and distinct clinical syndromes. Significant overlap exists in this regard, thus precluding specific diagnosis based on clinical and epidemiologic grounds. Among the parainfluenza viruses, type 3 infects infants first, with more than 50% showing serologic evidence of infection in the first year of life. Parainfluenza virus type 3 is second only to RSV as a cause of bronchiolitis and pneumonia in this youngest age group. Parainfluenza virus type 1, which exhibits characteristic epidemiology with biennial outbreaks in the fall of odd-numbered years, and type 2 infections occur later in childhood between ages 2 through 6. The peak incidence of infection with parainfluenza virus 1, manifested principally as croup, occurs between ages 1 and 2. The lower infection rate with parainfluenza type 1 and 2 viruses in very young infants suggests that maternally derived antibody is protective, in contrast to parainfluenza virus type 3 infection, in which maternal antibody has only limited benefit. After primary infection, a relatively brief period of immunity against homotypic reinfection develops; however, the fact that reinfections are common later in childhood highlights the lack of durable immunity.

CLINICAL MANIFESTATIONS. Illness associated with primary parainfluenza virus infection varies by age and the virus serotype, although substantial overlap occurs. Underlying medical conditions, such as cardiopulmonary or immune disorders, also will influence the severity of disease. In general, parainfluenza virus types 1 and 2 are associated with croup whereas parainfluenza virus type 3 causes bronchiolitis and pneumonia. Other causes of croup include influenza A and RSV. Infection typically starts with upper respiratory signs and symptoms, notably coryza, rhinorrhea, pharyngitis without cervical adenopathy, and low-grade fever. In 15%, signs of lower respiratory tract disease develop. If croup evolves, the child manifests a raspy, barking cough with notable inspiratory stridor, dyspnea, and respiratory distress. These latter symptoms, which may be spasmodic, are due to subglottic inflammation and edema. Typically, in mild to moderate illness symptoms last 3 to 5 days but may be quite unpredictable and result in sudden respiratory failure. In hospitalized infants, hypoxia is universal, and hypercarbia is present in half. In severe stridor, differentiation from epiglottis due to Haemophilus influenzae type b (see Chapter 330) may be suggested by lateral neck radiography, which can show subglottic edema and narrowing, in contrast to epiglottic swelling. Although also a cause of croup, parainfluenza virus type 3 more commonly causes disease indistinguishable from RSV: tracheobronchitis, bronchiolitis, and pneumonia. Cough, rales, and wheezing associated with hypoxia and air trapping on radiography are common. Reinfection with the parainfluenza viruses is less severe and typically causes cold symptoms in normal children and adults. However, similar to the situation with RSV, some adults may develop severe disease. Nursing home outbreaks with a high incidence of pneumonia have been reported, and parainfluenza viruses have been implicated in severe pneumonia in immunocompromised children and adults. In a report of more than 1000 bone marrow transplant recipients, 61 parainfluenza virus infections were documented; of these patients 44% developed pneumonia and 27% died, with most having had preceding upper respiratory symptoms. This latter finding is clinically useful in distinguishing parainfluenza virus pneumonia from cytomegalovirus pneumonia in this group. Many of the parainfluenza infections in immunosuppressed persons are acquired nosocomially. Similar to RSV infection, the most severe illnesses and 90% of the deaths due to parainfluenza virus pneumonia occur in the first 100 days after transplantation when lymphopenia is most pronounced. Fever, cough, shortness of breath, and sputum production are the most common symptoms, whereas bilateral pulmonary infiltrates are the most common radiographic finding.

DIAGNOSIS. Although the clinician may suspect parainfluenza virus based on clinical and epidemiologic grounds, specific diagnosis requires isolating the virus or detecting viral antigen in respiratory secretions. Monkey kidney or human embryonic kidney cell cultures are optimal for virus recovery, generally in 5 to 10 days, with the exception of type 4 virus, which requires up to 3 weeks in culture. Indirect immunofluorescent tests are also available for rapid antigen detection and, although specific, are less sensitive than culture. Diagnosis of parainfluenza infection in adults may be more difficult than in children, but virus can usually be recovered from the nasal or

pharyngeal secretions of bone marrow transplant recipients with pneumonia and also generally from bronchoalveolar specimens in this group.

THERAPY AND PREVENTION. Specific antiviral treatment for parainfluenza virus is currently unavailable. Aerosolized ribavirin, approved for use in RSV infection, has in vitro activity against the parainfluenza viruses. Uncontrolled studies of ribavirin therapy of immunocompromised children and adults with severe parainfluenza virus pneumonia suggest possible benefit when administered at a dose of 20 mg/mL for 12 to 20 hours per day for 7 to 14 days. Treatment of croup in children, under usual circumstances, includes mist and supplemental oxygen. Aerosolized bronchodilators (racemic epinephrine) have definite but only transient benefit, whereas corticosteroid use is controversial. Antibiotics are indicated only when bacterial superinfection is documented, an uncommon occurrence. Immunization to prevent parainfluenza virus infection with live attenuated vaccines is under study. Lewis, VA, Champlin R, Englund J, et al: Respiratory disease due to parainfluenza virus in adult bone marrow transplant recipients. Clin Infect Dis 23:1033-1037, 1996. Clinical description of parainfluenza viurs infections in bone marrow transplant patients. Marx A, Torok TJ, Holman RC, et al: Pediatric hospitalizations for croup (laryngotracheobronchitis): Biennial increases associated with human parainfluenza virus 1 epidemics. J Infect Dis 176:1423-1427, 1997. Describes the epidemiology and associated clinical illness of parainfluenza virus infections in the United States from 1979 to 1993. Reed G, Jewett PH, Thompson J, et al: Epidemiology and clinical impact of parainfluenza virus infections in otherwise healthy infants and young children < 5 years old. J Infect Dis 175:807-813, 1997. This report describes the epidemiology and clinical characteristics of parainfluenza virus infection among outpatient infants and children during a 20-year period at a single center.

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1797

Chapter 379 - INFLUENZA Frederick G. Hayden

Influenza is an acute febrile respiratory illness that occurs in annual outbreaks of varying severity. The causative virus infects the respiratory tract, is highly contagious, and typically produces prominent systemic symptoms early in the illness. Influenza virus infection can produce various clinical syndromes in adults, including common colds, pharyngitis, tracheobronchitis, and pneumonia. Conversely, infections with other respiratory viruses, such as respiratory syncytial virus or adenovirus, may produce influenzal illness. Influenza A viruses can cause worldwide epidemics (pandemics) and have done so four times this century (Table 379-1) . The pandemic of 1918-1919 caused at least 500,000 deaths in the United States and over 20 million worldwide. Influenza epidemics are associated with enormous morbidity, economic loss, and often substantial mortality. Each epidemic causes on average over 20,000 deaths and about 150,000 hospitalizations in the United States.

ETIOLOGY. Influenza viruses belong to the family Orthomyxoviridae and are divided into three types (A, B, and C) distinguished by the antigenicity of their internal and external proteins (Table 379-2) . The virion (Fig. 379-1) is a medium-sized enveloped pleomorphic particle covered with two types of surface glycoprotein spikes, the hemagglutinin (H or HA) and neuraminidase (N or NA). The envelope is composed of a lipid bilayer overlying the matrix (M1) protein that surrounds the segmented viral genome. The genome comprises eight segments of single-stranded RNA. Influenza C viruses have seven segments and only a single surface glycoprotein. Whereas influenza B and C viruses are human pathogens, influenza A viruses infect diverse animal species, including birds, horses, swine, and marine mammals. Influenza A viruses are further classified into subtypes based on their HA and NA glycoproteins. Each strain within a subtype is identified by site, sample number, and year of isolation. Three hemagglutinins (H1, H2, and H3) and two neuraminidases (N1 and N2) have been recognized in human influenza A viruses. In addition, in 1997 an avian H5N1 subtype virus caused a cluster of severe illnesses in humans in Hong Kong, and cases of avian H9N2 subtype virus infection have been recently documented in humans.

EPIDEMIOLOGY. ANTIGENIC VARIATION. Influenza viruses are unique among the respiratory viruses with regard to their extent of antigenic variation, epidemic behavior, and association with excess mortality during community outbreaks. The changing antigenicity of the surface glycoproteins accounts in part for the continuing epidemics of influenza in humans. Antibody to the HA neutralizes viral infectivity and thus is the major determinant of immunity. Anti-NA antibody limits viral replication and therefore the severity of infection. Variation involves either relatively minor (antigenic drift) or major (antigenic shift) changes in antigenicity. Significant antigenic variation is much less frequent with influenza B than with influenza A and may not occur with influenza C. Antigenic drift refers to small changes that occur frequently (every year or every few years) within an influenza A or B virus. For example, the original H3N2 variant, A/Aichi/68, has undergone successive drifts resulting in epidemic strains that include the recent circulation of A/Sydney/5/97-like viruses. Antigenic drift results from an accumulation of point mutations in the RNA segment coding for the HA that cause amino acid substitutions in at least one of five antigenic sites on the HA. Immunologic selection favors the new variant over the old for transmission because of the less frequent presence of antibody in the population to the new virus. Antigenic shift results from the appearance of an influenza A virus with HA or with HA and NA glycoproteins new to humans or possible reappearance of virus after decades of absence. Because of the lack of immunity to the new strain within the human population, a virulent new strain can cause pandemic disease (see Table 379-1) . Infection by one subtype does not provide cross-protection against another. The origin of new pandemic strains and the basis for their apparent recirculation remain incompletely defined. Reassortment of gene segments may occur when two influenza viruses simultaneously infect a single cell. At least 15 HA and 9 NA subtypes exist in animal influenza A viruses, particularly aquatic birds, and these serve as the reservoir or new genes for human pandemic strains. Although avian influenza viruses generally do not cause infections directly in humans, bird to human transmission of an avian H5N1 subtype virus has been documented. Spread from swine and other animals to humans rarely occurs. EPIDEMIC OR INTERPANDEMIC INFLUENZA. An "epidemic" is an outbreak of influenza confined to one geographic location. In a given community, epidemics of influenza A virus infection have a characteristic pattern. They usually begin rather abruptly, reach a sharp peak in 2 or 3 weeks, and last 6 to 10 weeks. Increased numbers of school children with febrile respiratory illness are often the first indication of influenza in a community. This is soon followed by illnesses among adults and about a week later by increased hospital admissions of patients with influenza-related complications. Hospitalization rates in high-risk persons increase two- to fivefold during major epidemics (Table 379-3) . School and employment absenteeism increases, as does mortality from pneumonia and influenza, especially in older persons (see Table 379-3) . The latter finding is a highly specific indicator of influenza activity. Epidemics occur almost exclusively during the winter months in temperate areas but influenza activity may continue year-round in the tropics. Regional differences in the time of occurrence of influenza outbreaks are common, and major outbreaks may occur in some communities or regions whereas others are experiencing no activity whatsoever. During epidemics, the overall attack rates typically average 10 to 20%. Attack rates of 40 to 50% are not uncommon in closed populations, including hospital and nursing homes, and in certain highly susceptible age groups. In recent years it has been recognized that two different strains within a single subtype, two different influenza A subtypes (H1N1 and H3N2), or both influenza A and B viruses may co-circulate. In addition, simultaneous outbreaks of influenza A and respiratory syncytial viruses have been found. Strains circulating at the end of one season's epidemic are likely to be responsible for the next season's outbreak (the so-called herald wave phenomenon). Furthermore, other than the association of influenza outbreaks with colder seasons, the factors are unknown that allow an epidemic to develop or those responsible for the tapering off of an epidemic, when only some susceptible persons have been infected. Pneumonia and influenza (P + I)-related deaths fluctuate annually, with peaks in the winter months. When such P + I deaths

YEAR

TABLE 379-1 -- ANTIGENIC SUBTYPES OF INFLUENZA A VIRUS ASSOCIATED WITH PANDEMIC INFLUENZA INTERVAL (YEARS) DESIGNATION EXTENT OF ANTIGENIC CHANGE IN INDICATED SURFACE PROTEIN* SEVERITY OF PANDEMIC

1889

?

H2N2

?

Severe

1900

11

H3N8?

H+++N?

Moderate

1918

18

H1N1

H+++N+++

Very severe

1957

39

H2N2

H+++N+++

Severe

1968

11

H3N2

H+++N-

Moderate

1977

9

H1N1

H+++N+++

Mild §

*Compared with antecedant or co-circulating virus: + = minor change; ++ = moderate change; +++ = major change; - = no change. Formerly designated as H0N1 (swine virus prototype) or Hsw1N1. Population had some immunity to the N2 neuraminidase. §Most of population immune due to prior infection with earlier circulating antigenically identical virus.

1798

DESIGNATION

TABLE 379-2 -- INFLUENZA VIRUS PROTEINS LOCATION (APPROXIMATE NO. PER FUNCTION OTHER VIRION)

Hemagglutinin (HA)

Surface (500)

Cell attachment and penetration; fusion activity

Subtype- and strain-specific antigens

Neuraminidase (NA)

Surface (100)

Virus release; enzymatic activity

Subtype- and strain-specific antigens; site of action of zanamivir, GS4071

Membrane or M1 matrix

Internal (3000)

Major structural envelope protein; virus assembly

Type-specific antigen

M2

Surface (20-60)

Virus uncoating and assembly; ion channel

Site of action of amantadine/rimantadine

Nucleoprotein (NP)

Internal (1000)

Associated with RNA and polymerase Type-specific antigen proteins

Polymerases (PB1, PB2, Internal (30-60) PA)

RNA replication and transcription

Probable site of action of ribavirin

NS1

Nonstructural (infected cells)

Regulation of virus replication

Interferon antagonist

NEP

Internal (130-200)

Nuclear export factor

Formerly NS2

Adapted from Lamb RA, King RM: Orthomyxoviridae. In Fields BN, Knipe DM, Howley PM (eds): Fields Virology, 3rd ed. Philadelphia, Lippincott-Raven, 1996, p 1355. exceed the predicted number, this is due to influenza A or occasionally to influenza B virus or respiratory syncytial virus activity. Although mortality is greatest during pandemics, substantial total mortality occurs with epidemics. Over 85% of P + I deaths occur among persons aged 65 and older (see Table 379-3) . Other cardiopulmonary and chronic diseases also show increased mortality after influenza epidemics. PANDEMIC INFLUENZA. Pandemics of influenza A result from the emergence of a new virus capable of sustained person-to-person transmission and to which the population contains no or limited immunity. The virus spreads worldwide and infects persons of all ages (see Table 379-1) . The pandemics of 1957, 1968, and 1977 all began in mainland China, and Southeast Asia has been postulated to be the epicenter for such strains. The interval between pandemics is variable and unpredictable. The most severe pandemics have resulted when there were major antigenic alterations in both the major surface antigens. Furthermore, it appears that virulence is a virus-coded function that also varies among strains. The intrinsic virulence of recent H1N1 viruses appears to be milder than that of H3N2 viruses. After one or more waves of pandemic influenza, the level of immunity in the population increases. Repeated epidemics caused by strains showing antigenic drift within the subtype occur in subsequent years. After 10 to 40 years of circulation of variants within this given subtype, the population's

Figure 379-1 Diagram of influenza virus structure. Eight segments of viral RNA are contained within the envelope and matrix (M1) shell. Each codes for one or two proteins that form the virus or regulate its intracellular replication. The presumed functions of each are listed in Table 379-2 . (Courtesy of Dr. Robert G. Webster.)

immunity to all variants within the subtype is very high, and the conditions for the emergence of a new virus are favorable.

PATHOGENESIS AND PATHOLOGY. Influenza virus infection is transmitted from person to person by virus-containing respiratory secretions. Small-particle aerosols appear most important, but transmission by other routes, including fomites, may be possible. Virtually all cells lining the respiratory tract can support viral replication. Once the virus initiates infection of the respiratory tract epithelium, successive cycles of viral replication infect large numbers of cells and result in destruction of ciliated epithelium. The incubation period averages 2 days and varies from 1 to 4 days. The quantity of virus in respiratory tract specimens correlates with severity of illness, which suggests that a major mechanism in producing illness is virally mediated cell death. Elevations of proinflammatory cytokines like interferon-alpha, interleukin-6, and tumor necrosis factor-alpha occur in blood and respiratory secretions and may contribute to systemic symptoms and fever. The duration of viral shedding depends on age and generally lasts for 3 to 5 days in adults and often into the second week in children. Viremia or extrapulmonary dissemination is rarely found. Nasal and bronchial biopsy specimens from persons with uncomplicated influenza reveal desquamation of the ciliated columnar epithelium. Individual cells show shrinkage, pyknotic nuclei, and loss of cilia. In addition, the lungs in fatal influenza show extensive hemorrhage, hyaline membrane formation, and paucity of polymorphonuclear (PMN) cell infiltration. Secondary bacterial infections develop as a result of altered bacterial flora, damage to bronchial epithelium with depressed mucociliary clearance, decreased PMN and alveolar macrophage functions, and/or alveolar fluid. Neutralizing, hemagglutination-inhibiting (HAI), antineuraminidase, complement-fixing, enzyme-linked immunosorbent assay (ELISA), and immunofluorescent antibodies begin to develop in the sera of persons with primary influenza virus infection during the second week after infection and reach a peak by 4 weeks. Secretory antibodies develop in the respiratory tract after influenza infection and consist predominantly of IgA antibodies that reach peak titers in 14 days. Cell-mediated immune responses also occur. Immunity

AGE (YEARS)

TABLE 379-3 -- AGE-SPECIFIC RATES FOR ILLNESS AND MORTALITY DURING URBAN INFLUENZA EPIDEMICS PHYSICIAN VISITS PER 100 ARD HOSPITALIZATIONS PER 10,000 P + I MORTALITY PER 100,000

1 mL) or laboratory materials containing high viral titers Definite parenteral exposure Deep intramuscular injury with a needle contaminated with blood or a body fluid

Recommended

Small volume injection of blood or body fluid ( 400 cells per microliter at the time of enrollment), and were followed for a median of 53 months. Table 412-1 shows the diseases and their rates per 100 person-years of observation in the PCHIS. Because an HIV-negative control group made up of subjects from the two largest HIV transmission categories (homosexual/bisexual men and injecting drug users [IDUs]) was included, it was demonstrated that acute bronchitis, a disorder not usually regarded as opportunistic, is significantly more common among HIV-infected persons. It should be noted that because there were no study centers in areas in which histoplasmosis and coccidioidomycosis are endemic, there were few instances of these relatively common fungal infections of the lung noted in the cohort. This observation raises an important point: the spectrum of HIV-associated lung diseases varies with geographic location as well as with severity of immune compromise and the demographic (including transmission category) make-up of the HIV-infected population in any given medical center or geographic area. TABLE 412-1 -- CUMULATIVE FREQUENCY OF DISEASES WITH RESPIRATORY TRACT INVOLVEMENT IN A COHORT OF PERSONS WITH HIV INFECTION (INCLUDES MULTIPLE EPISODES PER PERSON) DIAGNOSIS EPISODES PER 100 PERSON-YEARS Acute bronchitis

9.72

Pneumocystis carinii pneumonia

5.65

Bacterial pneumonia

5.63

Nontuberculous mycobacterial diseases

0.74

Interstitial lung disease

0.60

Pulmonary tuberculosis

0.58

Cytomegalovirus

0.42

Kaposi's sacroma

0.33

Lymphoma

0.19

Cryptococcosis

0.16

RELATIONSHIP OF RESPIRATORY TRACT DISEASES TO CD4+ LYMPHOCYTE COUNT, DEMOGRAPHIC CHARACTERISTICS, AND TRANSMISSION CATEGORY PCP is the most common lung disease in persons with CD4+ counts < 200 cells per microliter. However, in the PCHIS, 11 (6%) cases of PCP occurred in persons with CD4+ lymphocyte counts > 200 cells per microliter. The patients with higher counts were marked by having other HIV-associated symptoms or findings such as fever, unintentional weight loss, oral thrush, and lymphadenopathy. Other lung diseases that usually occur only in persons with advanced HIV infection include fungal infections, pulmonary Kaposi's sarcoma (KS), lymphoma, and nontuberculous mycobacterial infections. In the case of Mycobacterium avium complex, it is difficult to determine if the organism is actually causing lung disease or is simply colonizing the airways. Thus, the frequency of M. avium complex lung disease is difficult to

establish. The same difficulty applies to determining the frequency of cytomegalovirus (CMV) pulmonary disease. It is not yet known if the increase in CD4+ count that occurs with combination antiretroviral therapy is associated with a reduction in risk of opportunistic infections or a change in their relative frequency. Both demographic characteristics and HIV transmission category bear some relationship to the frequency of various lung diseases. Bacterial pneumonia tends to be more common among IDUs (with or without HIV infection) than in the other HIV transmission categories. Presumably, this relates, at least in part, to the effects of opiates on ventilation, cough, and ability to protect the airway. Tuberculosis is also more common in IDUs. Injection drug use had been shown to be a risk factor for tuberculosis prior to the HIV epidemic, so the finding of an increased amount of tuberculosis among drug users with HIV infection is not surprising. Data from the PCHIS have shown that whites have a higher rate of PCP than blacks. Although the basis for this is unknown, the finding is consistent with the observation that PCP is rare in Africa. It has generally been assumed that the rarity of P. carinii in Africa is related to the organism being less common in the environment. However, the finding of a racial difference in risk suggests that genetic factors may play a role in predisposing whites to or protecting blacks from the disease.

CLINICAL FEATURES OF HIV-ASSOClATED DISORDERS OF THE RESPIRATORY TRACT Disorders Not Necessarily Associated with Severe Immune Suppression Bronchitis

Acute bronchitis in the PCHIS was defined by the presence of cough with sputum production for at least 48 hours and a chest film that showed either no or stable parenchymal infiltrations occurring in a study subject who did not develop an identified pulmonary infection. Evaluations to attempt to determine the microbial cause of the bronchitis were not performed in the PCHIS. It was the general impression of the investigators that the illness tended to be self-limited but recurrent. Not surprisingly, bronchitis was more common among cigarette smokers. Airways disease may be recognized on plain chest films by the presence of peribronchial thickening (Fig. 412-2 A) and is more clearly seen on computed tomographic (CT) scans, especially thin-section scans (Fig. 412-2 B). In addition, bronchiectasis may also occur without a recognized antecedent lung infection (Fig. 412-3) . Bronchiectasis may also be a sequela of bacterial lung infection or, occasionally, PCP. Although in the PCHIS cohort the episodes of acute bronchitis were neither associated with nor portended any other significant pulmonary diseases, the disorder may be problematic in that the symptoms may be mistaken as an indication for further, often invasive, evaluations. In general, however, bronchitis is recognizable by the absence of parenchymal infiltrations on chest films and, thus, when the constellation of symptoms and findings described previously is noted, one should, generally, simply observe the patient, with or without antimicrobial therapy, and not undertake further evaluations. 1913

Figure 412-2 Bronchitis in HIV infection. A, A frontal view chest radiograph showing peribronchial thickening, right lower lung zone (arrows) consistent with bronchitis. B, A high-resolution CT scan of the chest showing bilateral peribronchial thickening (arrows) consistent with bronchitis. (Courtesy of Dr. James Gruden, Department of Radiology, San Francisco General Hospital.)

Bacterial Pneumonia (see related chapter for each infection in Part XXII)

As shown in Table 412-1 , bacterial pneumonia occurred at a rate of 5.63 episodes per 100 person-years of observation in the PCHIS cohort. Bacterial pneumonia was defined as the presence of cough that was productive of purulent sputum, an area of parenchymal infiltration on chest film, and a response to antimicrobial therapy. A specific causative agent was identified in 35% of cases, a proportion that is consistent with the results of studies of the etiology of community-acquired pneumonia in persons without HIV infection. Of the episodes for which the cause was established, Streptococcus pneumoniae accounted for 67% and Haemophilus influenzae 15%. These two agents have been generally ranked first and second in most reports of bacterial pneumonia in persons with HIV infection. In most reports, Staphylococcus aureus has been the third most common agent and seems to be especially common among persons with pulmonary KS. A long list of other bacterial pathogens has also been described as causing pneumonia in the setting of HIV infection (Table 412-2) . Bacterial pneumonia, especially pneumococcal pneumonia, commonly tends to be associated with bacteremia and, occasionally, sepsis syndrome. Other than the high frequency of bacteremia, the mode of clinical presentation of bacterial pneumonia does not differ in persons with and without HIV infection. Pneumonias caused by S. pneumoniae and H. influenzae tend to present as an acute illness of short duration characterized by fever, chills, and productive cough. Lobar consolidation is the most common finding on chest radiographs, and pleural fluid may be present.

Figure 412-3 High-resolution CT scan of the chest of the patient whose films are shown in Figure 365-2. The scan is at a lower level and shows dilated airways with thickened walls indicative of bronchiectasis (horizontal arrows) and areas of mucus plugging and infiltration (vertical arrows). (Courtesy of Dr. James Gruden, Department of Radiology, San Francisco General Hospital.)

The diagnostic evaluation should include sputum Gram stain and culture, Gram stain and culture of pleural fluid if present, and blood cultures. Antimicrobial therapy should be guided by the usual principles for treating infectious disorders. The response to therapy should be prompt and comparable to the response of nonimmunocompromised patients. Clinicians should have a low threshold for initiating further diagnostic evaluations if the response is not prompt or is incomplete or there is worsening after an initial response. In a retrospective review of pneumococcal pneumonia in patients with HIV infection, all patients who failed to respond to usual antimicrobial therapy had superimposed PCP. Another feature of HIV-associated bacterial pneumonia is the tendency for recurrence. This may be related to the failure to generate protective antibodies to infecting organism or to bronchiectasis. Tuberculosis

Because M. tuberculosis is a very pathogenic organism, little or no immune compromise is needed for tuberculosis to develop. For this reason, tuberculosis tends to occur earlier in the course of HIV disease than diseases caused by less pathogenic organisms. The degree of immunosuppression present in a given patient has an important influence on the clinical features of tuberculosis in the presence of HIV infection, as described in Table 412-3 . Persons with HIV infection and relatively well-preserved immune function tend to have "typical" features of tuberculosis, whereas tuberculosis that occurs among persons with advanced HIV disease commonly involves extrapulmonary sites and has diffuse lung infiltration with no cavitation and hilar and mediastinal adenopathy (Fig. 412-4) . In terms of symptoms, tuberculosis may present as an acute illness or as a more indolent progressive process. When the lungs are involved, sputum smears and cultures are as likely to be positive in persons with HIV infection as in non-HIV-infected patients. However, TABLE 412-2 -- REPORTED CAUSES OF BACTERIAL PNEUMONIA IN PERSONS WITH HIV INFECTION Streptococcus pneumoniae Haemophilus influenzae Staphylococcus aureus Nonpneumococcal streptococci Pseudomonas aeruginosa Moraxella catarrhalis Rhodococcus equi Neisseria meningitidis

Legionella species Nocardia species Actinomyces species

1914

TABLE 412-3 -- FEATURES OF TUBERCULOSIS IN PATIENTS WITH HIV INFECTION EARLY IN HIV DISEASE Clinical course

LATE IN HIV DISEASE

More indolent

More acute

Fewer systemic symptoms/signs

Systemic symptoms/signs may predominate

Sites of disease

Predominantly pulmonary

Predominantly extrapulmonary and disseminated

Chest film

Upper lobe cavitary lesions

Diffuse or lower lobe infiltration Adenopathy Occasionally normal when lungs involved

Tuberculin test

Usually positive

Usually negative

Sputum smear/culture

Usually positive

Usually positive in patients with pulmonary disease

Infectiousness

Infectious when lungs are involved

Infectious when lungs are involved

Response to therapy

Excellent

Excellent

because extrapulmonary sites are involved commonly, other diagnostic specimens are often necessary (Table 412-4) . Several studies have shown that persons with HIV infection and tuberculosis respond well to antituberculous therapy. In a series of patients, those who failed to respond to standard antituberculous therapy or who responded and then worsened had another superimposed disease, often PCP. Nonspecific and Lymphoid Interstitial Pneumonitis

In the PCHIS cohort, undiagnosed "interstitial disease" occurred at a rate of 0.60 cases per 100 person-years. It is not known, however, if these cases met the diagnostic criteria for either nonspecific interstitial pneumonitis (NIP) or lymphoid interstitial pneumonitis (LIP). LIP, although common in children with HIV infection, is thought to be rare in adults; thus, most of the cases in the PCHIS cohort were probably NIP. The cause of these conditions is not known, but it is speculated that they represent a response to the HIV itself. NIP tends to be self-limited in most instances and to resolve without therapy. LIP is more persistent and/or progressive but in some instances has seemed to respond to corticosteroids. The diagnosis of both NIP and LIP can be made only by biopsy. Although transbronchial biopsy tissue usually is not sufficient to provide a definitive diagnosis, findings that are consistent with NIP in the absence of any other identified diagnosis is sufficient to infer a diagnosis of NIP. Because of the apparent benign course of the disease and the lack of any therapeutic modalities, invasive tests to establish a diagnosis of NIP are not warranted.

Figure 412-4 Frontal view chest radiograph showing diffuse pulmonary parenchymal infiltration and bilateral hilar and right paratracheal adenopathy. The patient had acid-fast bacilli seen on microscopic examination of his sputum, and Mycobacterium tuberculosis was isolated from sputum and blood. (Courtesy of Dr. James Gruden, Department of Radiology, San Francisco Hospital.)

Disorders Associated with Severe Immune Suppression Pneumocystis carinii

Pneumonia (see Chapter 402)

PCP is the most common lung disease in persons with advanced HIV infection. The presentation tends to be indolent, characterized by slowly progressive shortness of breath and nonproductive cough, usually accompanied by fever. In the PCHIS cohort, it was noted that virtually all episodes of PCP were marked by cough or shortness of breath, or both. If at least one of these symptoms was not present, PCP was not found. This study also examined the utility of screening for P. carinii by performing chest radiographs, pulmonary function tests, and examination of induced sputum on asymptomatic subjects. No cases of PCP were found. Based on these data, an evaluation for P. carinii should not be undertaken unless an HIV-infected person complains of cough and/or shortness of breath. The radiographic findings of PCP are extremely varied. Most frequently there is diffuse "interstitial" infiltration, but there may be any manner of focal infiltrations, nodules or cavitary lesions, pneumatoceles, or miliary infiltration (Fig. 412-5) . Focal upper lobe involvement that mimics tuberculosis is more common in persons who have been given aerosol pentamidine as prophylaxis against PCP. Pneumatoceles and spontaneous pneumothorax may occur with first episodes of PCP but are more common with subsequent episodes. Commonly, the response to antipneumocystis therapy is slow, and radiographic abnormalities and gas exchange may worsen during the first 4 to 6 days of treatment. Co-administration of corticosteroids may minimize this initial worsening. Generally, particularly if the diagnosis has been established by bronchoscopy, most clinicians who repeat bronchoscopy early in the course of therapy find that it does not yield any additional diagnoses. However, worsening later in the course may be associated with a second, superimposed disease. Nontuberculous Mycobacterial Disease (see

Chapter 359)

Soon after AIDS was initially described, it was recognized that a group of closely related mycobacteria collectively named Mycobacterium TABLE 412-4 -- RESULTS OF MICROSCOPIC EXAMINATION AND MYCOBACTERIAL CULTURES IN PATIENTS WITH ADVANCED HIV INFECTION AND TUBERCULOSIS SPECIMEN NO. POSITIVE/NO. TESTED (% ) Acid-fast Smear Sputum

Culture 43/69 (62)

64/69 (93)

Bronchoalveolar lavage

9/44 (20)

39/44 (89)

Transbronchial lung biopsy

1/10 (10)

7/10 (70)

Blood

--

Lymph node Bone marrow

15/46 (33) 21/44 (48)

39/43 (91)

4/22 (18)

13/21 (62)

Cerebrospinal fluid

--

4/21 (19)

Urine

--

12/17 (71)

Other *

5/31 (16)

24/32 (75)

Data from Small PM, Schecter GF, Goodman PF, et al: Treatment of tuberculosis in patients with advanced human immunodeficiency virus infection. N Engl J Med 324:289, 1991. *Includes pleural fluid/biopsy; pericardial fluid/biopsy, stool, liver biopsy, abscess drainage, peritoneal fluid, bone biopsy.

1915

Figure 412-5 Radiographic findings of Pneumocystis carinii pneumonia (PCP). A, A frontal view chest radiograph showing diffuse hazy infiltration caused by early PCP. B, A frontal view chest radiograph with bilateral upper lobe infiltrations. C, A frontal view chest radiograph showing multiple bilateral thin-walled pneumatoceles (arrows). D, A frontal view chest radiograph with unilateral left-sided infiltration. (Courtesy of Dr. James Gruden, Department of Radiology, San Francisco General Hospital.)

avium complex was a common cause of disseminated infection in patients with the syndrome. Although M. avium complex organisms are commonly isolated from respiratory tract specimens in persons with advanced HIV infection, actual lung disease is unusual. Occasionally, however, the organism may cause focal lung disease. Endobronchial lesions may be seen on bronchoscopy, and on biopsy these lesions may contain granulomas, a histologic feature that is unusual in other organs involved in disseminated M. avium disease. Colonization of the lungs may precede and be a marker for subsequent disseminated M. avium infection. Disseminated M. avium complex disease occurs late in the course of HIV disease, usually when the CD4 + lymphocyte count is < 50 cells per microliter. Fever, weight loss, diarrhea, and abdominal pain are common symptoms. Pulmonary involvement is usually indicated by cough. Because it is difficult to distinguish between colonization and infection, the radiographic features of M. avium pulmonary disease are not well-defined. As noted above, focal infiltration may occur. Rarely, there may be diffuse lung involvement with an interstitial pattern on chest films. However, in the presence of a diffusely abnormal chest film, M. avium complex should not be accepted as the cause until other diseases have been excluded. Among the nontuberculous mycobacteria, M. kansasii is a distant second to M. avium complex as a cause of disease in HIV-infected persons; although its frequency seems to be increasing. As with M. avium complex, M. kansasii infections tend to be disseminated in persons with HIV infection. However, when M. kansasii is isolated from a respiratory tract specimen, it is more likely to be a cause of lung disease than is M. avium complex. As with most lung infections, M. kansasii usually presents with fever, cough, and, subsequently, shortness of breath. M. kansasii is probably more likely to cause diffuse infiltration on chest film than M. avium complex (see Chapter 359) . Fungal Infections (see

Chapters 393

to 402)

Both histoplasmosis and coccidioidomycosis are common HIV-associated infections in the areas in which the causative organisms are endemic and are seen sporadically outside of the endemic regions. The presenting clinical features of both histoplasmosis and coccidioidomycosis are nonspecific and variable. Histoplasmosis is commonly a protracted, febrile, wasting illness. Both infections are usually disseminated, with respiratory symptoms and abnormal chest films reported in varying proportions. Both histoplasmosis 1916

and coccidioidomycosis can present with an acute sepsis syndrome including acute respiratory failure. Chest radiographs are abnormal in the majority of patients, especially those who have respiratory symptoms. With histoplasmosis, the most common pattern is diffuse infiltration that is either reticulonodular or "alveolar." Coccidioidomycosis is associated with either localized or scattered nodular lesions or diffuse infiltration. For histoplasmosis, the diagnosis is commonly established by stain and culture of bone marrow, buffy coat, or blood. With coccidioidomycosis involving the lungs, specimens from the respiratory tract usually serve to establish the diagnosis. Cryptococcosis is not limited to an endemic area. The presenting complaints are nonspecific and include fever, weight loss, fatigue, and headache, often present for a long period prior to diagnosis. Most often pulmonary involvement is silent, although in one large retrospective review, 31% of patients had respiratory complaints at the time of presentation. The findings on chest radiographs have been varied. Focal and diffuse infiltration, localized or scattered nodules, some of which may be cavitary, pleural effusions, and hilar adenopathy all have been described. Aspergillosis has been diagnosed in a small number of patients with HIV infection. There are two patterns of Aspergillus pulmonary disease, one characterized by tissue invasion and the second largely an airway disease, obstructive bronchial aspergillosis. Reported risks in the setting of HIV infection have been neutropenia, use of corticosteroids, marijuana smoking, and use of broad-spectrum antimicrobial agents. Fever and cough that is sometimes productive of bronchial casts are the usual presenting complaints. The radiographic findings include focal infiltration, cavitary lesions, and pleura-based densities (Fig. 412-6) . Atelectasis and airway filling patterns may be seen with obstructive bronchial aspergillosis.

Figure 412-6 Invasive aspergillosis in an HIV-infected man. A, A frontal view chest radiograph showing infiltration in the right mid-lung zone. B, A CT scan of the chest at the level of the infiltration. The scan shows areas of necrosis (horizontal arrows) and probable chest wall invasion (vertical arrow). (Courtesy of Dr. James Gruden, Department of Radiology, San Francisco General Hospital.)

Figure 412-7 Kaposi's sarcoma (KS). A, A frontal view chest radiograph with typical findings of pulmonary KS. B, A high-resolution CT scan of the lower chest. Masslike peribronchovascular lesions typical of KS are seen. The lesions on the right side are surrounded by areas of fainter infiltration (arrows), a so-called halo sign that is highly suggestive of KS. (Courtesy of Dr. James Gruden, Department of Radiology, San Francisco General Hospital.)

Cytomegalovirus

CMV is commonly isolated from respiratory tract specimens in HIV-infected patients. However, it is unusual for lung disease to be attributable to this agent even when specific cytomegalic cells are seen on biopsy specimens. Thus, the diagnosis of CMV pneumonia can be made only when the virus is isolated in culture, specific histopathologic changes are seen on biopsy, and no other diagnosis is established. Because it is difficult to determine if CMV is the cause of lung disease in a given patient, the radiographic features of CMV pneumonia are not well-defined. In general, however, it is thought to cause diffuse infiltration that is not distinguishable from the pattern caused by many other organisms and by nonspecific interstitial pneumonitis. Neoplastic Diseases

In the PCHIS cohort, KS involving the lungs occurred at a rate of 0.33 cases per 100 person-years of observation (14 [13%] pulmonary cases of 105 total cases), and pulmonary involvement with lymphoma occurred at a rate of 0.19 cases per 100 person-years. However, among persons with advanced HIV disease, pulmonary KS has been diagnosed in 8 to 14% of patients being evaluated for respiratory symptoms, in 21 to 49% of patients with respiratory symptoms and mucocutaneous lesions, and in 47 to 75% of patients with known KS undergoing autopsy. It is likely that the reported frequency of KS is less than actually occurs because the lung involvement may be clinically silent. The diagnosis of pulmonary KS is nearly always established by the appearance of lesions on bronchoscopy. Typically, endobronchial KS is seen as flat, red or purple submucosal lesions that are similar in appearance to submucosal hemorrhages induced by bronchoscope 1917

trauma (see Color Plate 10 G). The lesions may be found in any location, from vocal cords to peripheral airways, and tend to favor airway bifurcations. Because of their submucosal location, the lesions are difficult to biopsy; however, the findings are sufficiently characteristic in appearance to enable a high degree of diagnostic certainty. In a few instances, pulmonary parenchymal KS has been diagnosed by transbronchial or open biopsy in persons with no endobronchial lesions seen. The chest radiographs of patients who had pulmonary KS without coexisting infection showed lesions that were predominantly central and consisted mainly of bronchial wall thickening and nodules (Fig. 412-7) . Kerley B lines and pleural effusions were noted in 71 and 52%, respectively. Hilar or mediastinal adenopathy was present in 15%. Non-Hodgkin's lymphoma is the second most frequent malignancy involving the lungs in patients with HIV infection. The frequency of pulmonary involvement in reported series is 0 to 25%. The presentation, even in patients who have pulmonary involvement, is generally dominated by systemic symptoms. The most common chest radiographic findings are patchy parenchymal infiltrates, nodules, and solitary masses. Intrathoracic adenopathy has been reported in a minority of cases. The

diagnosis can be established by transbronchial biopsy, needle aspiration biopsy, or thoracoscopic or open biopsy.

AN INTEGRATED APPROACH TO DIAGNOSIS Although the differential diagnosis of lung disease in a person with HIV infection is quite broad, the probabilities of the various diagnoses can be reduced in a given patient by knowing the patient's symptoms, HIV transmission category, and CD4+ lymphocyte count and further refined by the findings on the chest film. A general approach to the diagnostic evaluation in patients with a CD4+ lymphocyte count of 300 cells per microliter is shown in Figure 412-8 . The first step in the diagnostic evaluation is to define the patient's symptoms, especially whether or not the patient has cough and/or shortness of breath. If cough is present, it is important to ascertain if it is productive of purulent sputum. It is very uncommon for patients with PCP to have purulent sputum. Moreover, depending on the stain used, the presence of purulent debris in respiratory tract specimens makes it difficult to detect P. carinii in smears of sputum or bronchoalveolar lavage (BAL) fluid. As noted previously, acute bronchitis and bacterial pneumonia are relatively more frequent among persons with higher CD4+ lymphocyte cell counts. Additionally, IDUs have higher rates of bacterial pneumonia and tuberculosis than persons in other HIV transmission categories. Also as noted, the differential diagnosis varies somewhat with the geographic area, with histoplasmosis and coccidioidomycosis being common in their respective endemic areas. As in all patients with significant respiratory symptoms, radiographic examination of the chest is usually the first test performed. If the chest film shows no abnormalities in a patient with purulent sputum, the likely diagnosis is bronchitis. Patients with a diagnosis of bronchitis should be followed to be certain that the symptoms resolve and, if there is no resolution or worsening, further evaluation should be undertaken. It must be kept in mind that both tuberculosis and PCP may present with normal chest films. Patients who have normal chest films and a nonproductive cough may also have bronchitis, but if the CD4+ lymphocyte count is < 300 cells per microliter, P. carinii should be considered. In this circumstance, pulmonary function testing with measurement of the diffusing capacity for carbon monoxide (DL CO) should be performed. If the DL CO is < 75% of the predicted normal value, further evaluation directed toward detecting P. carinii should be undertaken. An alternative approach is to replace measurement of the DL CO with thin-section CT scanning, using a limited number of images to reduce cost. This approach has the potential advantage of being able to distinguish among PCP, emphysema and vascular obliteration caused by foreign particle embolization from intravenous drug use (Fig. 412-9) . If the chest film is abnormal, the next step depends on the type of abnormality. Focal infiltration, especially consolidation, in a patient with purulent sputum is most consistent with a diagnosis of bacterial pneumonia or tuberculosis (see Fig. 412-8) . Sputum

Figure 412-8 Algorithm of the diagnostic approach to patients who are known or suspected of having HIV infection resulting in significant immunocompromise. < 300 CD4+ lymphocytes per microliter. DL CO = Pulmonary diffusing capacity for carbon monoxide; AFB = acid-fast bacilli; BAL = bronchoalveolar lavage; Tb Bx = transbronchial lung biopsy.

Figure 412-9 High-resolution CT scan of the chest of a patient who complained of shortness of breath but whose plain chest film was normal. The scan shows patchy "ground-glass" infiltration in the anterior portions of both lungs. The patient was found to have P. carinii in an induced sputum sample. The findings noted in the scan are typical of early P. carinii pneumonia. (Courtesy of Dr. James Gruden, Department of Radiology, San Francisco General Hospital.)

1918

SPECIMEN

TABLE 412-5 -- EXAMINATION OF RESPIRATORY TRACT SPECIMENS TEST

Spontaneous sputum

Gram stain, AFB stain, cultures for mycobacteria and pyogenic bacteria

Induced sputum

P. carinii stain, AFB stain, mycobacterial culture

Bronchoalveolar lavage fluid

P. carinii stain, AFB stain, mycobacterial and fungal cultures

Transbronchial biopsy tissue

Touch preparations and tissue stains for P. carinii, AFB stain, hematoxylin and eosin tissue stain, culture for mycobacteria and fungi

Needle aspiration biopsy tissue P. carinii stain, AFB stain, cytologic examination, cultures for mycobacteria and fungi AFB = Acid-fast bacilli. should be obtained for Gram stain, acid-fast stain, and cultures for pyogenic organisms and mycobacteria. If there is a poor response or worsening, further evaluation, especially for P. carinii, should be performed. To this point much of the diagnostic approach is applicable for evaluating respiratory symptoms regardless of the HIV status of the patient. In the group of patients thought likely to have an HIV-related opportunistic infection, however, there is considerable variation both in philosophy and in specific diagnostic tests used. Cogent arguments have been made for empiric treatment with antipneumocystis agents for patients thought highly likely to have PCP, with specific tests for the organism being reserved for patients who fail to respond. With or without an empiric therapeutic trial, when it is decided to seek a specific diagnosis, the approach used varies. In some institutions, as described subsequently, the first step is to examine induced sputum, with bronchoscopy being performed only in those patients with negative sputum examinations. In other institutions, bronchoscopy is the first procedure used to obtain respiratory tract specimens. Also based on experience and preference, there are variations in the bronchoscopic procedure. Usually, BAL is performed with all procedures. Many clinicians also routinely perform a transbronchial biopsy at the time of initial bronchoscopy, whereas others perform biopsies on a case-by-case basis, and others do so only if the BAL does not provide a diagnosis (and perhaps not even then). If there is diffuse or focal infiltration in a person with a nonproductive cough, generally the evaluation should be directed toward opportunistic organisms. In many institutions the next diagnostic step is to induce sputum by having the patient inhale a hypertonic (3%) saline mist generated by an ultrasonic nebulizer. Careful attention to the details of selecting patients and inducing, processing,

Figure 412-10 Schematic representation of the use of preventive interventions in persons with HIV infection. The timing of the interventions is based on the CD4+ lymphocyte count and the risk of the common HIV-associated lung infections. INH = Isoniazid; PCP = P. carinii pneumonia; TMP-SMX = trimethoprim-sulfamethoxazole; MAC = Mycobacterium avium complex.

and examining the sputum specimens is essential to obtain good results. Diagnosis of mycobacterial disease and fungal infections can also be established by examining induced sputum. However, in HIV-infected patients, because of the high frequency of oral candidiasis, fungal cultures are frequently overgrown with Candida species. Because the negative predictive value of a negative examination of induced sputum for P. carinii is in the range of 60%, patients having a negative sputum examination generally should undergo bronchoscopy with BAL unless another diagnosis has been established or the procedure is contraindicated. At San Francisco General Hospital, P. carinii infection, either alone or with another diagnosis, was found in 32% of bronchoscopic examinations in patients who had a negative sputum examination. KS was found in 15%, nontuberculous mycobacteria in 25%, M. tuberculosis in 5%, and fungal pathogens in 4%. In addition, nearly all of the pathogens were found by BAL, and only rarely did transbronchial biopsy provide additional information. In patients whose chest films show focal or isolated nodular or mass lesions, needle aspiration biopsy, if the lesion is accessible, is an efficient diagnostic approach, and in some instances fluoroscopically guided transbronchial biopsy should be attempted. Enlarged intrathoracic lymph nodes may also be approached via needle aspiration biopsy, either through the bronchoscope (Wang needle) or via a transthoracic approach. The tests that should be performed on the various sorts of specimens described above are listed in Table 412-5 .

PREVENTING LUNG DISEASES IN PERSONS WITH HIV INFECTION

Much of the improved survival for patients with HIV infection in recent years owes to the prevention of PCP. Hence, the use of antipneumocystis agents such as trimethoprim-sulfamethoxazole, dapsone, pentamidine aerosol, and atovaquone for persons with HIV infection and CD4+ lymphocyte counts < 200 cells per microliter is a high-priority intervention. This is described in more detail in Chapter 402 . Preventive interventions for tuberculosis also should be accorded a high priority. All HIV-infected persons should receive a tuberculin skin test, and, if the test is positive ( 5 mm induration), isoniazid preventive therapy should be given regardless of the CD4 + lymphocyte count. Isoniazid should also be given to all HIV-infected persons who have been exposed to a person with infectious tuberculosis regardless of the tuberculin test result. The use of isoniazid preventive therapy for nonexposed persons who are defined as anergic has not been shown to be of benefit. A combination of rifampin and pyrazinamide given for 2 months has also been shown to be effective in preventing tuberculosis in persons with HIV infection who have a positive tuberculin skin test. It is not established whether pneumococcal vaccine reduces the rate of pneumococcal disease in persons with HIV infection. However, because of the low likelihood of adverse reactions to the vaccine, any benefit would not be offset by risk. Data from the PCHIS cohort suggest that trimethoprim-sulfamethoxazole as antipneumocystis prophylaxis decreases the frequency of pneumococcal disease, thus providing an additional benefit for this preventive intervention. Finally, it has been shown that prophylactic administration of newer macrolide agents (clarithromycin, azithromycin) reduces the frequency of M. avium complex disease by approximately 70%. Current recommendations are that macrolide prophylaxis be given to persons with HIV infection and CD4+ counts of < 100 cells per microliter. Although less effective than the macrolides, rifabetin may also be used to prevent M. avium complex disease. Persons who are candidates for rifabutin should be carefully evaluated for tuberculosis. Rifabutin administered to a person who has undiagnosed tuberculosis would quickly result in resistance of M. tuberculosis to rifabutin and rifampin, a major antituberculosis drug. The relationship of preventive interventions to CD4+ lymphocyte count is summarized in Figure 412-10 . Chin DP: Mycobacterium avium complex and other nontuberculous mycobacteria in patients with HIV. Semin Respir Infect 8:124, 1993. Describes the epidemiology, clinical presentation, diagnosis, and management of the nontuberculous mycobacterial diseases with a focus on M. avium complex. Hopewell PC: Tuberculosis in persons with human immunodeficiency virus infection: 1919

Clinical and public health aspects. Semin Resp Crit Care Med 18:471, 1997. Describes the overall impact of HIV infection on all aspects of tuberculosis. Irwin DH, Kaplan LD: Pulmonary manifestations of acquired immunodeficiency syndrome malignancies. Semin Respir Infect 8:139, 1993. Describes the clinical features and management of pulmonary Kaposi's sarcoma and non-Hodgkin's lymphoma. Stansell JD: Pulmonary fungal infections in HIV infected persons. Semin Respir Infect 8:116, 1993. Reviews the epidemiology, clinical features, diagnosis, and management of the fungal infections that involve the lungs in patients with HIV infection. Stancell JD, Huang L: Pneumocystis carinii pneumonia: In Sande MA, Volberding PA (eds.): The Medical Management of AIDS, 5th ed. Philadelphia, WB Saunders, 1997, p 275. A comprehensive review of the epidemiology, pathogenesis, clinical features, diagnosis, and treatment of PCP. Wallace JM, Hansen NI, Lavange L, et al: Respiratory disease trends in the pulmonary complications of HIV infection study cohort. Am J Respir Crit Care Med 155:72, 1997. Describes the frequency and spectrum of lung diseases after 50 months of follow-up in a cohort of HIV-infected persons from the major transmission categories. Included are subjects who have little apparent immunosuppression.

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Chapter 413 - GASTROINTESTINAL MANIFESTATIONS OF AIDS John G. Bartlett

The gastrointestinal tract is an especially common site for clinical expression of human immunodeficiency virus (HIV) infection and is an important factor in morbidity from opportunistic infections in late-stage disease, as well as gastrointestinal complications from antiretroviral agents or other drugs. Nearly all opportunistic infections occur when the CD4 count is less than 200/mm3 , and almost all seem to respond well to immune reconstitution when achieved with antiretroviral therapy.

ORAL LESIONS. Oral candidiasis ("thrush") is encountered at some time in 80 to 90% of all patients with advanced stages of HIV infection. The usual finding is white patches that show yeast forms and pseudohyphae on KOH preparation. Thrush is often asymptomatic, and treatment in such cases is unnecessary. Common symptoms include mouth pain, dysphagia, and taste change. The diagnosis is usually made by visual appearance. Treatment consists of topical agents (nystatin, clotrimazole troches, or amphotericin B), oral therapy with azoles or amphotericin B, or in severe refractory cases, intravenous amphotericin. Relapse rates are high, so continuous therapy with topical agents or azoles is often necessary. Oral hairy leukoplakia is characterized by white patches consisting of white fibrillar projections that are usually located on the tongue and are often confused with thrush. Oral hairy leukoplakia is usually asymptomatic, but occasional patients complain of pain or voice changes; symptomatic patients usually respond to treatment with acyclovir. Herpes simplex virus (HSV) often causes painful oral lesions that have the typical appearance of vesicles on an erythematous base and break down to form ulcers. Herpetic oral lesions are common in the general population, but they tend to be more severe and prolonged in patients with advanced HIV infection. The usual treatment is acyclovir, famciclovir, or valacyclovir given orally; severe cases may require intravenous acyclovir or, for acyclovir-resistant strains, foscarnet given parenterally. The major source of confusion is aphthous ulcers of unknown etiology, which seem to respond best to thalidomide or to corticosteroids given topically or systemically. Patients with Kaposi's sarcoma often have involvement of the oral cavity, most frequently with typical purplish raised lesions on the palate, although any site in the oral cavity may be involved. Most are asymptomatic; symptomatic lesions generally respond to irradiation, laser treatments, or vinblastine injections. Periodontal disease is relatively common, with either gingivitis or periodontitis. Treatment consists of topical chlorhexidine (Peridex) or systemically administered metronidazole.

ESOPHAGITIS. Dysphagia or odynophagia generally indicates an esophageal lesion. The most common cause is candidiasis, and most such patients also have thrush. Patients with odynophagia in late-stage HIV infection are usually treated empirically with fluconazole. Alternative causes of esophagitis include herpes simplex, cytomegalovirus (CMV), or aphthous ulcers (Table 413-1) . Endoscopy is recommended for patients with atypical symptoms and those who fail to respond to fluconazole. Occasional cases are due to fluconazole-resistant Candida spp. and require intravenous amphotericin B. Ulcerative esophagitis is usually due to CMV or aphthous ulceration; HSV esophagitis is unusual. Herpes simplex may be treated with acyclovir, CMV responds to ganciclovir, and aphthous ulcers are optimally treated with systemic corticosteroids or thalidomide.

GASTRIC LESIONS. Patients with acquired immunodeficiency syndrome (AIDS) often have gastric achlorhydria; less common gastric lesions are Kaposi's sarcoma and opportunistic infections. Gastric intolerance to medications is common, especially with zidovudine, ritonavir, didanosine, indinavir, saquinavir, macrolides, trimethoprim-sulfamethoxazole, and pentamidine. Symptoms include nausea, vomiting, anorexia, and epigastric pain and usually resolve promptly when use of the implicated drug is discontinued.

SMALL BOWEL AND COLON LESIONS. Acute and/or chronic diarrhea is a frequent complication and may be due to medications, opportunistic infections, or common causes seen in the general population such as viral gastroenteritis or irritable bowel syndrome. The antiretroviral agent that most commonly causes diarrhea is nelfinavir. Treatment with bacterial agents may be complicated by Clostridium difficile-associated diarrhea or colitis, but the frequency and severity do not appear to be increased by immunosuppression per se. DIAGNOSTIC EVALUATION. The approach to patients with HIV infection and diarrhea requires knowledge of four factors: medication history, CD4 count, a distinction between acute and chronic diarrhea, and emphasis on features that distinguish between colitis and enteritis. Regarding the latter, patients with colitis usually have cramps, fever, fecal leukocytes, and small-volume "fraction" stools. Enteritis is characterized by large-volume watery stools without fecal leukocytes or cramps and often without fever. The most common microbial causes of acute diarrhea in HIV-infected patients are Salmonella spp., C. difficile, and enteric viruses. Common opportunistic pathogens that cause chronic diarrhea in late-stage HIV include cryptosporidia, microsporidia, CMV, and Mycobacterium avium (Table 413-2) . The diagnostic evaluation begins with a review of medications and discontinuation of treatment with suspected agents. Many patients with other forms of TABLE 413-1 -- ESOPHAGEAL COMPLICATIONS OF HIV INFECTION AGENT

FREQUENCY* (% )

CLINICAL FEATURES

DIAGNOSIS

TREATMENT

95

Togaviruses Rubella Arenavirus Lymphocytic choriomeningitis Rhabdovirus Rabies Orthomyxoviruses

Winter and spring

Influenza Parainfluenza Paramyxoviruses Measles Mumps

Winter and spring

Retroviruses

All year

Human immunodeficiency virus, type 1 DNA viruses

100 All year

Herpesviruses Herpes simplex, type 1

15

60

Adenoviruses

Rare

Rare

Arthropod-borne viruses RNA viruses Togaviruses Eastern equine encephalitis

Summer

50

30

Western equine encephalitis

Summer

5

30

10

5 mV), and duration (>10 milliseconds), and are polyphasic. In addition, for a given degree of voluntary effort, few motor units are recruited and the ones that are fire too rapidly (>15-20 Hz). This indicates a loss of motor units with a compensatory increased firing rate in the remaining units, a pattern known as decreased recruitment. Myopathic motor unit potentials are small, brief polyphasic potentials ( distal

Increased (up to 50× normal)

Perimysial and perivascular inflammation; CD4+ T cells, B cells; MAC, Ig, C deposition on vessels

Yes

Myocarditis, interstitial lung disease, vasculitis, other connective tissue diseases, malignancy

Polymyositis

F> M

Adult

No

Proximal > distal

Increased (up to 50× normal)

Endomysial inflammation CD8+ T cells, macros

Inclusion body myositis

M> F

Elderly (>50 yr)

No

Proximal = distal; Predilection for finger/wrist flexors, knee extensors

Increased (90% after the introduction of an effective vaccine in 1967, and now there are only a few hundred to a few thousand cases per year. Uncommonly, a less acute, mumps-like illness may occur in adults in association with cytomegalovirus, influenza, or coxsackie A virus infection. Sjogren's syndrome is characterized in about one third of patients by gradual development of firm, nontender or only slightly tender, bilateral enlargement of major salivary glands (see Chapter 291) . The enlargement may slowly wax and wane. Salivary secretion decreases gradually, and, if hypofunction is severe and prolonged, the resulting dry mouth can impair speech and swallowing and be associated with rapidly progressive dental caries, symptomatic erythematous candidiasis, and difficulty in wearing dentures. In severe cases, the oral mucosa is dry and sticky, and saliva is not expressible from the major ducts. About one third of patients show signs of erythematous candidiasis (see above). The salivary component of Sjogren's syndrome should be diagnosed from a labial salivary gland biopsy specimen containing at least five glands. Examination must show focal lymphocytic sialadenitis in most or all of the specimen and exclude nonspecific chronic sialadenitis or abnormalities indicative of another disease, such as noncaseating granuloma. A patient's symptoms of oral dryness (xerostomia) are important, but are subjective and caused by a wide variety of conditions (Table 514-7.) Results from salivary functional or imaging studies are not specific to Sjogren's syndrome. Several chronic granulomatous diseases, such as sarcoidosis, tuberculosis, and leprosy, can cause bilateral enlargement and decreased function of salivary glands. The clinical and serologic features of sarcoidosis may closely mimic those of Sjogren's syndrome, and the distinction must be made by biopsy of a minor salivary gland. A few adult patients with HIV infection, and most children who are infected in utero, develop major salivary gland enlargement and reduced salivary secretion that are caused by lymphocytic infiltration. Parotid gland enlargement usually represents a solid or cystic benign lymphoepithelial lesion (see Table 514-3) . Recurrent parotitis of childhood includes episodes of unilateral or bilateral parotid enlargement. During flares of this illness, salivary secretion may be reduced, but usually without prominent secondary symptoms or signs. This condition, of unknown cause, usually subsides after puberty. Some serologic evidence suggests an

association with Epstein-Barr virus infection. Asymptomatic Parotid Enlargement (Sialadenosis) Parotid glands can develop bilateral, symmetric enlargement that is soft and nontender to palpation and not associated with salivary TABLE 514-7 -- CAUSES OF DECREASED SALIVARY SECRETION Temporary Effects of short-term drug use (e.g., antihistamines) Virus infections (e.g., mumps) Dehydration Psychogenic causes (fear, depression) Chronic Effects of chronically administered drugs (especially antidepressants, MAO inhibitors, neuroleptics, parasympatholytics, some combinations of drugs for treating hypertension) Systemic Diseases (with or without Gland Enlargement) Sjogren's syndrome Granulomatous diseases (sarcoidosis, tuberculosis, leprosy) Amyloidosis HIV infection Diabetes mellitus (uncontrolled) Graft-versus-host disease Depression Therapeutic radiation to the head and neck Absent or malformed glands (rare)

2246

hypofunction (see Table 514-6) . Diagnosis is established by the clinical presentation and (if necessary to exclude sarcoidosis) a normal labial salivary gland biopsy. Usually, results of sialography and salivary scintigraphy are within normal limits. Biopsy of the affected glands is not indicated for diagnosis. This chronic, noninflammatory, and non-neoplastic condition is usually associated with a variety of systemic diseases, including diabetes mellitus, hyperlipoproteinemia, hepatic cirrhosis, anorexia/bulimia, chronic pancreatitis, acromegaly, and gonadal hypofunction. It can also result from use of phenylbutazone or be a reaction to iodine-containing contrast media. Impaired Salivary Secretion Without Gland Enlargement The very common symptom of dry mouth (xerostomia) is most often a side effect of chronically administered drugs. Many classes of drugs reduce unstimulated salivary secretion through anticholinergic or other mechanisms (Table 514-7) . At least initially, most of these drugs do not interfere with salivary production in response to gustatory, olfactory, or masticatory stimuli. Patients usually experience the symptoms soon after beginning to use the drug but will produce enough saliva during a meal for normal chewing and swallowing. The effects are dose-dependent and are produced by most tricyclic antidepressants, most neuroleptics, monoamine oxidase inhibitors, and all anticholinergics. A combination of drugs for treatment of hypertension may cause symptoms of dry mouth, but usually not to the extent of the drugs listed above. Several systemic diseases affect salivary secretion. As noted above, most patients with Sjogren's syndrome, some with sarcoidosis, and a few patients with HIV infection experience symptoms of dry mouth to various degrees, with or without salivary gland enlargement. In addition, patients who have primary or secondary amyloidosis with salivary gland deposition may develop impaired secretion. Depressed patients who are not taking antidepressants apparently have decreased resting salivary secretion and complain more frequently of symptoms of dry mouth. Irradiation of the head and neck region to treat a malignant tumor usually produces profound dry mouth before therapy is completed. Secretory capacity recovers only slightly in the months following treatment. Less severe dry mouth can accompany graft-versus-host disease following bone marrow transplantation; secretory capacity usually recovers when the reaction resolves. Clinical Management of Patients with Impaired Salivary Secretion Significant chronic salivary hypofunction from any cause produces a risk for dental caries in approximate proportion to the secretory impairment, but caries can largely be prevented if appropriate measures are taken as soon as the hypofunction begins. Remaining teeth should be protected by a comprehensive dental caries prevention program, monitored by a dentist, that includes daily application of an appropriate topical fluoride and removal of dental plaque, counseling on control of cariogenic dietary carbohydrates, and placement of appropriate dental restorations as necessary. Symptomatic treatment of mild to moderately severe salivary hypofunction can include sialogogues such as sugarless hard candies or chewing gum, frequent sips of water, and use of saliva substitutes at night. Severe hypofunction, especially that following irradiation, can be improved by oral pilocarpine, 5 to 10 mg three times a day, if not contraindicated. Chronic erythematous oral candidiasis is a frequent sequela of chronic xerostomia, and its treatment and retreatment, as noted above, will improve the patient's oral symptoms.

PLATE 17 EYE DISEASES

Figure 514- A, Herpes simplex corneal epithelial keratitis in diffuse light and (inset) in light passed through a cobalt blue filter after fluorescein staining.

Figure 514- B, Papilledema in a young person. Note disk swelling, hemorrhages, and exudates, with preservation of the physiologic cup.

Figure 514- C, Angioid streaks in pseudoxanthoma elasticum. Breaks in the retinal pigment epithelium basement (Bruch's) membrane radial and circumferential to the disk indicate an underlying defect in elastic tissue formation.

Figure 514- D, Optic disk drusen (also called hyaline bodies). Although obvious here, these calcified excrescences may be difficult to see in young persons, in whom the disk elevations they produce is mistaken for papilledema.

Figure 514- E, Roth's spots. Multiple white centered hemorrhages in a man with recurrent subacute bacterial endocarditis. White centered hemorrhages are also seen with leukemia and diabetes. The small white scars are probably the residua of previous episodes.

Figure 514- F, Corneal abrasion. Corneal epithelial defects are best observed with topical fluorescein stain under blue illumination. Pain is often out of proportion to clinical findings. Prophylactic topical antibiotics are required until the epithelium has healed. (Courtesy of Deborah P. Langston, M.D.)

Figure 514- G, Retinitis pigmentosa. Fundus photograph shows "bone spicule" pigmentation of the midperipheral fundus, waxy pallor of the optic disk, and attenuated retinal vessels, the most consistent finding in RP. (Courtesy of John I. Loewenstein, M.D.)

Figure 514- H, Age-related macular degeneration (ARMD). Fundus photograph of nonexudative ARMD shows discrete macular drusen, which are subretinal deposits of lipofuscin.

( A through E, Photographs taken by Harry Kachadoorian, C.R.A., University of Massachusetts Medical School, Worcester, MA.)

PLATE 18 EYE DISEASES

Figure 514- A, CMV retinitis. Fundus photograph shows retinal hemorrhage and exudate, the "cheese-pizza" fundus. CMV retinitis may be sectoral or diffuse. Early peripheral lesions may be asymptomatic. Patients at risk, therefore, require frequent examination. (Courtesy of John I. Loewenstein, M.D.)

Figure 514- B, Diabetic retinopathy. Fundus photograph of background (nonproliferative) diabetic retinopathy demonstrates scattered dot and blot intraretinal hemorrhages and retinal exudates. A circinate exudate is seen surrounding a microaneurysm.

Figure 514- C, Central retinal artery occlusion. Fundus photograph shows diffuse retinal edema. The heavily pigmented fovea with its uniquely thin inner retina produces a "cherry red spot" against the dusky macula. A small area of retina adjacent to the optic disk is spared, owing to the presence of a cilioretinal artery.

Figure 514- D, Central retinal vein occlusion. The disk is swollen with diffuse retinal hemorrhages and cotton-wool spots.

Figure 514- E, Chalazion. Inspissated secretions from an obstructed meibomian gland are extruded into surrounding tissue, causing chronic granulomatous inflammation. Pictured are multiple lipogranulomas involving all four eyelids. (Courtesy of Peter A.D. Rubin, M.D.)

Figure 514- F, Eyelid abscess. Preseptal cellulitis, commonly resulting from minor penetrating trauma, may evolve into an abscess. Treatment requires incision and drainage followed by systemic antibiotics. (Courtesy of Peter A.D. Rubin, M.D.)

Figure 514- G, Acute dacryocystitis. External photograph shows erythema and edema in the region of the lacrimal sac. Pressure applied to the lesion produces purulent reflux through the canaliculi. Conservative treatment requires oral antibiotics and warm compresses. Pointing lesions such as the one pictured require incision and drainage. (Courtesy of Peter A.D. Rubin, M.D.)

Figure 514- H, Bacterial conjunctivitis. Purulent discharge and conjunctival hyperemia suggest bacterial conjunctivitis. Viral conjunctivitis produces watery discharge, foreign body sensation, preauricular lymphadenopathy, and conjunctival follicles seen on slit lamp examination. (Reproduced with permission from the American Academy of Ophthalmology.)

Daniels TE, Fox PC: Salivary and oral components of Sjogren's syndrome. Rheum Dis Clin North Am 18:571, 1992. This review outlines the clinical features of the salivary component of Sjo gren's syndrome and clinical management of patients with dry mouth. Greenspan JS, Greenspan D (eds): Oral Manifestations of HIV Infection. Chicago, Quintessence, 1995. This volume of proceedings from an international workshop provides a comprehensive view of the oral manifestations of HIV infection, including their epidemiology, salivary and periodontal manifestations, and the pathogenesis and treatment of opportunistic mucosal infections. Regezi JA, Sciubba JJ: Oral Pathology: Clinical-pathologic Correlations, 3nd ed. Philadelphia, WB Saunders, 1999. This useful and comprehensive text discusses and illustrates the clinical features, differential diagnosis, pathogenesis, and pathology of most diseases affecting the oral mucosa, jaws, and salivary glands.

MD Consult L.L.C. http://www.mdconsult.com Bookmark URL: /das/book/view/882/564.html/top

Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 515 - UPPER AIRWAY DISEASES Kingman P. Strohl

The nose, ears, pharynx, and larynx are involved in such functions as conducting airflow to and from the lungs, taste, deglutition, speech, hearing, and smell. These chambered, highly specialized structures develop from the foregut and second through fourth branchial arches and are highly served by neural systems for motor control and sensation. Disease in any segment of the upper airway can have several functional consequences, and loss of any function can arise from both local processes and neural mechanisms. Because the larynx and pharynx act in series as the conducting airway to the trachea, bronchi, and the more distal gas-exchanging units of the lungs, dyspnea and air hunger result from swelling, encroachment, or neural dysfunction of these segments. Other presentations of upper airway disease include rhinorrhea and nasal obstruction, sneezing, postnasal and pharyngeal secretions, cough, dysphagia, changes in voice, swelling of the upper and lower jaw, hearing loss, tinnitus, snoring and apneas during sleep, epistaxis and pain. Anatomic and functional assessments often reveal the cause of symptoms. For example, muffled speech and drooling in the presence of neck or jaw swelling indicate encroachment of the pharyngeal airway and require immediate assessment and monitoring of airway patency. Watching the patient with dysphagia while he/she drinks and eats may differentiate a neural from an anatomic process. Examining the upper airways requires an appreciation of the anatomic complexities of the area and a facility with the otoscope, tongue blade, tuning fork, and manual (gloved) palpation of the mouth. Knowledge of salivary gland and lymph node locations, bimanual examination of the floor of the mouth, and percussion of the teeth are needed to distinguish among periodontal abscess, mandibular swelling, fracture, or tumor. Referral to the appropriate specialist (orthodontist, oral surgeon, or otolaryngologist) saves time, prevents progression and complications, and/or avoids unnecessary procedures. Clues to a systemic illness may arise from examining the upper airways in the absence of symptoms. Nasal polyps are associated with both aspirin-sensitive asthma and cystic fibrosis. Nasal ulceration, nasal drip, and sinusitis may be seen in chronic cocaine use and withdrawal as well as in pulmonary vasculitis, especially that of Wegener's granulomatosis (see Chapter 294) Parotid gland enlargement is associated with sarcoidosis, diabetes, amyloid, and collagen vascular diseases. Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) presents to the internist with gastrointestinal bleeding and is characterized by dilated thin-walled capillaries and draining veins seen in the nose, lips, and mouth.

HEARING DEFICITS (see Chapter 517) Otitis (also see Chapter 517) Otitis media (Table 515-1) may occur at any age; however, the most frequent presentation is under age 10. Presenting symptoms include pain and conductive hearing loss, more often unilateral. In acute presentations, most patients acknowledge a preceding upper respiratory tract infection; symptoms improve with antibiotics. When the presentation is subacute or chronic, treatment should TABLE 515-1 -- OTITIS MEDIA TYPE Acute

MECHANISMS

TREATMENT

Streptococcus pneumoniae, and Haemophilus influenzae; rarely Staphylococcus aureus, Streptococcus pyogenes, Proteus, Pseudomonas

Oral antibiotics

Serous Failure to clear fluid (Starling effect)

Antihistamines and decongestants

Chronic Persistent eustachian tube obstruction (rarely tuberculosis)

Drainage tubes ± all of the above

2247

include not only antibiotics but also consideration of mechanical factors, such as eustachian tube functional or anatomic obstruction and/or tympanic membrane rupture, which require surgical collaboration. There are special concerns about otitis relevant to internal medicine. First, there may be serious complications from untreated or inadequately treated disease. Infection from the middle ear extending into the mastoid sinus and adjacent structures in the temporal bone may result in unilateral distal facial nerve palsy, osteomyelitis, infection of the basal structures of the skull, and/or intracranial extension, including dural abscess, brain abscess, and meningitis. Patients can present with sepsis and/or coma with increased intracranial pressure. Identification of the infecting organism is crucial. Problems in the inner ear may be addressed surgically after definitive intravenous antibiotic therapy. Second, the spectrum of organisms in immunocompromised hosts includes fungal infections ( Aspergillus and Candida) that, if undetected, lead to complications. A third special circumstance is patients with longstanding endotracheal or nasogastric intubation. Nasal inflammation can block the eustachian tube and produce otitic and sinus infections with nosocomial organisms. Unexplained fever in the medical intensive care unit should involve examination of the upper airway and, occasionally, radiographic imaging and aspiration of the middle ear or sinuses for culture. External otitis is characterized by severe pain edema, and discharge along the auditory meatus. In contrast to otitis media, the ear and the tragus are painful to the touch, and otoscopic examination is painful. Often there is a history of water in or trauma to the ear canal. Culture could reveal Pseudomonas organisms but usually is not needed. Treatment with topical broad-spectrum antibiotics combined with topical corticosteroids, so-called otic drops, resolves symptoms and results in cure in 3 to 5 days. Narcotic analgesics may be needed to manage pain. Oral antibiotics are indicated when regional lymphadenitis or erythema/cellulitis is present. Infections of the external ear can present more severely in immunocompromised hosts and especially in diabetic patients, who have decreased host defenses and reduced sensation. This condition is sometimes called "malignant" otitis (see Chapter 473) . Spread of infection from the ear inferiorly results in facial nerve paralysis (not to be dismissed as Bell's palsy); infection of the jugular foramen; involvement of the glossopharyngeal, vagus, and accessory nerves; and infection of the sheath of the jugular vein, with extension inferiorly and contralaterally into the neck and rostrally into the lateral sinus. Medial spread involves the middle ear and the mastoid, whereas anterior spread involves the temporomandibular joint. Broad-spectrum intravenous antibiotics should be instituted promptly. Surgical intervention is indicated to identify organisms when nerve involvement or foreign body obstruction is suspected. With recurrent external otitis, a history of repetitive trauma or exposure to water (so-called swimmer's ear) is likely. In the former, counseling may be needed on proper ear hygiene; in the latter, over-the-counter ear drops containing an alcohol/glycerine mixture can be recommended for use after bathing or swimming.

RHINITIS (See Chapter 274) Rhinitis comprises a group of disorders characterized by nasal itching, drip, and obstruction. These symptoms relate to irritation and inflammation of the mucosa and increased nasal secretions. Antigen challenge in susceptible hosts, histamine challenge, or activating nonmyelinated nerves with substance P can reproduce symptoms found in acute allergic reactions and acute rhinitis. Subacute and chronic symptoms and nasal obstruction result from the activation of mucosal prostanoids and cytokine networks to promote the nasal inflammatory response, recruit inflammatory cells, and promote healing. Acute insults take 3 to 5 days to resolve unless

bacterial superinfection, concomitant eustachian tube or sinus obstruction, or repeated exposure to a causative noninfectious agent or allergen occurs. A persistent inflammatory state can develop in susceptible individuals and result in chronic symptoms, nasal polyps, and altered or decreased sense of smell (anosmia). The most frequent cause of acute rhinitis is the common cold (see Chapter 375) . An upper respiratory tract infection is commonly a self-limited illness. The severity of viral infections can be attenuated by amantadine or similar agents if taken near the time of exposure. Antihistamines, decongestants, and cool mist relieve symptoms. Topical decongestants like oxymetrazoline, used as directed, relieve nasal obstruction; however, rebound congestion and the potential complications of chronic vascular constriction follow if therapy is prolonged beyond 1 week. Bacterial superinfection presenting as sinusitis or otitis should be suspected if recurrent fever, regional lymphadenopathy, persistent mucopurulent discharge, or persistent symptoms last longer than 5 days. In this situation, oral antibiotics are useful.

SINUSITIS A mucopurulent discharge and a painful face suggest sinusitis, an inflammation of the lining of the paranasal sinuses. Most cases occur as a complication of the common cold or other upper respiratory tract infections, with occasional presentations due to extension of a periodontal infection under the maxillary sinus. Less than 1% of upper respiratory tract infections result in the clinical syndrome of acute sinusitis, and fewer meet the criteria for chronic sinusitis. Sinusitis is more common in adults, perhaps because the paranasal sinuses do not develop fully until the second and third decade of life. Bedside transillumination can suggest the presence of sinusitis. Normal light transmission to the frontal sinus from the supraorbital ridge or to the maxillary sinus through the hard palate excludes sinusitis; reduced or absent transmission is less helpful because considerable intraindividual anatomic variation exists. Radiographic evaluation is relatively sensitive. A coronal computed tomography image with bone window settings is the preferred test. Magnetic resonance imaging and ultrasonography have limited but specialized applications. Sinus aspiration and endoscopic sinuscopy may be necessary to recover organisms or to effect drainage. Surgical interventions are indicated for treatment failure, suppurative complications, diagnosis of nosocomial infection, and fever of unknown origin with sinus opacification. Most causes of sinusitis are bacterial infections similar to those that produce otitis. The course of acute sinusitis is 3 to 4 weeks because of the anatomic difficulties in drainage. Decongestants improve nasal obstruction and may improve sinus drainage. The routine use of antihistamines is controversial because of concerns that mucociliary clearance may be impaired. Oral antibiotics are often prescribed. Occasionally, surgical interventions are used when disease is chronic and resistant to empiric therapy. Fungal sinusitis is uncommon and presents with a chronic course. Aspergillus is most common, but Candida, Mucor, and Penicillium organisms may be recovered from infected sinus aspirates. Invasive disease with eye, mouth, and brain extension occurs in patients with acquired immunodeficiency disease or on chemotherapy. Finally, maxillary antrum tumors produce a unilateral bloody nasal discharge that can be confused with sinusitis. Clues to a malignant process are the chronicity of symptoms, refractoriness to conventional therapy, and the presence of bony destruction of the antrum on radiographic examination.

MASSES, SWELLING, AND PAIN OF THE JAW (See Chapter 514) Occasionally the internist sees patients with swelling of the face and jaw. The differential diagnosis is based on careful history and examination. Duration of symptoms, presence of a fever, history of local trauma, orthodontic difficulties, shortness of breath, or dysphagia may help localize lesions and identify potential complications. The anatomic locations of the salivary glands and lymph nodes are distinct (Fig. 515-1) . The site of swelling of the jaw is determined on physical examination by palpation, running the finger intraorally along the inner and outer borders of the mandible, and comparing the right and left sides. Inspection and tooth percussion with a metal rod localize periodontal processes. Fracture of the lower jaw usually presents with a history of trauma, although sometimes minor in nature. Jaw fractures are treated like compound fractures because the teeth communicate with the oral cavity. Occasionally, soft tissue swelling from secondary infection obscures a fracture. Aseptic necrosis caused by a 2248

Figure 515-1 Appropriate position of the lymph nodes (left) and the salivary glands (right). Arrows indicate routes of lymphatic drainage.

vascular disease or a mandibular hairline fracture can also present with swelling and pain. Periodontal abscess results from poor dental hygiene or tooth trauma, particularly in the elderly, the diabetic, or the immunocompromised host. Complications result from periodontal abscess because infection can track rapidly along tissue planes to the basal structures of the skull and to the neck and mediastinum. Ludwig's angina (see Chapter 338) is an infection presenting with a painful swelling of the anterior floor of the mouth, drooling, and dysphagia. Left unrecognized or untreated, it can progress rapidly to respiratory obstruction. Intravenous antibiotics and corticosteroids must frequently be accompanied by surgical exploration and drainage. Nonpainful swelling of the lower jaw suggests tumor of the bone or soft tissues. The most common nonmalignant tumor is an epulis (meaning "on the gum"), a granulomatous and fibrous tissue growth. Other growths include osteoma, cyst, ameloblastoma (a tumor of the cells that make enamel), and malignant epithelioma. Bilateral enlargement of the mandible occurs in acromegaly, Paget's disease, osteitis fibrosa from hyperparathyroidism, and leontiasis ossea. The last is a rare condition with jaw changes resembling acromegaly but without enlargement of the hands or feet. Pain in the lower jaw without swelling is commonly due to dental caries, periodontal disease, or temporomandibular dysfunction (otomandibular syndrome). Trigeminal neuralgia presents with a unilateral dull pain, a distinct anatomic distribution, and a trigger zone for intense pain; neuralgia occurs in cranial nerve VII division II more than in III or I. In contrast, herpes zoster more commonly involves division I. Pain from cardiac angina also may be referred to the jaw and has been mistaken for periodontal disease.

DYSPHAGIA (see Chapter 124) HOARSENESS Simple hoarseness is the inability to pitch the voice and results from failure to use the larynx to produce tones. This change in voice occurs with voluntary acts, e.g., whispering, or with diseases affecting vocal cord motion and position. The most common cause of an acute onset of hoarseness is a bacterial or viral infection. Inhaled irritants (smoke or fumes) and overuse of the larynx present similarly. Inflammation and edema inhibit precise tension or closure of the cords. Treatment is rest and avoidance of irritants. Inhaled corticosteroids may produce cough and further irritation. Stridor suggests more than edema and inflammation of the vocal folds and warrants evaluation for extrinsic or intrinsic airway encroachment. Intermittent or recurrent hoarseness is usually associated with smoking and/or allergy. Hoarseness persisting 2 weeks or more should be investigated by directly examining the laryngeal structures. Chronic hoarseness can result from benign and malignant processes, including gastroesophageal reflux, laryngeal carcinoma or polyps, arthritis, hypothyroidism, goiter, and infections (tuberculosis, syphilis, and histoplasmosis). Post-nasal drip is an uncommon cause. Chronic hoarseness due to malignancy in the chest, with entrapment of the left recurrent laryngeal nerve, and to pharyngeal or esophageal carcinomas, with entrapment of nerves or extrinsic compression, usually occurs after the primary tumor has declared itself by other symptoms. Hoarseness due to recurrent laryngeal nerve paralysis may present years after thyroid or parathyroid surgery, trauma to the neck, or goiter and is attributed to fibrosis and/or aging. Hoarseness following endotracheal intubation is common but should resolve within 3 to 5 days after removing the tube. Idiopathic, isolated unilateral, and bilateral vocal cord paralysis is rare. Treatment of chronic hoarseness is directed at the underlying cause. Nerve-grafting procedures can restore function in a paralyzed cord and laser therapy can be used for vocal folds entrapped after prolonged intubation, tracheostomy, or granuloma formation. UPPER AIRWAY OBSTRUCTION Presenting symptoms of pharnyeal or laryngeal obstruction are air hunger and stidor at rest or on exertion; the presentation may be acute or chronic. There may be signs of increased airway resistance with inspiratory chest retractions and active expiratory efforts. Assessment of the patient with symptoms at rest should focus first on restoring or assuring a patent airway before an examination. Most common misdiagnoses are asthma and heart failure, so that a failure to respond to empiric treatment should raise suspicion for an upper airway cause for dyspnea, wheezing, and hypercapnic respiratory failure. Direct examination may precipitate complete airway closure and should be performed in a controlled setting like an emergency department. If the patient is stable, a flow-volume loop is one non-invasive test that will reveal the presence of flow limitation on inspiration or on both inspiration or expiration. A soft tissue lateral radiograph with the neck extended may localize the site of the obstruction. Causes of acute obstruction include bacterial epiglottis, trauma, angioneurotic edema, allergic reactions, and foreign body aspiration. Chronic obstruction can be a presenting feature of neoplastic disease (sqamous cell carcinoma being the most common), cricoarytenoid arthritis, vocal cord polyps, bilateral vocal cord paralysis,

goiter, and neurofibromatosis. Glottic dysfunction, also called factitious asthma, is an uncommon disorder characterized by intermittent episodes of dyspnea and wheezing. The patient may present with hypercapnia but with a 2249

normal arterial-alveolar gradient, indicating that gas exchange in the distal airways and lung units is normal. Patients have complete resolution of symptoms in minutes to hours, a finding also inconsistent with asthma or heart failure. Recognition and subsequent treatment with assurance and medicinal restraint is coupled with stress reduction measures and, occasionally, antidepressant medications for better outcome, as measured by fewer presentations for assessment and/or hospitalizations.

SNORING (See Chapter 87) Snoring is produced by vibrations of the soft tissues of the nasopharynx initiated by turbulent flow through a narrowed airway. Airway caliber is determined by anatomic factors, neuromuscular tone to skeletal muscle, and the pressure differences across the airway wall. Snoring occurs during sleep, a state in which postural tone to the skeletal muscles and reflex adjustments to respiratory loads are reduced. The airway closing at the level of the nasopharynx and/or oropharynx during sleep produces apnea (cessation of airflow) and is believed to represent an extension of the process that produces snoring. (see Chapter 87) Heavy snoring is terminated by changes in the sleep state or brief arousals from sleep. Repetitive arousals result in inadequate sleep and daytime sleepiness and increased sensitivity to central nervous system (CNS) depressants. So common is snoring (30 to 50% of the population at age 50 report snoring) that it is the theatrical signature for sleep and the subject of social comment. Loud snoring, enough to be heard in the next room, is present in 5 to 10% of the population. In adults, examination reveals a reddened soft palate with or without anatomic narrowing of the nasal and oropharyngeal passages, micrognathia, or hypothyroidism. Other predisposing factors may include family history, obesity, respiratory depressants (alcohol and drugs), sleep restriction, nasal obstruction, and aging. Treatment is symptomatic for the bed partner, and one must first exclude hypothyroidism and then address predisposing factors. Medical therapy is directed toward weight loss, nasal decongestants, and drugs to reduce upper airway inflammation. Surgical therapy is directed at the naso-oropharynx with ablative or surgical procedures to reduce the size of the uvula or posterior palate. In children, tonsillar hypertrophy and craniofacial anomalies are more common, and surgical intervention is more successful. Epidemiologic studies have suggested an association between snoring and increased risk of hypertension, myocardial infarction, and stroke, even when adjusted for obesity, smoking, and age. The link may be through the 17-fold increase in risk for apnea in people who report snoring. A clue to the presence of apnea is the bed partner reporting observed apneas or respiratory pauses followed by a loud snort during sleep. Multiple apneas (>10 per hour of sleep) during sleep may result in daytime symptoms, commonly excessive daytime sleepiness. Because snoring is very common, the trait by itself should not trigger a search for sleep apnea. Snoring, hypertension, or obesity alone is a poor indication for a detailed evaluation for sleep apnea. Snoring in combination with observed apneas, excessive daytime sleepiness, hypertension poorly controlled by medical therapy, and heart disease is a better indication for examining the patient during sleep to quantify the presence, type, number, and severity of respiratory disturbances during sleep. Butler CC, Rollnick S, Kinnersley P, et al: Reducing antibiotics for respiratory tract symptoms in primary care: consolidating `why' and considering `how.' Br J Gen Pract 48:1865, 1998. This review identifies consulting skills, guidelines and monitoring strategies, patient education, and use of anti-inflammatory drugs for recurrent and chronic sinusitis. Stewart MH, Siff JE, Cydulka RK: Evaluation of the patient with sore throat, earache, and sinusitis: An evidence based approach. Emerg Med Clin North Am; 17:153, 1999. This article provides a window to the current literature regarding initial assessment of these common disorders.

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Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 516 - SMELL AND TASTE Robert W. Baloh

Millions of people suffer from disorders of taste and smell, yet there is relatively little information available on how to evaluate or treat these patients. These disorders have been neglected because they are seldom fatal and, unlike abnormalities of vision and hearing, are not considered serious handicaps. Chemosensory disorders, however, often reduce the enjoyment and quality of life and are important to patients who suffer from them. Disorders of taste interfere with digestion because taste stimulants alter salivary and pancreatic flow, gastric contractions, and intestinal motility. Smell also contributes to the anticipation and ingestion of food because much of what we taste derives from olfactory stimulation during ingestion and chewing. The inability to detect noxious tastes and odors can result in food or gas poisoning, particularly in elderly subjects. In the extreme, chemosensory disorders can lead to overwhelming stress, anorexia, and depression.

ANATOMY The sensory receptor for taste, the taste bud, is made up of 50 to 150 cells arranged to form a pear-shaped organ. The life span of these cells is 10 to 14 days, and they are constantly being renewed from dividing epithelial cells surrounding the bud. Taste buds are located on the tongue, soft palate, pharynx, larynx, epiglottis, uvula, and the upper one third of the esophagus. The taste buds located on the anterior two thirds of the tongue and on the palate are innervated by the chorda tympani branch of the seventh cranial nerve. The ninth cranial nerve innervates the posterior one third of the tongue. The ninth and tenth nerves innervate taste buds in the pharynx and larynx. Afferent signals from the taste buds project to the nucleus of the solitary tract in the medulla and then via a series of relays to the thalamus and postcentral somatosensory cerebral cortex (primary ipsilateral). Free nerve endings of the fifth cranial nerve are found on the tongue and in the oral cavity, and lesions involving these pathways also can alter taste perception. Olfactory receptors lie in a roughly dime-sized area of specialized pigmented epithelium that arches along the superior aspect of each side of the nasal mucosa. Specialized bipolar sensory cells in this region thrust short receptor hairs into the overlying mucosa to detect aromatic molecules as they dissolve. As with taste buds, the specialized receptor portion of the bipolar neuron undergoes continuous renewal, turning over approximately every 30 days. Thin axons of the bipolar neurons course through small holes in the cribriform plate of the ethmoid bone to form connections in the overlying olfactory bulb on the ventral surface of the frontal lobe. From here, second- and third-order neurons project directly and indirectly to the prepiriform cortex and parts of the amygdaloid complex of both sides of the brain, representing the primary olfactory cortex.

PATHOPHYSIOLOGY OF CHEMOSENSORY DISORDERS Disorders of taste and smell can be divided into local, systemic, and neurologic (Table 516-1) . The taste buds and the specialized receptor portion of the bipolar olfactory cells are constantly being renewed, and the process of renewal can be affected by nutritional, metabolic, and hormonal states, therapeutic radiation, drugs, and age. For example, with interruption of mitosis by antiproliferative agents, a return of normal taste function takes a minimum of 10 days, while a return to normal olfactory function takes more than 30 days. Numerous local conditions such as colds and allergies, chronic sinusitis, and nasal polyposis can influence the sense of smell by restricting airway patency. Accidental blows to the head can shear the fine axons of the bipolar olfactory neurons, resulting in loss of smell. Lesions of the fifth, seventh (chorda tympani), and ninth nerves can lead to disordered taste sensation. Olfactory and gustatory disturbances can serve as important diagnostic signs for focal neurologic lesions (e.g., frontal lobe tumors). Hallucinations of smell and taste occur with epileptogenic lesions affecting the mesial temporal lobe and insular region, respectively. Finally, olfactory disturbances and hallucinations occur with a number of psychiatric illnesses (particularly depressive illness and schizophrenia).

EXAMINATION OF TASTE AND SMELL Olfaction can be tested grossly at the bedside with a few easily recognized odors such as coffee, chocolate, and the roselike aroma 2250

TABLE 516-1 -- COMMON CAUSES OF LOSS OF TASTE AND SMELL TASTE

SMELL

Local

Radiation therapy

Allergic rhinitis, sinusitis, nasal polyposis, upper respiratory infection

Systemic

Cancer, renal failure, hepatic failure, nutritional deficiency (B3 , zinc), Cushing's syndrome, hypothyroidism, diabetes mellitus, infection (viral), drugs (antirheumatic and antiproliferative)

Renal failure, hepatic failure, nutritional deficiency (B12 ), Cushing's syndrome, hypothyroidism, diabetes mellitus, infection (viral hepatitis, influenza), drugs (nasal sprays, antibiotics)

Neurologic Bell's palsy, familial dysautonomia, multiple sclerosis

Head trauma, multiple sclerosis, Parkinson's disease, frontal tumor

of the compound phenylethyl alcohol. (Avoid nasal irritants.) Each nostril is tested separately to determine whether the problem is unilateral or bilateral. Gustatory sensation is typically tested with weak solutions of sugar, salt, and acetic acid, or vinegar. The patient must keep the tongue protruded and respond to questions either by nodding the head or pointing to names of the tastes written on cards. The anterior two thirds and posterior one third of the tongue should be tested separately.

COMMON CAUSES OF LOSS OF SMELL AND TASTE The most frequently encountered causes of loss of smell are local obstructive disease, viral infections, head injuries that sever the neurons crossing through the cribriform plate, and normal aging. Patients can lose their sense of smell not only from chronic allergies and sinusitis but also from the nasal sprays and drops that they use to treat these conditions. The most common causes of loss of the sense of taste are viral infections and drug ingestion, particularly antirheumatic and antiproliferative drugs. Many of the systemic disorders listed in Table 516-1 probably have their effect by decreasing the rate of turnover of sensory receptors on the tongue and olfactory epithelia. Disturbances of smell and taste in malnourished patients may be due to specific deficiencies in vitamins and minerals, such as zinc. Viral illnesses such as influenza and viral hepatitis produce disorders of both taste and smell. Multifocal neurologic disorders such as multiple sclerosis can affect the central olfactory and gustatory pathways at multiple levels, and therefore abnormalities of taste and smell are common in such patients. Treatment of olfactory dysfunction due to nasal disease is aimed at opening the air passageways while preserving the olfactory epithelium. Intranasal steriods, antibiotics, and allergic therapies are useful in selected cases. Drugs known to affect taste or smell should be removed for a trial. Vitamin and mineral therapies are of unproven benifit. Ackerman BH, Kasbekar N: Disturbances of taste and smell induced by drugs. Pharmacotherapy 17:482, 1997. Reviews all the common drugs that affect taste and smell. Deems DA, Doty RL, Settle G, et al: Smell and taste disorders, a study of 750 patients from the University of Pennsylvania smell and taste center. Arch Otolaryngol Head Neck Surg 117:519, 1991. A comprehensive look at the diagnosis and management of smell and taste disorders at a large university clinic. Schiffman SS: Taste and smell losses in normal aging and disease. JAMA 278:1357, 1997. Extensive review of the literature on disorders of taste and smell in the elderly.

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Chapter 517 - HEARING AND EQUILIBRIUM Robert W. Baloh

The neural pathways subserving hearing and those most important for equilibrium and spatial orientation are anatomically proximate in much of their course from their end organs in the inner ear to their termination in the superior portion of the temporal lobe. Because of the close anatomic linkage, disorders that affect hearing often affect equilibrium, and vice versa. For this reason they are considered together here. Despite their anatomic propinquity, however, substantial pathophysiologic differences make clinical examination of the two systems quite different. The auditory system is physiologically relatively isolated, so that its function and dysfunction can be tested independently of other neural systems. The vestibular system, in contrast, has many close physiologic links with other neural systems (particularly the cerebellum, oculomotor system, and autonomic nervous system) and can be tested only indirectly by noting secondary effects on these systems. Abnormalities of the auditory system lead to only a few well-defined and unique symptoms (i.e., hearing loss or tinnitus). Abnormalities of the vestibular system can cause symptoms that mimic disorders of the other neural structures. Such symptoms include dizziness, visual distortion (oscillopsia), imbalance, nausea, vomiting, and even syncope.

HEARING Anatomy and Physiology of Hearing In normal hearing, sound waves are transmitted from the tympanic membrane via the three ossicles of the air-filled middle ear (air conduction) to the oval window and the basilar membrane of the fluid-sealed cochlea. The ossicles serve to increase the gain from the tympanum to oval window about 18-fold, compensating for the loss that sound waves moving from air to fluid would otherwise suffer. In the absence of this system, sound may reach the cochlea by vibration of the temporal bone (bone conduction) but with much less efficiency (approximately 60 dB loss). Hair cells, tonotopically organized along the cochlear basilar membrane, detect the vibratory movement of that membrane and transduce vibration into nerve impulses. The nerve impulses are relayed via nerve cells that synapse at the base of hair cells and have their bodies in the spiral ganglion to the cochlear nucleus of the ipsilateral pontine tegmentum. The spiral cochlea mechanically analyzes the frequency content of sound. For high-frequency tones, only sensory cells in the basilar region are activated, whereas for low-frequency tones, all or nearly all sensory cells are activated. Therefore, with lesions of the cochlea and its afferent nerve, the hearing levels for different frequencies are usually unequal, typically resulting in better hearing sensitivity for low-frequency than for high-frequency tones. Within the brain stem, auditory signals ascend from the ventral and dorsal cochlear nuclei to reach the superior olivary nuclei of both sides. Thus nervous system lesions central to the cochlear nucleus do not cause monaural hearing loss and, conversely, unilateral central lesions do not cause deafness. From these structures the pathway projects by way of the lateral lemnisci to the inferior colliculi. Each inferior colliculus transmits to the other and to its ipsilateral medial geniculate body, which in turn sends the final projection to the transverse auditory gyrus lying in the superior portion of the ipsilateral temporal lobe. The normal ear can detect sound frequencies ranging between 20 and 20,000 Hertz (Hz); the upper range drops off fairly rapidly with advancing age. The ear is most sensitive between 500 and 4000 Hz, which roughly corresponds to the frequency range most important for understanding speech. The hearing level in this range has several practical implications in terms of the degree of handicap and the potential for useful correction with amplification. A 30- to 40-dB hearing level in the speech range would impair normal conversation, whereas an 80-dB hearing level would make everyday auditory communication almost impossible (the social definition of deafness).

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Localization of Lesions within the Auditory Pathways Conductive hearing loss results from lesions involving the external or middle ear. It is typically characterized by an approximately equal loss of hearing at all frequencies and by well-preserved speech discrimination once the threshold for hearing is exceeded. Patients with conductive hearing loss can hear speech in a noisy background better than in a quiet background because they can understand loud speech as well as anyone. Sensorineural hearing loss results from lesions of the cochlea and/or auditory division of the eighth cranial nerve. With sensorineural hearing loss the hearing levels for different frequencies are usually unequal, typically resulting in better hearing for low- than for high-frequency tones. Patients with sensorineural hearing loss often have difficulty hearing speech that is mixed with background noise and may be annoyed by loud speech. Three important manifestations of sensorineural lesions are diplacusis, recruitment, and tone decay. Diplacusis and recruitment are common with cochlear lesions; tone decay usually accompanies eighth nerve involvement. Central hearing disorders result from lesions of the central auditory pathways. As a rule, patients with central lesions do not have impaired hearing for pure tones, and they can understand speech as long as it is clearly spoken in a quiet environment. If the listener's task is made more difficult with the introduction of background noise or competing messages, performance deteriorates more markedly in patients with central lesions than in normal subjects. Examination of Hearing Bedside Test

A quick test for hearing loss in the speech range is to observe the response to spoken commands at different intensities (whisper, conversation, shouting). Tuning fork tests permit a rough assessment of the hearing level for pure tones of known frequency. The clinician can use his or her own hearing level as a reference standard. In the Rinne test, nerve conduction is compared with bone conduction by holding a tuning fork (preferably 512 Hz) against the mastoid process until the sound can no longer be heard. It is then placed 1 inch from the ear and, in normal subjects, can be heard about twice as long by air as by bone. If bone conduction is better than air conduction, the hearing loss is conductive, but care must be taken to assure that the bone conduction is not heard in the normal ear. In the Weber test, the tuning fork is placed on the patient's forehead or upper teeth. Normally this sound is referred to the center of the head. If it is referred to the side of unilateral hearing loss, the hearing loss is conductive; if it is referred away from the side of unilateral hearing loss, the loss is sensorineural. Audiometry

Pure tone testing is the cornerstone of most auditory examinations. Pure tones at selected frequencies are presented via either earphones (air conduction) or a vibrator pressed against the mastoid portion of the temporal bone (bone conduction), and the minimal level that the subject can hear (threshold) is determined for each frequency. Two speech tests are routinely used. The speech reception threshold (SRT) is the intensity at which the patient can correctly repeat 50% of the words presented. The SRT is a test of hearing sensitivity for speech and should reflect the hearing level for pure tones in the speech range. The speech discrimination test is a measure of the patient's ability to understand speech when it is presented at a level that is easily heard. In patients with eighth nerve lesions, speech discrimination scores can be severely reduced, even when pure tone thresholds are normal or nearly normal; by comparison, in patients with cochlear lesions, discrimination tends to be proportional to the magnitude of hearing loss. Brain stem auditory evoked responses (BAER) can be recorded from scalp electrodes at 0 to 10 msec (early), 10 to 50 msec (middle), and 50 to 500 msec (late) following a click (a high-frequency stimulus). The early potentials reflect electrical activity at the cochlea, eighth cranial nerve, and brain stem; the later potentials reflect cortical activity. Computer averaging of the responses to 1000 to 2000 clicks separates the evoked potential from background noise. Early evoked responses may be

used to estimate the magnitude of hearing loss and to differentiate among cochlea, eighth nerve, and brainstem lesions. Causes of Hearing Loss Conductive Hearing Loss

The logic for identifying common causes of hearing loss is shown in Figure 517-1 . The history, examination, and audiometry usually provide the key differential features. The most common cause of conductive hearing loss is impacted cerumen in the external canal. This benign condition is usually first noticed after bathing or swimming when a droplet of water closes the remaining tiny passageway. The most common serious cause of conductive hearing loss is inflammation of the middle ear, otitis media, either infected (suppurative) or noninfective (serous). Fluid accumulates in the middle ear, impairing the conduction of airborne sound to the cochlea. Since the air cavity of the middle ear is in direct connection with the mastoid air cells, infection can spread through the mastoid bone and, occasionally, into the intracranial cavity. Chronic otitis media with perforation of the tympanic membrane can result in an invasion of the middle ear and other pneumatized

Figure 517-1 Evaluation of hearing loss.

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areas of the temporal bone by keratinizing squamous epithelium (cholesteatoma). Cholesteatomas can produce erosion of the ossicles and bony labyrinth, resulting in a mixed conductive sensorineural hearing loss. Otosclerosis commonly produces progressive conductive hearing loss by immobilizing the stapes with new bone growth in front of and below the oval window. The hearing loss is typically conductive, although in some persons the cochlea may be invaded by foci of otosclerotic bone, producing an additional sensorineural hearing loss. Otosclerosis usually stabilizes when the hearing level reaches 50 to 60 dB, and rarely progresses to deafness. Other common causes of conductive hearing loss include trauma, congenital malformations of the external and middle ear, and glomus body tumors. Sensorineural Hearing Loss

Genetically determined deafness, usually from hair cell aplasia or deterioration, may be present at birth or may develop in adulthood. The diagnosis of hereditary deafness rests on the finding of a positive family history. In many instances the inheritance is through a recessive gene or a dominant gene with low penetrance, making it difficult to determine the genetic nature of the disorder. Mutations in cennexin 26, a key component of gap junctions in the inner ear, account for the majority of cases of inherited deafness identified so far. Intrauterine factors resulting in congenital hearing loss include infection (especially rubella); toxic, metabolic, and endocrine disorders; and anoxia associated with Rh incompatibility and difficult deliveries. Acute unilateral deafness usually has a cochlear basis. Bacterial or viral infections of the labyrinth, head trauma with fracture or hemorrhage into the cochlea, or vascular occlusion of a terminal branch of the anterior inferior cerebellar artery all can extensively damage the cochlea and its hair cells. An acute idiopathic, often reversible, unilateral hearing loss strikes young adults and is presumed to reflect an isolated viral infection of the cochlea and auditory nerve terminals. Sudden unilateral hearing loss often associated with vertigo and tinnitus can result from a perilymphatic fistula. Such fistulae may be congenital or may follow stapes surgery or head trauma. Drugs cause acute and subacute bilateral hearing impairment. Salicylates, furosemide, and ethacrynic acid have the potential to produce transient deafness when taken in high doses. More toxic to the cochlea are aminoglycoside antibiotics (gentamicin, tobramycin, amikacin, kanamycin, streptomycin, and neomycin). These agents can destroy cochlear hair cells in direct relation to their serum concentrations. Some antineoplastic chemotherapeutic agents, particularly cisplatin, cause severe ototoxicity. Subacute relapsing cochlear deafness occurs with Me nie re syndrome, a condition associated with fluctuating hearing loss and tinnitus, recurrent episodes of abrupt and often severe vertigo, and a sensation of fullness or pressure in the ear. Recurrent endolymphatic hypertension (hydrops) is believed to cause the episodes. Pathologically, the endolymphatic sac is dilated, and the hair cells become atrophic. The resulting deafness is subtle and reversible in the early stages but subsequently becomes permanent and is characterized by diplacusis and loudness recruitment. The disorder is usually unilateral, but in about 20 to 40% of patients bilateral involvement occurs. The gradual, progressive, bilateral hearing loss commonly associated with advancing age is called presbycusis. Presbycusis is not a distinct disease entity but rather represents multiple effects of aging on the auditory system. It may include conductive and central dysfunction, although the most consistent effect of aging is on the sensory cells and neurons of the cochlea. The typical audiogram of presbycusis is a symmetric high-frequency hearing loss gradually sloping downward with increasing frequency. The most consistent pathology associated with presbycusis is degeneration of sensory cells and nerve fibers at the base of the cochlea. The recurrent trauma of noise-induced hearing loss affects approximately the same cochlear region and is almost as common, particularly among those with exposure to loud explosive or industrial noises. Loud, blaring, modern music has become a recent offender. The loss almost always begins at 4000 Hz and does not affect speech discrimination until late in the disease process. With only brief exposure to loud, noise (hours to days), there may be only a temporary threshold shift, but with continued exposure, permanent injury begins. The duration and intensity of exposure determine the degree of permanent injury. Hearing loss from direct damage to the acoustic nerve in the petrous canal occasionally results from infection within or trauma to the surrounding bone; severe deafness of abrupt onset marks the event and is usually associated with acute vertigo due to concurrent vestibular nerve injury. Progressive unilateral hearing loss, that arises insidiously, initially in the high frequencies, and worsens by almost imperceptible degrees is characteristic of benign neoplasms of the cerebellopontine angle, such as acoustic neuromas. In about 10% of cases, the hearing loss can be acute, apparently owing to either hemorrhage into the tumor or compression of the labyrinthine vasculature. Central Hearing Loss

Central hearing loss is unilateral only if it results from damage to the pontine cochlear nuclei on one side of the brain stem from conditions such as ischemic infarction of the lateral brain stem (e.g., occlusion of the anterior inferior cerebellar artery), a plaque of multiple sclerosis, or, rarely, invasion or compression of the lateral pons by a neoplasm or hematoma. Bilateral degeneration of the cochlear nuclei accompanies some of the rare recessive inherited disorders of childhood. As noted, clinically important unilateral hearing loss never results from neurologic disease arising rostrad to the cochlear nucleus. Although bilateral hearing loss could, in theory, result from bilateral destruction of central hearing pathways, in practice this is rare because involvement of neighboring structures in the brain stem or hemisphere would usually produce overwhelming neurologic disability. Treatment of Hearing Loss If an underlying disorder has not yet destroyed the auditory system and can be ameliorated medically or surgically, hearing may be improved or preserved. Most patients with otosclerosis respond to stapedectomy. Closure of a perilymph fistula may improve hearing. Antibiotic and decongestive treatment of otitis media should prevent permanent hearing loss. A low-salt diet and diuretics are effective in selective cases of Meniere syndrome, particularly if episodes are precipitated by premenstrual water retention. Hearing aids amplify sound, usually with the goal of making speech intelligible. Patients with conductive hearing loss require simple amplification, but those with sensorineural hearing loss often need frequency-selective amplification to make hearing aids useful. Recent advances in acoustic technology have markedly improved the outlook for the latter. Serial audiograms in patients with noise or ototoxic drug exposure are critical for prevention of permanent hearing loss. Tinnitus The evaluation of common causes of tinnitus (Fig. 517-2) begins with a careful history to identify common offending drugs. With objective tinnitus, the patient hears a sound arising external to the auditory system, a sound that can usually be heard by the examiner with a stethoscope. Objective tinnitus usually has benign causes such as noise from temporomandibular joints, opening of eustachian tubes, or repetitive muscle contractions. Sometimes, in a quiet room, the patient can hear the pulsatile flow in the carotid artery or a continuous hum of normal venous outflow through the jugular vein. The latter can be obliterated by compression of the jugular vein or extreme lateral rotation of the neck. Pathologic objective tinnitus occurs when patients hear turbulent flow in vascular anomalies or tumors (e.g., glomus jugulare tumor). Objective tinnitus may also be an early sign of increased intracranial pressure. Such tinnitus, which probably arises from turbulent flow through compressed venous structures at the base of the brain, is usually overshadowed by other neurologic abnormalities. Subjective tinnitus can arise from sites anywhere in the auditory system. The sounds most frequently reported are metallic ringing, buzzing, blowing, roaring, or, less often, bizarre clanging, popping, or nonrhythmic beating. Tinnitus heard as a faint, moderately high-pitched, metallic ring can be observed by almost anyone who concentrates attention on auditory events in a quiet room. Sustained louder tinnitus accompanied by audiometric evidence of deafness occurs in association with both

conductive and sensorineural hearing loss. Tinnitus observed with otosclerosis tends to have a roaring 2253

Figure 517-2 Evaluation of tinnitus.

or hissing quality, while that associated with Meniere syndrome often produces sounds that vary widely in intensity with time and quality, sometimes including roaring or clanging. Tinnitus with auditory nerve lesions tends to be higher pitched and ringing in quality. Audiometric and brain stem-evoked response testing can help distinguish between lesions involving the conducting apparatus, the cochlea, and the auditory nerve. Tinnitus without observable deafness appears sporadically and for variable lengths of time in many persons without other evidence of an ongoing pathologic process. Treatment of Tinnitus Most patients with tinnitus can be helped by detailed interview together with the relevant examination and laboratory investigations followed by reassurance when appropriate. Often exacerbating factors such as chronic anxiety and depression can be treated. In patients with hearing loss and tinnitus, a hearing aid may improve tinnitus because the amplification of ambient sound may effectively mask the tinnitus. This mechanism probably explains the frequent observation that removal of cerumen from the external auditory canal to improve ambient hearing also improves tinnitus. Also, when cerumen is attached to the tympanic membrane, tinnitus may result from local mechanical effects on the conductive system. For patients who find their tinnitus most obtrusive when trying to sleep, a bedside FM clock radio tuned between stations can provide an effective masking sound that will switch itself off after the patient falls asleep. A careful drug history should be taken, and a drug-free trial period should be considered when possible. Some patients who notice that caffeine, alcohol, or nicotine exacerbates their tinnitus experience significant relief when these drugs are discontinued.

EQUILIBRIUM--VESTIBULAR SYSTEM Anatomy and Physiology of the Vestibular System The paired vestibular end organs lie within the temporal bones next to the cochlea. Each organ consists of three semicircular canals that detect angular acceleration and two otolith structures, the utricle and saccule, that detect linear acceleration (including gravitational). Like the cochlea, these organs possess hair cells that act as force transducers, converting the forces associated with head acceleration into afferent nerve impulses. The hair cells of the three semicircular canals, each of which is oriented at right angles to the others, are concentrated in the crista, where they are embedded in a gelatinous mass called the cupula. Movement of the head causes the endolymph to flow either toward or away from the cupula, bending the hair cells and, depending on the direction of endolymphatic movements, either exciting or inhibiting the afferent nerve firing. Because the afferent nerves arising from the semicircular canals are tonically active, the baseline activity can be increased or decreased depending on the direction of hair cell bending. Furthermore, the two sets of semicircular canals are approximately mirror images of each other, so that rotational movement of the head that excites one canal inhibits the analogous canal on the opposite side. The hair cells of the utricle and saccule are concentrated in an area called the macule. The macule of the utricle lies approximately in the plane of the horizontal canal, and the macule of the saccule is approximately in the plane of the anterior canal. The hair cells are embedded in a membrane that contains calcium carbonate crystals or otoliths; the density of otoliths is considerably greater than that of the endolymph. Linear accelerations of the head combine with the linear acceleration of gravity to distort the otolith membrane, thereby bending the underlying hair cells and modulating the activity of the afferent nerve terminals at the base of the hair cells. The afferent vestibular nerves have their cell bodies in Scarpa's ganglion. The nerve fibers travel in the vestibular portion of the eighth cranial nerve contiguous to the acoustic portion. Fibers from different receptor organs terminate in different vestibular nuclei at the pontomedullary junction. There are also direct connections with many portions of the cerebellum, the greatest representation being in the flocculonocular lobe, the so-called vestibular cerebellum. Efferent fibers from the brain stem travel through the vestibular nerve to reach hair cells of the semicircular canals and macules. Efferent fibers are inhibitory in nature and, like the efferent fibers of the cochlea, may function to enhance inputs to which the brain attends. From the vestibular nuclei, second-order neurons make important connections to the vestibular nuclei of the other side, to the cerebellum, to motor neurons of the spinal cord, to autonomic nuclei in the brain stem, and, most importantly for the examining clinician, to the nuclei of the oculomotor system. Fibers from the vestibular nuclei also ascend through the brain stem and thalamus to reach the cerebral cortex bilaterally.

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Localization of Lesions within the Vestibular Pathways Vertigo can be caused by either the peripheral or central vestibular apparatus. In general, peripheral vertigo is more severe, is more likely to be associated with hearing loss and tinnitus, and often leads to nausea and vomiting. Nystagmus associated with peripheral vertigo is usually inhibited by visual fixation. Central vertigo is generally less severe than peripheral vertigo and is often associated with other signs of central nervous system disease. The nystagmus of central vertigo is not inhibited by visual fixation and frequently is prominent when vertigo is mild or absent. Examination of the Vestibular System Most vestibular problems presenting to the physician are episodic, and often there are neither symptoms nor signs when the physician examines the patient. The history, therefore, can become paramount for identifying vestibular dysfunction. The history should attempt to distinguish vertigo (the illusion of movement in space) from lightheadedness (presyncope), ataxia (disequilibrium of the body without true movement in space), and psychogenic symptoms (the feeling of dissociation or, sometimes, disequilibrium). If the history is not clear, bedside provocative tests to mimic the symptom may assist in making a pathophysiologic diagnosis. Hyperventilation, which lowers the Pa CO2 and decreases cerebral blood flow, causes a lightheaded sensation associated with syncope. Patients with compressive lesions of the vestibular nerve, such as with an acoustic neuroma or cholesteatoma, or with demyelination of the vestibular nerve root entry zone may develop vertigo and nystagmus after hyperventilation. Presumably, metabolic changes associated with hyperventilation trigger the partially damaged nerve to fire inappropriately. Bedside tests of vestibulospinal function are often insensitive because most patients can use vision and proprioceptive signals to compensate for any vestibular loss. Patients with acute unilateral peripheral vestibular lesions may past point or fall toward the side of the lesion, but within a few days balance returns to normal. Patients with bilateral peripheral vestibular loss have more difficulty compensating and usually show some imbalance on the Romberg and tandem walking tests, particularly with eyes closed. The vestibulo-ocular reflex can be tested at the bedside using the doll's-eye and head-thrust tests. In an alert human, rotating the head back and forth in the horizontal plane induces compensatory horizontal eye movements that are dependent on both the visual and vestibular systems. The doll's-eye test is a test of vestibular function in a comatose patient, since such patients cannot generate pursuit or corrective fast components. In this setting conjugate compensatory eye movements indicate normally functioning vestibulo-ocular pathways. Because the vestibulo-ocular reflex has a much higher frequency range than the smooth pursuit system, a qualitative bedside test of vestibular function can be made with the head-thrust test. It is performed by grasping the patient's head and applying brief, small-amplitude, high-acceleration head thrusts first to one side and then the other. The patient fixates on the examiner's nose and the examiner watches for corrective saccades, which are a sign of an inappropriate compensatory slow phase. The caloric test uses a nonphysiologic stimulus to induce endolymphatic flow in the horizontal semicircular canal and horizontal nystagmus by creating a temperature gradent from one side of the canal to the other. With a cold caloric stimulus, the column of endolymph nearest the middle ear falls because of its increaseddensity. This causes the cupula to deviate away from the utricle (ampullofugal flow) and produces horizontal nystagmus with the fast phase directed away from the stimulated ear. A warm stimulus produces the opposite effect, causing ampullopedal endolymph flow and nystagmus directed toward the stimulated ear (mnemonic: COWS--cold opposite, warm same). Because of its ready availability, ice water (approximately 0°C) can be used for bedside caloric testing. To bring the horizontal canal into the vertical plane, the patient lies in the supine position with head tilted 30 degrees forward. Infusion of 1 to 3 mL of ice water induces a burst of nystagmus usually lasting about a minute. Greater than a 20% asymmetry in nystagmus duration suggests a lesion on the side of the decreased response. The ice water caloric test is a useful way to test the integrity of the oculomotor pathways in a comatose patient. In this case, ice water induces only a slow tonic deviation toward the side of stimulation. Examination for pathologic vestibular nystagmus should include a search for spontaneous and positional nystagmus (see Table 513-3) . Because vestibular nystagmus secondary to peripheral vestibular lesions is inhibited with fixation, the yield is increased by impairing fixation (such as with +30 lenses, Frenzel glasses). Two general types of positional nystagmus can be identified on the basis of nystagmus duration: static and paroxysmal. One induces static positional nystagmus by slowly placing the patient into the supine, then right lateral, and then left lateral positions. This type of positional nystagmus persists as long as the position is held. Because direction-changing and direction-fixed forms of static positional nystagmus occur with both peripheral and central vestibular lesions, their presence indicates only a

dysfunction somewhere in the vestibular system. As with spontaneous nystagmus, however, lack of suppression with fixation and signs of associated brain stem dysfunction suggest a central lesion. Paroxysmal positional nystagmus (also called positioning nystagmus) is induced, after a brief delay, by a rapid change from erect sitting to supine head-hanging left, center, or right position (the so-called Dix-Hallpike test). It is initially high in frequency but dissipates rapidly (within 30 seconds to 1 minute). The most common variety of paroxysmal positional nystagmus, benign paroxysmal positional nystagmus, usually has a 3- to 10-second latency before onset and rarely lasts longer than 30 seconds. The nystagmus is always torsional with the upper pole of the eye beating toward the ground. It is usually prominent in only one head-hanging position, and a burst of nystagmus in the reverse direction occurs when the patient reassumes the sitting position. Another key feature is the severe vertigo and nystagmus that the patient experiences with the initial positioning, which, with repeated positioning, rapidly disappear (fatigability). Benign paroxysmal positional nystagmus is a sign of vestibular end-organ dysfunction (see below). Electronystagmography (ENG), which is a technique for recording eye movements, allows precise quantification of both physiologic and pathologic nystagmus. A standard ENG test battery includes (1) tests of visual ocular control (saccades, smooth pursuit, and optokinetic nystagmus); (2) a careful search for pathologic nystagmus with fixation and with eyes open in darkness, and (3) measurement of induced physiologic nystagmus (caloric and rotational). ENG can be helpful in identifying a vestibular lesion and localizing it within the peripheral and central pathways. Evaluating the "Dizzy" Patient The history is key because it determines the type of dizziness (vertigo, light-headed, feeling of dissociation, disequilibrium), associated symptoms (neurologic, audiologic, cardiac, psychiatric), precipitating TABLE 517-1 -- DISTINGUISHING BETWEEN VESTIBULAR AND NONVESTIBULAR TYPES OF DIZZINESS VESTIBULAR NONVESTIBULAR Common descriptive terms

Spinning (environment moves), merry-go-round, drunkenness, tilting, motion sickness, off-balance

Light-headed, floating, dissociated from body, swimming, giddy, spinning inside (environment stationary)

Course

Episodic

Constant

Common precipitating factors

Head movements, position change

Stress, hyperventilation, cardiac arrhythmia, situations

Common associated symptoms

Nausea, vomiting, unsteadiness, tinnitus, hearing loss, impaired vision, oscillopsia

Perspiration, pallor, paresthesias, palpitations, syncope, difficulty concentrating, tension headache

From Baloh RW, Honrubia V: Clinical Neurophysiology of the Vestibular System, 2nd ed. Philadelphia, FA Davis, 1990.

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factors (position change, trauma, stress, drug ingestion), and predisposing illness (systemic viral infection, cardiac disease, cerebrovascular disease) (Table 517-1) . The examination should include complete neurologic, head and neck, and cardiac assessments. When focal neurologic signs are found, neuroimaging usually leads to specific diagnosis. When vertigo is present without focal neurologic symptoms or signs, audiometry and electronystagmography aid in localizing the lesion to the labyrinth or eighth nerve. Patients with hyperventilation syndrome and/or acute anxiety should be identified after the history and examination so that needless tests are not obtained. A detailed cardiac evaluation (including Holter monitoring) often identifies the cause of episodic presyncopal light-headedness. Common Causes of Vertigo (Figure 517-3) Physiologic Vertigo

Physiologic vertigo includes common disorders such as motion sickness, space sickness, and height vertigo. In these conditions, vertigo (defined as an illusion of movement) is minimal or absent while autonomic symptoms predominate. With height vertigo, patients often experience acute anxiety and panic reaction. Individuals with motion sickness and space sickness typically develop perspiration, nausea, vomiting, increased salivation, yawning, and generalized malaise. Gastric motility is reduced and digestion impaired. Even the sight or smell of food is distressing. Hyperventilation is a common sign, and the resulting hypocapnia leads to changes in blood volume, with pooling in the lower parts of the body predisposing to postural hypotension and syncope. An unusual variant of motion sickness continues when the subject returns to stationary conditions after prolonged exposure to motion. Typically, affected patients report that they feel the persistent rocking sensation of a boat long after returning to solid ground. Rarely, the syndrome can last for months to years after exposure to motion and can even be incapacitating. The cause is unknown. Physiologic vertigo can often be suppressed by supplying sensory cues that help to match the signals originating from different sensory systems. Thus, motion sickness, which is exacerbated by sitting in a closed space or reading (giving the visual system the miscue that the environment is stationary), may be improved by looking out at the environment and watching it move. Height vertigo, caused by a mismatch between sensation of normal body sway and lack of its visual detection, can often be relieved either by sitting or by visually fixating a nearby stationary object. Benign Positional Vertigo (BPV)

BPV is by far the most common cause of vertigo. Patients with this condition develop brief episodes of vertigo (less than 1 min) with position change, typically when turning over in bed, getting in and out of bed, bending over and straightening up, or extending the neck to look up. BPV can result from head injury, viral labyrinthitis, and vascular occlusion, or it may occur as an isolated symptom (in about 50% of cases). The latter is particularly common in the elderly. This syndrome is important to recognize because in the vast majority of patients, the symptoms spontaneously remit. BPV does commonly recur, however. The diagnosis rests on finding characteristic fatigable paroxysmal positional nystagmus after a rapid change from the sitting to the head-hanging position (see above). BPV results from free-floating calcium carbonate crystals (normally attached to the utricular macule) that inadvertently enter the long arm of the posterior semicircular canal. The crystals move within the endolymph and displace the cupula. Consistent with this theory, the burst of paroxysmal positional nystagmus is in the plane of the posterior canal of the "down ear," and the positional nystagmus disappears after the ampullary nerve has been surgically resected from the posterior canal on the diseased side. If the history and physical findings are typical, a simple bedside positioning maneuver can remove the debris from the posterior semicircular canal in most patients (Fig. 517-4) . If the history or findings are atypical, the condition must be distinguished from other causes of positional vertigo that may occur with tumors or infarcts of the posterior fossa. Acute Peripheral Vestibulopathy ("Acute Labyrinthitis")

One of the most common clinical neurologic syndromes at any age is the acute onset of vertigo, nausea, and vomiting lasting for several days and not associated with auditory or neurologic symptoms. Most affected patients gradually improve over 1 to 2 weeks, but some develop recurrent episodes. A large percentage report an upper respiratory tract illness 1 to 2 weeks prior to the onset of vertigo. This syndrome occasionally occurs in epidemics (epidemic vertigo) may affect several members of the same family, and more often erupts in the spring and early summer. All of these factors suggest a viral origin, but attempts to isolate an agent have been unsuccessful, except for occasional findings of a herpes zoster infection. Pathologic studies showing atrophy of one or more vestibular nerve trunks, with or without atrophy of their associated sense organs, are evidence of a vestibular nerve site and, probably, viral cause for many patients with this syndrome (viral neurolabyrinthitis). Meniere Syndrome

The typical clinical features of Meniere syndrome are described earlier. This disorder accounts for about 10% of all patients with vertigo. The diagnosis is based on documenting episodic severe attacks accompanied by fluctuating hearing levels on audiometric testing beginning in the low frequencies.

Figure 517-3 Evaluation of vertigo.

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Figure 517-4 Treatment maneuver for benign positional vertigo affecting the right ear. The procedure is reversed for treating the left ear. The numbers in the posterior semicircular canal (PSC) correspond to the position of the calcium carbonate crystals in each head position as they are moved toward the utricle (UT). Each position change is performed as rapidly as possible to accelerate the particles. Positions 2 and 3 are the same except that the therapist has moved from the front to the back of the patient to continue the maneuver easily. The entire sequence should be repeated until no nystagmus is elicited. (Courtesy of Carol A. Foster, MD, University of Colorado School of Medicine.)

Migraine

Vertigo is a common symptom with migraine. It can occur with headaches or in separate isolated episodes, and it can predate the onset of headache. So-called benign paroxysmal vertigo of childhood is often the first symptom of migraine. The mechanism of vertigo with migraine is not clear, but damage to the inner ear occurs in about one fourth of patients. A few develop typical features of Meniere syndrome. Post-traumatic Vertigo

Vertigo, hearing loss, and tinnitus often follow a blow to the head that does not result in temporal bone fracture, the so-called labyrinthine concussion. Although they are protected by a bony capsule, the delicate labyrinthine membranes are susceptible to blunt trauma. Blows to the occipital or mastoid region are particularly likely to produce labyrinthine damage. Transverse fractures of the temporal bone typically pass through the vestibule of the inner ear, tearing the membranous labyrinth and lacerating the vestibular and cochlear nerves. Complete loss of vestibular and cochlear function is the usual sequela, and the facial nerve is interrupted in approximately 50% of cases. Examination of the ear often reveals hemotympanum, but bleeding from the ear seldom occurs because the tympanic membrane usually remains intact. As noted above, benign positional vertigo is also a common sequela of head trauma. Fistulae of the oval and round windows can result from impact noise, deep-water diving, severe physical exertion, or blunt head injury without skull fracture. The mechanism of the rupture is a sudden negative or positive pressure change in the middle ear or a sudden increase in cerebrospinal fluid pressure transmitted to the inner ear via the cochlear aqueduct and internal auditory canal. Clinically, the rupture leads to the sudden onset of vertigo or hearing loss, or both. Surgical exploration of the middle ear is warranted when there is a clear relationship between the onset of vertigo or hearing loss, or both, and the onset of severe exertion, barometric change, head injury, or impact noise. Postconcussion Syndrome

The so-called postconcussion syndrome refers to a vague dizziness (rarely vertigo) associated with anxiety, difficulty in concentrating, headache, and photophobia induced by a head injury resulting in concussion. Occasionally, similar, less pronounced symptoms are associated with mild head injury judged to be trivial at the time. The cause is unknown, but animal studies indicate that small multifocal brain lesions (petechiae) commonly occur after concussive brain injury. Other Peripheral Causes of Vertigo

Vertigo can be associated with chronic bacterial otomastoiditis, either from direct invasion of the inner ear by the bacteria or by erosion of the labyrinth by a cholesteatoma. Radiographic studies of the temporal bone readily identify these disorders. Just as otosclerosis can result in sensorineural hearing loss, it can also produce vertigo by involving the bony labyrinth. The typical audiometric findings of a combined conductive and sensorineural hearing loss should suggest this diagnosis. Several drugs that damage the auditory system, such as the aminoglycosides, may also damage the vestibular labyrinth. The patient may suffer acute vertigo, either along with or independent of hearing loss and tinnitus, if the toxic effect is asymmetric. More often there is a progressive symmetric loss of vestibular function leading to imbalance but not vertigo. Unfortunately, many patients being treated with ototoxic drugs are initially bedridden and unaware of the vestibular impairment until they recover from their acute illness and try to walk. Then they discover that they are unsteady on their feet and that the environment tends to jiggle in front of their eyes (oscillopsia). Younger patients adapt after weeks to the labyrinthine failure; older ones may be left permanently disabled. Usually there is no nystagmus (because of the symmetric involvement), but the patient is ataxic. Caloric and rotational tests during electronystagmography can document impairment or absence of vestibular function. The best treatment is prevention. If the drug is discontinued early during the course of symptoms, the disorder may stabilize or improve. Vascular Insufficiency

Vertebrobasilar insufficiency is a common cause of vertigo in the elderly (see also Chapter 470) . Whether the vertigo originates from ischemia of the labyrinth, brain stem, or both structures is not always clear because the blood supply to the labyrinth, eighth cranial nerve, and vestibular nuclei originate from the same source, the basilar vertebral circulation. Vertigo with vertebrobasilar insufficiency is abrupt in onset, usually lasting several minutes, and is frequently associated with nausea and vomiting. Associated symptoms resulting from ischemia in the remaining territory supplied by the posterior-circulation include visual illusions and hallucinations, drop attacks and weakness, visceral sensations, visual field defects, diplopia, and headache. These symptoms occur in episodes either in combination with the vertigo or alone. Vertigo may be an isolated initial symptom of vertebrobasilar ischemia, but repeated episodes of vertigo without other symptoms should suggest another diagnosis. Vertebrobasilar insufficiency usually is caused by atherosclerosis of the subclavian, vertebral, and basilar arteries. Occasionally, episodes of vertebrobasilar insufficiency are precipitated by postural hypotension, Stokes-Adams attacks, or mechanical compression from cervical spondylosis. Magnetic resonance imaging (MRI) of the brain is usually normal because the vascular insufficiency is transient and function returns to normal between episodes. MR angiography can identify occlusive vascular disease most commonly involving the vertebral-basilar junction. Vertigo is a common symptom associated with infarction of the lateral brain stem or cerebellum, or both. The diagnosis usually is clear, based on the characteristic acute history and pattern of associated symptoms and neurologic findings. Occasionally cerebellar infarction or hemorrhage presents with severe vertigo, vomiting, and ataxia without associated brain stem symptoms and signs that might suggest the erroneous diagnosis of an acute peripheral vestibular disorder. The key differential point is the finding of clear 2257

cerebellar signs (extremity- and gait ataxia) and gaze-evoked nystagmus. Such patients must be watched carefully for several days because they may develop progressive brain stem dysfunction owing to compression by a swollen cerebellum. Cerebellopontine-Angle Tumors

Most tumors growing in the cerebellopontine angle (e.g., acoustic neuroma, meningioma, epidermal cyst) grow slowly, allowing the vestibular system to accommodate so that they produce a vague sensation of disequilibrium rather than acute vertigo. Occasionally, however, episodic vertigo or positional vertigo heralds the presence of a cerebellopontine-angle tumor. In virtually all patients, retrocochlear hearing loss is present, best identified by an abnormal brain stem auditory evoked response. MRI with contrast is the most sensitive diagnostic study for identifying a cerebellopontine angle tumor. Other Central Causes of Vertigo

Acute vertigo may be the first symptom of multiple sclerosis, although only a small percentage of young patients with acute vertigo eventually develop multiple sclerosis. Vertigo in multiple sclerosis is usually transient and often associated with other neurologic signs of brain stem disease, in particular, internuclear opthalmoplegia or cerebellar dysfunction. Vertigo may also be a symptom of parainfectious encephalomyelitis or, rarely, parainfectious cranial polyneuritis. In this instance, the accompanying neurologic signs establish the diagnosis. The Ramsay-Hunt syndrome (geniculate ganglion herpes) is characterized by vertigo and hearing loss associated with facial paralysis and, sometimes, pain in the ear. The typical lesions of herpes zoster, which may follow the appearance of neurologic signs, are found in the external auditory canal and over the palate in some patients. Rarely is herpes zoster responsible for vertigo in the absence of the full-blown syndrome. Granulomatous meningitis or leptomeningeal metastasis and cerebral or systemic vasculitis may involve the eighth nerve, producing vertigo as an early symptom. In these disorders cerebrospinal fluid analysis usually suggests the diagnosis. Patients suffering from temporal lobe epilepsy occasionally experience vertigo as the aura. Vertigo in the absence of other neurologic signs or symptoms is never caused by epilepsy or other diseases of the cerebral hemispheres. Treatment of Vertigo

Treatment of vertigo can be divided into three general categories: specific, symptomatic, and rehabilitative. Specific therapies include antibiotics for bacterial or syphilitic labyrinthifis, anticoagulants for vertebrobasilar insufficiency, and surgery for acoustic neuroma. When possible, treatment should be directed at the underlying disorder. In most cases, however, symptomatic treatment is either combined with specific therapy or is the only treatment available (e.g., with acute peripheral vestibulopathy). Many different classes of drugs have been found to have antivertiginous properties, and in most instances the exact mechanism of action is uncertain. All of these agents produce potentially unpleasant side effects, and the decision on which drug or combination to use is based on their known complications and on the severity and duration of the vertigo. An episode of prolonged, severe vertigo is one of the most distressing symptoms that one can experience. Affected patients prefer to lie still with eyes closed in a quiet, dark room. Antivertiginous drugs with sedation such as Phenergan (25 mg four times daily [q.i.d.]) or diazepam (5 mg q.i.d.) may be helpful. Prochlorperazine suppositories (25 mg) may stop vomiting. In more chronic vertiginous disorders, when the patient is trying to carry on normal activity, less

sedating antivertiginous medications such as meclizine (25 mg q.i.d.) or transdermal scopolamine (0.5 mg every 3 days) may provide relief. Vestibular rehabilitation exercises are designed to help the patient compensate for permanent loss of vestibular function. Baloh RW: Dizziness, Hearing Loss and Tinnitus. New York, Oxford University Press, 1998. Monograph reviewing basic and clinical aspects of auditory and vestibular function. Katz J: Handbook of Clinical Audiology, 4th ed. Baltimore, Williams & Wilkins, 1994. Classic textbook and excellent reference source. Lanska DJ, Remler B: Benign paroxysmal positioning vertigo: Classic descriptions, origins of the provocative positioning technique, and conceptual developments. Neurology 48:1167, 1997. How and why the positioning maneuver works.

MD Consult L.L.C. http://www.mdconsult.com Bookmark URL: /das/book/view/882/567.html/top

Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Chapter 518 - HEAD AND NECK CANCER Adriane P. Concus Mark I. Singer

Head and neck cancers, excluding those of cutaneous origin, comprise 3.5% of all new cancer diagnoses in the United States each year. Of these 42,000 cases, over 90% are squamous cell carcinomas of the upper aerodigestive tract. Despite newer approaches to treatment and decreased disease morbidity, long-term survival has not changed significantly over the past several decades. Head and neck cancers still have an overall 5-year survival of 60% and currently are responsible for just over 2% of cancer deaths annually in the United States. Head and neck cancers carry enormous debilitating potential. Adverse effects on breathing, swallowing, and speech, along with disfigurement from either the tumor itself or its treatment, all too often lead to social isolation for head and neck cancer patients. A multidisciplinary approach, including input from otolaryngology, medical and radiation oncology, dentistry, social work, and speech therapy, provides the most comprehensive and effective care for head and neck cancer patients. Head and neck cancers are staged according to the American Joint Committee on Cancer (AJCC) staging system using a T (primary tumor size), N (regional node), M (distant metastasis) classification system (Table 518-1) . Each primary site has its own unique T-staging approach based on differences in anatomic structure, biologic behavior, and lymphatic drainage, but there is one common staging system for nodal and distant metastases. Head and neck cancers drain through cervical lymphatics, generally to successively contiguous ipsilateral nodes, although the base of tongue, tonsil fossae, and pharynx are common sites for bilateral nodal metastasis. For prognostic purposes and developing treatment plans, the neck is divided into five levels (Fig. 518-1) . Level I, the submental and submandibular region, drains the anterior oral cavity. Level II, the jugulodigastric region, is the first echelon of nodes for the tongue, posterior oral cavity, and tonsil fossae. Hypopharynx and larynx cancers drain into level III, the midjugular nodes, and level IV, the low jugular chain. Level V, the posterior cervical triangle, drains the occiput and scalp as well as higher level neck nodes; patients with positive level V lymph nodes are very rarely cured of their disease. Carcinomas of the thyroid and parathyroids, which are covered elsewhere (see Chapters 239 and 264 , respectively), are part of the differential diagnosis of any neck mass and must be considered in the evaluation of any complaint of dysphagia or hoarseness.

SQUAMOUS CELL CARCINOMA OF THE UPPER AERODIGESTIVE TRACT Over 90% of head and neck cancers are primary squamous cell carcinomas of the upper aerodigestive tract. This complex anatomic area extends from the vermilion border of the lips to the level of the cricoid cartilage and includes the nose, paranasal sinuses, and nasopharynx. The upper aerodigestive tract is lined with stratified squamous and columnar epithelium, interspersed with minor salivary glands, lymph nodes, lymphatic and blood vessels, and nerves. The behavior of squamous cell carcinoma in different locations in the upper aerodigestive tract varies depending on the lymphatic drainage and anatomic barriers to spread such as fascia, fibroelastic membranes, perichondrium, and periosteum. For instance, true vocal cord cancers are typically contained within the larynx because of the poor lymphatic drainage of the glottis. The hypopharynx, in contrast, is an area rich in venous and lymphatic supply with few barriers to spread; squamous cell carcinoma arising in this location most frequently is advanced at detection and has the poorest prognosis of the upper aerodigestive tract malignancies. About half of upper aerodigestive tract squamous cell carcinoma occurs in the oral cavity and oropharynx, one third in the larynx, and the remainder in the hypopharynx, nasopharynx, and paranasal sinuses. ETIOLOGY. Head and neck mucosal squamous cell carcinoma 2258

TABLE 518-1 -- AMERICAN JOINT COMMITTEE ON CANCER (AJCC) STAGING FOR HEAD AND NECK SQUAMOUS CELL CARCINOMA LARYNX ORAL CAVITY OROPHARYNX HYPOPHARYNX Tis Carcinoma in situ

Carcinoma in situ

Carcinoma in situ

Carcinoma in situ

T1 Tumor limited to one subsite of the larynx

Tumor 2 cm

Tumor 2 cm

Tumor 2 cm, limited to one subsite of the hypopharynx

T2 Tumor involving more than one subsite and/or impaired vocal cord mobility

Tumor > 2 cm and 4 cm

Tumor >2 cm and 4 cm

Tumor > 2 cm and 4 cm, involving more than one subsite

Tumor > 4 cm

Tumor > 4 cm, involving more than one subsite; paralyzed vocal cord

T3 Paralyzed vocal cord; involvement of pre-epiglottic or Tumor > 4 cm postcricoid areas (supraglottic primary) T4 Extension outside the larynx; cartilage invasion

Extension to soft tissues or bone Invasion of adjacent bone Invasion of adjacent bone/muscle/cartilage outside the oral cavity or muscle

N0 No cervical lymph nodes positive

M0 No distant metastasis

N1 Single ipsilateral lymph node 3 cm

M1 Distant metastasis present

N2a Single ipsilateral lymph node >3 cm and 6 cm

Mx Distant metastasis cannot be assessed

N2b Multiple ipsilateral lymph nodes, each 6 cm N2c Bilateral or contralateral lymph nodes, each 6 cm N3 Single or multiple lymph nodes >6 cm Stage

T

N

M

Stage I

T1

N0

M0

Stage II

T2

N0

M0

Stage III

T3

N0

M0

T1-3

N1

M0

T4

N0-1

M0

Any T

N2-3

M0

Any T

Any N

M1

Stage IV

carcinogenesis is a multistep process of initiation, promotion, and progression reflected histologically by the transitions from the normal epithelial phenotype to dysplasia, carcinoma in situ, and invasive carcinoma. The most important predisposing risk factors for the development of primary head and neck squamous cell carcinoma is the use of alcohol and tobacco in all of its forms. Alcohol potentiates the carcinogenic effects of tobacco, and the use of the two together is more than additive in enhancing carcinogenesis. Seventy-five per cent of head and neck cancer patients have a history of both tobacco and alcohol use. Other associated etiologic agents include viruses. The human papillomavirus, in particular types 6, 11, 16, and 18, has been implicated in the development of upper aerodigestive tract squamous cell carcinoma. The Epstein Barr virus has been associated with nasopharyngeal carcinoma, as have dietary factors popular in southeast Asia where this type of carcinoma is most prevalent.

Figure 518-1 Levels of the neck, as commonly subdivided for designation of nodal metastases. (Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Manual for Staging of Cancer, 4th ed. Philadelphia, Lippincott-Raven, 1992.)

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Head and neck squamous cell carcinoma has a higher incidence in immunocompromised individuals, including those with human immunodeficiency virus (HIV) infection and those on chronic immunosuppression after organ transplantation. Familial studies also have suggested a genetic susceptibility. Cytogenetic changes, including loss of chromosomal heterozygosity, oncogene expression, and markers of dysregulated cell growth and proliferation are now being investigated as links in the carcinogenic process. Mutation of the p53 tumor suppressor gene, the most common head and neck squamous cell carcinoma genetic abnormality, is found in 40 to 70% of patients and is associated with poorer response to treatment and worse prognosis. The theory of field cancerization views the entire upper aerodigestive tract of a head and neck squamous cell carcinoma patient as "condemned mucosa," hypothesizing that chronic carcinogen exposure puts the entire area at risk for undergoing malignant transformation. Indeed, 4 to 7% of patients with a previous head and neck squamous cell carcinoma will develop a second primary squamous cell carcinoma each year, with a lifetime risk of 10 to 40%. Thus, a head and neck squamous cell carcinoma patient is a patient for life, requiring regular visits to exclude a second primary. NATURAL HISTORY. Presenting symptoms for head and neck squamous cell carcinoma are varied and often related to the site of tumor origin. Tumors in the larynx or hypopharynx can cause hoarseness, dysphagia, odynophagia, stridor, and otalgia (ear pain referred from the pharynx by means of the glossopharyngeal nerve). An ill-fitting denture, non-healing "mouth sores," oral pain, or slurred speech may reflect an oral cavity tumor. Epistaxis, nasal obstruction, or headaches may be due to a paranasal sinus tumor. Unilateral serous otitis media in an adult is a nasopharyngeal neoplasm until proven otherwise. Other symptoms of head and neck cancers include trismus and cranial nerve palsies. Patients whose presenting compliant is an incidentally noted neck mass tend not to do as well because survival of those with nodal metastases at the time of diagnosis is half that of patients with stage I or II disease. Two thirds of patients with squamous cell carcinoma of the upper aerodigestive tract have regional nodal metastases at the time of diagnosis; 20% have distant metastases. Head and neck squamous cell carcinoma spreads first through lymphatics to regional lymph nodes, mandating locoregional control as a goal of primary treatment. Distant systemic metastases occur most often in lung and bone, although liver, skin, brain, and other tissues also can be affected. Systemic metastases virtually never occur in the absence of regional lymphadenopathy. Hypercalcemia is seen in up to 25% of patients in far-advanced stages of the disease. Patients who die of head and neck squamous cell carcinoma succumb either to local tumor effects or to the effects of distant metastases. DIAGNOSIS. The evaluation of a patient suspected of having an upper aerodigestive tract squamous cell carcinoma proceeds first to establish a tissue diagnosis. Lesions are varied in appearance. Early lesions can be as innocuous as an area of erythroplakia or, less often, leukoplakia. Larger tumors can be fungating, ulcerative, sessile, polypoid, or submucosal. Tumors in easily accessible areas can be sampled in the outpatient setting. Lesions in less accessible areas, such as the larynx or hypopharynx, usually require biopsy under general anesthesia. For staging purposes and because of the incidence of concurrent second primary lesions, a thorough endoscopic examination of the entire upper aerodigestive tract, typically done under general anesthesia with biopsies of all suspicious lesions, is indicated for all patients newly diagnosed with a head and neck squamous cell carcinoma. Radiologic staging, usually with contrast medium-enhanced computed tomography (CT) or magnetic resonance imaging (MRI), helps assess the size, extent, and surgical resectability of a primary tumor and highlights the presence of suspicious nodal metastases that may not have been palpable on physical examination. Lymph nodes larger than 1 cm, those with irregular shape, and those with contrast ring enhancement or a heterogeneous appearance suggestive of central necrosis are radiologically suspicious for carcinoma. A routine chest radiograph screens for pulmonary metastases. Liver function tests or an abdominal ultrasound evaluation are sometimes included to screen for liver metastases. Although still considered experimental, positron emission tomographic (PET) scanning identifies active tumor by highlighting metabolically active tissue and is particularly promising in the evaluation of previously irradiated anatomy, whose signal characteristics on MRI or CT can be non-specific. For suspected laryngeal tumors, videostroboscopy can help document the current mobility of the vocal cords, the size and location of a laryngeal mass, and any impairment of vocal cord vibration, reflecting a submucosal process. EVALUATION OF A NECK NODE. There is no substitute for a thorough head and neck examination in the evaluation of a neck mass. If a likely primary cancer is identified, that site is sampled and the neck node is presumed to be a metastasis from that primary site. If malignancy is suspected and no primary site is identified on physical examination, fine-needle aspiration (FNA) is indicated. In experienced hands, the specimen will give highly accurate histologic results (>95% sensitivity and specificity). CT or MRI can evaluate the size of the neck mass and possible invasion of adjacent structures and, in some cases, identify a primary source for the cancer. In particular, submucosal masses may not be apparent on physical examination but may appear as enhancing lesions on CT or MRI. If FNA identifies a malignant node but the primary source is still not identified, then direct laryngoscopy should be performed with directed random biopies of the sites most likely to have neck metastases at the time of diagnosis and most likely to have a small focus of carcinoma hiding among redundant folds of tissue: the tonsil fossae, pyriform sinuses, nasopharynx, and base of tongue/vallecula. If no primary site is found, the tumor is considered a squamous cell carcinoma of unknown primary site and treated with radiation to the neck as well as to the upper aerodigestive tract, focusing on the same areas where random specimens have been taken. Salvage neck dissection may follow irradiation for residual carcinoma or neck mass. Excisional biopsy of a neck node is virtually never indicated because fine-needle biopsy can give reliable results and because violation of the lymphatics may invite seeding of the neck with cancer. En bloc resection of the cervical lymphatic tissues (i.e., neck dissection) is the accepted oncologically sound treatment. The one exception to this rule is in the evaluation of lymphoma, for which excisional biopsy is performed to establish lymph node architecture, which is required for diagnosis and to direct treatment. TREATMENT. The goal of treatment of head and neck squamous cell carcinoma is locoregional control of disease. Surgical extirpation and radiation remain the mainstays of treatment. Either surgery or irradiation can be used as the primary treatment modality for stage I and stage II squamous cell carcinoma in most anatomic locations. Surgery provides slightly better locoregional control, whereas irradiation provides better preservation of function, such as speech and swallowing. Surgical salvage of irradiation failures has slightly better success than irradiation salvage of surgical failures. Stage III and stage IV tumors are treated with both surgery and irradiation. Irradiation can be done preoperatively, but current philosophy favors postoperative irradiation to avoid the wound healing problems and alteration of lymphatic drainage patterns that irradiation may induce and to have better determination of the anatomic extent of the tumor. A study of 277 head and neck squamous cell carcinoma patients by the Radiation Treatment Oncology Group (RTOG) found a locoregional control advantage for postoperative irradiation compared with preoperative irradiation; survival rates over 10 years of follow-up were similar. Current indications for postoperative irradiation include multiple positive neck nodes, close or positive surgical margins, and perineural spread. Ideal surgical treatment for squamous cell carcinoma of the oral cavity and pharynx is to remove the primary tumor en bloc with a 2-cm margin of normal tissue. For lesions abutting or invasive to bone, surgery should include cortical or segmental mandibulectomy or partial maxillectomy. Squamous cell carcinoma has a propensity

for perineural spread; for advanced lesions, affected nerves, such as the lingual or hypoglossal, may need to be sacrificed. Because the glottic larynx has minimal lymphatic supply, early tumors of the glottis can be treated with more conservative surgical procedures. Vocal cord stripping, laser resection, and cordectomy have all been advocated for mid-cord Tis or T1 glottic squamous cell carcinoma. For slightly larger lesions and irradiation failures in anatomically favorable locations in the larynx, partial laryngectomy procedures have succeeded both in curing the cancer and preserving voice. The rare favorable T1 or T2 hypopharynx squamous cell carcinoma can 2260

be treated with partial pharyngectomy alone, but larger larynx and hypopharynx cancers require laryngectomy and (for hypopharynx involvement) partial or total pharyngectomy. The head and neck surgeon relies heavily on intraoperative frozen section biopsies of surgical margins to confirm complete removal of the tumor. Principles of surgical treatment for regional lymph node metastases include en bloc resection of the draining nodal lymphatic areas. The standard radical neck dissection removes all nodal tissues of the neck and associated structures, including the spinal accessory nerve, internal jugular vein, and sternocleidomastoid muscle. Variations on this procedure, preserving one or more of these non-lymphatic structures (modified neck dissection), can be tailored to the individual case. Treatment of the N0 neck for large squamous cell carcinoma primary tumors remains controversial. If the risk of occult positive nodal metastasis exceeds 20 to 30%, a selective neck dissection (removal of the first three or four echelons of nodal drainage, sparing other neck structures) is often included for staging purposes at the time of primary tumor resection. A pathologically N0 neck does not require further treatment. Alternatively, irradiation can be used to treat a neck considered at risk, with surgical treatment reserved for future recurrence. Primary sites with high rates of occult nodal metastasis include the anterior floor of mouth, the tongue, and hypopharynx. Postoperative irradiation should start within 4 to 6 weeks after the surgical procedure. Typical postoperative irradiation delivers, in 180- to 200-cGy daily fractions, total doses to the primary site ranging from 6000 cGy for small lesions up to 7500 cGy for large bulky

Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Part XXVII - SKIN DISEASES

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Chapter 519 - STRUCTURE AND FUNCTION OF SKIN Frank Parker

The skin is a dynamic organ containing a variety of tissues, cell types, and specialized structures, which together serve multiple functions important to health and survival. The skin interfaces with our dry, hostile environment and provides many functions crucial to survival, including protection against the elements (e.g., ultraviolet irradiation, mechanical and chemical injury, invasion by infectious agents, and prevention of desiccation and dehydration) and thermoregulation. The skin functions as a sensory receptor that monitors diverse environmental stimuli and plays an active role in immunologic surveillance. In many circumstances, the skin also actively reflects internal disease process. The skin's variety of functions can be correlated with specific properties and anatomy of the epidermis and dermis. The epidermis differentiates to form enucleate cornified cells that act as a relatively impermeable protective barrier (stratum corneum) to the outward loss of body fluids and the inward penetration of various chemicals, allergens, and microorganisms. The lamellae of cornified stratum corneum surface cells, together with the brown pigment melanin, also help protect against the carcinogenic effects of ultraviolet radiation. Two anatomic features of the dermis play a vital role in thermoregulation: its unique massive microcirculatory system and its specialized cutaneous appendages, the sweat glands. Finally, the skin is important immunologically. Both epidermis (Langerhan's cells) and dermis (the epidermal-dermal junction structures) participate in a number of immunologic reactions that generate a variety of inflammatory skin diseases. Skin problems are exceedingly common: Some 30% of Americans have dermatologic conditions requiring a physician's care. Fungal infections, other skin infections, and eczemas represent the most common problems. Furthermore, the health of the skin, the hair, and the nails are of cosmetic importance and can contribute to or detract from psychological well-being.

ANATOMIC CONSIDERATIONS The skin is composed of two mutually dependent layers: the outer epidermis and the inner dermis, both cushioned on the fat-containing subcutaneous tissue, the panniculus adiposus (Figs. 519-1 . and 519-2) EPIDERMIS. The epidermis is a continuously renewing multilayered organ that constantly differentiates. The stratified structure contains two main zones of cells (keratinocytes): an inner region of viable cells known as the stratum germinativum and an outer layer of anucleate cells known as the stratum corneum, or horny layer. Three strata of cells are recognized in the germinativum: the basal, spinous, and granular layers, each representing progressive stages of differentiation and keratinization of the epidermal cells as they evolve into the dead, tightly packed stratum corneum cells on the skin surface. The epidermis is derived from the mitotic division of the basal cells resting on the basement membrane (basal lamina), with the daughter cells moving outward to the surface, where they become polyhedral as they synthesize increasing quantities of keratin. These stratum spinosum cells attach to one another mechanically by desmosomes, which are complex modifications of the cellular membranes that impart a spinous or quill-like appearance to the cells. Desmosomes play a crucial role in maintaining the adherence of the epidermal cells to one another. They contain several intracellular proteins (i.e., desmoplakins, which are the paraneoplastic pemphigus autoantigens) and transmembrane proteins (desmogleins, which function as the pemphigus foliaceus and pemphigus vulgaris autoantigens). With further outward displacement the differentiating cells of the spinous layer become flattened, and refractile keratohyalin granules appear in the cytoplasm, accounting for the designation of granular layer that rests just below the stratum corneum. These granules are the site of active synthesis of filaggrin, which causes keratin filaments to aggregate in parallel array, forming the tough, "chemically resistant" internal structure of the stratum corneum cells. The transformation from viable granular cells to anucleate, non-viable

Figure 519-1 Structure of the skin. (Adapted from the 17th edition of the Cecil Textbook of Medicine with the permission of Dr. Marie-Louise Johnson.)

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Figure 519-2 Diagrammatic representation of the light microscopic and electron microscopic anatomy of the skin.

cornified cells is abrupt. The cornified layer consists of up to 25 layers of tightly packed, highly flattened horny cells. The differentiation of the epidermal cells involves the formation of fibrous proteins known as keratin. The process of maturation of the epidermis (cornificiation) is complete in the stratum corneum, yielding cells with mature keratin, namely, a system of filaments embedded in a continuous matrix (which is probably derived from the keratohyaline granules) within a thickened cell membrane. The stratum corneum limits the rate of passage of ions and molecules into and out of the skin. The insolubility and protective qualities of the stratum corneum are the result of (1) masses of keratin fibers embedded in keratohyaline within the corneocytes, (2) the thickened cell membrane or cornified envelope, and (3) the deposition glucosylceramide and acylceramines in the intercellular spaces between the corneocytes by lamellated membrane bound organelles found in the upper spinous layer. The basal layer of epidermis has a permanent population of germinal cells whose progeny undergo the specific pattern of differentiation just described. The new keratinocytes require about 14 days to evolve into stratum granulosum cells and another 14 days to reach the surface of the stratum corneum and be shed. Proper control of proliferation of basal cells and their subsequent orderly differentiation into keratinized stratum corneum cells produce the smooth, pliable surface of the skin. Alterations in the homeostatic state of cell division, defects in differentiation, or changes in exfoliation from the surface can lead to irregularities in the skin surface, characterized as roughening, scaling, and hyperkeratosis (accumulation of excessive layers of stratum corneum). Two other cell types are found in the epidermis: the melanocyte and the Langerhans' cell. Both are dendritic cells with cytoplasmic arms that stretch out to contact the keratinocytes in their vicinity. The melanocytes are pigment (melanin)-producing cells that are arrayed in the basal epidermal layer and hair follicles, whereas the

Langerhans' cells are usually found in the suprabasal layers of the epidermis, and at times in the dermis. Each dendritic cell has a different origin and function. Melanocytes evolve in the neural crest of the embryo and migrate to the skin in early embryonic life. These cells synthesize brown, red, and yellow melanin pigments that give the skin its distinctive coloration. Melanocytes contain submicroscopic organelles (melanosomes) that synthesize melanin. A specific enzyme, tyrosinase, found within the melanosome, oxidizes tyrosine to dihydroxyphenylalanine (DOPA) and then to DOPA quinone. Additional non-enzymatic oxidation and polymerization occur to form the final product, melanin. Two kinds of melanin are recognized: eumelanin (brown-black biochrome) and phaeomelanin (yellow-red biochrome that contains large quantities of cysteine). The genetic make-up of the individual determines which melanin is produced, thus providing the various colors and hues of skin and hair. Once melanosomes are fully melanized, the resulting granules are transported out the dendritic processes of the melanocyte and transferred into the adjacent epidermal cells or hair. Langerhans' cells, derived from bone marrow, contain a unique submicroscopic racket-shaped organelle (Birbeck granule) that plays a major immunologic role in the skin (see Fig. 519-2) . They contain surface receptors for immunoglobulins, and Ia-antigens, capturing external antigenic materials that contact the skin and circulating them to draining lymph nodes. Langerhans' cells thus play a central role in delayed hypersensitivity reactions of the skin (allergic contact dermatitis). DERMIS. Beneath the epidermis lies the principal mass of the skin, the dermis, which is a tough, resilient tissue with viscoelastic properties. It consists of a three-dimensional matrix of loose connective tissue composed of fibrous proteins (collagen and elastin) embedded in an amorphous ground substance (glycosaminoglycans). At the microscopic level the collagen fibers resemble an irregular meshwork oriented somewhat parallel to the epidermis. Coarse elastic fibers are entwined in the collagenous fibers and are particularly abundant over the face and neck. This fibrous and elastic matrix serves as a scaffolding within which networks of blood vessels, nerves, and lymphatics intertwine and the epidermal appendages, sweat glands, and pilosebaceous units rest. DERMOEPIDERMAL JUNCTION.

The structures situated at the interface between the epidermis and dermis constitute an anatomic functional unit of complex membranes and lamellae laced by divergent types of filaments that together serve to support the epidermis, weld the epidermis to the dermis, and act as a filter to the transfer of materials and inflammatory or neoplastic cells across the junction zone. At the level of light microscopy, this boundary zone is seen as an undulating pattern of rete ridges (downward finger-like or ridgelike extensions of the epidermis) and dermal papillae (upward projections of the dermis into the epidermis) (see Fig. 519-2) . Periodic acid-Schiff (PAS) staining discloses a thin uniform zone of intense reaction along this undulating junction that represents the basement membrane. Electron microscopic, immunoelectron microscopic, immunologic, biochemical, and genetic studies have elucidated the complexity of this region and are providing new insights into the pathogenesis of a variety of cutaneous diseases. Keratin filaments, hemidesmosomes, lamina lucida, lamina densa, anchoring filaments, and anchoring fibrils each function to maintain different levels of basement membrane adhesion (Fig. 519-3) . A variety of inherited mechanobullous diseases (epidermolysis bullosa) as well as autoimmune bullous diseases (pemphigoid, herpes gestationis, bullous systemic lupus erythematosus) involve separation and bullous formation at various levels of the dermoepidermal junction. CUTANEOUS APPENDAGES.

Two to 3 million eccrine sweat glands distributed over all parts of the body surface participate in thermoregulation by producing hypotonic sweat that evaporates during heat or emotional stress (see Fig. 519-1) . The combined output of these glands may exceed 1.5 L/hour. Each gland is a simple tubule with a coiled secretory segment deep in the dermis and a straight 2265

Figure 519-3 Structures and diseases of the dermoepidermal junction.

duct extending up to the skin's surface. The glands respond to thermal stimulation and emotional stress. Apocrine sweat glands in the axillae, circumanal and perineal areas, external auditory canals, and areolae of the breasts secrete viscid, milky material that accounts for axillary odor when bacteria degrade the secretion. Presumably, they are the vestigial remnants of lower species that communicate by cutaneous chemicals. PILOSEBACEOUS APPENDAGES.

Hair units, or pilosebaceous appendages, are found over the entire skin surface except on the palms, soles, and glans penis (see Fig. 519-1) . Hair follicles consist of a shaft surrounded by an epithelial sheath continuous with the epidermis, the sebaceous gland, and the arrector pili smooth muscle. The bulb contains the proliferating pool of undifferentiated cells that gives rise to various layers comprising the hair and the follicle. The proliferating cells in the bulb differentiate into a hair consisting of keratinized, hard, imbricated, flattened cortex cells surrounding a central medullary space. The sebaceous glands are multilobular holocrine glands that connect into the pilosebaceous canal (hair canal) through the sebaceous duct. Germinative undifferentiated sebaceous cells at the periphery of each lobule of the gland generate daughter cells that move to the central areas of each acinus as they differentiate and form sebum (a complex oily substance composed of triglycerides and diglycerides, fatty acids, wax esters, squalene, and sterols). Most sebaceous glands adjoin a hair follicle, although some open directly on the skin surface. Sebaceous glands are also found normally in the buccal mucosa (Fordyce's spots), around the female areola (Montgomery's tubercles), on the prepuce (Tyson's glands), and in the eyelids (meibomian glands). The sebaceous glands and certain hair follicles are androgen-dependent target organs. Follicles particularly responsive to androgen stimulation are found over the frontal and vertex areas of scalp, beard, chest, axillae, and upper and lower pubic triangles. Hair follicles are formed in early embryonic life, and no more develop after birth. Males and females have approximately the same number of hair follicles distributed over the body, but the degree of hairiness depends on two distinct features of hair growth--the hair cycle and the hair pattern. Hair growth consists of recurring cycles of growth, regression, and resting. The resting hair lies high in the follicle, where it forms a stubby hair bulb that is easily shed. Growth begins with a burst of mitotic activity, and the follicle grows downward to reconstitute a new hair bulb. The hair bulb cells divide rapidly and keratinize to form a new hair shaft that dislodges the old resting club telogen hair. Regression provides a brief respite when mitosis ceases and the hair follicle pulls upward in the dermis as the hair shaft evolves into a resting club hair. In the adult scalp 85% of the hairs are in a growth state, 14% in a resting state, and 1% in regression. Considerable variation in timing of the hair cycle occurs from one region of the body to another, and the duration of growth determines the length of hairs. Hair cycles also vary with the second important feature of hair growth, namely, hair pattern or the type of hair growing in each follicle. Two types of hairs are seen: vellus hair (fine, soft, short, non-pigmented, and common on "non-hairy" areas of the body) and terminal hair (coarse, long, pigmented, and found on hairy areas of the body). Dramatic changes occur at puberty in both hair cycle and hair pattern mediated by either testosterone or dihydrotestosterone (DHT). The increased hairiness results from the conversion of vellus hair follicles to large terminal follicles. In the axillae and lower pubic triangle this conversion is mediated by testosterone and androstenedione. In other regions such as the beard, chest, upper pubic triangle, nostrils, and external ears, this conversion is mediated by DHT. Paradoxically, DHT also mediates the reverse process, namely, the miniaturization of large terminal follicles into vellus hairs. Such physiologic miniaturization occurs with the reshaping of the frontal hairline from a straight line to an M-shaped configuration at puberty; this process occurs in all men and in the majority of women. Maternal androgens ensure full development and function of sebaceous glands at birth. The vernix caseosa covering the neonate is mostly sebum. Normally sebaceous glands atrophy after birth and until puberty, when androgens again stimulate their activity. Acne is often one of the earliest signs of puberty. Disorders of androgen excess in adult women (e.g., polycystic ovary syndrome) are also associated with increased sebaceous activity and acne. Estrogens in large amounts decrease gland size and secretion.

FUNCTIONS OF THE SKIN PROTECTION. Several structures in the skin, including the stratum corneum, melanin, cutaneous nerves, and the dermal connective tissue, provide important survival functions. The skin protects

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against the loss of essential fluids, the entrance of toxic agents and microorganisms, and damage from ultraviolet radiation, mechanical shearing forces, and extreme environmental temperatures. The stratum corneum serves as a low-permeability barrier that retards water loss from the inner epidermal hydrated layers andalso shields against environmental damage. The barrier properties of the horny layer are of practical importance from several points of view: Excessive drying or inflammatory reactions in the skin (e.g., eczema) lead to roughness, scaling, and disruption of the normally compact layers of horny cells. These changes lead to increased transepidermal water loss and, if severe (as in generalized exfoliative dermatitis, erythroderma, or burns), can contribute to fluid and electrolyte imbalance. With breaks in the horny layer, external substances more readily gain entrance to the underlying epidermis. Thus, various chemical substances, including medications placed on injured skin, have a greater opportunity to be absorbed or to act as haptens or antigens, thereby increasing the possibility of allergic contact dermatitis. Allergic contact dermatitis becomes particularly common when topical antibiotics are applied to chronically inflamed skin. The disruption of the barrier also increases the chance of colonization of pathologic bacteria in the skin, especially in the presence of tissue fluid exudates, which serve as excellent culture media. Percutaneous absorption of various topical medications used in treating skin conditions can be enhanced by hydrating the stratum corneum with the use of occlusive plastic wraps. The stratum corneum normally harbors a number of aerobic and anaerobic resident organisms (i.e., Staphylococcus epidermidis, diphtheroids, Propionibacterium acnes, and Pityrosporon). Breaks in the stratum corneum, poor hygiene, and excessive humidity with maceration (especially in intertriginous areas) all contribute to cutaneous infections such as impetigo, erysipelas, folliculitis, furunculosis, and ecthyma. A second structural component that provides protection is the melanocyte, which produces melanin pigment. Melanin is a large polymer that has the unique capability of absorbing light over the broad range of 200- to 2400-nm wavelengths. It serves as an excellent screen against the untoward effects of solar ultraviolet radiation, such as aging and wrinkling of the skin and the development of cutaneous neoplasms. The importance of melanin is dramatically illustrated by the high incidence of skin cancers in sun-exposed areas of the body, particularly in light-skinned, blue-eyed, easily sunburned individuals and in albinos. Ultraviolet light exposure also causes aging and wrinkling of the skin. Neither sex nor race affects the number of melanocytes in the epidermis. Negroid skin contains the same number of melanocytes as white skin, but the pigmentation is more intense as a result of the synthesis of more melanin that is dispersed throughout the melanocytes and adjacent keratinocytes. Accordingly, black skin is much less likely to form skin cancers, and it ages more slowly than white skin. Dermal nerves play an important role in bodily protection. Nerve endings are extensively distributed in the skin in two general morphologic types: free nerve endings and specialized endings (Pacini's and Meissner's corpuscles), which mediate many sensations, including pain, pressure, and itch. Loss of sensation (e.g., diabetic neuropathy) may result in deep traumatic ulcers (trophic ulcers) without the patient's awareness. Damage to the dermatomal nerves (e.g., herpes zoster) may result in prolonged burning pain and hypesthesias (postherpetic neuralgia). Itch is mediated by cutaneous nerves. It may occur in conjunction with a number of dermatologic diseases or without clinically TABLE 519-1 -- SKIN DISEASES ASSOCIATED WITH ITCHING Xerosis (dry skin) Insect infestations (scabies, pediculosis, insect bites) Dermatitis (atopic, contact, nummular) including poison ivy contact Drugs (opiates, aspirin, quinidine) Lichen planus Urticaria Dermatitis herpetiformis (burning itch) Sunburn Fiberglass dermatitis Seborrheic dermatatis

TABLE 519-2 -- PRURITUS ASSOCIATED WITH SYSTEMIC DISEASE SYSTEMIC DISEASE

POSTULATED CAUSE

Uremia

Secondary hyperparathyroidism, high skin calcium concentration, proliferation of mast cells, xerosis

Obstructive biliary disease

High concentrations of bile salts in skin

Primary biliary cirrhosis Cholestatic hepatitis secondary to drugs (chlorpropamide) Intrahepatic cholestasis of pregnancy Extrahepatic biliary obstruction Hematologic and myeloproliferative disorders

Unknown

Lymphoma including Hodgkin's disease Mycosis fungoides Polycythemia vera Iron-deficiency anemia Endocrine disorders

Unknown

Thyrotoxicosis Hypothyroidism Diabetes Carcinoid Visceral malignancies

Serotonin Unknown

Breast, stomach, lung Psychiatric disorders

Unknown

Stress Delusions of parasitosis Neurologic disorders

Unknown

Multiple sclerosis (paroxysmal itching) Notalgia paresthetic--local itch of back, medial shaft scapula (local neuropathy) Brain abscess Central nervous system infarct evident skin disease (pruritus) (Tables 519-1 and 519-2) . Itch and pain are carried on unmyelinated C fibers found in the upper portion of the dermis of the skin, mucous membranes, and cornea.The afferent C fibers enter the dorsal horn of the spinal cord, synapse, cross the midline, and ascend the spinothalamic tracts to the

thalamus. Then the impulse proceeds to the sensory area of the postcentral gyrus of the cortex. Cutting the spinothalamic tract, as in an anterolateral hemichordotomy, abolishes pain and itch. A variety of peripheral mediators stimulate the C fibers and induce itching. These mediators include histamine, trypsin, proteases, peptides (bradykinin, vasoactive intestine peptide, substance P--all potent histamine releasers), and bile salts. Prostaglandins are modulators of pruritus rather than primary mediators; they lower the threshold to itching evoked by both histamine and pain. Central modulators of pruritus, such as systemic morphine, cause itch while relieving pain by acting on central opiate receptors. Regrettably, no single pharmacologic agent effectively treats all kinds of pruritus. Generalized itching in the absence of primary skin disease (pruritus) may be an important sign of internal disease (see Table 519-2) . An important cause of pruritus is psychic stress. Some patients with psychogenic pruritus believe the itching is caused by invisible parasites in the skin. Such patients scratch until excoriations and prurigo papules (thickened papular areas of skin due to constant rubbing) evolve in areas that the patient can readily reach (extremities, scalp, upper back). Dry skin (xerosis) is a common cause of itching in older individuals. Certain drugs (aspirin, opiates) can cause itching without a visible rash. Patients with polycythemia vera display a unique form of itching triggered by sudden changes in temperature, especially when they emerge from a warm bath. The itch is prickly in nature and lasts minutes to hours. The tough, viscoelastic properties imparted to the skin by the fibrous proteins (collagen and elastin) and amorphous ground substance that make up the dermis protect the skin against shearing forces. The viscous and elastic properties of the ground substance allow it to resist compression and accept molding, thus reducing point pressure on sensitive skin structures. THERMOREGULATION. Thermoregulation is subserved concomitantly by the cutaneous vasculature and the sweat glands. A massive 2267

network of interconnecting musculocutaneous arteries and venules, as well as capillaries, arteriovenous shunts, and small venules, play a crucial role in the maintenance of body temperature. Most of the skin's blood resides in the large venous plexus, through which blood slowly moves close to the surface to dissipate heat. Equally important in thermoregulation is the formation of eccrine sweat, which provides cooling by evaporation from the skin's surface. Every gram of water that evaporates from the skin loses 580 calories of heat. Blood flow through the skin is 10 to 20 times that required to supply needed metabolites and oxygen. Under basal conditions about 8.5% of the total blood flow passes through the skin, controlled primarily by the sympathetic nervous system. Blood flow can increase up to 3.5 L/min with exercise in a warm environment, thereby dissipating large amounts of heat. Both central (hypothalamic heating) and peripheral thermoreceptors stimulate sweating via the sympathetic nervous system, but in the case of sweat glands, acetylcholine is the postganglionic transmitter. Increase in body core temperature is the strongest stimulus for inducing sweating, whereas peripheral (cutaneous) thermoreceptors are only one tenth as effective in eliciting perspiration. Response to cold begins when cool blood passes the hypothalamus, which elicits both heat conservation and production mechanisms. Sympathetic stimuli constrict cutaneous blood vessels, and hypothalamic impulses activate shivering, which increases heat production by as much as 50%. Conversely, when warm blood irrigates the hypothalamus, central heat production ceases, and cutaneous blood vessels dilate to allow heat loss from the skin surface. Vasodilatation also occurs reflexly through direct warming of the skin surface (in warm environments). In addition, stimulation of the hypothalamus produces sweating and increases evaporative heat loss. Periodic exposure to heat or to heat and work stresses (i.e., daily 1- or 2-hour exposures for 10 to 14 days) enhances the secretory capacity of the eccrine sweat glands (acclimatization). The crucial role of cutaneous vasculature in thermoregulation and cardiovascular homeostasis can be reversed by widespread inflammatory conditions of the skin causing erythroderma. Diseases such as generalized dermatitis, psoriasis, drug reactions, and underlying lymphomas can cause generalized, inflammatory-based cutaneous vasodilatation that can divert 10 to 20% of cardiac output through the skin. To maintain blood pressure, cardiac output must increase; older individuals with impaired cardiac reserve can develop high-output failure accompanied by tremendous loss of body heat with wide swings in temperature and shivering. THE SKIN AS AN ENDOCRINE ORGAN. Many metabolic activities of the skin are under hormonal regulation. Not only do sebaceous glands and certain hair follicles respond readily to androgens, but they are capable of many diverse steroid transformations, as described earlier. DHT causes sebaceous glands to enlarge at puberty, stimulates the growth of certain hair (male sexual hair of the beard, chest, upper pubic triangle, nose, and ears), and generates the growth and development of the external genitalia. Drugs such as cimetidine and spironolactone have antiandrogenic activity and have been used to treat acne and hirsutism. In addition, thyroid hormones can regulate hair growth and alter the texture of the skin (fine, sparse hair and smooth, soft skin in hyperthyroidism; coarse hair and cool, rough, thick skin in hypothyroidism). Other hormones affect melanin pigment formation, melanocyte-stimulating hormone, and estrogen-stimulating skin pigmentation. THE SKIN AS AN IMMUNOLOGIC ORGAN. The epidermis and the dermoepidermal junctional area participate actively in immunologic reactions. The skin includes immunologically important cells including keratinocytes, Langerhans' cells, and melanocytes as well as immunologic structures such as the lamina lucida and basal lamina that are involved in bullous reactions of the skin. EPIDERMAL IMMUNOLOGICALLY IMPORTANT CELLS.

The most important immunologic cell in the epidermis is the Langerhans' cell, comprising 2 to 5% of the total epidermal cell population. Langerhans' cells contribute to a number of immunologic reactions, including macrophage-T cell interaction, T and B lymphocyte interactions, graft-versus-host (GVH) reactions, and skin graft rejection. The Langerhans cell synthesizes and expresses Ia antigens (class II antigens, immune response gene-associated antigens) that are crucial in processing and presenting allergens to sensitized T lymphocytes critical in the elicitation of delayed hypersensitivity contact dermatitis. Lymphokines, made by the Langerhans cells during these immunologic reactions, augment and enhance these processes and also contribute to the accompanying inflammatory response. Keratinocytes participate in immunologic responses by expressing Ia antigens on their surfaces in such conditions as GVH reaction, mycosis fungoides, allergic contact dermatitis, lichen planus, and tuberculoid leprosy. In these conditions the keratinocytes make lymphokines, particularly interleukin-1, which provides a second signal supplementing macrophages (Langerhans' cells) in mitogen- and antigen-induced T-cell activation. In addition, epidermal cells make other cytokines, such as prostaglandin E2 and leukotrienes, that participate in inflammatory reactions in the skin. Keratinocytes are the immunologic target in the pemphigus group of diseases in which circulating autoantibodies against intercellular antigen of the epidermis and mucous membrane epithelium initiate intraepidermal acantholytic bullae. THE DERMOEPIDERMAL JUNCTION.

A variety of inflammatory diseases often characterized by bullous reactions seem to be mediated by immunoreactants, including IgG, IgA, and IgM, and complement deposition along the dermoepidermal junctional area. The anatomic site of blister formation correlates with the position of deposition of these immunoreactants. The antigens in several diseases have been isolated and partially characterized. The use of immunofluorescent techniques at the light microscopic and especially the ultrastructural level has been helpful in more precisely diagnosing these bullous conditions (Table 519-3) . INFLAMMATORY REACTIONS IN THE SKIN AND WOUND HEALING. Cutaneous inflammation reflects the sum of the effects of biologic products of cells (mast cells, infiltrating neutrophils, monocytes, macrophages, lymphocytes) as well as the effects of the products of the complement system, membrane-derived arachidonic acid metabolic pathways (prostaglandins and leukotrienes), and the Hageman factor-dependent pathways of coagulation, fibrinolysis, and kinin generation. Early phases of wound healing also encompass many of these reactions. CUTANEOUS INFLAMMATION.

Several pathophysiologic reactions initiate inflammation, including infectious, immunologic, and toxic processes that affect the epidermis or dermis, or both. Mast cells in the skin function not only as the sentinel cells in immediate-type hypersensitivity reactions but also as major effector cells in inflammatory reactions. They release (1) histamine, prostaglandin D2, and leukotrienes, which cause vascular dilatation and increased permeability, redness, swelling, pain, and itch; (2) chemotactic factors for

eosinophils and neutrophils; (3) proteases that interact with the complement, kinin, and fibrinolytic pathways; and (4) heparin, which contributes to local angiogenesis. Degranulation of mast cells occurs in response to various antigens that cross-link IgE on the mast cell surface (immediate hypersensitivity reactions), to by-products of complement activation C3a and C5a (as occurs in leukocytoclastic vasculitides), and to radiocontrast media, aspirin, insect venom, and various physical stimuli. Circulating peripheral blood cells infiltrate local tissue sites in response to chemotactic factors released by mast cells and other infiltrating cells. Basophils release histamine and chemotactic substances, such as those involved in allergic contact reactions, bullous pemphigoid, erythema multiforme, and inflammatory responses. Neutrophils release myeloperoxidase, acid hydrolases, and neutral proteases that are active against microbes and cause tissue destruction (dermatitis herpetiformis, psoriasis, leukocytoclastic vasculitis, and bacterial infections of the skin). Eosinophils release major basic protein and peroxidase (allergic drug reactions in the skin, bullous pemphigoid). Lymphocytes release lymphokines that modulate immunologic and inflammatory responses (lichen planus, lupus erythematosus, allergic contact dermatitis, tuberculoid leprosy). Monocytes and macrophages engulf foreign proteins and microorganisms (granulomatous reactions in the skin such as sarcoidosis, deep fungus and acid-fast bacilli infections, and cutaneous foreign body responses). Both classic and alternate complement pathways release products that induce mast cell degranulation and induce inflammation. The activation of the system appears to contribute to inflammatory reactions in hereditary complement deficiencies causing lupus erythematosus-like syndromes or pyodermas, as well as necrotizing vasculitis. 2268

DISEASES

TABLE 519-3 -- IMMUNOFLUORESCENT CUTANEOUS FINDINGS IN IMMUNOLOGICALLY MEDIATED SKIN DISEASE BIOPSY FINDINGS OF DIRECT ULTRASTRUCTURAL SITE OF BLISTER FORMATION SERUM FINDINGS: INDIRECT IMMUNOFLUORESCENCE LOCALIZATION OF ON ROUTINE LIGHT IMMUNOFLUORESCENCE (IIF) IMMUNOREACTANTS (DIF) IMMUNOREACTANTS MICROSCOPIC PATHOLOGY

Bullous Diseases Pemphigus (all forms)

Deposits of IgG in intercellular areas between keratinocytes

Between keratinocytes

Suprabasilar in pemphigus vulgaris; substratum corneum in pemphigus foliaceus

IgG antibodies to intracellular areas of keratinocytes in 95% of patients

Bullous pemphigoid

IgG and/or complement (C) in BMZ

Lamina lucida and hemidesmosomes--upper part lucida and sub-basal cells

Subepidermal

IgG Ab to BMZ in 70%

Cicatricial pemphigoid

IgG and/or C in BMZ

Lamina lucida

Subepidermal

IgG antibodies BMZ in 10%

Herpes gestationis

Complement in BMZ--occasionally IgG

Lamina lucida--close to lamina densa

Subepidermal--sub-basal cell--above lamina densa

IgG antibodies BMZ in 20% (HG factor in 25%)

Dermatitis herpetiformis

IgA and C in dermal papillae (granular deposits)

Granular IgA associated with microfibril bundles in dermal papilla

Subepidermal in dermal papillae--papillar dermal microabscesses

No circulating antibodies

Epidermolysis bullosa acquisita

IgG, C3 in BMZ

Sublamina densa amorphous granular deposits

Subepidermal

Frequent IgG autoantibodies

Linear IgA bullous dermatosis in childhood

IgA and complement in linear deposition in BMZ

Subepidermal

No circulating antibodies

Subepidermal

Circulating antibodies to BMZ; ANA found in 90%

--

Connective Tissue Diseases Bullous Systemic LE IgG, IgM, and complement in BMZ in involved and normal skin--linear homogenous

Just beneath lamina densa (basal lamina)

Discoid LE

IgG, other Ig, and C in lesional skin at BMZ

--

--

No circulating antibodies to BMZ, ANA titers normal

Systemic LE

IgG band at BMZ in normal skin (over 90% in sun-exposed areas)

--

--

Elevated ANA titers

Systemic sclerosis

Nucleolar IgG

--

Epidermal thinning and increased dermal collagen

MCTD

IgG/IgM in BMZ in some patients; nuclear IgG in epidermis

--

--

Speckled ANA and ENA (extractable nuclear antigens)

Dermatomyositis

Negative

--

--

ANA often normal range

ANA, speckled, 85%, centromere + in CREST syndrome

ANA = antinuclear antibody; BMZ = basement membrane zone; LE = lupus erythematosus; MCTD = mixed connective tissue disease.

WOUND HEALING IN THE SKIN.

Healing proceeds temporally in three phases: substrate, proliferative, and remodeling. The initial substrate phase, encompassing the first 3 to 4 days after wounding, is so named because the cellular and other interactions lead to preparation for subsequent events. During this phase, vascular and inflammatory components prevail (vascular clotting in the severed vessels; leukocyte and macrophage chemotaxis into the area to ingest bacteria, debride the wound, and degrade collagen). The proliferative phase (10 to 14 days after wounding) results in regeneration of epidermis, neoangiogenesis, and proliferation of fibroblasts with increased collagen synthesis and closure of the skin defect. The final remodeling takes place over 6 to 12 months, during which time a more stable form of collagen is laid down to form a scar of progressively increasing tensile strength. In some instances so much collagen is deposited in the healing wound that an elevated hypertrophic scar (red, raised scar within the boundaries of the original wound) or keloid (scar tissue extending beyond the boundaries of original injury into surrounding normal tissue) is produced. Keloids occur most commonly over the anterior chest, upper back, and deltoid regions. They rarely regress, and they recur after excision. THE COSMETIC IMPORTANCE OF SKIN. Aging alters virtually all the structures and functions of the skin. Environmental insults, especially chronic sun exposure, cause far greater damage to the skin than time itself. Epidermal turnover rate decreases approximately 50% between the third and seventh decades. Concurrent loss of dermal elastic and collagen fibers accounts for the paper-thin, transparent quality of aged skin and the easy rupture of dermal vessels. An increasing cross-linkage of collagen and elastin accompanies aging, making the dermis more rigid and less able to withstand shearing forces. Aged skin, when "tented up," only slowly returns to its original form, whereas young skin readily snaps back. Sun-damaged aged skin shows microscopic collagen damage. Dermal collagen is replaced by amorphous basophilic staining material. This condition, termed elastosis, results in deep wrinkling and furrowing, especially over the face and back of the neck, and yellow papules and nodules in a reticular pattern on the face. Decreases in the number of functioning sebaceous and sweat glands contribute to the dryness of aged skin and to impaired thermoregulation in aged persons. Reduction in the vascular network in the skin surrounding hair bulbs and eccrine and sebaceous glands may be responsible for the atrophy of these appendages with age. A 50% reduction in the number of Langerhans' cells may account in part for the age-associated decrease in immune responsiveness and allergic contact dermatitis reactions in the elderly. Loss of enzymatically active melanocytes (10 to 20% per decade) causes irregular pigmentation of the skin and graying of the hair. Gradual reduction occurs in the number of body hairs, especially in the scalp, axillary, and pubic regions (related in part to decreased androgen production). Linear growth of nails also decreases by 30 to 50% between early and late adulthood. Often nails become brittle and thickened. A number of proliferative growths are associated with aging skin, including skin tags (acrochordon), cherry angiomata, seborrheic keratosis, lentigines, and sebaceous hyperplasia. Arndt KA, LeBoit PE, Robinson JK, Wintroub BU: Cutaneous Medicine and Surgery. Philadelphia, WB Saunders, 1996. Fitzpatrick TB, Johnson RA, Wolff K, et al: Color Atlas and Synopsis of Clinical Dermatology: Common and Serious Diseases, 3rd ed. New York, McGraw-Hill 1997. Comprehensive texts of general dermatology.

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Chapter 520 - EXAMINATION OF THE SKIN AND AN APPROACH TO DIAGNOSING SKIN DISEASES Frank Parker

THE DERMATOLOGIC HISTORY A proper dermatologic history should initially address where the patient's skin condition first appeared. The patient should be asked to describe, in his or her own words, what the condition first resembled, any associated symptoms (e.g., pain, burning), and how the condition has progressed. The careful review of any medications, prescribed or over-the-counter, is critical. The relationship of the onset of the skin condition to the use of medications is particularly crucial in evaluating the possibility of a drug eruption or the development of an allergic contact dermatitis secondary to therapy. Any history of atopic diseases such as asthma, hay fever, and eczema should be sought. A careful family history of skin diseases can aid in the diagnosis of heritable dermatologic conditions. Many patients may have already tried a variety of therapies, topical or systemic, prescribed or over-the-counter; the effects of these therapies as well as any home remedies or "alternative" methods should be described. A thorough social history is important, because some dermatoses may be related to occupational or recreational activities. Exposure to environmental elements such as sun, cold, and heat may provoke or exacerbate some skin conditions. The physician should also inquire about household and sexual contacts, particularly when a parasite or an infectious cause is being considered. Psychological stress, although seldom a sole cause of cutaneous conditions, can certainly exacerbate many dermatoses (e.g., acne, psoriasis, seborrhea, atopic dermatitis).

THE PHYSICAL EXAMINATION Excellent lighting is paramount, and natural light usually serves as the best source, although fluorescent light may be used as well. Usually direct lighting is sufficient, although, in many cases, tangential lighting can aid in identifying subtle changes in many dermatoses (e.g., elevation or depression of lesions). The examination should start with the hair and scalp and then move to the face and mucous membranes of the oral mucosae. Clues in the mouth (e.g., oral lesions of lichen planus) may help explain more distant cutaneous lesions. The back, chest, abdomen, and extremities, including palms, soles, and nails, should be examined. Skin generally covered by undergarments must also be examined because serious lesions, such as melanoma, can arise in these areas. Signs of aging, nutritional status, trauma, and hygiene should be sought. Color changes related to underlying systemic conditions (e.g., jaundice with hepatobiliary conditions, cyanosis with various cardiopulmonary diseases, diffuse hyperpigmentation with Addison's disease, paleness with anemia) all are important. In each region of the body, the physical examination includes three maneuvers: (1) observation for color or surface changes, which may often be preceded by use of an alcohol sponge to wipe off existing cosmetics, oil, or foreign material so the skin's natural color can be observed; (2) touching or light stroking to detect texture changes, warmth, and/or moisture, with an understanding that the smoothness or roughness of the skin depends on factors as normal keratinization, proper hydration of the stratum corneum, and normal cutaneous blood flow; and (3) palpation and stretching of the skin to determine its consistency and pliability, with the appreciation that elasticity depends on the normal structure and function of dermal connective tissue and ground substance and that certain infiltrates can be detected by palpation. Because there are many hundreds of dermatoses, a logical process of elimination is required to narrow the possibilities, first to specific categories of diseases, then, it is hoped, to one final diagnosis. Dermatologic conditions are usually separated into specific morphologic categories (e.g., papulosquamous diseases) (see Chapter 522) . Once a condition is determined to fit into a specific category, additional information such as history and laboratory data can help to eliminate other possibilities. Three steps are involved in this systematic approach. First, the entire skin is examined for primary and secondary skin lesions (Table 520-1) that allow the examiner to place the patient in one of nine diagnostic groups (the second step) (Table 520-2) (Color Plates 15 A- F and 16 A- F). Many skin conditions are found in each group, but all of the conditions in a given group express the same primary and secondary lesions. The third step is to identify the patient's specific disease by looking for distinctive features, such as the distribution of skin lesions, any unusual shapes of the lesions, the arrangement of several lesions (annular, serpiginous, dermatomal), the dominant hue and color of the lesion, and its surface characteristics (particularly the appearance of scales or verrucous or vegetative changes). STEP 1: DESCRIPTION OF PRIMARY AND SECONDARY SKIN LESIONS. Primary skin lesions are uncomplicated abnormalities that represent the initial pathologic change, uninfluenced by secondary effects such as infection, trauma, or therapy. Secondary lesions reflect progression of the disease or scratching or infection of the primary lesions. Most primary changes can also develop as secondary manifestations: for example, pustules may appear as primary lesions of folliculitis or as secondary lesions when scaling, itching lesions are scratched and infected. The challenge is to recognize the primary skin lesion so as to make the correct etiologic diagnosis. The terminology used to describe primary and secondary skin changes (see Table 520-1) is the basic language of dermatology; if this terminology is not used correctly, it is difficult to arrive at the precise diagnosis of skin diseases. Each descriptive word is not only a short account of what is seen on the surface of the skin but also relays specific information about processes within the skin. STEP 2: ASSIGNMENT OF THE LESION TO A MAJOR GROUP OF DISEASES. Each disease within a given group shares the same primary and secondary skin lesions. Some diseases have overlapping traits so they may be assigned to more than one group (see Table 520-2) . TABLE 520-1 -- THE LANGUAGE OF DERMATOLOGY: PRIMARY AND SECONDARY SKIN LESIONS Primary Skin Lesions Macule--circumscribed flat change in skin color (e.g., cafe au lait spot) Papule--solid elevated area with top; can be flat, pointed or rounded (e.g., acne) Plaque--evolves from a confluence of papules leading to flat-topped, circumscribed elevations (e.g., psoriasis) Scale--desiccated, thin plates of cornified epidermal cells that result from altered keratinization (e.g., ichthyosis) Wheal--circumscribed, flat-topped, firm elevation of skin with a well-demarcated, palpable margin; results from tense edema in papillary dermis (e.g., urticaria) Nodule--large, solid, deep-seated, raised mass in dermal or subcutaneous tissues; usually larger than 1 cm (e.g., erythema nodosum) Vesicle/bulla--circumscribed, elevated lesion containing clear serous or hemorrhagic fluid; vesicles are 1 cm (e.g., herpes simplex and pemphigus vulgaris) Pustule--a vesicle containing purulent exudate (e.g., folliculitis)

Atrophy--loss of epidermal or dermal tissue with some depression of skin surface and substance; epidermal atrophy leads to fine wrinkling of the skin surface (e.g., lichen sclerosis et atrophicus) Secondary Skin Lesions Lichenification--dry, leathery thickening of the skin with exaggerated skin markings (e.g., chronic eczema) Scar--an area where fibrosis of the dermis or subcutaneous tissues results from an antecedent destructive process and replaces normal skin (e.g., healing wound) Erosion--a moist, circumscribed, often depressed area that reflects loss of partial or full-thickness epidermis (e.g., ruptured bulla) Fissure--a deep linear split in the skin extending through the epidermis (e.g., eczema) Crust--dried, exudate of serum, blood, sebum, or purulent material on the surface of the skin (e.g., acute eczema) Telangiectasia--dilated, small blood vessels in the skin (e.g., discoid lupus erythematosus and necrobiosis lipoidica diabeticorum)

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TABLE 520-2 -- MAJOR GROUPS OF DERMATOLOGIC DISEASES BASED ON THE CLINICAL MORPHOLOGY OF THE SKIN CONDITION GROUP

CLINICAL MORPHOLOGY

EXAMPLES OF DISEASES IN THE GROUP

Eczema or dermatitis

Macules (erythema), papules, vesicles, lichenification, fine scaling, excoriations, crusting

Contact dermatitis, atopic dermatitis, stasis dermatitis, photodermatitis, scabies, dermatophytoses, exfoliative dermatitis, candidiasis

Maculopapular eruptions

Macules, erythema, papules

Viral exanthems, drug reactions, verruca vulgaris, Kawasaki's disease, vasculitic and purpuric eruptions

Papulosquamous dermatoses

Papules, plaques, erythema with unique scales

Psoriasis, Reiter's syndrome, pityriasis rosea, lichen planus, seborrheic dermatitis, ichthyosis, secondary syphilis, mycosis fungoides, parapsoriasis

Vesiculobullous diseases

Vesicles, bullae, erythema

Herpes simplex and zoster, hand-foot-and-mouth disease, insect bites, bullous impetigo, scalded skin syndrome, pemphigus, pemphigoid, dermatitis herpetiformis, porphyria cutanea tarda, erythema multiforme

Pustular diseases

Pustules, cysts, erythema

Acne vulgaris and rosacea, pustular psoriasis, folliculitis, gonococcemia

Urticaria, persistent figurate erythemas, cellulitis

Wheals and figurate, raised erythema, scaling

Urticaria, erythema annulare centrifugum, erysipelas, necrotizing fasciitis

Nodular lesions

Nodules and tumors, some associated with erosions and ulceration

Benign and malignant tumors--basal cell cancer, squamous cell cancer, rheumatoid nodules, xanthomas

Telangiectasia, atrophic, scarring, ulcerative diseases

Atrophic, sclerotic telangiectasia and ulcerative changes

Connective tissue diseases, radiation dermatitis, lichen sclerosus et atrophicus, vascular insufficiency (arterial and venous), pyoderma gangrenosum

Hypermelanosis and hypomelanosis

Increased and decreased melanin deposition in skin

Acanthosis nigricans, cafe au lait spots, vitiligo, tuberous sclerosis, xeroderma pigmentosum, chloasma, freckles

STEP 3: NARROWING THE POSSIBILITIES TO THE EXACT DIAGNOSIS. Of great importance in this step is the distribution of the skin disease, because many conditions have typical patterns or affect specific regions. For example, psoriasis commonly affects extensor surfaces, whereas atopic dermatitis commonly affects flexor surfaces of the extremities (Fig. 520-1) . Photoreactions are confined to parts of the body exposed to sunlight. Involvement of the palms and soles is seen in erythema multiforme, secondary syphilis, some forms of psoriasis, and Rocky Mountain spotted fever. Contact dermatitis to exogenous allergens or irritants often presents as unusual patterns and distributions corresponding to the areas where the offending material came in contact with the skin. An important clue in differentiating diseases lies in the shape of the individual lesions and the arrangement of several lesions in relation to each other. A linear arrangement of lesions may indicate a contact reaction to an exogenous substance brushing across the skin, a pathologic process involving a vascular or lymphatic vessel, or a cutaneous nevus. "Zosteriform" refers to lesions arranged along the cutaneous distribution of a spinal dermatome; these lesions are typically unilateral and denote herpes zoster or, occasionally, metastatic carcinoma of the breast or the dermatomal hemangiomatous growths of Sturge-Weber syndrome. "Annular" lesions are round to oval with an area of central clearing; annular macules are observed in drug eruptions, secondary syphilis, and lupus erythematosus. Resolving hives may also leave annular configurations, whereas annular lesions with scaling suggest dermatophytosis or pityriasis rosea. "Target lesions" are a special type of annular lesion in which an erythematous annular macule or papule develops a second red ring or a purplish papule or vesicle in the center; target lesions are seen in erythema multiforme. "Arciform" lesions form partial circles or arcs and may be seen in dermatophyte infections. "Polycyclic" patterns evolve when numerous annular lesions enlarge and run together. "Herpetiform" refers to a grouping of lesions such as occurs in herpes simplex or dermatitis herpetiformis. "Umbilicated" vesicles are important diagnostic findings. Vesicular lesions with central delling or depression are suggestive of viral cutaneous infection, including herpes simplex, herpes zoster, varicella,

Figure 520-1 Configurational and regional diagnostic aids for the diagnosis of primary and secondary skin lesions.

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and molluscum contagiosum (an umbilicated papular lesion). "Poikiloderma" refers to epidermal atrophy, reticulate hyperpigmentation, hypopigmentation, and erythema with telangiectasia; poikilodermatous skin lesions are typically seen in collagen vascular disease, cutaneous T-cell lymphoma (mycosis fungoides), and radiation skin damage. "Sporotrichoid or chancriform syndrome" describes nodular, ulcerative lesions on an extremity with satellite lymph nodes similar to the initial appearance of primary syphilis and sporotrichosis; primary skin inoculation of histoplasmosis, coccidioidomycosis, and blastomycosis may initially present in this manner, as may infection with Nocardia or Mycobacterium marinum. Other physical features influence diagnoses. Dry, lichenified lesions suggest a chronic state, whereas wet, weeping, macerated lesions suggest acute reactions. Abscesses are soft and fluctuant, whereas nodules are usually firm. Redness caused by dilatation of superficial blood vessels blanches with pressure, whereas erythema caused by extravasated blood, as occurs in petechiae and purpuric lesions, does not blanch. Hues of brown to black usually indicate melanin, although some drugs cause brown-black pigmentation in the skin (e.g., minocycline). The variation in color from melanin is related to the depth of the pigment in the skin, with deeper pigment having a more blue-black color.

DIAGNOSTIC TESTS AND AIDS IN EXAMINATION OF THE SKIN Certain aids and procedures, when combined with the history and physical examination, assist accurate diagnosis. VISUAL AIDS. MAGNIFICATION.

Magnification of skin lesions can detect the follicular plugging seen in discoid lupus erythematosus or fine telangiectasia in the pearly, opalescent borders of basal cell cancers.

TRANSILLUMINATION.

Oblique lighting in a darkened room can help to detect slight degrees of elevation or depression of lesions as well as fine wrinkling or atrophy of the epidermis. The application of a penlight directly to nodular lesions in a dark room may give clues as to their density and make-up. Cystic lesions allow transmission of some light, whereas nodules composed of cellular infiltrates do not. DIASCOPY.

Firm pressure with a microscope slide against skin lesions differentiates the erythema of capillary dilatation from that of extravasated blood. Sarcoidosis, tuberculosis, and other granulomatous inflammatory reactions in the skin are suggested if diascopy of the lesions shows a characteristic "apple jelly" or glassy, fawn-colored appearance. LONG-WAVE ULTRAVIOLET (UV) OR WOOD'S LIGHT EXAMINATION.

Long-wave ultraviolet light (UVA) (360 nm) is useful in evaluating several conditions of the skin. Wood's light exaggerates the differences in the degree of pigmentation when the skin is examined with the lamp in a dark room. Melanin is a universal absorber of UV light, so decreased melanin shows more reflection (light color) and increased melanin less reflection (darker color). Pigment in the epidermis is exaggerated with UVA light, but pigment in the dermis is not, so a reasonable guess as to the site of melanin in the skin can be made. Wood's light may be the only means of recognizing the hypomelanotic ash leaf-shaped macules of tuberous sclerosis. The extent of vitiligo and melanotic nevi (which appear darker than surrounding normal skin) can also be determined. Some superficial fungal infections of the scalp fluoresce blue-green; erythrasma, a superficial intertriginous bacterial infection that produces a porphyrin, fluoresces a brilliant coral red; Pseudomonas infections may give off yellow-green color under a Wood's light. CLINICAL TESTS. PATCH TESTS.

Patch testing is used to validate a diagnosis of allergic contact sensitization and to identify the causative allergen. Because the entire skin of sensitized humans is allergic, the test reproduces the dermatitis in one small area where the allergen is applied, usually on the back. The suspected allergen is applied to the skin, occluded, and left in place 48 hours. A positive test reproduces a delayed hypersensitivity eczematous response at the test site from 48 hours up to a week later. Considerable experience is required to perform and interpret patch tests. Photopatch testing is performed to detect photocontact allergy. Suspected photoallergens are placed on the skin in two sets. One set of allergens is irradiated with appropriate wavelengths of light after the patches are in place on the skin for 24 hours; the second set of the same photoallergens is kept covered to serve as controls. Photoallergens cause an erythematous reaction that is evident 24 hours after exposure to light. PHYSICAL CONTACT TESTING.

Darier's sign is the development of an urticarial and flare reaction after vigorously rubbing cutaneous mast cell (urticaria pigmentosa) lesions of the skin. The rubbing degranulates the mast cells, releasing histamine. Nikolsky's sign demonstrates disadherence of the epidermal cells to one another. Pushing, rubbing, or rotating normal skin near bullous lesions causes the epidermis to be dislodged, leaving a moist, glistening defect. This sign is present in various forms of pemphigus and in toxic epidermal necrolysis. The Koebner phenomenon occurs in certain skin diseases that tend to evolve new skin lesions after traumatic injury in areas of apparently normal skin. Thus, psoriasis may evolve within surgical scars and after sunburn or in the wake of a drug reaction involving the skin. Lichen planus may also exhibit this phenomenon. Pathergy, the development of pustular and ulcerative lesions at the site of needle puncture, is suggestive of Behcet's syndrome and pyoderma gangrenosum. Hair-pull examination is done to assess hair loss in the scalp. It is often useful to pull vigorously on scalp hairs to determine whether there is an increased number of falling hairs (normally only one or two can be removed with a tug of a group of hairs between the thumb and forefinger); ascertain the ratio of anagen to telogen hairs; and examine the hairs under a microscope for various congenital malformations of the shaft. Normally 10 to 15% of scalp hairs are in their resting phase, but the percentage rises in naturally shed hair. PARING HYPERKERATOTIC LESIONS TO DIFFERENTIATE WARTS FROM CALLUSES.

After the hyperkeratosis is pared away, the wart displaces and obliterates epidermal ridges and small bleeding points, and black and red dots become visible. In calluses, the epidermal ridges are not interrupted, and no vessels are seen within the callus. LABORATORY PROCEDURES. GRAM STAIN AND CULTURES.

Gram stain for bacteria and bacteriologic cultures are important when the primary lesion is a pustule or furuncle or appears to be impetigo. When an unusual cutaneous infection is considered in an immunosuppressed patient, a skin biopsy specimen can be minced or ground in a sterile mortar and cultured for aerobic and anaerobic bacteria, including typical and atypical mycobacteria, deep fungi, and Candida. A more rapid method of screening for infectious agents in immunosuppressed patients (often the first sign of septicemia in such patients is pustules, nodules, or ulcerative lesions) is to perform frozen sections on a skin biopsy specimen taken from the lesion and to obtain Gram stains, acid-fast bacterial stains, and periodic acid-Schiff stains (to identify fungal and yeast elements). This approach may provide a diagnosis within a few hours. EXAMINATION AND CULTURE FOR FUNGI AND CANDIDA.

The presence of mycelia may be ascertained by applying 10% potassium hydroxide (KOH) to scale or exudative material scraped from suspected lesions and briefly heating the slide to dissolve the keratin. Hyphal elements can be observed by direct microscopic examination. Dermatophyte hyphae appear as long, branching, refractile, walled structures; Candida organisms appear as shorter, linear hyphae in association with budding yeast forms; tinea versicolor is seen as round yeast forms with short, club-shaped hyphae (so-called spaghetti and meatballs pattern). KOH examination of skin scrapings is mandatory to exclude tinea. A classic dictum is "if the skin lesion is scaly, scrape it." TZANCK SMEAR.

The microscopic examination of cells from the base of vesicles reveals the presence of giant epithelial cells and multinucleated giant cells in herpes simplex, herpes zoster, and varicella. Material is obtained from the base of a vesicle by gentle scraping with a scalpel and is spread on a glass slide and stained with Giemsa's or Wright's stain for the examination (Color Plate 14 C). SKIN BIOPSY.

Lesions characteristic of the eruption (primary lesions) should be sampled. Lesions altered by scratching, infection, crusting, or lichenification are not likely to provide useful information. Clinical indications for biopsy include lesions thought to be malignant; lesions that fail to heal, increase in size, bleed easily, or 2272

Figure 520-2 Methods of skin biopsy.

ulcerate spontaneously; tumors or growths of uncertain nature; and many inflammatory conditions, especially those for which the diagnosis is uncertain.

Four types of biopsies can be performed. The choice of technique determines the size and shape of the specimen obtained (Fig. 520-2) . The procedure selected should secure the tissue most likely to contain the pathologic alterations and leave the smallest cosmetic defect (Table 520-3) . For the most complete histopathologic assessment, an elliptical, full-thickness excision is best because, in one procedure, the entire lesion is removed and secured for diagnosis and the remaining defect is easily sutured. The excisional biopsy technique is indicated when malignant melanoma is TABLE 520-3 -- SOME GENERAL PRINCIPLES TO IMPROVE BIOPSY TECHNIQUES Skin Biopsies and Various Skin Diseases Shave biopsies can be used for pedunculated skin lesions. An inflammatory dermatosis should not have a shave biopsy but rather a punch or incisional biopsy. A pigmented lesion that is even slightly "atypical" or suggestive of a melanoma should be removed by an excisional biopsy if possible. Never perform a shave biopsy for suspicious pigmented lesions. Non-pigmented tumors should be sampled from the thickest portion. Ulcers should be sampled at the edge--not the center. Punch or incisional biopsy is preferred. Vesicles or bullae should be sampled immediately adjacent to the blister edge. For immunofluorescence studies, it is preferable to sample some lesions, such as dermatitis herpetiformis, away from the blister, whereas other diseases, such as pemphigus, should be sampled from the blister edge. If an infectious process is suspected, part of the biopsy specimen should be sent for culture and special stains. Annular lesions should be sampled from the leading edge. Mechanical Features About Skin Biopsies Punch biopsy specimens smaller than 3 mm may not provide enough material to allow the pathologist to make a diagnosis. Warn patients about residual scars after the biopsy. Shave biopsies leave circular scars; biopsies may form a keloid especially on the mid-chest, shoulder, and back. Scalp biopsies bleed profusely. Use lidocaine with epinephrine and anesthetize the biopsy site 5-10 minutes before the biopsy is done. Try to sample above the knees, especially in elderly patients with poor peripheral circulation or diabetes, because sampled areas on the lower leg heal slowly and often become infected. Do not leave punch biopsies open; suture them. Use soft sutures such as silk in body folds for patient comfort. suggested or when a lesion is deep in skin or subcutaneous tissue and its orientation in surrounding tissue is relevant for diagnosis. A second procedure is the paramedian incisional biopsy, in which a thin but deep elliptical section is taken through the center of the lesion including normal skin at each end. This approach is especially useful in diagnosing large keratoacanthomas. A third biopsy method is the shave, or parallel incision, in which lidocaine is injected locally under the lesion to lift it above the skin surface and a scalpel (the knife horizontal to the skin surface) is used to "shave" off the protruding part of the skin and lesion. This technique is useful for diagnosing malignant and benign tumors when subsequent treatment by curettage and electrodesiccation is anticipated. It should never be used when melanoma is suspected, because the specimen obtained is too superficial for adequate histologic grading. Shave biopsy is convenient for removing superficial benign tumors such as seborrheic keratoses or skin tags. In the fourth technique, punch biopsy, the clinician uses a tubular blade to cut out a circular plug of skin by slightly rotating and pushing the cutting edge deep into the dermis. The specimen is clipped off at its base with scissors, and the defect can be readily closed with sutures. Punch biopsies are used to diagnose inflammatory diseases and tumors. If a first skin biopsy does not provide an answer, it is often necessary and appropriate to resample the area.

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Chapter 521 - PRINCIPLES OF THERAPY Frank Parker

The goals of therapy are to define and remove the cause of a disorder, restore the structural and functional integrity of the skin, and relieve symptoms such as itching, pain, or cosmetic disfigurement. The barrier function of damaged skin is impaired, but protection can be provided with dressings as well as by minimizing scratching and avoiding abrasive clothing, soaps, and chemicals. Removal of debris, such as excessive scale, hyperkeratoses, crusts, and infection, is also crucial. Topical and systemic medications, dressings, and other treatments can alter skin temperature and blood flow and thus favorably affect the metabolism of the skin.

TOPICAL MODES OF THERAPY SOAKS AND WET DRESSINGS. Water, with or without various additives, can provide many benefits to the skin, including soothing comfort, antipruritic effects and increased rate of epidermal healing with hydration and debridement of crusts, dead skin, and bacteria. BATHS. A bath is useful when the area of involvement is too large to apply compresses. Baths with whirlpool action are favored for debridement of large or deep ulcers. The tub should be one-half full and the soak should last no longer than 20 to 30 minutes to avoid maceration. Medicated baths can evenly distribute soothing antipruritic and anti-inflammatory agents to widespread lesions. Bath oil prevents drying by leaving a thin film of emollient on the skin. Warm baths cause vasodilation and may increase itching; cool baths constrict vessels and usually soothe pruritus. The best time to apply lubricants is immediately after the bath so that they may hold water in the hydrated stratum corneum. WET DRESSINGS. Water and medication can be applied to the skin with dressings (finely woven cotton, linen, or gauze) soaked in solution. As water evaporates, the skin cools, and pruritus lessens. For maximal benefit from evaporation, dressings should be no more than a few layers thick and should be reapplied every few minutes for 15 to 30 minutes several times a day. Wet compresses, especially with frequent changes, provide gentle debridement of crusts, scales, and cutaneous debris. If the compresses are permitted to dry (wet to dry compresses) and become adherent, the debriding effect is increased but there may be further damage to the skin. Dried-out dressings should be re-moistened to facilitate removal. Wet compresses also leach water-binding proteins from the stratum corneum and epidermis and lead to later skin dryness, which is desirable for 2273

treating acute vesicular, bullous, oozing, or weeping conditions as well as for crusty, swollen, and infected skin. Open wet dressings are applied directly to the skin, leaving the dressing exposed to the air to evaporate. Frequent reapplication debrides exudate, crust, and bacterial contamination and also dries out the skin, thus rapidly decreasing oozing and weeping. Closed wet dressings, in which the moist fabric dressings are applied to the skin and covered with an impervious material such as plastic, oil cloth, or Saran wrap, may be useful when maceration and heat retention are required. For example, closed wet dressings may be appropriate when there is excessive keratin of the palms or soles or when an early abscess needs heat to localize the infection. DRY DRESSINGS. Dry dressings protect the skin from dirt and irritants and can be used to apply medications, prevent scratching and rubbing by the patient or from clothing and sheets, and keep dirt away. Such dressings also prevent scratching and rubbing. In cases of neurodermatitis or stasis dermatitis, dry dressings often are left in place for several days. Soft casts or cast-like boots (e.g., Unna boot) serve the same purposes. The medication most commonly added to baths and dressings is aluminium acetate, which coagulates bacterial and serum protein. As a 5% preparation it is known as Burow's solution, and it must be further diluted for use. Burow's solution can be readily made by dissolving tablets or powder packets in appropriate amounts of water. (One tablet or packet in 500 mL = 1:20 concentration.) Potassium permanganate and silver nitrate are seldom used because they stain the skin and may be absorbed if used over large raw areas of skin. Wounds may also be cleansed and debrided by absorption beads or granules that absorb debris and exudate from wounds (Debrisan, DuoDerm granules), hydrogen peroxide, whirlpool treatments, and various enzymatic products, including trypsin/chymotrypsin, fibrinolysin, collagenase, and streptokinase. Antimicrobial agents are seldom applied by surface dressings because huge quantities would be required to reach therapeutic concentrations. Occlusive dressings can treat acute wounds and chronic venous, diabetic, and pressure ulcers. In general, these materials provide good protection, help promote healing, and provide pain reduction of skin ulcerations. TOPICAL MEDICATIONS. Most topical medications consist of two major agents, the active ingredient or specific medications, and the vehicle or base in which the active material is dissolved. BASES OR VEHICLES.

Bases come in a variety of forms. Powders promote dryness by absorbing evaporative moisture, and they reduce maceration and friction in intertriginous areas. Powders may be inert chemicals (corn starch, talcum) or contain medications. Lotions are suspensions of insoluble powders in water. As water evaporates on the skin surface, it collects and leaves a uniform film of powder behind. The addition of alcohol increases the cooling effect. Creams are emulsions of oil in water (more water than oil); they vanish into the skin because water evaporates and the residual oil is spread thinly and imperceptibly over the skin. Ointments consist of oils with variably smaller amounts of water added in suspension; they have a pleasant lubricating effect on dry or diseased skin, but they give a greasy feeling to the skin and clothing. Oils in bases provide a softening effect by forming an occlusive layer that traps water and retards evaporation. Thus, ointments with large amounts of oil give a more sustained, softening effect than creams or lotions. Some ointments containing large percentages of inert oil may be occlusive and retain heat, increase pruritus, and increase percutaneous absorption of active ingredients. The more occlusive ointments should not be used on oozing or infected areas, because the resulting occlusion and warmth may increase bacterial growth. Pastes are mixtures of powder and ointment (e.g., zinc oxide paste). Sprays are propelled aerosols. Selection of a base or emollient depends on the condition being treated and the needs of the patient. Lotions are useful for pruritic, oozing reactions. Petrolatum, by contrast, retains heat and promotes hydration and even maceration of the stratum corneum. Ointments are used most often on dry, scaling conditions in which

endogenous hydration of the stratum corneum is defective. ACTIVE AGENTS.

Topical corticosteroids provide effective local anti-inflammatory and antipruritic effects. They cause immediate and profound cutaneous vasoconstriction, which prevents mobilization of polymorphonuclear leukocytes and monocytes into the reaction site, and also interfere with the inflammatory activities of already-present cells (e.g., mast cells). Topical corticosteroids are intrinsically active and have a rapid therapeutic effect. They slow the mitotic rate of fibroblasts, decrease collagen synthesis, and possibly enhance collagen catabolism. All effective topical corticosteroids have the basic hydrocortisone structure. A 1% concentration of hydrocortisone ointment or cream serves as a norm for comparing potency of subsequently modified topical corticosteroids. By fluorinating hydrocortisone or adding acetonide, the potency of the corticosteroid is greatly enhanced (Table 521-1) . The potency of a preparation also relates to the concentration of active drug in the vehicle and the nature of the vehicle. Of the various types of vehicles used in corticosteroid preparations, ointments are the most efficient because they most effectively dissolve corticosteroids, and the occlusive nature of ointments increases stratum corneum permeability. Second in order of efficiency is acetone-alcohol gel, whereas creams and lotions are less useful. The potency of corticosteroids corresponds closely to the degree of anti-inflammatory effectiveness as well as to the incidence and severity of associated side effects. Epidermal and dermal atrophy can be pronounced; decreased collagen synthesis and reduced stromal support for dermal blood vessels lead to telangiectasia, purpura, and striae. These changes are especially likely to occur in intertriginous occluded areas of the skin and on the face. Fluorinated corticosteroids can cause a perioral scaling, papular and pustular dermatitis, or facial redness, telangiectasia, and acne rosacea-like eruption. Potent topical corticosteroids applied for prolonged periods around the eyes can occasionally cause glaucoma and even cataracts. Topical corticosteroids can also predispose to or worsen skin infections such as folliculitis, tinea, and candidiasis. Systemic absorption of potent topical corticosteroids may transiently lower plasma cortisol levels when they are used with an occlusion over as little as 20% of the body. Intermediate-potency corticosteroids are useful in most dermatologic conditions (Table 521-2) . Ointments are useful for thickened skin or for dry, exposed areas whereas creams or gel preparations rapidly evaporate. Low-potency corticosteroids are used to treat the face and the thin and occluded skin of the groin and genital area. Lotions and gels are best for hairy areas. High-potency corticosteroid preparations should not be used to treat most dermatologic conditions; they generally should be reserved for areas of skin that have been substantially thickened by disease, such as dense plaques of psoriasis or chronic dermatitis. Topical corticosteroids are usually applied once or twice a day. TABLE 521-1 -- POTENCY RANKING OF SOME COMMONLY USED TOPICAL CORTICOSTEROIDS POTENCY

GENERIC NAME

CLINICAL APPLICATION

Most potent

Clobetasol propionate cream and ointment 0.5%, halobetasol propionate cream and ointment 0.5%, betamethasone dipropionate cream and ointment 0.5%, clobetasol propionate cream and ointment 0.5%, halcinonide cream and ointment 0.1%, fluocinonide ointment 0.5%

Recalcitrant psoriasis, discoid lupus, recalcitrant lichen planus, nummular eczema

Intermediate potency

Triamcinolone acetonide 0.1%, betamethasone valorate cream 0.1%, amcinonide cream 0.17%

Dermatitis--allergic-contact, atopic eczema, neurodermatitis

Low potency

Hydrocortisone cream and ointment 2.5% and 1.0%, desonide cream and ointment 0.5%, locoid ointment 0.1%, dexamethasone sodium phosphate cream 0.1%

Intertrigo, pruritus ani, seborrheic dermatitis

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TABLE 521-2 -- GUIDELINES FOR SELECTING TOPICAL CORTICOSTEROIDS LOCATION OR TYPE OF LESION

SUGGESTED POTENCY OF CORTICOSTEROID

SUGGESTED VEHICLE

Areas of Body Trunk, arms, legs

Intermediate or low

Ointment or cream

Palms, soles

Intermediate or high

Ointment

Scalp

Intermediate or low

Lotion, gel, aerosol

Intertriginous areas

Low

Cream, lotion

Face

Low

Cream, lotion

Area around eyes

Low

Cream or ophthalmic preparation

Ears

Intermediate or low

Cream, gel, or lotion

Dry, scaling, fissuring, lichenified lesion

Intermediate

Ointment

Thickened, hyperkeratotic skin patches

High

Ointment

Oozing, weeping lesions

Intermediate

Lotion, cream

Ulcerative lesions

Do not use topical corticosteriods

Types of Lesion

The stratum corneum acts as a reservoir and continues to release topical corticosteroid into the skin after the initial application. Chronic dermatoses become less responsive after prolonged use, but changing to another topica1 corticosteroid often overcomes this problem. Intralesional corticosteroids, which dissolve in the tissues slowly over weeks to months, are used to shrink inflammatory acne cysts and hypertrophic scars and keloids. They are occasionally injected into unresponsive, localized dermatoses such as alopecia areata, granuloma annulare, discoid lupus erythematosus, psoriasis, and lichen simplex chronicus. Triamcinolone acetonide is the most widely used, and its maximal duration of action is 4 to 6 weeks. Triamcinolone hexacetonide is longer acting (6 to 8 weeks), whereas betamethasone (Celestone) and dexamethasone (Decadron) are of shorter duration (2 to 4 weeks). To avoid disfiguring atrophy, great care is necessary in using low concentrations ( 3 mm). Thrombocytopenia causes petechiae, whereas abnormalities in the clotting cascade commonly cause ecchymoses. Necrotic ecchymoses are found when thrombi form in dermal vessels and lead to infarction and hemorrhage, e.g., disseminated intravascular coagulation (DIC). Palpable purpura results from inflammatory damage to cutaneous blood vessels, as in vasculitis. NON-PALPABLE PURPURAS.

Non-palpable purpuras include thrombocytopenic conditions, senile or actinic purpura, hypergammaglobulinemic conditions, blood clotting abnormalities, Schamberg's disease, and disseminated intravascular coagulation. Actinic (senile) purpura, which is a common problem in older individuals, is the result of increased vessel fragility from connective tissue damage to the dermis caused by chronic sun exposure and aging. Minor trauma induces ecchymoses, usually on the dorsum of the hands and forearms. The skin in these areas is thin and fragile. Topical or systemic steroids can induce similar purpura. Other causes of vascular fragility of the skin include amyloidosis and the Ehlers-Danlos syndrome. Schamberg's disease, or pigmented purpuric dermatitis, is an idiopathic capillaritis that causes petechial lesions of the lower legs (occasionally the arms and trunk) in association with hyperpigmentation. The lesions have the appearance of cayenne pepper. Occasionally Schamberg's disease is secondary to a drug reaction. Petechiae and purpura also occur in hypergammaglobulinemic purpura, which is a syndrome characterized by episodes of fever and arthralgias and appears to be the result of immune complex-mediated damage to small blood vessels. In DIC (Chapter 186) , uncontrolled clotting within blood vessels and diffuse thrombosis lead to hemorrhage, ecchymosis, and infarction. DIC occurs in association with bacterial sepsis (particularly meningococcemia), as a post-viral or post-streptococcal phenomenon (purpura fulminans), or in conjunction with malignancies such as prostatic carcinoma and acute myelocytic leukemia. The most distinctive hemorrhagic skin lesions are stellate (star-shaped) purpuric ecchymoses with necrotic centers. The center of the lesion is dark gray, indicative of necrosis and impending slough. Petechiae, hemorrhagic bullae, acral cyanosis, mucosal bleeding, and prolonged bleeding from wound sites can occur. A variety of infectious diseases cause cutaneous petechiae, purpura, or ecchymoses. In meningococcemia (Chapter 329) the organisms produce acute vasculitis or local Schwartzman-like reactions with erythematous macules, petechiae, purpura, and ecchymoses on the trunk and legs. The lesions may become confluent, often with central necrosis. Patients with acute meningococcemia are ill with fever, malaise, headache, meningeal signs, and hypotension. The skin lesions of disseminated gonococcemia (Chapter 362) begin as tiny red papules and petechiae and then evolve into painful purpuric pustules and vesicles scattered on the distal extremities. Fever, polyarthritis, or monoarticular arthritis may be present. The rash of Rocky Mountain spotted fever (Chapter 371) , appears between the second and sixth days of the illness, initially as small, erythematous macules that blanch on pressure, but then evolving into petechiae, purpura, and ecchymoses. The rash first occurs on the acral areas and then spreads up the extremities and trunk. Small areas of necrosis may occur on the fingers, toes, and ear lobes. Fever, severe headache, toxicity, confusion, and myalgias commonly occur. Infective endocarditis (Chapter 326) is associated with petechial and purpuric skin lesions. Petechiae appear in crops in the conjunctivae, buccal mucosa, upper chest, and extremities. Splinter hemorrhages (linear, red to brown streaks under the fingernails or 2281

TABLE 522-3 -- TYPES OF VASCULITIS AND ASSOCIATED SKIN LESIONS TYPE OF VASCULITIS

BLOOD VESSELS INVOLVED

TYPE OF SKIN LESION

Leukocytoclastic or hypersensitivity angiitis: Henoch-Schonlein purpura, cryoglobulinemia, hypocomplementemic vasculitis

Dermal capillaries, venules, and occasional small muscular arteries in internal organs

Purpuric papules, hemorrhagic bullae, cutaneous infarcts

Rheumatic vasculitis: systemic lupus erythematosus; rheumatoid vasculitis

Dermal capillaries, venules, and small muscular arteries in internal organs

Purpuric papules; ulcerative nodules; splinter hemorrhages; periungual telangiectasia and infarcts

Granulomatous vasculitis Churg-Strauss syndrome

Dermal small and larger muscular arteries and Erythematous, purpuric, and ulcerated nodules, medium muscular arteries in subcutaneous tissue and plaques, and purpura other organs

Wegener's granulomatosis

Small venules, arterioles of dermis, and small muscular arteries

Ulcerative nodules; peripheral gangrene

Small and medium muscular arteries in deep dermis, subcutaneous tissue, and muscle

Deep subcutaneous nodules with ulceration; livedo reticularis; ecchymoses

Periarteritis: classic type limited to skin and muscle

Giant cell arteritis: temporal arteritis, polymyalgia rheumatica, Medium muscular arteries and larger arteries Takayasu's disease

Skin necrosis over scalp

toenails), Osler's nodes (2- to 15-mm, tender red nodules on the pads of the fingers and toes), and Janeway lesions (small, painless plaques and palpable, purpuric nodules on the palms or soles) may be seen. The skin lesions are related to immune complex vasculitis or septic emboli. Similar lesions may occur in association with atrial myxomas (Chapter 70) and cholesterol emboli (Chapters 67 and 112) . PALPABLE PURPURAS.

Vasculitis and necrotizing angiitis characterize disorders in which there is segmental inflammation in the blood vessel wall with accumulation of neutrophils and fibrinoid necrosis. The vascular reaction is mediated by immune complexes. Papules with purpura result from extravasation of blood from the damaged vessels (Color Plate 13 C). Although all sizes of blood vessels may be affected, the vasculitis in the skin involves venules. If the process is extensive or if large vessels are involved, skin necrosis and ulceration may occur. Depending upon the size of the affected blood vessels, at least five types of vasculitis may involve the skin. The size and type of vessels in the skin, in turn, determine the kind of morphologic lesion (Table 522-3) . In general, as the vasculitis involves progressively larger and more deeply situated vessels, the skin lesions become more nodular, with larger ulcerative or gangrenous processes. The term granulomatous vasculitis refers to angiitis associated with a histiocytic proliferation that also involves necrotizing granulomas in the connective tissue of multiple organs, causing rhinorrhea, sinusitis, cough, arthralgias, and ocular and neurologic symptoms (Churg-Strauss syndrome) (Chapter 292) . Necrotizing leukocytoclastic vasculitis can occur in a variety of settings including sepsis; connective tissue disease, especially systemic lupus erythematosus and rheumatoid arthritis; cryoglobulinemia, especially with hepatitis C; drug reactions; and, occasionally, underlying carcinomas, lymphomas, or leukemias. Circulating immune complexes have been demonstrated in patients with necrotizing angiitis. Immunoglobulins and complement are found in the affected vessel wall by direct immunofluorescence. The immune complexes lodge in the small vessel walls and activate the complement system, forming the anaphylatoxins C3a and C5a, which recruit neutrophils that induce inflammatory and necrotic damage to the vessel with accompanying fragmented nuclei of the neutrophils (so-called nuclear dust). Several syndromes are associated with leukocytoclastic vasculitis, depending on the organ systems affected. Henoch-Schonlein syndrome (Chapters 106 and 292) occurs most often in children, frequently preceded by an upper respiratory infection and accompanied by arthralgias, abdominal pain, and renal vasculitis; IgA and complement are usually found in the involved vessels on direct immunofluorescence. Hypocomplementemic vasculitis is characterized by urticaria-like lesions, arthritis, facial and laryngeal edema, and low serum complement level; IgG and C3 are present in vessels taken from early skin lesions. Facial and laryngeal edema may also occur. A third form consists of purpura, arthralgia, weakness, and mixed cryoglobulinemia (mixed cryoglobulins contain IgG and IgM with anti-IgG or rheumatoid factor activity), which may be idiopathic or occasionally associated with systemic lupus erythematosus, infectious mononucleosis, lymphomas, or primary biliary cirrhosis. If the vasculitis is idiopathic and cutaneous, the skin responds to prednisone (60 to 80 mg/day) or dapsone (100 to 150 mg/day). Systemic vasculitides may require

prednisone and cyclophosphamide (2 mg/kg/day). Necrotizing cutaneous vasculitis may occur with hepatitis B or hepatitis C, after intestinal bypass surgery for morbid obesity, or in patients with jejunal diverticula or other gastrointestinal conditions characterized by bacterial overgrowth. An arthritis-dermatitis syndrome associated with intestinal bypass surgery is characterized by polyarthritis and palpable purpura or purpuric nodules and pustules on the trunk, legs, feet, and arms. Antigenic components of the intestinal bacterial overgrowth lead to the formation of cryoprotein immune complexes that deposit in the skin and joints, causing a hypersensitivity vasculitis and non-deforming arthritis. Antibiotics such as chloramphenicol, sulfamethoxazole-trimethoprim, tetracycline, and metronidazole may improve the condition.

PAPULOSQUAMOUS SKIN DISEASES Papulosquamous conditions include those that are both papular (even if only mildly elevated) and squamous or scaly (hyperkeratotic) (Table 522-4) . They generally represent conditions in which the epidermis is thickened and the process of cornification is altered; concomitant dermal inflammation usually occurs. PSORIASIS. Psoriasis is the prototypical papulosquamous condition, characterized by well-demarcated erythematous papules and plaques with silvery scale (Color Plate 12 D). Psoriasis is, at least in part, genetically determined. It is usually a chronic condition of epidermal proliferation and dermal inflammation. Psoriasis begins most commonly in early adult life, but it may begin at any age. The disease may remain localized to just a few areas or may cause continuous generalized disease, occasionally resulting in total-body erythema and scale, termed erythroderma. The pathogenesis of psoriasis is unknown, but it appears to be a multifactorial disease in patients who are genetically predisposed. There is an increased prevalence of psoriasis in individuals with human leukocyte antigens (HLAs) HLA BW17, B13, and BW37. Thirty per cent of patients have a family history of disease. The basic alteration represents an accelerated cell cycle in an increased TABLE 522-4 -- PAPULOSQUAMOUS SKIN DISEASES Psoriasis Reiter's syndrome Pityriasis rosea Lichen planus Secondary syphilis Pityriasis rubra pilaris Pityriasis lichenoides et varioliformis acuta Pityriasis lichenoides et varioliformis chronica Mycosis fungoides

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number of dividing epidermal basal cells, culminating in rapid epidermal cell proliferation. Cellular turnover is increased up to seven-fold, and the transit time from the basal layer to the top of the stratum corneum is 3 to 4 days rather than the usual 28. This rapid turnover of keratinocytes alters keratinization, resulting in thickened epidermis (seen as papules and plaques) and parakeratotic stratum corneum (silver scales). T lymphocytes play a role, but the exact mechanism underlying this benign proliferative reaction is unknown. Classically, lesions of psoriasis are distributed symmetrically over areas of bony prominence such as elbows and knees. Frequently they may also be found periumbilically, in the intergluteal cleft, or even on the glans of the penis (a location that, if involved, can be very helpful in making the diagnosis). The palms and soles can be symmetrically involved with well-circumscribed plaques or even diffuse erythema with scale. The only discernible lesions may be very superficial pustules on the palms and soles with fine scale remaining after rupture. Nail involvement occurs in up to 50% of cases and can be a diagnostic clue. The nails may have small ice pick-like depressions on the surface of the nail plate; although some normal persons have one or two similar lesions, this finding is much more diffuse in psoriatic patients. Onycholysis (nail plate separation from the nail bed), which can also occur with a psoriatic plaque in the distal nail bed, may also cause a red-brown discoloration that is reminiscent of an oil stain under the nail. When the individual silvery scales are plucked from psoriatic plaques, tiny pinpoint capillary bleeding may be seen (Auspitz's sign). Another helpful diagnostic sign is Koebner's phenomenon, in which trauma to the skin induces new skin lesions. Thus, scratches or surgical incisions elicit linear papulosquamous lesions that should alert the physician to the diagnosis. This phenomenon may also explain the high incidence of psoriasis on the elbows and knees. Other aggravating factors include streptococcal infections, emotional stress, overuse of alcohol, and drugs such as lithium or beta-blockers. There are several common variants of psoriasis: guttate psoriasis, in which numerous small papular lesions with silvery scaling evolve suddenly over the body, often 1 to 3 weeks after streptococcal pharyngitis; inverse psoriasis, in which plaques evolve in intertriginous areas and thus lack the typical silver scale because of maceration and moisture; and pustular psoriasis, a form of the disease in which superficial pustules may stud typical plaques, be confined to the palms and soles, or be associated with a rare generalized erythematous skin condition accompanied by fever and leukocytosis. Erythrodermic psoriasis with generalized erythema and scale covering the entire body may occur secondary to overvigorous therapy, a generalized Koebner phenomenon, a superimposed drug reaction, or withdrawal from oral corticosteroids. Erythroderma can be quite serious, even life-threatening, and often requires hospitalization. Psoriatic arthritis (Chapter 287) may be found in up to 10 to 15% of patients. At times, Reiter's syndrome (Chapter 287) may be confused with psoriasis. The skin lesions of the two disorders are indistinguishable clinically and histologically. In Reiter's syndrome, pustular and hyperkeratotic papules and plaques commonly occur on the palms and soles (keratoderma blennorrhagicurn), and scaling, red patches evolve on the glans penis and within the groin (balanitis circinata). Reiter's syndrome is suggested by asymptomatic erosions on the tongue and buccal mucosa, urethritis, iritis or conjunctivitis, arthritis, and occasionally diarrhea. The goal of therapy is to decrease epidermal proliferation and underlying inflammation. There is no curative agent for psoriasis, and treatment suppresses the condition only as long as it is administered. Topical therapy in some form is usually a mainstay of treatment. Intermediate- or strong-potency topical steroids may be used once or twice a day. Topical tar or anthralin preparations can be used and even compounded with topical steroids. UVB with tar or UVA with oral psoralens (PUVA) can provide excellent relief. Calcipotriene (Dovonex) when used twice a day as an ointment or cream is a "steroid-sparing" topical form of vitamin D that may be as effective as medium-potency steroids. Topical tazarotene (Tazorac) is the first topical retinoid to treat psoriasis. Because of potential side effects, systemic therapy should be considered only in recalcitrant disease. Antimetabolites or antimitotic agents, including methrotrexate, azathioprine, and hydroxyurea, are the most commonly used. Methotrexate is used in once-weekly low doses. Because these agents affect bone marrow and liver enzymes (in the case of methotrexate), laboratory monitoring is required. In addition, liver biopsies are usually performed in patients with cumulative doses of 1.5 to 2.0 g of methotrexate. Etretinate, a retinoid, is particularly useful in pustular and erythrodermic forms of psoriasis; it is being replaced by its active metabolite, acitretin, which is less lipophilic and has a shorter half-life. However, because some acitretin may be converted back to etretinate, particularly in the presence of alcohol, pregnancy must be avoided and blood counts, plasma triglyceride levels, and liver enzyme levels should be monitored. PITYRIASIS ROSEA. Oval or round, tannish pink or salmon-colored, scaling papules and plaques appear rapidly over the trunk, neck, upper arm, and legs (Color Plate 12 A). Several features of this self-limited papulosquamous condition are unique. The generalized eruption is preceded by a single lesion, termed the "herald patch," that is commonly misdiagnosed as "ringworm" or tinea corporis. The patch can occur anywhere but often appears on the neck or lower trunk area and precedes the general rash by several days to a week. The oval patches have an unusual fine, white scale located near the border of the plaques. The lesions follow skin cleavage lines, in a pattern likened to a Christmas tree. Itching can be quite prominent but is not invariable. The condition spontaneously resolves in 1 to 2 months. Recurrences are extremely rare, and the diagnosis of recurrent pityriasis rosea should lead the clinician to consider other possible papulosquamous conditions. Pityriasis rosea occasionally is preceded by a mild upper respiratory infection, and its greatest incidence is in the winter months, suggesting a viral cause. However, the disease does not occur

endemically and is not transmitted person-to-person. Such conditions as tinea corporis and guttate psoriasis may be considered in the differential diagnosis, but two possibilities should always be entertained: drug eruption and secondary syphilis. If the rash persists longer that 2 or 3 months or generalizes to involve the entire extremities, and especially the face, a drug reaction should be considered. Gold compounds, barbiturates, captopril, and clonidine can cause such a rash. Secondary syphilis should be suspected and a serologic test obtained if the rash involves palms and soles and if fever, coryza, or mucus membrane erosions (so-called mucus membrane patches) are present. Treatment of pityriasis rosea is usually not necessary unless pruritus is present. Topical corticosteroids and antihistamines may relieve itching and decrease erythema. Ultraviolet light (UVB), given as three to five treatments to elicit a mild erythema reaction, often clears the rash. LICHEN PLANUS. Lichen planus, an idiopathic, pruritic, inflammatory condition of the skin, is included in the papulosquamous group of disease because the primary lesion is a unique papule. The papules are flat topped (planus) and polygonal in configuration and have a lilac or purple hue. They may have visible scales on their surface, but more characteristic are subtle, fine white dots or white reticulated lines (Wickham's striae) surmounting the shiny, flat tops (resembling the appearance of a lichen). Wickham's striae are more visible under a hand lens after the application of a drop of mineral oil to the surface of the papule. The Koebner phenomenon occurs in lichen planus, so linear streaks of papules at the sites of skin trauma may be noted. Although lichen planus can occur anywhere on the body, typical locations are the ankles, wrists, mouth, and genitalia. There may be only a few papules or innumerable ones in a generalized distribution. Mucus membranes are commonly involved, with the lesions appearing most frequently as asymptomatic white streaks in a reticulated pattern on the buccal mucosa, tongue, gums, or lips. In erosive lichen planus, blisters and erosions cause severe discomfort and herald a more prolonged course with resistance to treatment. Lichen planus may appear as violaceous annular lesions involving the male genitalia and, rarely, the legs and arms; it can also present as hyperkeratotic, follicular, scarring alopecia (lichen planopilaris). All lichen planus lesions leave residual hyperpigmented macules in their wake. The cause of lichen planus is not known, but as many as 20 to 30% of patients have hepatitis C. Certain drugs such as thiazides, phenothiazines, gold, quinidine, and antimalarials can cause lichen 2283

planus-like, generalized eruptions. Also, some patients with chronic graft-versus-host disease may experience lichenoid lesions. Treatment of lichen planus is at times unrewarding. Topical steroids, particularly ultrapotent steroids for short periods (2 to 3 weeks), can be very helpful. Sometimes ultraviolet light is useful to control pruritus. Mucous membrane lesions tend to be more difficult to treat, but corticosteroids and even "swish and spit" cyclosporine have been used with mixed results. OTHER PAPULOSQUAMOUS LESIONS. Secondary syphilis presents with red or copper-colored scaling papules and plaques that are sometimes annular and are usually generalized and often include the palms and soles. Mucous membranes may be involved with white or red patches, and condyloma warts may be seen in the anal and genital areas (Chapter 365) . Pityriasis rubra pilaris presents with red, scaling plaques and patches with follicular horny excretions, especially on the dorsum of the hands and fingers. Diffuse, yellow hyperkeratoses may be seen on the palms and soles. The distribution is often diffuse, with rough scaling erythema involving the entire body with islands of normal skin. There may be lacy white plaques in the mouth. The lesions usually remit spontaneously in 2 to 4 years. Changes similar to those of psoriasis are sometimes seen. Pityriasis lichenoides et varioliformis acuta appears as red, discrete, palpable papules that vacuolate and then become hemorrhagic, crust, scale, and leave a scar. The lesions may be scattered over the trunk and extremities and may resemble leukocytoclastic vasculitis. The lesions may resolve in a few months or persist for years. Pityriasis lichenoides et varioliformis chronica presents as larger red, slightly scaling papules and plaques, which are usually non-pruritic. The lesions are usually on the trunk, but the mucous membranes may sometimes be involved. The lesions respond to UVB light treatments. Mycosis fungoides (Chapters 179 and 196) presents with persistent, pruritic, red, thickened plaques with scales as seen with eczema, or with thick mica-like scales suggestive of psoriasis. The lesions, which may ulcerate, often appear first in the girdle area and tend to be scattered asymmetrically over the trunk and extremities (Color Plate 13 E and 15 D). There may be islands of normal skin within the reddened areas. Biopsy findings are diagnostic.

ICTHYOSIFORM DERMATOSES The ichthyosiform dermatoses present at birth or in childhood. Lamellar ichthyosis, epidermalitic hyperkeratosis, and X-linked ichthyosis appear at birth. Ichthyosis vulgaris has its onset during childhood, tends to spare the flexural areas, and is associated with atopy (Color Plate 12 B).

VESICULOBULLOUS DISEASES Vesicles and bullae, when intact, are readily recognized primary skin lesions (Table 522-5) . Crusts or superficial erosions are secondary lesions that suggest a preceding fluid-filled primary lesion. The causes of blistering disease includes bacterial and viral infections, contact dermatitis, and autoimmune and metabolic diseases. The pathogenesis of the blister formation is often helpful in understanding its anatomic location: Blisters occur either within the epidermis (intraepidermal) or at the dermoepidermal junction (subepidermal) Intraepidermal vesicles or bullae usually contain clear fluid (but may become filled with purulent material secondarily) and have very thin roofs, so they are flaccid in appearance and are easily broken. At times the blisters are difficult to recognize, and only erosions, crusts, or the thin shreds of the epidermal blister roofs remain. Subepidermal blisters, on the other hand, have an epidermal roof and are tense and remain intact. Hemorrhagic fluid is common in subepidermal blisters because of their location close to dermal capillaries. Biopsy of early vesicles or blisters is imperative in diagnosis. Immunofluorescence studies on biopsy material may differentiate certain immunologically mediated diseases. Pathologic studies are most informative when performed early, before therapy has been initiated. INTRAEPIDERMAL VESICULOBULLOUS DISEASES. Pathologic TABLE 522-5 -- VESICULOBULLOUS DISEASES Intraepidermal vesiculobullous diseases Bullous impetigo Staphylococcal scalded skin syndrome Toxic epidermal necrolysis Herpes simplex Varicella (herpes zoster) Pemphigus diseases Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus

Pemphigus erythematosus Familial benign pemphigus Dermal-epidermal vesiculobullous diseases Bullous pemphigoid Herpes gestationis Cicatricial pemphigoid Dermatitis herpetiformis Erythema multiforme (Stevens-Johnson syndrome) Porphyria cutanea tarda Bullous disease of renal disease Bullous disease in diabetics Epidermolysis bullosa Epidermolysis bullosa acquisita processes involved in epidermal blister formation include spongiosis, primary cell damage, and acantholysis. In spongiosis, which is a common form of blister formation in eczematous processes, edema between cells of the prickle layer and liquefaction of cells gradually increase the size of the fluid spaces. Primary epidermal cell damage with fluid accumulation is seen in viral infections and friction damage. Blisters may also occur when cellular desmosomal attachments and intercellular cementing substances are immunologically or chemically altered, causing dyshesion, referred to as acantholysis (pemphigus). Bullous impetigo, a subcorneal infection of the skin with staphylococcal and/or streptococcal organisms, causes large, fragile, clear or cloudy bullae that form thin, honey-yellow crusts and a delicate collarette-like remnant of blister roof after the blisters rupture (Color Plate 16 D). Autoinoculation results in satellite lesions. The superficial epidermal blistering is caused by the toxic effects of an epidermal toxin elaborated by certain strains of these bacterial organisms. A more serious variant of bullous impetigo is staphylococcal scalded skin syndrome, usually affecting infants and characterized by the formation of rapidly progressive, painful, erythematous patches in which large flaccid bullae evolve and shed as large sheets of skin, leaving a denuded, scalded-appearing surface. With only slight trauma the skin readily slides off, much as wet wallpaper slides off a wall. In contrast to localized bullous impetigo, in which the Staphylococcus aureus may be recovered in the skin lesions, the bullae of scalded skin syndrome are sterile, although a staphylococcal infection may be found in the conjunctiva, nose, or pharynx. The widespread intraepidermal blistering results from an epidermal toxin that is elaborated by specific strains of Staphylococcus aureus and hematogenously carried to the skin. A somewhat similar condition, toxic epidermal necrolysis, occurs in adults, often secondary to drugs (e.g., ampicillin, allopurinol) and occasionally to Staphylococcus infections in an immunosuppressed patient. Toxic epidermal necrolysis is a reaction to a variety of antigenic materials that cause a suprabasilar split in the epidermis with necrosis of much of the overlying epidermis. Because of the more extensive destruction of epidermis and barrier stratum corneum layer (as opposed to staphylococcal scalded skin syndrome, in which the split is subcorneal), toxic epidermal necrolysis is often fatal and, when extensive, should be treated as a widespread burn. Toxic epidermal necrolysis also often involves the mucous membranes and therefore may be confused with Stevens-Johnson syndrome (see later). Viral infections of the skin may cause vesicles and bullae by virtue of direct infection of the keratinocytes and the destructive effect on the cells. Vesicles caused by viruses often display two important characteristics: (1) They tend to occur in groups on an 2284

indurated erythematous base, and (2) they often take on an umbilicated appearance. Herpes simplex infections (Chapter 365) cause vesicles. A complication of herpes simplex infection, erythema multiforme, is a hypersensitivity skin and mucous membrane reaction that evolves 1 to 2 weeks following herpetic recurrences as a result of a herpesvirus-containing immune complex reaction to the herpes antigen. Herpes infection is only one etiologic stimulus leading to erythema multiforme (see late). Diagnosis of herpes infections (including herpes-zoster and varicella-zoster) is made with a Tzanck test preparation of material taken from the roof of vesicles or by culture of the blister fluid (Color Plate 14 C). Varicella infection (Chapters 383) , when initially encountered, causes chickenpox, a generalized pruritic eruption with widespread, delicate vesicles on an erythematous base; the lesions have been likened to a dew drop on a rose petal. They often become umbilicated, hemorrhagic, and pustular and may leave scars. Chickenpox lesions occur predominantly on the trunk but also involve the head, extremities, and mucous membranes of the mouth and conjunctiva. Successive crops of lesions evolve for a week. Herpes zoster is a recrudescence of latent varicella virus in persons who previously had varicella. Zoster appears as grouped, umbilicated, and, at times, hemorrhagic vesicles and pustules on an erythematous base situated unilaterally along the distribution of cranial or spinal nerve roots. Several immediately adjacent dermatomes are frequently involved. Bilateral involvement is rare. Zoster is frequently associated with a prodrome of severe radicular pain in the involved areas. A common useful sign in making the diagnosis is dysesthesia of the dermatomal areas--the patient often bitterly complains that the rubbing of clothing on the area is intolerable. Most patients with herpes zoster are above 50 years of age, and cancer patients (especially those with lymphomas such as Hodgkin's disease) are particularly prone to this infection. In such patients or in immunocompromised individuals, cutaneous dissemination and visceral involvement of liver, lung, and central nervous system may occur. Treatment of herpes zoster is usually symptomatic with Burow's solution compresses, analgesics, and acyclovir (800 mg five times per day orally for 10 days), especially in immunocompromised patients. Post-herpetic neuralgia is common in individuals above age 50 (Chapter 383) . Systemic corticosteroids may reduce acute herpetic pain; whether they reduce the risk of post-herpetic neuralgia is debatable. Capsaicin cream or oral amitriptyline can help treat post-herpetic pain. Insect bites including flea and fire ant bites may also induce vesicles or bullae. The lesions are a response to injected toxins or foreign chemicals or proteins in the bite or an allergic reaction to them. Pemphigus diseases cause blistering in the epidermis by virtue of the process of acantholysis. Pemphigus vulgaris and a variant, pemphigus vegetans, which heal with hypertrophic, "vegetative" surfaces, are acquired autoimmune diseases of the skin and mucous membrane. The superficial bullae evolve just above the basal layer, readily rupture, and leave denuded, bleeding, weeping, and crusted erosions over the body that do not heal. The oral mucosa is almost always involved and is frequently the presenting site. The painful erosions characteristically spill over the vermilion border of the lips and onto the skin. Lesions of the skin occur anywhere but often in pressure and friction areas. The blisters arise on normal-appearing skin. Untreated pemphigus vulgaris progresses slowly with extensive denudation, leading to fluid and electrolyte imbalance, sepsis, and death. Pain from mouth lesions prevents adequate food intake. A skin biopsy sample of early vesicles should be obtained for routine histologic examination. The edge of a bulla, including adjacent normal skin, should be examined by direct immunofluorescence to make the diagnosis. Immunofluorescence shows deposits of immunoglobulins (usually IgG) and/or C3 in the intercellular spaces around keratinocytes. Antibodies to the intercellular areas of the epidermis are found in the serum. Circulating antibodies to the epidermis are directed against several polypeptide components of the epidermal desmosomes. Their titers somewhat reflect disease activity, and they may contribute to the defective epidermal adhesion. High doses of systemic steroids (100 to 200 mg/day of prednisone over prolonged periods) usually control the disease. Methotrexate and other cytotoxic agents are useful as steroid-sparing agents. Treatment with intramuscular gold often is successful and occasionally induces long-term remissions. Pemphigus foliaceus is a less severe disease in which the acantholytic separation within the epidermis is in the upper portion of the prickle layer. Pemphigus erythematosus may be a localized variant of pemphigus foliaceus presenting with superficial blisters, erosions, and crusting and oozing over the scalp and face in a seborrheic dermatitis-like rash or often simulating the butterfly rash of systemic lupus erythematosus. Mucous membrane involvement is unusual in pemphigus foliaceus and pemphigus erythematosus, and lower doses of systemic steroids generally control these conditions. Immunofluorescent studies on skin from the edge of lesions reveal immunoglobulin and/or C3 in the intercellular areas of the upper portions of the epidermis. Familial benign pemphigus, or Hailey-Hailey disease, is a dominantly inherited disorder with suprabasal cell acantholysis; the groups of bullae arise on erythematous skin in the flexural areas (neck, axillae, groin). Spreading erosions display vesicles and pustules at the borders with a moist, granular center. Warm weather and superficial bacterial infections seem to cause flares, and spontaneous exacerbations and remissions continue for years. Familial benign pemphigus differs from other forms of pemphigus in its genetic pattern, absence of mouth lesions, benign course, and absence of intercellular antibodies. Antibiotics, both topical and systemic, may improve acute flares of the disease. If Candida sp, infection is superimposed, topical antifungal agents are often of benefit. When chronic vegetating lesions are

present, surgical removal with skin grafting may be useful. DERMAL-EPIDERMAL VESICULOBULLOUS DISEASES. Separation of the epidermis from the dermis occurs in a variety of bullous diseases resulting from autoimmune and immunologic reactions, metabolic disturbances, and a number of inherited mechanicobullous conditions (see Table 522-5) . In bullous pemphigoid, which is an autoimmune disorder of the elderly, tense, large blisters occur on normal or erythematous skin, often in the groin, axillae, and flexural areas (Color Plate 13 A). Only one third of patients have oral blisters. Healing usually occurs without scarring in some blisters while new lesions are evolving. Itching may be severe or absent. The skin biopsy result displays a subepidermal blister through the lamina lucida (at the electron microscopic level), and direct immunofluorescence reveals deposition of the IgG immunoglobulin and complement directed against an antigen in the lamina lucida. The prognosis is good, and the disease usually subsides after months or years. Widespread bullae require therapy with 40 to 60 mg/day of oral prednisone and occasionally with immunosuppressive agents. Large doses of erythromycin or tetracycline (2 g/day) can occasionally control the disease. Another subepidermal blistering disease, herpes gestationis, is a rare autoimmune condition that occurs during pregnancy and the postpartum period. The name of the disease is misleading, for it is not associated with herpesvirus infection. The blisters develop at any time throughout the course of pregnancy, although they most often begin during the second and third trimesters and subside a few weeks post partum. Some patients may experience transient flares or recurrences with each menstrual period or following the use of oral contraceptives. There are recurrences with subsequent pregnancies. Herpes gestationis is a pruritic condition with numerous tense vesicles arising on both normal-appearing and erythematous areas of skin. Arcuate and polycyclic red plaques are seen with peripheral blistering. The lesions first appear on the abdomen and then spread to involve the entire integument. Skin biopsy findings are indistinguishable from those of bullous pemphigoid by light microscopy, and examination of perilesional skin by direct immunofluorescence reveals C3 and less often an IgG linear band just below the epidermis. There is an associated fetal mortality rate as high as 30%, and there is also an increased rate of premature live births. Transient vesiculobullous lesions may infrequently occur in some otherwise healthy infants of affected mothers. Occasionally the patients' intractable pruritus and extensive bullae respond to high-potency topical steroid ointments and diphenhydramine, but most patients require oral prednisone (20 to 60 mg/day) throughout pregnancy with intermittent tapering. Erythema multiforme is an immunologic reaction in the skin and mucous membranes often mediated by circulating immune complexes that evolve in response to a number of antigenic stimulae (infections, drugs, connective tissue disease). As the name implies, 2285

the skin reaction is characterized by a variety of lesions, namely, erythematous plaques, blisters, and target or bull's-eye lesions (Color Plate 13 B). When the mucus membranes of the mouth and eye are involved, the condition is called Stevens-Johnson syndrome. Typically the cutaneous lesions favor the extremities (often the palms) and are symmetrical. Target lesions are diagnostic and are recognized by a central, dark purple area or a blister surrounded by a pale, edematous, round zone, surrounded in turn by a peripheral rim of erythema. In Stevens-Johnson syndrome, the skin disease is more widespread, with blisters and painful erosions in the mouth and eyes. The patients look and feel ill, with fever, prostration, and difficulty in eating. On histologic examination, subepidermal separation is found in the blistering center of the target lesion, and when early lesions undergo biopsy, immunofluorescence reveals immunoglobulin and complement in the walls of the small dermal blood vessels; the inflammation and bullae form in response to vascular damage and leaking. In one half of cases, no cause is found for the reaction, but causes, especially drugs (penicillins, barbiturates, phenytoin, and sulfonamides) and infections (herpes simplex, streptococcal infections, Mycoplasma pneumoniae) should be sought in all cases. Recurrent herpes simplex infection is the most common cause of recurrent erythema multiforme. It is not clear whether medical therapy favorably alters the course of idiopathic erythema multiforme, although treatment of a precipitating infection is appropriate, and acyclovir may prevent recurrences of herpes-associated erythema multiforme. Stopping suspected drugs is also imperative. The value of systemic steroids in erythema multiforme and Stevens-Johnson syndrome is controversial. In addition intravenous (IV) fluids may be required in patients with severe oral involvement, and topical anesthetics (viscous lidocaine [Xylocaine]) may help to decrease mouth discomfort. Cicatricial pemphigoid is an autoimmune condition with subepidermal IgG and linear deposits in the basement membrane zone. Scarring and blisters develop on the mucous membranes, and 25% of patients have blisters on the skin as well. Dermatitis herpetiformis is associated with immunologic deposition of IgA in dermal papillae. The lesions are grouped and symmetrical with distributed vesicles and papules found on the scalp, scapulae, buttocks, elbows, and knees. The disease is associated with intense burning and itching. There is a high incidence of associated celiac sprue (Chapter 134) . Porphyria cutanea tarda (Chapter 219) is associated with tense bullae that leave scars in some exposed areas. Bullous disease of renal disease is associated with bullae on the extremities, whereas bullous disease in diabetics presents with large bullae on acral areas. Epidermolysis bullosa is associated with splits above, below, and within the dermal-epidermal zone and is found in a variety of inherited conditions. It presents with tense blisters that erode and scar; severe forms may involve the mouth and esophagus. Epidermolysis bullosa acquisita causes blisters below the lamina densa, where IgG and C3 deposits are found. Tense blisters lead to scars in pressure and trauma sites on the hands and feet as well as on the mucous membranes. A circulating antibody to sublaminal dense antigen is typically found. Paraneoplastic pemphigus presents with cutaneous intraepidermal acantholytic bullae in association with lymphoma, thymoma, chronic lymphocytic leukemia, and Waldenstrom's macroglobulinemia. Lesions are severe, painful erosions on the oral pharynx, lips, conjunctiva, and skin.

PUSTULAR DISEASES OF THE SKIN Pustules usually bring to mind infection, but not all pustular dermatoses are caused by pathogenic microorganisms (Table 522-6) . Pustular conditions often occur in association with erythematous papules, cysts, and nodules and they may open to form crusts. NON-INFECTIOUS PUSTULAR SKIN DISEASES. Acne, the most common pustular condition of the skin, is an inflammatory disorder affecting pilosebaceous units primarily over the face and upper trunk. Several pathogenic factors play a role as individuals enter puberty: Androgens stimulate the sebaceous glands and increase sebum production; abnormal keratinization and impaction in the pilosebaceous canal (comedones) obstruct sebum flow; proliferation of anaerobic bacteria, primarily Propionibacterium acnes, predisposes TABLE 522-6 -- PUSTULAR DISEASES OF THE SKIN Non-infectious pustular skin diseases Acne Rosacea Perioral dermatitis Pustular psoriasis Miliaria pustulosa Infectious Folliculitis, including hot tub folliculitis Fungal infections Candidiasis Dermatophytes Deep fungal infections (blastomycosis, sporotrichosis, coccidioidomycosis) Medication-induced pustules Lithium

Corticosteroids Androgens Growth hormone Systemic bacterial and fungal infections to rupture of the pilosebaceous unit with extravasation into the surrounding dermis, resulting in sterile, inflammatory papules, pustules, and cysts; and these cysts later lead to disfiguring scarring. Other factors that may play a role in exacerbating acne include oil-based cosmetics, drugs (androgenic hormones, antiepileptics [phenytoin], high-progestin birth control pills, systemic corticosteroids when taken in high doses, and iodide- and bromide-containing agents), and endocrinologic conditions such as polycystic ovary disease and adrenal or ovarian tumors. Therapy is usually successful in controlling the disease until the patient outgrows this condition. Topical agents, such as benzoyl peroxide and topical vitamin A preparations (such as tazarotene, adapalene), remove comedones and are particularly effective because their action allows sebum to flow freely onto the surface of the skin. Topical and oral antibiotics (tetracycline and erythromycin) are indicated in patients with inflammatory papules and pustules. Oral 13- cis-retinoic acid (Accutane), which decreases sebaceous gland size and sebum production, should be used primarily for severe cystic acne because in high daily doses it produces undesirable side effects and can be teratogenic. Spironolactone, the potassium-sparing diuretic, has antiandrogenic properties that have made it a useful adjunctive therapy in doses of 100 to 200 mg/day in women with difficult-to-control acne. Oral contraceptives may also benefit some women with moderate to severe acne, particularly if flares are correlated to menstrual cycles. Rosacea is a chronic inflammatory disorder affecting the blood vessels and pilosebaceous units of the face in middle-aged individuals. Patients with rosacea have papules and pustules superimposed on diffuse erythema and telangiectasia over the central portion of the face. An important component is easy flushing and blushing of the face often accentuated when alcohol, caffeine, or hot spicy foods are ingested. Hyperplasia of the sebaceous glands, connective tissue, and vascular bed of the nose sometimes causes rhinophyma, which is a large, red, bulbous nose (Color Plate 12 C). Ocular complications, which occur in a significant number of rosacea patients, include blepharitis, chalazion, conjunctivitis, and progressive keratitis that can lead to scarring and blindness. Rosacea can usually be differentiated from adult acne by the lack of comedones and the prominent vascular (flushing/telangectasia) component. Other causes of a red face in adults such as the malar eruption of acute systemic lupus erythematosus and the heliotrope rash of dermatomyositis, seborrheic dermatitis, and perioral dermatitis must be considered. Rosacea and the eye complications usually respond well to tetracycline and/or oral metronidazole, but the antibiotic must be continued for life (at the lowest dose that suppresses the condition) because rosacea recurs when therapy stops. Topical antibiotics (metronidazole [MetroGel] or Noritate) can be helpful alone or in combination with low-potency topical steroids (e.g., hydrocortisone 1% lotion) once or twice a day; higher-potency steroids can actually worsen the disease. Non-infectious causes of pustular disease include perioral dermatitis, which may be caused by potent topical steroids and is a 2286

variant of acne. It presents as perioral and periorbital red scaling patches, papules, and pustules. Pustular psoriasis is a variant of psoriasis characterized by pustules localized to the palms and soles or generalized over the entire body. Patients often experience toxicity, with fever and leukocytosis. Miliaria pustulosa is caused by an occlusion of sweat glands in hot environments. It presents as discrete red papules or pustules with a red base and is found principally over the trunk, especially the back. INFECTIOUS CAUSES OF SKIN PUSTULES. Folliculitis, a Staphylococcus aureus infection of the hair follicle, appears as pustules with a red rim with hair emanating from the center of the pustule. Folliculitis typically occurs in hairy regions where clothing rubs (buttocks, thighs) or on the face. The key to diagnosis is finding a central hair in the pustule. Occasionally, the follicular infection can extend more deeply to form a larger, red, fluctuant nodule from one (furuncle) or more follicles (carbuncle). Systemic antibiotics such as erythromycin or dicloxacillin usually clear extensive infections; topical antiseptic cleansers such as povidone-iodine or chlorhexidine can resolve mild folliculitis and may be useful in preventing recurrences. Hot tub folliculitis is a generalized, pruritic folliculitis caused by Pseudomonas aeruginosa that is acquired in contaminated hot tubs, whirlpools, or swimming pools. It usually begins 6 hours to 5 days after hot tub soaking and affects many people using the facility. It appears as a vesicular and then pustular eruption over the trunk, buttocks, legs, and arms but spares the head and neck (Color Plate 16 C). Pseudomonas organisms can often be cultured from fresh pustules. In most instances, the folliculitis resolves within 7 to 10 days without specific treatment. Infected tubs and pools should be cultured for Pseudomonas sp. and disinfected. Candidiasis appears as beefy red patches in intertriginous, moist areas characteristically surrounded by satellite pustules. Paronychia, a painful red swelling in the periungual regions of the finger, may also drain pus in which Candida organisms can be found with a KOH preparation. Topical agents such as clotrimazole and miconazole must be used two or three times a day for many weeks before the infection clears. Dermatophytes can, at times, infect hair follicles and result in pustules, particularly in the beard (tinea barbae) and scalp (kerions). These lesions are readily confused with a bacterial folliculitis. Kerions appear as indurated, boggy, inflammatory plaques studded with pustules. These intense inflammatory reactions to superficial dermatophytes (especially Trichophyton verrucosum) respond to griseofulvin therapy, although a short course of oral corticosteriods is also useful. Deep fungal infections such as blastomycosis, sporotrichosis, and coccidioidomycosis may cause pustules as well as verrucous, ulcerative papules and nodules. Sporotrichosis characteristically spreads up cutaneous lymphatics and appears as nodular, pustular lesions in a linear distribution. Certain medications can lead to a follicular eruption, including lithium and hormonal/steroid preparations. A variant of hormonal folliculitis is seen in human immunodeficiency virus (HIV)-positive patients taking growth hormone or androgens; these lesions resemble corticosteroid-induced acne vulgaris (monomorphous, upper chest/back and proximal extremities) and respond to a decreased dosage of medication as well as to acne medications. Eosinophilic follicultis is an extremely pruritic variant seen in HIV patients whose CD4 counts are typically below 200. Erythematous and urticarial papules and pustules present on the upper chest, back, and proximal extremities; they may be treated with potent topical steroids, antihistamines, and even itraconazole. SYSTEMIC INFECTIONS CAUSING PUSTULES ON THE SKIN. A variety of septicemias including gonococcemia (Chapter 362) , staphylococcal septicemia (Chapter 327) , and Candida sp. septicemia (Chapter 400) (in immunosuppressed patients) cause pustular lesions associated with purpura.

URTICARIA, PERSISTENT FIGURATE ERYTHEMAS, CELLULITIS Urticaria, persistent figurate erythemas, and cellulitis are skin lesions of disparate appearance and origin. The common feature is TABLE 522-7 -- URTICARIA, PERSISTENT FIGURATE ERYTHEMAS, AND CELLULITIS Urticarial reactions Drugs Viral infectins Sinus and tooth infections Systemic parasites Pollens Injections (blood products and vaccinations)

Light (solar urticaria) Cold (cold urticaria) Heat or exercise (cholinergic urticaria) Pressure or rubbing of the skin (dermatographism) Urticaria-like skin lesions Erythema multiforme Juvenile rheumatoid arthritis Erythema marginatum Urticaria pigmentosa (mastocytosis) Figurate erythemas Persistent figurate erythema Erythema repens Erythema annulare centrifugum Erythema chronicum migrans Cellulitis Group A streptococcus Staphylococcus aureus Necrotizing fasciitis a raised, edematous, red plaque with a sharply demarcated border (Table 522-7 and Color Plate 15 E). URTICARIAL REACTIONS. Urticaria, the most common condition in this group, appears as wheals, which are transient erythematous and edematous swellings of the dermis caused by a local increase in permeability of capillaries and small venules. This increased permeability results from histamine and other chemical substances released from cutaneous mast cells by Type I IgE hypersensitivity reactions, as well as by non-immunologic mechanisms (Chapters 20 and 224) . Certain agents such as aspirin and opiates and some foods degranulate mast cells directly without an allergic mechanism. Other urticarial reactions are immunologically mediated by such allergens as infections (viral hepatitis, sinus and tooth infections), infestations (systemic parasites), drugs, pollens, and injections (blood products, vaccinations). Physical modalities including light (solar urticaria), cold (cold urticaria), heat or exercise (cholinergic urticaria), or pressure or rubbing of the skin (dermatographism) also cause hives. Hives are transient: Any given lesion persists