Cecil Essentials of Medicine [10th Edition] 9780323722728, 0323722725, 9780323722711, 9780323722759, 0323722717

Citation preview

https://t.me/mebooksfree

Any screen. Any time. Anywhere. Activate the eBook version of this title at no additional charge. e.

Elsevier eBooks for Medical Education gives you the power to browse and search

Unlock your eBook today. 1. Visit studentconsult.inkling.com/redeem 2. Scratch box below to reveal your code 3. Type code into “Enter Code” box 4. Click “Redeem” 5. Log in or Sign up 6. Go to “My Library”

It’s that easy!

Place Peel Off Sticker Here

For technical assistance: email [email protected] call 1-800-401-9962 (inside the US) call +1-314-447-8300 (outside the US) Use of the current edition of the electronic version of this book (eBook) is subject to the terms of the nontransferable, limited license granted on studentconsult.inkling.com. Access to the eBook is limited to the first individual who redeems the PIN, located on the inside cover of this book, at studentconsult.inkling.com and may not be transferred to another party by resale, lending, or other means. 2020_ME

Cecil Essentials of

Medicine

10

TENTH EDITION

https://t.me/mebooksfree

CECIL ESSENTIALS OF

MEDICINE EDITORS Edward J. Wing, MD, FACP, FIDSA Former Dean of Medicine and Biological Sciences Professor of Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Fred J. Schiffman, MD, MACP Sigal Family Professor of Humanistic Medicine Vice Chair, Department of Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Elsevier 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-­2899

CECIL ESSENTIALS OF MEDICINE, TENTH EDITION Copyright © 2022 by Elsevier, Inc. All rights reserved.

ISBN: 978-­0-­323-­72271-­1

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2016, 2010, 2007, 2004, 2001, 1997, 1993, 1990, and 1986. Library of Congress Control Number: 2021932451

Content Strategist: Marybeth Thiel Senior Content Development Specialist: Jennifer Ehlers Publishing Services Manager: Catherine Jackson Senior Project Manager: Daniel Fitzgerald Designer: Maggie Reid Printed in the United States of America. Last digit is the print number: 9 8 7 6 5 4 3 2 1

In Memoriam Thomas E. Andreoli, MD Dr. Thomas Andreoli, along with Drs. Lloyd Hollingsworth (Holly) Smith, Jr., Fred Plum, and Charles C.J. Carpenter, was one of the four founding editors of Cecil Essentials of Medicine. He served as editor for editions one through eight before he passed away on April 14, 2009. Dr. Andreoli was born in the Bronx, New York, in 1935, attended Catholic primary and high schools, and graduated from St. Vincent College and the Georgetown School of Medicine. He trained as a resident at Duke University under legendary Chair of Medicine Dr. Eugene Stead, who recognized him as a brilliant physician and scientist and encouraged his research career. Dr. Andreoli received his research training at the NIH and then in the laboratory of Dr. Tosteson at Duke. His research focused on the biochemical and biophysical properties of renal tubular cell membranes and their role in water and electrolyte transport. He made fundamental discoveries on the normal renal physiology, illuminating the way to subsequent work by many others on renal health and disease. His research was recognized with numerous awards and election to honorific societies both in the United States and in Europe. Dr. Andreoli also served as editor of The American Journal of Physiology: Renal Physiology and Editor in Chief of Kidney International. Tom’s national prominence and leadership qualities were recognized early in his career when he became head of Nephrology at the University of Alabama in Birmingham. There he helped faculty and trainees develop outstanding research, organized clinical services, and created a hemodialysis program to build one of the outstanding Divisions of Nephrology in the country. In 1979, Dr. Andreoli was appointed Chair of the Department of Internal Medicine at the University of Texas, Houston, where he assembled an outstanding faculty focused on research, clinical care, and teaching. In 1988, he accepted the position as Chairman of Internal Medicine at the University of Arkansas School of Medicine, a position he held until his death. There he again assembled a distinguished faculty who were outstanding researchers but also dedicated to outstanding clinical care and teaching. Morning report and clinical rounds with Dr. Andreoli were rigorous and riveting, focusing on the individual patient, not only their diagnoses and treatment but also on each patient’s personal concerns and well-­being. Dr. Andreoli was revered by medical students, his house staff, faculty, and colleagues, and I (EJW) personally can attest to what he regarded as his most cherished role—the mentorship and education of the next generation of physicians. One of Dr. Andreoli’s great interests was Cecil Essentials of Medicine, for which he was the editor/chief editor for eight of its ten editions, an interest that reflected his commitment to the education of students, house staff, and other physicians in the “essentials” of Internal Medicine. Dr. Andreoli was devoted to his family. He was married to Elizabeth Berglund Andreoli from 1987 until his death. He was previously married to Dr. Kathleen Gainor Andreoli, mother of his three children and their ten grandchildren. Being of Italian ancestry and from Bronx, New York, it is not surprising that Dr. Andreoli was a passionate fan of the New York Yankees, Italian opera, which he could sing in Italian, and Frank Sinatra. Dr. Andreoli’s legacy lives on in his numerous previous students, house staff, colleagues, and in this book. Charles C.J. Carpenter, MD Dr. Charles C.J. Carpenter joined Drs. Thomas Andreoli, Lloyd Hollingsworth Smith, Jr., and Fred Plum as a founder of Cecil Essentials of Medicine. He served as editor for seven editions and was followed in that role by Dr. Ivor Benjamin and then Dr. Edward Wing. Sadly, Chuck passed away on March 19, 2020, surrounded by his wife and children. He was Professor Emeritus of Medicine at The Warren Alpert Medical School of Brown University and Physician-­in-­Chief Emeritus at The Miriam Hospital. Chuck was born in Savannah, Georgia, on January 5, 1931. He attended college at Princeton and medical school at Johns Hopkins where he also did his house staff training, including chief residency, and then joined the Johns Hopkins faculty. With his young family, he travelled to Calcutta, India, where he carried out landmark studies for the treatment of cholera.

Before coming to Brown in 1986, he was Chair of Medicine at Baltimore City Hospital and Case Western Reserve University. His contributions to medical science and clinical care were many. While in Calcutta, using basic scientific evidence coupled with practical approaches, Dr. Carpenter developed “oral rehydration therapy” to address the cholera epidemic there. This treatment has saved millions of lives. While at Case, one of his innovations was to develop the nation’s first Division of Geographic Medicine because of his strong belief that all physicians should be medical citizens of the world. In 1987, as he became deeply involved in the clinical management of persons living with HIV, he initiated a unique program in which Brown University faculty and trainees assumed responsibility for all HIV care in the Rhode Island State prison system. Dr. Carpenter served as Chairman of the American Board of Internal Medicine and President of the Association of American Physicians. He has been a member of the NIH AIDS Executive Committee, the National Advisory Allergy and Infectious Diseases Council, and the USPHS AIDS Task Force. He was Chair of the Antiretroviral Treatment Panel of the International AIDS Society-­USA and authored their recommendations on antiretroviral treatment. He also served as Chair of the Treatment Committee to evaluate the President’s Emergency Plan for HIV/AIDS Relief. He became the director of the Brown University International Health Institute and the director of the Lifespan/Brown Center for AIDS Research with several Boston hospitals. Throughout his career, Dr. Carpenter was the recipient of many international, national, and regional awards, accepting each with characteristic humility. With both small and large groups of learners, Chuck made certain that every member of his team was well educated, and each felt that they contributed to the well-­being of their patients. His ability to sit calmly at the bedside, hold the patient’s hand, comfort them, and listen in a genuinely focused way, influenced so many physicians. He was truly grateful for the opportunity to care for those less fortunate than he, and the feeling of being privileged to do so was clearly transmitted to all. Dr. Carpenter was a wonderful blend of profound compassion combined with the adherence to scholarship and teaching. Sir William Osler wrote that physicians should “Do the kind thing and do it first.” Chuck lived by this precept. Vigor and insight characterized his approach to clinical and ethical challenges, always with younger colleagues at his side. In a recent tribute to him, many emphasized that Dr. Carpenter dedicated his life to his patients, many of whom were the most vulnerable members of society. We hope that we will have some of his strength and use his example as our compass as we are challenged to reduce suffering and improve the health of all for whom we are responsible. He is survived by his wife of 61 years, Sally; three sons, Charles, Murray, and Andrew; and seven g­ randchildren.

ABOUT THE EDITORS Dr. Edward J. Wing was an editor of Cecil Essentials of Medicine, editions 8 and 9, and is the lead editor of edition 10. He graduated from Williams College in 1967 and from the Harvard Medical School in 1971. He was a resident in Internal Medicine at the Peter Bent Brigham and completed an Infectious Diseases Fellowship at Stanford University. Joining the faculty at the University of Pittsburgh in 1975, he focused his NIH-­funded research on mechanisms of cell-­mediated immunity as well as various clinical aspects of Infectious Diseases. From 1990 to 1998, the University and UPMC appointed him as Physician-­in-­Chief at Montefiore Hospital, then Chief of Infectious Diseases, and finally Interim Chair of Medicine. In 1998, Dr. Wing became Chair of Medicine at Brown University (1998–2008) where he consolidated the department across hospitals, practice plans, and training programs. As Dean of Medicine and Biological Sciences at Brown University (2008–2013) he strengthened ties with affiliated hospitals (Lifespan and Care New England), increased research, and oversaw the construction of a new medical school building. International exchange programs with medical schools in Kenya, the Dominican Republic, and Haiti were established during his years as chairman and dean. Dr. Wing has cared for patients with HIV since the beginning of the epidemic in outpatient clinics. He continues to be active in research, clinical care, and teaching.

Dr. Fred J. Schiffman, who along with Dr. Edward Wing is editor of Cecil Essentials of Medicine, 10th edition, attended Wagner College and then the New York University School of Medicine, from which he graduated in 1973. He performed his early house staff training at Yale-­ New Haven Hospital and then spent two years at the National Cancer Institute. He returned to Yale as Chief Medical Resident followed by a hematology fellowship. He became Medical Director of Yale’s Primary Care Center before coming to Brown University in 1983, where he has been a leader in the medical residency program as well as Associate Physician-­in-­Chief at The Miriam Hospital. Dr. Schiffman holds The Sigal Family Professorship in Humanistic Medicine at The Warren Alpert Medical School of Brown University. His scholarly interests include the structure and function of the human spleen and the intersection of the arts and medical care. He has directed or championed many projects and programs, including those that encourage and reinforce wellness and resilience in patients, families, and caregivers. He began a novel program that places medical students and physicians with other nonmedical professionals as they share in the viewing of works of art in the Museum of the Rhode Island School of Design. Dr. Schiffman recently led a Brown University edX course entitled, “Artful Medicine: Art’s Power to Enrich Patient Care,” with worldwide participation. Dr. Schiffman has also edited texts on hematologic pathophysiology, consultative hematology, and the anemias.

vii

CONTRIBUTORS Jinnette Dawn Abbott, MD

Akwi W. Asombang, MD, MPH

Ivor J. Benjamin, MD, FAHA, FACC

Professor of Medicine Director Interventional Cardiology Fellowship Cardiology Brown Medical School Associate Chief Faculty Development and Academic Advancement Cardiovascular Institute Lifespan Providence, Rhode Island

Assistant Professor of Medicine Division of Gastroenterology and Hepatology Warren Alpert Medical School Brown University Providence, Rhode Island

Professor of Medicine Medical College of Wisconsin Milwaukee, Wisconsin

Su N. Aung, MD, MPH Assistant Professor Division of Infectious Diseases University of California San Francisco San Francisco, California

Rajiv Agarwal, MD Professor of Medicine Indiana University Indianapolis, Indiana

Marwa Al-­Badri, MD Clinical Research Fellow Clinical, Behavioral, and Outcome Research Joslin Diabetes Center Boston, Massachusetts

Hyeon-­Ju Ryoo Ali, MD Cardiology Fellow Houston Methodist Hospital Houston, Texas

Jason M. Aliotta, MD Associate Professor of Medicine Division of Pulmonary, Critical Care and Sleep Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Khaldoun Almhanna, MD, MPH Associate Professor Hematology and Oncology Warren Alpert Medical School Brown University Providence, Rhode Island

Mohanad T. Al-­Qaisi, MD Gastroenterology and Hepatology University of Arizona College of Medicine Banner University Medical Center–Phoenix Phoenix VA Medical Center Phoenix, Arizona

Zuhal Arzomand, MD Rheumatologist Northern Virginia Arthritis and Rheumatology Alexandria, Virginia

Christopher G. Azzoli, MD Associate Professor of Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Christina Bandera, MD Chief Obstetrics and Gynecology Director of The Center for Gynecologic Cancers Rhode Island Hospital and The Miriam Hospital Clinical Assistant Professor of Surgery Warren Alpert Medical School Brown University Providence, Rhode Island

Debasree Banerjee, MD Assistant Professor Warren Alpert Medical School Brown University Pulmonary, Critical Care and Sleep Medicine Staff Physician Rhode Island Hospital and Miriam Hospital Providence, Rhode Island

Mashal Batheja, MD Chief of Hepatology Gastroenterology and Hepatology Phoenix VA Medical Center Clinical Assistant Professor University of Arizona–Phoenix Phoenix, Arizona

Jeffrey J. Bazarian, MD, MPH Professor of Emergency Medicine University of Rochester, School of Medicine and Dentistry Rochester, New York

Selim R. Benbadis, MD Professor Neurology University of South Florida Tampa, Florida

Eric Benoit, MD Assistant Professor of Surgery Tufts University School of Medicine Division of Trauma & Acute Care Surgery Lahey Hospital & Medical Center Burlington, Massachusetts

Marcie G. Berger, MD Professor Cardiovascular Medicine Medical College of Wisconsin Milwaukee, Wisconsin

Clemens Bergwitz, MD Associate Professor of Medicine Section Endocrinology and Metabolism Department of Medicine Yale School of Medicine New Haven, Connecticut

Nancy Berliner, MD Chief Division of Hematology Medicine Brigham and Women’s Hospital H. Franklin Bunn Professor Medicine Harvard Medical School Boston, Massachusetts

Jeffrey S. Berns, MD Professor of Medicine and Pediatrics Renal, Electrolyte and Hypertension Division Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Pooja Bhadbhade, DO Assistant Professor Department of Internal Medicine Division of Allergy, Clinical Immunology and Rheumatology University of Kansas Medical Center Kansas City, Kansas

Ratna Bhavaraju-­Sanka, MD Associate Professor of Neurology Department of Neurology University of Texas Health Science Center at San Antonio San Antonio, Texas

ix

x

CONTRIBUTORS

Tanmayee Bichile, MD

Richard Bungiro, PhD

William P. Cheshire, Jr., MD

Rheumatologist Lupus Center of Excellence Allegheny Health Network Pittsburgh, Pennsylvania Assistant Professor Drexel University College of Medicine Philadelphia, Pennsylvania

Senior Lecturer Molecular Microbiology & Immunology Brown University Providence, Rhode Island

Professor of Neurology Mayo Clinic Jacksonville, Florida

Ariel E. Birnbaum, MD Assistant Professor of Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Charles M. Bliss, Jr., MD Clinical Assistant Professor of Medicine Section of Gastroenterology Department of Medicine Boston University School of Medicine Boston, Massachusetts

Andrew S. Blum, MD, PhD Professor Neurology Warren Alpert Medical School Brown University Director Comprehensive Epilepsy Program Rhode Island Hospital Providence, Rhode Island

Waihong Chung, MD, PhD Anna Marie Burgner, MD, MEHP Assistant Professor of Medicine Vanderbilt University Medical Center Nashville, Tennessee

Fellow Gastroenterology Rhode Island Hospital Providence, Rhode Island

Jonathan Cahill, MD

Emma Ciafaloni, MD

Associate Professor Neurology Warren Alpert Medical School Brown University Providence, Rhode Island

Professor of Neurology and Pediatrics University of Rochester Rochester, New York

Andrew Canakis, DO Resident Physician Department of Medicine Boston University School of Medicine Boston, Massachusetts

Associate Director Division of Hematology Oncology Department of Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Brian Casserly, MD

Hematology and Oncology University Hospitals Cleveland Medical Center Cleveland, Ohio

Respiratory Physician Pulmonary, Critical Care and Sleep Medicine University Hospital Limerick Limerick, Ireland

Russell Bratman, MD

Abdullah Chahin, MD, MA, MSc

Assistant Professor of Medicine Department of Medicine Division of Endocrinology Warren Alpert Medical School Brown University Providence, Rhode Island

Assistant Professor in Medicine Department of Internal Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Philip A. Chan, MD Professor of Medicine Cedars-­Sinai Medical Center Professor of Medicine Emeritus The David Geffen School of Medicine at UCLA Los Angeles, California

Alma M. Guerrero Bready, MD Attending Physician Division of Hospital Medicine Rhode Island Hospital Providence, Rhode Island

Division Head of Cardiology Professor of Medicine Knight Cardiovascular Institute Oregon Health and Sciences University Portland, Oregon

Michael P. Cinquegrani, MD Benedito A. Carneiro, MD, MS

Bryan J. Bonder, MD

Glenn D. Braunstein, MD

Joaquin E. Cigarroa, MD

Associate Professor of Medicine Brown University Providence, Rhode Island

Kimberle Chapin, MD Director of Microbiology Department of Pathology Rhode Island Hospital Professor of Medicine Professor of Pathology Warren Alpert Medical School Brown University Providence, Rhode Island

Professor of Medicine Cardiovascular Medicine Medical College of Wisconsin Milwaukee, Wisconsin

Andreea Coca, MD, MPH Associate Professor of Medicine Rheumatology University of Pittsburgh Pittsburgh, Pennsylvania

Harvey Jay Cohen, MD Walter Kempner Professor of Medicine Center for the Study of Aging and Human Development Duke University School of Medicine Durham, North Carolina

Scott Cohen, MD, MPH Medical Director Wisconsin Adult Congenital Heart Disease Program Associate Professor of Internal Medicine and Pediatrics Sections of Cardiovascular Medicine and Pediatric Cardiology Medical College of Wisconsin Milwaukee, Wisconsin

Beatrice P. Concepcion, MD, MS Assistant Professor of Medicine Vanderbilt University Medical Center Nashville, Tennessee

CONTRIBUTORS

xi

Nathan T. Connell, MD, MPH

Kwame Dapaah-­Afriyie, MD, MBA

Michael G. Earing, MD

Associate Physician Hematology Division Brigham and Women’s Hospital Assistant Professor of Medicine Harvard Medical School Boston, Massachusetts

Professor of Medicine (Clinician Educator) Brown University—Miriam Hospital Providence, Rhode Island

Associate Professor of Medicine & Pediatrics Medicine University of Rochester Rochester, New York

Director University of Chicago Adult Congenital Heart Disease Program Professor Internal Medicine and Pediatrics Sections of Adult Cardiovascular Medicine and Pediatric Cardiology University of Chicago Chicago, Illinois

Andre De Souza, MD

Pamela Egan, MD

Assistant Professor of Medicine Division of Hematology Oncology Department of Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Assistant Professor of Medicine Department of Medicine Warren Alpert Medical School Brown University Hematologist Division of Hematology and Oncology Rhode Island Hospital Providence, Rhode Island

Maria Constantinou, MD Assistant Professor of Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Roberto Cortez, MD Senior Resident Surgery Rhode Island Hospital/Warren Alpert Medical School Brown University Providence, Rhode Island

Timothy J. Counihan, MD, FRCPI Hon. Professor in Medicine School of Medicine National University of Ireland Galway Galway, Ireland

Anne Haney Cross, MD Professor Neurology Washington University St. Louis, Missouri

Cheston B. Cunha, MD, FACP Associate Professor of Medicine Medical Director, Antimicrobial Stewardship Infectious Disease Division Warren Alpert Medical School Brown University Providence, Rhode Island

Joanne S. Cunha, MD Assistant Professor of Medicine Warren Alpert Medical School Brown University Director Rheumatology Fellowship Program at Brown University Providence, Rhode Island

Susan Cu-­Uvin, MD Professor of Obstetrics and Gynecology Professor of Medicine Brown University Providence, Rhode Island

Noura M. Dabbouseh, MD Amita Health Heart and Vascular Hinsdale, Illinois

Erin M. Denney-­Koelsch, MD

An S. De Vriese, MD, PhD Division of Nephrology and Infectious Diseases AZ Sint-­Jan Brugge, Brugge, and Ghent University Ghent, Belgium

Neal D. Dharmadhikari, MD Fellow Gastroenterology Boston Medical Center Boston, Massachusetts

Leah Dickstein, MD Fellow in Neurocritical Care Department of Neurosurgery Division of Neurocritical Care David Geffen School of Medicine at UCLA Los Angeles, California

Don Dizon, MD, FACP, FASCO Director of Womens’ Cancers Lifespan Cancer Institute Director of Medical Oncology Rhode Island Hospital Professor of Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Robyn T. Domsic, MD, MPH Associate Professor of Medicine Division of Rheumatology and Clinical Immunology University of Pittsburgh Pittsburgh, Pennsylvania

Kim A. Eagle, MD Albion Walter Hewlett Professor of Internal Medicine Department of Internal Medicine University of Michigan Ann Arbor, Michigan

Wafik S. El-­Deiry, MD, PhD, FACP American Cancer Society Research Professor Director of the Cancer Center at Brown University and Joint Program in Cancer Biology Mencoff Family University Professor of Medical Science Professor of Pathology and Laboratory Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Mitchell S. V. Elkind, MD, MS Professor Neurology Vagelos College of Physicians and Surgeons Professor Epidemiology Mailman School of Public Health Columbia University New York, New York

Tarra B. Evans, MD Gynecologic Oncologist The Center for Gynecologic Cancers Rhode Island Hospital Clinical Assistant Professor of Surgery Warren Alpert Medical School Brown University Providence, Rhode Island

Michael B. Fallon, MD Professor of Medicine Gastroenterology, Hepatology and Nutrition Chair Department of Internal Medicine University of Arizona–Phoenix Phoenix, Arizona

xii

CONTRIBUTORS

Dimitrios Farmakiotis, MD

Andrew E. Foderaro, MD

Assistant Professor of Medicine Internal Medicine, Infectious Diseases Warren Alpert Medical School Brown University Providence, Rhode Island

Assistant Professor in Medicine Clinician Educator Pulmonary, Critical Care and Sleep Medicine Brown University Providence, Rhode Island

Francis A. Farraye, MD Director Professor of Medicine Inflammatory Bowel Disease Center Mayo Clinic Jacksonville, Florida

Ronan Farrell, MD Fellow Gastroenterology Brown University Providence, Rhode Island

Theodore C. Friedman, MD, PhD Chairman Department of Internal Medicine Chief of the Division of Endocrinology, Metabolism and Molecular Medicine Endowed Professor of Cardio-­Metabolic Medicine Charles R. Drew University of Medicine & Science Professor of Medicine UCLA Los Angeles, California

Michael Raymond Goggins, MB BCh BAO, MRCPI Medicine University Hospital Limerick Limerick, Ireland

Geetha Gopalakrishnan, MD Associate Professor Department of Medicine Division of Endocrinology Warren Alpert Medical School Brown University Providence, Rhode Island

Vidya Gopinath, MD Assistant Professor of Medicine, Clinician-­ Educator Warren Alpert Medical School Brown University Providence, Rhode Island

Mary Anne Fenton, MD Clinical Associate Professor Department of Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Joseph Metmowlee Garland, MD, AAHIVM Associate Professor of Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Fernando C. Fervenza, MD, PhD Professor of Medicine Nephrology and Hypertension Mayo Clinic Rochester, Minnesota

Sean Fine, MD Assistant Professor Gastroenterology Brown University Providence, Rhode Island

Eric J. Gartman, MD Associate Professor of Medicine Division of Pulmonary, Critical Care, and Sleep Medicine Warren Alpert Medical School Brown University Staff Physician Division of Pulmonary, Critical Care, and Sleep Medicine Providence VA Medical Center Providence, Rhode Island

Arkadiy Finn, MD Assistant Professor of Medicine Clinician Educator Warren Alpert Medical School Brown University Division of Hospital Medicine The Miriam Hospital Providence, Rhode Island

Timothy Flanigan, MD Professor of Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Brisas M. Flores, MD Fellow Gastroenterology Boston Medical Center Boston, Massachusetts

Susan L. Greenspan, MD, FACP Division of Geriatric Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

Osama Hamdy, MD, PhD Medical Director Obesity Clinical Program Endocrinology Joslin Diabetes Center Associate Professor of Medicine Harvard Medical School Boston, Massachusetts

Johanna Hamel, MD Assistant Professor of Neurology, Pathology and Laboratory Medicine University of Rochester Medical Center Rochester, New York

Abdallah Geara, MD Assistant Professor of Clinical Medicine Renal-­Electrolyte and Hypertension University of Pennsylvania Philadelphia, Pennsylvania

Raul Macias Gil, MD Infectious Disease Fellow Division of Infectious Diseases Brown University Providence, Rhode Island

Timothy Gilligan, MD, FASCO Associate Professor of Medicine Vice-­Chair for Education Hematology and Medical Oncology Department Cleveland Clinic Taussig Cancer Institute Cleveland, Ohio

Sajeev Handa, MD, SFHM Assistant Professor of Medicine Chief Hospital Medicine Rhode Island/Miriam & Newport Hospitals Providence, Rhode Island

Mitchell T. Heflin, MD, MHS Professor of Medicine Professor in the School of Nursing Associate Dean for Interprofessional Education and Care (IPEC) Duke University School of Medicine Durham, North Carolina

Robert G. Holloway, MD, MPH Professor Department of Neurology University of Rochester Medical Center Rochester, New York

CONTRIBUTORS

xiii

Christopher S. Huang, MD

Rayford R. June, MD

Pooja Koolwal, MD

Clinical Associate Professor of Medicine Department of Medicine Section of Gastroenterology Boston University School of Medicine Boston, Massachusetts

Assistant Professor of Medicine Division of Rheumatology Department of Medicine Penn State College of Medicine Hershey, Pennsylvania

Assistant Professor Department of Internal Medicine Division of Nephrology UT Southwestern Medical Center Dallas, Texas

Zilla Hussain, MD

Tareq Kheirbek, MD, ScM, FACS

Mary P. Kotlarczyk, PhD

Assistant Professor of Medicine and Medical Sciences Warren Alpert Medical School Brown University Esophageal Disorders Gastroenterology Lifespan Physicians Group Providence, Rhode Island

Assistant Professor of Surgery Clinical Educator Surgery Brown University Providence, Rhode Island

Assistant Professor of Medicine Division of Geriatric Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

T. Alp Ikizler, MD Catherine McLaughlin-­Hakim Chair Professor of Medicine Vanderbilt University Medical Center Nashville, Tennessee

Iris Isufi, MD Assistant Professor of Medicine (Hematology) Internal Medicine Yale University New Haven, Connecticut

Nicole M. Kuderer, MD Alok A. Khorana, MD, FACP, FASCO Sondra and Stephen Hardis Endowed Chair in Oncology Research Taussig Cancer Institute Cleveland Clinic Cleveland, Ohio

Sena Kilic, MD Clinical Associate Division of Cardiology Knight Cardiovascular Institute Oregon Health & Science University Portland, Oregon

David Kim, MD

Professor of Neurology and Otolaryngology Department of Neurology University of Texas Health Science Center San Antonio, Texas

Chief Resident Surgery Rhode Island Hospital/Warren Alpert Medical School Brown University Providence, Rhode Island

Paul G. Jacob, MD, MPH

James Kleczka, MD

Assistant Professor Division of Infectious Diseases Vanderbilt University Medical Center Nashville, Tennessee

Associate Professor Department of Medicine Medical College of Wisconsin Milwaukee, Wisconsin

Matthew D. Jankowich, MD

James R. Klinger, MD

Associate Professor of Medicine Pulmonary, Critical Care and Sleep Medicine Warren Alpert Medical School Brown University Providence VA Medical Center Providence, Rhode Island

Professor of Medicine Pulmonary, Critical Care, and Sleep Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Carlayne E. Jackson, MD

Patrick Koo, MD, ScM Niels V. Johnsen, MD, MPH Assistant Professor Department of Urology Vanderbilt University Medical Center Nashville, Tennessee

Jessica E. Johnson, MD Infectious Diseases West Virginia University School of Medicine Morgantown, West Virginia

Associate Professor of Medicine (Affiliate) University of Tennessee Health Science Center College of Medicine Erlanger Hospital Department of Medicine Chattanooga, Tennessee

Chief Medical Officer Medicine Advanced Cancer Research Group Seattle, Washington

Awewura Kwara, MD Professor Department of Medicine University of Florida College of Medicine Gainesville, Florida

Jennifer M. Kwon, MD, MPH Professor Neurology University of Wisconsin School of Medicine and Public Health Madison, Wisconsin

Richard A. Lange, MD, MBA President Texas Tech University Health Sciences Center El Paso Dean Paul L. Foster School of Medicine El Paso, Texas

Jerome Larkin, MD Associate Professor of Medicine Infectious Diseases Warren Alpert Medical School Brown University Providence, Rhode Island

Alfred I. Lee, MD, PhD Associate Professor of Medicine Hematology/Oncology Division Yale School of Medicine New Haven, Connecticut

Daniel J. Levine, MD Director Advanced Heart Failure Cardiology Brown University Providence, Rhode Island

xiv

CONTRIBUTORS

David E. Lewandowski, MD Cardiology Fellow Cardiology Medical College of Wisconsin Milwaukee, Wisconsin

Kelly V. Liang, MD, MS Assistant Professor of Medicine Renal-­Electrolyte Division University of Pittsburgh Pittsburgh, Pennsylvania

Kimberly P. Liang, MD, MS Assistant Professor of Medicine Rheumatology and Clinical Immunology University of Pittsburgh Pittsburgh, Pennsylvania

John R. Lonks, MD, FACP, FIDSA, FSHEA Associate Professor of Medicine Department of Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Gary H. Lyman, MD, MPH Professor Public Health Sciences Fred Hutchinson Cancer Research Center Professor Medicine University of Washington Seattle, Washington

Jeffrey M. Lyness, MD David R. Lichtenstein, MD Director of Endoscopy Gastroenterology Boston University Medical Center Associate Professor of Medicine Gastroenterology Boston Medical Center Boston, Massachusetts

Douglas W. Lienesch, MD Chief Rheumatology Division Christiana Care Health System Newark, Delaware

Geoffrey S.F. Ling, MD, PhD Professor of Neurology Johns Hopkins Baltimore, Maryland

Senior Associate Dean for Academic Affairs and Professor of Psychiatry & Neurology Office of Academic Affairs University of Rochester School of Medicine & Dentistry Rochester, New York

Shane Lyons, MD, MRCPI, MRCP(UK) Specialist Registrar in Neurology Department of Neurology St James’s Hospital Dublin, Ireland

Diana Maas, MD Associate Professor of Medicine Division of Endocrinology Medical College of Wisconsin Milwaukee, Wisconsin

Assistant Professor of Medicine Department of Medicine University of Arizona Hepatologist Banner Advanced Liver Disease and Transplant Institute Banner University Medical Center Phoenix Phoenix, Arizona

Yi Liu, MD Resident Physician Medicine Beth Israel Lahey Health Burlington, Massachusetts

Nicole L. Lohr, MD, PhD Associate Professor Medicine Medical College of Wisconsin Milwaukee, Wisconsin

Professor Neurology University of Rochester Rochester, New York

F. Dennis McCool, MD Professor of Medicine Division of Pulmonary and Critical Care Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Russell J. McCulloh, MD Associate Professor Pediatrics University of Nebraska College of Medicine Division Chief Pediatric Hospital Medicine University of Nebraska Medical Center Omaha, Nebraska

Kelly McGarry, MD, FACP Professor of Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Eavan Mc Govern, MD, PhD Consultant Neurologist Senior Clinical Lecturer Beaumont Hospital Royal College of Surgeons in Ireland Ireland

Robin L. McKinney, MD Talha A. Malik, MD, MSPH

Ester Little, MD, FACP

Frederick J. Marshall, MD

Assistant Professor of Medicine Gastroenterology and Hepatology Mayo Clinic Arizona Scottsdale, Arizona

Assistant Professor of Pediatrics Pediatric Critical Care Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Sonia Manocha, MD

Anthony Mega, MD

Rheumatologist Lupus Center of Excellence Allegheny Health Network Pittsburgh, Pennsylvania Assistant Professor Drexel University College of Medicine Philadelphia, Pennsylvania

Associate Professor of Medicine Program Director Hematology/Oncology Fellowship Division Hematology/Oncology Warren Alpert Medical School Brown University Lifespan Cancer Institute Providence, Rhode Island

Susan Manzi, MD, MPH Chair Medicine Institute Director Lupus Center of Excellence Allegheny Health Network Professor of Medicine Temple University School of Medicine Philadelphia, Pennsylvania

Shivang Mehta, MD Assistant Professor of Medicine Gastroenterology, Hepatology, and Nutrition Department of Internal Medicine University of Arizona–Phoenix Phoenix, Arizona

CONTRIBUTORS

Douglas F. Milam, MD

Alan R. Morrison, MD, PhD

Thomas A. Ollila, MD

Associate Professor Department of Urology Vanderbilt University Medical Center Nashville, Tennessee

Assistant Professor of Medicine Medicine (Cardiology) Warren Alpert Medical School Brown University Providence, Rhode Island

Assistant Professor of Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Maria D. Mileno, MD Associate Professor of Medicine Division of Infectious Diseases Warren Alpert Medical School Brown University Attending Physician, Infectious Disease Consultant Brown Medicine The Miriam Hospital Former Director of Travel Medicine Services Providence, Rhode Island

Abhinav Kumar Misra, MBBS, MD Assistant Professor of Medicine Pulmonary, Critical Care and Sleep Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Orson W. Moe, MD Professor Internal Medicine and Physiology Division of Nephrology Director Charles and Jane Pak Center for Mineral Metabolism and Clinical Research Chief Division of Nephrology UT Southwestern Medical Center Dallas, Texas

Niveditha Mohan, MBBS Associate Professor Department of Medicine Division of Rheumatology and Clinical Immunology University of Pittsburgh Pittsburgh, Pennsylvania

Larry W. Moreland, MD Margaret J. Miller Endowed Professor of Arthritis Research Division of Rheumatology and Clinical Immunology Professor of Medicine, Immunology, Clinical and Translational Science Chief Division of Rheumatology and Clinical Immunology University of Pittsburgh Pittsburgh, Pennsylvania

xv

Steven M. Opal, MD Steven F. Moss, MD Professor of Medicine Division of Gastroenterology and Hepatology Warren Alpert Medical School Brown University Providence, Rhode Island

Clinical Professor of Medicine Infectious Diseases Division Department of Medicine Warren Alpert Medical School Brown University Rhode Island Hospital Providence, Rhode Island

Christopher J. Mullin, MD, MHS

Biff F. Palmer, MD

Assistant Professor of Medicine, Clinician Educator Pulmonary, Critical Care, and Sleep Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Professor of Internal Medicine Internal Medicine University of Texas Southwestern Medical Center Dallas, Texas

Sinéad M. Murphy, MB, BCh, MD, FRCPI Consultant Neurologist Neurology Tallaght University Hospital Clinical Associate Professor Medicine University of Dublin, Trinity College Dublin, Ireland

Sagarika Nallu, MD, FAAP, FAAN, FAASM Director of Pediatric Sleep Medicine Department of Pediatrics University of South Florida Tampa, Florida

Javier A. Neyra, MD, MSCS Assistant Professor of Medicine Director Critical Care Nephrology Division of Nephrology, Bone and Mineral Metabolism University of Kentucky Medical Center Lexington, Kentucky

Ghaith Noaiseh, MD Associate Professor Department of Internal Medicine Division of Allergy, Clinical Immunology and Rheumatology University of Kansas Kansas City, Kansas

Jen Jung Pan, MD, PhD Associate Professor of Medicine Gastroenterology and Hepatology Department of Internal Medicine University of Arizona–Phoenix Phoenix, Arizona

Anna Papazoglou, MD Clinical Instructor Postdoctoral Research Scholar Division of Rheumatology and Clinical Immunology University of Pittsburgh Pittsburgh, Pennsylvania

Aric Parnes, MD Attending Hematologist Medicine Brigham and Women’s Hospital Assistant Professor Harvard Medical School Boston, Massachusetts

Nayan M. Patel, DO, MPH Assistant Professor of Medicine Gastroenterology and Hepatology Department of Internal Medicine University of Arizona–Phoenix Phoenix, Arizona

Ari Pelcovits, MD Department of Medicine Division of Hematology and Oncology Warren Alpert Medical School Brown University Providence, Rhode Island

xvi

CONTRIBUTORS

Mark A. Perazella, MD

Harlan Rich, MD, AGAF, FACP

Abbas Rupawala, MD

Medical Director Yale Physician Associate Program Department of Medicine Professor of Medicine Section of Nephrology Yale University School of Medicine Director Acute Dialysis Services Yale-­New Haven Hospital New Haven, Connecticut

Associate Professor of Medicine and Medical Science Warren Alpert Medical School Brown University Clinical Director Division of Gastroenterology Brown Medicine/Brown Physicians, Inc. Providence, Rhode Island Medical Director Brown Medicine Endoscopy Center Riverside, Rhode Island

Assistant Professor of Medicine Internal Medicine Brown University Co-­Director IBD Center Internal Medicine Brown Medicine/Brown Physicians’ Inc. Providence, Rhode Island

Michael F. Picco, MD, PhD Director Division of Gastroenterology and Hepatology Mayo Clinic Jacksonville, Florida

Jennifer H. Richman, MD Associate Professor Psychiatry University of Rochester School of Medicine and Dentistry Rochester, New York

Kate E. Powers, DO Pediatric Pulmonologist and Associate Director of the Cystic Fibrosis Pediatric Program Pediatrics Hasbro Children’s Hospital Assistant Professor of Pediatrics Pediatrics Warren Alpert Medical School Brown University Providence, Rhode Island

Laura A. Previll, MD, MPH Assistant Professor Duke University School of Medicine Durham VAMC Durham, North Carolina

Nilum Rajora, MD Associate Professor Department of Internal Medicine Division of Nephrology UT Southwestern Medical Center Dallas, Texas

Lisa R. Rogers, DO Senior Staff Department of Neurosurgery Henry Ford Hospital Detroit, Michigan

Ralph Rogers, MD Assistant Professor Internal Medicine, Infectious Diseases Warren Alpert Medical School Brown University Providence, Rhode Island

Michal G. Rose, MD Professor of Medicine Medicine (Medical Oncology) Yale School of Medicine New Haven, Connecticut Director Cancer Center VA Connecticut Healthcare System West Haven, Connecticut

Jenna Sarvaideo, DO Assistant Professor of Medicine Division of Endocrinology Medical College of Wisconsin Milwaukee, Wisconsin

Ramesh Saxena, MD, PhD Professor Internal Medicine/Division of Nephrology UT Southwestern Medical Center Dallas, Texas

Fred J. Schiffman, MD, MACP Sigal Family Professor of Humanistic Medicine Vice Chair, Department of Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Ruth B. Schneider, MD Assistant Professor Neurology University of Rochester Rochester, New York

Kristin A. Seaborg, MD Assistant Professor Pediatric Neurology University of Wisconsin School of Medicine and Public Health Madison, Wisconsin

James A. Roth, MD

Anil Seetharam, MD

Associate Professor Cardiovascular Medicine Medical College of Wisconsin Milwaukee, Wisconsin

Clinical Associate Professor of Medicine Gastroenterology/Transplant Hepatology University of Arizona College of Medicine Phoenix, Arizona

Sharon Rounds, MD

Stuart Seropian, MD

Department of Medicine Division of Hematology and Oncology Warren Alpert Medical School Brown University Providence, Rhode Island

Professor Warren Alpert Medical School Brown University Pulmonary/Critical Care Staff Physician Providence VA Medical Center Providence, Rhode Island

Professor of Clinical Medicine (Hematology) Internal Medicine Yale University New Haven, Connecticut

Rebecca Reece, MD

Jason C. Rubenstein, MD

Assistant Professor of Medicine Infectious Diseases West Virginia University School of Medicine Morgantown, West Virginia

Associate Professor Cardiovascular Medicine Medical College of Wisconsin Milwaukee, Wisconsin

Adolfo Ramirez-­Zamora, MD Associate Professor of Neurology Neurology University of Florida Gainesville, Florida

John Reagan, MD

Jigme Michael Sethi, MD Professor of Medicine (Affiliate) University of Tennessee Health Science Center College of Medicine Erlanger Hospital Department of Medicine Chattanooga, Tennessee

CONTRIBUTORS

xvii

Sanjeev Sethi, MD, PhD

Christopher Song, MD, FACC

Pushpak Taunk, MD

Professor Laboratory Medicine and Pathology Mayo Clinic Rochester, Minnesota

Assistant Professor of Medicine Clinician Educator Warren Alpert Medical School Brown University Providence, Rhode Island

Assistant Professor Division of Digestive Diseases and Nutrition University of South Florida Morsani College of Medicine Tampa, Florida

Thomas Sperry, MD

Philip Tsoukas, MD

Cardiology Fellow Hypertension Section, Cardiology Division University of Texas Southwestern Medical Center Dallas, Texas

Clinical Fellow, Rheumatology Temple University Hospital Philadelphia, Pennsylvania

Elizabeth Shane, MD Professor Medicine Columbia University Associate Dean Medical Education College of Physicians & Surgeons New York, New York

Jeffrey M. Statland, MD Esseim Sharma, MD Cardiovascular Disease Fellow Cardiology Brown University Providence, Rhode Island

Associate Professor of Neurology University of Kansas Medical Center Kansas City, Kansas

Allan R. Tunkel, MD, PhD Professor of Medicine and Medical Science Senior Associate Dean for Medical Education Warren Alpert Medical School Brown University Providence, Rhode Island

Emily M. Stein, MD Jeffrey M. Turner, MD

Assistant Professor Department of Internal Medicine Division of Nephrology UT Southwestern Medical Center Dallas, Texas

Director of Research Metabolic Bone Service Division of Endocrinology Hospital for Special Surgery Associate Professor of Medicine Weill Cornell Medical College New York, New York

Barry S. Shea, MD

Jennifer L. Strande, MD, PhD

Assistant Professor of Medicine Pulmonary, Critical Care and Sleep Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Adjunct Professor Department of Medicine Medical College of Wisconsin Milwaukee, Wisconsin

Fellow Division Pulmonary, Critical Care and Sleep Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Rochelle Strenger, MD

Stacie A. F. Vela, MD

Clinical Associate Professor Department of Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Section Chief Gastroenterology Phoenix VA Health Care System Clinical Associate Professor Medicine University of Arizona–Phoenix Phoenix, Arizona

Shani Shastri, MD, MPH

Lauren Shevell, MD, MPH Fellow Hematology/Oncology University of Michigan Ann Arbor, Michigan

Thomas R. Talbot, MD, MPH Joseph A. Smith, Jr., MD Professor Department of Urology Vanderbilt University Medical Center Nashville, Tennessee

Professor Department of Medicine Vanderbilt University School of Medicine Chief Hospital Epidemiologist Vanderbilt University Medical Center Nashville, Tennessee

Zoe G.S. Vazquez, MD

Paul M. Vespa, MD, FCCM, FAAN, FANA, FNCS

Assistant Professor Neurology University of Rochester Medical Center Rochester, New York

Assistant Dean for Research in Critical Care Medicine Gary L. Brinderson Family Chair in Neurocritical Care Director of Neurocritical Care Professor of Neurology and Neurosurgery University of California–Los Angeles David Geffen School of Medicine at UCLA Los Angeles, California

Yael Tarshish, MD

Wanpen Vongpatanasin, MD

Resident Physician Warren Alpert Medical School Brown University Providence, Rhode Island

Professor of Medicine Hypertension Section/Cardiology Division Internal Medicine University of Texas Southwestern Medical Center Dallas, Texas

Robert J. Smith, MD Professor of Medicine Emeritus Warren Alpert Medical School Brown University Providence, Rhode Island

Associate Professor of Medicine Section of Nephrology Yale University School of Medicine New Haven, Connecticut

Christopher G. Tarolli, MD, MSEd

Davendra P.S. Sohal, MD, MPH Associate Professor of Medicine Director of Experimental Therapeutics Clinic Medical Director Division of Hematology/Oncology University of Cincinnati Cincinnati, Ohio

xviii

CONTRIBUTORS

Marcella D. Walker, MD

Brandon J. Wilcoxson, MD

Rayan Yousefzai, MD

Associate Professor of Medicine Internal Medicine, Division of Endocrinology Columbia University, College of Physicians and Surgeons New York, New York

Senior Instructor of Medicine Palliative Care University of Rochester Medical Center Rochester, New York

Heart Failure Cardiologist Cardiology Houston Methodist Hospital Houston, Texas

Edward J. Wing, MD, FACP, FIDSA

Thomas R. Ziegler, MD

Professor of Oncology Medicine Roswell Park Comprehensive Cancer Center Buffalo, New York

Former Dean of Medicine and Biological Sciences Professor of Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Professor of Medicine and Co-­Director Emory University Hospital Nutrition and Metabolic Support Service Emory University School of Medicine Atlanta, Georgia

Sharmeel K. Wasan, MD

Ellice Wong, MD

Assistant Professor of Medicine Medicine Section of Gastroenterology Boston University School of Medicine Program Director Gastroenterology Boston Medical Center Boston, Massachusetts

Assistant Professor Medicine (Medical Oncology) Yale School of Medicine New Haven, Connecticut Attending Internal Medicine, Hematology/Oncology VA Connecticut Healthcare System West Haven, Connecticut

Thomas J. Weber, MD

John J. Wysolmerski, MD

Associate Professor Medicine/Endocrinology Duke University Durham, North Carolina

Professor of Medicine Section of Endocrinology and Metabolism Department of Internal Medicine Yale School of Medicine New Haven, Connecticut

Eunice S. Wang, MD

Rebecca Zon, MD Resident Internal Medicine Brigham and Women’s Hospital Boston, Massachusetts

ACKNOWLED GMENTS Dr. Schiffman and I wish to thank first of all, the authors of the 128 chapters that make up the tenth edition of Cecil Essentials of Medicine. They have worked diligently to compose the material for each chapter and apply their mastery as they added the newest information, in clear language, to the text. Their efforts are apparent in the excellence of the book, and we are immensely grateful for their work. We wish to also thank Marybeth Thiel, Jennifer Ehlers, and Dan Fitzgerald from Elsevier who guided and supported our work as editors and whose expertise has made this volume possible. Finally, we are always thankful to our wives, Dr. Rena Wing and Ms. Gerri Schiffman, without whose love, support, and especially humor, this book would not have happened.

xix

This page intentionally left blank

     

CONTENTS SECTION I  Introduction to Medicine

SECTION IV Preoperative and Postoperative Care

1  Introduction to Medicine, 2

22  Preoperative and Postoperative Care, 240

SECTION II  Cardiovascular Disease

SECTION V  Renal Disease

2  Structure and Function of the Normal Heart and Blood Vessels, 4

23  Renal Structure and Function, 251

Edward J. Wing, Fred J. Schiffman

Kim A. Eagle, Kwame Dapaah-Afriyie, Arkadiy Finn

Orson W. Moe, Javier A. Neyra

Nicole L. Lohr, Ivor J. Benjamin

24  Approach to the Patient With Renal Disease, 258

James Kleczka, Noura M. Dabbouseh

25  Fluid and Electrolyte Disorders, 268

3  Evaluation of the Patient With Cardiovascular Disease, 10

Rajiv Agarwal Biff F. Palmer

4  Diagnostic Tests and Procedures in the Patient With Cardiovascular Disease, 24

26  Glomerular Diseases, 282

5  Heart Failure and Cardiomyopathy, 43

27  Major Nonglomerular Disorders of the Kidney, 298

6  Congenital Heart Disease, 55

28  Vascular Disorders of the Kidney, 312

7  Valvular Heart Disease, 64

29  Acute Kidney Injury, 324

8  Coronary Heart Disease, 77

30  Chronic Kidney Disease, 334

Esseim Sharma, Alan R. Morrison

Daniel J. Levine, Hyeon-Ju Ryoo Ali, Rayan Yousefzai Scott Cohen, Michael G. Earing Christopher Song

David E. Lewandowski, Michael P. Cinquegrani

Sanjeev Sethi, An S. De Vriese, Fernando C. Fervenza

Nilum Rajora, Shani Shastri, Pooja Koolwal, Ramesh Saxena Abdallah Geara, Jeffrey S. Berns

Mark A. Perazella, Jeffrey M. Turner T. Alp Ikizler, Anna Marie Burgner, Beatrice P. Concepcion

9  Cardiac Arrhythmias, 99

10  Pericardial and Myocardial Disease, 123

Marcie G. Berger, Jason C. Rubenstein, James A. Roth

SECTION VI  Gastrointestinal Disease

11  Other Cardiac Topics, 131

Jennifer L. Strande

31  Common Clinical Manifestations of Gastrointestinal Disease: Abdominal Pain, 343

Jinnette Dawn Abbott, Sena Kilic

12  Vascular Diseases and Hypertension, 139 Thomas Sperry, Wanpen Vongpatanasin

SECTION III Pulmonary and Critical Care Medicine 13  Lung in Health and Disease, 162

Charles M. Bliss, Jr.

32  Common Clinical Manifestations of Gastrointestinal Disease: Gastrointestinal Hemorrhage, 347 Waihong Chung, Abbas Rupawala

33  Common Clinical Manifestations of Gastrointestinal Disease: Malabsorption, 351 Brisas M. Flores, Sharmeel K. Wasan

Sharon Rounds, Debasree Banerjee, Eric J. Gartman

34  Common Clinical Manifestations of Gastrointestinal Disease: Diarrhea, 358

Michael Raymond Goggins, Brian Casserly, Eric J. Gartman

35  Endoscopic and Imaging Procedures, 363

Patrick Koo, F. Dennis McCool, Jigme Michael Sethi

36  Esophageal Disorders, 370

Zoe G.S. Vazquez, Matthew D. Jankowich, Debasree Banerjee

37  Diseases of the Stomach and Duodenum, 379

Abhinav Kumar Misra, Matthew D. Jankowich, Barry S. Shea

38  Inflammatory Bowel Disease, 392

Christopher J. Mullin, James R. Klinger

39  Diseases of the Pancreas, 402

14  General Approach to Patients With Respiratory Disorders, 165 15  Evaluating Lung Structure and Function, 169 16  Obstructive Lung Diseases, 185 17  Interstitial Lung Diseases, 199

18  Pulmonary Vascular Diseases, 216

19  Disorders of the Pleura, Mediastinum, and Chest Wall, 221 Eric J. Gartman, F. Dennis McCool

20  Respiratory Failure, 227

Andrew E. Foderaro, Abhinav Kumar Misra

21  Transitions in Care From Pediatric to Adult Providers for Individuals With Pulmonary Disease, 234 Kate E. Powers, Debasree Banerjee, Robin L. McKinney

Ronan Farrell, Sean Fine

Andrew Canakis, Christopher S. Huang

Harlan Rich, Zilla Hussain, Neal D. Dharmadhikari

Alma M. Guerrero Bready, Akwi W. Asombang, Steven F. Moss Talha A. Malik, Michael F. Picco, Francis A. Farraye David R. Lichtenstein, Pushpak Taunk

SECTION VII Diseases of the Liver and Biliary System 40  Laboratory Tests in Liver Diseases, 417 Michael B. Fallon, Ester Little

41  Jaundice, 420

Mohanad T. Al-Qaisi, Mashal Batheja, Michael B. Fallon

xxi

xxii

CONTENTS

42  Acute and Chronic Hepatitis, 426

66  Adrenal Gland, 645

43  Acute Liver Failure, 434

67  Male Reproductive Endocrinology, 657

44  Cirrhosis of the Liver and Its Complications, 437

68  Diabetes Mellitus, Hypoglycemia, 662

45  Disorders of the Gallbladder and Biliary Tract, 448

69  Obesity, 678

Nayan M. Patel, Jen Jung Pan, Michael B. Fallon Anil Seetharam, Michael B. Fallon Shivang Mehta, Michael B. Fallon

Stacie A. F. Vela, Michael B. Fallon

SECTION VIII  Hematologic Disease 46  Hematopoiesis and Hematopoietic Failure, 457 Eunice S. Wang, Nancy Berliner

47  Clonal Disorders of the Hematopoietic Stem Cell, 470

Theodore C. Friedman Glenn D. Braunstein Robert J. Smith

Osama Hamdy, Marwa Al-Badri

70  Malnutrition, Nutritional Assessment, and Nutritional Support in Adult Patients, 686 Thomas R. Ziegler

71  Disorders of Lipid Metabolism, 692 Russell Bratman, Geetha Gopalakrishnan

Eunice S. Wang, Nancy Berliner

SECTION XI  Women’s Health

Ellice Wong, Michal G. Rose, Nancy Berliner

72  Women’s Health Topics, 701

48  Disorders of Red Blood Cells, 489

49  Clinical Disorders of Granulocytes and Monocytes, 501

Vidya Gopinath, Yael Tarshish, Kelly McGarry

Ellice Wong, Michal G. Rose, Nancy Berliner

50  Disorders of Lymphocytes, 506 Iris Isufi, Stuart Seropian

SECTION XII  Men’s Health

Lauren Shevell, Alfred I. Lee

73  Men’s Health Topics, 714

51  Normal Hemostasis, 522 52  Disorders of Hemostasis: Bleeding, 530 Aric Parnes

53  Disorders of Hemostasis: Thrombosis, 550 Rebecca Zon, Nathan T. Connell

Niels V. Johnsen, Douglas F. Milam, Joseph A. Smith, Jr.

SECTION XIII Diseases of Bone and Bone Mineral Metabolism

SECTION IX  Oncologic Disease

74  Normal Physiology of Bone and Mineral Homeostasis, 729

54  Cancer Biology, 563

75  Disorders of Serum Minerals, 739

55  Cancer Epidemiology, 571

76  Metabolic Bone Diseases, 748

56  Principles of Cancer Therapy, 577

77  Osteoporosis, 757

Andre De Souza, Wafik S. El-Deiry Gary H. Lyman, Nicole M. Kuderer

Davendra P.S. Sohal, Alok A. Khorana

57  Lung Cancer, 583

Zoe G.S. Vazquez, Jason M. Aliotta, Christopher G. Azzoli

58  Gastrointestinal Cancers, 589 Khaldoun Almhanna

59  Genitourinary Cancers, 595

Andre De Souza, Benedito A. Carneiro, Anthony Mega, Timothy Gilligan

Clemens Bergwitz, John J. Wysolmerski Emily M. Stein, Yi Liu, Elizabeth Shane Marcella D. Walker, Thomas J. Weber Susan L. Greenspan, Mary P. Kotlarczyk

SECTION XIV Musculoskeletal and Connective Tissue Disease 78  Approach to the Patient With Rheumatic Disease, 767 Niveditha Mohan

60  Breast Cancer, 601

79  Rheumatoid Arthritis, 771

61  Gynecological Cancer, 607

80  Spondyloarthritis, 778

Mary Anne Fenton, Rochelle Strenger Christina Bandera, Tarra B. Evans, Don Dizon

62  Other Solid Tumors (Head and Neck, Sarcomas, Melanoma, Unknown Primary), 615

Christopher G. Azzoli, Ariel E. Birnbaum, Maria Constantinou, Thomas A. Ollila

63  Complications of Cancer and Cancer Treatment, 620 Pamela Egan, Ari Pelcovits, John Reagan

SECTION X  Endocrine Disease and Metabolic Disease 64  Hypothalamic-Pituitary Axis, 626 Diana Maas, Jenna Sarvaideo

65  Thyroid Gland, 635 Theodore C. Friedman

Larry W. Moreland, Rayford R. June Douglas W. Lienesch

81  Systemic Lupus Erythematosus, 783

Sonia Manocha, Tanmayee Bichile, Susan Manzi

82  Systemic Sclerosis, 794

Anna Papazoglou, Robyn T. Domsic

83  Systemic Vasculitis, 801

Kimberly P. Liang, Kelly V. Liang

84  Crystal Arthropathies, 807

Pooja Bhadbhade, Ghaith Noaiseh

85  Osteoarthritis, 813

Joanne S. Cunha, Zuhal Arzomand, Philip Tsoukas

86  Nonarticular Soft Tissue Disorders, 818 Niveditha Mohan

87  Rheumatic Manifestations of Systemic Disorders and Sjögren’s Syndrome, 822 Andreea Coca, Ghaith Noaiseh

CONTENTS

xxiii

SECTION XV  Infectious Disease

112 Autonomic Nervous System Disorders, 1013

88 Host Defenses Against Infection, 830 Richard Bungiro, Edward J. Wing

113 Headache, Neck and Back Pain, and Cranial Neuralgias, 1017

Kimberle Chapin

114 Disorders of Vision and Hearing, 1025

Maria D. Mileno

115 Dizziness and Vertigo, 1033

Russell J. McCulloh, Steven M. Opal

116 Disorders of the Motor System, 1037

Su N. Aung, Allan R. Tunkel

93 Infections of the Head and Neck, 882

117 Congenital, Developmental, and Neurocutaneous Disorders, 1048

94 Infections of the Lower Respiratory Tract, 887

118 Cerebrovascular Disease, 1056

95 Infections of the Heart and Blood Vessels, 895

119 Traumatic Brain Injury and Spinal Cord Injury, 1069

96 Acute Bacterial Skin and Skin Structure Infections, 903

120 Epilepsy, 1073

97 Intraabdominal Infections, 910

121 Central Nervous System Tumors, 1087

98 Infectious Diarrhea, 916

122 Demyelinating and Inflammatory Disorders, 1092

99 Infections Involving Bone and Joints, 922 Jerome Larkin

123 Neuromuscular Diseases: Disorders of the Motor Neuron and Plexus and Peripheral Nerve Disease, 1101

Abdullah Chahin, Steven M. Opal

124 Muscle Diseases, 1111

Paul G. Jacob, Thomas R. Talbot

125 Neuromuscular Junction Disease, 1122

89 Laboratory Diagnosis of Infectious Diseases, 842 90 Fever and Febrile Syndromes, 848 91 Bacteremia and Sepsis, 858

92 Infections of the Central Nervous System, 865 David Kim, Roberto Cortez, Tareq Kheirbek John R. Lonks, Edward J. Wing

Raul Macias Gil, Cheston B. Cunha Sajeev Handa Eric Benoit

Awewura Kwara

100 Urinary Tract Infections, 925 101 Health Care–Associated Infections, 929 102 Sexually Transmitted Infections, 935 Philip A. Chan, Susan Cu-Uvin

103 Human Immunodeficiency Virus Infection, 944

William P. Cheshire, Jr.

Shane Lyons, Timothy J. Counihan

Eavan Mc Govern, Timothy J. Counihan Jonathan Cahill

Ruth B. Schneider, Adolfo Ramirez-Zamora, Christopher G. Tarolli Kristin A. Seaborg, Jennifer M. Kwon Mitchell S. V. Elkind

Geoffrey S.F. Ling, Jeffrey J. Bazarian Andrew S. Blum

Bryan J. Bonder, Lisa R. Rogers

Anne Haney Cross

Carlayne E. Jackson, Ratna Bhavaraju-Sanka Johanna Hamel, Jeffrey M. Statland Emma Ciafaloni

Joseph Metmowlee Garland, Timothy Flanigan, Edward J. Wing

SECTION XVII  Geriatrics

Dimitrios Farmakiotis, Ralph Rogers

126 The Aging Patient, 1126

Jessica E. Johnson, Rebecca Reece

SECTION XVIII  Palliative Care

104 Infections in the Immunocompromised Host, 963 105 Infectious Diseases of Travelers: Protozoal and Helminthic Infections, 973

SECTION XVI  Neurologic Disease 106 Neurologic Evaluation of the Patient, 981

Laura A. Previll, Mitchell T. Heflin, Harvey Jay Cohen

127 Palliative Care, 1141

Brandon J. Wilcoxson, Erin M. Denney-Koelsch, Robert G. Holloway

Frederick J. Marshall

107 Disorders of Consciousness, 986 Leah Dickstein, Paul M. Vespa

108 Disorders of Sleep, 992

Sagarika Nallu, Selim R. Benbadis

109 Cortical Syndromes, 997

SECTION XIX  Alcohol and Substance Use 128 Alcohol and Substance Use, 1151 Richard A. Lange, Joaquin E. Cigarroa

Sinéad M. Murphy, Timothy J. Counihan

APPENDIX Coronavirus Disease 2019 (COVID-19), 1166

Frederick J. Marshall

Index, 1174

110 Dementia and Memory Disturbances, 1001 111 Major Disorders of Mood, Thoughts, and Behavior, 1007 Jeffrey M. Lyness, Jennifer H. Richman

Edward J. Wing

VIDEO CONTENTS 3 Evaluation of the Patient With Cardiovascular Disease

37 Diseases of the Stomach and Duodenum

James Kleczka, Noura M. Dabbouseh

Alma M. Guerrero Bready, Akwi W. Asombang, Steven F. Moss

Audio 3.1: Ebstein Abnormalities Audio 3.2: Mitral Valve Prolapse

Video 37.1: Esophagastroduodenoscopy (EGD) 39 Diseases of the Pancreas

4 D  iagnostic Tests and Procedures in the Patient With Cardiovascular Disease

David R. Lichtenstein, Pushpak Taunk

Video 39.1: ERCP for Gallstone Pancreatitis With Sphincterotomy and Common Bile Duct Stone Extraction

Esseim Sharma, Alan R. Morrison

Video 4.1: 3D Echocardiographic Imaging Video 4.2: Color Doppler Imaging Video 4.3: Dynamic Contrast Echocardiographic Image Video 4.4: Transesophageal Echocardiography Video 4.5: Cardiac Single-­Photon Emission Computed Tomography Imaging Video 4.6: Dynamic Cardiac MRI Image Video 4.7: ECG-­Gated Dynamic CT Imaging

45 Disorders of the Gallbladder and Biliary Tract Stacie A. F. Vela, Michael B. Fallon

Video 45.1: Endoscopic Ultrasound of Large Gallbladder Stone Video 45.2: Sphincterotomy 65 Thyroid Gland

Theodore C. Friedman

35 Endoscopic and Imaging Procedures

Video 65.1: Thyroid Examination

Andrew Canakis, Christopher S. Huang

Video 35.1: Capsule Endoscopy of the Normal Small Intestine Video 35.2: Capsule Endoscopy Video of an Actively Bleeding Vascular Ectasia Video 35.3: Capsule Endoscopy Image and Video of an Ulcerated Small Intestinal Tumor

115 Dizziness and Vertigo Jonathan Cahill



Video 115.1: Gaze-­Evoked Nystagmus Video 115.2: Unidirectional, Peripheral Vestibular Spontaneous Pattern of Nystagmus Video 115.3: Nystagmus of Posterior Canal Benign Paroxysmal Positional Vertigo

xxv

This page intentionally left blank

     

SECTION

I

Introduction to Medicine 1  Introduction to Medicine, 2

https://t.me/mebooksfree

1

1 Introduction to Medicine Edward J. Wing, Fred J. Schiffman

Cecil Essentials of Medicine presents a core of internal medicine and neurology information that every physician should know. This book provides an essential framework so physicians can appropriately assemble the key elements of history, physical examination, and laboratory data to understand their patient’s illness and develop an appropriate diagnostic and therapeutic strategy. Furthermore, in order to understand advances in medicine, physicians must have a strong background for the acquisition and categorization of new medical knowledge. Cecil Essentials of Medicine is designed for medical students as well as physicians in training, and we hope it will be an appropriate vehicle for course and examination review. We also believe, however, that physicians at all stages in their careers will find it to be a valuable resource for review and reference. This book also serves as a companion to the 26th edition of Goldman-Cecil Medicine, which is more comprehensive in scope and detailed in its content. Cecil Essentials of Medicine is organized into sections, most often representing organ systems, with introductory and then organspecific, disease-based chapters. The chapters themselves are subdivided. For example, the cardiovascular disease chapter is divided into Epidemiology, Anatomy, Pathophysiology, Clinical Diagnosis, and Treatment. The Suggested Readings sections at the end of each chapter include selected critical reviews, guidelines, and important randomized controlled trials. They are not meant to be an exhaustive reference list, but rather to highlight the essential information that physicians should know. We believe that the information in Cecil Essentials of Medicine will encourage evidence-based diagnostic and therapeutic decision making. Importantly, the rational approach to medical problem-solving must be interwoven with the attentive presence of the physician at

2

the bedside, clinic or office, undistracted by electronic devices (particularly the computer), displaying mindful humanistic patient care. Humanistic practice includes integrity, compassion, altruism, respect, service, and empathy, but also excellence. Both the art and the science of medicine must be part of the approach to any patient encounter. The editors believe that these concepts have been best expressed by Frances Peabody, who famously stated that “the significance of the intimate personal relationship between physician and patient cannot be too strongly emphasized, for in an extraordinary large number of cases both the diagnosis and treatment directly depend upon it. One of the essential qualities of the clinician is interest in humanity for the secret of the care of the patient is in caring for the patient,” and by Sir William Osler, who said, “The practice of medicine is an art not a trade; a calling not a business; a calling in which your heart will be exercised equally with your head.” We believe that the fundamentally important bond between caregiver and patient is the starting point to the care of the patient. This is followed by a thorough history and a directed physical examination, which allow a diagnosis in the great majority of encounters. Laboratory data and imaging are supplementary. The focus of the diagnostic process should be on diseases that are common and treatable. Common presentations of common diseases account for the vast majority of cases; next in frequency are unusual presentations of common diseases; less common are typical presentations of rare diseases. Concentrate on common diseases, but know the rare ones as well. We sincerely hope that Cecil Essentials of Medicine will be used to provide the basic and clinical data that are essential for us to practice medicine in a manner informed by both compassion and evidence, so that we may truly heal those with whose care we are entrusted.

SECTION

II

Cardiovascular Disease 2 Structure and Function of the Normal Heart and Blood Vessels, 4

  7  Valvular Heart Disease, 64   8  Coronary Heart Disease, 77

3 Evaluation of the Patient With Cardiovascular Disease, 10 4 Diagnostic Tests and Procedures in the Patient With Cardiovascular Disease, 24 5  Heart Failure and Cardiomyopathy, 43 6  Congenital Heart Disease, 55

  9  Cardiac Arrhythmias, 99 10  Pericardial and Myocardial Disease, 123 11  Other Cardiac Topics, 131 12  Vascular Diseases and Hypertension, 139

3

2 Structure and Function of the Normal Heart and Blood Vessels Nicole L. Lohr, Ivor J. Benjamin

DEFINITION The circulatory system comprises the heart, which is connected in series to the arterial and venous vascular networks. These vascular networks are arranged in parallel and connect at the level of the capillaries (Fig. 2.1). The heart is composed of two atria, which are low-pressure capacitance chambers that function to store blood during ventricular contraction (systole) and then fill the ventricles with blood during ventricular relaxation (diastole). The two ventricles are high-pressure chambers responsible for pumping blood through the lungs (right ventricle) and to the peripheral tissues (left ventricle). The left ventricle is thicker than the right, in order to generate the higher systemic pressures required for perfusion. There are four cardiac valves that facilitate unidirectional blood flow through the heart. Each of the four valves is surrounded by a fibrous ring, or annulus, that forms part of the structural support of the heart. Atrioventricular (AV) valves separate the atria and ventricles. The mitral valve is a bileaflet valve that separates the left atrium and left ventricle. The tricuspid valve is a trileaflet valve that separates the right atrium and right ventricle. Thin, fibrous connective tissue (chordae tendineae) attaches the ventricular aspects of these valves to the papillary muscles of their respective ventricles for proper opening of the valves. Additional valves include the aortic valve that separates the left ventricle from the aorta, and the pulmonic valve that separates the right ventricle from the pulmonary artery. A thin, double-layered membrane called the pericardium surrounds the heart. The inner, or visceral, layer adheres to the outer surface of the heart, also known as the epicardium. The outer layer is the parietal pericardium, which attaches to the sternum, vertebral column, and diaphragm to stabilize the heart in the chest. Between these two membranes is a pericardial space filled with a small amount of fluid (30 min more severe

Pericarditis

Left of the sternum; may radiate to neck or left shoulder, often more localized than pain of myocardial ischemia Anterior chest; may radiate to back, interscapular region

Sharp, stabbing, knifelike

Aortic dissection

Quality

Excruciating, tearing, knifelike

A patient who is given the opportunity to outline his or her symptoms in his or her own words can help lead a clinician toward the right diagnosis. For example, many patients who deny chest pain when asked specifically about this symptom will go on to describe the symptom of chest pressure, which patients often feel is distinct from “pain.” Gathering further historical details such as provoking factors (e.g., activity, extreme emotional stress, or rest or unprovoked symptoms), location, quality, intensity, and radiation of the symptom is imperative when taking a thorough history. One should delve into aggravating or alleviating factors and whether there are other symptoms that accompany the primary symptom. It is also important to note the pattern of the symptom in terms of stability or progression in intensity or frequency over time. An assessment of functional status should always be a part of the history in a patient with cardiovascular disease; a recent decline in exercise tolerance can help determine severity of disease. A detailed past medical history and review of systems are necessary in order to understand if the cardiovascular condition is isolated or part of a syndrome. For example, a patient may have arrhythmias in the setting of hyperthyroidism. Rheumatologic disorders often affect the heart. And cancer can increase the risk of thromboembolism, of pericardial effusion and, with some therapies, cardiomyopathy. A comprehensive list of medications must be reviewed, and a social history must be taken detailing alcohol use, smoking, and occupational history. Patients should also be questioned regarding major risk factors such as hypertension, hyperlipidemia, and diabetes mellitus. A thorough family history is needed, not only to identify such entities as early-onset CAD but also to assess for other potentially inherited disorders, such as familial cardiomyopathy or arrhythmic disorders (e.g., long-QT syndrome).

Chest Pain Chest pain is one of the cardinal symptoms of cardiovascular disease, but it may also be present in many noncardiovascular diseases (Tables 3.1 and 3.2). Chest pain may be caused by cardiac ischemia but also may be related to aortic pathology such as dissection, pulmonary

Duration 90%). There are several types of cyanosis. Central cyanosis often manifests in discoloration of the lips or trunk and usually represents low oxygen saturations due to right-to-left shunting of blood. This can occur with structural cardiac abnormalities such as large atrial or ventricular septal defects, but it also happens with impaired pulmonary function, as in severe chronic obstructive lung disease. Peripheral cyanosis is typically secondary to vasoconstriction in the setting of low cardiac output. This can also occur with exposure to cold and can represent local arterial or venous thrombosis. When localized to the hands, peripheral cyanosis suggests Raynaud’s phenomenon. Cyanosis in childhood often indicates congenital heart disease with right-to-left shunting of blood, causing lower oxygen content in systemically circulated blood.

Other There are other, nonspecific symptoms that may indicate cardiovascular disease. Although fatigue is present with myriad medical conditions, it is common in patients with cardiac disease and can be a manifestation of coronary disease, volume overload, low cardiac output, hypotension, or hypertension. Iatrogenic causes of fatigue in cardiac patients include aggressive medical treatment of hypertension and overdiuresis in patients with heart failure. Fatigue may also be a direct result of medical therapy for cardiac disease itself, such as with β-blocking agents. Although cough is commonly associated with pulmonary disease, it may also indicate high intracardiac pressures which can lead to pulmonary edema. Cough may be present in patients with heart failure or significant left-sided valve disease. A patient with congestive heart failure may describe a cough productive of frothy pink sputum, as opposed

to frank bloody or blood-tinged sputum, which is more typically seen with primary lung pathology. Nausea and emesis can accompany acute myocardial infarction and are often the only symptoms of MI. These “abdominal” symptoms may also be a reflection of heart failure leading to hepatic or intestinal congestion due to high right heart pressures. Anorexia, abdominal fullness, and cachexia may occur with endstage heart failure, and the term “cardiac cachexia” has been coined to describe this syndrome. Nocturia is also a symptom described with heart failure; renal perfusion improves when the patient lies in a prone position, leading to an increase in urine output. Hoarseness of voice can occur due to compression of the recurrent laryngeal nerve. This may happen with enlarged pulmonary arteries, enlarged left atrium, or aortic aneurysm (Ortner’s syndrome). Despite the myriad symptoms of cardiovascular disease described here, many patients with significant cardiac disease are asymptomatic. Patients with CAD may have periods of asymptomatic ischemia that can be documented on ambulatory electrocardiographic monitoring. Up to one third of patients who have suffered a myocardial infarction are unaware that they had an event. This is more common in diabetics and in older patients. A patient may have severely depressed ventricular function for some time before presenting with symptoms. In addition, patients with atrial fibrillation can be entirely asymptomatic, with this rhythm discovered only after a physical examination or electrocardiogram is performed. It is also important to note that cardiovascular disease is a leading cause of morbidity and mortality in women, but women have not classically been included in large longitudinal or epidemiologic studies of cardiac disease. Thus, much of our knowledge has been gathered from the study of men, and women may have atypical symptoms and presentations for cardiovascular disease. A high clinical suspicion for cardiovascular disease, the leading cause of death in both men and women, is imperative during evaluation, especially of the patient with cardiovascular disease risk factors. At times, patients do not report having symptoms related to usual activities of daily living, yet symptoms are present when functional testing is performed. Therefore, assessing functional capacity is a very important part of the history in a patient with known or suspected cardiovascular disease. The ability or inability to perform various activities plays a substantial role in determining the extent of disability and in assessing response to therapy and overall prognosis, and it can influence decisions regarding the timing and type of therapy or intervention. The New York Heart Association Functional Classification is a commonly used method to assess functional status based on “ordinary activity” (Table 3.3). Patients are classified in one of four functional classes. Functional class I includes patients with known cardiac disease who have no limitations with ordinary activity. Functional classes II and III describe patients who have symptoms with less and less activity, whereas patients in functional class IV have symptoms at rest. The Canadian Cardiovascular Society has provided a similar classification of functional status specifically for patients with angina pectoris. These tools are very useful in classifying a patient’s symptoms at a given time, allowing comparison at a future point and determination as to whether the symptoms are stable or progressive.

DIAGNOSIS AND PHYSICAL EXAMINATION General Like the detailed history, the physical examination is also vital when assessing a patient with cardiovascular disease. This consists of more than simple cardiac auscultation. Many diseases of the cardiovascular system can affect and be affected by other organ systems. Therefore, a detailed general physical examination is essential. The general

CHAPTER 3  Evaluation of the Patient With Cardiovascular Disease

TABLE 3.3  Classification of Functional

Statusa Class I

Uncompromised

Class II

Slightly compromised

Class III

Moderately compromised Severely compromised

Class IV

Ordinary activity does not cause symptoms; symptoms occur only with strenuous or prolonged activity. Ordinary physical activity results in symptoms; no symptoms at rest. Less than ordinary activity results in symptoms; no symptoms at rest. Any activity results in symptoms; symptoms may be present at rest.

aSymptoms

refers to undue fatigue, dyspnea, palpitations, or angina in the New York Heart Association classification and refers specifically to angina in the Canadian Cardiovascular Society classification.

appearance of a patient is helpful: Examination of skin color, breathing pattern, presence of pain, and overall nutritional status can provide clues regarding the diagnosis. Examination of the head may reveal evidence of hypothyroidism, such as hair loss and periorbital edema, and examination of the eyes may reveal exophthalmos associated with hyperthyroidism. Both conditions can affect the heart. Retinal examination may reveal macular edema or flame hemorrhages that can be associated with uncontrolled hypertension. Findings such as clubbing or edema when examining the extremities, and jaundice or cyanosis when evaluating the skin, may provide clues to undiagnosed cardiovascular disease.

Examination of the Jugular Venous Pulsations Examination of the neck veins can provide a great deal of insight into right heart hemodynamics. The right internal jugular vein should be used, because the relatively straight course of the right innominate and jugular veins allows for a more accurate reflection of the true right atrial pressure. The longer and more winding course of the left-sided veins does not allow for as accurate a transmission of hemodynamics. For examination of the right internal jugular vein, the patient should be placed at a 45-degree angle—higher in patients with suspected elevated venous pressures and lower in those with lower venous pressures. The head should be turned slightly leftward, and a light shined at an angle over the neck can help the exam. Although the internal jugular vein itself is not visible, the pulsations from that vessel are transmitted to the skin and can be seen in most cases. The carotid artery lies in close proximity to the jugular vein, and its pulsations can sometimes be seen as well. Therefore, one must be certain one is observing the correct vessel. Several techniques can help the clinician differentiate carotid and venous pulsations. A normal carotid pulsation pattern usually appears as a smooth and rapid upstroke, whereas a venous pulsation tends to have three “waves,” the a wave of atrial contract, the c wave of the tricuspid valve closure, and the v wave of ventricular contraction. Variations in the appearance of these waves can help the clinician diagnose arrhythmia, constriction and tamponade, valvular heart disease, and heart failure. These are further discussed in the following text. The carotid and venous pulsations can further be distinguished by response to attempted compression of the pulsations or vessel. An arterial pulse will not be obliterated by this maneuver, whereas a venous pulse likely will become diminished or absent with compression. The arterial pulsations will not change with changes

15

in positioning, whereas venous pulsations, as they are essentially reflections of a column of fluid draining into the right heart, will appear higher in the neck/head when a patient is more supine and lower when a patient is more upright. Finally, compression of the abdomen will cause an elevation or increase in prominence of the appearance of a venous wave and will not affect an arterial waveform in the neck. Both the level of venous pressure and the morphology of the venous waveforms should be noted. Once the pulsations have been located, the vertical distance from the sternal angle (angle of Louis) to the top of the pulsations is determined. Because the right atrium lies about 5 cm vertically below the sternal angle, this number is added to the previous measurement to arrive at an estimated right atrial pressure in centimeters of water. The right atrial pressure is normally 5 to 9 cm H2O. It can be higher in patients with decompensated heart failure, disorders of the tricuspid valve (regurgitation or stenosis), restrictive cardiomyopathy, or constrictive pericarditis. With inspiration, negative intrathoracic pressure develops, venous blood drains into the thorax, and venous pressure in the normal patient falls; the opposite occurs during expiration. In a patient with conditions such as decompensated heart failure, constrictive pericarditis, or restrictive cardiomyopathy, this pattern is reversed (Kussmaul sign), and the venous pressure increases with inspiration. When the neck veins are examined, firm pressure should be applied for 10 to 30 seconds to the right upper quadrant over the liver. In a normal patient, this will cause the venous pressure to increase briefly and then return to normal. In the patient with conditions such as heart failure, constrictive pericarditis, or substantial tricuspid regurgitation, the neck veins will reveal a sustained increase in pressure due to passive congestion of the liver. This finding is called hepatojugular reflux. The normal waveforms of the jugular venous pulse are depicted in Fig 3.1A. The a wave results from atrial contraction. The x descent results from atrial relaxation after contraction and the pulling of the floor of the right atrium downward with right ventricular contraction. The c wave interrupts the x descent and is generated by bulging of the cusps of the tricuspid valve into the right atrium during ventricular systole. This occurs at the same time as the carotid pulse. Atrial pressure then increases as a result of venous return with the tricuspid valve closed during ventricular systole; this generates the v wave, which is typically smaller than the a wave. The y descent follows as the tricuspid valve opens and blood flows from the right atrium to the right ventricle during diastole. Understanding of the normal jugular venous waveforms is paramount, as these waveforms can be altered in different disease states. Abnormalities of these waveforms reflect underlying structural, functional, and electrical abnormalities of the heart (see Fig. 3.1B to G). Elevation of the right atrial pressure leading to jugular venous distention can be found in heart failure (both systolic and diastolic), hypervolemia, superior vena cava syndrome, and valvular disease. The a wave is exaggerated in any condition in which a greater resistance to right atrial emptying occurs. Such conditions include pulmonary hypertension, tricuspid stenosis, and right ventricular hypertrophy or failure. Cannon a waves occur when the atrium contracts against a closed tricuspid valve, which can occur with complete heart block or any other situation involving AV dissociation. The a wave is absent during atrial fibrillation. With significant tricuspid regurgitation, the v wave becomes very prominent and may merge with the c wave, diminishing or eliminating the x descent. With tricuspid stenosis, there is impaired emptying of the right atrium, which leads to an attenuated y descent. In pericardial constriction and restrictive

16

SECTION II  Cardiovascular Disease

QRS T

P

ECG S1

S4

S2

S3

phono

A a

x

v

c

a wave caused by atrial contraction, v wave during ventricular systole

y

x'

v c

B

Atrial fibrillation, no a wave present

a v

Enhanced a wave

C a

c-v Dominant c-v wave

D

x

y

x

y

Exaggerated x and y descents in constrictive pericarditis

E

F

cannon a

cannon a

a

Exaggerated x descent and loss of y descent in tamponade

cannon a

cannon a

a JVP

G P

P

P

P

P

P

P

P

P

ECG P

Fig. 3.1 Normal and abnormal jugular venous pulse (JVP) tracings. (A) Normal jugular pulse tracing with simultaneous electrocardiogram (ECG) and phonocardiogram. (B) Loss of the a wave in atrial fibrillation. (C) Large a wave in tricuspid stenosis. (D) Large c-v wave in tricuspid regurgitation. (E) Prominent x and y descents in constrictive pericarditis. (F) Prominent x descent and diminutive y descent in pericardial tamponade. (G) JVP tracing and simultaneous ECG during complete heart block demonstrates cannon a waves occurring when the atrium contracts against a closed tricuspid valve during ventricular systole. P, P waves correlating with atrial contraction; S1 to S4, heart sounds.

cardiomyopathy, the y descent occurs rapidly and deeply, and the x descent may also become more prominent, leading to a waveform with a w-shaped appearance. With pericardial tamponade, the x descent becomes very prominent while the y descent is diminished or absent.

Examination of Arterial Pressure and Pulse Arterial blood pressure is measured noninvasively with the use of a sphygmomanometer. Before the blood pressure is taken, the patient ideally should be relaxed, allowed to rest for 5 to 10 minutes in a quiet room, and seated or lying comfortably. The cuff is typically applied

CHAPTER 3  Evaluation of the Patient With Cardiovascular Disease

A

17

120 mm Hg

D

80 mm Hg 150 mm Hg

B 30 mm Hg Wide pulse pressure 100 mm Hg

C

80 mm Hg Delayed peak, narrow pulse pressure variable

D

variable

Bi-phase peak

90 mm Hg Alternating higher and lower pressure 60 mm Hg

E

90 mm Hg 70 mm Hg

F

60 mm Hg Expiration

Inspiration

Expiration

Fig. 3.2  Normal and abnormal carotid arterial pulse contours. (A) Normal arterial pulse with simultaneous electrocardiogram (ECG). The dicrotic wave (D) occurs just after aortic valve closure. (B) Wide pulse pressure in aortic insufficiency. (C) Pulsus parvus et tardus (small amplitude with a slow upstroke) associated with aortic stenosis. (D) Bisferiens pulse with two systolic peaks, typical of hypertrophic obstructive cardiomyopathy or aortic insufficiency, especially if concomitant aortic stenosis is present. (E) Pulsus alternans, characteristic of severe left ventricular failure. (F) Paradoxic pulse (systolic pressure decrease >10 mm Hg with inspiration), most characteristic of cardiac tamponade.

to the upper arm, approximately 1 inch above the antecubital fossa. A stethoscope is then used to auscultate under the lower edge of the cuff. The cuff is rapidly inflated to approximately 30 mm Hg above the anticipated systolic pressure and then slowly deflated (at approximately 3 mm Hg/sec) while the examiner listens for the sounds produced by blood entering the previously occluded artery. These sounds are the Korotkoff sounds. The first sound is typically a very clear tapping sound that, when heard, represents the systolic pressure. As the cuff continues to deflate, the sounds will disappear; this point represents the diastolic pressure. In normal situations, the pressure in both arms is relatively equal. If the pressure is measured in the lower extremities rather than the arms, the systolic pressure is typically 10 to 20 mm Hg higher. If the pressures in the arms are asymmetric, this may suggest atherosclerotic disease involving the aorta, aortic dissection, or obstruction of flow in the subclavian or innominate arteries. The pressure in the lower extremities can be lower than arm pressures in the setting of abdominal aortic, iliac, or femoral disease. Coarctation of the aorta

can also lead to discrepant pressures between the upper and lower extremities. Leg pressure that is more than 20 mm Hg higher than the arm pressure can be found in the patient with significant aortic regurgitation, a finding called Hill’s sign. A common mistake in taking the arterial blood pressure involves using a cuff of incorrect size. Use of a small cuff on a large extremity leads to overestimation of pressure. Similarly, use of a large cuff on a smaller extremity underestimates the pressure. Examination of the arterial pulse in a cardiovascular patient should include palpation of the carotid, radial, brachial, femoral, popliteal, posterior tibial, and dorsalis pedis pulses bilaterally. The carotid pulse most accurately reflects the central aortic pulse. One should note the rhythm, strength, contour, and symmetry of the pulses. A normal arterial pulse (Fig. 3.2A) rises rapidly to a peak in early systole, plateaus, and then falls. The descending limb of the pulse is interrupted by the incisura or dicrotic notch, which is a sharp deflection downward due to closure of the aortic valve. As the pulse moves toward the periphery, the systolic peak is higher and the dicrotic notch is later and less noticeable.

18

SECTION II  Cardiovascular Disease

The normal pattern of the arterial pulse can be altered by a variety of cardiovascular diseases (see Fig. 3.2B to F). The amplitude of the pulse increases in conditions such as anemia, pregnancy, thyrotoxicosis, and other states with high cardiac output. Aortic insufficiency, with its resultant increase in pulse pressure (difference between systolic and diastolic pressure), leads to a bounding carotid pulse often referred to as a Corrigan pulse or a water-hammer pulse. The amplitude of the pulse is diminished in low-output states such as heart failure, hypovolemia, and mitral stenosis. Tachycardia, with shorter diastolic filling times, also lowers the pulse amplitude. Aortic stenosis, when significant, leads to a delayed systolic peak and diminished carotid pulse, referred to as pulsus parvus et tardus. A bisferiens pulse is most perceptible on palpation of the carotid artery. It is characterized by two systolic peaks and can be found in patients with pure aortic regurgitation. The first peak is the percussion wave, which results from the rapid ejection of a large volume of blood early in systole. The second peak is the tidal wave, which is a reflected wave from the periphery. A bisferiens pulse may also be found in those with hypertrophic cardiomyopathy, in which the initial rapid upstroke of the pulse is interrupted by LVOT obstruction. The reflected wave produces the second impulse. Pulsus alternans is beat-to-beat variation in the pulse and can be found in patients with severe left ventricular systolic dysfunction. Pulsus paradoxus is an exaggeration of the normal inspiratory fall in systolic pressure. With inspiration, negative intrathoracic pressure is transmitted to the aorta, and systolic pressure typically drops by as much as 10 mm Hg. In pulsus paradoxus, this drop is greater than 10 mm Hg and can be palpable when marked (>20 mm Hg). It is characteristic in cardiac tamponade but can also be seen in constrictive pericarditis, pulmonary embolism, hypovolemic shock, pregnancy, and severe chronic obstructive lung disease. Because peripheral vascular disease often accompanies CAD, a detailed examination of the peripheral pulses is a crucial part of the physical exam of a patient with known or suspected ischemic heart disease. In addition to the carotid, brachial, radial, femoral, popliteal, dorsalis pedis, and posterior tibial pulses, the abdominal aorta should be palpated. When the abdominal aorta is palpable below the umbilicus, the presence of an abdominal aortic aneurysm is suggested. Impaired blood flow to the lower extremities can cause claudication, a cramping pain located in the buttocks, thigh, calf, or foot, depending on the location of disease. With significant stenosis in the peripheral vasculature, the distal pulses may be significantly reduced or absent. Blood flow in a stenotic artery may be turbulent, creating an audible bruit. With normal aging, the peripheral arteries become less compliant and this change may obscure abnormal findings.

Examination of the Precordium A complete cardiovascular examination should always include careful inspection and palpation of the chest. Abnormalities of the chest wall including skin findings should be observed. The presence of pectus excavatum is associated with Marfan syndrome and mitral valve prolapse. Pectus carinatum can also be found in patients with Marfan syndrome. Kyphoscoliosis can lead to right-sided heart failure and secondary pulmonary hypertension. One should also assess for visible pulsations, in particular in the regions of the aorta (second right intercostal space and suprasternal notch), pulmonary artery (third left intercostal space), right ventricle (left parasternal region), and left ventricle (fourth to fifth intercostal space at the left midclavicular line). Prominent pulsations in these areas suggest enlargement of these vessels or chambers. Retraction of the left parasternal area can be observed in patients with severe left ventricular hypertrophy, whereas systolic retraction at the apex or in the left axilla (Broadbent sign) is more characteristic of constrictive pericarditis.

Palpation of the precordium is best performed when the patient, with chest exposed, is positioned supine or in a left lateral position with the examiner located on the right side of the patient. The examiner should then place the right hand over the lower left chest wall with fingertips over the region of the cardiac apex and the palm over the region of the right ventricle. The right ventricle itself is typically best palpated in the subxiphoid region with the tip of the index finger. In those patients who have chronic obstructive lung disease, are obese, or are very muscular, the normal cardiac pulsations may not be palpable. In addition, chest wall deformities may make pulsations difficult or impossible to palpate. The normal apical cardiac impulse is a brief and discrete (1 cm in diameter) pulsation located in the fourth to fifth intercostal space along the left midclavicular line. In a patient with a normal heart, this represents the point of maximal impulse (PMI). If the heart cannot be palpated with the patient supine, a left lateral position should be tried. If the left ventricle is enlarged for any reason, the PMI will typically be displaced laterally. With volume overload states such as aortic insufficiency, the left ventricle dilates, resulting in a brisk apical impulse that is increased in amplitude. With pressure overload, as in long-standing hypertension and aortic stenosis, ventricular enlargement is a result of hypertrophy, and the apical impulse is sustained. Often, it is accompanied by a palpable S4 gallop. Patients with hypertrophic cardiomyopathy can have double or triple apical impulses. Those with apical aneurysm may have an apical impulse that is larger and dyskinetic. The right ventricle is usually not palpable. However, in those with right ventricular dilation or hypertrophy, which can be related to severe lung disease, pulmonary hypertension, or congenital heart disease, an impulse may be palpated in the left parasternal region. In some cases of severe emphysema, when the distance between the chest wall and right ventricle is increased, the right ventricle is better palpated in the subxiphoid region. With severe pulmonary hypertension, the pulmonary artery may produce a palpable impulse in the second to third intercostal space to the left of the sternum. This may be accompanied by a palpable right ventricle or a palpable pulmonic component of the second heart sound (S2). An aneurysm of the ascending aorta or arch may result in a palpable pulsation in the suprasternal notch. Thrills are vibratory sensations best palpated with the fingertips; they are manifestations of harsh murmurs caused by such problems as aortic stenosis, hypertrophic cardiomyopathy, and septal defects.

Auscultation Techniques

Auscultation of the heart is accomplished by use of a stethoscope with dual chest pieces. The diaphragm is ideal for high-frequency sounds, whereas the bell aids in auscultation of low-frequency sounds. When one is listening for low-frequency tones, the bell should be placed gently on the skin with minimal pressure applied. If the bell is applied more firmly, the skin will stretch and higher-frequency sounds will be heard (as when using the diaphragm). Auscultation should ideally be performed in a quiet setting with the patient’s chest exposed and the examiner best positioned to the right of the patient. Four major areas of auscultation are evaluated, starting at the apex and moving toward the base of the heart. The mitral valve is best heard at the apex or location of the PMI. Tricuspid valve events are appreciated in or around the left fourth intercostal space adjacent to the sternum. The pulmonary valve is best evaluated in the second left intercostal space. The aortic valve is assessed in the second right intercostal space. These areas should be evaluated from apex to base using the diaphragm and then evaluated again with the bell. Auscultation of the back, the axillae, the right side of the chest, and the supraclavicular areas should also be done. Having the patient perform maneuvers such as leaning forward,

19

CHAPTER 3  Evaluation of the Patient With Cardiovascular Disease exhaling, standing, squatting, and performing a Valsalva maneuver may help to accentuate certain heart sounds (Table 3.4).

Normal Heart Sounds All heart sounds should be described according to their quality, intensity, and frequency. There are two primary heart sounds heard during auscultation: S1 and S2. These are high-frequency sounds caused by closure of the valves. S1 occurs with the onset of ventricular systole and is caused by closure of the mitral and tricuspid valves. S2 is caused by closure of the aortic and pulmonic valves and marks the beginning of ventricular diastole. All other heart sounds are timed based on these two sounds. S1 has two components, the first of which (M1) is usually louder, heard best at the apex, and caused by closure of the mitral valve. The second component (T1), which is softer and thought to be related to closure of the tricuspid valve, is heard best at the lower left sternal border. Although there can be two components, S1 is typically heard as a single sound. S2 also has two components, which typically can be easily distinguished. A2, the component caused by closure of the aortic valve, is usually louder and heard earlier and is best heard at the right upper

TABLE 3.4  Effects of Physiologic

Maneuvers on Auscultatory Events Major Physiologic Effects

Useful Auscultatory Changes

Respiration

↑ Venous return with inspiration

Valsalva (initial ↑ BP, phase I; followed by ↓ BP, phase II)

↓ BP, ↓ venous return, ↓ LV size (phase II)

Standing

↓ Venous return ↓ LV size

Squatting

↑ Venous return ↑ Systemic vascular resistance ↑ LV size ↑ Arterial pressure ↑ Cardiac output

↑ Right heart murmurs and gallops with inspiration; splitting of S2 (see Fig. 3.3) ↑ HCM ↓ AS, MR MVP click earlier in systole; murmur prolongs ↑ HCM ↓ AS, MR MVP click earlier in systole; murmur prolongs ↑ AS, MR, AI ↓ HCM MVP click delayed; murmur shortens ↑ Gallops ↑ MR, AI, MS ↓ AS, HCM ↑ AS

Maneuver

Isometric exercise (e.g., handgrip) Post PVC or prolonged R-R interval Amyl nitrate

Phenylephrine

↑ Ventricular filling ↑ Contractility ↓ Arterial pressure ↑ Cardiac output ↓ LV size ↑ Arterial pressure ↑ Cardiac output ↓ LV size

Little change in MR ↑ HCM, AS, MS ↓ AI, MR, Austin Flint murmur MVP click earlier in systole; murmur prolongs ↑ MR, AI ↓ AS, HCM MVP click delayed; murmur shortens

↑, Increased intensity; ↓, decreased intensity; AI, aortic insufficiency; AS, aortic stenosis; BP, blood pressure; HCM, hypertrophic cardiomyopathy; LV, left ventricle; MR, mitral regurgitation; MS, mitral stenosis; MVP, mitral valve prolapse; PVC, premature ventricular contraction; R-R, interval between the R waves on an ­electrocardiogram.

sternal border. P2, caused by closure of the pulmonic valve, is recognized best over the left second intercostal space. With expiration, a normal S2 is perceived as a single sound. With inspiration, however, venous return to the right heart is augmented, and the increased capacitance of the pulmonary vascular bed results in a delay in pulmonic valve closure. A slight decline in pulmonary venous return to the left ventricle leads to earlier aortic valve closure. Therefore, physiologic splitting of S2, with A2 preceding P2 during inspiration, is a normal finding. Additional heart sounds can at times be heard in normal individuals. A third heart sound can sometimes be heard in healthy children and young adults. This is referred to as a physiologic S3, which is rarely heard after the age of 40 years in a normal individual. A fourth heart sound is caused by forceful atrial contraction into a noncompliant ventricle; it is rarely audible in normal young patients but is relatively common in older individuals. Murmurs are auditory vibrations generated by high flow across a normal valve or normal flow across an abnormal valve or structure. Murmurs that occur early in systole and are soft and brief in duration are not typically pathologic and are termed innocent murmurs. These usually are caused by flow across normal left ventricular or right ventricular outflow tracts and are found in children and young adults. Some systolic murmurs may be associated with high-flow states such as fever, anemia, thyroid disease, and pregnancy and are not innocent, although they are not typically associated with structural heart disease. They are called physiologic murmurs because of their association with altered physiologic states. All diastolic murmurs are pathologic.

Abnormal Heart Sounds Abnormalities in S1 and S2 are related to either intensity (Table 3.5) or respiratory splitting (Table 3.6). S1 is accentuated with tachycardia and with short PR intervals, whereas it is softer in the setting of a long PR interval. S1 varies in intensity if the relationship between atrial and ventricular systole varies. In those patients with atrial fibrillation, atrial filling and emptying is not consistent because of the variable HR leading to beat-to-beat changes in the intensity of S1. This also can occur with heart block or AV dissociation. In early mitral stenosis, S1 is often accentuated, but with severe stenosis, there is decreased leaflet excursion and S1 is diminished in intensity or altogether absent (Figs. 3.3 and 3.4). As previously mentioned, splitting of S1 is not frequently heard. However, it is more apparent in conditions that delay closure of the tricuspid valve, including right bundle branch block and Ebstein’s anomaly (Audio Clip 3.1, Ebstein Abnormalities).

TABLE 3.5  Abnormal Intensity of Heart

Sounds Loud

Soft

Varying

S1

A2

P2

Short PR interval Mitral stenosis with pliable valve Long PR interval Mitral regurgitation Poor left ventricular function Mitral stenosis with rigid valve Thick chest wall Atrial fibrillation Heart block

Systemic hypertension Aortic dilation Coarctation of the aorta Calcific aortic stenosis Aortic regurgitation

Pulmonary hypertension Thin chest wall Valvular or subvalvular pulmonic stenosis

—

—

A2, Component of second heart sound caused by closure of aortic valve; P2, component of second heart sound caused by closure of pulmonic valve; S1, first heart sound.

20

SECTION II  Cardiovascular Disease

S2 can be accentuated in the presence of hypertension, when the aortic component will be louder, or in pulmonary hypertension, when the pulmonic component will be enhanced. In the setting of severe aortic or pulmonic stenosis, leaflet excursion of the respective valves is reduced and the intensity of S2 is significantly diminished. It may become absent altogether if the accompanying murmur obscures what remains of S2. There are several patterns of abnormal splitting of S2. S2 can remain single throughout respiration if either A2 or P2 is not present or if they occur simultaneously. A2 can be absent, as previously mentioned, with severe aortic stenosis. P2 can be absent with a number of congenital abnormalities of the pulmonic valve. Splitting may be persistent throughout the respiratory cycle if A2 occurs early or if P2 is delayed, as in the presence of right bundle branch block. In that case, splitting is always present but the interval between A2 and P2 varies somewhat. In fixed splitting, the interval between A2 and P2 is consistently wide and unaffected by respiration. This finding is observed in the presence of an ostium secundum atrial septal defect or right ventricular failure. Paradoxical splitting of S2 occurs when P2 precedes A2. This leads to splitting with expiration and a single S2 with inspiration. It is commonly found in situations of delayed electrical activation of the left ventricle, as in patients with left bundle branch block or right ventricular pacing. It can also be seen with prolonged mechanical contraction of the left ventricle, as in patients with aortic stenosis or hypertrophic cardiomyopathy. The third heart sound, S3, is a low-pitched sound heard best at the apex in mid diastole. Because it is low pitched, it is best recognized with use of the bell on the stethoscope. As stated previously, S3 can be physiologic in children but is pathologic in older individuals and often associated with underlying cardiac disease. An S3 occurs during the rapid filling phase of diastole and is thought to indicate a sudden limitation of the expansion of the left ventricle. This can be seen in cases of volume overload or tachycardia. Maneuvers that increase venous return accentuate an S3, whereas those that reduce venous return diminish the intensity. The fourth heart sound, S4, is also a low-frequency sound, but in contrast to S3, it is heard in late diastole, just before S1. The S4 gallop occurs as a result of active ejection of blood into a noncompliant left ventricle. Therefore, when atrial contraction is absent, such as in atrial fibrillation, an S4 cannot be heard. This heart sound is also best recognized with the use of a bell at the apex. It can be heard in patients with left ventricular hypertrophy, acute myocardial infarction,

or hyperdynamic left ventricle. At times, an S3 and an S4 can be heard in the same patient. In tachycardic states, the two sounds can fuse in mid diastole to form a summation gallop. S3 and S4 gallops are heard in mid diastole and late diastole, respectively. There are other abnormal sounds that can be heard during systole and early diastole. Ejection sounds are typically heard in early systole and involve the aortic and pulmonic valves. These are high-frequency sounds that can be heard with a diaphragm shortly after S1.

ECG S1 S2

S1 Loud S2 S1

Pulmonic stenosis Systemic hypertension Coronary artery disease Any condition that can lead to paradoxical splitting of S2

S1

S2

S4 gallop S3-4 Summation gallop

S1

S1

S2 Expiration

S2 A P

Physiologic splitting Inspiration

S1

A

P Expiration

S1

A

P Inspiration

A

P

A

P

Fixed Split S2

Paradoxically Split S2

P

A

Left bundle branch block Right ventricular pacing Angina, myocardial infarction Aortic stenosis Hypertrophic cardiomyopathy Aortic regurgitation

Abnormally wide but physiologic splitting

Expiration Fixed splitting

S1

Right bundle Atrial septal branch block defect Left ventricular pacing Severe right Pulmonic stenosis ventricular Pulmonary dysfunction embolism Idiopathic dilation of the pulmonary artery Mitral regurgitation Ventricular septal defect

S2, Second heart sound.

S3 gallop S2

S4

TABLE 3.6  Abnormal Splitting of S2

Single S2

S2 S3

S1

S1

Widely Split S2 With Normal Respiratory Variation

Loud S1

S2

Inspiration S1

Expiration S2

Paradoxical splitting

S1 Inspiration

First Second heart heart sound sound Fig. 3.3  Abnormal heart sounds can be related to abnormal intensity, abnormal presence of a gallop rhythm, or abnormal splitting of the second heart sound (S2) with respiration. A2, Component of S2 caused by closure of aortic valve; ECG, electrocardiogram; P2, component of S2 caused by closure of pulmonic valve.

CHAPTER 3  Evaluation of the Patient With Cardiovascular Disease

21

TABLE 3.7  Grading System for Intensity of

Murmurs

M1 T1

A2 P2

Grade

Description

1 2 3 4 5

Barely audible murmur Murmur of medium intensity Loud murmur, no thrill Loud murmur with thrill Very loud murmur; stethoscope must be on the chest to hear it; may be heard posteriorly Murmur audible with stethoscope off the chest

6 S4

S1 ES First heart sound (S1)

C

S2 OS S3 Second heart sound (S2)

Fig. 3.4  The relationship of extra heart sounds to the normal first (S1) and second (S2) heart sounds. S1 is composed of the mitral (M1) and tricuspid (T1) closing sounds, although it is frequently perceived as a single sound. S2 is composed of the aortic (A2) and pulmonic (P2) closing sounds, which are usually easily distinguished. A fourth heart sound (S4) is soft and low pitched and precedes S1. A pulmonic or aortic ejection sound (ES) occurs shortly after S1. The systolic click (C) of mitral valve prolapse may be heard in mid systole or late systole. The opening snap (OS) of mitral stenosis is high pitched and occurs shortly after S2. A tumor plop or pericardial knock occurs at the same time and can be confused with an OS or an S3, which is lower in pitch and occurs slightly later.

Ejection sounds are caused by the opening of abnormal valves to their full extent, such as with a bicuspid aortic valve or congenital pulmonic stenosis. They are frequently followed by a typical ejection murmur of aortic or pulmonic stenosis. Ejection sounds can also be heard with systemic or pulmonary hypertension, in which case the exact mechanism is not clear. Midsystolic to late systolic sounds are called ejection clicks. They are most commonly associated with mitral valve prolapse. They are also high pitched and easily auscultated with the diaphragm. The click occurs because of maximal displacement of the prolapsed mitral leaflet into the left atrium and resultant tensing of chordae and redundant leaflets (Audio Clip 3.2, Mitral Valve Prolapse). The click is usually followed by a typical murmur of mitral regurgitation. Any maneuver that decreases venous return will cause the click to occur earlier in systole, whereas increasing ventricular volume will delay the click (see Table 3.4). The opening of abnormal mitral or tricuspid valves can be heard in early diastole. This opening snap is most frequently associated with rheumatic mitral stenosis. It is heard if the valve leaflets remain pliable and is generated when the leaflets abruptly dome during diastole. The frequency, intensity, and timing of the click have diagnostic significance. For example, the shorter the interval between S2 and the opening snap, the more severe the degree of mitral stenosis, because this is a reflection of higher left atrial pressure. The pericardial knock of constrictive pericarditis and tumor plop generated by an atrial myxoma also occur in early diastole and may be confused with an opening snap. They can typically be differentiated from an S3 gallop because they are higher-frequency sounds.

Murmurs Murmurs are a series of auditory vibrations generated by either abnormal blood flow across a normal cardiac structure or normal flow across an abnormal cardiac structure, both of which result in turbulent flow.

These sounds are longer than individual heart sounds and should be described on the basis of their location, frequency, intensity, quality, duration, shape, and timing in the cardiac cycle. The intensity of a given murmur is typically graded on a scale of 1 to 6 (Table 3.7). Murmurs of grade 4 or higher are associated with palpable thrills. The intensity or loudness of a murmur does not necessarily correlate with the severity of disease. For example, a murmur can be quite harsh when it is associated with a moderate degree of aortic stenosis. If stenosis is critical, however, the flow across the valve is diminished and the murmur becomes rather quiet. In the presence of a large atrial septal defect, flow is almost silent, whereas flow through a small ventricular septal defect is typically associated with a loud murmur. The frequency of a murmur can be high or low; higher-frequency murmurs are more correlated with high velocity of flow at the site of turbulence. It is also important to notice the configuration or shape of a murmur, such as crescendo, crescendo-decrescendo, decrescendo, or plateau (Fig. 3.5). The quality of a murmur (e.g., harsh, blowing, rumbling) and the pattern of radiation are also helpful in diagnosis. Physical maneuvers can sometimes help clarify the nature of a particular murmur (see Table 3.4). Murmurs can be divided into three different categories (Table 3.8). Systolic murmurs begin with or after S1 and end with or before S2. Diastolic murmurs begin with or after S2 and end with or before S1. Continuous murmurs begin in systole and continue through diastole. Murmurs can result from abnormalities on the left or right side of the heart or in the great vessels. Right-sided murmurs become louder with inspiration because of increased venous return. This can help differentiate them from left-sided murmurs, which are unaffected by respiration. Systolic murmurs should be further differentiated based on timing (i.e., early systolic, midsystolic, late systolic, and holosystolic murmurs). Early systolic murmurs begin with S1, are decrescendo, and end typically before mid systole. Ventricular septal defects and acute mitral regurgitation may lead to early systolic murmurs. Midsystolic murmurs begin after S1 and end before S2, often in a crescendo-­ decrescendo shape. They are typically caused by obstruction to left ventricular outflow, accelerated flow through the aortic or pulmonic valve, or enlargement of the aortic root or pulmonary trunk. Aortic stenosis, when less than severe in degree, causes a midsystolic murmur that may be harsh and may radiate to the carotids. Pulmonic stenosis leads to a similar murmur that does not radiate to the carotid arteries but may change with inspiration. The murmur of hypertrophic cardiomyopathy may be mistaken for aortic stenosis; however, it does not radiate to the carotids and becomes exaggerated with diminished venous return. Innocent or benign murmurs may also occur as a result of aortic valve sclerosis, vibrations of a left ventricular false tendon, or vibration of normal pulmonary leaflets. They are generally less

Aorta

AVO

MVO LA LV

S1 E Systolic ejection murmur Holosystolic regurgitant murmur

S2

OS

S1 E

S1

S2

S1

S1

S2

S1

Diastolic rumbling murmur of mitral stenosis

Decrescendo diastolic murmur

Fig. 3.5  Abnormal sounds and murmurs associated with valvular dysfunction displayed simultaneously with left atrial (LA), left ventricular (LV), and aortic pressure tracings. The shaded areas represent pressure gradients across the aortic valve during systole or across mitral valve during diastole; they are characteristic of aortic stenosis and mitral stenosis, respectively. AVO, Aortic valve opening; E, ejection click of the aortic valve; MVO, mitral valve opening; OS, opening snap of the mitral valve; S1, first heart sound; S2, second heart sound.

TABLE 3.8  Classification of Heart Murmurs Class Systolic Ejection

Description

Characteristic Lesions

Begins in early systole; may extend to mid or late systole Crescendo-decrescendo pattern Often harsh in quality Begins after S1 and ends before S2

Valvular, supravalvular, and subvalvular aortic stenoses Hypertrophic cardiomyopathy Pulmonic stenosis Aortic or pulmonary artery dilation Malformed but nonobstructive aortic valve ↑ Transvalvular flow (e.g., aortic regurgitation, hyperkinetic states, atrial septal defect, physiologic flow murmur) Mitral regurgitation Tricuspid regurgitation Ventricular septal defect Mitral valve prolapse

Holosystolic

Extends throughout systolea Relatively uniform in intensity

Late

Variable onset and duration, often preceded by a nonejection click

Diastolic Early

Mid

Late

Begins with A2 or P2 Decrescendo pattern with variable duration Often high pitched, blowing Begins after S2, often after an opening snap Low-pitched rumble heard best with bell of stethoscope Louder with exercise and left lateral position Loudest in early diastole Presystolic accentuation of mid-diastolic murmur

Aortic regurgitation Pulmonic regurgitation

Systolic and diastolic components “Machinery murmurs”

Patent ductus arteriosus Coronary atrioventricular fistula Ruptured sinus of Valsalva aneurysm into right atrium or ventricle Mammary soufflé Venous hum

Mitral stenosis Tricuspid stenosis ↑ Flow across atrioventricular valves (e.g., mitral regurgitation, tricuspid regurgitation, atrial septal defect) Mitral stenosis Tricuspid stenosis

Continuous

A2, Component of S2 caused by closure of aortic valve; P2, component of S2 caused by closure of pulmonic valve; S1, first heart sound; S2, second heart sound. aEncompasses both S and S . 1 2

CHAPTER 3  Evaluation of the Patient With Cardiovascular Disease harsh and shorter in duration. High-flow states such as those found in patients with fever, during pregnancy, or with anemia may also lead to midsystolic “flow” murmurs. Holosystolic murmurs begin with S1 and end with S2; the classic examples are the murmurs associated with mitral regurgitation and tricuspid regurgitation. They may also occur with ventricular septal defects and patent ductus arteriosus. Late systolic murmurs begin in mid to late systole and end with S2. They can be characteristic of more severe aortic stenosis and are also typical of murmurs associated with mitral valve prolapse. Diastolic murmurs are also classified by timing (i.e., early diastolic, mid diastolic, and late diastolic). Early diastolic murmurs begin with S2 and can result from aortic or pulmonic regurgitation; they are usually decrescendo in shape. Shorter and quieter murmurs typically represent an acute process or mild regurgitation, whereas longer-lasting and louder murmurs are likely due to more severe regurgitation. Middiastolic murmurs begin after S2 and are usually caused by mitral or tricuspid stenosis. They are low pitched and are often referred to as diastolic rumbles. Because they are of low frequency, they are better auscultated with the bell of the stethoscope. Similar murmurs can be heard with obstructing atrial myxomas. Severe chronic aortic insufficiency can lead to premature closure of the mitral valve, causing a mid-diastolic rumble called an Austin-Flint murmur. Late diastolic murmurs occur immediately before S1 and reflect presystolic accentuation of the mid-diastolic murmurs resulting from augmented mitral or tricuspid flow after atrial contraction. Continuous murmurs begin with S1 and last though part or all of diastole. They are generated by continuous flow from a vessel or chamber with high pressure into a vessel or chamber with lower pressure. They are referred to as machinery murmurs and are caused by aortopulmonary connections such as a patent ductus arteriosus, AV malformations, or disturbances of flow in arteries or veins.

Other Cardiac Sounds Pericardial rubs occur in the setting of pericarditis and are coarse, scratching sounds similar to rubbing leather. They are typically heard best at the left sternal border with the patient leaning forward and holding the breath at end-expiration. A classic pericardial rub has three components: atrial systole, ventricular systole, and ventricular diastole. One might also hear a pleural rub caused by localized irritation of surrounding pleura. Continuous venous murmurs, or venous hums, are almost always present in children. They can be heard in adults during pregnancy, in the setting of anemia, or with thyrotoxicosis. They are heard best at the base of the neck with the patient’s head turned to the opposite direction.

Prosthetic Heart Sounds Prosthetic heart valves produce characteristic findings on auscultation. Bioprosthetic valves produce sounds that are similar to those of native heart valves, but they are typically smaller than the valves that they replace and therefore have an associated murmur. Mechanical valves have crisp, high-pitched sounds related to valve opening and closure. In most modern valves such as the St. Jude valve, which is a bileaflet mechanical valve, the closure sound is louder than the opening sound.

23

An ejection murmur is common. If there is a change in murmur or in the intensity of the mechanical valve closure sound, dysfunction of the valve should be suspected. For a deeper discussion of this topic, please see Chapter 45, “Approach to the Patient with Possible Cardiovascular Disease,” in Goldman-Cecil Medicine, 26th Edition.

SUGGESTED READINGS Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services: Total expenses and percent distribution for selected conditions by type of service: United States, 2008. Medical Expenditure Panel Survey: Household Component Summary Tables. Available at: http:// www.meps.ahrq.gov/mepsweb/data_stats/quick_tables_search.jsp? component=1&subcomponent=0. Accessed August 5, 2014. Calkins H, Shyr Y, Frumin H, et al: The value of the clinical history in the differentiation of syncope due to ventricular tachycardia, atrioventricular block, and neurocardiogenic syncope, Am J Med 98:365–373, 1995. Go AS: The epidemiology of atrial fibrillation in elderly persons: the tip of the iceberg, Am J Geriatr Cardiol 14:56–61, 2005. Goldman L, Ausiello D: Cecil Medicine: part VIII. Cardiovascular disease, Philadelphia, 2012, Saunders. Heart Disease Fact Sheet. CDC Division for Heart Disease and Stroke Prevention. https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_heart_ disease.htm. Hirsch AT, Criqui MH, Treat-Jacobson D, et al: Peripheral arterial disease: detection, awareness, and treatment in primary care, JAMA 286:1317–1324, 2001. Hoffman JI, Kaplan S, Liberthson RR: Prevalence of congenital heart disease, Am Heart J 147:425–439, 2004. National Heart, Lung and Blood Institute, National Institutes of Health. Unpublished tabulations of National Vital Statistics System mortality data. 2008. Available at: http://www.cdc.gov/nchs/nvss/mortality_public_use_ data.htm. Accessed August 5, 2014. National Heart, Lung and Blood Institute, National Institutes of Health, ­Unpublished tabulations of National Hospital Discharge Survey, 2009. Available at http://www.cdc.gov/nchs/nhds/nhds_questionnaires.htm. Accessed August 5, 2014. National Heart, Lung and Blood Institute. Unpublished tabulations of ­ National Health Interview Survey, 1965-2010. Available at: http://www. cdc.gov/nchs/nhis/nhis_questionnaires.htm. Accessed August 5, 2014. National Heart, Lung and Blood Institute, National Institutes of Health. Morbidity and mortality: 2012 Chart book on cardiovascular, lung, and blood diseases. Available at https://www.nhlbi.nih.gov/research/reports/ 2012-mortality-chart-book.htm. Accessed September 26, 2014. National Vital Statistics System, Centers for Disease Control and Prevention: Mortality tables. Available at http://www.cdc.gov/nchs/nvss/mortality_ tables.htm. Accessed August 5, 2014. Pickering TG, Hall JE, Appel LJ, et al: Recommendations for blood ­pressure ­measurement in humans and experimental animals: part 1. Blood pressure measurement in humans: a statement for professionals from the ­Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research, Circulation 111:697–716, 2005.

4 Diagnostic Tests and Procedures in the Patient With Cardiovascular Disease Esseim Sharma, Alan R. Morrison

ELECTROCARDIOGRAPHY The electrocardiogram (ECG) is one of the most basic yet powerful diagnostic tools in cardiovascular medicine. It is critical in the investigation of cardiac arrhythmias, myocardial infarction, and pericardial disease, and may provide additional insight into a variety of other cardiac and noncardiac conditions. The ECG is a simple and noninvasive procedure that makes use of electrodes placed on the skin of the chest at specific locations in order to measure the electrical activity of the heart. The output is a scroll of wave forms represented as a temporal sequence of deflections on the ECG (Fig. 4.1). The horizontal axis of the graph paper represents time, and at a standard paper speed of 25 mm/second, which is also known as the sweep speed, each small box (1 mm) represents 0.04 seconds, and each large box (5 mm) represents 0.20 seconds. The vertical axis represents voltage or amplitude (1 mm = 0.1 mV). Because the standard ECG demonstrates a 10-second window of time, the heart rate can be calculated by simply counting the number of QRS complexes and multiplying by 6. Alternatively, the heart rate can be estimated by dividing the number of large boxes between complexes (i.e., R-R interval) into 300.

Lead Positioning The standard ECG consists of 12 leads: six limb leads (I, II, III, aVR, aVL, and aVF) and six chest or precordial leads (V1 to V6) (Fig. 4.2). The limb leads view the electrical activity of the heart in the vertical plane, while the precordial leads view the horizontal plane. The electrical activity recorded in each lead represents the direction and magnitude (i.e., vector) of the electrical force as seen from that lead position. Electrical activity directed toward a particular lead is represented as an upward (positive) deflection, and electrical activity directed away from a particular lead is represented as a downward (negative) deflection. Accurate lead placement is essential to reliable interpretation of the ECG. The limb leads consist of bipolar leads (I, II, and III) and unipolar or augmented leads (leads aVR, aVL, and aVF). The bipolar leads represent electrical forces between the two leads, while augmented leads represent the electrical forces towards the lead. Lead I measures electrical activity between the right and left arms (left arm positive), lead II between the right arm and left leg (left leg positive), and lead III between the left arm and left leg (left leg positive). A vector perpendicular to the limb leads would be isoelectric. In aVR, aVL, and aVF, the vector is positive if electrical forces are directed toward the right arm for aVR, left arm for aVL, and left leg for aVF. Taken together, the six limb leads form a frontal plane of 30-degree arc intervals (Fig. 4.3). The six standard precordial leads (V1 to V6) are attached to the anterior chest wall and are also unipolar leads. Lead placement

24

should be as follows: V1: fourth intercostal space, right sternal border; V2: fourth intercostal space, left sternal border; V3: midway between V2 and V4; V4: fifth intercostal space, left midclavicular line; V5: level with V4, left anterior axillary line; V6: level with V4, left midaxillary line. Nonstandard lead configurations can be used in specific clinical scenarios. In patients where there is concern for right ventricular infarction, standard V1 and V2 leads are switched, and V3R to V6R are placed at locations on the right chest wall in a mirror image of the standard left-sided chest leads. Posterior leads may be used to increase the sensitivity for diagnosing lateral and posterior wall infarction or ischemia—areas that are often deemed to be electrically silent on traditional 12-lead ECGs. To do this, six additional leads are placed in the fifth intercostal space continuing posteriorly from the position of V6. Shifting the right precordial leads (V1-V3) superiorly to the second intercostal space can be used to unmask Brugada syndrome.

Electrocardiographic Intervals In the normal heart, the electrical impulse originates in the sinoatrial (SA) node, located superiorly in the right atrium, and is conducted through the atria. Given that depolarization of the SA node is too weak to be detected on the surface ECG, the first, low-amplitude deflection on the surface ECG represents a summation atrial vector and is called the P wave. The P wave has an electrical axis that moves in sum toward the AV node, generally downward and to the left. The interval between the onset of the P wave and the next rapid deflection (QRS complex) is known as the PR interval. It primarily represents the time taken for the impulse to travel through the atrioventricular (AV) node. The normal PR segment ranges from 0.12 to 0.20 seconds. A PR interval greater than 0.20 seconds defines first-degree AV nodal block. After the wave of depolarization has moved through the AV node, the ventricular myocardium is depolarized in a sequence of four phases. The interventricular septum depolarizes from left to right. This phase is followed by depolarization of the right ventricle and inferior wall of the left ventricle, then the apex and central portions of the left ventricle, and finally the base and the posterior wall of the left ventricle. Ventricular depolarization results in a high-amplitude complex on the surface ECG known as the QRS complex. The first downward deflection of this complex is the Q wave, the first upward deflection is the R wave, and the subsequent downward deflection is the S wave. In some individuals, a second upward deflection may occur after the S wave, and it is called R prime (R′). Normal duration of the QRS complex is less than 0.10 second. Complexes longer than 0.12 seconds in duration are usually secondary to some form of interventricular conduction delay, including right or left bundle branch block.

CHAPTER 4  Diagnostic Tests and Procedures in the Patient With Cardiovascular Disease The isoelectric segment after the QRS complex is the ST segment, which represents a brief period during which relatively little electrical activity occurs in the heart. The junction between the end of the QRS complex and the beginning of the ST segment is the J point. The upward deflection after the ST segment is the T wave, which represents ventricular repolarization. The QT interval, which reflects the duration and transmural gradient of ventricular depolarization and repolarization, is measured from the onset of the QRS complex to the end of the T wave. The observed QT (QTob) interval varies with heart rate, but for rates between 60 and 100 beats/minute, the normal QT interval ranges from 0.35 to 0.44 seconds. For heart rates outside this range, the QT interval can be corrected (QTc) using the following formula (with R-R interval in seconds): QTc =

QTob

√R − R interval

Importantly, patients with interventricular conduction delay due to the presence of bundle branch blocks or pacing will have prolonged QT intervals due to the dispersion of ventricular repolarization, which

0.2 sec 0.04 sec

1 mv

R

T P

PR interval

ST Q S segment QT interval

Fig. 4.1 Normal electrocardiographic complex with labeling of waves and intervals.

25

is not necessarily pathologic. Adjustment of the QT interval in these cases remains controversial. The TP segment is the isoelectric interval that follows the end of the T wave and lasts till the beginning of the P wave. Because it represents an electrically silent portion of the ECG, the TP segment can be used to measure excursions of other segments, such as the ST or PR segments, to determine the presence of elevation or depression. In some individuals, the T wave may be closely followed by a U wave (0.5 mm deflection, not shown in Fig. 4.1), which can be seen for a variety of reasons, including hypokalemia and central nervous system abnormalities.

Axis The cardiac axis refers to the overall direction of myocardial depolarization measured in the vertical plane and provides clinically useful information. Though the axis can be calculated for any of the ECG segments mentioned above, the mean QRS axis is the most clinically useful. Fig. 4.3 illustrates the axial reference system, a reconstruction of the Einthoven triangle, and the polarity of each of the six limb leads of the standard ECG. The normal QRS axis ranges from −30 to +90 degrees. An axis more negative than −30 defines left axis deviation, and an axis greater than +90 defines right axis deviation. Extreme axis deviation is present when the mean QRS axis is between −90 and +180 degrees. A positive QRS complex in leads I and aVF suggests a normal QRS axis between 0 and 90 degrees. While the precordial leads are not useful in determining cardiac axis, they are helpful in determining the direction of cardiac activation in the horizontal plane. Normally, a small R wave occurs in lead V1, reflecting septal depolarization, along with a deep S wave, reflecting predominantly left ventricular activation. From V1 to V6, the R wave becomes larger (and the S wave smaller) because the predominant forces directed at these leads originate from the left ventricle. The transition from a predominant S wave to a predominant R wave usually occurs between leads V3 and V4. A delay in this transition is termed “poor R wave progression” and can be seen in patients with prior anterior myocardial infarctions, among other conditions. In patients with ventricular arrhythmias, the pattern of S and R waves in the precordial leads is essential in localizing the foci of the arrhythmia.

I

aVR

V1

V4

II

aVL

V2

V5

III

aVF

V3

V6

Fig. 4.2  Normal 12-lead electrocardiogram.

26

SECTION II  Cardiovascular Disease Left-axis −90° −120°

dev iati on ( −60°

ABNORMAL ELECTROCARDIOGRAPHIC PATTERNS Chamber Abnormalities and Ventricular Hypertrophy

−3 0° to −9

viation (+90° t o −9 xis de 0°)

) 0°

−30°

−150° aVL

aVR

− +180°

0°

II

+30°

+60°

+120°

(−3 0° to +

aVF

tio n

III

+150°

de via

ht a Rig

90°)

I

No

+90°

is ax

Fig. 4.3  Hexaxial reference figure for frontal plane axis determination, indicating values for abnormal left and right QRS axis deviations.

Because of the downward and leftward vector direction, the P wave is normally upright in leads I, II, and aVF, inverted in aVR, and biphasic in V1. Left atrial abnormality (i.e., enlargement, hypertrophy, or increased wall stress) is characterized by a wide P wave in lead II (0.12 second) and a deeply inverted terminal component in lead V1 (able to contain one small box or 1 mm2). Right atrial abnormality is identified when the P waves in the limb leads are tall and peaked and at least 2.5 mm high and (able to contain two stacked small boxes). Left ventricular hypertrophy may result in increased QRS voltage, slight widening of the QRS complex, late intrinsicoid deflection, left axis deviation, and abnormalities of the ST-T segments (Fig. 4.4A). Multiple criteria with various degrees of sensitivity and specificity for detecting left ventricular hypertrophy are available. The most frequently used criteria are given in Table 4.1. Right ventricular hypertrophy is characterized by tall R waves in leads V1 through V3; deep S waves in leads I, aVL, V5, and V6; and right axis deviation (see Fig. 4.4B). The R wave is greater than 7 mm and the R-S ratio is greater than 1 in lead V1. Other causes of a tall R-wave in V1 must be excluded, including posterior wall myocardial infarction,

I

aVR

V1

V4

II

aVL

V2

V5

III

aVF

V3

V6

A

I

aVR

V1

V4

II

aVL

V2

V5

III

aVF

V3

V6

B Fig. 4.4  (A) Left ventricular hypertrophy as seen on an electrocardiographic recording. Characteristic findings include increased QRS voltage in precordial leads (i.e., deep S in lead V2 and tall R in lead V5) and downsloping ST depression and T-wave inversion in lateral precordial leads (i.e., strain pattern) and leftward axis. (B) Right ventricular hypertrophy with tall R wave in right precordial leads, downsloping ST depression in precordial leads (i.e., RV strain), right axis deviation, and evidence of right atrial enlargement.

CHAPTER 4  Diagnostic Tests and Procedures in the Patient With Cardiovascular Disease

TABLE 4.1 Electrocardiographic

TABLE 4.2 Electrocardiographic

Left Atrial Abnormality P-wave duration ≥0.12 second Notched, slurred P wave in leads I and II Biphasic P wave in lead V1 with a wide, deep, negative terminal component

Left Anterior Fascicular Block QRS duration ≤0.1 second Left axis deviation (more negative than −45 degrees) rS pattern in leads II, III, and aVF qR pattern in leads I and aVL

Manifestations of Atrial Abnormalities and Ventricular Hypertrophy

Right Atrial Abnormality P-wave duration ≤0.11 second Tall, peaked P waves of ≥2.5 mm in leads II, III, and aVF Left Ventricular Hypertrophy Voltage criteria R wave in lead aVL ≥12 mm R wave in lead I ≥15 mm S wave in lead V1 or V2 + R wave in lead V5 or V6 ≥35 mm Depressed ST segments with inverted T waves in the lateral leads Left axis deviation QRS duration ≥0.09 second Left atrial enlargement Right Ventricular Hypertrophy Tall R waves over right precordium (R-to-S ratio in lead V1 >1.0) Right axis deviation Depressed ST segments with inverted T waves in leads V1 to V3 Normal QRS duration (if no right bundle branch block) Right atrial enlargement

Wolff-Parkinson-White, right bundle branch block, muscular dystrophy, dextrocardia, and lead misplacement.

Interventricular Conduction Delays The ventricular conduction system consists of two main branches, the right and left bundles. The left bundle further divides into the anterior and posterior fascicles. Conduction block can occur in either of the major branches or in the fascicles (Table 4.2). Fascicular block results in a change in the sequence of ventricular activation but does not substantially prolong overall conduction time. Left anterior fascicular block abnormality is identified when extreme left axis deviation occurs (i.e., more negative than −45 degrees), when the R wave is greater than the Q wave in leads I and aVL, and when the S wave is greater than the R wave in leads II, III, and aVF. Left posterior fascicular block is relatively uncommon but is associated with right axis deviation (>90 degrees); small Q waves in leads II, III, and aVF; and small R waves in leads I and aVL. Fascicular blocks can be seen in conjunction with right bundle branch block (RBBB), and left or right axis deviations can indicate concurrent left anterior or posterior fascicular blocks, respectively. Complete bundle branch blocks cause QRS prolongation greater than 120 milliseconds. A left bundle branch block (LBBB) can be indicative of underlying coronary or myocardial disease—most commonly fibrosis due to ischemic injury or hypertrophy. In LBBB, depolarization proceeds down the right bundle, across the interventricular septum from right to left, and then to the left ventricle. Characteristic electrocardiographic findings include a wide QRS complex; a broad R wave in leads I, aVL, V5, and V6; a deep QS wave in leads V1 and V2; and ST depression and T-wave inversion opposite the terminal deflection of the QRS (Fig. 4.5A). Given the

27

Manifestations of Fascicular and Bundle Branch Blocks

Right Posterior Fascicular Block QRS duration ≤0.1 second Right axis deviation (+90 degrees or greater) qR pattern in leads II, III, and aVF rS pattern in leads I and aVL Exclusion of other causes of right axis deviation (e.g., chronic obstructive pulmonary disease, right ventricular hypertrophy) Left Bundle Branch Block QRS duration ≥0.12 second Broad, slurred, or notched R waves in lateral leads (I, aVL, V5, and V6) QS or rS pattern in anterior precordium leads (V1 and V2) ST-T-wave vectors opposite to terminal QRS vectors Right Bundle Branch Block QRS duration ≥0.12 second Large R′ wave in lead V1 (rsR′) Deep terminal S wave in lead V6 Normal septal Q waves Inverted T waves in leads V1 and V2

abnormal sequence of ventricular activation and repolarization with LBBB, many ECG abnormalities, such as Q-wave myocardial infarction (MI) and left ventricular hypertrophy, are difficult to evaluate. Sgarbossa’s criteria can help to identify the presence of MI in the setting of LBBB, though its sensitivity is limited. A new LBBB may be a sign of an acute myocardial infarction in the correct clinical setting (Fig. 4.6B). With RBBB, the interventricular septum depolarizes normally from left to right, as this depolarization depends on the left bundle. Thus, the initial QRS deflection remains unchanged, and thus it is important to note that ECG abnormalities such as Q-wave MI can still be interpreted. After septal activation, the left ventricle depolarizes, followed by the right ventricle. The ECG is characterized by a wide QRS complex; a large R′ wave in lead V1 (R-S-R′); and deep S waves in leads I, aVL, and V6, representing delayed right ventricular activation (see Fig. 4.5B). Ventricular repolarization is still abnormal, and secondary ST and T wave changes will be present just as in LBBB. Although RBBB may be associated with underlying cardiac disease, it is quite common and may often reflect the fibrosis of aging.

Myocardial Ischemia and Infarction Myocardial ischemia and myocardial infarction (MI) may be associated with abnormalities of the ST segment, T wave, and QRS complex. Myocardial ischemia primarily affects repolarization of the myocardium and is often associated with horizontal or downsloping ST-segment depression and T-wave inversion. These changes may be transient, such as during an anginal episode or an exercise-related stress, or they may be long-lasting in the setting of progressive angina or MI. T-wave inversion without ST-segment depression can be a nonspecific finding and must be correlated with the clinical findings

28

SECTION II  Cardiovascular Disease

A

B

Left bundle branch block

Right bundle branch block

I

II

III

I

II

III

aVR

aVL

aVF

aVR

aVL

aVF

V1

V2

V3

V1

V2

V3

V4

V5

V6

V4

V5

V6

Diagnostic criteria for LBBB

Diagnostic criteria for RBBB

QRS duration > 0.125 seconds Broad R wave in I, aVL,V5–V6 Deep QS complex as in V1–V2 T-wave inversion in lateral leads

QRS duration > 0.125 seconds R > S in V1 RSR in V1 Deep wide S wave in I and V6

Fig. 4.5  (A) Left bundle branch block (LBBB). (B) Right bundle branch block (RBBB). Criteria for bundle branch blocks are summarized in Table 4.2.

to invoke ischemia or injury. Diffuse T-wave inversions across the precordial leads are often seen in patients with acute cerebral disease, such as stroke or seizures. ST-segment elevation of 2 mm or more in two or more contiguous leads suggests more extensive myocardial injury, and in the right clinical presentation, is often considered to be an acute MI until proven otherwise (Fig. 4.6A). Vasospastic or Prinzmetal angina may be associated with reversible ST-segment elevation without MI. ST-segment elevation may occur in other settings not related to acute ischemia or infarction. Persistent, localized ST-segment elevation in the same leads as pathologic Q waves is consistent with a ventricular aneurysm. Acute pericarditis is also associated with diffuse ST-segment elevation across multiple contiguous and noncontiguous leads but is also associated with PR depression relative to the TP interval. Diffuse J-point elevation in association with upward-coving ST segments is a normal variant common among young men and is often referred to as early repolarization. A pathologic Q wave is one of the criteria used to diagnose MI. Infarcted myocardium is impaired at conducting normal electrical activity, and electrical forces are directed away from the surface electrode overlying the infarcted region, producing a Q wave on the surface ECG. A thorough understanding of contiguous leads allows for identification of each region of the myocardium relative to the surface lead, enabling the examiner to localize the area of infarction (Table

4.3). Pathologic Q waves are defined as follows: any Q wave 20 ms or greater or QS complex in leads V2 to V3, or a Q wave 30 ms or greater and 0.1 mV deep or greater or QS complex in leads I, II, aVL, aVF or V4 to V6 in any 2 leads of a contiguous lead grouping (I, aVL, V6; V4 to V6; II, III, and aVF). Not all MIs result in the permanent formation of Q waves. Small R waves can return many weeks to months after an MI. Abnormal Q waves, or pseudoinfarction pattern, may be associated with nonischemic cardiac disease, such as ventricular preexcitation, cardiac amyloidosis, sarcoidosis, idiopathic or hypertrophic cardiomyopathy, myocarditis, and chronic lung disease.

Abnormalities of the ST Segment and T Wave A number of drugs and metabolic abnormalities may affect the ST segment and T wave (Fig. 4.7). Hypokalemia may result in prominent U waves in the precordial leads along with prolongation of the QT interval. Hyperkalemia may result in tall, peaked T waves. Hypocalcemia typically lengthens the QT interval, whereas hypercalcemia shortens it. A commonly used cardiac medication, digoxin, often results in diffuse, scooped ST-segment depression. Cardiac pacing, LBBB, and RBBB affect ventricular repolarization and alter the ST segment and T-wave. Minor or nonspecific ST-segment and T-wave abnormalities may occur in many patients and have no definable cause. In these instances, the physician must determine the significance of the abnormalities based on clinical findings.

I

II

III

aVR

aVL

aVF

V1

V2

V3

V4

V5

V6

Control

2 hours later

24 hours later

48 hours later

8 days later

6 months later

A

I

aVR

V1

V4

II

aVL

V2

V5

III

aVF

V3

V6

V1

III

B Fig. 4.6  (A) Evolutionary changes in a posteroinferior myocardial infarction (MI). Control tracing is normal. The tracing recorded 2 hours after onset of chest pain demonstrated development of early Q waves, marked ST-segment elevation, and hyperacute T waves in leads II, III, and aVF. A larger R wave, ST-segment depression, and negative T waves have developed in leads V1 and V2. These early changes indicate acute posteroinferior MI. The 24-hour tracing demonstrates further evolutionary changes. In leads II, III, and aVF, the Q wave is larger, the ST segments have almost returned to baseline, and the T wave has begun to invert. In leads V1 to V2, the duration of the R wave exceeds 0.04 seconds, the ST segment is depressed, and the T wave is upright. (In this example, electrocardiographic changes of true posterior involvement extend past lead V2; ordinarily, only leads V1 and V2 may be involved.) Only minor further changes occur through the 8-day tracing. Six months later, the electrocardiographic pattern shows large Q waves, isoelectric ST segments, and inverted T waves in leads II, III, and aVF and shows large R waves, isoelectric ST segment, and upright T waves in leads V1 and V2, indicative of an old posteroinferior MI. (B) Electrocardiogram from a patient with an underlying left bundle branch block (LBBB) who experienced an acute anterior MI. Characteristic ST segment elevation and hyperacute T waves are seen in leads V1 through V6 and leads I and aVL despite the presence of the LBBB. This is not always the case, and a patient with typical symptoms, an LBBB, and no definite ischemic ST-segment elevations should be treated as if the individual is having a myocardial infarction or acute coronary syndrome.

29

30

SECTION II  Cardiovascular Disease

TABLE 4.3  Electrocardiographic Localization of Myocardial Infarction Infarct Location

Leads Depicting Primary Electrocardiographic Changes

Likely Vessel Involveda

Inferior Septal Anterior Anteroseptal Extensive anterior Lateral High lateral Posteriorb Right ventricularc

II, III, aVF V1, V2 V3, V4 V1 to V4 I, aVL, V1 to V6 I, aVL, V5 to V6 I, aVL Prominent R in V1 ST elevation in V1; more specifically, V4R in setting of inferior infarction

RCA LAD LAD LAD LAD CIRC CIRC RCA or CIRC RCA

CIRC, Circumflex artery; LAD, left anterior descending coronary artery; RCA, right coronary artery. aThis is a generalization; variations occur. bUsually in association with inferior or lateral infarction. cUsually in association with inferior infarction.

Normal

Hyperkalemia

Hypokalemia

Hypercalcemia Hypocalcemia Hypothermia

Digitalis

Quinidine Procainamide Disopyramide Phenothiazines Tricyclic antidepressants CNS insult (e.g., intracerebral hemorrhage)

Mild to moderate (K = 5-7 mEq/L): Tall, symmetrically peaked T waves with a narrow base More severe (K = 8-11 mEq/L): QRS widens, PR segment prolongs, P wave disappears; ECG resembles a sine wave in severe cases ST depression T-wave flattening Large positive U wave, QT prolongation due to U wave Shortened QT interval due to a shortened ST segment Prolonged QT interval due to a prolonged ST segment; T-wave duration normal Osborne or J waves: J-point elevation with a characteristic elevation of the early ST segment. Slow rhythm, baseline artifact due to shivering often present. ST depression T-wave flattening or inversion Shortened QT interval, increased Uwave amplitude Prolonged QT interval, mainly due to prolonged T-wave duration with flattening or inversion QRS prolongation Increased U-wave amplitude Diffuse, wide, deeply inverted T waves with prolonged QT

u

T

u

Fig. 4.7  Metabolic and drug influences on the electrocardiographic recording. CNS, Central nervous system; ECG, electrocardiogram.

AMBULATORY ELECTROCARDIOGRAPHIC RECORDING Ambulatory ECG monitoring allows clinicians to monitor and capture the presence and frequency of cardiac arrhythmias over a specified

period of time. Multiple types of ambulatory recording modalities are available, and the decision to use one or the other largely depends on the duration of surveillance required. Determination of the surveillance duration is influenced by many factors, including the frequency of symptoms (daily, weekly, monthly, or longer), reason for the study

CHAPTER 4  Diagnostic Tests and Procedures in the Patient With Cardiovascular Disease (i.e., quantifying arrhythmia burden vs. catching an arrhythmic event), and severity of symptoms (lightheadedness vs. stroke). A Holter monitor collects ECG data from two or three surface leads on a recorder that the patient wears under their clothing, typically for 24 to 72 hours. The device stores all data over this period of time. Patients are asked to write their symptoms in a diary, so that symptoms can be correlated with the rhythm at that time. From these recordings, algorithms analyze and identify abnormal strips for clinician review. Holter monitors are most useful for patients with frequent, daily symptoms, or for quantifying arrhythmic burden such as frequent premature ventricular contractions. Electrocardiographic devices are more recent innovations that also provide continuous ECG recordings through small ECG sensors placed on the chest, usually over a period of two weeks, and can be used instead of Holter monitors. For patients with more infrequent symptoms, an event recorder can be used to record data for up to a month. Like Holter monitors, surface leads are placed on the chest and connected to a recording device. Unlike Holter monitors, the device only maintains data for 30 to 60 second loops, after which it is erased. Data are only saved when algorithms identify ECG abnormalities, or when patients press a button indicating the presence of symptoms. Therefore, patients must be able to trigger the device. These data are usually uploaded to a monitoring center, where patients can be called for further questioning or counseling. Implantable loop recorders (ILRs) are small recording devices that are implanted subcutaneously in the left parasternal chest wall. They can record symptoms for up to two years. Like event recorders, data are maintained on a loop, though for a much greater period of time (about thirty minutes). Data are stored either automatically or through a small magnetic activator that patients pass over the device. A device programmer is then used to extract the data in the office. ILRs are especially useful in patients with rare but serious symptoms, or when quantifying arrhythmic burden, such as atrial fibrillation, may be critical to informing the treatment plan. In addition to clinician prescribed monitoring devices, there has been a recent surge in the use of personal wearable devices such as smartwatches that have the capacity to record and store single lead ECG tracings. Some of these devices may even alert patients to the presence of abnormal heart rhythms. Though the diagnostic utility of these devices is unclear at this time, clinicians are likely to encounter them at an increasing rate in practice, and abnormalities seen on these devices may be used to prompt further investigation.

CHEST RADIOGRAPHY Chest radiography is one of the most ubiquitous and commonly performed diagnostic tests in the world. It is an integral part of the initial evaluation and work-up for patients presenting with a number of cardiovascular-related complaints, particularly chest pain, shortness of breath, and postprocedural complaints involving cardiac devices. Regardless of the clinical indication, chest radiography provides useful information regarding cardiac structures that may provide additional insight into a patient’s condition. Routinely, chest radiography is performed in the posteroanterior and lateral projections (Fig. 4.8). In the posteroanterior view, cardiac enlargement may be identified when the transverse diameter of the cardiac silhouette is greater than one half of the transverse diameter of the thorax. The heart may appear falsely enlarged when it is displaced horizontally, such as with poor inflation of the lungs or when the image is taken in an anteroposterior projection, which magnifies the heart shadow. The differential diagnosis for cardiac silhouette enlargement

31

on chest radiography includes cardiomegaly, pericardial effusion, prominent epicardial fat pad, or an anterior mediastinal mass. Left atrial enlargement is suggested when the left-sided heart border is straightened or bulges toward the left. Right atrial enlargement may be confirmed when the right-sided heart border bulges toward the right. Left ventricular enlargement results in downward and lateral displacement of the apex. A rounding of the displaced apex suggests ventricular hypertrophy. Right ventricular enlargement is best assessed on the lateral view and may be diagnosed when the right ventricular border occupies more than one third of the retrosternal space between the diaphragm and thoracic apex. The aortic arch and thoracic aorta may become dilated and tortuous in patients with severe atherosclerosis, long-standing hypertension, and aortic dissection. A widened mediastinum, which is defined as a width of greater than 8.0 centimeters at the level of the aortic knob, can be seen in acute aortic dissection, although it is not very sensitive or specific for acute dissection. Pulmonary venous congestion due to elevated left ventricular end-diastolic pressure results in redistribution of blood flow in the lungs and prominence of the apical vessels, which can be seen on chest radiography. Transudation of fluid into the interstitial space may result in fluid in the fissures and along the horizontal periphery of the lower lung fields (i.e., Kerley B lines). As venous pressures further increase, fluid collects in the alveolar space, which early on collects preferentially in the inner two thirds of the lung fields, resulting in a characteristic butterfly appearance. Chest radiography is also used to evaluate device and lead positioning after implantation of defibrillators or pacemakers. The posteroanterior view helps to evaluate for device and lead integrity as well as potential device placement complications such as pneumothorax. A lateral view is necessary to evaluate ventricular lead positioning. In the lateral view, a right ventricular lead will course anteriorly, while a left ventricular lead will course posteriorly. The shape of the pulse generator can help in determining the device manufacturer, which is necessary to know for device interrogation.

ECHOCARDIOGRAPHY Echocardiography is a widely used, noninvasive technique in which sound waves are used to image cardiac structures and evaluate blood flow. Transthoracic echocardiography is safe, simple, fast, and relatively inexpensive. It can provide a wealth of information on a patient’s cardiovascular status, including ventricular function, valvular function, chamber size, possible coronary artery disease, pericardial disease, congenital heart disease, aortopathy, cardioembolic sources, volume status, and hemodynamics, among many other things. A piezoelectric crystal housed in a transducer placed on the patient’s chest wall produces ultrasound waves. As the sound waves encounter structures with different acoustic properties, some of the ultrasound waves are reflected to the transducer and recorded. Steering the ultrasound beam across a 90-degree arc multiple times per second creates two-dimensional imaging (Fig. 4.9). The development of three-dimensional echocardiographic imaging techniques allows for greater accuracy in measurements of chamber volumes and mass, as well as the assessment of geometrically complex anatomy and valvular lesions. Video 4.1 shows a three-dimensional image. Doppler echocardiography allows assessment of the direction and velocity of blood flow in the heart and great vessels. When ultrasound waves encounter moving red blood cells, the energy reflected to the transducer is altered. The magnitude of this change (i.e., Doppler shift) is represented as velocity on the echocardiographic display and can be used to determine whether the blood flow is normal or abnormal

32

SECTION II  Cardiovascular Disease

A

B Fig. 4.8  Schematic illustration of the parts of the heart, outlines of which can be identified on a routine chest radiograph. (A) Posteroanterior chest radiograph. (B) Lateral chest radiograph. Ao, Aorta; LA, left atrium; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RV, right ventricle.

RV LV

IVS

Ao

RV

MV

LV

LA PE

RA

LA

PW

A

B Fig. 4.9  Portions of standard two-dimensional echocardiograms show the major cardiac structures in a parasternal long-axis view (A) and apical four-chamber view (B). Video 4.3 shows a moving image of a two-dimensional echocardiogram. Ao, Aorta; IVS, interventricular septum; LA, left atrium; LV, left ventricle; MV, mitral valve; PE, pericardial effusion; PW, posterior left ventricular wall; RV, right ventricle. (Image courtesy Sheldon E. Litwin, MD, Division of Cardiology, University of Utah, Salt Lake City, Utah.)

(Fig. 4.10). The velocity of a particular jet of blood can be converted to pressure, allowing assessment of pressure gradients across valves or between chambers. Color Doppler imaging allows visualization of blood flow through the heart by assigning a color to the red blood cells based on their velocity and direction (Fig. 4.11, Video 4.2). By convention, blood moving away from the transducer is represented in shades of blue, and blood moving toward the transducer is represented in red. Color Doppler imaging is particularly useful in identifying valvular insufficiency and abnormal shunt flow between chambers. The use of Doppler techniques to record myocardial velocities or strain rates can aid in the assessment of myocardial function and hemodynamics. Ultrasound contrast agents composed of microbubbles can be used in patients who have poorly visualized cardiac structures, such as obese patients or those with chronic lung disease. Ultrasound contrast opacifies the endocardial cavity and aids in assessment of cardiac function (Fig. 4.12). Video 4.3 shows a dynamic contrast

echocardiographic image. These contrast agents are also necessary in the assessment of potential left ventricular thrombus. Agitated saline, commonly referred to as “bubbles,” can be used to assess for intra­ cardiac shunts. Transesophageal echocardiography (TEE) allows two-dimensional and Doppler imaging of the heart through the esophagus by having the patient swallow a gastroscope mounted with an ultrasound crystal in its tip. Given the proximity of the esophagus to the heart, high-resolution images can be obtained, especially of the left atrium, mitral valve apparatus, and aorta. TEE is particularly useful in diagnosing left atrial appendage thrombi, aortic dissection, endocarditis, prosthetic valve dysfunction, and left atrial masses (Fig. 4.13, Video 4.4). TEE has been used for decades intraoperatively during cardiac surgery, and it is now being used with increasing frequency to guide percutaneous cardiac procedures such as transcatheter aortic valve replacement, transcatheter mitral valve repair, and left atrial appendage occlusion.

CHAPTER 4  Diagnostic Tests and Procedures in the Patient With Cardiovascular Disease

Fig. 4.10  Doppler tracing in a patient with aortic stenosis and regurgitation. The velocity of systolic flow is related to the severity of obstruction.

LV

LA

Fig. 4.11  Color Doppler recording demonstrates severe mitral regurgitation. The regurgitant jet seen in the left atrium is represented in blue because blood flow is directed away from the transducer. The yellow components are the mosaic pattern traditionally assigned to turbulent or high-velocity flow. The arrow points to the hemisphere of blood accelerating proximal to the regurgitant orifice (i.e., proximal isovelocity surface area [PISA]). The size of the PISA can be used to help grade the severity of regurgitation. Video 4.2 shows a dynamic echocardiographic image in a patient with mitral regurgitation. LA, Left atrium; LV, left ventricle. (Image courtesy Sheldon E. Litwin, MD, Division of Cardiology, University of Utah, Salt Lake City, Utah.)

NUCLEAR CARDIOLOGY The traditional radiotracer approach to assess ventricular function is equilibrium radionuclide angiocardiography (ERNA), which uses technetium-99m-labeled red blood cells. Serial ERNA can be performed at rest and during various levels of exercise of pharmacologic perturbations to evaluate ventricular function and reserve. ERNA has high reproducibility because there are no geometric assumptions and there is much less operator dependence in the image acquisition. Diastolic parameters can be readily assessed from the ventricular volume curve, which may be very helpful in the assessment of diastolic dysfunction. In radionuclide imaging of the heart, patients are injected with a radioactive tracer, which distributes throughout the myocardium in proportion to blood flow. Highly specialized cameras then capture the

33

distribution of the radioactive tracer, which allows for quantification of left ventricular size, systolic function, and myocardial perfusion, depending on the tracer used. The two main types of myocardial imaging used in cardiology, often in stress testing, are single-photon emission tomography (SPECT) and positron emission tomography (PET). In SPECT imaging, images of the heart are obtained for qualitative and quantitative analyses at rest and after stress (i.e., exercise or pharmacologic vasodilation). Radionuclide tracers are injected prior to rest images and just prior to the completion of stress. The most frequently used radionuclide in SPECT imaging is technetium-99m sestamibi. In the normal heart, the radioisotope is equally distributed throughout the myocardium at rest and stress. In patients with ischemia, a localized area of decreased radiotracer uptake occurs after stress but may partially or completely reverse during rest. A persistent defect at peak exercise and rest (i.e., fixed defect) is consistent with MI or scarring. The use of new approaches such as combined low-level exercise and vasodilators, prone imaging, attenuation correction, and computerized data analysis has improved the quality and reproducibility of the data from these studies. New camera technologies, including those with solid state detector arrays, have demonstrated improved image resolution and allow for reduced radiation exposure. Myocardial perfusion imaging may also be combined with ECG-gated image acquisition (gated SPECT) to allow simultaneous assessment of ventricular function and perfusion. Using this technique, regional wall motion can be evaluated to help assess potential perfusion defects (Video 4.5). PET has been widely used in oncology for many years but has become increasingly popular in cardiology (Video 4.5). The commonly used tracers in cardiac PET imaging include rubidium-82 and fluorine-18 fluorodeoxyglucose (FDG). When compared to SPECT, PET has several technical advantages, including higher spatial and temporal resolution, less radiation exposure, and the ability to quantify absolute rather than relative coronary blood flow. These advantages mean that PET is more sensitive and specific compared to SPECT in diagnosing coronary disease, especially in the presence of multivessel disease. Additionally, because PET gives an absolute rather than relative quantification of coronary blood flow, it can be used to assess abnormal microvascular coronary circulation. Despite these clinical advantages of PET over SPECT, the lack of availability of PET cameras and radiotracers, as well as high costs and reimbursement issues, limits the widespread adoption of PET. In patients with suspected cardiac sarcoidosis, FDG-PET is the imaging modality of choice for diagnosis. FDG-PET can also be used to detect myocardial viability by the use of perfusion and metabolic tracers. In patients with left ventricular dysfunction, metabolic activity in a region of myocardium supplied by a severely stenotic coronary artery suggests viable tissue that may regain more normal function after revascularization (Fig. 4.14).

CARDIAC MAGNETIC RESONANCE IMAGING Cardiac magnetic resonance imaging (cMRI) is a noninvasive method that is increasingly used for studying the heart and vasculature and has, in fact, become the gold standard for measuring myocardial function, volumes, and scarring. cMRI offers high-resolution dynamic and static images of the heart that can be obtained in any plane, allowing quantification of left ventricular and valvular function. High-quality images can be obtained in a larger proportion of subjects than is typically possible with echocardiography. Obesity, claustrophobia, inability to perform multiple breath-holds of 10 to 20 seconds, and arrhythmias are causes of reduced image quality.

34

SECTION II  Cardiovascular Disease

A

B Fig. 4.12  Echocardiogram enhanced with intravenous ultrasound contrast agent: apical four-chamber view (A) and apical long-axis view (B). Highly echo-reflectant microbubbles make the left ventricular cavity appear white, whereas the myocardium appears dark. Video 4.3 shows a dynamic image of echocardiographic contrast. (Image courtesy Sheldon E. Litwin, MD, Division of Cardiology, University of Utah, Salt Lake City, Utah.)

LA V

LA

V MV

LV

B

A

Fig. 4.13 Transesophageal echocardiogram demonstrates a vegetation (arrow) adherent to the ring of a bileaflet, tilting-disk mitral valve prostheses. (A) In systole, the leaflets are closed with the vegetation seen in the left atrium. (B) In diastole, the leaflets are open, with the vegetation prolapsing into the left ventricle. Transesophageal echocardiography is the diagnostic test of choice for assessing prosthetic mitral valves because the esophageal window allows unimpeded views of the atrial surface of the valve. Video 4.4 shows a dynamic transesophageal echocardiographic image. LA, Left atrium; LV, left ventricle; MV, prosthetic mitral valve disks; V, vegetation. (Courtesy Sheldon E. Litwin, MD, Division of Cardiology, University of Utah, Salt Lake City, Utah.)

cMRI also offers significant advantages over other imaging techniques for the characterization of tissues (e.g., muscle, fat, scar). cMRI is useful in the evaluation of ischemic heart disease because stress-rest myocardial perfusion (Fig. 4.15A) and areas of prior infarction (see Fig. 4.15B to D) can be visualized with excellent spatial resolution. Delayed or late gadolinium enhancement (LGE) in the myocardium is characteristic of scar or permanently damaged tissue (Video 4.6). The greater the transmural extent of LGE is in a given segment, the lower the likelihood of improved function in that segment after revascularization. Because of the better spatial resolution, LGE can identify localized or subendocardial scars that are not detectable with nuclear imaging techniques. MRI is excellent for evaluating a variety of cardiomyopathies (Fig. 4.16). In addition to morphology and function, characteristic patterns of LGE have been reported in myocarditis, cardiac amyloidosis, sarcoidosis, and hypertrophic cardiomyopathy (HCM). In patients with

HCM, specific patterns on MRI can help identify those patients at highest risk of sudden cardiac death who would require defibrillators. Similarly, MRI has also been used to help assess right ventricular morphology and function in patients with suspected arrhythmogenic right ventricular cardiomyopathy. The role of MRI in all aspects of cardiac imaging continues to grow.

STRESS TESTING Stress testing is an important noninvasive tool for evaluating patients with known or suggested coronary artery disease (CAD). During exercise, the increased demand for oxygen by the working skeletal muscles is met by increases in heart rate and cardiac output. In patients with significant CAD, the increase in myocardial oxygen demand cannot be met by a proportional increase in coronary blood flow, and myocardial ischemia may produce chest pain and characteristic ECG

CHAPTER 4  Diagnostic Tests and Procedures in the Patient With Cardiovascular Disease

35

[13N]-ammonia

[18F]-deoxyglucose

[13N]-ammonia

[18F]-deoxyglucose

[13N]-ammonia

[18F]-deoxyglucose

Fig. 4.14 Resting myocardial perfusion (obtained with [13N]-ammonia) and metabolism (obtained with [18F]-deoxyglucose) is seen in positron emission tomography images of a patient with ischemic cardiomyopathy. The study demonstrates a perfusion-metabolic mismatch (reflecting hibernating myocardium) in which large areas of hypoperfused (solid arrows) but metabolically viable (open arrows) myocardium involve the anterior, septal, and inferior walls and the left ventricular apex. Video 4.5 shows a dynamic image obtained with cardiac single-photon emission computed tomography imaging. (Courtesy Marcelo F. Di Carli, MD, Brigham and Women’s Hospital, Boston, Mass.)

abnormalities. Combined with the hemodynamic response to exercise, these changes can give useful diagnostic and prognostic information for the patient with cardiac abnormalities. The most common indications for stress testing include establishing a diagnosis of CAD in patients with chest pain, assessing prognosis and functional capacity of patients with chronic stable angina or after an MI, evaluating exercise-induced arrhythmias, and assessing for ischemia after a revascularization procedure. Contraindications to stress testing include acute coronary syndromes, poorly controlled hypertension (blood pressure >220/110 mm Hg), severe aortic stenosis (valve area 220 mm Hg systolic), worsening angina during exercise, developing marked or widespread ischemic ECG changes, significant arrhythmias, or hypotension. For patients who are able to exercise, the most commonly used exercise protocols are the Bruce and modified Bruce protocols. These protocols require a patient to walk on a treadmill as the speed and incline of the belt increases with each advancing stage. Any patient who can exercise should do so, as duration of exercise and provoked symptoms provide valuable clinical and prognostic information for the physician. The modified Bruce or similar protocols are ideal for older, overweight, unstable, or debilitated patients. Additionally, in patients

unable to exercise on a treadmill, bicycle or arm ergometer testing may also be used. In patients who cannot exercise or in those where exercise will interfere with image acquisition, pharmacologic agents may be used. The most commonly used pharmacologic stress agents are dobutamine, adenosine, and regadenoson, an adenosine derivative and selective adenosine A2A receptor agonist. Dobutamine is a synthetic sympathomimetic that stimulates alpha-1, beta-1, and beta-2 receptors, increasing inotropy and chronotropy, thereby increasing myocardial oxygen demand. It should be used cautiously in patients with a history of atrial or ventricular arrhythmias as it can exacerbate both. Regadenoson is an adenosine receptor agonist that induces coronary vasodilation and is more commonly used in radionuclide myocardial perfusion imaging. Its use is contraindicated in patients with asthma or COPD and active wheezing as well as patients with significant bradyarrhythmias without a pacemaker. It should be used with caution in patients with a history of seizures as it can lower the seizure threshold.

STRESS IMAGING Exercise or pharmacologic stress testing must be combined with imaging modalities to assess for characteristic changes seen in flow-limiting coronary artery disease. The most basic form of imaging is an ECG, which can be combined with adjunctive echocardiography or radionuclide imaging to increase the diagnostic accuracy of the testing.

CHAPTER 4  Diagnostic Tests and Procedures in the Patient With Cardiovascular Disease

A

B

C

D

37

Fig. 4.16 Cardiac magnetic resonance imaging (MRI) is used in the evaluation of cardiomyopathies. (A) Severe left ventricular hypertrophy in a patient with hypertrophic cardiomyopathy. Diastolic frame shows open mitral valve (arrow). (B) Systolic frame shows systolic anterior motion of the mitral valve with flow disturbance in the left ventricular outflow tract (arrow). (C) Patient has left ventricular noncompaction as evidenced by deep trabeculations in the left ventricular apex (arrow). (D) Patient with ischemic cardiomyopathy has transmural apical infarction and adjacent mural thrombus (arrow). Video 4.6 shows a dynamic cardiac MRI image. (Images courtesy Sheldon E. Litwin, MD, Division of Cardiology, University of Utah, Salt Lake City, Utah.)

TABLE 4.4  Diamond and Forrester Pretest Probability of Coronary Artery Disease by Age, Sex,

and Symptoms Age (Years)

Sex

Typical/Definite Angina Pectoris

Atypical/Probable Angina Pectoris

Nonanginal Chest Pain

≤39

Men Women Men Women Men Women Men Women

Intermediate Intermediate High Intermediate High Intermediate High High

Intermediate Very low Intermediate Low Intermediate Intermediate Intermediate Intermediate

Low Very low Intermediate Very low Intermediate Low Intermediate Intermediate

40-49 50-59 ≥60

High: >90% pretest probability. Intermediate: between 10% and 90% pretest probability. Low: between 5% and 10% pretest probability. Very low: 2 mm), especially if present in more than five leads; ST changes persisting into recovery for more than 5 minutes; and failure to increase systolic blood pressure to 120 mm Hg or more or a sustained decrease of 10 mm Hg or more below baseline. The ECG is not diagnostically useful in the setting of left ventricular hypertrophy, LBBB, Wolff-Parkinson-White syndrome, or chronic digoxin therapy. In these instances, further imaging modalities such as echocardiography, nuclear imaging, or positron-emission tomography (PET) are needed to help diagnose ischemia.

Stress Echocardiography Two-dimensional echocardiography and Doppler echocardiography are often used in conjunction with exercise or pharmacologic stress testing. The pharmacologic agent typically used is dobutamine. A baseline echocardiogram is performed at rest and during stress. Changes in wall motion are indicative of ischemia and coronary artery disease. In areas of the left ventricle that have wall motion abnormalities at rest, improvement of these wall motion abnormalities with exercise or lowdose dobutamine is indicative of viability. Relative to myocardial perfusion imaging, the sensitivity of stress echocardiography is slightly lower whereas the specificity is slightly higher. A poor baseline echocardiogram due to limited acoustic windows will limit stress test results. The estimated cost-effectiveness of stress echocardiography is significantly better than nuclear perfusion imaging because of the overall lower cost.

Myocardial Perfusion Imaging (See Also Nuclear Cardiology Section) Stress testing, using myocardial perfusion imaging with SPECT to compare relative coronary blood flow at stress and at rest, helps to identify areas of perfusion mismatch, indicative of ischemia. Like with other stress modalities, exercise or pharmacologic stress can be used. Commonly used pharmacologic agents include dipyridamole, adenosine, and regadenoson, which are all coronary vasodilators. It is important to note that patients with LBBB have to undergo pharmacologic stress when receiving myocardial perfusion imaging, even if they are able to exercise, as the abnormal septal motion caused by the LBBB can lead to a false perfusion defect during exercise.

Stress Cardiac Magnetic Resonance Imaging Though either exercise or pharmacologic stress may be combined with cMRI, the contemporary use of stress cMRI usually refers to stress perfusion cMRI with gadolinium contrast that is performed with regadenoson. This technique allows for evaluation of wall motion, perfusion, scar, viability, and microvascular dysfunction, as well as chamber quantification and function, allowing for a comprehensive evaluation of the myocardium and myocardial function. Changes in late gadolinium enhancement between rest and stress has performance characteristics for diagnosing CAD that are at least as good and likely superior to

those of conventional stress tests using nuclear myocardial perfusion imaging or echocardiography, and on par with PET imaging.

COMPUTED TOMOGRAPHY OF THE HEART Newer applications of computed tomography (CT) have greatly advanced our ability to diagnose cardiovascular disease noninvasively. The development of fast gantry rotation speeds and the addition of multiple rows of detectors (i.e., multidetector CT) have allowed unprecedented visualization of the great vessels, heart, and coronary arteries with images acquired during a single breath-hold lasting 10 to 15 seconds. CT is used to diagnose aortic aneurysm, acute aortic dissection, and pulmonary embolism, and it is useful for defining congenital abnormalities and detecting pericardial thickening or calcification associated with constrictive pericarditis. ECG-gated dynamic CT images have been used to quantify ventricular size, function, and regional wall motion (Video 4.7), and in contrast to echocardiography, CT is not limited by lung disease or chest wall deformity. However, obesity and implanted prosthetic materials (i.e., mechanical valves or pacing wires) may affect image quality. The greatest excitement and controversy about cardiac CT relates to the evaluation of coronary atherosclerosis. Electron beam and multidetector CT scans can be used to quickly and reliably visualize and quantitate the extent of coronary artery calcification (Fig. 4.17). The presence of coronary calcium is pathognomonic of atherosclerosis, and the extent of coronary calcium (usually reported as an Agatston score) is a powerful marker of future cardiovascular events. The coronary calcium score adds substantial, independent improvement in risk prediction to the commonly employed clinical risk scores (e.g., Framingham risk score). Moreover, the calcium score is a good marker of the overall atherosclerotic burden. Indications for coronary calcium scoring continue to grow, especially in refining risk predictions in asymptomatic patients at intermediate risk for arteriosclerotic cardiovascular disease. Contrast-enhanced coronary computed tomography angiography (CCTA) has improved dramatically in recent years. CCTA has a sensitivity of more than 95% in diagnosing significant coronary artery obstruction. Unlike myocardial perfusion imaging, CCTA is an anatomic test, and thus does not give information on perfusion or blood flow across a lesion. Thus, in patients with known coronary disease, CCTA cannot easily differentiate between ischemic and nonischemic chest pain. New technology is being developed to noninvasively determine the hemodynamic significance of a lesion through CCTA, similar to fractional flow reserve in coronary catheterization, though this technology still needs to be rigorously tested and standardized. Evaluation of coronary arteries with CCTA can be significantly limited in patients with extensive coronary calcifications, cardiac devices, or prior stents due to technical limitations. Concerns that limit the widespread use of cardiac CT most frequently cite the risks of radiation and contrast exposure and the lack of prospective studies showing improvement in outcome with this testing modality. In early studies, the calculated radiation exposure of CCTA was about double that of a diagnostic invasive coronary angiogram, although with prospective ECG-gating, most studies are now equal to or less than a diagnostic angiogram. Contrast use is often higher in a CCTA than in a diagnostic invasive coronary angiogram. The role of CCTA in routine clinical practice continues to evolve.

CARDIAC CATHETERIZATION Cardiac catheterization is an invasive technique in which fluid-filled catheters are introduced percutaneously into the arterial and/or venous circulation. This method allows direct measurement of intracardiac

CHAPTER 4  Diagnostic Tests and Procedures in the Patient With Cardiovascular Disease

A

B

C

D

E

F

39

Fig. 4.17  Computed tomography coronary angiography compared with conventional radiographic contrast angiography. (A and B) Volume-rendering technique demonstrates stenosis of the right coronary artery and normal left coronary artery. (C and D) Maximal intensity projection of the same arteries demonstrates severe noncalcified plaque in the right coronary artery with superficial calcified plaque. (E and F) Invasive angiography of the same arteries. (From Raff GL, Gallagher MJ, O’Neill WW, et al: Diagnostic accuracy of noninvasive coronary angiography using 64-slice spiral computed tomography, J Am Coll Cardiol 46:552-557, 2005.)

pressures and oxygen saturation and, with the injection of a contrast agent, visualization of the coronary arteries, cardiac chambers, and great vessels. Cardiac catheterization is indicated when a clinically suggested cardiac abnormality requires confirmation and its anatomic and physiologic importance needs to be quantified. Coronary angiography for the diagnosis of CAD is the most common indication for this test. Compared with catheterization, noninvasive testing with echocardiography is safer, often cheaper, and equally effective in the evaluation of most valvular and hemodynamic conditions. Most often, catheterization precedes some type of beneficial intervention, such as

coronary artery angioplasty, coronary bypass surgery, or valvular surgery. Although cardiac catheterization is usually safe (0.1% to 0.2% overall mortality rate), procedure-related complications such as vascular injury, renal failure, stroke, and MI can occur.

Left Heart Catheterization and Coronary Angiography Left heart catheterization and coronary angiography first requires the introduction of wires and fluid-filled catheters into the arterial system of the body. In the past, femoral arterial access was the default route, but now, radial arterial access has become increasingly more common.

40

SECTION II  Cardiovascular Disease

mm Hg

200

100

LV

AO

20

Fig. 4.18  Electrocardiographic tracing and left ventricular (LV) and aortic (AO) pressure curves in a patient with aortic stenosis. A pressure gradient occurs across the aortic valve during systole.

It has replaced femoral arterial access as the default access site in most centers. Radial arterial access is associated with less bleeding, fewer vascular complications, and increased patient comfort and early mobility after the procedure when compared with femoral arterial access. However, it is also associated with higher radiation exposure and increased procedural time. After access is obtained, wires and fluid-filled catheters are advanced to the aortic root and through the aortic valve into the left ventricle under fluoroscopic guidance. Here, left ventricular size, wall motion, and ejection fraction can be accurately assessed by injecting contrast into the left ventricle (i.e., left ventriculography). Aortic and mitral valve insufficiency can be qualitatively assessed during angiography by observing the reflux of contrast medium into the left ventricle and left atrium, respectively. Left ventricular pressures can be directly measured and recorded, and the catheter can slowly be pulled back across the left ventricular outflow tract (LVOT) and aortic valve to directly assess for any pressure differential that would be consistent with aortic stenosis or LVOT obstruction (Fig. 4.18). The coronary anatomy can be defined by injecting contrast medium into the coronary tree. Atherosclerotic lesions appear as narrowing of the internal diameter (lumen) of the vessel. A hemodynamically important stenosis is defined as 70% or more narrowing of the luminal diameter. However, the hemodynamic significance of a lesion can be underestimated by coronary angiography, particularly when the atherosclerotic plaque is eccentric or elongated. Intravascular ultrasound, optical coherence tomography, or miniaturized pressure sensors can be used during invasive procedures to help evaluate the severity or estimate the physiologic significance of intermediate lesions.

Right Heart Catheterization Right heart catheterization is a useful invasive technique that can be performed at bedside or with fluoroscopic guidance. The pulmonary artery (Swan-Ganz) catheter, which is a balloon-tipped catheter used for right heart catheterization, can be left in a patient for a prolonged period of time in a critical care setting to provide continuous information on cardiovascular hemodynamics and filling pressures. Right heart catheterization can be helpful when used in appropriate situations, such as when differentiating noncardiogenic from cardiogenic

pulmonary edema, managing mixed shock, managing cardiogenic shock, and classifying and treating pulmonary hypertension. Right heart catheterization is performed by first accessing the venous system. Common sites of entry for right heart catheterization include the internal jugular vein (usually the right), the right brachial vein, or the femoral veins. The procedure can be performed at the bedside or under fluoroscopic guidance with a balloon-tipped (Swan-Ganz) catheter. The catheter is advanced from the vein to the right atrium, right ventricle, and pulmonary artery, where pressures are measured and recorded. The catheter can then be advanced further until it wedges in the distal pulmonary artery. The transmitted pressure measured in this location originates from the pulmonary venous system and is known as the pulmonary capillary wedge pressure. In the absence of pulmonary venous disease, the pulmonary capillary wedge pressure reflects left atrial pressure, and if no significant mitral valve pathologic condition exists, it reflects left ventricular diastolic pressure. A more direct method of obtaining left ventricular filling pressures is through left heart catheterization, as described in the previous section. With these two methods of obtaining intracardiac pressures, each chamber of the heart can be directly assessed and the gradients across any of the valves determined (Fig. 4.19). Cardiac output can be determined by one of two widely accepted methods: the Fick oxygen method and the indicator dilution technique. The basis of the Fick method is that total uptake or release of a substance by an organ is equal to the product of blood flow to that organ and the concentration difference of that substance between the arterial and venous circulation of that organ. If this method is applied to the lungs, the substance released into the blood is oxygen; if no intrapulmonary shunts exist, pulmonary blood flow is equal to systemic blood flow or cardiac output. The cardiac output can be determined by the following equation: Cardiac output =

Oxygen consumption (Arterial oxygen content _ Venous oxygen content)



Oxygen consumption is measured in milliliters per minute by collecting the patient’s expired air over a known period while simultaneously measuring oxygen saturation in a sample of arterial and mixed venous blood (i.e., arterial and venous oxygen content, respectively, measured in milliliters per liter). The cardiac output is expressed in liters per minute and then corrected for body surface area (i.e., cardiac index). The normal range of cardiac index is 2.6 to 4.2 L/min/m2. Cardiac output can also be determined by the indicator dilution technique, which most commonly uses cold saline as the indicator. With this method, cold saline is injected into the blood, and the resulting temperature change downstream is monitored. This action generates a curve in which temperature change is plotted over time, and the area under the curve represents cardiac output. Detection and localization of intracardiac shunts can be performed by sequential measurement of oxygen saturation in the venous system, right side of the heart, and two main pulmonary arteries. In patients with left-to-right shunt flow, an increase in oxygen step-up (i.e., saturation increase from one chamber to the successive chamber) occurs as arterial blood mixes with venous blood. By using the Fick method for calculating blood flow in the pulmonary and systemic systems, the shunt ratio can be calculated. Noninvasive approaches have largely supplanted catheterization laboratory assessment of shunts. In the past, the Swan-Ganz catheter was routinely used in most patients with shock; however, randomized trials have since been published suggesting no improvement in outcomes in critically ill patients in whom pulmonary artery catheterization was performed.

CHAPTER 4  Diagnostic Tests and Procedures in the Patient With Cardiovascular Disease

41

A

ECG

B Radial artery pressure (mm Hg)

100

0

C 40 Pulmonary capillary wedge pressure (mm Hg) 20 0

D Right atrial pressure (mm Hg)

20

10

0 Fig. 4.19  Electrocardiographic (ECG) (A) and Swan-Ganz flotation catheter (C) recordings are shown. The recordings of a catheter in the radial artery and Swan-Ganz floating catheter in the right atrium are shown in B and D, respectively. The left portion of tracing C was obtained with the balloon inflated, yielding the pulmonary arterial wedge pressure. The right portion of tracing C was recorded with the balloon deflated, depicting the pulmonary arterial pressure. In this patient, the pulmonary arterial wedge pressure (i.e., left ventricular filling pressure) is normal, and the pulmonary artery pressure is elevated because of lung disease.

Certainly, improvements in noninvasive imaging techniques have made the Swan-Ganz catheter much less important in diagnosing cardiac conditions such as cardiac tamponade, constrictive pericarditis, right ventricular infarction, and ventricular septal defect. This led to a decline in the routine use of Swan-Ganz catheters in intensive care units. However, the use of these catheters has resurged, likely due to the increased use of advanced heart failure therapies and mechanical support, where continuous hemodynamic monitoring is essential for optimal therapy titration (Table 4.5).

ENDOMYOCARDIAL BIOPSY Biopsy of the right ventricular endomyocardium can be performed. With this technique, a bioptome is introduced into the venous system through the right internal jugular vein and guided into the right

ventricle by fluoroscopy. Small samples of the endocardium are taken for histologic evaluation. The primary indication for endomyocardial biopsy is the diagnosis of rejection after cardiac transplantation and documentation of cardiac amyloidosis; however, endomyocardial biopsy may have some use in diagnosing specific etiologic agents responsible for myocarditis.

NONINVASIVE VASCULAR TESTING Assessment for the presence and severity of peripheral vascular disease is an important component of the cardiovascular evaluation. Comparison of the systolic blood pressure in the upper and lower extremities is one of the simplest tests to detect hemodynamically important arterial disease. Normally, the systolic pressure in the thigh is similar to that in the brachial artery. An ankle-to-brachial pressure

42

SECTION II  Cardiovascular Disease

TABLE 4.5  Differential Diagnosis Using a Bedside Balloon Flow-Directed (Swan-Ganz) Catheter Disease State

Thermodilution Cardiac Output

PCW Pressure

RA Pressure

Comments

Cardiogenic shock Septic shock (early)

↓ ↑

↑ ↓

nl or ↓ ↓

Volume overload Volume depletion Noncardiac pulmonary edema Pulmonary heart disease RV infarction Pericardial tamponade

nl or ↑ ↓ nl nl or ↑ ↓ ↓

↑ ↓ nl nl ↓ or nl nl or ↑

↑ ↓ nl ↑ ↑ ↑

↑ Systemic vascular resistance ↑ Systemic vascular resistance; myocardial dysfunction can occur late

Papillary muscle rupture Ventricular septal rupture

↓ ↑

↑ ↑

nl or ↑ nl or ↑

↑ PA pressure Equalization of diastolic RA, RV, PA, and PCW pressure Large v waves in PCW tracing Artifact caused by RA → PA sampling higher in PA than RA; may have large v waves in PCW tracing

nl, Normal; PA, pulmonary artery; PCW, pulmonary capillary wedge; RA, right atrium; RV, right ventricle; ↑, increased; ↓, decreased.

ratio (i.e., ankle-brachial index) of less than or equal to 0.9 is abnormal. Patients with claudication usually have an index ranging from 0.5 to 0.8, and patients with rest pain have an index less than 0.5. In some patients, measuring the ankle-brachial index after treadmill exercise may help to determine the importance of borderline lesions. During normal exercise, blood flow increases to the upper and lower extremities with corresponding decreases in peripheral vascular resistance, whereas the overall ankle-brachial index remains unchanged. In the presence of a hemodynamically significant lesion, the reduced flow across the lesions causes a consequent pressure decrease, and as a result, the ankle-brachial index decreases in proportion to the severity of the stenosis. Some patients, especially those with diabetes or chronic kidney disease, may have falsely elevated ankle-brachial indices due to vascular stiffness (>1.3). In these patients, a toe-brachial index can be measured. In general, a toe-brachial index less than 0.6 indicates abnormal perfusion in the foot, though the site of the occlusive disease would have to be identified with further studies. After significant vascular disease in the extremities has been identified, plethysmography can be used to determine the location and severity of the disease. With this method, a pneumatic cuff is positioned on the leg or thigh, and when inflated, temporarily obstructs venous return. Volume changes in the limb segment below the cuff are converted to a pressure waveform, which can be analyzed. The degree of amplitude reduction in the pressure waveform corresponds to the severity of arterial disease at that level. Doppler ultrasound uses reflected sound waves to identify and localize stenotic lesions in the peripheral arteries. This test is particularly useful for patients with severely calcified arteries, for whom pneumatic compression is not possible and ankle-brachial indices are inaccurate. In combination with real-time imaging (i.e., duplex imaging), this technique is useful in assessing specific arterial segments and bypass grafts for stenotic or occlusive lesions. Magnetic resonance angiography and CTA allow high-quality and comprehensive imaging of the entire peripheral arterial circulation in

a single study. The three-dimensional nature of these studies and the ability to perform extensive postprocessing views, including cross-sectional views, of all vessels, even those that are very tortuous, are attractive features of these modalities.

SUGGESTED READINGS Fihn SD, Blakenship JC, Alexander KP, et al: 2014 ACC/AHA/AATS/PCNA/ SCAI/STS Focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease, Circulation 130:17491767, 2014. Kligfield P, Gettes LS, Bailey JJ, et al: Recommendations for the standardization and interpretation of the electrocardiogram: part I: the electrocardiogram and its technology a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society endorsed by the International Society for Computerized Electrocardiology, J Am Coll Cardiol 49:1109-1127, 2007. Otto CM: Textbook of clinical echocardiography, ed 6, Chapter 2, Normal anatomy and flow patterns on transthoracic echocardiography, Philadelphia, Elsevier, pp. 33-65, 578p. Rybicki FJ, Udelson JE, Peacock, WF, et al: 2015 ACR/ACC/AHA/AATS/ACEP/ ASNC/NASCI/SAEM/SCCT/SCMR/SCPC/SNMMI/STR/STS Appropriate utilization of cardiovascular imaging in emergency department patients with chest pain: a joint document of the American College of Radiology Appropriateness Criteria Committee and the American College of Cardiology Appropriate Use Criteria Task Force, J Am Coll Cardiol 13:e1-e29, 2016. St. John Sutton M, Morrison AR, Sinusas AJ, Ferrari VA: Heart failure: a companion to braunwald’s heart disease, ed 4, Mann DL, Felker GM, editors: Philadelphia, Elsevier Inc, 2019, Chapter 32, Cardiac imaging in heart failure, p.418-448. 739p. Wolk MJ, Bailey SR, Doherty JU, et al: ACCF/AHA/ASE/ASNC/HFSA/HRS/ SCAI/SCCT/SCMR/STS 2013 Multimodality appropriate use criteria for the detection and risk assessment of stable ischemic heart disease, J Am Coll Cardiol 63:380-406, 2014.

5 Heart Failure and Cardiomyopathy Daniel J. Levine, Hyeon-Ju Ryoo Ali, Rayan Yousefzai

DEFINITION AND CLASSIFICATION Heart failure (HF) is a clinical syndrome defined by inability of the heart to maintain output under normal filling pressures and/or impairment in relaxation of ventricles causing an increase in filling pressures. Patients experience fatigue and exercise intolerance if cardiac output is low and dyspnea and peripheral edema if the ventricular filling pressure is elevated. There are numerous ways to classify HF—by the type of cardiac impairment, causes of cardiomyopathy, patient’s symptoms, or hemodynamic profiles.

Ejection Fraction Most patients with HF have disorders in both systolic and diastolic function. However, ejection fraction (EF) is an important distinguishing characteristic in most clinical trials and, therefore, in guidelines for therapy. By imaging, cardiac function can be categorized as reduced EF (20 mm Hg or mean Doppler systolic gradient >20 mm Hg, upper extremity/lower extremity gradient >10 mm Hg or mean

CHAPTER 6  Congenital Heart Disease Doppler gradient >10 mm Hg plus either decreased LV systolic function of aortic regurgitation, upper extremity/lower extremity gradient >10 mm Hg or mean Doppler gradient >10 mm Hg with collateral flow) should be considered for surgical repair or catheter intervention with balloon angioplasty with or without stent placement. Surgical repair in the adult patient is technically difficult and is associated with high rates of morbidity. As a result, catheter-based intervention has become the preferred method in most experienced congenital heart disease centers, and balloon angioplasty for a native or recurrent coarctation of the aorta should be considered if stent placement or surgery is not an option.

Prognosis After surgical repair, long-term survival is good but directly correlates with the age at repair. Those repaired after 14 years of age have a lower 20-year survival rate than those repaired earlier (79% vs. 91%). Longterm outcome data for catheter-based treatment is limited, but studies suggest that stented patients have lower acute and long-term complications at 60 months (25% for surgery vs. 12.5% for stents). Irrespective of the type of repair, the most common long-term complication is persistent or new systemic hypertension at rest or during exercise. Other long-term complications include aneurysms of the ascending or descending aorta (especially after Dacron patch repair), recoarctation at the site of previous repair, coronary artery disease, aortic stenosis or regurgitation (in the setting of a bicuspid aortic valve), and endarteritis. Intracranial aneurysms are seen in approximately 10% of patients with a coarctation, and increasing age and hypertension have been identified as risk factors.

Patent Ductus Arteriosus

Definition and Epidemiology Patent ductus arteriosus (PDA) represents 9% to 12% of congenital heart defects. It is patent in the fetus but normally closes within several days of birth. However, it remains open in about 1 of 2500 to 5000 births. In infants born prematurely, the incidence is even higher, occurring in 8 of 1000 live births. The incidence of PDA is 30 times greater for babies born at high altitudes than for those born at sea level.

Pathology A PDA allows transit of blood from the aorta into the pulmonary artery and recirculation through the pulmonary vasculature and the left side of the heart. This can result in left-sided chamber enlargement (see Fig. 6.1). As with VSDs, the size of the defect is the primary determinant of the clinical course in the adult patient. PDAs can be clinically categorized as silent PDAs; small, hemodynamically insignificant PDAs; moderate-size PDAs; large PDAs; and previously repaired PDAs.

Clinical Presentation A silent PDA is a tiny defect that cannot be heard by auscultation and is detected only by other nonclinical means such as echocardiography. Life expectancy is always normal for this population, and the risk of endocarditis is extremely low. Patients with a small PDA have an audible, long-ejection or continuous murmur that is heard best at the left upper sternal border and radiating to the back. They have normal peripheral pulses. Because there is negligible left-to-right shunting, these patients have normal LA and LV sizes and normal pulmonary artery pressure. Like those with silent PDAs, these patients are asymptomatic and have a normal life expectancy. However, they do have a higher risk of endocarditis. Patients with moderate-size PDAs may be diagnosed during adulthood. These patients often have wide, bouncy peripheral pulses and an

59

audible, continuous murmur. They have significant volume overload and develop some degree of LA and LV enlargement and some degree of pulmonary hypertension. These patients are symptomatic with dyspnea, palpitations, and heart failure. Patients with large PDAs typically have signs of severe pulmonary hypertension and Eisenmenger’s syndrome. By adulthood, the continuous murmur is typically absent, and there is differential cyanosis (i.e., lower extremity saturations are lower than the right arm saturation).

Diagnosis Patients with silent and small PDAs appear normal by echocardiography and chest radiography. Calcifications may be seen on the posteroanterior and lateral films of an older patient with a PDA. In patients with significant left-to-right shunting, there typically is dilation of the central pulmonary arteries with increased pulmonary vascular markings. On an ECG, broad P waves and tall QRS complexes suggest LA and LV volume overload. A tall R wave in lead V1 with a right axis deviation suggests significant pulmonary hypertension. Measurement of oxygen saturation should be performed in feet and both hands in adults with moderate or large PDAs to assess for the presence of right to left shunting. Echocardiography is important to estimate the size of the defect, degree of LA or LV enlargement, and degree of pulmonary artery hypertension.

Treatment PDA closure is recommended if there is left atrial or left ventricular enlargement present that is attributable to a PDA with left-to-right shunting. Patients with a PDA and severe, irreversible pulmonary hypertension should not have their PDA closed. Catheter device closure is the preferred method in most centers. Surgical closure is reserved for patients with PDAs too large for device closure and for distorted anatomy such as a large ductal aneurysm. Because patients with clinical evidence of a PDA are at increased risk for endocarditis and the low risk of catheter-based device closure, a small audible PDA should be considered for device closure.

Prognosis Patients with a large PDA who have developed Eisenmenger’s syndrome have a prognosis similar to that of other patients with Eisenmenger’s syndrome. Patients who underwent PDA repair before the development of pulmonary hypertension have a normal life expectancy without restrictions.

Pulmonary Valve Stenosis Definition and Epidemiology

Pulmonary valve stenosis occurs in approximately 4 of 1000 live births and constitutes 5% to 8% of congenital cardiac defects. It is one of the most common adult forms of unoperated congenital heart disease. It can occur in isolation or with other congenital heart defects, such as an ASD.

Pathology In congenital pulmonary valve stenosis, the pulmonary valve leaflets are often fused or thickened, which obstructs blood flow out of the right ventricle. The obstruction elevates RV pressure, and compensatory RV hypertrophy develops. Pulmonary stenosis is often tolerated better than aortic stenosis. Over time, RV dilation and dysfunction may occur.

Clinical Presentation Most patients with pulmonary valve stenosis are asymptomatic and have a cardiac murmur at presentation. Most unoperated adults with

60

SECTION II  Cardiovascular Disease

severe stenosis have jugular venous distention, and on palpation, an RV lift at the left lower sternal border and a thrill at the left upper sternal border can be identified. On auscultation, the second heart sound is widely split, and a systolic ejection click may or may not be heard, depending on the mobility of the pulmonary valve leaflets. In most cases, there is a harsh, crescendo-decrescendo systolic ejection murmur, which is heard best at the left upper sternal border; it radiates to the back and varies with inspiration.

Pathology

Diagnosis

Clinical Presentation

With moderate to severe pulmonary valve stenosis, the ECG demonstrates right axis deviation, RV hypertrophy, and RA enlargement. The ECG is usually normal for patients with mild pulmonary valve stenosis. On the chest radiograph, a prominent main pulmonary artery caused by poststenotic dilatation is a common finding regardless of the degree of stenosis. In patients with severe pulmonary valve stenosis, cardiomegaly due to RA and RV enlargement is often seen. Echocardiography is the diagnostic method of choice. It allows visualization of the valve anatomy and degree of stenosis and enables estimation of the valve gradient.

Treatment Survival into adult life and the need for intervention directly correlate with the degree of obstruction. In the Second Natural History Study of Congenital Heart Disease, patients with trivial stenosis (i.e., peak gradient ≤25 mm Hg) who were followed for 25 years remained asymptomatic and had no significant progression of obstruction over time. For those with moderate pulmonary valve stenosis (i.e., peak gradient between 25 and 49 mm Hg), there was an approximately 20% chance of requiring intervention by 25 years of age. Most patients with severe stenosis (i.e., peak gradient of ≥50 mm Hg) require intervention (i.e., surgery or balloon valvuloplasty) by age 25 years. Patients with moderate to severe pulmonary stenosis may be considered for intervention even in the absence of symptoms. Since 1985, percutaneous balloon valvuloplasty has been the accepted treatment for patients of all ages. Before 1985, surgical valvotomy had been the gold standard. Today, adults with moderate or severe valvular pulmonary stenosis and otherwise unexplained symptoms of heart failure, cyanosis from interatrial right to left shunting, or exercise are recommended to undergo balloon valvuloplasty if feasible; otherwise surgical valvotomy is recommended (if the valve is extremely dysplastic or calcified).

Prognosis After surgical valvotomy for isolated pulmonary stenosis, long-term survival is excellent. However, with longer follow-up the incidence of late complications and the need for reintervention do increase. The most common indication for reintervention is pulmonary valve replacement for severe pulmonary regurgitation. Other long-term complications include recurrent atrial arrhythmias, endocarditis, and residual subpulmonary obstruction.

Aortic Valve Stenosis

Definition and Epidemiology Aortic valve stenosis is a common abnormality in adults with congenital heart disease. It is usually caused by a bicuspid aortic valve, which occurs in 1% to 2% of adults and is three times more common in males. It typically is an isolated lesion but can be associated with a dilated ascending aorta and other defects such as coarctation of the aorta or VSD.

Aortic valve stenosis results in pressure overload of the left ventricle, which increases wall stress and causes compensatory LV hypertrophy. Diastolic dysfunction and oxygen delivery-demand mismatch ensues. The patient may remain well compensated and asymptomatic for many years, but compensatory mechanisms eventually begin to fail and LV dysfunction can develop. Patients with a bicuspid aortic valve have abnormal structure of the aortic wall that often leads to ascending aortic dilation.

Most patients with aortic valve stenosis are asymptomatic and are diagnosed after a murmur is detected. The severity of obstruction at the time of diagnosis correlates with the pattern of progression. Symptoms are rare until patients have severe aortic valve stenosis (i.e., mean gradient by echocardiography of ≥40 mm Hg). Symptoms include chest pain, exertional dyspnea, near-syncope, and syncope. With any of these symptoms, the risk of sudden cardiac death is very high, and surgical intervention is mandated. Patients with moderate to severe stenosis typically have decreased peripheral pulses, an increased apical impulse, and a palpable thrill at the base of the heart. On auscultation, these patients have an ejection click followed by a crescendo-decrescendo systolic murmur, which is heard best at the left midsternal border and radiating to the right upper sternal border and the neck. Correlation between the degree of stenosis and the intensity of the murmur is not good. However, it is rare for a murmur of 2/6 or less to be associated with severe stenosis. Some patients with aortic stenosis also have aortic regurgitation, in which case a decrescendo diastolic murmur at the left midsternal border that radiates to the apex is detected at presentation.

Diagnosis Many patients with significant aortic stenosis have LV hypertrophy identified on the ECG. However, the correlation between the severity of stenosis and the finding of LV hypertrophy on the ECG is unreliable. On chest radiography, most patients with severe aortic stenosis have a normal heart size unless there is concurrent aortic regurgitation. Post-stenotic dilation of the ascending aorta is common irrespective of degree of stenosis, and ascending aorta dilation is a common finding. It appears on the chest radiograph as a widened mediastinum. Echocardiography is the gold standard for evaluation of the severity of aortic valve stenosis and the anatomic morphology of the aortic valve. Cardiac catheterization is primarily indicated to evaluate coronary artery disease before surgical intervention, because approximately one-half of adults with symptomatic aortic valve stenosis have concurrent coronary artery disease.

Treatment Patients with severe aortic stenosis and symptoms or asymptomatic patients with severe aortic valve stenosis and reduced LV systolic function (0.5 cm/year or family history of dissection) or 4.5 cm at the time of an aortic valve replacement.

CHAPTER 6  Congenital Heart Disease

Prognosis The natural history of aortic valve stenosis in adults varies but is characterized by progressive stenosis over time. By 45 years of age, approximately 50% of bicuspid aortic valves have some degree of stenosis. Most patients requiring surgical valvotomy to relieve the stenosis before adulthood do well. However, by the 25-year follow-up, up to 40% of patients required a second operation for residual stenosis or regurgitation.

CYANOTIC HEART DISEASE Tetralogy of Fallot Definition and Epidemiology Tetralogy of Fallot (TOF) is the most common cyanotic heart disease seen in adulthood, and it represents 10% of congenital heart defects. It consists of a large VSD, pulmonary stenosis (which may be valvular, subvalvular, and or supravalvular), an aorta that overrides the VSD, and RV hypertrophy.

Pathology Newborns with TOF are cyanotic because of the right-to-left shunt through the VSD and decreased pulmonary blood flow. The amount of pulmonary blood flow depends on the severity of the obstruction through the RV outflow tract. By the time TOF patients reach adulthood, most have had complete repair or palliative surgery. Many adults with repaired TOF have had a transannular patch (i.e., synthetic patch across the pulmonary annulus) placed to relieve the RV outflow tract obstruction. This patch causes obligatory free pulmonary regurgitation. Free pulmonary regurgitation can be well tolerated by the right ventricle for many years, but usually in the third or fourth decades, the right ventricle begins to dilate, and it may become dysfunctional. Significant RV dilation and dysfunction can lead to LV dysfunction, significant tricuspid regurgitation, and atrial or ventricular arrhythmias. Almost 29% of adults with repaired TOF also have a dilated ascending aorta due to increased blood flow through the aorta before repair.

Clinical Presentation Patients with repaired TOF typically have normal oxygen saturation levels. On palpation, there often is an RV lift at the left lower sternal border. On auscultation, there typically is a widely split second heart sound with a to-and-fro murmur in the pulmonary area due to significant pulmonary regurgitation or, less commonly, aortic regurgitation. A holosystolic murmur due to tricuspid regurgitation may be heard at the left lower sternal border. Symptoms in the adult with repaired TOF may include exertional dyspnea, palpitations, syncope, and sudden cardiac death.

Diagnosis The ECG almost universally reveals a right bundle branch block pattern in patients who underwent repair of TOF. The QRS duration from the standard surface ECG correlates with the degree of RV dilation and dysfunction. A maximum QRS duration of 180 milliseconds or more is a highly sensitive and relatively specific marker for sustained ventricular tachycardia and sudden cardiac death. Patients with significant pulmonary regurgitation often have cardiomegaly with dilated central pulmonary arteries identified on the chest radiograph. A right aortic arch occurs in 25% of cases, and it can be detected by close observation of the chest radiograph. An echocardiogram is useful for evaluating the RV outflow tract (e.g., pulmonary regurgitation, residual stenosis), biventricular size and function, tricuspid valve function, and ascending aortic size. MRI is the gold standard for assessing RV size and function

61

(Fig. 6.2). It can also give an accurate assessment of the degree of pulmonary insufficiency and branch pulmonary artery anatomy.

Treatment Treatment for TOF is surgical repair. Repair is typically performed between 3 to 12 months of age and consists of patch closure of the VSD and relief of the pulmonary outflow tract obstruction by patch augmentation of the RV outflow tract or pulmonary valve annulus, or both. Reintervention is necessary in approximately 10% of adults with repaired TOF after 20 years of follow-up. With longer follow-up, the incidence of reintervention continues to increase. The most common indication for reintervention is pulmonary valve replacement in patients with moderate or greater pulmonary valve regurgitation and symptoms. Pulmonary valve replacement is also reasonable for preservation of ventricular size and function in asymptomatic patients with repaired tetralogy of Fallot and ventricular enlargement or dysfunction and moderate or greater pulmonary regurgitation. Pulmonary valve replacement can be performed surgically, or in some patients, percutaneously. Patients with repaired tetralogy of Fallot may be considered for an ICD for primary prevention if multiple risk factors for sudden death are present, including LV systolic or diastolic dysfunction, nonsustained ventricular tachycardia, QRS greater than 180 ms, extensive right ventricular scarring or inducible sustained ventricular tachycardia at an electrophysiologic study.

Prognosis In the developed world, the unoperated adult with TOF has become a rarity because most patients undergo palliation (i.e., stenting) or repair in childhood. Survival of the unoperated patient to the seventh decade has been described but is rare. Only 11% of unrepaired patients are alive at 20 years of age and only 3% at 40 years. Late survival after repair of TOF is excellent. Survival rates at 32 and 35 years are 86% and 85%, respectively, compared with 95% for age- and sex-matched controls. Importantly, most patients live an unrestricted life. However, many patients over time develop late symptoms related to numerous, long-term complications after TOF repair. Late complications include endocarditis, aortic regurgitation with or without aortic root dilation (typically due to damage of the aortic valve during VSD closure or to an intrinsic aortic root abnormality), LV dysfunction (from inadequate myocardial protection during previous repair or chronic LV volume overload due to long-standing palliative arterial shunts), residual pulmonary obstruction, residual pulmonary valve regurgitation, RV dysfunction (due to pulmonary regurgitation or pulmonary stenosis), atrial arrhythmias (typically atrial flutter), ventricular arrhythmias, and heart block.

Transposition of the Great Arteries Definition and Epidemiology

Transposition of the great arteries (TGA) represents 3.8% of all congenital heart disease. In complete TGA, the aorta arises from the right ventricle and the pulmonary artery from the left ventricle. As a result, the systemic venous flow (i.e., blood with low oxygen content) is returned to the right ventricle and is then pumped to the body through the aorta without passing through the lungs for gas exchange. The pulmonary venous flow (i.e., oxygenated blood) returning to the left ventricle is then pumped back to the lungs. As a result, the systemic and pulmonary circulations run in parallel. Oxygenation and survival depend on mixing between the systemic and pulmonary circulations at the atrial, ventricular, or PDA level. In 50% of cases, there are other anomalies: VSD (30%), pulmonary stenosis (5% to 10%), aortic stenosis, and coarctation of the aorta (≤5%). The first definitive operations for TGA (i.e., atrial switch procedures) were described by Senning in 1959 and Mustard in 1964. In these procedures, the systemic and pulmonary venous returns are

62

SECTION II  Cardiovascular Disease

Fig. 6.2  Short axis magnetic resonance images of the right and left ventricles with epicardial and endocardial tracings of both ventricular cavities. There are a predefined number of slices through the heart with a constant thickness. The volumes of the left and right ventricles in each slice are calculated and summed together in end diastole and end systole to determine the total right and left ventricular volumes (i.e., Simpson’s method).

rerouted in the atrium by constructing baffles. The systemic venous return from the superior and inferior vena cavae is directed through the mitral valve and into the left ventricle, which is connected to the pulmonary artery. The pulmonary venous return is then directed through the tricuspid valve into the right ventricle, which is connected to the aorta. These procedures leave the left ventricle as the pulmonary ventricle and the right ventricle as the systemic ventricle. Over the past 20 years, the arterial switch procedure has gained popularity. During the procedure, the great arteries are transected and reanastomosed to the correct ventricle (i.e., left ventricle to the aorta and right ventricle to the pulmonary artery) along with coronary artery transfer. Operative survival after the arterial switch procedure is very good, with a surgical mortality rate of 2% to 5%.

Pathology Most infants who do not have surgical intervention die in the first few months of life. For adults born with complete TGA who have had an atrial switch procedure, the right ventricle continues to be the systemic ventricle, and the left ventricle is the subpulmonic ventricle. Longterm follow-up series have demonstrated that the right ventricle can function as the systemic ventricle for 30 to 40 years, but with longer follow-up, systemic ventricular dysfunction continues to increase. At the 35-year follow-up, approximately 61% of patients have developed moderate or severe RV dysfunction. Another common postoperative problem is the tricuspid valve. After the atrial switch procedure, the tricuspid valve remains the systemic atrioventricular valve and must tolerate systemic pressures. Due to changes in RV morphology and abnormal chordal attachments, the tricuspid valve is prone to become dysfunctional and develop significant regurgitation. Significant coronary lesions, such as occlusions or stenoses, occur in 6.8% of patients who have had the arterial switch procedure. These lesions are likely related to suture lines or kinking at the time of reimplantation of the coronary arteries into the neo-aorta. Systemic LV function is usually normal. LV dysfunction is associated with coronary anomalies.

Clinical Presentation In the repaired adult with an atrial switch procedure, the physical examination may reveal a murmur consistent with tricuspid valve insufficiency and a prominent second heart sound due to the anterior

position of the aorta. Patients who have had an atrial switch procedure tend to have worsening functional status as the length of follow-up increases. They often have resting sinus bradycardia or a junctional rhythm. Palpitations due to atrial arrhythmias are common, occurring in up to 48% of patients 23 years after the atrial switch procedure. In those who undergo the arterial switch procedure, the physical examination may reveal a murmur of neo-aortic or neo-pulmonic regurgitation. These patients usually have normal function status, but because of denervation of the heart, myocardial ischemia may manifest as atypical chest discomfort.

Diagnosis After the atrial switch procedure, the ECG may show a loss of sinus rhythm with evidence of RV hypertrophy. Ambulatory monitors are important to monitor for bradyarrhythmias, sinus node dysfunction, and atrial arrhythmias. Chest radiographs may show an enlarged cardiac silhouette in those with a dilated systemic right ventricle. An echocardiogram can demonstrate qualitative systemic RV size and function and the degree of tricuspid regurgitation. MRI is often used to accurately quantify systemic RV size and function, tricuspid valve function, and atrial baffle anatomy. After the arterial switch, echocardiography is used to assess pulmonary artery and branch pulmonary artery stenosis, neo-aortic and neo-pulmonic valve regurgitation, and ventricular function. MRI or computed tomography may be used to assess the anatomy of the branch pulmonary arteries. An exercise stress test is often used to evaluate myocardial ischemia.

Treatment Treatment options are limited for adults with complete TGA repaired by atrial switch who have failing systemic right ventricles or significant tricuspid regurgitation, and evidence of significant benefit is lacking. However, potential treatments include medical therapy, revision of atrial baffles, pulmonary artery banding, resynchronization therapy, ventricular assist devices, and possible transplantation. Medical therapy, including consideration of anticoagulation, in patients with atrial tachyarrhythmias is recommended. After the arterial switch procedure, catheter-based or surgical reintervention for pulmonary artery stenosis may be required in 5% to 25% of patients. Coronary artery revascularization is rarely required (0.46% of patients), as is neo-aortic valve repair or replacement (1.1%

CHAPTER 6  Congenital Heart Disease of patients). Guideline-directed recommendations for aortic valve replacement are reasonable to follow for patients with d-TGA and severe neo-aortic valve regurgitation.

Prognosis Long-term follow-up studies after the atrial switch procedure show a small but ongoing attrition rate, with numerous intermediate- and long-term complications. Long-term complications include systemic RV dysfunction and tricuspid valve regurgitation, loss of sinus rhythm with the development of atrial arrhythmias (50% incidence by age 25), endocarditis, baffle leaks, baffle obstruction, and sinus node dysfunction requiring pacemaker placement. Intermediate-term complications related to the arterial switch procedure include coronary artery compromise, pulmonary outflow tract obstruction (at the supravalvular level or takeoff of the peripheral pulmonary arteries), neo-aortic valve regurgitation, endocarditis, and neo-aorta dilation. As a result of the long-term complications associated with the atrial switch procedure, the arterial switch operation has been the procedure of choice since 1985. Long-term data on the survival after the arterial switch operation do not exist, but intermediate-term results are promising: 88% at 10 and 15 years. For a deeper discussion on this topic, please see Chapter 61, “Congenital Heart Disease in Adults,” in Goldman-Cecil Medicine, 26th Edition.

SUGGESTED READINGS Bradley EA, Ammash N, Martinez SC: “Treat to close”: Non-repairable ASDPAH in the adult, Int J Card 291:127–133, 2019. Campbell M: Natural history of atrial septal defect, Br Heart J 32:820–826, 1970. Cohen M, Fuster V, Steele PM, et al: Coarctation of the aorta. Long-term follow-up and prediction of outcome after surgical correction, Circulation 80:840–845, 1989.

63

Cohen SB, Ginde S, Bartz PJ, et al: Extracardiac complications in adults with congenital heart disease, Congenit Heart Dis 8:370–380, 2013. Co-Vu JG, Ginde S, Bartz PJ, et al: Long-term outcomes of the neoaorta after arterial switch operation for transposition of the great arteries, Ann Thorac Surg 95:1654–1659, 2013. Cramer JW, Ginde S, Bartz PJ, et al: Aortic aneurysms remain a significant source of morbidity and mortality after use of Dacron patch aortoplasty to repair coarctation of the aorta: results from a single center, Pediatr Cardiol 34:296–301, 2013. Crumb SR, Dearani JA, Fuller S, et al: 2018 AHA/ACC guideline for the management of adults with congenital heart disease, J Am Coll Cardiol 1–175. Earing MG, Connolly HM, Dearani JA, et al: Long-term follow-up of patients after surgical treatment for isolated pulmonary valve stenosis, Mayo Clin Proc 80:871–876, 2005. Earing MG, Webb GD: Congenital heart disease and pregnancy: maternal and fetal risks, Clin Perinatol 32:913–919, 2005. Gatzoulis MA, Freeman MA, Siu SC, et al: Atrial arrhythmia after surgical closure of atrial septal defects in adults, N Engl J Med 340:839–846, 1999. Gunther T, Mazzitelli D, Haehnel CJ, et al: Long-term results after repair of complete atrioventricular septal defects: analysis of risk factors, Ann Thorac Surg 65:754–759, 1998, discussion 759-760. Hickey EJ, Gruschen V, Bradely TJ, et al: Late risk of outcomes for adults with repaired tetralogy of Fallot from an inception cohort spanning four decades, Eur J Cardiothorac Surg 35:156–164, 2009. Khairy P, Van Hare GF, Balaji S: PACES/HRS expert consensus statement on the recognition and management of arrhythmias in adult congenital heart disease, Can J Cardiol e1–e63, 2014. Losay J, Touchot A, Serraf A, et al: Late outcome after arterial switch operation for transposition of the great arteries, Circulation 104(Suppl 1):I121– I1126, 2001. Perloff JK, Warnes CA: Challenges posed by adults with repaired congenital heart disease, Circulation 103:2637–2643, 2001. Soto B, Becker AE, Moulaert AJ, et al.: Classification of ventricular septal defects, Br Heart J 43:332–343, 1980. Stout KK, Daniels CJ, Aboulhosn JA, et al.: Transposition of the great arteries, Circulation 114:2699–2709, 2006.

7 Valvular Heart Disease Christopher Song

INTRODUCTION In developing countries, rheumatic heart disease (RHD) remains a common cause of valvular heart disease (VHD). In industrialized countries, the burden of rheumatic disease has significantly decreased, and the most common etiology is degenerative disease. The prevalence of VHD in the US adult population is 2.5%. Prevalence increases with age to as high as 13.3% in those 75 years and older. Moderate or severe VHD is associated with excess mortality. Therefore, with an aging population, valvular heart disease is and will continue to be a major public health problem. The “2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease” provides a classification of the progression of VHD with 4 stages, A through D (Table 7.1). Timing of intervention for most VHD is guided by the onset of symptoms, severity of VHD, and evidence of adverse cardiac remodeling. Therefore, a thorough history and physical examination along with a comprehensive transthoracic echocardiogram (TTE) are essential in the evaluation of patients with known or suspected VHD. Other cardiac testing modalities can help to determine the severity of VHD and the presence of symptoms. Once intervention is contemplated, each individual patient’s surgical risk should be assessed. If surgical risk is high or prohibitive, transcatheter approaches may be an option.

AORTIC STENOSIS Definition and Etiology Valvular aortic stenosis (AS) is defined by restriction in leaflet motion resulting in left ventricular (LV) outflow obstruction. Less common causes of LV outflow obstruction include lesions at the supravalvular or subvalvular level. There are three primary etiologies of valvular AS: congenital, rheumatic, and calcific disease. The etiology often dictates age at presentation. Patients with congenital aortic stenosis and unicuspid aortic valves usually present before the age of 30. Those with a bicuspid aortic valve or rheumatic valve disease typically present between the age of 40 and 60. Patients with calcific trileaflet valve typically present after age 70. However, patients with Paget disease or end-stage renal disease may present at a younger age.

Pathophysiology The initiation phase of calcific aortic valve disease is similar to atherosclerosis. The process is thought to begin with mechanical stress and endothelial damage leading to inflammation and lipid deposition. The propagation phase is dominated by calcification leading to progressive restriction of the valve leaflets and eventual LV outflow obstruction.

64

In bicuspid aortic valves there is an associated increase in mechanical stress which leads to accelerated calcification of the valve leaflets. Bicuspid aortic valve occurs in about 1% of the population and it is twice as common in males as in females. Patients with a bicuspid aortic valve often have an associated aortopathy such as coarctation or aortic aneurysm. Once AS becomes hemodynamically significant, it leads to resistance in LV ejection and an increase in LV systolic pressure and wall stress. In order to maintain normal wall stress, wall thickness increases resulting in concentric hypertrophy. The left ventricle can remain in this compensated state for a prolonged period. However, as valvular stenosis and hypertrophy progress, LV end-diastolic pressure increases and, eventually, LV dilation and systolic dysfunction ensue.

Natural History and Clinical Presentation Patients with AS are usually asymptomatic for a prolonged period. Symptom onset occurs when valve obstruction is severe and usually prior to the onset of LV systolic dysfunction. In fact, LV chamber size and systolic function can remain normal until the AS is end-stage. The onset of symptoms in AS indicates a significant increase in mortality risk. This was first described by Ross and Braunwald in their seminal paper in 1968. They also found that specific symptoms were associated with different survival rates. The average survival of patients with symptoms of angina, syncope, and heart failure was 5, 3, and 2 years, respectively (Fig. 7.1). These “classic” symptoms are now thought to be symptoms of end-stage disease. With the advent of echocardiography and close follow-up of patients, the most common presenting symptoms are dyspnea on exertion or decreased exercise tolerance, exertional dizziness, and exertional angina. Given the nonspecific nature of these symptoms along with the prognostic and therapeutic implications of diagnosing a patient with severe symptomatic AS, one must be thorough in screening patients for these symptoms but also be cautious in attributing these symptoms to AS.

Physical Examination The physical examination is useful in the initial detection of AS and correlates with severity (Table 7.2). However, no physical examination findings can reliably exclude severe AS. When palpating the carotid artery, a delayed, low amplitude pulse may be appreciated (pulsus parvus et tardus). With precordial palpation, a heaving and sustained apical impulse may be noted due to LV hypertrophy or systolic dysfunction. A fourth heart sound (S4) can be palpable in the setting of a noncompliant left ventricle. In addition, a

CHAPTER 7  Valvular Heart Disease

65

TABLE 7.1  Stages of Progression of VHD Stage

Definition

Description

A B C

At risk Progressive Asymptomatic severe

D

Symptomatic severe

Patients with risk factors for development of VHD Patients with progressive VHD (mild-moderate severity and asymptomatic) Asymptomatic patients who have the criteria for severe VHD: C1: asymptomatic patients with severe VHD in whom the left and right ventricle remain compensated C2: asymptomatic patients with severe VHD with decompensation of the left or right ventricle Patients who have developed symptoms as a result of VHD

Percent survival

Data from Nishimura R, Otto C, Bonow RO, et al: 2014 AHA/ACC guideline for the management of patients with valvular heart disease. J Am Coll Cardiol 2014;63:e57-e185.

100

Latent period

80

(Increasing obstruction, myocardial overload)

60

Onset severe symptoms Angina Syncope Failure 2 3 5 AV. survival, years

40 20

Average age death 40

50

60 63 70 80 Age, years Fig. 7.1  Natural history of severe aortic stenosis without surgery once symptoms develop. (Data from Ross J Jr, Braunwald E: Aortic stenosis, Circulation 38:61, 1968.)

precordial thrill may be appreciated due to turbulent blood flow across a stenotic aortic valve. The findings on cardiac auscultation are reflective of reduced mobility and delayed closure of the aortic valve leaflets and resistance to flow. The aortic component (A2) of the second heart sound (S2) becomes delayed to occur simultaneously with the pulmonic component (P2) forming a single S2. In severe AS, A2 may become inaudible or paradoxical S2 can be observed. An aortic ejection click can be heard in mild to moderate AS, when the leaflets are stiff but still mobile. The classic murmur AS is described as a harsh crescendo-decrescendo systolic murmur that is best heard at the right upper sternal border that radiates to the carotid arteries. The murmur begins after the first heart sound (S1) and ends before S2. Like the carotid pulse, the timing of the murmur correlates with severity of AS. An early peaking murmur is indicative of mild or moderate AS whereas a late peaking murmur is typically a sign of severe AS. The murmur may also radiate to the apex where a distinct musical quality can be appreciated. This is known as Gallavardin’s phenomenon and often mistaken as the presence of concomitant mitral regurgitation (MR).

Diagnosis An electrocardiogram (ECG) and chest radiograph are commonly obtained and can have nonspecific findings such as LV hypertrophy or cardiomegaly, respectively. The primary tool for diagnosing AS is echocardiography. TTE can accurately assess the aortic valve structure, the severity of AS, and the effects of AS on the cardiac chambers. Doppler imaging can be used to estimate the gradients across a stenotic aortic valve and calculate an aortic valve area. Criteria for mild, moderate, and severe AS are well established (Table 7.3). In most cases the severity of AS by TTE correlates with the clinical evaluation. If there is a discrepancy, further testing can be considered.

An exercise treadmill study can be done to objectively assess functional capacity. A cardiac catheterization with hemodynamic measurements provides an alternative assessment of the severity of AS. Computed tomography can quantify aortic valve calcium, which has been shown to correlate with AS severity by TTE and with clinical outcomes. In patients with LV systolic dysfunction, it may be unclear if a patient has true severe AS or pseudosevere AS. A low-dose dobutamine stress echocardiogram can help to differentiate between the two. In true severe AS the valve area is fixed, regardless of dobutamine. In pseudosevere AS the aortic valve opening is limited by the low LV outflow and the valve area will increase with dobutamine. This test can also provide information about the contractile reserve of the left ventricle, which has prognostic implications when considering valve replacement.

Treatment The management of asymptomatic AS involves close monitoring, early detection of symptoms, and treatment of cardiovascular risk factors and comorbidities such as hypertension, hyperlipidemia, and coronary artery disease. No treatments have been shown to prevent the progression of AS. Once a patient develops severe symptomatic AS, medical therapy has limited benefit and aortic valve replacement (AVR) is recommended. Medical therapy should focus on preventing and optimizing concomitant cardiovascular conditions and treating symptoms. Nonetheless, AVR has been shown to improve symptoms and survival and it is the only effective treatment in severe symptomatic AS. Those with severe asymptomatic AS may also meet indications for AVR if they have concurrent LV systolic dysfunction, very severe AS, rapidly progressing AS, or if they are undergoing another cardiac surgery. There are two broad approaches to AVR: surgical and transcatheter. For decades, surgical AVR was the mainstay of therapy for severe AS. With surgical AVR, either a mechanical or bioprosthetic valve can be considered. With favorable flow characteristics, mechanical valves can last for the patient’s lifetime (Fig. 7.2). However, these valves require anticoagulation with warfarin. While bioprosthetic valves, made from bovine or porcine material, do not require anticoagulation, they are less durable and typically require re-replacement after 10 to 20 years (Fig. 7.3). Rather than an open procedure requiring sternotomy, transcatheter aortic valve implantation (TAVI) most commonly involves accessing the femoral artery and using a catheter to deliver a bioprosthetic valve into position by expanding a balloon and effectively crushing the native aortic valve against the aortic wall (Fig. 7.4). Less common approaches include transapical, transaortic, and subclavian. The role of TAVI was initially established in patients with severe symptomatic AS and prohibitive surgical risk. TAVI led to significant mortality benefit

66

SECTION II  Cardiovascular Disease

TABLE 7.2  AS Exam Findings by Severity Exam Finding

Mild

Moderate

Severe

Carotid pulse Apical impulse S4 gallop Systolic ejection click Systolic murmur peak S2

Normal Normal Absent Present Early systole Normal

Slow rising Heaving May be present May be present Mid systole Normal or single

Parvus et tardus Heaving and sustained Present Absent Mid or late systole Single or paradoxical

TABLE 7.3  Measures of AS Severity on Echocardiography Indicator (cm2)

Aortic valve area Mean gradient (mm Hg) Peak jet velocity (m/s)

Normal

Mild

Moderate

Severe

>2.0

1.5-2.0 4

1.5 cm2 Rheumatic valve changes with commissural fusion and diastolic doming of the mitral leaflets MVA ≤1.5 cm2 (MVA 1.5 cm2 if there is evidence of hemodynamically significant MS during exercise PMBV may be considered for severely symptomatic patients (NYHA class III/IV) with severe MS (MVA ≤1.5 cm2, stage D) who have suboptimal valve anatomy and are not candidates for surgery or at high risk for surgery Concomitant MVR may be considered for patients with moderate MS (MVA 1.6 to 2.0 cm2) undergoing other cardiac surgery MVR and excision of the left atrial appendage may be considered for patients with severe MS (MVA ≤1.5 cm2, stages C and D) who have had recurrent embolic events while receiving adequate anticoagulation cm2,

I I I IIa IIa IIb IIb IIb

IIb IIb

Modified from Nishimura R, Otto C, Bonow RO, et al: 2014 AHA/ACC guideline for the management of patients with valvular heart disease. J Am Coll Cardiol 2014;63:e57-e185.

Pathophysiology In PS, the valve is typically trileaflet with thickening and fusion of the commissures resulting in restricted leaflet opening during systole. Post-stenotic dilation of the main pulmonary artery can occur due to eccentric flow through the stenotic valve. Over time, RVH can occur due to increased afterload.

Natural History and Clinical Presentation Isolated PS is generally well tolerated and survival is comparable to the general population. Patients with mild PS are asymptomatic and may not be diagnosed with PS until adulthood. Moderate PS is usually identified in childhood and patients are usually symptomatic due to RV pressure overload. Decreasing right-sided cardiac output leads to

symptoms of dyspnea on exertion and fatigue. In more advanced disease, patients can have RV failure and cyanosis.

Physical Examination On physical examination, patients with PS can have a parasternal lift as a result of RVH. The jugular veins may demonstrate prominent a waves. The murmur of PS is a systolic ejection murmur best heard at the left upper sternal border radiating to the back with the duration correlating with severity. A late peaking murmur indicates more severe disease. A systolic ejection click may be heard in mild to moderate PS. S2 can have wide splitting due to prolonged ejection time of the right ventricle. Fixed splitting of S2 occurs in severe disease when the RV output becomes fixed.

70

SECTION II  Cardiovascular Disease

Diagnosis TTE can be used to diagnose PS, assess the severity of PS, and evaluate the right ventricle. Using Doppler measurements, the gradients across a stenotic pulmonic valve can be estimated. If TTE is inconclusive or for patients with complex anatomy, cardiac magnetic resonance imaging (CMR) can be considered as an alternative imaging modality to assess the severity of valve disease and quantitatively measure RV size and function.

Treatment Intervention is guided by the valve anatomy, gradients measured on TTE, and the presence of symptoms. Percutaneous balloon valvotomy is recommended in asymptomatic patients with a peak gradient of greater than 60 mm Hg or a mean gradient of 40 mm Hg, or in symptomatic patients with a peak gradient of 50 mm Hg or a mean gradient of 30 mm Hg. A surgical approach is usually recommended for dysplastic valves, in the presence of severe pulmonic regurgitation, or if there is another indication for surgery.

TRICUSPID STENOSIS Definition and Etiology In tricuspid stenosis (TS), there is restriction of blood flow between the right atrium and right ventricle. The etiology of TS is most commonly rheumatic and is generally associated with MS. Isolated TS is rare but can be seen in congenital tricuspid valve atresia, right heart tumors, carcinoid syndrome, and endocarditis.

Pathophysiology TS causes flow obstruction at the level of the tricuspid valve resulting in a diastolic pressure gradient between the right atrium and right ventricle. This leads to elevated right atrial pressure (RAP) and systemic venous congestion. With exertion or tachycardia, diastolic filling time decreases and the diastolic pressure gradient increases. With inspiration, the decrease in intrathoracic pressure results in increased venous return which also increases the pressure gradient across the tricuspid valve. Conversely, expiration leads to a decrease in the pressure gradient.

Natural History and Clinical Presentation The natural history of patients with TS is variable. Most patients with rheumatic TS have concomitant significant aortic and/or mitral valve disease. Tricuspid valve atresia is managed with multiple surgeries starting in the neonatal period into early childhood. Patients present with signs and symptoms of systemic venous congestion including ascites, peripheral edema, and hepatomegaly. Patients may report a fluttering sensation in the neck from prominent a waves.

Physical Examination With an increase in RAP there is jugular venous distension. A prominent a wave can often be appreciated. A rise in jugular venous pressure with inspiration (Kussmaul sign) may also be seen. Other signs of systemic venous congestion can be present including hepatomegaly, ascites, peripheral edema, and anasarca. The murmur of TS is described as a low-frequency, diastolic murmur best heard at the left lower sternal border. There may also be an opening snap. These sounds are difficult to distinguish from the murmur and opening snap of MS. However, with right-sided murmurs, the intensity of the TS murmur should increase with inspiration (Carvallo sign).

Diagnosis TS can be diagnosed using TTE. In rheumatic TS, as seen in MS, the leaflets are restricted, thickened, and calcified. TTE is also used to assess for concomitant valve disease and to estimate the right atrial size

and pressure. Using Doppler, the diastolic pressure gradients can be measured across the tricuspid valve and the tricuspid valve area can be estimated. A valve area of 1.0 cm2 or less is considered to be severe TS.

Treatment There are limited data to guide treatment in TS. Options include medical therapy such as diuretics to help with systemic venous congestion, surgical intervention, or percutaneous balloon valvotomy. The decision for surgical versus percutaneous approach should be individualized and based on valve anatomy, surgical risk, and operator experience. A surgical approach is typically reserved for symptomatic patients with severe TS or asymptomatic patients with severe TS requiring cardiac surgery for another indication.

AORTIC REGURGITATION Definition and Etiology Aortic regurgitation (AR) is the result of inadequate coaptation of the aortic valve leaflets during diastole leading to regurgitant flow of blood from the aorta to the left ventricle. The ability of the left ventricle to accommodate this additional volume is dependent on the chronicity of the disease. Therefore, acute severe AR and chronic AR should be considered as separate disease processes. The two most common causes of acute severe AR in a native aortic valve are endocarditis and aortic dissection. Endocarditis can lead to leaflet destruction, leaflet perforation, or perivalvular abscess that can rupture into the left ventricle. Aortic dissection can result in AR by dilation of the sinuses, involvement of the commissures or leaflets, or prolapse of the dissection flap across the aortic valve. In developing countries, chronic AR is usually due to rheumatic heart disease. In developed countries, aortic root dilation, calcific degeneration, and bicuspid aortic valve are the most common causes. However, many other disease processes can affect the aortic valve or the ascending aorta and lead to chronic AR (Table 7.7).

Pathophysiology In acute severe AR, a large regurgitant volume enters an unprepared left ventricle which results in a decrease in effective stroke volume and rapid increase in LV end-diastolic pressure with subsequent pulmonary edema, cardiogenic shock, and possible hemodynamic collapse. In chronic AR, the left ventricle is able to make compensatory changes to maintain cardiac output. The regurgitant flow from the aorta into the left ventricle results in an increase in LV end-diastolic volume and wall stress. In response, there is eccentric hypertrophy, chamber dilation, and an increase in ventricular compliance. Therefore, LV end-diastolic pressure can remain normal despite a significant increase in LV volume. In addition, these compensatory changes can lead to an increase in total stroke volume, which results in an elevation in systolic pressure. During diastole, there is rapid equalization of pressures between the aorta and left ventricle resulting in a low diastolic pressure. This accounts for the wide pulse pressure and several of the characteristic physical examination findings seen in chronic AR.

Natural History and Clinical Presentation Patients with acute severe AR often present with pulmonary edema and cardiogenic shock. Other presenting symptoms will depend on the etiology, which is usually aortic dissection or endocarditis. In contrast, there is a prolonged asymptomatic period in chronic AR. Even with severe AR, exercise tolerance can be preserved as an increase in heart rate during exercise leads to shorter diastolic filling times, and thus less AR. However, with progressive LV dilation,

CHAPTER 7  Valvular Heart Disease

71

TABLE 7.7  Causes of Chronic Aortic Regurgitation Mechanism

Etiology

Congenital/leaflet abnormalities

Bicuspid, unicuspid, or quadricuspid aortic valve Ventricular septal defect Senile calcification Infective endocarditis Rheumatic disease Radiation-induced valvulopathy Toxin-induced valvulopathy: anorectic drugs, 5-hydroxytryptamine Annuloaortic ectasia Connective tissue disease: Loeys Dietz, Ehlers-Danlos, Marfan syndrome, osteogenesis imperfecta Idiopathic aortic root dilation Systemic hypertension Autoimmune disease: systemic lupus erythematosus, ankylosing spondylitis, reactive arthritis Aortitis: syphilis, Takayasu arteritis Aortic dissection Trauma

Acquired leaflet abnormalities

Congenital/genetic aortic root abnormalities Acquired aortic root abnormalities

Modified from: Zoghbi W, Adams D, et al: Recommendations for noninvasive evaluation of native valvular regurgitation. JASE 2017;30:303-371.

patients can develop LV systolic dysfunction and symptoms of heart failure.

Physical Examination Patients with acute severe AR will have physical examination findings consistent with cardiogenic shock and pulmonary edema such as hypotension, pallor, peripheral vasoconstriction, and rales. Wide pulse pressures and the characteristic findings seen in chronic AR are typically not appreciated. With regards to the heart sounds in acute severe AR, A2 may be diminished, P2 is more prominent due to pulmonary hypertension, and S3 can be heard. The murmurs heard in acute AR include an early, low-pitched, diastolic murmur and a soft systolic murmur due to increased flow across the aortic valve. The presence of both results in a characteristic “to-and-fro” murmur. However, depending on the diastolic gradient between the aorta and left ventricle, these murmurs may be inaudible. The wide pulse pressure seen in chronic AR can lead to several physical findings (Table 7.8). The murmur of chronic AR is a blowing early diastolic murmur best heard at the left upper sternal border with the patient sitting up, leaning forward, and at end-expiration. As AR progresses, this murmur can become holodiastolic and harsher in quality. In very severe AR, the murmur can become soft or even absent. An Austin-Flint murmur, a mid to late diastolic rumble best heard at the apex in severe AR and due to vibration of the anterior mitral leaflet as it is struck by the jet of AR, may also be appreciated. Additionally, a short midsystolic ejection murmur radiating to the neck can be heard as a result of increased stroke volume.

Diagnosis In both acute and chronic AR, echocardiography can evaluate the presence, severity, and mechanism of AR, the effect of AR on the other cardiac chambers, and the presence of concomitant valve disease. In the case of acute severe AR with suspected aortic dissection or endocarditis, a transesophageal echocardiogram (TEE) should be considered over TTE given its superior sensitivity and specificity for these diagnoses. Computed tomography (CT) imaging has similar sensitivity and specificity for diagnosing aortic dissection. However, TEE also allows for concomitant evaluation of the aortic valve structure, AR, and the other cardiac structures.

In the assessment of chronic AR, when the TTE results are inconclusive or discrepant from clinical findings, alternative imaging modalities can be considered. TEE generally provides superior image quality compared to TTE. CMR can accurately quantify the severity of AR as well as chamber sizes and LV systolic function. Aortography and cardiac catheterization may also be considered to evaluate AR, aortic root, and left-sided filling pressures. However, their role has diminished because of the availability and accuracy of noninvasive imaging.

Treatment In acute severe AR, emergent or urgent surgical intervention is usually indicated in the setting of aortic dissection or infective endocarditis. Prior to surgery, the mainstay of medical therapy is afterload reduction. This can be achieved with intravenous nitroprusside. Diuretics and ionotropic agents may be helpful in the setting of cardiogenic shock and pulmonary edema. Beta-blockers, while helpful for aortic dissection, can lead to further hemodynamic deterioration as the increase in diastolic filling time leads to more AR. Vasopressors and intra-aortic balloon pumps are contraindicated in this setting. With chronic AR, there is a limited role for medical therapy. Vasodilators such as hydralazine, angiotensin-converting enzyme (ACE) inhibitors, and calcium-channel blockers can be used in patients who are asymptomatic and hypertensive. There is conflicting evidence for their use to delay surgery. AVR is recommended once a patient has severe symptomatic AR or severe asymptomatic AR with a LV systolic dysfunction (left ventricular ejection fraction (LVEF) of less than 50%) or chamber dilation (LV end systolic diameter (LVESD) of greater than 50 mm or LV end diastolic diameter (LVEDD) of greater than 65 mm). AVR is also indicated in patients with severe asymptomatic AR if there is another indication for cardiac surgery. The options for mechanical and biologic prostheses are similar to those for surgical AVR for AS. However, a percutaneous approach is not available.

MITRAL REGURGITATION Definition and Etiology Mitral regurgitation (MR) is defined by the inadequate coaptation of the mitral leaflets during systole resulting in regurgitant flow from the left ventricle to the left atrium. Similar to AR, MR leads to LV volume overload

72

SECTION II  Cardiovascular Disease

TABLE 7.8  Signs of Chronic Aortic

Regurgitation Name

Description

Corrigan pulse

Rapid upstroke and collapse of pulses; “water hammer pulses” Head bob with each heartbeat Systolic and diastolic sounds heard over femoral arteries; “pistol shot pulse” Systolic and diastolic bruit heard with compression of femoral artery Capillary pulsations Pulsation of uvula Pulsation of retinal arteries and pupils Popliteal systolic cuff pressure exceed brachial pressure by >20 mm Hg >15 mm Hg decrease in diastolic blood pressure with arm elevation Pulsations of liver Pulsations of spleen

Musset sign Traube sign Duroziez sign Quincke pulses Mueller sign Becker sign Hills sign Mayne sign Rosenbach sign Gerhard sign

Anterior mitral annulus Medial commissure

Lateral commissure Anterior mitral leaflet

C Posterior annulus

Posterior mitral leaflet (3 scallops)

Chordae tendineae

Lateral papillary m.

Pathophysiology The pathophysiology of MR and the differences in the pathophysiology between acute and chronic MR are illustrated in Fig. 7.8. In acute severe MR, there is a sudden increase in preload and decrease in afterload. This leads to an increase in the total stroke volume (TSV) and LVEF. However, the forward stroke volume (FSV) decreases resulting in reduced cardiac output. Simultaneously, there is an acute rise in LAP causing pulmonary edema. This ultimately leads to cardiogenic shock. In chronic compensated MR, the progressive rise in LV preload leads to increased wall stress. In response, there is eccentric hypertrophy of the left ventricle and an increase in the LV end diastolic volume. This not only increases LVEF and TSV, but it also allows for the maintenance of a normal FSV. However, as MR progresses, LV systolic dysfunction and dilation occur. In this setting, LVEF, TSV, and FSV all decrease, resulting in chronic decompensated MR. In chronic MR, the compliant left atrium is able to accommodate a large regurgitant volume from the left ventricle. However, this eventually results in left atrial dilation and pulmonary hypertension.

Natural History and Clinical Presentation

M

L

Given the complexity of the mitral apparatus, it is useful to categorize the causes of MR as primary or secondary (Table 7.9). Primary MR is due to an intrinsic abnormality of the mitral leaflets. Secondary MR is a result of distortion of the mitral annulus in the setting of ventricular remodeling. Distinguishing between primary and secondary MR is important because the management and outcomes differ. Alternatively, MR can be classified based on leaflet motion using the Carpentier classification (Fig. 7.7).

Medial papillary m.

Fig. 7.6  Mitral apparatus. (From Otto C: Textbook of Clinical Echocardiography, 6th ed., Elsevier, 2018.)

and the ability of the left ventricle to compensate for this additional volume is dependent upon chronicity. Therefore, like AR, acute severe MR and chronic MR should be considered as two distinct disease processes. The mitral apparatus consists of the left atrial wall, mitral annulus, anterior and posterior leaflets, chordae tendineae, papillary muscles, and the LV myocardium underlying the papillary muscles (Fig. 7.6). Disturbance to any component of the mitral apparatus can result in MR. Acute MR can be caused by ischemic and nonischemic etiologies. Papillary muscle rupture or displacement can be seen in the setting of an acute myocardial infarction or ischemia. Nonischemic causes include infective endocarditis, ruptured chordae tendineae, trauma, RHD, and dynamic LV outflow obstruction.

Patients with acute severe MR are acutely ill and often in cardiogenic shock. Along with hemodynamic instability, patients may have symptoms related to the etiology of MR. For example, in the setting of an acute myocardial infarction with papillary muscle rupture, a patient may present with chest pain along with ischemic ECG changes and elevated cardiac enzymes. Patients with infective endocarditis may have fevers, positive blood cultures, vascular phenomena, immunologic phenomena, or a predisposing condition such as intravenous drug use. With chronic MR, the natural history and clinical presentation are quite different because the left ventricle has time to remodel and compensate via the mechanisms noted above. Often times, patients have a prolonged asymptomatic phase. Over time, as the left-sided filling pressures increase, patients may develop fatigue or decreased exercise tolerance. Eventually, patients can have signs and symptoms of congestive heart failure (CHF) such as dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, and/or peripheral edema. With left atrial dilation, patients may develop AF.

Physical Examination Patients with acute severe MR are often in pulmonary edema and cardiogenic shock. Physical examination may be remarkable for pallor, cool extremities due to peripheral vasoconstriction, rales, jugular venous distension, and diminished peripheral pulses. The murmur of acute severe MR is usually soft, low-pitched, decrescendo, and early systolic. However, in about half of the patients, no murmur may be appreciated due to the low-pressure gradient between the left ventricle and the left atrium. Therefore, the absence of a systolic murmur does not necessarily rule out acute severe MR. In chronic MR, S1 is diminished due to inadequate coaptation of the mitral leaflets. S2 is widely split with a reduced forward stroke volume leading to an early A2 and pulmonary hypertension delaying P2. An S3 can also be appreciated with the increased diastolic flow across the mitral valve into a left ventricle. The murmur of chronic MR is

CHAPTER 7  Valvular Heart Disease

73

TABLE 7.9  Mechanisms of Mitral Regurgitation Valvular Abnormality Primary Mitral Regurgitation Degenerative Rheumatic Infectious endocarditis Systemic inflammatory conditions Malignancy associated Genetic connective tissue disorders (Marfan syndrome, Ehlers-Danlos syndrome) Irradiation Drug-induced (anorexigen, ergotamine) Congenital Secondary Mitral Regurgitation

Mitral valve prolapse, thickening/calcification Leaflet thickening/restriction Vegetations, tissue destruction, leaflet perforation Libman-Sacks lesions Marantic endocarditis Elongated, redundant leaflet tissue Diffuse leaflet thickening/calcification Diffuse leaflet thickening Cleft/parachute mitral valve Ventricular distortion of mitral apparatus (coronary artery disease, cardiomyopathy) Mitral annular dilation (usually with atrial fibrillation)

Modified from Otto C: Practice of Clinical Echocardiography, Fifth Edition. Philadelphia, Elsevier, 2017. Normal

Acute MR EDV=120 ESV=50

Chordae tendineae Anterolateral papillary muscle

Posterolateral papillary muscle

A

Type I

LAP 10

EDV=120 ESV=30

LAP 25 TSV=70 FSV=70 RSV=0

TSV=90 EF=0.58

FSV=45 RSV=45

EF=0.75

A

B

Chronic Compensated MR

Chronic Decompensated MR

Type II

EDV=220 ESV=100

EDV=200 ESV=60

LAP 15

C

LAP 25 TSV=140 FSV=70 RSV=70

TSV=120

EF=0.7

D

FSV=60 RSV=60

EF=0.55

Fig. 7.8  Pathophysiology of mitral regurgitation. (From Otto C: Textbook of Clinical Echocardiography, 5th ed., Elsevier, 2013.)

Type IIIa

Type IIIb (ischemic)

most commonly a blowing, high-pitched, holosystolic murmur best heard at the apex. Depending on the direction of the MR jet, the murmur may radiate toward the axilla or the neck. In MR due to mitral valve prolapse, a midsystolic click can be heard followed by a mid or late systolic murmur.

Diagnosis

B Fig. 7.7  (A) Mitral apparatus. (B) Carpentier classification of mitral regurgitation. (From Interventional Cardiology Clinics, Volume 5, Issue 1, 2016.)

An electrocardiogram (ECG) and chest radiograph may have nonspecific findings such as left atrial enlargement or cardiomegaly, respectively. Pulmonary edema can be seen on chest radiograph in the setting of CHF. However, the diagnosis of MR is ultimately made by TTE, which can assess for the presence and severity of MR, the effect of MR on the other cardiac chambers, the presence of concomitant valve disease, and possibly the etiology of MR. If TTE is inadequate, there are other imaging modalities that are useful. CMR can be used to accurately

74

SECTION II  Cardiovascular Disease

quantify the chamber sizes, LVEF, and the severity of MR. TEE can provide superior image quality to TTE, including three-dimensional imaging, and help to clarify the severity and anatomic mechanism of MR. In the case of acute severe MR, if the level of suspicion is high and the TTE does not show significant MR, a TEE can be performed. Alternatively, a right heart catheterization can be considered. In the presence of significant MR, the pulmonary capillary wedge waveform would have prominent v waves from the regurgitant flow from the left atrium. Finally, in patients who have symptoms that are out of proportion to the severity of MR, exercise echocardiography can be considered to assess for changes in MR and pulmonary artery pressure with exercise.

Mitralclip device

Arm

Gripper

Treatment In acute severe MR, emergent or urgent surgical intervention is usually indicated. Until surgery can be performed, afterload reduction is essential. This is achieved with an intra-aortic balloon pump which not only reduces afterload but also improves cardiac output and coronary blood flow. Nitroprusside can also be given to reduce afterload and ionotropic agents can be given for hemodynamic support. In the absence of hypotension, diuretics can be given to treat pulmonary edema. There is no clear role for medical therapy in treating the primary process of chronic MR. The use of vasodilators in normotensive patients with normal LV systolic function is not recommended. Hypertensive patients can be treated with standard antihypertensive therapy which may limit worsening of MR. Patients with LV systolic dysfunction can be given guideline-directed medical therapy (ACE inhibitors/angiotensin-receptor blockers/angiotensin receptor–neprilysin inhibitor, β-blocker, aldosterone antagonist, and diuretics). The indication for mitral valve intervention depends on several factors. If a patient has severe symptomatic MR, mitral valve surgery is recommended. If a patient has severe asymptomatic MR and LVEF between 30% and 60%, LVESD 40 mm or greater, or if there is a progressive decrease in LVEF or increase in LVESD, then mitral valve surgery is also recommended. Also, in patients with severe asymptomatic MR with new onset AF or pulmonary hypertension, mitral valve repair can be considered if the likelihood of successful repair is greater than 95% and the expected mortality is less than 1%. In general, there is a higher chance of successful repair in primary MR involving the posterior leaflet. Mitral valve repair is preferred over mitral valve replacement, when possible. For patients with prohibitive surgical risk, transcatheter mitral valve repair (TMVR) can be considered (Figs. 7.9 and 7.10). Patients with prohibitive surgical risk, at least moderate to severe primary MR with NYHA class III or IV symptoms despite optimal medical therapy, favorable anatomy, and reasonable life expectancy (≥2 years), should be referred to a heart valve team for evaluation for TMVR. Trials assessing the benefit of TMVR in secondary MR have yielded conflicting results. Nonetheless, TMVR has been approved for moderate to severe or severe secondary MR.

Mitralclip system

Clip delivery system

Steerable guide handle

Steerable guide, Steerable sleeve and delivery catheter

Delivery catheter handle

Stabilizer

Mitralclip device

Fig. 7.9  Mitralclip delivery system. (Modified from Abbott Vascular.)

PULMONIC REGURGITATION Definition and Etiology Pulmonic regurgitation (PR) is a result of inadequate coaptation of the pulmonic leaflets resulting in diastolic flow from the pulmonary artery to the right ventricle. Physiologic to mild PR is common in normal adults. Primary PR is due to an abnormality of the valve leaflets. Causes of primary PR include iatrogenic, endocarditis, RHD, carcinoid syndrome, and congenital. Secondary PR occurs in the setting of normal valve leaflets and can be seen in patients with pulmonary artery dilation or severe pulmonary arterial hypertension. Severe PR is most

Fig. 7.10  Transcatheter mitral valve repair. (From Interventional Cardiology Clinics, Volume 5, Issue 1, 2016.)

CHAPTER 7  Valvular Heart Disease commonly seen in patients with of tetralogy of Fallot who underwent surgical valvotomy or balloon valvuloplasty.

75

Regurgitant diastolic flow from the main pulmonary artery to the right ventricle leads to RV volume overload. Eventually, patients may develop RV dilation, RV dysfunction, and TR.

Secondary TR occurs in the setting of normal valve anatomy and is much more common. TR is most often a result of RV dilation, annular dilation, or leaflet tethering. This can occur in any condition with increased right-sided filling pressures or pulmonary hypertension such as left-sided heart failure, mitral valve disease, stenosis of the pulmonic valve or pulmonary artery, primary pulmonary disease, left-to-right shunting, and Eisenmenger syndrome.

Natural History and Clinical Presentation

Pathophysiology

Patients with PR typically have a prolonged asymptomatic phase. As RV systolic function declines, cardiac output decreases and patients can develop fatigue or decreasing exercise tolerance. With RV dilation, TR and elevated right-sided filling pressure may develop along with signs and symptoms of right-sided heart failure such as ascites, peripheral edema, and hepatosplenomegaly.

With regurgitant systolic flow into the right atrium, there is a progressive increase in RAP and RV volume. This leads to signs and symptoms of right-sided heart failure and low cardiac output due to RV systolic dysfunction.

Pathophysiology

Physical Examination The murmur of PR is an early diastolic murmur best heard over the left upper sternal border that increases in intensity with inspiration. A systolic ejection murmur may also be heard with more significant amounts of PR due to increased RV flow. With concomitant pulmonary hypertension, a high frequency, blowing, diastolic murmur (Graham-Steell murmur) may be present. On examination of the neck veins, a prominent a wave can be seen in pulmonary hypertension and a prominent v wave in TR.

Diagnosis ECG may have nonspecific findings such as RVH or arrhythmias. A right bundle branch block with intraventricular conduction delay can be observed in patients with a history of tetralogy of Fallot repair and severe PR. RV dilation may be seen on chest radiograph. TTE can confirm the diagnosis of PR and also evaluates the severity, etiology, and, hemodynamic effects of PR, as well as concomitant valvular disease or pulmonary hypertension. CMR can also provide a quantitative assessment of PR and RV size and function.

Treatment Medical therapy of secondary PR should target the underlying cause. Patients with right-sided heart failure can be given diuretics. However, surgical intervention is recommended for severe symptomatic PR. Surgery can also be considered for patients with severe asymptomatic PR with RV dilation or dysfunction, symptomatic arrhythmias, or progressive TR. In general, patients with native PR undergo surgical valve replacement. Due to the risk of prosthesis regurgitation and device embolization, a percutaneous approach is rarely recommended for native PR. Alternatively, for those with prosthetic PR, percutaneous valve replacement is an option.

Natural History and Clinical Presentation Since the right atrium is a compliant chamber, it is able to accommodate the regurgitant volume when TR is mild or moderate. Therefore, patients are usually asymptomatic. Once severe, patients may have symptoms of venous congestion and right-sided heart failure such as hepatosplenomegaly, ascites, and peripheral edema. Patients with significant pulmonary hypertension may have signs of reduced cardiac output such as fatigue and dyspnea on exertion.

Physical Examination TR leads to elevated RAP. This is demonstrated on physical examination by distended jugular veins. A prominent c-v wave due to the regurgitant flow may be observed. Kussmaul sign, a paradoxical rise in jugular venous pressure with inspiration, can be seen in the setting of RV dysfunction. With right-sided heart failure, peripheral edema, ascites, anasarca, and painful hepatosplenomegaly may be present. On cardiac exam, wide splitting of S2 and a loud P2 can be heard with pulmonary hypertension. S3 or S4 may also be present in the setting of RV dilation or hypertrophy. The murmur of TR is holosystolic and best heard at the mid left sternal border. The intensity of the murmur will increase with maneuvers that increase venous return such as inspiration, leg raise, and hepatic compression. An RV heave may be appreciated on palpation in the setting of RV dilation.

Diagnosis

TRICUSPID REGURGITATION

TR is diagnosed by TTE. Echocardiography can help to determine the severity and etiology of TR and RV size and function. In addition, Doppler can be used to estimate the pulmonary artery systolic pressure. If the TTE is inconclusive, CMR can quantify TR, RV size, and RV function. Right heart catheterization can provide direct measurements of right-sided pressures, pulmonary pressures, and pulmonary vascular resistance.

Definition and Etiology

Treatment

TR is defined by the inadequate coaptation of the tricuspid leaflets during systole resulting in regurgitant flow from the right ventricle to the right atrium. Physiologic TR is present in about 70% of healthy adults. Primary TR, a result of an abnormality of the valve structure, is rare. Possible causes include iatrogenic direct valve injury, chest wall trauma or deceleration injury, endocarditis, RHD, carcinoid syndrome, ischemic heart disease (causing papillary muscle dysfunction), myxomatous degeneration, Marfan syndrome, or drug-induced (fenfluramine, phentermine). The most common congenital heart disease affecting the tricuspid valve is Ebstein’s anomaly.

Medical therapy for severe TR and right-sided heart failure consists of diuretics to treat volume overload. If possible, the primary disease process should be treated such as in ischemic heart disease, left-sided heart failure, mitral valve disease, and pulmonary arterial hypertension. Isolated tricuspid valve surgery is only recommended in patients with severe symptomatic primary TR or severe asymptomatic TR with progressive RV dysfunction. If a patient is undergoing left-sided valve surgery, tricuspid valve surgery is recommended for those with concomitant severe TR or at least mild functional TR with tricuspid annular dilation or right-sided heart failure.

76

SECTION II  Cardiovascular Disease

SUGGESTED READINGS Mack M, Leon M, et al: Transcatheter aortic-valve replacement with a b ­ alloonexpandable valve in low risk patients, NEJM 380:1695–1705, 2019. Nishimura R, Otto C, Bonow RO, et al.: 2014 AHA/ACC Guideline for the management of patients with valvular heart disease, J Am Coll Cardiol 63:e57–e185, 2014.

Nishimura R, Otto C, Bonow RO, et al.: 2017 AHA/ACC focused update of the 2014 AHA/ACC Guideline for the management of patients with valvular heart disease, J Am Coll Cardiol 70:252–289, 2017. Nkomo V, Gardin J, et al.: Burden of valvular heart diseases: a ­populationbased study, Lancet 368:1005–1011, 2006. Obadia J, Messika-Zeitoun D, et al.: Percutaneous repair or medical treatment for secondary mitral regurgitation, NEJM 379:2297–2306, 2018.

8 Coronary Heart Disease David E. Lewandowski, Michael P. Cinquegrani

DEFINITION AND EPIDEMIOLOGY The term coronary heart disease (CHD) describes a number of cardiac conditions that result from the presence of atherosclerotic lesions in the coronary arteries. The development of atherosclerotic plaque within the coronary arteries can result in obstruction to blood flow, producing ischemia, which can be acute or chronic in nature. Atherosclerosis is a disease process that starts at a young age and can be present for years in an asymptomatic form until the degree of vessel obstruction leads to ischemic symptoms. Obstructive atherosclerotic lesions can cause chronic symptoms of exercise- or stress-related angina; or, in the case of plaque rupture and acute thrombosis, sudden death, unstable angina, or myocardial infarction (MI) may ensue. In the United States, more than 18 million people experience some form of CHD. Approximately 10 million suffer from symptoms of angina, and at least 360,000 deaths occur each year from acute MI or CHD-related sudden death. Despite progress in therapy and overall reductions in CHD-related mortality, CHD remains the number one cause of death in both men and women, accounting for 27% of deaths in women (more than deaths due to cancer). The incidence of CHD increases with age for both men and women. There are at least 1.3 million MIs per year in the United States and many more cases of unstable angina. CHD frequently results in lifestyle-limiting symptoms due to angina or impairment of left ventricular (LV) function. The cost of care related directly to CHD and indirectly to lost productivity from CHD is in the range of $156 billion per year. CHD remains a major life-threatening disease process associated with significant economic impact.

RISK FACTORS FOR ATHEROSCLEROSIS There are a number of well-known risk factors for coronary artery disease (CAD), some of which are modifiable (Table 8.1). Although women ultimately also carry a significant atherosclerotic burden, men develop CAD at younger ages, and the prevalence of the disease also increases as men age. Another potent risk factor for the development of CAD is a family history of premature CAD. This speaks to a nonmodifiable, genetically based risk. Commonly, multiple family members develop symptomatic CAD before the age of 55 years (65 years for women). Risks are additive, making it very important to appreciate the modifiable risk factors such as hyperlipidemia, hypertension, diabetes mellitus, metabolic syndrome, cigarette smoking, obesity, sedentary lifestyle, and heavy alcohol intake. Patients are risk-stratified for the likelihood of developing clinically significant coronary artery disease through the ASCVD (atherosclerotic cardiovascular disease)

score. Taking into account multiple patient-specific factors, the score estimates the patient’s 10-year probability of experiencing an adverse event such as nonfatal MI, cardiovascular death, or stroke. The score can help guide blood pressure goals, the need for statin therapy, and other key preventative measures against CAD. Metabolic syndrome deserves particular attention given that up to 25% of the adult US population may satisfy the definition of the disorder as laid out by the National Cholesterol Education Program Adult Treatment Panel. The definition of metabolic syndrome requires the presence of at least three of the following five criteria: waist circumference greater than 102 cm in men or 88 cm in women, triglyceride level 150 mg/dL or higher, high-density lipoprotein (HDL) cholesterol level lower than 40 mg/dL in men or 50 mg/dL in women, blood pressure 130/85 mm Hg or higher, and fasting serum glucose level 110 mg/dL or higher. The features of metabolic syndrome are largely modifiable risk factors for CAD. Hyperlipidemia, in particular elevated levels of low-density lipoprotein (LDL) cholesterol, plays a pivotal role in the development and evolution of atherosclerosis. HDL-cholesterol is believed to be protective, likely due to its role in transporting cholesterol from the vessel wall to the liver for degradation. Increased levels of HDL are inversely proportional to the risk of CAD-related problems. The interplay among circulating lipids is complex. Elevated levels of triglycerides are a risk factor for CAD and are frequently associated with reduced levels of protective HDL. Hyperlipidemia is highly modifiable, and clinical trials have shown that drug treatment directed at lowering LDL-cholesterol significantly reduces the risk of CAD-related complications or death. As with hyperlipidemia, hypertension contributes to the risk of CAD-related complications. Hypertension, probably through sheer stress, causes vessel injury that supports the development of atherosclerotic plaque. Increasing severity of hypertension is associated with greater risk of CAD. Control of hypertension is associated with a reduced risk of CAD. Recent guidelines advise more aggressive blood pressure goals for patients at high risk for coronary artery disease. Antihypertensive medications are advised for patients with a blood pressure greater than 130/80 and diabetes, chronic kidney disease, or an ASCVD 10-year risk of greater than 10%. Diabetes mellitus is a prominent risk factor for CAD, and the disease is becoming epidemic. Diabetes mellitus typically is associated with other risk factors, such as elevated triglycerides, reduced HDL, and hypertension, which accounts for the enhanced risk of CAD-related problems in diabetic patients. It is not clear that control of hyperglycemia in diabetic patients translates into a reduced risk of CAD, but the presence of diabetes mellitus drives the need to ensure good treatment

77

78

SECTION II  Cardiovascular Disease

TABLE 8.1  Risk Factors and Markers for

Coronary Artery Disease

Nonmodifiable Risk Factors Age Male sex Family history of premature coronary artery disease Modifiable Independent Risk Factors Hyperlipidemia Hypertension Diabetes mellitus Metabolic syndrome Cigarette smoking Obesity Sedentary lifestyle Heavy alcohol intake Markers Elevated lipoprotein(a) Hyperhomocysteinemia Elevated high-sensitivity C-reactive protein (hsCRP) Coronary arterial calcification detected by EBCT or MDCT EBCT, Electron beam computed tomography; MDCT, multidetector computed tomography.

of other modifiable risk factors. Although metformin remains the first-line agent for glycemic control, the new sodium-glucose cotransporter-2 (SGLT-2) inhibitors and the glucagon-like peptide-1 (GLP-1) receptor agonists have shown improvements in ASCVD outcomes in patients with diabetes and established CAD. Chronic kidney disease (CKD) is increasingly being recognized as a unique risk factor in the development of CAD. Although not recognized as a CAD risk equivalent to diabetes, patients with CKD, particularly end-stage renal disease (ESRD) on dialysis, have dramatically elevated risks of CAD compared to the general population. In addition, outcomes of acute coronary syndrome (ACS) in CKD patients are worse compared to the general population. Cigarette smoking has long been known as a significant risk factor for both CAD and lung cancer. Cigarette smoking is associated with increased platelet reactivity and increased risk of thrombosis, as well as lipid abnormalities. This addictive habit is modifiable, and smoking cessation can lead to a decrease in CAD event rates by 50% in the first 2 years of cessation. Similar to diabetes mellitus, obesity (body mass index >30 kg/m2) is associated with risk factors such as hypertension, hyperlipidemia, and glucose intolerance. Although multiple risk factors are frequently present in obese people, obesity itself carries some independent risk for CAD. The location and type of adipose tissue appear to influence CAD risk, with abdominal obesity posing a greater risk for CAD in men and women. Numerous clinical studies have shown the benefit of regular aerobic exercise in decreasing the risk for CAD-related problems, both in the people without known CAD and in those with the disease. Sedentary lifestyles carry an increased risk that is modifiable through exercise. Another common attribute of life, alcohol consumption, can influence the risk of CAD in both directions. One to two ounces of alcohol per day may reduce the risk for CAD-related events, but more than 2 ounces of alcohol per day is associated with an increased risk of events. Lower levels of alcohol consumption can increase HDL levels, although it is not clear that this is the mechanism of benefit. In contrast, excessive alcohol consumption is associated with hypertension, a definite risk for CAD, although other effects of high-dose alcohol may also be at play.

Additional factors that may have some role in adding CAD risk include lipoprotein(a) and homocysteine. Lipoprotein(a) is structurally similar to plasminogen and may interfere with the activity of plasmin, thus contributing to a prothrombotic state. Hyperhomocysteinemia has been associated with increased vascular risks, including coronary, cerebral, and peripheral vascular disease. It is not clear that a causal link exists, and the use of folic acid supplementation to lower homocysteine levels has not been shown to reduce the risk of MI or stroke. C-reactive protein (CRP) is a marker of systemic inflammation, and it indicates an increased risk for coronary plaque rupture. Highsensitivity assays for CRP (hsCRP) have measured elevated levels that correlate with risk for MI, stroke, peripheral vascular disease, and sudden cardiac death. Another marker for the presence of CAD is coronary calcification. The process of atherosclerosis is often associated with deposition of calcium within the plaque. Coronary artery calcification can be detected by fluoroscopy during cardiac catheterization as well as by computed tomography (CT) scanning using multidetector computed tomography (MDCT). CT technology allows for a quantitative measure of coronary calcium deposits that correlates with the probability of having significant obstructive lesions. Advantages to this method include low cost and relatively low radiation exposure. This technology can be used in conjunction with ASCVD score stratification to identify patients at elevated risk for MI. Patients in whom coronary calcification is identified should be approached with aggressive risk-factor modification. Historically, low-dose aspirin therapy (75-162 mg daily) has been recommended for patients deemed “high-risk” for CAD for the prevention of CAD-related adverse events. More recently, several trials looking at aspirin use for patients without CAD (primary prevention) failed to find a mortality benefit. Furthermore, in patients over age 70 there was a significantly increased risk of bleeding associated with aspirin use that outweighed any small reduction in ASCVD events. Given these findings, the use of aspirin for patients without established CAD is no longer routinely recommended. Aspirin use in patients with established CAD (secondary prevention) is still highly recommended.

PATHOLOGY The process of atherosclerosis is known to begin at a young age. Autopsies of teenagers frequently demonstrate the presence of atherosclerotic changes in coronary arteries. Atherosclerosis is a process linked to the subintimal accumulation of small lipoprotein particles that are rich in LDL. Subintimal deposits of LDL are oxidized, setting off a cascade of events that culminate in not only the development of atherosclerotic plaque but also vascular inflammation. Vascular inflammation drives progression of atherosclerosis as well as the potential rupture of plaque leading to vessel occlusion. The process of lipoprotein uptake by the vessel wall is enhanced by vascular endothelial injury, which may be triggered by hypercholesterolemia, the toxic effects of cigarette smoking, sheer stresses associated with hypertension, or vascular effects of diabetes mellitus. Oxidized LDL aggregates trigger the expression of endothelial cell surface adhesion molecules, including vascular adhesion molecule-1, intracellular adhesion molecule-1, and selectins, which results in the binding of circulating macrophages to the endothelium. In response to cytokines and chemokines released by endothelial and smooth muscle cells, macrophages migrate into the subintimal region, where they ingest oxidized LDL aggregates. These LDL-laden macrophages are also called foam cells (based on the microscopic appearance),

CHAPTER 8  Coronary Heart Disease and the accumulation of foam cells represents the development of atherosclerosis. Foam cells break down, releasing pro-inflammatory substances that promote ongoing accumulation of both macrophages and T lymphocytes. This process potentiates the development of atherosclerotic plaque. Growth factors are also released that promote smooth muscle cell and fibroblast proliferation. The net result is the development of a fibrous cap, which covers a lipid-rich core. Important contributors to the pathologic evolution of atherosclerotic plaque include impaired endothelial synthesis of nitric oxide and prostacyclin, both of which play major roles in vascular homeostasis. The loss of these vasodilators leads to abnormal regulation of vascular tone and also plays a role in evolving a local prothrombotic state. Platelets adhere to areas of vascular injury and are not only prothrombotic but also release growth factors that help drive the aforementioned proliferation of smooth muscle cells and fibroblasts. A key structural constituent of the fibrous cap is collagen, and its synthesis by fibroblasts is inhibited by cytokines elaborated by accumulating T lymphocytes. Foam cell degradation also releases matrix metalloproteinases that break down collagen, leading to weakening of the fibrous core and making it prone to rupture. T lymphocytes tend to accumulate at the border of plaque, which is the frequent site of plaque rupture. As the fibrous cap thins through collagen degradation and eventually ruptures, blood is exposed to the thrombogenic triggers of collagen and lipid. In this setting, platelets are activated and begin to aggregate at the site of rupture. Platelets release vasoconstrictor substances thromboxane and serotonin, but more importantly, they serve as the trigger for thrombin formation, which leads to local thrombosis. Thrombin accumulation along with ongoing platelet activation can lead to rapid accumulation of thrombus in the vessel lumen. The combination of platelet-mediated thrombus accumulation and vasoconstriction can significantly limit blood flow, leading to myocardial ischemia. The degree of ischemia and its duration can culminate in MI. Complete vessel occlusion by thrombus leads to the greatest degree of myocardial ischemia and infarction, typically resulting in an ST elevation myocardial infarction (STEMI). Incomplete vessel occlusion limits blood flow enough to cause symptomatic myocardial ischemia and lesser degrees of MI, resulting in the syndromes of unstable angina or non–ST segment elevation myocardial infarction (NSTEMI). MI is the most profound consequence of atherosclerotic plaque pathology, but significant disability can also develop when atherosclerotic plaques expand in size, leading to obstruction of blood flow and resultant myocardial ischemia. Plaque growth, driven by smooth muscle cell proliferation, initially causes the vessel to expand toward the adventitia (Glagov remodeling). Once a limit of lateral expansion is reached, the enlarging plaque encroaches on the vessel lumen. Typically, when the diameter of the lumen is decreased by at least 70%, myocardial ischemia and symptoms of angina can develop under conditions of increasing demand for blood flow. In the case of exercise, increases in heart rate and blood pressure lead to increasing myocardial oxygen demand; when flow-limiting atherosclerotic lesions are present, oxygen demand may not be met by supply and myocardial ischemia ensues. The greater the degree of vessel obstruction, the more likely it is that myocardial ischemia and angina will occur at low workloads, even to the point of angina at rest. Fig. 8.1 shows an angiogram demonstrating a coronary artery obstruction before and after angioplasty. Other forms of stress, such as emotional stress or cold exposure, can also cause symptoms of angina in patients with significant obstructive plaque through mechanisms such as hypertension (increased myocardial oxygen demand) or sympathetically mediated vasoconstriction and tachycardia.

79

CLINICAL PRESENTATIONS OF CORONARY ARTERY DISEASE The clinical syndromes that patients experience due to the presence of CAD principally relate to the occurrence of myocardial ischemia. Myocardial ischemia develops when there is a mismatch of oxygen delivery and oxygen demand. Given that extraction of oxygen by the myocardium is very high, any increase in oxygen demand must be met with an increase in coronary blood flow. Oxygen demand is directly related to increases in heart rate, myocardial contractility, and wall stress (which are related to blood pressure and cardiac dimensions). There is a reflex increase in myocardial oxygen demand driven by these factors as the heart is required to deliver more systemic blood flow in the face of various stresses, the most common of which is increased exertion. Coronary blood flow also depends on the vascular tone of arterioles that are under the control of vasodilators derived from normal functioning endothelium and autonomic tone. Coronary blood flow increases to meet an increase in myocardial oxygen demand through endothelium-mediated vasodilation. In the face of atherosclerosis, endothelial dysfunction may develop, resulting in reduced endothelium-mediated vasodilation. Endothelial dysfunction coupled with a flow-limiting stenosis sets the stage for the development of myocardial ischemia. The coronary vessel distal to a flow-limiting stenosis tends to be maximally dilated. As myocardial oxygen demand increases, the myocardium distal to a flow-limiting stenosis is no longer able to augment flow by additional dilation. An overall limitation in the ability to increase coronary blood flow due to flow-limiting stenosis and endothelial dysfunction results in supply/ demand mismatch and myocardial ischemia. The major clinical manifestation of myocardial ischemia is chest discomfort (angina pectoris), which is usually described as a pressure or sensation of midsternal tightness. It may be quite pronounced in intensity or relatively subtle. Myocardial ischemia produces not only the sensation of angina pectoris but also a number of derangements in myocyte function. As in any tissue, inadequate oxygen delivery leads to a transition to anaerobic glycolysis, increased lactate production causing cellular acidosis, and abnormal calcium homeostasis. The net consequences of these cellular abnormalities include reductions in myocardial contractility and relaxation. Decreased myocardial contractility results in systolic wall motion abnormalities in the area of ischemia, and the abnormality of relaxation causes reduced ventricular compliance. These changes cause an increase in LV filling pressures above the normal range. The cellular abnormalities related to myocardial ischemia also translate into changes in cellular electrical activity that appear as abnormalities in the electrocardiogram (ECG). Myocardial ischemia may result in either ST depression or ST elevation, depending on the duration, severity, and location of the ischemia. The cellular, mechanical, and electrical abnormalities caused by ischemia typically precede the patient’s perception of angina. Myocardial dysfunction due to ischemia may recover quickly to normal if the duration of ischemia is brief. Prolonged myocardial ischemia can lead to conditions of myocardial stunning or myocardial hibernation. In the case of stunning, the mechanical dysfunction induced by prolonged ischemia persists for hours or days until function returns to normal. In the face of chronic ischemia, myocyte viability may be maintained, but because of ischemia, mechanical dysfunction persists; in this condition, known as hibernation, restoration of blood flow can result in recovery of myocardial function. The heart’s conduction system is less prone to ischemic injury, but ischemia can lead to impaired conduction. Ischemic disruption of myocyte electrical homeostasis also sets the stage for potentially life-threatening arrhythmias.

80

SECTION II  Cardiovascular Disease

A

B Fig. 8.1  Angiograms of the right coronary artery. (A) Discrete stenosis is observed in the middle segment of the artery (arrow). (B) The same artery is shown after successful balloon angioplasty of the stenosis and placement of an intracoronary stent (arrow).

Angina Pectoris and Stable Ischemic Heart Disease Definition

Angina pectoris is a clinical manifestation of obstructive CAD, which in turn is usually the result of atherosclerotic plaque formation over a number of years. The term angina pectoris refers to the symptom of chest discomfort that may be described by the patient as a sensation of chest tightness or burning. Of the 18,000,000 adults in the United States with heart disease, as many as 9,400,00 have angina pectoris. It is estimated that 785,000 people experience a new ischemic episode annually, and recurrent events occur in at least 470,000 Americans each year.

Pathology As a symptom, angina pectoris is experienced when myocardial ischemia develops. Myocardial ischemia and angina pectoris may occur in the face of obstructive atherosclerotic plaque that limits blood flow in the face of increased demand such as exertion or emotional excitement. Myocardial oxygen demand is directly related to increases in heart rate and blood pressure; these variables, in turn, can be manipulated with medical therapy to reduce the demand. Restricted oxygen supply, in the form of reduced blood flow, can also induce myocardial ischemia. Blood flow reduction is a prominent feature of acute presentations of CAD such as NSTEMI and STEMI, but atherosclerosis-mediated coronary vasoconstriction, or coronary vasospasm, is also a potential cause of flow limitation leading to myocardial ischemia. Another example of supply limitation is anemia, whereby reduced oxygen-carrying capacity coupled with obstructive lesions leads to myocardial ischemia and symptoms of angina pectoris. The term stable angina pectoris refers to myocardial ischemia caused by either plaque-mediated flow limitation in the face of excess demand or supply limitation due to coronary vasospasm.

Clinical Presentation Angina pectoris may manifest in either stable or unstable patterns (Table 8.2), but the symptom expression is similar. Typically, patients complain of retrosternal discomfort that they may describe as pressure,

tightness, or heaviness. The symptom can be subtle in its presentation, and inquiry as to the presence of “chest pain” may lead to a negative response in a patient experiencing angina pectoris. When taking a history aimed at discerning angina pectoris, one needs to seek answers to these more nuanced descriptions of symptoms. In addition to chest discomfort, patients may have associated discomfort in the arm, throat, back, or jaw. They also may experience dyspnea, diaphoresis, or nausea associated with angina pectoris. There is a good deal of variability in the expression of symptoms related to myocardial ischemia, although each person tends to have a unique signature of symptoms. Some have no chest discomfort but only radiated arm, throat, or back symptoms; dyspnea; or abdominal discomfort. Myocardial ischemia can also manifest in a “silent” form, particularly in the elderly and in patients with long-standing diabetes mellitus. The duration of angina pectoris varies, probably depending on the magnitude of the underlying myocardial ischemia. Exertionrelated angina pectoris, the hallmark of stable obstructive CAD, typically resolves with rest or with decreased intensity of exercise. In stable angina pectoris, the duration of events is usually in the range of 1 to 3 minutes. Prolonged symptoms in the 20- to 30-minute range are indicative of a more serious problem such as NSTEMI or STEMI. The physical examination of patients with CAD is typically normal. However, if the patient is physically examined during an episode of myocardial ischemia, either at rest or after exertion, significant changes may be present. As with any form of discomfort, there may be a reflex increase in heart rate and blood pressure. Elevated heart rate and blood pressure may act to sustain the duration of angina by increasing myocardial oxygen demand in the face of supply-limiting coronary stenosis. Acute mitral regurgitation can develop if the distribution of myocardial ischemia includes a papillary muscle, the supporting structure of the mitral valve. The physical examination in such cases would demonstrate a new systolic murmur consistent with mitral regurgitation. If severe enough in degree, this mitral regurgitation will cause decreased LV compliance and, consequently, an acute elevation in left atrial and pulmonary vein pressure leading to pulmonary congestion. In this setting, the patient will have not only

CHAPTER 8  Coronary Heart Disease

81

TABLE 8.2  Angina Pectoris Type

Pattern

Stable

Stable pattern, induced by physical exertion, Baseline often normal or nonexposure to cold, eating, emotional stress specific ST-T changes Lasts 5-10 min Relieved by rest or nitroglycerin

Unstable

Prinzmetal or variant angina

Increase in anginal frequency, severity, or duration Angina of new onset or now occurring at low level of activity or at rest May be less responsive to sublingual nitroglycerin Angina without provocation, typically occurring at rest

ECG

Abnormality

Medical Therapy

≥70% Luminal narrowing of Aspirin one or more coronary arteries Sublingual nitroglycerin from atherosclerosis Anti-ischemic medications Statin

Signs of previous MI ST-segment depression during angina Same as stable angina, Plaque rupture with platealthough changes during let and fibrin thrombus, discomfort may be more causing worsening coronary pronounced obstruction Occasional ST-segment elevation during discomfort Transient ST-segment elevation Coronary artery spasm during pain Often with associated AV block or ventricular arrhythmias

Aspirin and clopidogrel Anti-ischemic medications Heparin or LMWH Glycoprotein IIb/IIIa inhibitors

Calcium-channel blockers Nitrates

AV, Atrioventricular; ECG, electrocardiography; LMWH, low-molecular-weight heparin; MI, myocardial infarction.

the symptom of angina pectoris but also the symptom of dyspnea and the physical finding of rales. Ischemia-induced increases in LV filling pressure due to diminished compliance also can occur independently of ischemia-induced mitral regurgitation. Decreased LV compliance can produce the abnormal heart sound S4; in the case of severe diffuse myocardial ischemia causing LV systolic dysfunction, an S3 may also be perceived. Resolution of myocardial ischemia results in not only a cessation of angina pectoris but also a return to the patient’s baseline physical examination status.

Diagnosis and Differential Diagnosis Three basic forms of testing have played major roles in assessing patients with chest discomfort possibly due to CAD. All of these tests capitalize on the effect of myocardial ischemia on various aspects of cardiac physiology. First, myocardial ischemia induced by exercise or by spontaneous coronary occlusion results in subendocardial ische­ mia, which appears on an ECG as diffuse ST depression (Fig. 8.2). Once ischemia resolves, the ECG returns to normal. Second, myocardial ischemia typically affects a segment of heart muscle, and that territory develops a wall motion abnormality that can be detected by either echocardiography or nuclear scintigraphy. Third, the basis for myocardial ischemia is a decrease in coronary and myocardial blood flow. This abnormality can be detected by assessing the distribution of radioactive tracers such as thallium 201 or technetium sestamibi using specialized detectors for imaging myocardial perfusion. All stress test techniques used in diagnosing patients with possible CAD rely on these means of detecting the impact of myocardial ischemia on cardiac electrical activity, mechanical function, or myocardial perfusion. Stress testing in its various forms frequently plays a pivotal role in the assessment of patients with possible CAD. In using stress testing, it is important to understand the significance of pretest probability of CAD in interpreting the results of any stress test method. For a patient with a high pretest probability of CAD, a positive test is highly predictive of underlying CAD, and a negative test carries the weight of being falsely negative. The opposite is true in a patient with a low pretest probability of CAD: A negative test is associated with a high negative predicative value for the presence of CAD, but a positive test is likely to be falsely positive. Stress testing is useful not only as a diagnostic tool but also in the long-term management of established CAD. Exercise stress testing, through its ability to quantify exercise capacity, can monitor the

effectiveness of medical therapy directed at reducing myocardial ischemia. The findings of an exercise stress test also have predictive value in that patients with ischemia induced at low workloads are more likely to have extensive multivessel disease, whereas those who achieve high workloads are less prone to ischemic complications of CAD. A higher risk for poor outcomes related to CAD is implied by (1) ECG changes of ST depression early during exercise and persisting late into recovery; (2) exercise-induced reduction in systolic blood pressure; and (3) poor exercise tolerance (55 years of age Accelerated, resistant, or malignant hypertension Unexplained atrophic kidney or size discrepancy >1.5 cm between kidneys Sudden, unexplained (“flash”) pulmonary edema Unexplained chronic kidney disease in an individual with atherosclerotic vascular disease elsewhere Development of acute kidney injury or worsening of chronic kidney disease after starting an ACE inhibitor or ARB ACE, Angiotensin-converting enzyme; ARB, angiotensin II–receptor blocker.

is not specific for RAS. Edema is not typically found unless significant CKD or another edematous condition also exists. Laboratory evaluation may reveal hypokalemia (K+ 28 mEq/L) due to secondary hyperaldosteronism, although neither may be present. A reduced GFR with an elevated serum creatinine concentration may be found, but a normal serum creatinine concentration does not rule out hemodynamically significant RAS. Plasma renin activity and aldosterone concentrations may be elevated, but their measurement is of limited clinical utility in assessing hypertensive patients for RAS or in making therapeutic decisions. Urinalysis results are usually normal, although low-grade proteinuria (usually 20 beats/min or Paco2 55 yr Obesity (BMI >30 kg/m2) BUN level of 20 mg/dL or higher and any rise in BUN during the first 24 hr of admission associated with increased mortality Serum creatinine >1.8 mg/dL within first 24 hr Hemoconcentration with Hct ≥44 on admission or failure of Hct to decrease in first 24 to 48 hr with volume resuscitation predicts severe pancreatitis Serum marker reflecting a systemic inflammatory response, CRP >150 mg/dL Pleural effusion Pancreatic necrosis Acute extrapancreatic fluid collections

Patient characteristics

Laboratory values

Imaging findings

Scoring systems

Ranson’s criteria

Acute Physiologic and Chronic Health Evaluation (APACHE II) system Bedside Index for Severity of Acute Pancreatitis (BISAP)

Eleven prognostic indicators, including five available on admission (age >55 yr, WBC >16,000/mm3, glucose >200 mg/ dL, LDH >350 IU/L, AST >250 U/L) and six measured at the end of the first 48 hr (Hct decreased >10, BUN >5 mg/dL, Po2 4 mEq/L, serum calcium 6 L); mortality rate of 10–20% for three to five signs and >50% for six or more signs Calculated by assigning points based on age, heart rate, temperature, respiratory rate, mean arterial pressure, Pao2, pH, potassium, sodium, creatinine, Hct, WBC, GCS, and previous health status Five variables available in initial 24 hr: BUN >25 mg/dL, impaired mental status (GCS score 60 yr, and pleural effusion on imaging. Each variable adds 1 point to the total score, and scores of 3, 4, and 5 correspond to mortality rates of 5.3%, 12.7%, and 22.5%, respectively.

AST, Aspartate aminotransferase; BMI, body mass index; BUN, blood urea nitrogen; CRP, C-reactive protein; GCS, Glasgow Coma Scale; Hct, hematocrit; LDH, lactate dehydrogenase; SIRS, systemic inflammatory response syndrome; WBC, white blood cells. aSIRS predisposes to multiple organ dysfunction and pancreatic necrosis. SIRS is defined by two or more of these criteria persisting for more than 48 hours.

150 mg/dL (sensitivity of 80%, specificity of 76%, positive predictive value of 67%, and negative predictive value of 86%). Imaging studies predicting a severe outcome include a pleural effusion seen on chest radiography within the first 24 hours or pancreatic imaging identifying necrosis. Unfortunately, CT evidence of severe acute pancreatitis lags

behind clinical findings, and an early CT study can underestimate the severity of the disorder. Severe pancreatitis is predicted by organ dysfunction, including shock (systolic blood pressure 2.0 mg/L after

408

SECTION VI  Gastrointestinal Disease

rehydration). SIRS predisposes to multiple organ dysfunction and pancreatic necrosis. Well-established scoring systems include Ranson’s criteria, Acute Physiologic and Chronic Health Evaluation II (APACHE II), APACHE combined with scoring for obesity (APACHE-O), the Glasgow Scoring System, and Bedside Index for Severity of Acute Pancreatitis (BISAP). With increasing scores, the likelihood of a complicated, prolonged, and fatal outcome increases. Unfortunately, because these scoring systems have a high false-positive rate (i.e., in many patients with high score, severe pancreatitis does not develop), they are not universally used. During the first 48 to 72 hours, a rising hematocrit or BUN, persistent SIRS after fluid resuscitation or the presence of pancreatic or peripancreatic necrosis on cross-sectional imaging constitute evidence of evolving severe pancreatitis.

Treatment Early steps in the management of patients with acute pancreatitis can decrease severity, morbidity, and mortality (Fig. 39.4). Prevention of complications depends largely on monitoring, vigorous hydration, and early recognition of pancreatic necrosis and choledocholithiasis. Patients with multiorgan dysfunction and those with predicted development of severe disease are at greatest risk for adverse outcomes and should be treated when possible in a care unit with intensive monitoring capability and multidisciplinary input.

Supportive Care Patients with acute pancreatitis are treated supportively with aggressive intravenous hydration, parenteral analgesics, and bowel rest. Supplemental oxygen is recommended initially for all patients. Nasogastric tube suction is indicated for symptomatic relief in patients with nausea, vomiting, and ileus. No specific treatments are effective in limiting systemic complications. Agents that put the pancreas to rest (e.g., somatostatin, calcitonin, glucagon, H2-receptor antagonists) and enzyme inhibitors (e.g., aprotinin, gabexate mesylate) have not been shown to lower disease-related morbidity and mortality.

Antibiotics Antibiotic therapy is no longer recommended for patients with sterile necrosis due to the lack of proven benefit. For patients with suspected infected necrosis, appropriate antibiotics are initiated before the confirmatory diagnosis, with the initial choice taking into consideration the likely pathogenic organisms and the ability of the antimicrobials to penetrate into necrotic pancreatic tissues. After culture results are available, the antibiotics can be tailored appropriately.

Fluid Management Vigorous fluid resuscitation is important for maintaining the microcirculation and perfusion of the pancreas during the early phase of acute pancreatitis. Early aggressive intravenous hydration during the first 12 to 24 hours after the onset of symptoms translates into a potential benefit of reduced pancreatic necrosis and organ failure. Vigorous fluid therapy is of little value after 24 hours. Crystalloid, the preferred intravenous fluid, is administered at an initial rate of 250 to 500 mL/ hour or 5 to 10 mL/kg/hr with a preceding bolus infusion for individuals with severe volume depletion. Lactated Ringer’s solution may be the preferred crystalloid replacement because in one comparative study, it reduced the incidence of inflammatory markers by more than 80% compared with normal saline infusion. Goal-directed fluid therapy is recommended for patients with acute pancreatitis. Goal-directed therapy is defined as titration of intravenous fluids every few hours to specific clinical and biochemical targets of perfusion (e.g., heart rate, blood pressure, urine output, BUN, and hematocrit). Caution must be

used for the elderly and those with underlying cardiovascular or renal impairment.

Analgesia Despite the theoretical concern that narcotic analgesia may result in sphincter of Oddi spasm and worsening pancreatitis, there is no evidence to support withholding narcotics from patients with acute pancreatitis. The physician should consider liberal use of patient-controlled analgesia, although this approach has not been compared prospectively with on-demand analgesia. There is no evidence to indicate superiority of a specific opiate. Patients administered repeated doses of narcotic analgesics should have oxygen saturation monitored due to risks of unrecognized hypoxia.

Nutritional Care Patients with mild acute pancreatitis can begin oral feeding within 24 hours of admission without waiting for resolution of pain or normalization of serum pancreatic enzyme levels. Early introduction of a low-fat solid diet is as safe as the traditional approach of progressive advancement from a clear liquid diet and is associated with a shorter length of hospital stay. For patients with predicted severe pancreatitis or small bowel ileus, early introduction of oral intake may not be tolerated due to postprandial abdominal pain, nausea, and vomiting. These individuals can have nutrition introduced as nasoenteric or nasogastric feeding. Enteral feeding is preferable to total parenteral nutrition (TPN) because it is less expensive than TPN and is associated with a reduction in systemic infection, need for surgical intervention, organ failure, and mortality. Enteral feeding is usually well tolerated, even by patients with an ileus. Nasogastric feeding offers a safe alternative to nasojejunal feeding because it appears to be equally safe and effective. Parenteral nutrition should be reserved for patients who cannot achieve sufficient caloric intake through the enteral route or those in whom enteral access cannot be maintained.

Management of Recurrence and Necrosis Gallstone pancreatitis. The risk of gallstone pancreatitis (see also Chapter 45) recurrence is as high as 50% to 75% within 6 months of the initial episode, and cholecystectomy before discharge is recommended for patients with mild attacks of pancreatitis. Cholecystectomy performed during the initial admission for patients with suspected biliary pancreatitis is associated with substantial reductions in mortality and gallstone-related complications, readmission for recurrent pancreatitis, and pancreaticobiliary complications. Cholecystectomy is often delayed in patients with severe pancreatitis to allow for better exposure of the ductal anatomy at the time of surgery. Urgent ERCP (Video 39.1) with identification and clearance of bile duct stones is recommended for patients with documented choledocholithiasis on imaging, cholangitis or strong evidence of ongoing biliary obstruction, as suggested by imaging and laboratory data. Biliary sphincterotomy leaving the gallbladder in situ is considered an effective alternative for those who are not candidates for cholecystectomy. Acute fluid collections and pseudocysts. Acute peripancreatic fluid collections do not require any specific therapy, other than supportive therapy that is standard for acute pancreatitis. Most remain sterile and are reabsorbed spontaneously during the first several weeks after the onset of acute pancreatitis. When a localized acute peripancreatic fluid collection persists beyond 4 weeks, it is likely to develop into a pancreatic pseudocyst. While patients with asymptomatic pseudocysts should be followed, for those who are symptomatic, pseudocyst drainage should be considered. Indications for pseudocyst drainage include suspicion of infection or progressive

CHAPTER 39  Diseases of the Pancreas

409

Establish the diagnosis of acute pancreatitis with 2 of the following: 1. Characteristic abdominal pain 2. Amylase/lipase 3x upper limit of normal 3. Characteristic findings on abdominal imaging

Initial resuscitation • Vigorous fluids to maintain urine output 0.5 mL/kg/hr: • Severe volume depletion: 500–1000 mL/hr • Not severe: 300–500 mL/hr • No volume depletion: 250–350 mL/hr • Supplemental oxygen • Analgesia with parenteral narcotics

Assess initial disease severity

Work-up the etiology

• Bedside assessment • APACHE II score • Ranson’s criteria • BISAP score • Organ failure, SIRS • Pancreatic necrosis • CRP at 48 hr

• History (personal and FH) • Medications • LFTs • Serum TGs • Serum calcium • Abdominal US

Mild disease

Severe disease

• Prognostic signs favorable • Systemic complications absent • Usually interstitial pancreatitis • CT scan not indicated

• Prognostic signs unfavorable • APACHE II 8, Ranson’s 3, CRP 150 mg/dL, BISAP score 3 • Systemic complications present (MSOF, SIRS) • Usually necrotizing pancreatitis • CT scan indicated

Interstitial pancreatitis

Necrotizing pancreatitis

Medical treatment

Medical treatment

• ICU required • Fluid resuscitation • Treat systemic complications • Consider enteral feeding TPN • Consider ERCP

• ICU required • Fluid resuscitation • Treat systemic complications • Consider enteral feeding TPN • Consider ERCP

For GSP

Clinical improvement

No improvement or deterioration

Continue medical treatment

R/O infected necrosis by GPA

Infected necrosis

Sterile necrosis

Step-up approach

Continue medical treatment If no improvement—late necrosectomy

Percutaneous drainage followed by minimally invasive retroperitoneal necrosectomy (endoscopic or surgical)

Fig. 39.4  Management algorithm for acute pancreatitis. Some of the guidelines, such as the diagnostic utility of the C-reactive protein (CRP) level, require further validation. Antibiotic use, including the type and duration of treatment, continues to be examined, and these suggested approaches will likely be modified by the findings of future studies. APACHE II, Acute Physiologic and Chronic Health Evaluation II; BISAP, Bedside Index for Severity of Acute Pancreatitis; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; FH, family history; GPA, CT-guided percutaneous aspiration; GSP, gallstone pancreatitis; ICU, intensive care unit; LFTs, liver function tests; MSOF, multiple system organ failure; R/O, rule out; SIRS, systemic inflammatory response syndrome; TGs, triglycerides; TPN, total parenteral nutrition; US, ultrasound.

410

SECTION VI  Gastrointestinal Disease

enlargement with associated symptoms including biliary obstruction, abdominal pain, early satiety, and nausea and vomiting due to stomach compression or gastric outlet obstruction. In symptomatic patients, if the pseudocyst is mature and encapsulated, treatment can involve endoscopic, surgical, or percutaneous drainage. Based on available expertise, endoscopic ultrasound (EUS) guided drainage is preferred with cystogastrostomy or cystoduodenostomy. Sterile pancreatic and extrapancreatic necrosis. Sterile pancreatic necrosis usually is treated with supportive medical care during the first several weeks, even in patients with multiple organ failure. After the acute pancreatic inflammatory process has subsided and coalesced into an encapsulated structure (e.g., walled-off pancreatic necrosis), débridement may be required for intractable abdominal pain, vomiting caused by extrinsic compression of stomach or duodenum, biliary obstruction, failure to thrive or persistent systemic toxicity. Débridement is delayed for at least 4 to 6 weeks after the onset of pancreatitis and can be performed by a combination of endoscopic, radiologic, and surgical techniques. Asymptomatic pancreatic necrosis does not warrant intervention, regardless of the extent and location. Infected pancreatic and extrapancreatic necrosis. The development of infection in the necrotic collection is the main indication for therapy. The development of fever leukocytosis and increasing abdominal pain suggests infection of the necrotic tissue. A CT scan may reveal evidence of air bubbles in the necrotic cavity. Infected pancreatic necrosis is best treated with drainage or débridement, or both. Routine CT-guided fine-needle aspiration to diagnose infected necrosis is not recommended given that clinical and imaging signs are accurate in the majority of patients. In addition, there is a high false-negative rate of the samples. Thus, débridement warrants consideration when infected necrosis is suspected, even if infection is not documented. The consensus is that the best outcomes are achieved when invasive interventions are delayed for a minimum of 4 weeks after the onset of disease to allow liquefaction of necrotic tissues and a fibrous rim to form around the necrosis (i.e., walled-off pancreatic necrosis). This delay makes drainage end débridement easier and reduces the risk of complications or death. Patients with infected necrosis are initially treated with broad-spectrum antibiotics and medical support to allow encapsulation of the necrotic collections, which may facilitate intervention and reduce complications of bleeding and perforation. When there is dramatic clinical deterioration, patients are not stable and delay is not feasible, and early intervention with a percutaneous drain is required. Traditional management of infected pancreatic necrosis has been open surgical necrosectomy with closed irrigation by indwelling catheters, necrosectomy with closed drainage without irrigation, or necrosectomy and open packing. The open surgical approaches are associated with a high morbidity (34% to 95%) and mortality (11% to 39%) rates. A more conservative step-up approach using percutaneous catheter drainage as the initial treatment has gained favor, and a delay in invasive treatment is now standard. The step-up approach consists of antibiotic administration, percutaneous drainage as needed, and after a delay of several weeks, minimally invasive débridement, if required. This approach is superior to traditional open necrosectomy with respect to the risk of major complications or death. If the percutaneous approach fails, it is followed by a less invasive, video-assisted retroperitoneal débridement (VARD) or endoscopic transluminal drainage with or without necrosectomy, provided expertise is available.

CHRONIC PANCREATITIS Definition and Epidemiology Chronic pancreatitis is characterized by inflammation, fibrosis, and irreversible loss of acinar (exocrine) and islet (endocrine) cell function.

TABLE 39.3  Causes of Chronic Pancreatitis

(TIGAR-O)

Toxic-Metabolic Alcohol Tobacco Hypercalcemia Hypertriglyceridemia Chronic renal failure Idiopathic Early onset Late onset Tropical Genetic Autosomal dominant-cationic trypsinogen (PRSS1) Autosomal recessive-CFTR, SPINK1, chymotrypsin C Autoimmune Isolated (types 1 and 2) Syndromic (Sjögren’s, inflammatory bowel disease, primary biliary cholangitis) Recurrent Acute Pancreatitis Postnecrotic severe acute pancreatitis Post-irradiation Ischemic vascular Obstructive Benign-pancreas divisum, sphincter of Oddi dysfunction, post-traumatic pancreatic duct stricture Neoplastic-pancreatic ductal adenocarcinoma, IPMN, ampullary tumor CFTR, Cystic fibrosis transmembrane conductance regulator; IPMN, intraductal papillary mucinous neoplasia; PRSS1, serine protease 1; SPINK1, serine peptidase inhibitor Kazal type 1.

This disorder contrasts with acute pancreatitis, which is usually nonprogressive. The two conditions may overlap because recurrent attacks of acute pancreatitis may lead to chronic pancreatitis, and individuals with chronic pancreatitis may experience exacerbations of acute pancreatitis. The annual incidence of chronic pancreatitis ranges from 5 to 12 cases per 100,000 people, and the prevalence is about 50 cases per 100,000 people.

Pathology Chronic pancreatitis can be classified using a system termed “TIGAR-O,” which refers to toxic-metabolic, idiopathic, genetic, autoimmune, recurrent and severe acute pancreatitis, and obstructive (Table 39.3). The most common cause of chronic pancreatitis is chronic alcoholism, accounting for 45% to 65% of cases. Alcohol can cause episodes of acute pancreatitis, but at the time of the initial attack, structural and functional abnormalities often indicate underlying chronic pancreatitis. Because most alcohol users do not develop pancreatitis, the presumption is that unidentified genetic, dietary, or environmental influences must coexist with alcohol use. Smoking is a causal, dose-dependent risk factor for chronic pancreatitis. The effect of smoking is synergistic with alcohol consumption and contributes profoundly to the development and progression of the disease. Twenty percent of US patients with chronic pancreatitis have no immediately demonstrable cause. Gallstone pancreatitis, the major cause of acute pancreatitis, rarely leads to chronic pancreatitis. Calcific

CHAPTER 39  Diseases of the Pancreas pancreatitis is a major cause of chronic pancreatitis in South India and other parts of the tropics. Autoimmune pancreatitis, genetic mutations (CFTR, SPINK1, PRSS1, CTRC, CASR), obstruction (e.g., tumors, sphincter of Oddi dysfunction, pancreas divisum), hypertriglyceridemia, and hypercalcemia are potential causes of cases initially labeled idiopathic.

Clinical Presentation Most patients with chronic pancreatitis experience episodic or continuous pain. Occasionally, patients exhibit exocrine or endocrine insufficiency in the absence of pain. Other patients are asymptomatic and are found to have chronic pancreatitis incidentally on imaging. The pain of chronic pancreatitis is typically epigastric, often radiates to the back, is occasionally associated with nausea and vomiting, and may be partially relieved by sitting upright or leaning forward. The pain is often worse 15 to 30 minutes after eating. Early in the course of chronic pancreatitis, the pain may occur in discrete attacks; as the condition progresses, the pain tends to become continuous. The pain of chronic pancreatitis is poorly understood. Possible causes include inflammation of the pancreas, increased intrapancreatic pressure, neural inflammation, and extrapancreatic causes, such as stenosis of the common bile duct and duodenum. Glucose intolerance occurs with some frequency in chronic pancreatitis, but overt diabetes mellitus usually manifests late in the course of disease. Diabetes in patients with chronic pancreatitis is different from typical type 1 diabetes in that the pancreatic alpha cells, which produce glucagon, are also affected, increasing the risk of hypoglycemia. Clinically significant endocrine or exocrine insufficiency (i.e., protein and fat deficiencies) does not occur until more than 90% of pancreatic function is lost. Steatorrhea usually occurs before protein deficiencies because lipolytic activity decreases faster than proteolysis. Mild pancreatic exocrine insufficiency (PEI) may take the form of abdominal bloating or malabsorption of fat-soluble vitamins (A, D, E, K) and vitamin B12, although clinically symptomatic vitamin deficiency is uncommon. Because reduced vitamin D absorption can result in osteoporosis, osteopenia, and fractures, periodic assessment of vitamin D levels and bone densitometry are recommended. More severe PEI may lead to overt malabsorption and weight loss.

Diagnosis and Differential Diagnosis Because direct biopsy of the pancreas has considerable risk, the diagnosis of chronic pancreatitis is typically based on indirect tests of pancreatic structure and function. Marked structural changes usually correlate with severe functional impairment. In early chronic pancreatitis, however, mild abnormalities of pancreatic function can precede the morphologic changes seen on imaging. Studies of pancreatic structure may remain normal even with advanced deterioration of pancreatic function. Laboratory evaluations of serum pancreatic enzymes, such as amylase and lipase, are frequently normal in the setting of well-established chronic pancreatitis, even during painful exacerbations. Serum pancreatic enzymes neither confirm nor exclude the diagnosis.

Tests of Function Function tests assess pancreatic secretory reserve of ductal function or acinar function by measuring secretion of bicarbonate ions (HCO3−) or digestive enzymes, respectively. Direct tests (e.g., secretin stimulation) involve stimulation of the pancreas through the administration of hormonal secretagogues. Indirect tests measure the consequences of pancreatic insufficiency, and although more widely available, the results usually are not abnormal until enzyme output has declined by more than 90%. Thus they are insensitive to early pancreatic insufficiency.

411

Clinicians have preferentially relied on noninvasive methods to circumvent the challenges associated with direct pancreatic function tests. Clinically available indirect tests of pancreatic function include analyses of fecal fat, fecal elastase, and serum trypsin. The secretin stimulation test takes advantage of the normal response of pancreatic ductular cells to secrete HCO3− in response to physiologic and exogenously administered secretin. The observation that HCO3− production is impaired early in the course of chronic pancreatitis led to the use of this test to diagnose early-stage disease (sensitivity of 95%). The test involves oral placement of a double-lumen gastroduodenal catheter for aspiration and quantitative measurement of pancreatic enzyme and HCO3− production before and after stimulation with intravenous secretin. This test is primarily performed for patients with suspected chronic pancreatitis who have chronic abdominal pain but negative or equivocal results of imaging studies. Peak pancreatic fluid HCO3− concentrations of less than 80 mEq/L represent pancreatic insufficiency. The secretin stimulation test has been infrequently used in clinical practice because the study is labor intensive and is associated with discomfort. Endoscopic collection methods have simplified pancreatic fluid collection and made the test more suitable for clinical use. The 72-hour fecal fat determination is sometimes used for detection of steatorrhea (fecal fat >7 g/24 hours), but the test is not specific for pancreatic exocrine insufficiency. The test also lacks sensitivity because steatorrhea occurs only in advanced chronic pancreatitis. Because the quantitative fecal fat test is inconvenient, unpleasant for patients, and prone to laboratory error, a qualitative assay is used preferentially in clinical practice to assess for malabsorption. Determination of fecal elastase is the most commonly used noninvasive indirect test for the diagnosis of pancreatic exocrine insufficiency. Elastase, a protease synthesized by pancreatic acinar cells, is useful for evaluating insufficiency because it is stable in stool, unaffected by pancreatic enzyme replacement, and correlates well with stimulated pancreatic function test results. Moderate to severe exocrine insufficiency is based on fecal elastase values of less than 200 μg/g of stool. False-positive results can be seen with diarrheal illnesses, due to a dilutional effect.

Tests of Structure Imaging findings with CT scan, ultrasound, and MRI may show changes of chronic pancreatitis include ductal abnormalities (e.g., dilation, stones, irregular beaded walls, and side branch ectasia), parenchymal abnormalities (e.g., calcification, inhomogeneity, atrophy), gland contour changes, and pseudocysts (E-Fig 39.4). Imaging studies are often normal or inconclusive in the early stages of disease (see E-Fig. 39.4). CT imaging and MRI are also helpful in identifying complications of chronic pancreatitis including pseudocysts, portosplenic venous thrombosis, arterial pseudoaneurysms, and pancreatic duct fistulas. CT scanning is often considered the preferred initial test for diagnosis of chronic pancreatitis. Magnetic resonance cholangiopancreatography is a noninvasive diagnostic imaging modality that provides visualization of the pancreatic parenchyma similar to CT scanning but with improved duct imaging resulting in a greater sensitivity for diagnosis of chronic pancreatitis. MRI pancreatic duct images are similar to those obtained by ERCP but without the risk of precipitating acute pancreatitis. Stimulation of the pancreas using IV secretin enhances main and side branch pancreatic duct visualization, which may improve the diagnostic accuracy for chronic pancreatitis. ERCP provides reliable structural information about the pancreatic ductular system including ductal dilation, strictures, abnormal side branches, communicating pseudocysts, and ductal stones and fistulas. ERCP is highly effective for visualizing these ductal and duct-related findings,

CHAPTER 39  Diseases of the Pancreas

E-Fig. 39.4  Computed tomography scan shows calcifications and small pseudocysts in the pancreas that are consistent with a diagnosis of chronic pancreatitis.

411.e1

412

SECTION VI  Gastrointestinal Disease

with a sensitivity for the diagnosis of chronic pancreatitis of 71% to 93% and a specificity of 89% to 100%. The major limitation of ERCP is the development of procedure-related acute pancreatitis in up to 5% of patients. Thus, ERCP should not be used for diagnostic purposes but instead be reserved for patients with established chronic pancreatitis when endoscopic therapy is recommended (discussed later). Endoscopic ultrasound (EUS) as a diagnostic imaging study for chronic pancreatitis relies on quantitative and qualitative parenchymal tissue and ductal findings. EUS appears to be equally or more sensitive than other tests of structure and function. An international consensus panel proposed the Rosemont criteria for diagnosing chronic pancreatitis. Major criteria include hyperechoic foci with shadowing that indicates pancreatic duct calculi and parenchymal lobularity with honeycombing. Minor criteria include cysts, a dilated main duct (≥3.5 mm in diameter), irregular pancreatic duct contour, dilated side branches (≥1 mm in diameter), hyperechoic duct wall, parenchymal strands, nonshadowing hyperechoic foci, and lobularity with noncontiguous lobules. In the absence of any of these criteria, chronic pancreatitis is unlikely, whereas with detection of four or more criteria, the disease is likely, even when other imaging and pancreatic function tests may still be normal.

Treatment

Malabsorption Treatment of PEI is best achieved with pancreatic enzyme replacement therapy (PERT). Most commercial preparations consist of pancreatin, which is the shock-frozen powdered extract of porcine pancreas containing lipase, amylase, trypsin, and chymotrypsin. In order to treat malabsorption due to PEI, it is necessary to provide approximately 10 percent of the normal pancreatic enzyme output. This translates into approximately 30,000 international units (IU) or the equivalent 90,000 United States Pharmacopeia units (USP) of lipase per meal. For most patients, the recommended dose depends on the size and nature of the meal (i.e., fat content), residual pancreatic function, and therapeutic goals (i.e., elimination of steatorrhea, reduction in the abdominal symptoms of maldigestion, or improvement in nutrition). Due to residual pancreatic lipase secretion and physiologic gastric lipase secretion, it is appropriate to begin therapy with 40,000 to 50,000 USP of lipase with each meal and one half of that amount with snacks. Administration of acid-stable, encapsulated microspheres or microtablets filled with pancreatic enzymes has greatly increased the efficacy of enzyme supplementation. Enzyme preparations should be taken with meals. If more than one capsule/tablet per meal must be taken, it may be beneficial to take one part of the dose at the beginning and the rest during the meal. Other factors may accentuate steatorrhea, including concomitant small bowel bacterial overgrowth, which can occur in up to 25% of patients with chronic pancreatitis. Bacterial overgrowth may be caused by hypomotility due to pancreatic inflammation or chronic use of narcotic analgesics.

Pain The greatest challenge in treating chronic pancreatitis is controlling abdominal pain. Pain may improve over time, but the course is not predictable and improvement may take years. Therapy targets the mechanisms responsible for pancreatic pain, including pancreatic hyperstimulation, ischemia, obstruction of ducts, inflammation, and neuropathic hyperalgesia. Pain can develop in the early stages of chronic pancreatitis before morphologic changes can be demonstrated on imaging studies. Patients with chronic pancreatitis are at increased risk for pancreatic cancer, which may cause a change in the pain pattern, and extrapancreatic causes of pain must always be considered.

Pain management should proceed in a stepwise fashion and begin with lifestyle modifications such as alcohol and tobacco abstinence, a low-fat diet, and pancreatic enzyme supplementation, followed by a sequentially more aggressive and invasive approach for symptomatic failures, although it should be recognized that placebo alone is effective for up to 30% of patients. Several approaches can be considered for chronic pain relief. 1. Tobacco and alcohol abstinence. Abstention may decrease the frequency of painful attacks and reduce the likelihood of pancreatic function deterioration and development of pancreatic cancer. 2. Analgesics. Most patients with chronic pain require analgesics. Nonopioid analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs are used as initial treatment. If possible, the use of opioids should be avoided due to the risk of abuse, tolerance, and addiction. When deemed necessary, weak opioids (e.g., tramadol or codeine) are initially prescribed before escalation to stronger opioids (e.g., morphine, oxycodone, fentanyl) for poorly controlled pain. The risk of dependence to opioids is not known in this setting; however, patients with previous addictive behaviors such as substance use with alcohol or tobacco are at greater risk for analgesic dependence and addiction. Safe opioid prescribing practices are necessary with close monitoring of patients’ symptoms and adherence to a well-defined plan that includes a patient agreement, regular follow-up, urine drug testing, and query of the state’s online prescription monitoring program. 3. Secretion suppression. Oral pancreatic enzyme replacement, somatostatin analogue, and enteral nutrition are proposed treatments to blunt pain by reducing pancreatic secretion. These therapies are of unproven benefit and not routinely recommended as adjuncts to pain therapy. When PERT is initiated for pain management, the non–enteric-coated pancrelipases (i.e., pancreatic enzyme preparations) are preferred because the enteric-coated preparations theoretically release their enzymes further down the intestine, away from the stimulatory cholecystokinin (CCK) enterocytes. 4. Neural transmission modification. Gabapentinoids, including pregabalin, have been used effectively to treat neuropathic pain disorders, including diabetic neuropathy and neuropathic pain of central origin. Based on the finding that pancreatic pain is accompanied by similar alterations of central pain processing, studies suggest a benefit with pregabalin as an adjuvant treatment to decrease pain associated with chronic pancreatitis. Similarly, tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors can be administered on a trial basis. 5. Neuroablative techniques such as celiac plexus blockade can be performed by injection of a local anesthetic and a steroid into the region of the celiac ganglia. This can be accomplished through endoscopic (i.e., EUS) or percutaneous radiologic guidance. The results are disappointing with a pain reduction in a minority of individuals (15% to 50%) that is not durable with pain reduction or relief of up to 1 to 6 months. 6. Antioxidants. Oxidative stress can cause direct pancreatic acinar cell damage through several pathways. Supplementation with antioxidants, such as selenium, vitamins C and E, and methionine, may relieve pain and reduce oxidative stress. In a randomized trial, the reduction in the number of painful days per month was higher for the patients who received antioxidants compared with those who received placebo (7.4 vs. 3.2 days). Patients who received antioxidants also were more likely to become pain free (32% vs. 13%). 7.  Endoscopic decompression. Endoscopic decompression of the pancreatic duct is an option for obstruction caused by strictures, stones, or sphincter of Oddi dysfunction. Endoscopic therapies include pancreatic sphincterotomy, stricture dilation, stone

CHAPTER 39  Diseases of the Pancreas removal with intracorporeal or extracorporeal shock wave lithotripsy, and temporary plastic stent placement. Complete or partial pain relief is reported for approximately 50% to 80% of carefully selected patients during follow-up extending as long as 3 to 4 years. 8. Surgery. Surgical pancreatic ductal drainage, usually with lateral pancreaticojejunostomy (i.e., Puestow procedure), can be offered to those with a dilated (>6 mm in diameter) main pancreatic duct. Pain reduction is reported by approximately 80% of patients. This procedure is safe and has an operative mortality rate of less than 5%; however, only 35% to 60% of patients are free of pain at the 5-year follow-up. Individuals with nonobstructed, nondilated pancreatic ductal systems with disease predominating in the pancreatic head may be offered resection of the focally diseased portion of the gland with a pancreaticoduodenectomy or a duodenum-preserving pancreatic head resection also referred to as a Frey or Beger procedure. Highly selected patients with diffuse pancreatic parenchymal disease refractory to other forms of therapy may benefit from a total pancreatectomy with islet cell autotransplantation.

Management of Complications The complications of chronic pancreatitis include pseudocysts, pancreatic fistulas, biliary obstruction, pancreatic cancer, small bowel bacterial overgrowth, and isolated gastric varices due to splenic vein thrombosis. Pancreatic fistulas. Pancreatic fistulas occur as a result of duct disruption resulting in localized fluid collections, ascites, or pleural effusions. Treatment consists of bowel rest, endoscopic pancreatic duct stenting, and administration of a somatostatin analogue. Surgical intervention may be needed if this conservative approach is unsuccessful. Vascular complications. The splenic vein courses along the posterior surface of the pancreas, where it can be affected by inflammation from pancreatitis or malignancy that leads to thrombosis. Splenic vein thrombosis can result in isolated fundal gastric varices. Splenectomy is usually curative for patients who develop bleeding from gastric varices. Pseudoaneurysm formation is a complication of acute and chronic pancreatitis. Affected vessels, including the hepatic, splenic, pancreaticoduodenal, and gastroduodenal arteries, lie close to the pancreas. CT or MR imaging shows the pseudoaneurysm as a cystically dilated vascular structure in or adjacent to the pancreas. EUS with Doppler imaging can show blood flow within the pseudoaneurysm. Mesenteric angiography permits confirmation of the diagnosis and provides a means of therapy because selective embolization of the pseudoaneurysm can be accomplished during the procedure. Surgery for bleeding pseudoaneurysms is difficult and associated with high morbidity and mortality rates. Biliary and duodenal obstruction. Symptomatic obstruction of the bile duct or duodenum, or both, develops in a few patients with chronic pancreatitis. Postprandial pain and early satiety are characteristic of duodenal obstruction, whereas pain and cholestasis (sometimes with resultant cholangitis) suggest a bile duct stricture. These complications most commonly result from inflammation or fibrosis in the head of the pancreas or an adjacent pseudocyst. Endoscopic stenting may be attempted for bile duct strictures, but they are often refractory and typically require prolonged treatment. Endoscopic failures can be treated with surgical biliary decompression. The importance of decompression is underscored by the observation that it can reverse secondary biliary fibrosis associated with bile duct obstruction.

413

CARCINOMA OF THE PANCREAS Definition and Epidemiology Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States, with approximately 45,000 new cases diagnosed annually (see also Chapter 58). The peak incidence of PDAC occurs in the seventh decade of life. There is a modest male-to-female predominance (relative risk of 1.4:1), and blacks have a 30% to 40% higher incidence of PDAC than white individuals in the United States. Many environmental factors have been implicated as increasing the risk for pancreatic cancer. Cigarette smoking is the most consistent factor, with the increased risk attributed to the aromatic amines found in cigarette smoke. Other risk factors include obesity, lack of physical activity, and diabetes mellitus. Studies evaluating the relationship between diet and pancreatic cancer are inconclusive. A Western diet (i.e., high intake of fat and meat, particularly smoked or processed meats) has been linked to the development of pancreatic cancer in many studies. Chronic pancreatitis also increases the risk of PDAC (relative risk as high as 13-fold), particularly in those individuals with hereditary pancreatitis and tropical pancreatitis. Epidemiologic studies have failed to find a consistent association between alcohol or coffee consumption and the development of pancreatic cancer. Up to 10% of patients with pancreatic cancer have a family history of the disease, but most cannot be identified with a known genetic disorder. Recognized genetic disorders that predispose to pancreatic cancer include hereditary pancreatitis (PRSS1 gene), hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, hereditary breast and ovarian cancers (PALB2 and BRCA2 genes), Peutz-Jeghers syndrome (STK11 gene), familial atypical mole melanoma syndrome (CDKN2A gene), ataxia telangiectasia (ATM gene), and the Von Hippel–Lindau syndrome (VHL gene). Screening to detect precancerous lesions or early cancers should be considered for individuals with a cumulative predicted risk of PDAC greater than 5% or relative risk (RR) of 5 or greater (having ≥2 relatives with PDAC including ≥1 a first degree, or having a germline mutation of a predisposing gene and ≥2 relatives with PDAC or ≥1 a first degree, or Peutz–Jeghers syndrome even in the absence of a family history) and eligible for a possible pancreatic resection after discussion of the risks and benefits of such screening. Although imaging surveillance of highrisk family cohorts is practiced at some centers of expertise, there is no consensus about the optimal methods or frequency of pancreatic cancer screening. Screening with EUS and/or MRI can be considered but has not been shown to improve survival rates.

Pathology More than 95% of malignant neoplasms of the pancreas arise from the exocrine pancreas. The term pancreatic cancer usually refers to ductal adenocarcinoma of the pancreas, representing 85% to 90% of all pancreatic neoplasms. Exocrine pancreatic neoplasm is a more inclusive term that includes neoplastic pancreatic ductal and acinar cells and their stem cells (e.g., pancreatoblastoma). Other, less common exocrine cancers include adenosquamous carcinomas, squamous cell carcinomas, signet ring cell carcinomas, and undifferentiated carcinomas. Neoplasms arising from the endocrine pancreas (i.e., islet cell or neuroendocrine tumors) comprise no more than 5% of pancreatic neoplasms. Pancreatic cancers are composed of several distinct elements, including pancreatic cancer cells, tumor stroma, and stem cells. The precursor lesion of pancreatic cancer is pancreatic intraepithelial neoplasia, which progresses from mild dysplasia (PanIN grade 1) to more severe dysplasia (PanIN grades 2 and 3) and eventually to invasive carcinoma.

414

SECTION VI  Gastrointestinal Disease

TABLE 39.4  Definitions of Pancreatic Ductal Adenocarcinoma Treatment Categories Resectable

Metastatic Borderline resectable

Locally advanced

Clinical Presentation The clinical manifestations of pancreatic carcinoma may be nonspecific and are often insidious. The clinical presentation is dependent to a great extent on tumor location and stage. PDAC localized to the head of the pancreas (70% to 80%) are more frequently symptomatic than those located in the body or tail (20% to 30%). Most PDAC has reached an advanced stage by the time of diagnosis. Common presenting signs and symptoms of pancreatic cancer include jaundice, weight loss, and abdominal pain. The pain is usually constant, with radiation to the back. Because most cancers begin in the pancreatic head, patients may exhibit obstructive jaundice or a large, palpable gallbladder (i.e., Courvoisier’s sign). Painless jaundice is the most common manifestation in patients with a potentially resectable and curable lesion. Anorexia, nausea, and vomiting may also occur, along with emotional disturbances such as depression. Less common manifestations include superficial thrombophlebitis (i.e., Trousseau sign), acute pancreatitis, diabetes mellitus, ascites, paraneoplastic syndromes (e.g., Cushing’s syndrome), hypercalcemia, gastrointestinal bleeding, splenic vein thrombosis, and a palpable abdominal mass.

Diagnosis and Staging The goal of imaging in the evaluation of suspected pancreatic carcinoma is to establish the diagnosis with a high degree of certainty and to determine resectability in patients who are otherwise candidates for operative resection. The diagnosis of pancreatic cancer is frequently suggested by a pancreatic mass seen on imaging studies. Evidence of a dilated pancreatic duct, hepatic metastases, invasion of vessels, or a dilated common bile duct in the setting of biliary obstruction may also be found. The imaging appearance may be impossible to distinguish from benign causes of pancreatic masses such as focal pancreatitis or autoimmune pancreatitis. Pancreas protocol triple phase (i.e., arterial, late arterial, and venous phases) cross-sectional multidetector CT scanning is the best initial study to diagnose and stage pancreatic cancer by identifying a mass lesion and assessing for liver metastasis or vascular invasion. CT is reported to have a sensitivity of 90% to 97% for identifying PDAC, although it is less sensitive for diagnosing small (1000 units/mL). The use of tumor markers to diagnose carcinoma of the pancreas has yielded disappointing results. The tumor marker CA 19-9 has a sensitivity of 70% to 80% and a specificity of 85% to 95% for diagnosing selected patients already exhibiting signs and symptoms that suggest pancreatic cancer. However, for early-stage cancers, CA 19-9 has limited sensitivity. Use of CA 19-9 requires the Lewis blood group antigen, which is absent in 5% to 10% of the population. The greatest utility for CA 19-9 is to identify occult metastasis in patients with seemingly resectable tumors, for monitoring patients after apparently curative surgery, and for following those receiving chemotherapy for advanced disease. Rising CA 19-9 levels suggest recurrent disease even in the absence of radiographically detectable lesions.

Treatment Dividing patients with PDAC into resectable, borderline resectable, locally advanced, and metastatic categories is clinically useful (Table 39.4).

Resectable Disease Unfortunately, only 10% to 20% of carcinomas in the head of the pancreas and rare cancers of the body and tail are resectable for cure. Current criteria for resectability include the absence of distant metastases and the absence of tumor involvement of major arteries (superior mesenteric, celiac, and common hepatic). Venous involvement requires vascular patency and criteria for resectability will depend on the surgeon’s experience and ability to perform vascular reconstruction. Universal preoperative ERCP for patients with biliary obstruction is not recommended due to lack of proven benefit and the potential to increase adverse events. Selective use of ERCP with biliary stent placement is recommended for those patients with biliary obstruction and a clinical presentation of either cholangitis, intractable pruritus, marked hyperbilirubinemia, or when surgery is delayed for neoadjuvant therapy. Technical success of ERCP is achieved in over 90% of such patients with an acceptable complication rate of under 5%. At the

CHAPTER 39  Diseases of the Pancreas time of stent placement, ERCP tissue sampling techniques can confirm a diagnosis of pancreatic malignancy (sensitivity of 30% to 60% and specificity 100%). The standard operation for pancreatic cancer of the head or uncinate process is the Whipple procedure (i.e., pancreaticoduodenectomy). Whipple resection consists of removal of the pancreatic head, distal common bile duct, gallbladder, duodenum, proximal jejunum, gastric antrum, and regional lymph nodes. Reconstruction requires pancreaticojejunostomy, hepaticojejunostomy, and gastrojejunostomy. The pylorus-preserving version of the Whipple procedure leaves the stomach intact. The surgical mortality rate for this procedure is approximately 3% when performed by experienced pancreatic surgeons. Adjuvant therapy is indicated in all patients following resection of PDAC, irrespective of the pTNM stage, as it improves progression-free and overall survival rates.

Locally Advanced and Borderline Resectable The term borderline resectable is reserved for patients with focal tumor abutment of the visceral arteries (celiac, superior mesenteric artery [SMA], or common hepatic), defined as contact of the tumor with less than one half circumference of the vessel wall, or short-segment occlusion of the superior mesenteric vein (SMV) or SMV–portal vein confluence. The latter is considered a relative rather than absolute contraindication to curative resection as some surgeons are performing resection with vascular reconstruction for selected individuals under these circumstances. Also, for tumors of the tail of the pancreas, encasement of the splenic vein does not necessarily obviate resectability. Locally advanced disease refers to individuals with unresectable cancer due to arterial encasement (>180° or >50% vessel circumference) of SMA, celiac or common hepatic arteries or SMV/PV occlusion without an option for reconstruction. The use of preoperative neoadjuvant chemoradiation therapy in an effort to convert patients with unresectable borderline or locally advanced disease to a resectable status has increased the overall resection rate, but no difference in survival has been demonstrated.

Metastatic or Unresectable Disease Although practice varies across institutions, most surgeons consider a pancreatic cancer to be categorically unresectable if there is extrapancreatic involvement, including extensive peripancreatic lymphatic extension, nodal involvement beyond the peripancreatic tissues, or distant metastases (e.g., liver, peritoneum, omentum, extra-abdominal sites). Other indications of unresectability include vascular encasement (i.e., tumor contact with more than one-half of the vessel’s circumference), or direct involvement of the superior mesenteric artery, aorta, celiac artery, or hepatic artery, as defined by the absence of a fat plane between the tumor and these structures on CT imaging. Patients with metastatic or inoperable pancreatic cancer should be offered treatment with multidisciplinary input based on goals of care, patient preferences, performance status (PS) and social support systems. If protocol enrollment is not available or is declined, conventional systemic chemotherapy should be offered because it provides benefit improving disease-related symptoms and overall survival. • Patients under age 75 years with an ECOG PS 0 to 1 and bilirubin less than 1.5 mg/dL should be offered FOLFIRINOX or gemcitabine plus nab-paclitaxel; • Patients with an ECOG PS 2 and bilirubin less than 1.5 ULN should be offered gemcitabine plus nab-paclitaxel or gemcitabine; • Patients with an ECOG PS 0 to 2 and bilirubin 1.5 ULN or greater or comorbidities should be offered gemcitabine; and

415

• P  atients with an ECOG PS 3 to 4 should be offered best supportive care. For patients with inoperable cancers and poor performance status, palliative interventions to alleviate jaundice, pain, and intestinal obstruction often become the focus of therapy. When advanced disease is observed operatively, the surgeon must determine whether to perform additional palliative surgery. Biliary bypass is indicated in patients with obstructive jaundice. Duodenal bypass is indicated when features suggest impending gastric outlet obstruction. Alternative palliative endoscopic approaches are available for patients not undergoing exploratory surgery.

Prognosis Carcinoma of the pancreas accounts for approximately 5% of cancer deaths in the United States. The overall prognosis is poor because less than 20% of patients are alive beyond the first year after diagnosis, and only 7% survive to the fifth year. Although 15% to 20% of patients have resectable disease at initial diagnosis, most have locally advanced or metastatic cancer. Median survival is 8 to 12 months for patients with locally advanced unresectable disease and 3 to 6 months for those with metastases at diagnosis. A Whipple resection for pancreatic head cancers is the only chance for cure; however, the median survival after surgery is 15 to 20 months. Five-year survival after margin negative (R0) pancreaticoduodenectomy is approximately 25% to 30% following node-negative resection and 10% for node-positive disease. The overall 5-year survival rate is 10% to 25%, and up to 50% of those who survive 5 years ultimately die of recurrent cancer. Poor prognostic factors include a high tumor grade, a large tumor, high levels of CA 19-9 before and after surgery, tumor-positive surgical margins, and lymph node metastases. For a deeper discussion of these topics, please see Chapter 135, “Pancreatitis,” and Chapter 185, “Pancreatic Cancer,” in GoldmanCecil Medicine, 26th Edition.

SUGGESTED READINGS Baron TE, DiMaio CJ, Wang AY, et al: American Gastroenterological Association Clinical Practice update: management of pancreatic necrosis, Gastroenterology 158:67–75, 2020. Fogel EL, Shahda S, Sandrasegaran K, et al: A multidisciplinary approach to pancreas cancer in 2016: a review, Am J Gastroenterol 112:537–554, 2017. Forsmark CE: Management of chronic pancreatitis, Gastroenterology 144:1282–1291, 2013. Gardner TB, Adler DG, Forsmark CE: ACG clinical guideline: chronic pancreatitis, Am J Gastroenterol, 2020. Hidalgo M: Pancreatic cancer, N Engl J Med 362:1605–1617, 2010. Paulson AS, Cao HS, Tempero MA, et al: Therapeutic advances in pancreatic cancer, Gastroenterology 144:1316–1326, 2013. Singh VK, Yadav D, Garg PK: Diagnosis and management of chronic pancreatitis: a review, JAMA 322:2422–2434, 2019. Tenner S, Baillie J, DeWitt J, et al: American College of Gastroenterology guideline: management of acute pancreatitis, Am J Gastroenterol 108:1400–1415, 2013. Vege SS, DiMagno MJ, Forsmark CE, et al: Initial medical treatment of acute pancreatitis: American Gastroenterological Association Institute Technical review, Gastroenterology 154:1103–1139, 2018. Whitcomb DC: Genetic risk factors for pancreatic disorders, Gastroenterology 144:1292–1302, 2013. Yadav D, Lowenfels AB: The epidemiology of pancreatitis and pancreatic cancer, Gastroenterology 144:1252–1261, 2013.

SECTION

VII

Diseases of the Liver and Biliary System 40 Laboratory Tests in Liver Diseases, 417

44 Cirrhosis of the Liver and Its Complications, 437

41 Jaundice, 420 42 Acute and Chronic Hepatitis, 426 43  Acute Liver Failure, 434

416

45 Disorders of the Gallbladder and Biliary Tract, 448

40 Laboratory Tests in Liver Diseases Michael B. Fallon, Ester Little

INTRODUCTION The liver is a large and complex organ, involved in major metabolic, secretory, and nutritional functions. It plays a central role in glucose homeostasis, synthesis and secretion of bile, and synthesis of lipoproteins and plasma proteins, including clotting factors and vitamin storage (vitamins B12, A, D, E, and K). It is also the site of biotransformation, detoxification, and excretion of a multitude of endogenous and exogenous compounds. Given the diversity of the liver roles, the clinical manifestation of liver diseases is varied and can be quite subtle. The first step in evaluating a patient with liver disease is the clinical history, and signs of liver disease can also be seen on physical exam (e.g., jaundice, dark urine, light colored stools, gastrointestinal bleeding, spider angiomas, palmar erythema, hepatomegaly, splenomegaly, ascites, and asterixis). The history and physical findings guide the initial set of laboratory tests ordered.

LIVER CHEMISTRY TESTS The most widely used tests to evaluate the liver are aspartate and alanine aminotransferases (AST and ALT), alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGT), bilirubin, albumin, and prothrombin time. They are commonly referred to as “liver function tests.” However, this is misleading because (1) they do not accurately reflect the function of the liver, (2) abnormal levels can indicate diseases affecting other organs, and (3) they may be normal in patients with advanced liver disease. A better terminology is liver chemistry tests. These tests reflect patterns of abnormalities seen in liver and biliary cell injury.

Patterns of Abnormalities in Liver Chemistry Tests There are primarily three patterns of abnormalities in liver chemistry tests: one that reflects damage of the hepatocytes or hepatocellular damage (AST and ALT), one that reflects cholestasis and damage of the biliary cells (ALP and GGT), and one when patients have isolated elevation in bilirubin. The tests are interpreted based on limits of normality and may vary between different laboratories. However, for ALT, it is now recognized that the limit of normality should be the same for all, and many professional societies have included the following levels in their guidelines: normal ALT ranges from 29 to 33 units/L in adult men and 19 to 25 units/L in adult women. Table 40.1 depicts the most common liver chemistry tests and the disease processes associated with each set of tests.

Hepatocellular Damage ALT and AST are intracellular enzymes that catalyze the transfer of the α-amino group of aspartate or alanine to the α-keto group of

ketoglutaric acid, resulting in formation of pyruvate or oxaloacetic acid, respectively. Vitamin B6 is required to carry out this reaction. In the presence of cell injury or death, AST and ALT are released into circulation. ALT is found predominantly in hepatocytes and is more specific, whereas AST is also found in the heart, lungs, kidney, pancreas, brain, and skeletal muscle. In most hepatocellular disorders (i.e., viral hepatitis, autoimmune hepatitis, hemochromatosis, Wilson’s disease and some drug-induced liver injury) ALT is higher than or equal to AST. However, in alcoholic liver disease this ratio is reversed. A ratio greater than 2 is seen in 70% and greater than 3 in 96% of the patients with known alcoholic liver disease. Chronic and heavy alcohol consumption leads to vitamin B deficiency. The effect of vitamin B6 deficiency is more prominent on ALT than AST activity, causing the increase in AST/ALT ratio. Not uncommonly, the AST is also higher than ALT in patients with nonalcoholic fatty liver disease (NAFLD), mimicking alcoholic liver disease. The magnitude of elevation in aminotransferases also helps identify the possible cause of liver damage. Marked elevation, above 15 times the upper limit of normality (ULN), is seen in acute viral hepatitis, acetaminophen toxicity, hypoxic hepatopathy (shock, ischemia, hypoxemia) or acute bile duct obstruction. More modest elevations, usually 10 to 15 times the ULN, are seen in alcoholic hepatitis, autoimmune hepatitis, Wilson’s disease, Budd-Chiari, and malignant infiltration of the liver (usually from breast cancer, small cell lung cancer, lymphoma, melanoma). In patients with chronic viral hepatitis, ALT and AST levels are rarely above 10 times the ULN, except during exacerbations of chronic hepatitis B. Elevations less than four times the ULN are more commonly seen in nonalcoholic fatty liver disease, hemochromatosis, α1-antitrypsin deficiency, celiac disease, and thyroid disease. Once the liver damage has progressed to cirrhosis, the elevation in aminotransferases is mild and can be normal. Conversely, ALT and AST can be massively elevated in diseases not related to the liver, such as rhabdomyolysis and heat stroke. In addition to acetaminophen, multiple medications can cause elevation in the aminotransferases at different levels of magnitude, including diclofenac, fluoxetine, isoniazid, ketoconazole, lisinopril, phenytoin, rifampin, ritonavir, and statins. The rate at which the AST and ALT levels decrease as the patient improves can also help in identifying the cause. More rapid decline suggests ischemia or resolution of an acute biliary obstruction.

Cholestasis The tests that indicate cholestasis and biliary cell damage are ALP and GGT. Serum ALP comprises a group of isoenzymes derived from the liver, intestine, bone, and placenta. The liver isoenzyme (ALP-1) is present in the mucosal cells lining the bile ducts and increases in response to bile duct damage from inflammation or obstruction. In these circumstances,

417

418

SECTION VII  Diseases of the Liver and Biliary System

TABLE 40.1  Liver Chemistry Tests Liver Chemistry Test

What It Reflects

Associated Diseases

Aspartate aminotransferase and alanine aminotransferase

Hepatocellular damage

Alkaline phosphatase and γ-glutamyl transpeptidase

Cholestasis, biliary cell damage, and infiltrative processes

Isolated bilirubin elevation

Increased production and impaired uptake, conjugation or excretion of bilirubin Impaired synthetic liver function

Viral hepatitis, autoimmune hepatitis (AIH), alcoholic hepatitis, hemochromatosis, ischemic hepatitis, Budd-Chiari syndrome, α1-antitrypsin deficiency, Wilson’s disease, and drugs Primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), familial cholestatic syndromes, AIDS cholangiopathy, cholestasis of pregnancy, biliary obstruction by stones or cancer, drugs, sarcoidosis, amyloidosis, and malignancy infiltration Hemolysis, Gilbert, Crigler-Najjar, Dubin-Johnson, and Rotor syndromes

Decreased albumin and prolonged prothrombin time

GGT and 5′-nucleotidase (5′-NT) are simultaneously released. Thus, an elevation of ALP without elevation of GGT and 5′-NT indicates a nonhepatic cause. Fractionation of the different ALP isoenzymes by electrophoresis can be useful in determining alternative sources. ALP does not differentiate intrahepatic from extrahepatic cholestasis. Examples of disorders that cause intrahepatic cholestasis are primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), infections (AIDS cholangiopathy), familial cholestatic syndromes, cholestasis of pregnancy, total parenteral nutrition, ischemic cholangiopathy, liver allograft rejection, congestive hepatopathy (liver congestion secondary to right-sided heart failure), some medications (amiodarone, anabolic steroids, amoxicillin clavulanate, carbamazepine, estrogens, naproxen, phenytoin, rifampin), and infiltrative diseases (sarcoidosis, amyloidosis, malignant infiltration of the liver). Causes of extrahepatic cholestasis include bile duct stones or tumors, diverticulum of the ampulla of Vater, chronic pancreatitis, and pancreatic cancer. ALP is frequently below normal range in patients with Wilson’s disease, particularly those presenting with acute liver failure, in whom bilirubin is disproportionally elevated compared to alkaline phosphatase. GGT is very nonspecific, and in addition to liver diseases it can be elevated in pancreatic diseases, myocardial infarction, renal failure, alcoholism, chronic obstructive pulmonary disease, and from several medications. As noted above, 5′-NT would not be elevated in these conditions.

Isolated Bilirubin Elevation Patients with both hepatocellular diseases and cholestasis frequently also have bilirubin elevation secondary to leakage of bilirubin into the serum. However, some patients have elevated bilirubin with normal ALT, AST, ALP and GGT, which is termed isolated bilirubin elevation. In such cases, the first step is to fractionate the bilirubin to determine if it is caused by an elevation in the unconjugated (indirect) or conjugated (direct) bilirubin. An increase in unconjugated bilirubin results from overproduction (hemolysis), impaired uptake (Gilbert’s disease) or impaired conjugation (Crigler-Najjar syndrome). An increase in conjugated bilirubin is due to decreased excretion in the bile ducts (Dubin-Johnson and Rotor syndromes) or leakage of the pigment from hepatocytes into serum. More detailed discussion on cholestasis and isolated elevation of bilirubin can be found in Chapter 41.

LIVER SYNTHETIC FUNCTION Albumin From 300 g to 500 g of albumin is distributed in body fluids, and the adult liver synthesizes 15 g of albumin per day. Serum albumin concentration reflects the rate of synthesis, degradation, and volume of distribution. The synthesis of albumin is influenced by several factors including nutritional status, serum oncotic pressure, hormones, and cytokines.

Liver failure, severe acute hepatitis, and advanced liver disease with cirrhosis

The half-life of albumin in serum is 14 to 20 days. Low albumin is seen in prolonged liver dysfunction or acute liver impairment, and a decrease in albumin concentration reflects a reduction in albumin synthesis. Hypoalbuminemia does not always reflect liver synthetic dysfunction. Several other conditions may decrease albumin, including malnutrition, nephrotic syndrome, protein losing enteropathy, and systemic inflammation.

Coagulation Factors and Prothrombin Time The liver is the major site for the synthesis of 11 coagulation factors, including factors I, II, V, VII, IX, X, XII, and XIII. Deficiency in clotting factors occurs in more severe or more advanced stages of liver diseases. These factors can be measured individually or indirectly by determining the prothrombin time (PT). The PT is dependent on factors II, V, VII and X, all of which are synthesized in the liver. Prolonged PT is not specific to liver diseases and can be seen in several congenital or acquired disorders. When these conditions are excluded, a prolonged PT is usually secondary to deficiency of vitamin K (inadequate dietary intake, prolonged obstructive jaundice, intestinal malabsorption or prolonged broad spectrum antibiotic use) or by poor utilization of vitamin K because of advanced liver disease. The administration of a single parenteral dose of vitamin K normalizes the PT in cases of vitamin K deficiency. The magnitude of the prolongation of PT reflects the severity of the liver disease; however, PT does not correlate with the coagulation status or the risk of bleeding in patients with cirrhosis. In fact, in patients with cirrhosis there is also a decrease in synthesis of anti-hemostatic factors, and some patients become relatively hypercoagulable and have an increased risk of clot formation, despite having prolonged PT. This is an important and frequently misunderstood concept.

Gamma Globulins Elevation of individual gamma globulins can be suggestive of specific liver diseases. Some examples include elevation of immunoglobulin G (IgG) in patients with autoimmune hepatitis, elevation of immunoglobulin M (IgM) in PBC, and elevation of immunoglobulin A (IgA) in patients with alcoholic cirrhosis. IgG4-related disease is an autoimmune phenomenon in which increased IgG4 levels cause dysfunction in multiple organs, including bile ducts (IgG4-related cholangiopathy).

Specific Markers of Liver Diseases Specific laboratory tests are required for the diagnosis of some liver diseases. • α1-Antitrypsin (α1AT): it can be quantified and, if decreased, the A1AT phenotype can be determined • Autoimmune hepatitis: antinuclear antibody (ANA), anti–smooth muscle antibody (ASMA), anti–liver/kidney microsomal antibody type 1 (anti-LKM1)

CHAPTER 40  Laboratory Tests in Liver Diseases • Primary biliary cholangitis: antimitochondrial antibody (AMA) • Hemochromatosis: iron panel (serum iron, total iron binding capacity, transferrin saturation and ferritin) and HFE gene mutations • Wilson’s disease: serum ceruloplasmin and urinary copper levels • Viruses: different viruses (e.g., hepatitis A, B, C, D, E, Epstein-Barr virus, cytomegalovirus, and herpes virus) that cause hepatitis are detected using polymerase chain reaction.

Biomarkers of Liver Fibrosis Liver biopsy is the “gold standard” for evaluation of liver histopathology. Although the complications are few, it is an invasive test and the need for less invasive means to evaluate fibrosis led to several studies in search of surrogate markers for hepatic fibrosis. Many such tests combine clinical and serum markers and have been validated in specific populations, particularly chronic hepatitis C and nonalcoholic fatty liver disease. Caution is needed when using the results in other patient populations. In addition, serum markers are not liver specific and concurrent sites of inflammation may contribute to deranged serum levels. These tests are used to differentiate patients with more significant stages of fibrosis and cirrhosis (stages 3 and 4), from those with minimal or no fibrosis (stages 0 and 1). The stages are based on the METAVIR score and range from 0 to 4, where stage 4 corresponds to cirrhosis. Examples of such tests include the following: • APRI Score is based on the AST and platelet count (AST elevation/platelet count) × 100. It has been mostly studied in patients with HCV, HCV and HIV co-infection, alcoholic liver disease, and NAFLD. • FibroSure or FibroTest uses the measurement of α2-macroglobulin, α2-globulin, γ-globulin, apolipoprotein A1, GGT, and total bilirubin. It also utilizes the patient’s age and sex. The results classify the patients as having mild fibrosis, indeterminate fibrosis or significant fibrosis. It has been better studied in patients with HCV and has a better specificity than sensitivity. • HepaScore utilizes the combination of bilirubin, GGT, hyaluronic acid, α2-macroglobulin, age, and sex. Its performance is similar to the FibroTest.

419

• FIB 4 index combines platelet count, ALT, AST, and age. Better studied in HCV and NAFLD. • NAFLD fibrosis score considers the patient’s age, body mass index, blood glucose, aminotransferases, platelet count, and albumin. Other panel tests have included products of collagen synthesis or degradation, enzymes involved in matrix biosynthesis or degradation, extracellular matrix glycoproteins, and proteoglycans/glycosaminoglycans. The routine use of these panels in clinical practice is not clearly established and some suggest their use in combination with image modalities. Image tests applying mechanical waves and measuring their propagation speed through liver tissue using ultrasound and MRI have become more readily available. They have been studied in a broader spectrum of liver diseases and have better sensitivity and specificity than the serologic tests. Nevertheless, at this point none of these tests fully substitute for liver biopsy.

SUGGESTED READINGS Gao Y, Zheng J, Liang P, et al: Liver fibrosis with two-dimensional US shearwave elastography in participants with chronic hepatitis B: a prospective multicenter study, Radiology 289:407–415, 2018. Newsome PN, Cramb R, Davison SM, et al: Guidelines on the management of abnormal liver blood tests, Gut 67:6–19, 2018. Northup PG, Caldwell SH: Coagulation in liver disease: a guide for the clinician, Clin Gastroenterol Hepatol 11:1064–1074, 2013. Poynard T, De Ledinghen V, Zarski JP, et al: Relative performances of FibroTest, Fibroscan, and biopsy for the assessment of the stage of liver fibrosis in patients with chronic hepatitis C: a step toward the truth in the absence of a gold standard, J Hepatol 56:541–548, 2012. Rockey D, Caldwell SH, Goodman ZD, et al: AASLD position paper: liver biopsy, Hepatology 49:1017–1044, 2009. Sebastiani G, Halfon P, Castera L, et al: Comparison of three algorithms of non-invasive markers of fibrosis in chronic hepatitis C, Aliment Pharmacol Ther 35:92–104, 2012. Tapper EB, Saini SC, Sengupta N: Extensive testing or focused testing of patients with elevated liver enzymes, J Hepatol 66:313–319, 2017.

41 Jaundice Mohanad T. Al-Qaisi, Mashal Batheja, Michael B. Fallon

INTRODUCTION Jaundice is the condition of yellowish pigmentation of the skin, the conjunctival membranes over the sclera, and other mucous membranes that is caused by elevated serum bilirubin levels (hyperbilirubinemia). The term jaundice is derived from jaune, the French word for “yellow,” and the condition is also known as icterus (Greek for “yellow”). Normal serum bilirubin levels range from 0.5 to 1.0 mg/dL, and plasma bilirubin concentrations typically must exceed 2.5 mg/dL before jaundice becomes evident clinically. Although jaundice is commonly due to liver and biliary tract disease, it has many causes, so it is not surprising that the diagnosis and management of jaundice have challenged clinicians for centuries. In most cases, jaundice or hyperbilirubinemia per se is not a pathologic condition but rather a sign of one or more illnesses originating from or affecting the liver and blood. However, there is one notable exception: In newborns, high bilirubin levels can lead to pathologic cerebral changes. In this condition, which is known as kernicterus (kern is the German word for “nucleus”), persistent elevation of unconjugated bilirubin leads to its deposition in the cerebral basal ganglia (or nuclei). This process can be prevented and treated and therefore merits special recognition to prevent damage to the developing brain.

BILIRUBIN METABOLISM Hyperbilirubinemia can be classified based on the three phases of hepatic bilirubin metabolism: uptake, conjugation, and excretion into the bile (the rate-limiting step). In addition, jaundice can be classified into prehepatic, hepatic, and posthepatic causes (Table 41.1). Although the approaches are complementary, the latter classification may be more useful for the practicing clinician. The main source of bilirubin is the hemoglobin released from senescent red blood cells, and the liver serves as its primary site of metabolism and excretion. Abnormalities at any step in bilirubin production, metabolism, or excretion can lead to an increase in the serum bilirubin and clinical jaundice. Under normal conditions, human red blood cells have a lifespan of about 120 days. As they age, erythrocytes are broken down and removed from the circulation by phagocytes. Most bilirubin (80%) is derived from the breakdown of hemoglobin released from these cells; the remainder is derived from ineffective erythropoiesis in the bone marrow and from catabolism of myoglobin and hepatic hemoproteins such as the cytochrome P-450 isoenzymes. The normal rate of bilirubin production is approximately 4 mg/kg body weight per day (E-Fig. 41.1). As erythrocytes are destroyed within the reticuloendothelial system, free hemoglobin is ingested by macrophages and then split into heme and globin moieties. The heme ring is cleaved by the enzyme

420

microsomal heme oxygenase to form biliverdin (verde = “green”), which is then converted to the tetrapyrrole pigment bilirubin by the cytosolic enzyme biliverdin reductase. This unconjugated (or “indirect”) bilirubin is released into the plasma, where it is tightly bound to albumin. Because unconjugated bilirubin is insoluble in water, it cannot be excreted in urine or bile. However, it is permeable across lipid-rich environments and therefore can traverse the blood-brain barrier and the placenta. The unconjugated bilirubin-albumin complex is transported to the liver. Once in the space of Disse, this complex dissociates; unconjugated bilirubin is transported across the basolateral plasma membrane of liver cells and attaches to intracellular binding proteins (ligandins). It is then conjugated with glucuronic acid by the enzyme uridine diphosphate glucuronyl transferase (UDP-GT) to form bilirubin monoglucuronide and diglucuronide, making the molecule water soluble. This conjugated (or “direct”) bilirubin is excreted into bile via active transport across the canalicular membrane by means of a multispecific canalicular transport protein. In healthy persons, most bilirubin circulates in its unconjugated form with less than 5% of circulating bilirubin appearing in its conjugated form. If biliary excretion of conjugated bilirubin is impaired, it can exit the basolateral membrane and reenter the circulation, causing an increase in plasma levels. Because conjugated bilirubin is water soluble and less tightly bound to albumin than its unconjugated form, it is readily filtered by the glomerulus and appears in the urine, giving it a dark color (choluria). Once in bile, bilirubin enters the intestine, where bacteria convert it to colorless tetrapyrroles (urobilinogens) that are excreted in feces. Up to 20% of urobilinogen is reabsorbed and undergoes enterohepatic circulation or excretion in urine.

LABORATORY MEASUREMENT OF BILIRUBIN The van den Bergh reaction, which is the most commonly used test for detecting bilirubin in biologic fluids, combines bilirubin with diazotized sulfanilic acid to form a colored compound. The direct-reacting fraction is roughly equivalent to conjugated bilirubin and the indirect-reacting fraction (total minus direct fraction) to unconjugated bilirubin. This characteristic provides a means for classifying jaundice into two categories: unconjugated hyperbilirubinemia and conjugated hyperbilirubinemia.

UNCONJUGATED HYPERBILIRUBINEMIA Mechanisms that cause unconjugated hyperbilirubinemia include overproduction, impaired hepatic uptake, and decreased conjugation

CHAPTER 41  Jaundice

421

TABLE 41.1  Classification of Jaundice and Representative Causes Prehepatic Causes Predominantly unconjugated hyperbilirubinemia Hemolysis (e.g., sickle cell disease, autoimmune hemolytic anemia, mechanical cardiac valve with accelerated red cell destruction) Microbe-induced hemolysis (malaria, leptospirosis) Ineffective erythropoiesis (e.g., megaloblastic anemias) Hematoma resolution Hepatic Causes Unconjugated hyperbilirubinemia Decreased hepatic uptake Therapeutic drugs that interfere with bilirubin uptake (e.g., rifampin, metformin, methimazole, propylthiouracil, clopidogrel, sulfamethoxazole/trimethoprim) Herbal medicines (e.g., Teucrium viscidum, kava-kava, chaparral, greater celandine) Hyperthyroidism Diminished uptake and decreased cytosolic binding proteins (e.g., newborn or premature infants) Shunting of blood away from the liver (portal hypertension or surgical shunt) Decreased conjugation due to limited glucuronyl transferase activity Gilbert syndrome Crigler-Najjar syndrome types I and II Neonatal jaundice Breast-milk jaundice Drug-induced inhibition (e.g., chloramphenicol) Predominantly conjugated hyperbilirubinemia Impaired hepatic excretion Familial cholestasis (Dubin-Johnson syndrome, Rotor syndrome, benign recurrent cholestasis, cholestasis of pregnancy) Hepatocellular injury from infiltrative disorders, hemochromatosis, α1-antitrypsin deficiency, lymphoma, sarcoidosis, extensive metastases) Liver cirrhosis Hepatitis Drug-induced cholestasis (chlorpromazine, erythromycin estolate, isoniazid, halothane, and many others) Primary biliary cirrhosis Congestive heart failure Sepsis Posthepatic Causes Extrahepatic biliary obstruction Common bile duct obstruction from gallstones Benign and malignant tumors of the pancreas Tumors of bile ducts (cholangiocarcinoma) and ampulla of Vater Biliary strictures (postsurgical, gallstone-related, primary sclerosing cholangitis) Congenital disorders (biliary atresia, cystic fibrosis) Infectious cholangiopathy Chronic pancreatitis (fibrosis of the head of the pancreas)

of bilirubin. These disorders are not usually associated with significant hepatic disease.

Etiology of Hyperbilirubinemia There are many potential causes of hyperbilirubinemia, and the major categories are summarized in Table 41.1. It is helpful to consider them mechanistically as conditions affecting the balance of bilirubin production, liver metabolism, and excretion. The classic cause of bilirubin overproduction is hemolysis, whereas the most common cause of impaired bilirubin uptake and metabolism is cirrhosis or other liver disease (viral hepatitis, drugs, hepatotoxins or ischemia). Bile duct obstruction due to cancer (classically cholangiocarcinoma or pancreatic head cancer), stones, or strictures is the most common cause of obstructive jaundice. Because multiple mechanisms are often involved in an individual patient, the evaluation of jaundice can be complex.

Prehepatic Jaundice Prehepatic jaundice is associated with excessive bilirubin production (Fig. 41.1), which most often results from hemolysis (intravascular or extravascular), resolution of large hematomas, or mechanical injury to red cells, as in disseminated intravascular coagulation (see Chapter 48). Certain genetic diseases can lead to increased red cell lysis and therefore hemolytic jaundice. Sickle cell anemia is the classic cause, but others include glucose 6-phosphate dehydrogenase deficiency and hereditary spherocytosis. Infectious diseases also can cause hemolysis, either directly (e.g., malaria) or indirectly (e.g., autoimmune injury). Jaundice resulting from hemolysis is characteristically mild in degree, and serum bilirubin levels rarely exceed 5 mg/dL in the absence of coexisting hepatic disease. Ineffective erythropoiesis, which may be significantly increased in megaloblastic anemia, also leads to mild jaundice.

421.e1

CHAPTER 41  Jaundice

Metabolism Bilirubin Glucuronyl transferase

Production Bone marrow

Spleen

Hepatic hemoproteins Bilirubin glucuronides

Excretion

UDPGA Liver

Bilirubin glucuronides (with cholestasis)

UDP

Albumin

Bilirubin Senescent red cells (80%-85%)

Erythroid precursors (15%-20%)

Albumin

Colon Urobilinogen Kidney

Albumin

Hemoglobin

Bilirubin Ileum

Globin

Heme

E-Fig. 41.1  Bilirubin production, metabolism, and excretion. See text for details. UDP, Uridine diphosphate; UDPGA, uridine diphosphate glucuronic acid.

422

SECTION VII  Diseases of the Liver and Biliary System

A

B

Fig. 41.1  Hemolytic anemia associated with lymphoma. (A) Blood smear shows the destroyed red blood cells. (B) Lymphoma.

Fig. 41.2  Ultrasound image shows a cirrhotic liver with atrophy, irregular contours, and ascites.

Hemolysis should be considered in the evaluation of unconjugated hyperbilirubinemia and evaluated by examination of the peripheral blood smear (and, in some cases, the bone marrow smear and biopsy) as well as measurements of the reticulocyte count, haptoglobin, lactate dehydrogenase (LDH), erythrocyte fragility, and Coombs testing as indicated.

Hepatic or Hepatocellular Jaundice Typically, considerable reserve exists within the liver, so jaundice of hepatocellular origin can be indicative of significant injury or dysfunction. The differential diagnosis is broad because the liver is susceptible to many different forms of injury (Fig. 41.2). The most common categories are viral hepatitis, exposure to toxins (e.g., alcohol, carbon tetrachloride, amanita, and increasingly herbs and supplements), medications (INH, antibiotics), autoimmune disorders (e.g., autoimmune hepatitis, primary biliary cholangitis [PBC], primary sclerosing cholangitis [PSC]), and liver tumors (primary or metastatic). Impaired hepatic uptake of bilirubin can be a cause of unconjugated hyperbilirubinemia. When present, it is typically caused by competition for bilirubin uptake by drugs such as rifampin. Removal of the competing agent usually leads to resolution of the jaundice.

Impaired Conjugation Another common cause of unconjugated hyperbilirubinemia is Gilbert syndrome, a benign disorder that affects up to 7% of the population. This represents a normal variant that is not associated with intrinsic

liver disease. Rather, it typically manifests during the second or third decade of life as mild unconjugated hyperbilirubinemia that is exacerbated by fasting or physical stress. Most of those affected have a total bilirubin level of less than 3 mg/dL, mostly of the unconjugated (indirect) fraction. The underlying genetic variant responsible is a homozygous abnormality in the TATAA element of the promoter region of the UDP-GT gene that results in lower enzymatic levels. The diagnosis is strongly suggested by unconjugated hyperbilirubinemia in the setting of normal hepatic enzyme levels, no known liver disease, and no evidence of hemolysis. Liver biopsy usually is not indicated, and therapy is not warranted. However, the bilirubin level does decrease significantly with phenobarbital administration. It is important to be aware of this common cause of unconjugated hyperbilirubinemia so that the patient can be reassured and more costly or invasive tests can be avoided. Although Gilbert syndrome has generally been thought to have a benign course, sometimes people with this condition might be at an increased risk of developing gallstones. On the other hand, patients with Gilbert syndrome might be at a lower risk to develop cardiovascular disease, because unconjugated bilirubin has antioxidant properties that may offer some protective effect and mitigate progression of atherosclerosis. Crigler-Najjar syndrome is another cause of unconjugated hyperbilirubinemia in which the bilirubin levels may be much higher due to a genetically determined decrease or absence of UDP-GT activity. Conjugation may also be impaired by mild, acquired defects of UDP-GT induced by drugs such as chloramphenicol.

NEONATAL JAUNDICE About 50% of term and 80% of preterm babies develop jaundice, which usually appears 2 to 4 days after birth and resolves spontaneously after 1 to 2 weeks. Most jaundice in newborn infants occurs for two main reasons. First, the enzymatic and transport pathways responsible for bilirubin metabolism are relatively immature and are unable to conjugate bilirubin as efficiently or as quickly as in adults. Second, bilirubin production is increased. Of those two mechanisms, the major defect is in bilirubin conjugation, which may cause mild to moderate unconjugated hyperbilirubinemia between the second and fifth days of life lasting until day 8 in normal births or about day 14 in premature births. This neonatal jaundice is usually harmless, and no specific therapy is required other than close observation. More severe pathologic unconjugated hyperbilirubinemia can occur in neonates and usually is caused by a combination of hemolysis secondary to blood group incompatibility and defective conjugation. This neonatal jaundice is a serious condition that requires immediate

CHAPTER 41  Jaundice attention because severe hyperbilirubinemia can lead to permanent neurologic damage (kernicterus). Phototherapy provided by conventional lighting or a fiberoptic light is the treatment of choice; it reduces neonatal jaundice (as assessed by serum bilirubin levels) compared with no treatment. Low-threshold compared with high-threshold phototherapy reduces neurodevelopmental impairment and hearing loss and reduces serum bilirubin on day 5 in infants with extremely low birth weight. However, it increases the duration of phototherapy, and it has no effect on mortality or on the rate of exchange transfusion. Close phototherapy, compared with distant light-source phototherapy, reduces the duration of phototherapy in infants with hyperbilirubinemia. If jaundice does not improve with phototherapy, other causes of neonatal jaundice should be assessed.

CONJUGATED HYPERBILIRUBINEMIA Conjugated hyperbilirubinemia is associated with impaired formation or excretion of all components of bile, a situation termed cholestasis. The two major mechanisms of conjugated hyperbilirubinemia are defective excretion of bilirubin from hepatocytes into bile (intrahepatic cholestasis) and mechanical obstruction to the flow of bile through the bile ducts.

Impaired Hepatic Excretion (Intrahepatic Cholestasis) Intrahepatic cholestasis can result from a wide range of conditions, including those that impair canalicular transport (e.g., certain drugs, circulating inflammatory cytokines during sepsis) and those that cause destruction of the small intrahepatic bile ducts. PBC, for example, is a chronic, progressive liver disease that occurs primarily in women and is characterized by the indolent destruction and subsequent disappearance over time of small lobular bile ducts. The gradual decrease in the number of bile ducts leads to progressive cholestasis, portal inflammation, fibrosis, and eventually cirrhosis. A similar loss of intrahepatic ducts can occur as a result of chronic rejection after liver transplantation. Drug-induced cholestasis is increasingly common, and immune-­ mediated or idiosyncratic mechanisms can be the underlying cause. In some cases, there is associated hepatitis with significant cell injury (this can lead to hepatocellular damage and elevations in alanine aminotransferase [ALT] and aspartate aminotransferase [AST]). Representative drugs include, but are not limited to, nitrofurantoin, oral contraceptives, anabolic steroids, erythromycin, cimetidine, gold salts, chlorpromazine, prochlorperazine, imipramine, sulindac, tolbutamide, ampicillin, and other penicillin-based antibiotics. Given the broad access to drugs in Western societies and the unpredictable nature of the adverse liver effects, a high index of suspicion for drug-induced cholestasis is required. Drug-induced liver injury is generally considered a diagnosis of exclusion, after a thorough evaluation has ruled out other viral, autoimmune, and metabolic etiologies. Intrahepatic cholestasis of pregnancy (ICP), also known as idiopathic jaundice of pregnancy, is a cholestatic disorder that is characterized by pruritus in the absence of a skin rash and elevation of aminotransferases (often up to 100 IU/L), alkaline phosphatase, 5-nucleotidase, and total and direct bilirubin concentrations. Total levels of bilirubin rarely exceed 6 mg/dL. The levels of γ-glutamyl trans­peptidase are normal or only modestly elevated. ICP occurs in the second or third trimester of pregnancy and usually resolves spontaneously within 2 to 3 weeks after delivery. The diagnosis is suggested by the combination of pruritus and abnormal liver function tests with exclusion of other causes such as gallstones or intrinsic liver disease. ICP is associated with a higher risk for adverse perinatal outcome, including preterm birth, meconium passage, and fetal death.

423

The cause of ICP is not fully defined, but genetic, hormonal, and environmental factors are all likely to be involved. There is a high incidence of ICP in Chile and some other areas, and studies of potential genetic contributors are underway. Because adverse outcomes appear to occur predominantly after 37 weeks gestation, management by an experienced obstetrics team and consideration of early delivery are warranted. Ursodeoxycholic acid may be effective in ameliorating maternal pruritus and improving liver function test results; however, no medication has yet been shown to reduce the risk to the fetus. The hemophagocytic syndrome, also known as hemophagocytic lymphohistiocytosis (HLH), is an uncommon hyperinflammatory disorder caused by severe hypercytokinemia. It manifests as fever, splenomegaly, and jaundice, with hemophagocytosis in the bone marrow and other tissues pathologically. Primary or familial HLH, also called familial erythrophagocytic lymphohistiocytosis, is a heterogeneous autosomal recessive disorder that has been found to be more prevalent with parental consanguinity. Secondary HLH is associated with malignancy, immunodeficiency, and infection, especially viral infection. In HLH, there is an inherent defect of natural killer cells and cytotoxic T cells, so they are unable to cope effectively with the infectious agent or antigen. Liver biopsies in HLH reveal sinusoidal dilation with hemophagocytic histiocytosis. Postoperative jaundice typically occurs 1 to 10 days after surgery and has an incidence of approximately 15% after heart surgery and 1% after elective abdominal surgery. It is multifactorial in origin, with increased bilirubin load from bleeding and blood transfusions as well as impaired bilirubin conjugation and secretion caused by inflammatory cytokines. It typically resolves fully over time. In hepatocellular disease, all three steps of hepatic bilirubin metabolism are impaired. Excretion, the rate-limiting step, is usually most affected, leading to predominantly conjugated hyperbilirubinemia. Jaundice can be profound in acute hepatitis (see Chapter 42) without adverse prognostic implications. In chronic liver disease, however, persistent jaundice usually implies irreversible decrease in hepatic function and a poor prognosis.

Posthepatic Jaundice Posthepatic jaundice, also called obstructive jaundice, results from a complete or partial obstruction of intrahepatic or extrahepatic bile ducts (Fig. 41.3 and E-Fig. 41.2). The most common causes are gallstones in the common bile duct and tumors of the pancreatic head. Not infrequently, the first sign of pancreatic cancer is jaundice. Other causes include strictures of the common bile duct resulting from prior surgery or passage of gallstones. Primary sclerosing cholangitis should be considered in the setting of jaundice and biliary strictures that may be seen on imaging studies (magnetic resonance cholangiopancreatography [MRCP] or endoscopic retrograde pancreatography [ERCP]). Less common causes include congenital biliary atresia, pancreatitis, pancreatic pseudocysts, and parasites such as liver flukes (e.g., Clonorchis sinensis, Dicrocoelium dendriticum, Opisthorchis viverrini). Mirizzi syndrome is an uncommon cause of posthepatic jaundice observed in 0.7% to 1.4% of patients after cholecystectomy. This syndrome is caused by extrinsic compression from an impacted stone in the cystic duct that impinges on and obstructs the common bile duct (see Table 41.1). Portal hypertensive biliopathy (or vascular biliopathy) is characterized by anatomic and functional abnormalities of the intrahepatic, extrahepatic, and pancreatic ducts in patients with portal hypertension associated with extrahepatic portal vein obstruction or, less frequently, cirrhosis. These morphologic changes, consisting of dilatation and stenosis of the biliary tree, are caused by extensive venous collaterals that develop in an attempt to decompress the portal

424

SECTION VII  Diseases of the Liver and Biliary System

A

B

Fig. 41.3  Hepatocellular carcinoma compressing the bile ducts. (A) Sagittal view of computed abdominal tomography scan. (B) Endoscopic retrograde cholangiopancreatography demonstrates multiple strictures of the bile ducts.

venous blockage. The condition is usually asymptomatic until it has progressed to a more advanced stage such as biliary cirrhosis. Immunoglobulin G4 (IgG4)–related sclerosing disease has recently been recognized as a distinct disease entity that can affect the bile ducts, gallbladder, pancreas, and other sites. Most cases of IgG4-related pancreatobiliary disease are associated with elevated serum IgG4 levels, extensive IgG4-positive plasma cells, and infiltration of lymphocytes into various organs, which leads to fibrosis. Several established systems are used to diagnose IgG4 disease; they rely on a combination of imaging findings of the pancreas, bile duct, and other organs; serologic findings; pancreatic histologic findings; and response to corticosteroid therapy.

CLINICAL APPROACH TO THE EVALUATION OF JAUNDICE The differential diagnosis of jaundice is broad, thus a thorough history and physical examination along with judicious use of laboratory and imaging studies are necessary to define its underlying etiology. Jaundice appears as yellowing of the skin and sclera. Other conditions may mimic this presentation (e.g., carotenemia, Addison’s disease, quinacrine ingestion), but scleral and mucosal discolorations are absent in these conditions. In hypercarotenemia, for example, the yellowishorange coloration typically involves only the palms of the hands and soles of the feet. An elevated serum bilirubin level, usually higher than 3 mg/dL, confirms the clinical impression of jaundice. The most important initial step is to define whether the jaundice is predominantly caused by an elevation of unconjugated or conjugated bilirubin. If jaundice is primarily the result of unconjugated bilirubin, evaluation for hemolysis and other conditions with shortened red blood cell survival is required. In patients with elevated conjugated bilirubin, the clinical challenge lies in determining whether biliary obstruction or impaired hepatic excretion is responsible (see Chapter 40). In cholestatic jaundice caused by biliary obstruction, the alkaline phosphatase level is typically increased to more than three times normal, whereas serum transaminases are usually elevated less than 5-fold to 10-fold (E-Fig. 41.3; see Chapter 40). Patients with cholestasis may

also develop pruritus and malabsorption of fat and fat-soluble vitamins (vitamins A, D, E, and K). More specific causes of biliary obstruction are suggested by recurrent abdominal pain and nausea (gallstones) or epigastric pain radiating to the back with weight loss and gallbladder distention (carcinoma of the pancreatic head). In complete biliary obstruction, conjugated hyperbilirubinemia is prominent and usually peaks at about 30 mg/dL in the absence of renal failure. Eosinophilia may accompany drug-induced jaundice. Inquiring about the use of drugs known to cause cholestasis, serologic testing for antimitochondrial antibody in suspected PBC, and ERCP or MRCP to evaluate PSC may be helpful. In jaundice produced by hepatocellular disease (see Chapters 40 and 42), serum transaminases are characteristically elevated more than 10-fold and alkaline phosphatase levels are less than three times normal. Evidence of hepatocellular damage is commonly associated and includes a prolonged prothrombin time, hypoalbuminemia, and clinical features of hepatic dysfunction (palmar erythema, spider angiomas, gynecomastia, and ascites). A careful evaluation includes inquiry about the use of drugs known to cause hepatocellular injury, alcohol, risk factors for viral hepatitis, and preexisting liver disease. More selected laboratory studies, such as serologic testing for hepatitis, are usually required (see Chapter 42). A diagnostic approach to jaundice is outlined in E-Fig. 41.3. If extrahepatic obstruction is suspected, noninvasive studies such as ultrasound or computed tomography should be used to determine whether bile ducts are dilated. If dilated ducts are found on noninvasive imaging, then direct cholangiography (either endoscopic or radiologic) provides the most reliable approach to management and potential treatment of cholestatic jaundice. If intrahepatic cholestasis is suggested clinically and extrahepatic obstruction is excluded by noninvasive means or by direct cholangiography, then the emphasis is placed on further laboratory testing to define the specific cause. Liver biopsy is sometimes required to define a specific histologic diagnosis, rule out other causes of disease, and assess the degree of injury and fibrosis. For a deeper discussion on this topic, please see Chapter 138, “Approach to the Patient with Jaundice or Abnormal Liver Tests,” in Goldman-Cecil Medicine, 26th Edition.

CHAPTER 41  Jaundice

A

B

C

D

424.e1

E-Fig. 41.2  Various pathologies causing extrahepatic bile duct obstruction. (A) Cholangiocellular carcinoma. (B) Chronic pancreatitis. (C) Pancreatic cancer. (D) Klatskin tumor.

History, physical exam, laboratory tests

Suspected extrahepatic obstruction Suspected intrahepatic cholestasis

Are ducts dilated? (ultrasonography or computed tomography)

Observation, remove inciting agents ? special tests ? liver biopsy

No

No

Yes

Direct ductal visualization (percutaneous or retrograde cholangiography)

Corrective or palliative treatment -surgical -endoscopic -percutaneous

Obstruction No obstruction demonstrated E-Fig. 41.3  Approach to the patient with cholestatic jaundice. The algorithm demonstrates the systematic consideration of the available diagnostic options.

CHAPTER 41  Jaundice

SUGGESTED READINGS Berk PD: Approach to the patient with jaundice or abnormal liver tests. In Goldman L, Ausiello D, editors: Cecil textbook of medicine, ed 22, Philadelphia, 2004, Saunders, pp 897–905. Pathak B, Sheibani L, Lee RH: Cholestasis of pregnancy, Obstet Gynecol Clin North Am 37:269–282, 2010. Suárez V, Puerta A, Santos LF, et al.: Portal hypertensive biliopathy: a single center experience and literature review, World J Hepatol 5:137–144, 2013.

425

Trauner M, Wagner M, Fickert P, et al.: Molecular regulation of hepatobiliary transport systems: clinical implications for understanding and treating cholestasis, J Clin Gastroenterol 39(4 Suppl 2):S111–S124, 2005. Vlachou PA, Khalili K, Jang HJ, et al.: IgG4-related sclerosing disease: autoimmune pancreatitis and extrapancreatic manifestations, Radiographics 31:1379–1402, 2011. Woodgate P, Jardine LA: Neonatal jaundice, Clin Evid (Online) Epub Sep 15, 2011. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21920055. Accessed September 19, 2014.

42 Acute and Chronic Hepatitis Nayan M. Patel, Jen Jung Pan, Michael B. Fallon

INTRODUCTION The term hepatitis denotes inflammation of the liver. It is applied to a broad category of clinicopathologic conditions that result from the damage produced by viral, toxic, metabolic, pharmacologic, or immune-mediated injury to the liver.

ACUTE HEPATITIS Acute hepatitis implies a recent-onset inflammatory condition lasting less than 6 months. It can culminate either in complete resolution of the liver damage with return to normal function and structure or rapid progression of the acute injury toward extensive necrosis and a fatal outcome. Depending on the etiology, some may also progress to develop a chronic hepatitis. The most common causes of acute hepatitis are viral hepatitis (hepatitis A through E) and nonviral causes such as drug-induced liver injury, alcohol, toxins, autoimmune hepatitis, and Wilson’s disease.

Acute Viral Hepatitis Five hepatotropic viruses cause classic acute viral hepatitis (Table 42.1), but other viruses, including cytomegalovirus, herpesviruses, and Epstein-Barr virus can also cause liver injury. All of the hepatotropic viruses are ribonucleic acid (RNA) viruses except hepatitis B virus (HBV), which has a deoxyribonucleic acid (DNA) genome. Hepatitis A virus (HAV) is a nonenveloped, single-stranded RNA virus classified in the Picornaviridae family and in the Hepatovirus genus. It is stable at moderate temperature and low pH, allowing the virus to survive in the environment and be transmitted by the fecaloral route. The course is generally self-limited and does not lead to chronic infection. Hepatitis E virus (HEV) belongs to the genus Hepevirus in the Hepeviridae family and has four genotypes. HEV1 and HEV2 are restricted to human beings and are transmitted via contaminated water in developing countries. HEV1 occurs mainly in Asia, whereas HEV2 occurs in Africa and Mexico. HEV3 and HEV4 infect human beings, pigs, and other mammalian species and are responsible for sporadic cases of autochthonous hepatitis E in both developing and developed countries. HEV3 has a worldwide distribution. HEV4 mostly occurs in Southeast Asia. While typically self-limited, acute liver failure and hepatic decompensation can occur in patients who are pregnant, malnourished, or have preexisting liver disease. Additionally, patients with solid organ transplants can develop a chronic HEV infection. HBV is a small DNA virus that belongs to the Hepadnaviridae family. Approximately 250 million persons are carriers of HBV worldwide; of these, 75% reside in Asia and the Western Pacific. Both acute and chronic HBV infection can occur. Chronic hepatitis B infection is a major cause of hepatocellular carcinoma worldwide and can occur without cirrhosis because of integration of HBV DNA into hepatocytes.

426

Hepatitis C virus (HCV) is a single-stranded positive-sense RNA virus that belongs to the Flaviviridae family and has been classified as the sole member of the genus Hepacivirus. Approximately 74 million people are infected with HCV worldwide and 2.4 million in the United States. HBV has eight genotypes (labeled A through H), and HCV has six genotypes (1 through 6). Both HBV and HCV viruses are transmitted parenterally. HBV is present in virtually all body fluids and excreta of carriers. Transmission occurs most commonly through blood and blood products, contaminated needles, and sexual contact. Historically, HCV was the main cause of post-transfusion hepatitis before 1992. It is currently the most common cause of hepatitis among intravenous drug users. The Centers for Disease Control and Prevention now recommends one-time screening of persons born between 1945 and 1965 for hepatitis C because of the high prevalence of the disease in this birth cohort. Hepatitis D virus (HDV) is classified in a separate genus of the Deltaviridae family. It is a small, defective RNA virus that can propagate only in an individual who has coexistent HBV infection, either after simultaneous transmission of the two viruses or via superinfection of an established HBV carrier. HDV has at least eight genotypes, four of which (genotypes 5 through 8) seem to be of exclusively African origin. Of the 250 million chronic carriers of HBV worldwide, more than 15 million have serologic evidence of exposure to HDV. Like HBV, HDV is transmitted via the parenteral route through exposure to infected blood or body fluids. Because there is evidence for sexual transmission, people with high-risk sexual activity are at increased risk for infection.

Clinical and Laboratory Manifestations Acute viral hepatitis typically involves an asymptomatic incubation period from exposure to the first appearance of symptoms. This can be weeks to months depending on the type of viral hepatitis. Next a prodromal phase lasting several days that is characterized by constitutional and gastrointestinal symptoms including malaise, fatigue, anorexia, nausea, vomiting, myalgia, and headache occurs. A mild fever may be present (Fig. 42.1). Clinical manifestations of hepatitis A depend on the age of the host: fewer than 30% of infected young children showed symptomatic hepatitis, whereas about 80% of infected adults had severe acute hepatitis with remarkably elevated serum aminotransferases (Fig. 42.2). Arthritis and urticaria resembling serum sickness, attributed to immune complex deposition, are present in 5% to 10% of cases of acute hepatitis B and C. Taste and smell alterations may also occur. Jaundice soon appears, with bilirubinuria and acholic (pale) stools, which are often accompanied by an improvement in the patient’s sense of wellbeing. The liver is usually tender and enlarged; splenomegaly is found in about one fifth of patients. Notably, many patients with acute viral hepatitis are asymptomatic or have symptoms without jaundice (anicteric hepatitis). In such instances, medical attention often is not sought.

CHAPTER 42  Acute and Chronic Hepatitis

427

TABLE 42.1  Characteristics of Acute Viral Hepatitides Hepatitis A

Hepatitis B

Transmission

27–28 nm RNA virus Nonenveloped Fecal-oral

Incubation period (days) Onset Fulminant disease (%) Chronic hepatitis Treatment

15–50 Acute 0.01–0.5 No Supportive

Prophylaxis

Hygiene; immune globulin, vaccine

42 nm DNA virus 55–65 nm RNA virus Enveloped Enveloped Blood-borne, sexual, Similar to HBV; vertical percutaneous, perinatal and sexual route uncommon 30–180 14–180 Acute, insidious Insidious 1 2.5 to 3 mg/dL) results in jaundice and is defined as icteric hepatitis. Values higher than 20 mg/dL are uncommon and correlate in a general way with the severity of disease. Elevations in serum alkaline phosphatase (ALP) are usually limited to three times normal levels except in cases of cholestatic hepatitis. A complete blood cell count most commonly shows mild leukopenia with atypical lymphocytes. Anemia and thrombocytopenia may also be present. The icteric phase of acute viral hepatitis may last days to weeks and is followed by gradual resolution of symptoms and laboratory values.

3 4 5 6 12 Months after exposure Fig. 42.2  Serologic course of acute hepatitis A. ALT, Alanine aminotransferase; HAV, hepatitis A virus; IgM, immunoglobulin M.

Acute viral hepatitis can be diagnosed either directly, by detecting the nucleic acids of the infecting virus, or indirectly, by demonstrating an immune response in the host (Tables 42.2 and 42.3). Epstein-Barr virus and cytomegalovirus hepatitis are part of the differential diagnosis and also may be diagnosed by the appearance of specific antibodies of the immunoglobulin M (IgM) class. In acute hepatitis B, hepatitis B surface antigen (HBsAg) and e antigen (HBeAg) are present in serum. Both are usually cleared within 3 months in acute self-limited infection, but HBsAg may persist in some patients with uncomplicated disease for 6 months to 1 year. Clearance of HBsAg is followed after a variable period by the emergence of antibodies against hepatitis B surface antigen (anti-HBs), which confers long-term immunity. Antibodies against hepatitis B core antigen (antiHBc) and e antigen (anti-HBe) appear in the acute phase of the illness, but neither provides immunity. During the serologic window period, anti-HBc IgM, a marker of active viral replication suggesting recent infection, may be the only evidence of HBV infection (Fig. 42.3). Every patient who is HBsAg positive should be tested for antibodies against HDV (anti-HDV IgG), which persist even after the patient has cleared HDV infection. Active HDV infection is now confirmed by the detection of serum HDV RNA with sensitive real-time polymerase chain reaction (PCR) assays. However, because of the variability of the genome sequence, assays of HDV RNA can produce false-negative results. Testing of anti-HDV IgM antibodies still has a role in patients who test negative for HDV RNA but have clinical features of HDVrelated liver disease. While there is no diagnostic feature, suspicion for active HDV co-infection should be higher in acute liver failure from acute HBV infection. Acute hepatitis C can be detected within 2 weeks after exposure with the use of a sensitive PCR assay for HCV RNA. Serum antibodies

428

SECTION VII  Diseases of the Liver and Biliary System

TABLE 42.2  Serologic Markers of Viral Hepatitis Agent

Marker

Definition

Significance

HAV

Anti-HAV IgM Anti-HAV IgG

IgM antibody to HAV IgG antibody to HAV

HBV

HBsAg HBeAg

Hepatitis B surface antigen Hepatitis B e antigen

Anti-HBs

Antibody to surface antigen

Anti-HBe

Antibody to e antigen

Anti-HBc IgM Anti-HBc IgG

IgM antibody to core antigen IgG antibody to core antigen

Anti-HCV Anti-HDV IgM

Antibody to HCV IgM antibody to HDV

Anti-HDV IgG

IgG antibody to HDV

Anti-HEV IgM Anti-HEV IgG

IgM antibody to HEV IgG antibody to HEV

Marker of acute or recent infection Marker of acute or previous infection; post vaccination; confers protective immunity The presence of HBsAg indicates that the person is infectious Transiently positive in acute infection; may persist in chronic infection; reflection of active viral replication and high infectivity Marker of acute self-limited infection; post vaccination; confers protective immunity Transiently positive in convalescence; positive in chronic infection before seroconversion; usually a reflection of low infectivity Marker of acute or exacerbation of chronic infection Appears at the onset of symptoms in acute infection and persists for life; not seen in vaccinees without prior infection Marker of acute and chronic infection; does not provide immunity Positive in acute infection, negative in past infection but persists in a large proportion of patients with chronic infection Positive in all individuals exposed to HDV, and persists long-term, even after viral clearance Marker of acute or recent infectiona Marker of chronic or previous infectiona

HCV HDV

HEV

HAV, Hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis E virus; IgG, immunoglobulin G; IgM, immunoglobulin M. aSerologic testing is unreliable, and seroconversion might never occur in immunosuppressed persons.

TABLE 42.3  Interpretation of Diagnostic Markers in Hepatitis B

Acute infection Acute self-limited infection Vaccinated Chronic infection HBeAg positive HBeAg negative Immune escape Occult infection Reactivation of chronic infection

HBsAg

HBeAg

Anti-HBc IgM

Anti-HBc IgG

Anti-HBs

Anti-HBe

Blood HBV DNA

+ −

+ −

+ +

+ +

− +

+/− +/−

High −

−

−

−

−

+

−

−

+ + + − +

+ − − − +

− − − − +/−

+ + + + +

− − − − −

− + + +/− +/−

High Low High Very low High

anti-HBc IgG, Immunoglobulin G antibody against hepatitis B core antigen; anti-HBc IgM, immunoglobulin M antibody against hepatitis B core antigen; anti-HBe, antibody against hepatitis B e antigen; anti-HBs, antibody against hepatitis B surface antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV DNA, hepatitis B virus deoxyribonucleic acid.

to HCV develop within 12 weeks after exposure, or within 4 to 5 weeks after biochemical abnormalities are discovered. Importantly, these are not neutralizing antibodies and do not confer immunity (Fig. 42.4). At onset of symptoms, 30% of patients will be missed if checked by serum enzyme immunoassay (EIA) for HCV antibody alone. Commercial EIAs for hepatitis E to detect both IgM and IgG class antibodies are also available but may lack sensitivity and specificity. Diagnosis of HEV infection should be established by PCR assays in immunosuppressed patients, because serologic testing is unreliable, and seroconversion might never occur.

Complications Cholestatic hepatitis. In some patients, most commonly during HAV infection, a prolonged but self-limited period of cholestasis (total bilirubin >10 mg/dL) occurs that is characterized by marked conjugated hyperbilirubinemia, elevation of ALP, and pruritus. Further investigation may be required to rule out biliary obstruction (see Chapters 40, 41, and 45). Relapsing hepatitis. For unknown reasons, up to 10% of patients can experience a relapse of HAV infection after an initial resolution. This is characterized by biochemical relapse, but often milder clinical symptoms, and will typically resolve spontaneously.

CHAPTER 42  Acute and Chronic Hepatitis

Symptoms HBeAg

Anti-HBs antibodies

HBV DNA

Titer

Total anti-HBc antibodies

Anti-HBc IgM

HBsAg

0

4

8

Anti-HBs antibodies

12 16 20 24 28 32 36

52

Weeks after infection (on average) Fig. 42.3  Kinetics of hepatitis B virus (HBV) markers during acute self-resolving hepatitis B. The arrow indicates infection. HBc, Hepatitis B core; HBeAg, hepatitis B e antigen; HBs, hepatitis B surface; HBsAg, hepatitis B surface antigen; IgM, immunoglobulin M.

Anti-HCV antibodies Symptoms ALT HCV RNA Titer 1

2

Guillain-Barré syndrome, aseptic meningitis, and encephalitis have also been reported. Extrahepatic manifestations such as cryoglobulinemia and glomerulonephritis are associated with hepatitis B and C, and polyarteritis nodosa is associated with hepatitis B. These manifestations are more common in patients who fail to clear acute HBV or HCV and develop chronic hepatitis.

Management Unless complicated by fulminant hepatitis, cases of acute hepatitis A, B, and E are usually self-limited and are managed by supportive care including rest, maintenance of adequate hydration and dietary intake, and avoidance of alcohol use. Hospitalization may be needed for patients who cannot tolerate oral intake and for those with evidence of deteriorated liver function, such as hepatic encephalopathy or coagulopathy. In general, hepatitis A and E may be regarded as noninfectious after 3 weeks, whereas hepatitis B is potentially infectious to sexual contacts throughout its course, although the risk is low once HBsAg has been cleared. Studies of antiviral therapy in acute hepatitis B have not shown clear benefit, although some experts advocate the use of nucleos(t)ide analogues, specifically in the setting of acute liver failure due to hepatitis B. Treatment of acute hepatitis C is not always needed because 20% to 50% of patients will spontaneous clear the virus. This typically occurs within 6 months of the time of infection. If a decision is made to initiate treatment, current guidelines suggest monitoring HCV RNA for 12 to 16 weeks before starting treatment to allow for possible spontaneous clearance. Because of the safety and efficacy of direct acting antivirals (DAAs), the same regimen of medication for chronic hepatitis C is recommended for acute HCV.

Prevention

ULN 0

429

3

4 5 6 12 24 36 48 Months after infection Fig. 42.4  Kinetics of hepatitis C virus markers during acute self-resolving hepatitis C. ALT, Alanine aminotransferase; ULN, upper limit of normal.

Fulminant hepatitis. Massive hepatic necrosis occurs in fewer than 1% of patients with acute viral hepatitis; it leads to a devastating and often fatal condition called acute liver failure. This condition is discussed in detail in Chapter 43. Chronic hepatitis. Hepatitis A does not progress to chronic liver disease, although occasionally it has a relapsing course. Persistence of elevated levels of ALT and AST, viral antigens, or nucleic acids beyond 6 months in patients with hepatitis B or C suggests evolution to chronic hepatitis, although slowly resolving acute hepatitis may occasionally exhibit such test abnormalities for up to 12 months with eventual complete resolution. About 60% of organ transplant recipients infected with HEV fail to clear the virus and go on to develop chronic hepatitis. Chronic hepatitis is considered in detail later in this chapter. Rare complications. Acute viral hepatitis may rarely be followed by aplastic anemia, which tends to affect mostly male patients and results in a mortality rate greater than 80%. Pancreatitis, myocarditis, pericarditis, pleural effusion, and neurologic complications including

In patients with hepatitis A or E, both feces and blood contain virus during the prodromal and early icteric phases. General hygiene measures should include handwashing by contacts and careful handling, disposal, and sterilization of excreta, contaminated clothing, and utensils. HAV vaccination is appropriate for children older than 12 months of age, travelers to endemic areas, individuals with immunodeficiency or chronic liver disease, and those with high-risk behaviors or occupations. HAV vaccination is preferred over immunoglobulin for postexposure prophylaxis, based on results from randomized trials. With the availability of two candidate vaccines, one of which is already licensed for use in China, HEV prevention through vaccination is now a realistic possibility. HBV is rarely transmitted by body fluids other than blood; however, it is highly infectious, and strict adherence to universal precautions is mandatory. Efforts at preventing hepatitis B have involved the use of hepatitis B immunoglobulin (HBIG) and recombinant HBV vaccines. Prophylaxis with HBIG after blood or mucosal exposure should be given within 7 days along with HBV vaccine. Preventive vaccination is currently recommended for high-risk individuals—health care professionals, patients undergoing hemodialysis, patients with chronic liver disease, residents and staff of custodial care institutions, and sexually active homosexual men—and is advocated universally for children. In the United States, the first hepatitis B vaccination is recommended to be given within 12 to 24 hours of birth. No accepted prevention strategies other than universal precautions are available for HCV, and serum immunoglobulin is not useful for postexposure prophylaxis. The advent of widespread blood product screening for hepatitis C has made such infection after transfusion a rarity.

Alcoholic Liver Disease Alcohol abuse continues to be a major cause of liver disease in the Western world. The three major pathologic findings resulting from

430

SECTION VII  Diseases of the Liver and Biliary System

alcohol abuse are fatty liver, alcoholic hepatitis, and cirrhosis. These findings are not mutually exclusive and may all be present in the same patient. The first two conditions are potentially reversible. Alcoholic cirrhosis is discussed in Chapter 44.

Mechanism of Injury The mechanisms of liver injury caused by alcohol are complex. Ethanol and its metabolites, acetaldehyde and nicotinamide adenine dinucleotide phosphate, are directly hepatotoxic and cause a large number of metabolic derangements. Induction of cytochrome P-450 (i.e., CYP2E1) stimulates reactive oxidant species and cytokine pathways, particularly tumor necrosis factor-α (TNF-α). These are critical in initiating and perpetuating hepatic injury, as well as causing fibrosis through stellate cell activation. Excess alcohol leads to increased intestinal permeability, and the resultant endotoxemia from bacterial lipopolysaccharide leads to hepatic inflammation from upregulation of TNF-α. Hepatotoxic effects from alcohol vary considerably among individuals based on dose, duration, drinking patterns, sex, ethnicity, genetic factors, and comorbidities that may affect the liver. The amount of alcohol ingested is the most important risk factor for the development of alcoholic liver disease. Women have a lower threshold of injury than men and have decreased amounts of gastric alcohol dehydrogenase as compared to men. The risk of cirrhosis is increased in men who drink greater than 60 to 80 grams of alcohol daily and women who drink more than 20 grams of alcohol daily. Malnutrition and other forms of chronic liver disease may potentiate the toxic effects of alcohol on the liver.

Clinical and Pathologic Features Alcoholic fatty liver may manifest as incidentally discovered hepatomegaly or elevated aminotransferase levels on screening blood tests. Vague discomfort in the right upper quadrant of the abdomen may be the only symptom. Jaundice is rare, and aminotransferases are only mildly elevated (20,000 IU/mL), coupled with elevated serum aminotransferases, are in a high replicative phase (see Table 42.3). In contrast, patients in a low replicative phase are HBsAg and anti-HBe positive, have low blood HBV DNA (80%) and in many instances prolongs survival.

Nonalcoholic Fatty Liver Disease Nonalcoholic fatty liver disease (NAFLD) has a spectrum of presentations from simple steatosis, which usually does not progress to advanced liver disease, to NASH, which may exhibit or lead to cirrhosis. It is the most common cause of abnormal liver function tests among adults in the United States and Western Europe. NAFLD is commonly seen in people with central obesity, hypertension, diabetes, and hyperlipidemia, although it can be observed in persons with normal weight as well. Insulin resistance plays a central role in the pathophysiology of NAFLD. Estimates indicate that about 80 to 100 million Americans have NAFLD; of these, 18 million have NASH and almost 20% have signs of advanced disease (i.e., bridging fibrosis, cirrhosis) on histologic examination. Liver biopsy is the “gold standard” for diagnosis of NASH. The NAFLD Activity Score has been developed and represents the sum of scores for steatosis, lobular inflammation, and hepatocyte ballooning that are typically seen on liver biopsy. It ranges from 0 to 8, with a score of 5 or higher considered diagnostic of NASH. Liver biopsy is invasive, costly, and can cause complications including a small mortality risk (0.01% to 0.1%). The use of liver biopsy has declined with newer noninvasive assessments of liver fibrosis and steatosis. Liver biopsy predominantly is used when there is diagnostic uncertainty to the etiology of disease. Radiologic imaging studies based on ultrasound and MRI can determine fibrosis by measuring liver stiffness with transient elastography technology and can also estimate the degree of steatosis. Currently, this is no FDA-approved treatment available for NASH. Clinical trials of agents that therapeutically target the development of hepatic steatosis and fibrosis are underway and have shown beneficial effects on hepatic fibrosis. However, weight reduction with a goal of 5% to 7% of body weight loss and regular exercise are associated with biochemical and histologic improvement and are important components of therapy. Vitamin E and pioglitazone have been shown to improve hepatic inflammation in nondiabetic patients with NASH, but they are not routinely recommended because of questions regarding long-term safety and side effects.

Genetic and Metabolic Hepatitis Hemochromatosis is an autosomal recessive genetic disorder that causes low levels of the iron regulatory hormone hepcidin causing defective sensing of iron stores and leads to excessive absorption of iron from the digestive tract. In the United States, about 1 of every 250 Caucasians have the condition; however, clinical expression is variable. Elevated ferritin and transferrin saturation values are typically used to screen patients with evidence of chronic liver disease and guide the need for further genetic testing. Most patients with hemochromatosis are homozygous for the C282Y mutation in the HFE gene, and a subset of

CHAPTER 42  Acute and Chronic Hepatitis individuals who are heterozygous for both C282Y and the H63D mutation may also develop iron overload. Iron overload is very uncommon among those who are homozygous for the H63D mutation. Genetic mutations in a number of other proteins involved in iron sensing have also been associated with iron overload but are not routinely tested in clinical practice. Hemochromatosis is a systemic disease that causes iron deposition in parenchymal cells in various organs including the liver, heart, pancreas, and pituitary glands. Patients may develop liver cirrhosis and cancer, heart failure, diabetes mellitus, hypogonadism, and arthralgias. A high index of suspicion is required to detect the disorder in early stages. The standard treatment for hemochromatosis is therapeutic phlebotomy. For patients who cannot undergo phlebotomy, chelation therapy may be offered. Wilson’s disease is an autosomal recessive genetic disorder that results from mutations in the ATP7B gene located on chromosome 13. These mutations result in excessive accumulation of copper in a number of organs, most notably the liver, cornea, and brain. The prevalence of the disease is approximately 1 in 30,000 live births in most populations. Wilson’s disease can occur at any age. Measurement of the 24-hour urine copper excretion, slit lamp examination of corneas for Kayser-Fleischer rings, and direct measurement of hepatic copper confirm the diagnosis. Patients should receive lifelong chelation treatment with either penicillamine or trientine. Zinc may be used to maintain stable copper levels in the body. α1-Antitrypsin deficiency (AAT) is an autosomal recessive genetic disorder of chromosome 14 that causes retention of AAT in the liver, resulting in liver damage. AAT is a protease inhibitor of the proteolytic enzyme elastase. The normal gene product is designated as PiM, and

433

the deficiency variants are PiS (50% to 60%) and PiZ (10% to 20%). The most common carrier phenotypes are PiMS and PiMZ, and the disease phenotypes are PiZZ, PiSS, and PiSZ. Low serum AAT and diastase-positive staining of hepatocellular AAT inclusions on liver biopsy support the diagnosis. Phenotypic testing in the serum has been the traditional gold standard for the diagnosis. However, genotypic testing is now available and widely used. Lung disease results from a loss of protective effects in patients with low levels of circulating AAT. AAT replacement therapy is an option for those with lung disease but is not useful for patients with liver disease. For a deeper discussion on this topic, please see Chapters 139, “Acute Viral Hepatitis,” and 140, “Chronic Viral and Autoimmune Hepatitis,” in Goldman-Cecil Medicine, 26th Edition.

SUGGESTED READINGS Asselah T, Marcellin P: Interferon free therapy with direct acting antivirals for HCV, Liver Int 33(Suppl 1):93–104, 2013. Feldman M, Friedman LS, Brandt LJ: Sleisenger and Fordtran’s gastrointestinal and liver disease-2 Volume Set,ed 10, 2015, Chapters 78-82. Grant LM, Rockey DC: Drug-induced liver injury, Curr Opin Gastrointesterol 28:198–202, 2012. Hughes SA, Wedemeyer H, Harrison PM: Hepatitis delta virus, Lancet 378:73–85, 2011. Jeong SH, Lee HS: Hepatitis A: clinical manifestations and management, Intervirology 53:15–19, 2010. Kamar N, Bendall R, Legrand-Abravanel F, et al: Hepatitis E, Lancet 379:24772488, 2012. Liaw YF: Impact of therapy on the outcome of chronic hepatitis B, Liver Int 33(Suppl 1):111–115, 2013.

43 Acute Liver Failure Anil Seetharam, Michael B. Fallon

DEFINITIONS

ALF develops as a result of severe, unrelenting inflammation with hepatocyte necrosis and collapse of the liver’s architectural framework. This feature contrasts with the changes of cirrhosis and complications of portal hypertension that dominate chronic liver disease (see Chapter 44). ALF may result from infection with hepatotropic viruses A, B, C, D, or E (see Chapter 42) or from herpes simplex virus (HSV). Additionally, dose-dependent or idiosyncratic exposure to hepatotoxins such as acetaminophen, isoniazid, halothane, valproic acid, or mushroom toxins (Amanita phalloides) can produce ALF. Reye’s syndrome, a disease that predominantly affects children, and acute fatty liver of pregnancy often resemble ALF; and are characterized by microvesicular fatty infiltration and little hepatocellular necrosis. Rare causes of ALF include: Wilson’s disease, hepatic ischemia, autoimmune hepatitis, and malignancy (E-Figs. 43.1 and 43.2).

is essential and focused on potential exposure to viruses and hepatotoxins, pregnancy, an event associated with hypotension, and clues to suggest autoimmune causes. Early laboratory testing should focus on assessing the severity of hepatic dysfunction and on detection of possible acetaminophen exposure, for which specific antidote treatment must be promptly initiated. Further specialized laboratory testing is designed to identify specific viral causes—with tests for anti–hepatitis A immunoglobulin M (IgM), hepatitis B surface antigen (HBsAg), anti–hepatitis B core antigen (anti-HBc) IgM, hepatitis D antigen, anti–hepatitis C antibody and/or hepatitis C virus RNA, anti–hepatitis E IgM, anti-varicella IgM, and herpes simplex IgM—or other causes (e.g., ceruloplasmin level or autoimmune markers). Acute fatty liver of pregnancy may progress to ALF in the peripartum period; however, a pregnancy test should be performed in all females of childbearing age because viral illnesses (HSV, hepatitis E) may have a more severe course in pregnancy. A negative serum acetaminophen level does not exclude acetaminophen overdose because the drug is rapidly cleared from the blood. Importantly, acetaminophen overdose accounts for approximately 50% of all cases of ALF and 20% of all cases of presumed indeterminant causes in Western countries. Small quantities of acetaminophen (or acetaminophen-containing compounds) may precipitate ALF in the context of consistent alcohol use due to constitutive activation (by ethanol) of cytochrome pathways creating toxic acetaminophen metabolites. Imaging of the liver including ultrasound with Doppler may be utilized to assess liver architecture and blood flow into/out of the liver. Though not obligatory, a liver biopsy may be considered to assess for etiology; biopsy is often performed via the transjugular route secondary to coagulopathy and acuity of illness.

CLINICAL PRESENTATION

TREATMENT

The clinical presentation includes progressive jaundice and hepatic encephalopathy without clinical evidence of underlying chronic liver disease. Other common but nonspecific symptoms include nausea, vomiting, loss of appetite, right upper abdominal pain from hepatomegaly, fever, fatigue, dark urine, and clay-colored stools. Typically, the features of impaired hepatic synthetic and metabolic function predominate, with portal hypertension much less common compared to patients with established cirrhosis.

Treatment of ALF is largely supportive, because specific treatment for the underlying cause of liver failure is often not available. However, many processes that result in widespread liver cell necrosis and ALF are transient events, and liver cell regeneration with recovery of liver function often occurs if patients survive the initial insult. Acetaminophen toxicity and hypotension causing hepatic necrosis are representative. In contrast, ALF resulting from viral hepatitis or idiosyncratic drug-induced liver injury (DILI) typically has a longer time course and an uncertain prognosis. In either case, meticulous supportive treatment in an intensive care unit setting has been shown to improve survival. Patients with ALF should be treated in centers with experience with this disease and with a liver transplantation program. Numerous systemic complications can result from ALF, and each must be thoroughly identified and treated (Table 43.1). As liver failure progresses,

Acute liver failure (ALF) is an infrequent condition characterized by rapid deterioration of liver function resulting in altered mentation and coagulopathy in individuals without preexisting liver disease. A widely accepted working definition includes International Normalized Ratio (INR) greater than 1.5 and any degree of altered mentation (encephalopathy) in a subject without preexisting cirrhosis and illness of less than 26 weeks’ duration. Associated multisystem organ dysfunction and encephalopathy with chance for brainstem herniation mandate prompt recognition and transfer to an intensive care unit (ICU). Though etiologic specific treatment and supportive measures can be employed, liver transplantation remains the only chance for cure in those who do not spontaneously recover.

PATHOGENESIS

DIAGNOSIS The clinical presentation of ALF can be dramatic, with jaundice and advanced systemic manifestations as the first indication of a severe and potentially life-threatening illness. A thorough medical history

434

CHAPTER 43  Acute Liver Failure 1000

974

900 800

46%

ALF Study Group, Jan 2014

700

500

11%

400

12%

300

252

227

dd

-C

r

et er

hi

ar

i

’s ils on

ic

Bu

W

A

m

m Is ch e

m Au to i

H

ep

B H

ep

g ru D

AP AP

18

15

In d

26

th e

37

0

O

100

145

117

nc y

144

147

na

200

Pr eg

n

600

E-Fig. 43.1 Etiology of acute liver failure (ALF) in the United States Acute Liver Failure Study Group (N = 2070). APAP, Acetaminophen; autoimmune, autoimmune hepatitis; Hep, hepatitis; Indeter, indeterminate cause. (Reuben et al. Outcomes in adults with acute liver failure between 1998 and 2013: an observational cohort study Ann Intern Med. 2016 Jun 7; 164[11]: 724-732.)

E-Fig. 43.2 Central vein with complete drop-out of surrounding hepatocytes in a patient with acute liver failure from drug induced liver injury (H&E, 200×).

434.e1

CHAPTER 43  Acute Liver Failure

435

TABLE 43.1  Management of Selected Problems in Fulminant Hepatic Failure Organ System

Pathogenesis

Supportive Measures

Hepatic encephalopathy

Diminished hepatocyte function

Cerebral edema

Systemic and local inflammation and circulating neurotoxins, including arterial ammonia

Renal

Prerenal kidney injury from diminished effective circulating volume, acute tubular necrosis, or functional leading to acid/base/electrolyte imbalance Low systemic vascular resistance Diminished central vascular tone compromises peripheral tissue oxygenation

Identification of treatable causes (e.g., hypoglycemia, drugs used for sedation, sepsis, gastrointestinal bleeding, electrolyte imbalance, decreased Po2, increased Pco2) Lactulose and rifaximin Elevate head of bed 20–30 degrees Hyperventilate (Pco2 reduction) ICP monitor placement Mannitol Continuous renal replacement therapy

Cardiovascular

Hematologic

Infectious

Intravenous resuscitation with normal saline and changed to half-normal saline containing 75 mEq/L sodium bicarbonate if acidotic Vasopressor support to maintain a mean arterial pressure of at least 75 mm Hg or a cerebral perfusion pressure of 60–80 mm Hg Concomitant reduction in levels of both procoagulant and natural Vitamin K 10 mg IV × 1 anticoagulant proteins, in conjunction with elevation of factor Fresh-frozen plasma, platelets, and rFVIII generally reserved for active VIII (FVIII) and Von Willebrand factor, resulting in reduced bleeding or need for invasive procedure thrombin generation capacity Acid suppression to prevent luminal GI tract bleeding Immune dysfunction Surveillance cultures of blood, urine, and tracheal aspirate when applicable Low threshold to initiate broad-spectrum antibiotic and antifungal therapy

a syndrome of multisystem organ failure can result; this can include encephalopathy, coagulopathy, infection, and renal failure. Hepatic encephalopathy is often the first and most dramatic sign of liver failure. The precise pathogenesis of hepatic encephalopathy in ALF remains unclear and is likely multifactorial; however, it differs from that associated with chronic liver disease or portal hypertension in two important aspects. First, it often responds to therapy only when liver function improves, and second, it is frequently associated with hypoglycemia or cerebral edema, two other potentially treatable causes of coma. Therapy for hepatic encephalopathy in ALF differs slightly from the principles outlined in Chapter 44. Use of lactulose may be considered (orally or through a nasogastric tube) but should be discontinued if there is no significant improvement in mentation. Rifaximin, a nonabsorbable antibiotic, can be given as an adjunct orally or per tube. Intubation is often necessary to protect the airway from aspiration and to allow ventilation in patients with advanced encephalopathy. Cerebral edema, the pathogenesis of which is unknown, is a leading cause of death in ALF. Differentiation between cerebral edema and hepatic encephalopathy can be difficult, and computed tomography of the head is often unreliable as observable architectural changes of edema may lag behind clinical progression. Measurement of intracranial pressure (ICP) can be considered, although it is associated with complications including bleeding. The goal is to maintain an ICP of less than 20 mm Hg while maintaining a cerebral perfusion pressure (calculated as mean arterial pressure minus ICP) greater than 60 mm Hg. Supportive measures to limit ICP elevation include: control of agitation, head elevation of 20 to 30 degrees, hyperventilation, systemic vasopressors to maintain mean arterial pressure, administration of mannitol, barbiturate-induced coma, and urgent liver transplantation. As hepatic synthetic function deteriorates, hypoglycemia can occur as a result of impaired hepatic gluconeogenesis and insulin degradation. All patients at risk should receive 10% glucose IV infusions with frequent monitoring of blood glucose levels. Other metabolic abnormalities commonly occur, including hyponatremia, hypokalemia, respiratory alkalosis, and metabolic acidosis. Therefore, frequent

monitoring of blood electrolytes and pH is indicated. Renal replacement therapy may be employed to regulate acid/base/electrolyte balance, with continuous modes preferred over intermittent hemodialysis. Bleeding occurs frequently and is commonly caused by gastric erosions in the setting of impaired synthesis of clotting factors and prolonged prothrombin times. All patients should receive vitamin K and prophylactic gastric acid suppression. Fresh-frozen plasma administration is reserved for when clinically significant bleeding occurs or if major procedures, including ICP monitoring and central line placement, are performed. Studies in ALF have found a concomitant and proportional reduction in plasma levels of both procoagulants and natural anticoagulant proteins, in conjunction with a significant elevation in plasma levels of factors-VIII (FVIII) and Von Willebrand factor, resulting in an overall efficient, albeit reduced, thrombin generation capacity in comparison with healthy controls. Global hemostasis as assessed with thromboelastography (TEG) may be normal by several compensatory mechanisms, even in patients with markedly elevated INR. Up to 80% of patients with ALF develop infection at some point in their illness; both bacterial (≈80% of infections) and fungal (≈20% of infections) have been implicated. Patients are at higher risk for infection as a result of impaired immunity resulting from liver failure and the need for invasive monitoring. Severe infection may occur without fever or leukocytosis. Therefore, frequent cultures are recommended and warranted with abrupt changes in status, and there should be a low threshold for beginning antibiotic therapy. Although often employed to guide evaluation, no single prognostic model discriminates those who will spontaneously recover and those who will require transplant. The United States Acute Liver Failure Group (ALFSG) prospectively enrolled over 1900 subjects with ALF managed with and without transplantation and aimed to develop a model for ALF to predict transplant-free survival at 21 days. Clinical demographics and laboratory parameters were collected at enrollment and recorded serially up to 1 week. Variables of prognostic value adopted in the predictive model included: admission coma grade, liver

436

SECTION VII  Diseases of the Liver and Biliary System

failure etiology and vasopressor requirement, as well as admission INR and bilirubin values. The model correctly predicted outcome in 66.3% of subjects, slightly outperforming historic King’s College Criteria and the Model for End-stage Liver Disease (MELD) score. Liver transplantation (see Chapter 44) has been performed with success in patients with ALF and is the treatment of choice for patients who appear unlikely to recover spontaneously. Because of high risk of abrupt clinical deterioration, the optimal approach is for potential candidates to be transferred to transplantation centers before significant complications develop (e.g., coma, cerebral edema, hemorrhage, infection). ALF subjects who meet transplant program criteria for listing in the United Sates are granted status 1A, placing them at the highest priority on the waiting list.

PROGNOSIS Etiology of ALF and the degree of hepatic encephalopathy are key determinants of prognosis. Patients with ALF resulting from acetaminophen overdose or viral hepatitis A or B have a better survival rate than

do patients with Wilson’s disease or those with indeterminate etiology. The short-term survival rate for patients with ALF in coma is 20% without liver transplantation. Currently, ALF accounts for approximately 8% of all liver transplants, as per data from the Scientific Registry of Transplant Recipients (SRTR) with 1-year survival rates of 84% in the United States. Patients who survive without transplantation also have an excellent prognosis because liver tissue usually regenerates normally regardless of the cause of ALF.

SUGGESTED READINGS Bernal W, Wendon J: Acute liver failure, N Engl J Med 369(26): 2525–3, 2013. Koch DG, Tillman H, Durkalski V, Lee WM, Reuben A: Development of a model to predict transplant-free survival of patients with acute liver failure, Clin Gastroenterol Hepatol 14(8):1199–1206, 2016. Lee WM, Larson AM, Stravitz RT: AASLD position paper: the management of acute liver failure—update 2011. Available at: http://www.aasld.org/ practiceguidelines/Documents/AcuteLiverFailureUpdate2011.pdf.

44 Cirrhosis of the Liver and Its Complications Shivang Mehta, Michael B. Fallon

LIVER CIRRHOSIS Definition Cirrhosis is a slowly progressive disease that is characterized by formation in the liver of fibrous and scar tissue that eventually replaces normal hepatocytes and impairs portal blood flow. Fibrosis can be a self-perpetuating result of many initial processes, including infectious, inflammatory, toxic, metabolic, genetic, and vascular insults that lead to liver damage. Most of the clinical features of cirrhosis develop as a result of portal hypertension, hepatocellular dysfunction, or altered cellular differentiation.

Etiology Alcoholic liver disease, nonalcoholic steatohepatitis (NASH), and hepatitis C virus infection are the most common causes of cirrhosis in industrialized nations; hepatitis B virus is the major cause in Asia and in most of Africa. There are many other significant causes of cirrhosis, including biliary cirrhosis (primary and secondary), autoimmune hepatitis, inherited diseases (e.g., α1-antitrypsin deficiency), and drug-induced injury, that require specific evaluation. However, a significant number of patients with cirrhosis at presentation have no readily identifiable cause. These cases are referred to as idiopathic or cryptogenic in origin, and it remains a diagnosis of exclusion. Common and uncommon conditions that may lead to cirrhosis are listed in Table 44.1. Chronic active hepatitis, nonalcoholic fatty liver disease (NAFLD)/ NASH, and α1-antitrypsin deficiency are discussed in Chapter 42.

Pathology The typical sequence of events that leads to development of cirrhosis involves significant hepatocyte injury followed by ineffective repair that results in hepatic fibrosis. The injury can be acute or chronic in nature, depending on the mechanism. The fibrotic response to injury leads to development of nodules surrounded by fibrous tissue that consist of foci of regenerating hepatocytes, formation of fibrovascular membranes, rearrangement of blood vessels, and finally cirrhosis. This disruption of the normal hepatic lobular architecture distorts the vascular bed and contributes to development of portal hypertension and intrahepatic shunting. On gross morphology, cirrhosis can be referred to as macronodular (>3 mm regenerating nodules), commonly seen as a result of chronic active hepatitis, or micronodular (1.1 g/dL) correlates well with portal hypertension as the likely cause of fluid accumulation (see Table 44.4).

Clinical Presentation Patients usually report increasing abdominal girth, fullness of the flanks, and weight gain with or without peripheral edema. Ascites becomes clinically detectable with fluid accumulation greater than about 500 mL. Shifting dullness to percussion is the most sensitive clinical sign of ascites, but about 1500 mL of fluid must be present for reliable detection.

Treatment

ASCITES

Management of cirrhotic ascites depends on the cause. Patients with high SAAG (>1.1 g/mL), which is used as a surrogate measure for elevated portal pressures, usually respond to salt restriction (50 red blood cells/high-power field), or abnormal renal US findings HRS has two types, HRS-AKI type 1 and HRS-CKD (chronic kidney disease) type 2. HRS-AKI is characterized as an increase in serum creatinine 0.3 mg/dL or greater within 48 hrs or 50% or greater from baseline value according to ICA consensus document and/or urinary output 0.5 mL/kg body weight or less for longer than 6 hours. HRSCKD is defined as eGFR less than 60 mL/min per 1.73 m2 for 3 months or greater in the absence of other (structural) causes. Typically, the kidneys are histologically normal and can regain normal function in the event of recovery of liver function (e.g., after liver transplantation). Severe cortical vasoconstriction has been demonstrated angiographically, and such vasoconstriction reverses when these kidneys are transplanted into patients who do not have cirrhosis.

Treatment and Prognosis The mortality rate is high in HRS, and so prevention is important. In all patients with cirrhosis, precipitating factors (e.g., diuretics, lactulose, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors) should be avoided if possible. Patients should be promptly diagnosed and treated for any signs of SBP, and colloid (albumin) should be administered if rising creatinine levels are observed. Prevention of variceal bleeding should also be optimized by primary and secondary prophylaxis. Studies have shown an increased mortality rate with AKI among hospitalized cirrhotic patients. Several medical therapies are currently under review, including use of terlipressin, a vasopressin V1 receptor analogue, in combination with albumin for type 1 HRS. Other studies have evaluated the combination of octreotide and midodrine (an α-adrenergic agonist) and intravenous albumin. Placement of TIPS has also been reported to stabilize or even improve renal function, mainly in patients with HRS-CKD. However, a significant limitation of TIPS is the possibility of worsening hepatic function in decompensated cirrhosis. Liver transplantation has become the accepted treatment for HRS because it is the only known therapeutic intervention that reverses the process. It is limited by rapid progression of HRS and lack of available organs.

HEPATIC ENCEPHALOPATHY Definition HE is a complex, reversible neuropsychiatric syndrome that occurs in patients with chronic liver disease, portal hypertension, or portosystemic shunting. HE is also seen in patients with acute liver failure. HE develops in about 30% to 45% of cirrhotic patients, and when it is present, the survival probability is approximately 23% at 3 years.

Pathophysiology The pathogenesis of HE in the setting of cirrhosis is thought to be multifactorial and may differ in acute and chronic liver disease. Contributors include the inadequate hepatic removal of potential endogenous neurotoxins, altered permeability of the blood-brain barrier, and abnormal neurotransmission. Elevation of blood ammonia levels, derived from both amino acid deamination and bacterial hydrolysis of nitrogenous compounds in the gut, has been the best studied factor, but its specific role in the pathogenesis of HE remains uncertain. Many other potential contributors to HE have been investigated,

including increased tone of the inhibitory GABAA/benzodiazepine neurotransmitter system, activation of the astrocytic 18-kDa translocator protein (PTBR), production of endogenous benzodiazepine-like compounds, altered cerebral metabolism, zinc deficiency, increase in serotonin levels, upregulation of H1 receptors, altered melatonin production, and deposition of manganese in the basal ganglia.

Clinical Presentation The clinical features of HE include disturbances of higher neurologic function such as intellectual and personality disorders, dementia, inability to copy simple diagrams (constructional apraxia), disturbance of consciousness, disturbances of neuromuscular function (asterixis, hyperreflexia, myoclonus), and, rarely, a Parkinson-like syndrome and progressive paraplegia. One of the earliest manifestations of overt HE is alteration of the normal sleep-wake cycle.

Diagnosis There is no laboratory or imaging study that allows a specific diagnosis of HE. Rather, it is a clinical syndrome. Blood levels of ammonia are commonly measured, but elevated levels are neither sensitive nor specific for HE. Neuropsychometric and neurocognitive tests such as the Portosystemic Encephalopathy Syndrome Test (PSET) and the earlier Stroop Color-Word Test evaluate the patient’s attention, concentration, fine motor skills, and orientation and have been shown to be highly specific for the diagnosis of HE, but they are reasonably labor intensive. Therefore, a smartphone-based application known as EncephalApp was created incorporating the Stroop test that is validated for use in detection of covert/minimal HE. It is imperative that reversible causes of neurologic dysfunction, such as hypoglycemia, subdural hematoma, meningitis, and drug overdose, be considered and excluded early in the differential diagnosis of altered mental status in patients with cirrhosis.

Classification of Hepatic Encephalopathy There are three major types of HE: type A (Acute), which is associated with acute liver failure; type B (Bypass), which is associated with portosystemic shunts in the absence of liver disease; and type C (Cirrhosis), which is associated with liver cirrhosis and is subdivided into episodic, persistent, and minimal types. HE has been further graded based on the West Haven Criteria from 0 to 4. A new nomenclature, termed the Spectrum of Neurocognitive Impairment in Cirrhosis (SONIC) classification, has been proposed to improve recognition of earlier forms of HE that require specialized testing for detection and to facilitate research studies. Patients are divided into those who are unimpaired, those with covert HE, and those with overt HE (Table 44.5).

Treatment Treatment of HE starts with identifying and addressing any precipitating factors (Table 44.6), reducing and eliminating substrates for the generation of nitrogenous compounds, and preventing ammonia absorption from the bowel. Protein restriction was considered to be important in preventing excess ammonia production in the past; however, studies have demonstrated that dietary restriction of protein is not of significant benefit. Short-term protein restriction may be considered for patients with severe encephalopathy, but long-term restriction is associated with worsening malnutrition. Treatment with formulas rich in branched-chain amino acids has shown no benefit in improving encephalopathy or mortality. Nonabsorbable disaccharides (e.g., lactulose) are the mainstay treatment of HE. These agents are fermented to organic acids by colonic bacteria, processes that lower stool pH and trap NH4+ in the colon, thereby decreasing absorption. In addition, the cathartic effect

CHAPTER 44  Cirrhosis of the Liver and Its Complications

443

TABLE 44.5  Clinical Stages of Hepatic Encephalopathy as Defined by the West Haven Criteria

and the Proposed Sonic Classification WEST HAVEN CRITERIA

SONIC

Grade

Intellectual Function

Neuromuscular Function Classification

Mental Status

Special Tests

Asterixis

0 Minimal

Normal Normal examination findings. Subtle changes in work or driving Personality changes, attention deficits, irritability, depressed state Changes in sleep-wake cycle, lethargy, mood and behavioral changes, cognitive dysfunction Altered level of consciousness (somnolence), confusion, disorientation, and amnesia Stupor and coma

Normal Minor abnormalities of visual perception or on psychometric or number tests Tremor and incoordination

Unimpaired Covert HE

Not impaired Not impaired

Normal Abnormal

Absent Absent

Asterixis, ataxic gait, speech abnormalities (slow and slurred)

Overt HE

Impaired

Abnormal

Present (absent in coma)

1

2

3

4

Muscular rigidity, nystagmus, clonus, Babinski sign, hyporeflexia Oculocephalic reflex, unresponsiveness to noxious stimuli

SONIC, Spectrum of Neuro-Cognitive Impairment in Cirrhosis. Modified from Nevah MI, Fallon MB: Hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, and systemic complications of liver disease. In Feldman M, Friedman LS, Brandt LJ, editors: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 9, Philadelphia, 2010, Saunders.

TABLE 44.6  Hepatic Encephalopathy:

Precipitating Factors

Gastrointestinal bleeding Increased dietary protein Constipation Infection Central nervous system depressant drugs (benzodiazepines, opiates, tricyclic antidepressants) Deterioration in hepatic function Hypokalemia: most often induced by diuretics Azotemia: most often induced by diuretics Alkalosis: most often induced by diuretics Hypovolemia: most often induced by diuretics

of lactulose eliminates ammonia and other nitrogenous compounds. Patients are usually directed to achieve two to three soft stools per day as the goal of lactulose therapy. Reduction and elimination of nitrogenous compound substrates can also be achieved by administering enemas and using nonabsorbable antibiotics such as rifaximin in patients who do not tolerate or respond to lactulose. Rifaximin (Xifaxan), 550 mg PO twice daily, is approved by the US Food and Drug Administration for the treatment of HE and has a favorable side effect profile; however, cost is the limiting factor. Other agents that affect intestinal motility and ammonia generation are being evaluated, including acarbose and probiotics.

HEPATOPULMONARY SYNDROME AND PORTOPULMONARY HYPERTENSION The effects of cirrhosis and portal hypertension on the pulmonary circulation manifest as two distinct disorders, hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PoPH).

Hepatopulmonary Syndrome HPS occurs in 5% to 30% of patients with cirrhosis and is a progressive disease. It is characterized by gas exchange abnormalities (increased alveolar-arterial gradient and hypoxemia) resulting from intrapulmonary vascular dilation. The vascular dilation leads to vascular remodeling and angiogenesis, resulting in impaired oxygen transfer from the alveoli to the central stream of red blood cells within capillaries. Usually, this functional intrapulmonary right-to-left shunt significantly improves with the administration of 100% oxygen. HPS also has been reported in cases of hepatic venous outflow obstruction without cirrhosis.

Diagnosis HPS is diagnosed based on high clinical suspicion and measurement of a widened alveolar-arterial oxygen gradient on room air in the presence or absence of hypoxemia. The gradient is calculated by analyzing arterial blood gases. HPS is graded from mild, in which the arterial partial pressure of oxygen (Pao2) is greater than 80 mm Hg) to very severe (Pao2 25 to 35 mm Hg) to moderate (35 to 50 mm Hg) to severe (>50 mm Hg). Patients with mild PoPH do not appear to have increased operative risk. Moderate PoPH carries a high intraoperative risk and should be medically managed before transplantation. Severe PoPH is generally considered a contraindication to surgery. The exact mechanisms of PoPH are poorly understood. Histologically, it has characteristics similar to those of pulmonary hypertension.

Epidemiology Liver cancer is the fifth most common cancer in men and the seventh most common in women worldwide; HCC is the most common type of liver cancer. In the United States, approximately 90% of liver cancers are HCC, and cholangiocarcinomas account for most of the rest. In other areas of the world, including sub-Saharan Africa, China, Japan, and Southeast Asia, HCC is one of the most frequent malignancies and is an important cause of mortality, particularly among middle-aged men.

Etiology HCC often arises from a cirrhotic liver, and it is closely associated with chronic viral hepatitis. Hepatitis B virus DNA has been shown to integrate into the host cell genome, where it may disrupt tumor suppressor genes and activate oncogenes. In areas of high prevalence, vaccination to prevent infection with hepatitis B virus has reduced the incidence of HCC. The exact pathophysiologic mechanisms leading to tumor genesis in patients with other causes of cirrhosis (e.g., hemochromatosis, alcohol, hepatitis C viral infection) remain poorly understood. Risk factors for the development of HCC and its clinical manifestations are listed in (Table 44.7).

Diagnosis

The most common symptom of PoPH is dyspnea on exertion, but many cirrhotic patients with PoPH are asymptomatic.

Table 44.8 lists currently used imaging techniques for detection of HCC and the most common findings. A tissue specimen may be necessary to confirm the diagnosis in some cases, but it is not needed if characteristic clinical and radiologic features are present, especially if they are accompanied by a rise in serum α-fetoprotein levels. The Hepatic Carcinoma Early Detection Screening (HES) algorithm for early detection of HCC was developed and has been validated in the Veterans affairs (VA) cohort. The algorithm includes patient’s age, ALT level, platelet count, and current and rate of change to AFP level. It has shown an improvement in early detection in patients with cirrhosis in comparison to AFP alone.

Treatment

Staging

In addition to symptomatic treatment (oxygen for dyspnea and diuretics for volume overload), the medical management of PoPH is similar to that for pulmonary arterial hypertension. The drugs most commonly used in treatment for PoPH are prostacyclins (intravenous, inhaled or subcutaneous), oral treatments including phosphodiesterase inhibitors, and endothelin receptor antagonist. If moderate PoPH responds to therapy, liver transplantation may be considered. However, it has not been established whether successful liver transplantation reliably reverses PoPH. Liver transplantation is contraindicated in severe PoPH because of high transplant-related morbidity and mortality. However, there were no dedicated randomized clinical trials of these therapies until the PORTICO trial. The PORTICO trial was a double-blind, placebo-controlled, multicenter study of macitentan, an endothelin receptor antagonist. Macitentan showed improved pulmonary vascular resistance without hepatotoxicity. More novel agents are being studied.

Although many staging systems for HCC are in use, the Barcelona Clinic Liver Cancer (BCLC) system is most commonly used.

Clinical Presentation

Prognosis Untreated PoPH carries high rates of morbidity and mortality; the mean survival time from diagnosis is 15 months. A study on the U.S.based Registry to Evaluate Early and Long-term Pulmonary Arterial

Treatment Patients with well-compensated cirrhosis may undergo surgical resection or liver transplantation, with a 5-year survival rate of up to 70%. Nonsurgical options include percutaneous ethanol injection, transarterial chemoembolization (TACE), and radiofrequency ablation. The first-line treatment for many years was Sorafenib (a receptor tyrosine kinase angiogenesis inhibitor) for use in patients with unresectable HCC. However, recently another agent was approved, lenvatinib, which works by the same mechanism, and both have been shown to prolong survival of these patients. Second-line agents have also been approved, which include regorafenib, cabozantinib, and nivolumab.

Prognosis In patients with widespread, multifocal disease and in those with vascular invasion, the prognosis is poor, with a 5-year survival rate of 5% to 6%. Accordingly, emphasis is placed on prevention of viral hepatitis and other causes of liver disease and on screening by ultrasound of those who are at higher risk, including patients with known cirrhosis.

CHAPTER 44  Cirrhosis of the Liver and Its Complications

TABLE 44.7  Hepatocellular Carcinoma Associations Chronic hepatitis B infection Chronic hepatitis C infection Hemochromatosis (with cirrhosis) Cirrhosis (alcoholic, cryptogenic) Aflatoxin ingestion, Thorotrast exposure α1-Antitrypsin deficiency Androgen administration Common Clinical Presentations Abdominal pain Abdominal mass Weight loss Deterioration of liver function Unusual Manifestations Bloody ascites Tumor emboli (lung) Jaundice Hepatic or portal vein obstruction Metabolic effects Erythrocytosis Hypercalcemia Hypercholesterolemia Hypoglycemia Gynecomastia Feminization Acquired porphyria Clinical and Laboratory Findings Hepatic bruit or friction rub Serum α-fetoprotein >400 ng/mL

TABLE 44.8  Imaging Characteristics of

Hepatocellular Carcinoma

Ultrasonography Mass lesion with varying echogenicity but usually hypoechoic Dynamic Computed Tomography Arterial phase: tumor enhances quickly Venous phase: quick de-enhancement of tumor relative to parenchyma Magnetic Resonance Imaging T1-weighted images: hypointense T2-weighted images: hyperintense After gadolinium administration, tumor increases in intensity

445

(including polycythemia vera, essential thrombocytosis, and myelofibrosis) are now being recognized as possible causes of PVT. One study observed that as many as 25% to 65% of patients with splanchnic vein thrombosis in the absence of cirrhosis had a myeloproliferative disease. The Janus kinase 2 (JAK2) mutation is a marker for myeloproliferative disease and is often checked in patients with PVT. The disease produces the manifestations of portal hypertension, but the liver histology is usually normal.

Diagnosis The diagnosis is established by angiography, but noninvasive imaging modalities such as Doppler ultrasonography, computed tomography, and magnetic resonance imaging may reveal thrombus, collateral circulation near the porta hepatis, and splenomegaly. In long-standing PVT, tortuous venous channels develop within the organized clot, leading to cavernous transformation.

Treatment In acute PVT, thrombolysis may be attempted, but anticoagulation with warfarin remains the mainstay of therapy. In most patients, recanalization of the thrombus occurs within 6 months after initiation of anticoagulation. Recommendations for duration of anticoagulation after an acute event vary and are usually 3 to 6 months. Long-term anticoagulation may be used in cases of chronic thrombosis, especially when associated with hypercoagulable states. Concern exists that anticoagulation may precipitate hemorrhage from varices that arise as a consequence of portal hypertension; however, studies have not shown an increased risk for variceal bleeding in anticoagulated patients with chronic PVT. In fact, studies suggest a role for prophylactic anticoagulation (enoxaparin) for prevention of PVT and hepatic decompensation in cirrhosis. If variceal hemorrhage occurs, it is best managed with endoscopic obliteration. Prophylaxis with β-blockers to prevent variceal bleeding may decrease the portal pressure, potentially propagating thrombus, and therefore is not usually recommended. If endoscopic treatment fails, surgical management with portosystemic shunting may be attempted, but this approach is often difficult because of the absence of suitable patent vessels. The use of TIPS has also been studied in nonocclusive PVT and may be beneficial in establishing patency of the portal vein for future interventions such as liver transplantation in lieu of anticoagulation only.

Budd-Chiari Syndrome Definition and Etiology

Disorders of the hepatic vasculature are uncommon and include portal vein thrombosis (PVT), hepatic vein thrombosis (Budd-Chiari syndrome), and veno-occlusive disease. Affected patients usually have portal hypertension with or without associated liver dysfunction, which may mimic the presentation of cirrhosis.

Occlusion of the major hepatic veins or the inferior vena cava, especially in the intrahepatic and suprahepatic segments, causes BuddChiari syndrome. Most cases are associated with hematologic disease (e.g., polycythemia vera, paroxysmal nocturnal hemoglobinuria, essential thrombocytosis, other myeloproliferative disorders), pregnancy, oral contraceptive use, tumors (especially HCC), or other causes of a hypercoagulable state (e.g., factor V Leiden mutation, protein C and S deficiency). Abdominal trauma and congenital webs of the vena cava are also related to Budd-Chiari syndrome. About 20% of cases are idiopathic, but many of these patients prove to have early, subclinical myeloproliferative disease or genetic mutations associated with a hypercoagulable state.

Portal Vein Thrombosis

Clinical Presentation

Thrombosis of the portal vein may develop after blunt abdominal trauma, umbilical vein infection, neonatal sepsis, intra-abdominal inflammatory diseases (e.g., pancreatitis), or hypercoagulable states, and in association with cirrhosis. Myeloproliferative diseases

Budd-Chiari syndrome can manifest acutely, possibly in association with acute liver failure, or it can manifest as a subacute or chronic illness. Acute disease produces right upper quadrant abdominal pain, hepatomegaly, ascites, and jaundice, whereas the subacute or chronic form produces primarily portal hypertension. Elevation of serum

VASCULAR DISEASE OF THE LIVER

Definition and Etiology

446

SECTION VII  Diseases of the Liver and Biliary System

bilirubin and transaminase levels may be mild, but liver function is often poor, with profound hypoalbuminemia and coagulopathy.

Diagnosis The diagnosis can be established noninvasively with Doppler ultrasonography, which shows decreased or absent hepatic vein blood flow, and computed tomography, which shows delayed or absent contrast filling of the hepatic veins and hypertrophy of the caudate lobe. Magnetic resonance angiography may also demonstrate these findings. Hepatic venography is especially useful if the results of noninvasive imaging are inconclusive. Venography often shows an inability to catheterize and visualize the hepatic veins; the characteristic spiderweb pattern of collateral vessels may also be demonstrated, and the inferior vena cava may appear compressed owing to hepatomegaly or an enlarged caudate lobe. On liver biopsy, centrilobular congestion, hemorrhage, and necrosis (nutmeg liver) are seen, with cirrhosis developing in patients with chronic obstruction.

Treatment Treatment should be individualized and is dependent on the mode and severity of presentation and the potential cause of the disease. Supportive therapy to relieve ascites and edema (e.g., dietary sodium restriction, diuretics) and chronic anticoagulation may be considered for patients with chronic Budd-Chiari syndrome in whom methods to decompress congestion are not feasible. Thrombolysis followed by anticoagulation is most useful in patients with acute forms of the disease. In selected patients (such as those with venous webs or strictures or single-vessel thrombosis), angioplasty with or without stent placement may be used. Decompressive modalities are most useful before the development of cirrhosis and include transjugular intrahepatic portacaval and side-to-side portacaval shunts. In patients with cirrhosis, liver transplantation followed by continued anticoagulation is often considered the best option.

Veno-Occlusive Disease Definition and Etiology

Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome, often occurs after cytoreductive therapy and before bone marrow transplantation but may also follow exposure to other drugs or herbal preparations (e.g., azathioprine, pyrrolizidine alkaloids). Endothelial cell injury leads to obstruction at the level of the hepatic venules and the sinusoids.

Clinical Presentation The disease is characterized by jaundice, painful hepatomegaly, and fluid retention. Clinical manifestations can be rapidly progressive and lead to multiorgan dysfunction and death in 20% to 25% of patients.

Diagnosis The diagnosis is clinically suspected when weight gain, epigastric or right upper quadrant abdominal pain, and jaundice develop within the first 3 to 4 weeks after bone marrow transplantation. Laboratory abnormalities include hyperbilirubinemia, elevated transaminases, and, in severe cases, profound synthetic dysfunction. Doppler abdominal ultrasonography may reveal ascites, reversal of portal vein flow, and an elevated hepatic artery resistance index. Liver biopsy is diagnostic and is usually obtained with use of the transjugular approach. The advantages of this approach compared with the percutaneous route include the ability to measure the hepatic venous pressure gradient (which is typically elevated in veno-occlusive disease) and a lower incidence of bleeding.

Treatment Mild forms of the disease may favorably respond to supportive therapy alone. In moderate to severe disease, treatment has been attempted with tissue plasminogen activator and heparin, antithrombin III, prostaglandin E1, and glutamine plus vitamin E, although the efficacies of these treatments have not been clearly established. Defibrotide (a mixture of porcine-derived single-stranded phosphodiester oligonucleotides) has been evaluated as a potential treatment option for severe veno-occlusive disease; however, evidence for efficacy has been mixed.

LIVER TRANSPLANTATION MELD Score The Model for End-stage Liver Disease (MELD) score was originally calculated based on the serum creatinine concentration, prothrombin time (International Normalized Ratio), and bilirubin level and has been used to predict short-term mortality in cirrhosis and to prioritize patients awaiting liver transplantation. However, in 2016 an adjustment was made to the MELD score to include the serum sodium, now commonly referred to as the MELD-Na. The MELD-Na score ranges from 6 to 40. Higher scores are associated with more advanced disease and increased predicted mortality. Patients are typically considered for liver transplantation when the MELD-Na score reaches 15.

Prognosis Liver transplantation is a highly successful procedure in patients with progressive, advanced, and otherwise untreatable liver disease. Advances in surgical techniques and supportive care, the use of cyclosporine and tacrolimus for immunosuppression, and careful selection of patients have all contributed to the excellent results of liver transplantation. Between 70% and 80% of patients undergoing liver transplantation survive at least 5 years, usually with good quality of life. The most common indication for liver transplantation in the United States is chronic liver disease resulting from alcohol. Other liver diseases for which transplantation is commonly performed include cirrhosis from NAFLD, hepatitis C virus, autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. Patients with hepatitis B are candidates for liver transplantation if they can be given hepatitis B immunoglobulin or nucleoside analogues to help prevent recurrence. Excellent results have also been obtained in selected patients with acute liver failure (see Chapter 43). Liver transplantation for malignant hepatobiliary disease has been less successful because of recurrent disease in the transplanted liver. For a deeper discussion on this topic, please see Chapter 144, “Cirrhosis and Its Sequelae,” in Goldman-Cecil Medicine, 26th Edition.

SUGGESTED READINGS Angeli Paolo, Garcia-Tsao G, Nadim MK, Parikh CR. News in pathophysiology, definition and classification of hepatorenal syndrome: a step beyond the international Club of ascites (ICA) consensus document, J Hepatol 71(4):811– 822, 2019. Garcia‐Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases, Hepatology 65(1):310–335, 2017. Kamath PS, Kim W: The model for end-stage liver disease (MELD), Hepatology 45:797–805, 2007.

CHAPTER 44  Cirrhosis of the Liver and Its Complications Kim WR, Biggins SW, Kremers WK, et al: Hyponatremia and mortality among patients on the liver-transplant waiting list, N Engl J Med 359(10):1018– 1026, 2008. Krowka MJ, Miller DP, Barst RJ, et al: Portopulmonary hypertension: a report from the US-based REVEAL registry, Chest 141:906–915, 2012. Runyon BA: Management of adult patients with ascites due to cirrhosis: update 2012, AASLD Practice Guideline, AASLD 3(1):5–8, 2012.

447

Valla DC: Thrombosis and anticoagulation in liver disease, Hepatology 47:1384–1393, 2008. Villa E, Cammà C, Marietta M, et al: Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis, Gastroenterology 143:1253–1260, 2012.

45 Disorders of the Gallbladder and Biliary Tract Stacie A. F. Vela, Michael B. Fallon

INTRODUCTION The gallbladder and biliary tract transport bile from the liver into the intestines, a process central to digestion of fat and absorption of lipids and fat-­soluble vitamins. Gallbladder and biliary tract diseases are among the most common and costly of all digestive disorders. This chapter examines the principal gallbladder and biliary tract disorders, focusing on cholelithiasis. The reader is referred to Chapter 41 for a detailed discussion of bilirubin metabolism and the diagnostic approach to jaundice and to Chapter 35 for a review of the various imaging techniques used to study the biliary tract.

NORMAL BILIARY ANATOMY AND PHYSIOLOGY Fig. 45.1 outlines the basic anatomy of the liver and biliary tract. The liver produces 500 to 1500 mL of bile per day. The secretory product of individual hepatocytes contains bile acids, phospholipids, and cholesterol, which are transported across the apical membrane and into the canalicular space between cells. These canaliculi merge to form larger intrahepatic bile ducts and then the common hepatic duct. During fasting, tonic contractions of the sphincter of Oddi, located in the region of the ampulla of Vater, divert about one half of the bile through the cystic duct into the gallbladder, where it is stored and concentrated by water resorption. Cholecystokinin, which is released after food enters the small intestine, causes the sphincter of Oddi to relax, allowing delivery of a timed bolus of bile into the intestine. Bile acids are present in millimolar concentrations. They are detergent molecules that possess both fat-­soluble and water-­soluble moieties. Cholesterol is secreted by the liver to the intestine, where it undergoes fecal excretion (see E-­Fig. 41.1 in Chapter 41). In the intestinal lumen, bile acids solubilize dietary fat and promote its digestion and absorption. Bile acids are, for the most part, efficiently reabsorbed by the small intestinal mucosa, particularly in the terminal ileum. They are then recycled to the liver for re-­excretion, a process termed enterohepatic circulation.

GALLBLADDER DISORDERS Gallstones (Cholelithiasis) Gallstone formation constitutes a significant health problem, affecting 10% to 15% of the adult population. Complications from gallstones are a leading cause for hospital admissions related to gastrointestinal problems. In the United States, gallstone disease leads to more than 750,000 cholecystectomies annually, making this the most common elective abdominal surgery, with estimated costs of $6.5 billion per year. Gallstones are of two types: 75% are made of cholesterol, and 25% are pigmented stones (black or brown). The latter are composed of calcium bilirubinate and other calcium salts. The risk factors for cholelithiasis are shown in Table 45.1.

448

Pathogenesis of Cholelithiasis The three main factors that lead to cholesterol gallstone formation are cholesterol supersaturation of bile, nucleation, and gallbladder hypomotility. These are influenced by both genetic background and intestinal factors (Fig. 45.2). The liver is the most important organ in regulating total-­body cholesterol stores. Once it is secreted, cholesterol, which is insoluble in water, is solubilized in bile through the formation of mixed micelles with bile acids and phospholipids. In most individuals, there is more cholesterol in bile than can be maintained in stable solution. This is even more pronounced in the setting of insulin resistance. As bile becomes supersaturated, microscopic cholesterol molecules aggregate into coalescent vesicles that crystallize, a process referred to as nucleation. The gradual deposition of additional layers of cholesterol leads to the appearance of macroscopic stones. Factors that influence nucleation include bile transit time, gallbladder contraction, bile composition (concentrations of cholesterol, phospholipids, and bile salts), and presence of bacteria, mucin, and glycoproteins, which can act as a nidus to initiate cholesterol crystal formation. The interplay between pronucleating and antinucleating factors in the gallbladder may determine whether cholesterol gallstones will form from supersaturated bile. Gallbladder sludge is a super-­concentrated mixture of bile acids, bilirubin, cholesterol, mucus, and proteins that exhibits various degrees of fluidity and is prone to precipitate into a semisolid or solid form. The pathophysiologic factors leading to pigment stone formation are less well understood; however, increased production of bilirubin conjugates (hemolytic states), increased biliary calcium (Ca2+) and bicarbonate (HCO−3) levels, cirrhosis, and bacterial deconjugation of bilirubin to a less soluble form are all associated with pigment stone formation. Black pigment stones, which are composed primarily of calcium bilirubinate, are formed in sterile bile in the gallbladder and are common in chronic hemolytic states, in cases of cirrhosis, and in patients with ileal resection. Their brown pigment counterparts, composed primarily of calcium salts, are formed in the bile ducts and are seen in the setting of infection of the biliary tract. Many of the recognized predisposing factors for cholelithiasis and gallbladder sludge can be understood in terms of the pathophysiologic scheme outlined previously: 1. Biliary cholesterol saturation is increased by insulin resistance, estrogens, multiparity, oral contraceptives, obesity, rapid weight loss, and terminal ileal disease, which decreases the bile acid pool. 2. Nucleation is enhanced by biliary parasites, recurrent bacterial infection of the biliary tract, altered intestinal microbiome, and antibiotics such as ceftriaxone, which has a proclivity to concentrate and crystallize with calcium in the biliary tree. Total parenteral nutrition and blood transfusions also promote bile pigment accumulation and gelfaction of sludge.

CHAPTER 45  Disorders of the Gallbladder and Biliary Tract

Hepatocyte Endoscope

Endoplasmic reticulum

449

Common bile duct Pancreatic duct

Canaliculus Portal triad PV

Sphincter of Oddi

BD Mitochondrion Space of Disse HA

Endothelial cells

Left hepatic duct Cystic duct Common bile duct

Right hepatic duct

Pancreatic duct

Gallbladder

Pancreas

Duodenum

Minor papilla Ampulla of Vater

Fig. 45.1  Normal anatomy and histology of the liver and biliary tract. Materials destined for metabolism or excretion by the liver (such as unconjugated bilirubin) enter the sinusoidal bed and cross the endothelial barrier and the space of Disse. Unconjugated bilirubin is taken up by the hepatocyte, conjugated with glucuronide to become water soluble, and excreted into bile across the canalicular membrane of the hepatocyte. The canaliculi empty into bile ductules (BD), which lead to the interlobular (small), septal (medium), and large intrahepatic bile ducts and finally to the main branches of the common bile duct. The portal areas, or portal triads, are composed mainly of portal vein (PV), hepatic artery (HA), and BD branches. During fasting, tonic contraction of the sphincter of Oddi, located in the region of the ampulla of Vater, diverts about one half of the bile through the cystic duct into the gallbladder, where it is stored and concentrated to be released later during meal times. Disease at any level of the biliary tree can lead to cholestasis and obstructive jaundice. The inset shows an endoscopic retrograde cholangiopancreatography procedure. See Figs. 45.5, 45.6, and 45.7 for radiographic depictions in specific biliary tract disorders.



3. Bile stasis is caused by gallbladder hypomotility (resulting from pregnancy, somatostatin, or fasting), bile duct strictures, choledochal cysts, biliary parasites, and total parenteral nutrition.

Clinical Manifestations of Gallstones Gallstones develop at some point in 10% to 20% of Americans. Between 50% and 60% of these individuals remain asymptomatic, but about one third develop biliary colic or chronic cholecystitis, and 15% develop acute complications. The natural history of gallstone disease

is outlined in Fig. 45.3. Obstruction of the biliary tract at any level by stones or sludge is the underlying cause of the clinical manifestations of gallstone disease. Obstruction by gallstones can occur at the level of the cystic duct, common hepatic duct, common bile duct, or ampulla of Vater (see Figs. 45.1 and 45.3). Symptoms arise from contraction of the gallbladder during transient obstruction of the cystic duct by gallstones, and persistent obstruction of the cystic duct leads to superimposed inflammation or infection of the gallbladder (i.e., acute cholecystitis). Obstruction of the distal common bile duct may result

450

SECTION VII  Diseases of the Liver and Biliary System

in abdominal pain, cholangitis (infection of the biliary tract), or pancreatitis (resulting from pancreatic duct obstruction). The presence of a large stone in the cystic duct can cause common bile duct obstruction and is referred to as Mirizzi syndrome. Common conditions to consider in the differential diagnosis of gallstone disease are listed in Table 45.2.

Gallstones are best demonstrated by transabdominal ultrasonography; therefore, it is recommended as the initial test to evaluate cholelithiasis. The sensitivity and specificity of ultrasound are greater than 90%, but accuracy drops to 20% for visualization of stones within the common bile duct. This limitation has been overcome by endoscopic ultrasonography (EUS) (Video 45.1) and magnetic resonance cholangiopancreatography (MRCP), both of which have an accuracy of 90% to 95% for detecting cholelithiasis and common bile duct stones. Computed tomography, often done in the emergency department for evaluation of abdominal pain, can identify presence of gallstones but is not as reliable or cost-­effective as ultrasound. Oral cholecystography is no longer used for the routine evaluation of gallstones. If gallbladder removal is indicated, laparoscopic cholecystectomy has replaced open cholecystectomy as the treatment of choice for recurrent biliary pain. Open cholecystectomy is typically reserved for selected high-­ risk patients (e.g., prior abdominal surgery with adhesions, obesity, cirrhosis). If choledocholithiasis is suspected, laparoscopic cholecystectomy may be accompanied by perioperative endoscopic retrograde cholangiopancreatography (ERCP) (see Fig. 45.1 inset and Chapter 35) or intraoperative cholangiography. Factors that may predict the presence of choledocholithiasis include jaundice, pancreatitis, abnormal liver test results, and bile duct dilation. Cholecystectomy relieves biliary pain in virtually all patients with gallstone disease and prevents the development of future complications. Dissolution of cholesterol gallstones by orally administered chenodeoxycholic acid or ursodeoxycholic acid is successful in highly selected patients but is slow and costly and requires lifelong administration. Alternative methods to eliminate gallstones, including contact dissolution and fragmentation of stones, are used rarely.

Asymptomatic Gallstones

Acute Cholecystitis

Most gallstones, up to 75%, are clinically “silent,” and they are often uncovered as an incidental finding during abdominal ultrasound performed for another reason. The risk of developing symptoms is low, averaging 2% to 3% per year, 10% at 5 years, and 1% to 2% per year with major complications. Expectant management is an appropriate choice for the general population. Prophylactic cholecystectomy should be considered in those groups who are at increased risk for the development of complications, including (1) patients with diabetes, who have a greater morbidity and mortality from acute cholecystitis; (2) patients with a calcified (porcelain) gallbladder, large gallbladder polyps, or large stones (>3 cm), which are associated with an increased risk for gallbladder carcinoma; (3) patients with sickle cell anemia, in whom hepatic crises may be difficult to differentiate from acute cholecystitis; (4) children with gallstones, because they frequently develop symptomatic disease; and (5) Native Americans, who are predisposed to gallbladder cancer in the setting of gallstones.

Acute cholecystitis refers to distention, edema, ischemia, inflammation, and secondary infection of the gallbladder. This typically results from obstruction of the cystic duct by gallstones or, less commonly, from gallbladder cancer or sludge. The clinical hallmark of acute cholecystitis is the acute onset of upper abdominal pain that lasts for several hours. The pain gradually increases in severity and typically localizes to the epigastrium or right hypochondrium with radiation to the right lumbar, scapular, and shoulder area. Nausea and vomiting, anorexia, and low-­grade fever are common. Unlike biliary pain, the pain of acute cholecystitis does not subside spontaneously. The findings on physical examination in patients with acute cholecystitis may include inspiratory arrest on palpation of the right upper quadrant (Murphy sign), fever, and, less commonly, mild jaundice or a palpable gallbladder. Complications of acute cholecystitis include emphysematous cholecystitis (in people with diabetes, older adults, and individuals who are immunosuppressed), empyema, gangrene, and perforation of the gallbladder. Gallbladder perforation may occur directly into the peritoneum (“free”) or through a cholecystenteric fistula with gallstone migration and bowel obstruction (gallstone ileus). Mirizzi syndrome is the occurrence of profound jaundice resulting from extrinsic compression of the bile duct by an impacted stone in the cystic duct at the gallbladder neck. The diagnostic approach for suspected acute cholecystitis is similar to that for biliary pain. A transabdominal ultrasound study that demonstrates gallstones, along with pericholecystic fluid, gallbladder wall thickening, and localized tenderness when the ultrasound probe is placed over the gallbladder (ultrasonographic Murphy sign), provides strong supportive evidence for acute cholecystitis. Ultrasound is safe and widely available and has emerged as the initial test of choice because it is noninvasive as well as cost-­effective. Radionuclide scanning after intravenous administration of technetium-­ 99m–labeled

TABLE 45.1  Risk Factors for Cholelithiasis Primary Age Obesity Female sex Rapid weight loss Ethnic background (e.g., Native American) Secondary Drugs: oral contraceptives, ceftriaxone, octreotide, thiazide diuretics Pregnancy Diabetes mellitus Low socioeconomic status Sedentary lifestyle Total parenteral nutrition Hemolysis Cirrhosis Crohn’s disease Biliary parasites (e.g., Clonorchis sinensis) Terminal ileum resection

Symptomatic Gallstones and Biliary Colic Symptomatic cholelithiasis is defined by gallbladder pain in the presence of gallstones. Biliary colic refers to the constellation of symptoms experienced when the gallbladder contracts against outlet obstruction. Classically, biliary colic starts as a steady ache in the epigastrium or right upper quadrant; it has a sudden onset, reaches a plateau of intensity over a few minutes, and then subsides gradually over 30 minutes to several hours. Referred pain may be felt at the tip of the scapula or right shoulder. Nausea and vomiting may occur, but fever and a palpable mass (signs of acute cholecystitis) are not evident. Other symptoms, such as dyspepsia, fatty food intolerance, bloating and flatulence, heartburn, and belching, may occur in patients with gallstones; however, these symptoms are nonspecific and frequently occur in individuals with normal gallbladders.

Hypercholesteremia

451

Surface aspect Section

Diabetes

Cholesterol stones

Pregnancy

Obesity

Hyperbilirubinemia

Metabolic factors

CHAPTER 45  Disorders of the Gallbladder and Biliary Tract

Scleral icterus

Bilirubin stones

Hemolytic anemia

Stasis

Surface aspect

Sections

Sphincter of Oddi spasm

Mixed stones

Water absorption

Water absorption Cystic duct obstruction

Gravel

Bile acids absorbed from nonulcerated surface Inflammation

Surface aspect

Calcium and protein ooze into lumen from ulcerated area

Sections

Mixed stones with calcium

Fig. 45.2  Cholelithiasis: stone formation. (From Reynolds JC, Ward PJ, Martin JA, et al. The Netter Collection of Medical Illustrations, 2nd edition, Volume 9, Digestive System, Part III: Liver, Biliary Tract, and Pancreas. Elsevier, 2016, Plate 2-­13, Page 116.)

diisopropyl iminodiacetic acid (DISIDA) or hepatobiliary iminodiacetic acid (HIDA) is also accurate. If the gallbladder fills with the isotope, acute cholecystitis is highly unlikely; if contrast material enters the bile duct and duodenum without gallbladder visualization, acute cholecystitis is strongly supported.

Because of the high risk for recurrent acute cholecystitis, most patients need to undergo cholecystectomy, which is often performed within the first 24 to 48 hours after presentation or, less often, 4 to 8 weeks after an acute episode (Fig. 45.4). Cholecystostomy may be performed for patients who have a high operative risk. Antibiotics are

452

SECTION VII  Diseases of the Liver and Biliary System

ASYMPTOMATIC GALLSTONES 60% remain asymptomatic

18% develop biliary pain

20% (~6% overall) undergo elective cholecystectomy (1.2% mortality)

40% develop symptoms and/or complications 15% develop common duct stones

≤15% develop acute cholecystitis: virtually all undergo cholecystostomy (2.7% mortality)

Rare complications (increased mortality): Empyema of the gallbladder Perforation Gangrene Emphysematous cholecystitis

65% (~10% overall) ultimately require surgery for: Pain Jaundice Acute cholangitis Pancreatitis Cholecystenteric fistula Mirizzi syndrome

A

Intrahepatic

Gallbladder Cystic duct (Biliary colic or acute cholecystitis or Mirizzi syndrome)

Sites of gallstones

B

Common hepatic duct

Common bile duct (Choledocholithiasis or cholangitis)

Ampulla (Gallstone pancreatitis or obstructive jaundice)

Fig. 45.3  Natural history of asymptomatic gallstones. (A) The clinical syndromes associated with gallstones are shown, and the numbers represent the approximate percentage of adults who develop one or more of these symptoms or complications over a 15-­to 20-­year period. Over this period, about 30% of individuals with gallstones undergo surgery. (The risk for developing complications of gallstones varies considerably among series. The figures shown represent those derived from more recent studies.) (B) Clinical manifestations of symptomatic gallstones. Locations of blockages associated with various conditions are indicated. (Part B from Reynolds JC, Ward PJ, Martin JA, et al. The Netter Collection of Medical Illustrations, 2nd edition, Volume 9, Digestive System, Part III: Liver, Biliary Tract, and Pancreas. Elsevier, 2016, Plate 2-­14, Page 117.)

typically used when fever or leukocytosis is present. Expectant management is reserved for patients with uncomplicated disease who are not good operative candidates and those in whom the diagnosis is not clear.

Acalculous Cholecystitis Acalculous cholecystitis is an acute inflammatory condition in patients without gallstones. It accounts for approximately 5% of all cases of acute cholecystitis and carries higher morbidity and mortality rates than acute calculous cholecystitis. Acalculous cholecystitis is classically associated with the triad of prolonged fasting, immobility, and hemodynamic instability, such as may occur in critically ill patients, especially if they have required total parenteral nutrition or blood transfusions. Gallbladder ischemia and stasis are considered important

in the pathogenesis. It is also seen in patients with AIDS, often in association with cytomegalovirus or Cryptosporidia infection. Abdominal pain, fever, and leukocytosis in a patient with the classic triad along with ultrasonographic features of a thickened gallbladder wall and a positive Murphy sign in the absence of gallstones raise suspicion for this entity. As in acute cholecystitis, the gallbladder is not visualized on HIDA scanning. Management includes administration of antibiotics and cholecystectomy. If the patient is seriously ill, the gallbladder can be drained percutaneously as a temporizing measure that can bridge the patient to surgery. If a patient is not a candidate for cholecystectomy, some specialized centers have expertise in endoscopically placing a lumen opposing metal stent directly from the stomach or duodenum into the gallbladder for drainage.

CHAPTER 45  Disorders of the Gallbladder and Biliary Tract

TABLE 45.2  Differential Diagnosis of

Cholelithiasis

Peptic ulcer disease Gastroesophageal reflux disease Nonulcer dyspepsia Irritable bowel syndrome Sphincter of Oddi dysfunction Hepatitis and perihepatitis (Fitz-­Hugh–Curtis syndrome) Hepatic abscess Nephrolithiasis Pyelonephritis Perinephric abscess Pneumonia Angina pectoris Pancreatitis Ruptured ectopic pregnancy Appendicitis

Gallbladder Carcinoma Acute cholecystectomy or cholecystostomy

Ye s

Clinical diagnosis secure

No Reasonable operative risk

No

ic

st

o gn

ic

No

nd

iag

no

st

scan

Expectant management

Prompt improvement

Yes

Gallbladder carcinoma is relatively uncommon but has a high case fatality rate. The incidence and mortality are higher in Latin American countries (e.g., Chile) and in Southeast Asia. Carcinoma of the gallbladder often produces advanced disseminated disease with weight loss, jaundice, pruritus, and a large right upper quadrant mass. Symptoms may resemble those of acute or chronic cholecystitis, particularly if the tumor is small. Risk factors include gallbladder polyps, porcelain gallbladder, choledochal cysts, gallstones, and anomalous pancreaticobiliary junction. Although early-­stage tumors can be treated surgically, most cases are diagnosed at an advanced stage and are incurable.

Gallbladder Dyskinesia

ia

D

99mTc-DISIDA

No

No

Gallbladder polyps are outgrowths of the gallbladder mucosal wall that are seen in up to 5% of normal subjects undergoing gallbladder ultrasonography. Most of these lesions are not neoplastic but are hyperplastic or represent lipid deposits (cholesterolosis). The differential diagnosis includes cholesterol polyps, adenomyomatosis, inflammatory polyps, adenomas, and gallbladder cancer. Factors associated with increased risk of malignancy include age greater than 60 years, size greater than 1 cm, presence of gallstones, and increased size on subsequent imaging. Cholecystectomy is indicated if one or more of these risk factors are present or if the patient has biliary symptoms. Polyps that are smaller than 1 cm should be monitored with periodic ultrasound examination.

Yes

Advanced disease; toxic

are not seen on initial imaging. The treatment is laparoscopic cholecystectomy, but conversion to open cholecystectomy is required in up to 5% of cases.

Gallbladder Polyps

Yes

Acute RUQ pain and tenderness

453

Reevaluation and late cholecystectomy

Response to treatment Fig. 45.4 Algorithm for management of right upper quadrant (RUQ) pain and tenderness in patients with suspected acute cholecystitis. This scheme is based on a policy of early operation (conventional or laparoscopic) for appropriate patients and use of cholecystostomy (operative or percutaneous) for patients who are poor operative risks. 99mTc-­DISIDA, Technetium-­99m–labeled diisopropyl iminodiacetic acid.

Chronic Cholecystitis Chronic cholecystitis is a term used by pathologists to describe chronic inflammatory cell infiltration of the gallbladder on histopathology. Chronic cholecystitis is thought to be an evolving inflammatory process, caused by repeated episodes of low-­grade gallbladder obstruction over a period of days to years resulting in recurrent mucosal trauma and inflammation. The symptoms are those of biliary colic without clinical features of acute cholecystitis. Gallstones are the causative agent in most patients. However, there is little correlation between the number of gallstones and the degree of gallbladder wall inflammation. In approximately 12% of patients with chronic cholecystitis, there are no demonstrable stones. The diagnosis is made in a patient with gallstones who has the clinical signs and symptoms with no other obvious cause. Transabdominal ultrasound is the best initial test, and EUS may be used to demonstrate microlithiasis (gallstones ≤3 mm) if gallstones

Gallbladder dyskinesia is a disorder caused by abnormal motility or contraction of the gallbladder in the absence of gallstones resulting in symptoms of biliary colic. Laboratory studies and abdominal imaging findings are usually normal. HIDA scanning may show a decreased gallbladder ejection fraction, or there may be reproducible pain with administration of cholecystokinin (CCK). Cholecystectomy commonly shows acalculous cholecystitis.

BILIARY TRACT DISORDERS Choledocholithiasis In Western countries, most stones found in the common bile duct (choledocholithiasis) originate in the gallbladder. Up to 15% of individuals with cholelithiasis develop choledocholithiasis (Fig. 45.5). Less commonly, stones may form de novo in the biliary tree. Common bile duct stones may be asymptomatic (30% to 40%), or they may produce biliary colic and jaundice. Two major complications are acute cholangitis and acute pancreatitis. The diagnosis is supported by the results of liver function tests and abdominal imaging. Transabdominal ultrasound is the initial imaging modality of choice; it has a sensitivity of 20% to 90% for detection of a stone and 55% to 90% for detection of dilation of the common bile duct. EUS and MRCP have replaced ERCP for diagnosis of bile duct stones; the sensitivity and specificity are 94% and 95%, respectively, for EUS and 93% and 94% for MRCP. ERCP is reserved for therapeutic interventions.

Acute Cholangitis Acute (suppurative) cholangitis is a life-­threatening infection of the biliary tract that can occur as a result of choledocholithiasis. The biliary tree is usually a sterile environment. In the setting of obstruction, migration of bacterial pathogens can cause severe infection with a mortality rate up to 30%. The classic clinical manifestations are abdominal

454

SECTION VII  Diseases of the Liver and Biliary System

Fig. 45.5 Cholangiogram obtained on endoscopic retrograde cholangiopancreatography demonstrates a common bile duct stone.

pain, jaundice, and fever (Charcot’s triad). It is important to note that clinical findings may be absent or atypical in elderly or immunosuppressed patients. Cholangitis can be mild, moderate, or severe and, if severe, rapidly lead to sepsis, shock, and death. Diagnosis is based on a compatible clinical and laboratory picture (abnormal liver function test results and leukocytosis) together with radiologic or endoscopic evidence of common bile duct stones. Treatment of acute cholangitis includes administration of broad-­ spectrum antibiotics and prompt removal of stones, typically with ERCP and sphincterotomy (Video 45.2). The timing of ERCP should be planned based on the severity of illness. Cholecystectomy is subsequently performed after the patient has been stabilized.

Gallstone Pancreatitis Biochemical evidence of pancreatic inflammation complicates choledocholithiasis and acute cholecystitis in up to 30% and 15% of patients, respectively. There are two proposed mechanisms by which gallstones may induce pancreatitis: reflux of bile into the pancreatic duct due to transient obstruction of the ampulla and obstruction at the ampulla secondary to stones or edema. Evaluation of the biliary tree with transabdominal ultrasound, MRCP, or endoscopic ultrasound should be performed in the setting of gallstone pancreatitis to evaluate for choledocholithiasis. Laboratory testing alone can be misleading because edema of the head of pancreas during pancreatitis can cause cholestasis. If choledocholithiasis is confirmed, ERCP with sphincterotomy should be performed. Considering that gallstone pancreatitis recurs in 25% of patients, a cholecystectomy should be performed once the patient has recovered clinically from an attack of pancreatitis.

Biliary Neoplasms Cholangiocarcinoma and cancer of the ampulla of Vater are uncommon in the United States. Cholangiocarcinoma can arise at any level of the biliary system and is classified as intrahepatic (25%) or extrahepatic (75%). It is more common in older men, occurring predominantly in men 50 to 70 years of age. Risk factors include primary sclerosing cholangitis (PSC), choledochal cysts, chronic ulcerative colitis, liver flukes, and recurrent pyogenic cholangitis (Oriental cholangiohepatitis). Patients with these cancers usually have unremitting painless jaundice, although necrosis and sloughing of the tumor can cause intermittent biliary obstruction and the appearance of occult fecal blood.

Fig. 45.6 Cholangiogram obtained on endoscopic retrograde cholangiopancreatography demonstrates a Klatskin tumor at the bile duct bifurcation.

Cholangiocarcinoma located at the bifurcation of the extrahepatic bile duct (50% of cases) is known as a Klatskin tumor (Fig. 45.6). Surgical cure is possible in only a small proportion of patients with cholangiocarcinoma. If the tumor is unresectable, palliative biliary drainage may be indicated. Recently, liver transplant has also become an option for carefully selected patients with localized, but unresectable disease.

Nonmalignant Causes of Biliary Obstruction Biliary Strictures

Benign biliary strictures usually result from surgical injury or chronic pancreatitis. Biliary strictures resulting from surgical injury may cause symptoms even years after the initial injury. Early diagnosis is important because strictures that partially obstruct are clinically asymptomatic and can cause secondary biliary cirrhosis. Biliary stricture should be suspected in any patient with a history of surgery of the right upper quadrant or chronic pancreatitis who has persistently elevated levels of serum alkaline phosphatase and γ-­glutamyl transpeptidase. Endoscopic balloon catheter dilatation with or without stenting or surgical repair is useful in selected patients.

Other Causes of Biliary Obstruction Structural abnormalities such as choledochal cysts, Caroli’s disease (congenital segmental intrahepatic bile duct dilation), and duodenal diverticula may cause bile duct obstruction, often with secondary choledocholithiasis resulting from bile stasis. Hemobilia, with intermittent bile duct obstruction by blood clots, may be caused by hepatic injury, neoplasms, or hepatic artery aneurysms. Biliary parasites should always be considered as a cause of biliary obstruction in the appropriate epidemiologic setting. Ascaris lumbricoides is a common cause of cholangitis and jaundice in South America, Africa, and the Indian subcontinent. Clonorchis sinensis is the etiologic agent of Oriental cholangiohepatitis in Korea and Southeast Asia and in immigrants to the United States. The liver fluke Fasciola hepatica is a leading cause of biliary strictures and cholangitis worldwide, most commonly in the Bolivian Andes.

Primary Sclerosing Cholangitis PSC is an idiopathic condition of nonmalignant, nonbacterial, chronic inflammatory fibrosis and obliteration of the intrahepatic and

CHAPTER 45  Disorders of the Gallbladder and Biliary Tract

455

ERCP is an effective treatment of cholestasis in selected patients. Most patients with advanced PSC eventually progress to end-­stage liver disease, and evaluation for liver transplantation is appropriate in advanced disease. One third of patients with PSC will develop cholangiocarcinoma; therefore, thorough clinical and laboratory studies (liver function tests and cancer markers such as CA 19-­9) and radiologic follow-­up are warranted.

Sphincter of Oddi Dysfunction

Fig. 45.7 Cholangiogram obtained on endoscopic retrograde cholangiopancreatography demonstrates the characteristic beading of the intrahepatic and extrahepatic bile ducts in a patient with primary sclerosing cholangitis.

Sphincter of Oddi dysfunction is a benign disorder that can lead to noncalculous obstruction of the flow of bile or pancreatic juice at the level of the pancreaticobiliary junction. Patients typically have unexplained biliary-­type abdominal pain with or without elevated results on liver function tests and with or without bile duct dilation. In a selected group of patients, endoscopic or surgical sphincterotomy is of value. Identifying those who would benefit can be challenging and controversial because sphincter of Oddi dysfunction can be difficult to discern from functional abdominal pain. For a deeper discussion of this topic, please see Chapter 146, “Diseases of the Gallbladder and Bile Ducts,” in Goldman-­Cecil Medicine, 26th Edition.

Acknowledgment The authors gratefully acknowledge the work of Matthew P. Spinn, who contributed this chapter to the previous edition.

extrahepatic bile ducts. It most commonly occurs in young men (two thirds of patients are younger than 45 years of age), often in association with ulcerative colitis. Approximately 70% of patients with PSC have ulcerative colitis. The clinical spectrum of PSC is broad, ranging from asymptomatic patients with abnormal liver enzyme levels (typically an elevated alkaline phosphatase concentration) to patients with recurring episodes of fever, chills, abdominal pain, and jaundice. The diagnosis of PSC is made by MRCP or ERCP, which show characteristic changes (beading) of the intrahepatic and/or extrahepatic bile duct (Fig. 45.7). No proven therapy exists for PSC, although ursodeoxycholic acid and methotrexate are being used in some centers. Other forms of therapy include prophylactic antibiotics for prevention of recurrent bacterial cholangitis, treatment of pruritus, and repletion of fat-­soluble vitamins. Endoscopic dilatation of a dominant biliary stricture during

SUGGESTED READINGS Adeel S, Khan AS, Dageforde LA: Cholangiocarcinoma, Surg Clin North Am 99(2):315–335, 2019. Hyun JJ, Kozarek RA: Sphincter of Oddi dysfunction: sphincter of Oddi dysfunction or discordance? What is the state of the art in 2018? Curr Opin Gastroenterol 34(5):282–287, 2018. Pezzilli R, Zerbi A, Campra D, Capurso G, Golfieri R, Arcidiacono PG, et al: Consensus guidelines on severe acute pancreatitis, Dig Liver Dis 47(7):532–543, 2015. Sulzer JK, Ocuin LM: Cholangitis, Surg Clin North Am 99(2):175–184, 2019. Tazuma S, Unno M, Igarashi Y, Inui K, Uchiyama K, Kai M, et al: Evidencebased clinical practice guidelines for cholelithiasis 2016, J Gastroenterol 52(3):276–300, 2017.

SECTION

VIII

Hematologic Disease 46 Hematopoiesis and Hematopoietic Failure, 457

50 Disorders of Lymphocytes, 506 51  Normal Hemostasis, 522

47 Clonal Disorders of the Hematopoietic Stem Cell, 470

52  Disorders of Hemostasis: Bleeding, 530

48 Disorders of Red Blood Cells, 489

53 Disorders of Hemostasis: Thrombosis, 550

49 Clinical Disorders of Granulocytes and Monocytes, 501

456

46 Hematopoiesis and Hematopoietic Failure Eunice S. Wang, Nancy Berliner

HEMATOPOIESIS Hematopoiesis is the process of formation and development of blood cells. The constituents of peripheral blood arise by a complex and carefully regulated process of ontogeny. The pluripotent hematopoietic stem cell (HSC) maintains itself by self-renewal and undergoes multilineage differentiation to generate the appropriate numbers and types of cells in the circulating blood compartment (Table 46.1). The hematopoietic system is unique in that it is constantly undergoing this full cycle of maturation by which a primitive cell develops into a variety of highly specialized end-stage cells, all of which have different lifespans and occur in different quantities. The bone marrow must have the capacity to produce cells to compensate for the normal rapid turnover of hematopoietic cells resulting from senescence, normal use, and migration into tissue spaces. It must have a reserve capacity to produce additional cells in response to unusual demands that arise from bleeding, infection, or other stresses. Understanding the repeated cycle of cellular ontogeny and self-renewal that meets these challenges provides important insights into normal and pathologic mechanisms in hematology.

Hematopoietic Tissues Hematopoiesis commences in the embryonic yolk sac, in which early erythroblasts in blood islands form the first hemoglobinized cells. After 6 weeks’ gestation, the fetal liver begins producing primitive lymphocytoid cells, megakaryocytes, and erythroblasts, and the spleen becomes a secondary site of erythropoiesis. Hematopoiesis then shifts to its definitive long-term site in the bone marrow, the principal site for lifelong hematopoiesis in the normal host. Early in life, all fetal bones contain regenerative bone marrow, but the marrow becomes progressively replaced by fat with age. In adults, active marrow resides only in the axial skeleton (i.e., sternum, vertebrae, pelvis, and ribs) and in the proximal ends of the femur and humerus. Consequently, bone marrow samples, which are needed for many hematologic diagnoses, are usually obtained from the iliac crest or sternum. Under pathologic conditions that stress the capacity of the marrow space, as seen in diseases associated with marrow fibrosis (e.g., chronic myeloproliferative diseases) or in severe inherited hemolytic anemia (e.g., thalassemia major), extramedullary hematopoiesis may be reestablished in sites of fetal hematopoiesis, especially the spleen.

Stem Cell Theory of Hematopoiesis All mature hematopoietic cells are hypothesized to originate from a small population of pluripotent stem cells. Comprising less than 1% of all cells in the bone marrow, these cells bear no distinctive morphologic markings and are best defined by their unique functional properties. Stem cells have two distinctive characteristics. First, they are highly resilient and productive, capable of continuously replenishing huge

numbers of granulocytes, lymphocytes, and erythrocytes throughout life. The demand for a continuous, fluctuating supply of blood cells requires a hematopoietic system capable of producing large numbers of selected cells in a short time. For example, overwhelming infection by invading microorganisms triggers the release of neutrophils, whereas hypoxia or acute blood loss leads to increased red blood cell ­production. Second, HSCs represent a self-renewing cell population that is able to maintain its numbers while providing a continued ­supply of progenitor cells of many different lineages. Despite their vast proliferative potential, under normal conditions, most HSCs are quiescent, and few cells undergo expansion or differentiation at any one time. However, their ability to proliferate is striking. Studies with lethally irradiated mice have demonstrated the ability of a few transplanted cells (i.e., spleen colony-forming unit [CFU-S] cells) to regenerate multilineage hematopoiesis. The signals regulating the differentiation of pluripotent stem cells into committed progenitors are unknown. Data suggest that the first step in lineage commitment is a stochastic (chance) event; subsequent stages of maturation are hypothesized to occur under the influence of growth factors, or cytokines (Table 46.2). Cytokines act on different cells through specific cytokine receptors. Receptor activation induces signal-transduction pathways that lead to changes in gene transcription and eventual cell proliferation and differentiation. These growth factors also act as survival factors for the developing hematopoietic cells by preventing apoptosis (i.e., programmed cell death). This process occurs in the cellular milieu of the bone marrow, where hematopoiesis depends in part on the nonhematopoietic cells (i.e., fibroblasts, endothelial cells, osteoblasts, and fat cells) that make up that microenvironment. Research in HSC biology has focused on how these cells are regulated by growth factors, unique cell surface ligands, and key interactions between stem cells and the surrounding microenvironmental cells (i.e., mesenchymal stromal cells, adipocytes, immune cells) within specialized marrow regions termed stem cell niches.

Hematopoietic Differentiation Pathway Hematopoiesis has been hypothesized to proceed along a tightly regulated hierarchy (Fig. 46.1) governed by effects of intrinsic transcription factors and cytokines in the bone marrow microenvironment. As more primitive cells mature under the influence of specific regulatory cytokines, they undergo several cell divisions and become progenitor cells committed to one lineage. They also lose their self-renewal capacity. Morphologically, these cells are transformed from nonspecific blastlike cells into cells that can be identified by their color, shape, and granular and nuclear content. Functionally, they acquire distinguishing cell surface receptors and responses to specific signals. Maturing granulocytes and erythroid cells undergo several more cell divisions in the bone marrow, whereas lymphocytes travel to the thymus and lymph nodes for further development. Megakaryocytes cease cellular

457

458

SECTION VIII  Hematologic Disease

TABLE 46.1  Normal Values for Peripheral Blood Cells Cell Type and Size

Mean

Range

Hemoglobin

Women: 14 g/dL Men: 15.5 g/dL Women: 41% Men: 47% 60,000/μL (1%)

Women: 12-16 g/dL Men: 13.5-17.5 g/dL Women: 36-46% Men: 41-53% 35,000-85,000/μL (0.5-1.5%) 80-100 fL 150,000-400,000/μL 4500-11,000/μL 1800-7700/μL 1000-4800/μL 200-950 (4-11%)

Hematocrit Reticulocyte count Mean corpuscular volume Platelet count Total white blood cell count Neutrophils Lymphocytes Monocytes

250,000/μL 7400/μL 4400/μL (40-60%) 2500/μL (20-40%) 300/μL (55 years old) other comorbidities, or without fully HLA-matched donors available. Conditioning and immunosuppressive regimens are administered in doses sufficient to permit donor stem cell engraftment without aggressive cytoreduction. These so-called “mini” transplants result in chimeric marrows (i.e., part patient and part donor) and are not characterized by significant periods of cytopenias or hematopoietic compromise. Most responding patients convert to a fully donor-derived marrow over time. The use of newer immunosuppressive regimens has also allowed patients to receive transplants from related family members who are only 50% HLA matched (so called haplotype identical or haploidentical transplants). Almost all patients have compatible half-matched parents, siblings, children, or even grandchildren, thereby allowing for multiple family members to serve as donors. Although feasible and well tolerated in many patients, haploidentical transplants are associated with an enhanced risk of relapsed disease due to reduced GVL effects

CHAPTER 46  Hematopoiesis and Hematopoietic Failure and therefore are best utilized for those with optimal disease control at time of the procedure. Although historically used in the treatment of primary malignant stem cell disorders such as leukemia, the therapeutic potential of alloSCT is now increasingly being employed for patients with nonmalignant hematologic conditions (e.g., aplastic anemia, sickle cell anemia, congenital immunodeficiencies), solid tumors (e.g., renal cell carcinoma, melanoma), and particularly autoimmune diseases (e.g., amyloidosis, systemic lupus, multiple sclerosis).

Hematopoietic Stem Cell Sources Historically, alloSCT has employed donor bone marrow stem cells aspirated from the posterior iliac crest and intravenously infused after myeloablation and immunosuppressive therapy. The process of engraftment or reconstitution of normal hematopoietic function takes several weeks. Patients often require almost daily platelet and red blood cell transfusions, and they are hospitalized during this period of prolonged neutropenia to minimize life-threatening bacterial, viral, and fungal infections. Other complications include severe mucositis, hemorrhagic cystitis, GVHD, relapsed disease, and graft failure. The discovery that high-dose G-CSF treatment mobilizes large numbers of CD34+ hematopoietic progenitor and stem cells from bone marrow sites into circulating blood (i.e., 10-fold to 15-fold increase over baseline levels) has led to the routine use of PBSCs collected by apheresis procedures in place of bone marrow stem cells for allogeneic transplantation. Compared with marrow-derived stem cells, PBSCs engraft more rapidly after myeloablation. Patients receiving allogeneic PBSC transplants have decreased neutrophil recovery time, lower transfusion requirements, fewer inpatient hospital days, and similar rates of acute GVHD and long-term survival outcomes as traditional marrow-transplanted patients. Because PBSC collections often contain 3-fold to 4-fold more CD34+ stem cells and 10-fold more lymphoid cells than harvested marrow grafts, higher rates of chronic GVHD may occur. Umbilical cord blood (UCB) stem cells constitute a rich source of immature CD34+ HSCs. In the past, the less stringent HLA-compatibility requirements for UCB HSC matches has allowed the use of these transplants as a therapy for patients lacking fully compatible HLA-matched donors. Although still considered experimental, some transplantation centers have reported long-term outcomes after UCB HSC transplants similar to those for conventional marrow or peripheral PBSC transplants for primary hematologic diseases. However, the relatively limited numbers of CD34+ stem cells found in harvested UCB units accounts for a much slower hematopoietic recovery after the procedure and a statistically higher risk for nonengraftment compared with other stem cell sources. For this reason, UCB transplantation procedures have been limited to pediatric patients and smaller adults or to adult patients for whom there is more than one HLA-compatible UCB unit.

Aplastic Anemia

Definition and Epidemiology Aplastic anemia (AA) is a rare disorder characterized by pancytopenia with a markedly hypocellular bone marrow. This disease was first described in 1888 by Paul Ehrlich, who observed that autopsy bone marrow specimens from a young woman who died of severe anemia and neutropenia were extremely hypoplastic. Later studies demonstrated that patients with severe AA possessed only a fraction of normal pluripotent stem cell numbers despite normal functional marrow stromal cells and normal or even elevated levels of stimulatory cytokines. The incidence of AA ranges from 1 to 5 cases per million people in the general population. It occurs predominantly in young adults (20 to 25 years old) and older adults (60 to 65 years old). The incidence is 3-fold higher in developing countries (e.g., Thailand and China) compared

461

with industrialized Western nations (e.g., Europe and Israel), a fact that is not explained by differences in drug or radiation exposure.

Etiology AA arises as either an inherited disorder or an acquired syndrome or as an idiopathic phenomenon. A small number of cases occur in the context of a congenital bone marrow failure disorder, including Fanconi anemia, Schwachman-Diamond syndrome, and dyskeratosis congenita. The most common of these, Fanconi anemia, is an autosomal recessive disorder arising from mutations in genes encoding DNA repair proteins. The known causes of acquired AA are numerous (Table 46.4) and range from myeloablative radiation exposure to common viruses and medications. Prior bone marrow toxicity from drugs, chemicals (e.g., benzene, cyclic hydrocarbons found in petroleum products, rubber, glue, insecticides, chemical dyes), or radiation predisposes to AA because these agents directly injure proliferating and differentiating HSCs by inducing DNA damage. In contrast, cytotoxic chemotherapy, especially with alkylating agents, and radiation therapy target all rapidly cycling cells and often induce reversible bone marrow aplasia. Despite these many causes, most cases of AA are idiopathic. The etiology of both acquired and congenital AAs appear to be mechanistically linked through abnormal telomere maintenance. Telomeres are repeated nucleotide sequences that cap and protect chromosome ends from degradation. Cell division leads to normal telomere erosion; when telomeres reach a critically short length, cells cease to proliferate, senesce, and undergo apoptosis, often with accompanying DNA damage and genomic instability. Telomerase enzyme in normal HSCs preserves long telomeres and promotes quiescence and a prolonged cellular lifespan. Patients with autosomal dominant dyskeratosis congenita have mutations in the genes for telomerase complexes, predisposing to premature aging and enhanced marrow failure in the setting of accelerated telomere shortening. One third of patients with acquired AA also have short telomeres, likely due to a combination of genetic, environmental, and epigenetic factors. Autoreactive host lymphocytes can destroy normal hematopoiesis in AA. Bone marrow stromal cells and cytokine levels in patients with AA are normal. The fact that AA also occurs in diseases of immune dysregulation and after viral infections further suggests an immune-mediated mechanism for the disease. One hypothesis is that drug or viral antigens presented to the immune system trigger cytotoxic T-cell responses that persist and destroy normal stem cells. Only 1 in 100,000 patients develops severe AA as an idiosyncratic drug reaction. Whether these individuals have a genetically predisposed sensitivity to common exposures (e.g., nonsteroidal anti-inflammatory drugs, sulfonamides, Epstein-Barr virus) is unknown.

TABLE 46.4  Causes of Acquired Aplastic

Anemia

Drugs (dose related): chemotherapeutic agents, antibiotics (chloramphenicol, trimethoprim-sulfamethoxazole) Idiosyncratic causes (many unproved): chloramphenicol, quinacrine, nonsteroidal anti-inflammatory drugs, anticonvulsants, gold, sulfonamides, cimetidine, penicillamine Toxins: benzene and other hydrocarbons, insecticides Viral infection: hepatitis, Epstein-Barr virus, human immunodeficiency virus (HIV) Immune disease: graft-versus-host disease in immunodeficiency, hypogammaglobulinemia Paroxysmal nocturnal hemoglobinuria (PNH) Radiation exposure Pregnancy

462

SECTION VIII  Hematologic Disease

Clinical Presentation The clinical onset of AA can be insidious or abrupt. Patients often complain of symptoms related to their cytopenias: weakness, fatigue, dyspnea, or palpitations resulting from anemia; gingival bleeding, epistaxis, petechiae, or purpura caused by low platelet counts; or recurrent bacterial infections caused by low or nonfunctioning neutrophils. In some cases, patients will report recent upper respiratory syndrome. Results of the physical examination may be normal or characterized by ecchymoses and bleeding complications. Patients with congenital AA may have various abnormalities.

Diagnosis and Differential Diagnosis Diagnostic confirmation of AA requires bone marrow biopsy to confirm hypocellularity and to rule out other marrow processes. Normal bone marrow cellularity ranges from 30% to 50% up to age 70 years and is less than 20% after 70 years of age (E-Fig. 46.1A). In contrast, bone marrow cellularity in patients with AA usually ranges from 5% to 15%, with increased fat accumulation and few or no hematopoietic cells and primarily plasma cells and lymphocytes (see E-Fig. 46.1B). In AA, hematopoietic progenitor and precursor cells are morphologically normal but number less than 1% of normal levels, and they are markedly dysfunctional, with a decreased ability to form differentiated progenitor cell colonies in vitro. A hypocellular marrow with evidence of increased blasts, dysplastic hematopoietic cells (e.g., pseudo-Pelger-Huët abnormalities, micromegakaryocytes) (E-Fig. 46.2), and clonal cytogenetically abnormal cells in the peripheral blood or marrow are diagnostic of acute leukemia or myelodysplasia, not AA. In young patients, a diagnosis of Fanconi anemia is made by demonstrating enhanced sensitivity of cultured cells to mitomycin or diepoxybutane-induced chromosomal damage on special testing. Although patients with AA typically have a low reticulocyte count from low red blood cell production and a paucity of blood cells (E-Fig. 46.3A) and macrocytic red cells (see E-Fig. 46.3B) on the peripheral blood smear, these features are nondiagnostic because patients with other primary marrow disorders may exhibit similar findings.

Treatment and Prognosis Treatment of AA is based on the severity of disease and clinical characteristics. Patients with mild cytopenias can be monitored expectantly. However, patients with severe AA based on peripheral blood cell counts (defined as a neutrophil count 90%; long-term survival in pediatric patients >90% vs. 30-40% in adults Newly diagnosed AYA Improved 3-year survival of 73%; Dose intensification of steroids, IT chemotherapy, asparaginase and vincristine Newly diagnosed older adults Lower-dose chemotherapy with omission of anthracycline Younger patients with CD20+ disease Added to standard chemotherapy; not indicated for older patients or CD20-negative disease Ph-positive ALL Combined with steroids and standard chemotherapy MRD+ and Relapsed refractory CD19+ ALL Toxicities of cytokine release syndrome and CNS effects. Eliminates MRD+ disease in >70%. Overall survival of 7.7 months in relapsed disease. Relapsed/refractory CD22+ ALL Risk of veno-occlusive disease (15%) and hepatotoxicity, particularly with prior allogeneic stem cell transplant Relapsed/refractory CD19+ ALL aged 25 and younger Response rates of 80%. Toxicities of cytokine release and neurologic symptoms require treatment with steroid and anti-IL-6 antibody

CHAPTER 47  Clonal Disorders of the Hematopoietic Stem Cell

Relapsed or refractory disease. Although late recurrences can emerge at any time, most ALL relapses arise within 2 years of the initial diagnosis, with recurrence of chemoresistant leukemia cells in the bone marrow, CNS, or testes. All patients with relapsed ALL should be considered for additional therapy followed by alloSCT, which represents the only known cure for disease. Autologous SCT is not routinely recommended. Overall response rates to multiagent salvage chemotherapy incorporating the same agents used in frontline therapy range from 20% to 50% with duration of second remissions lasting less than 6 months. Other chemotherapy agents specifically indicated for relapsed disease include nelarabine for T-ALL, clofarabine for patients younger than 21 years old, and a liposomal formulation of vincristine in patients receiving at least two prior lines of therapy. Each drug induces clinical responses in up to a third of heavily pretreated patients as a single agent with tolerable toxicities. Perhaps the most exciting strategies for ALL therapy involve technologies specifically exploiting patient host immune responses to induce responses. Numerous immunotherapies targeting the leukemia cell antigens CD19 and CD22 have entered mainstream therapy for ALL as well as other lymphoid malignancies. BiTE results in significantly improved overall survival (7.7 months) as compared with standard chemotherapy (4 months). Patients with lower marrow disease burden and receiving treatment in first relapse benefit most, with 30% of patients proceeding on to alloSCT. Unique side effects of therapy include neurologic symptoms (ranging from change in mental status to seizures to encephalopathy) and cytokine release syndrome characterized by fever, hemodynamic instability, and life-threatening organ damage. Severity of complications is related to extent of tumor burden and is higher than experienced in BiTE therapy of MRDpositive ALL. Inotuzumab is a CD22-directed antibody conjugated to a DNA damaging agent (calicheamicin). Binding of this antibody drug conjugate to surface CD22 expressed on the ALL surface leads to its internalization, induction of DNA strand breakage, and cell death. In a randomized controlled trial, inotuzumab induced higher overall responses (88%) in patients with first relapsed ALL than standard chemotherapy (32%). Forty percent of patients receiving inotuzumab underwent subsequent alloSCT. However 15% of patients developed VOD, which was largely fatal and occurred primarily in individuals with prior alloSCT who had received multiple doses of therapy. Cellular immunotherapies that have revolutionized the treatment of all B-cell malignancies were first validated for the treatment of relapsed B-ALL. Chimeric antigen receptor T (CART) cells are autologous T cells collected from patients with relapsed ALL and genetically modified ex vivo to express CD19 chimeric antigen receptors. This effectively reprograms them to recognize and destroy CD19-expressing tumor cells. Infusion of a single dose of CART cells (tisagenlecleucel) following lymphodepleting chemotherapy in individuals (both children and young adults) with multiple relapsed/refractory ALL resulted in the complete eradication of disease in 80% to 90%. Although CARTmediated cytokine release and neurotoxicity can be life-threatening, strategies to mitigate these adverse events with early administration of steroids and the anti-IL-6 antibody (tocilizumab) have allowed CART to be successfully administered at numerous academic centers across the world.

PROSPECTUS FOR THE FUTURE Insights into the molecular and biologic underpinnings of MPNs and acute leukemia have led to an explosion of novel therapeutic

487

approaches that have transformed the clinical approach to each of these diseases in the past few years.

Myeloproliferative Disease The importance of the spectacular success of imatinib as targeted therapy for CML cannot be overstated. As the first successful therapy based on an understanding of pathogenesis, imatinib has become emblematic of the translation of an understanding of disease pathogenesis into tangible innovations in clinical care. At present, there are four additional new-generation TKIs for CML therapy in addition to imatinib. The best indicator of how these agents have altered the natural history of disease is the fact that certain patients with sustained undetectable disease for 2 to 3 years are now able to permanently discontinue TKI therapy without disease recurrence. Similarly, the discovery of JAK2 mutations in non-CML myelo­ proliferative diseases opened new avenues for targeted intervention in diseases for which previous therapy was largely supportive. JAK2 inhibition now constitutes standard-of-care therapy for PV and MF independent of JAK2 mutation status. Newer agents are actively being investigated for MPN therapy including hypomethylating agents, MDM2 inhibitors, antibody-drug conjugates, and anti-fibrosis agents.

Acute Leukemia Acute leukemias are clinically aggressive malignancies with survival rates of weeks to a few months if untreated. The availability of multiple targeted and nontargeted agents for distinct biological subsets has changed the therapeutic landscape for these diseases. The first acute leukemia exemplifying this was APL. The discovery of the link between the retinoic acid receptor and the origins of APL provided important insights into the unique sensitivity of this disease to ATRA therapy and paved the road for successful implementation of dual differentiation therapy with ATRA and arsenic. This regimen marks the first time that any acute leukemia was cured without cytotoxic chemotherapy or SCT. At present, pediatric ALL is now considered a highly curable cancer with long-term remission and survival rates of over 90%. Patients with relapsed disease are eligible to receive the latest advances in novel immunotherapeutic approaches. CART therapy has revolutionized therapy not only for ALL but for all B-cell malignancies such as lymphoma and myeloma. However, durability of response and disease relapse remain major issues. It is uncertain whether patients undergoing CART should also pursue subsequent alloSCT. Antibodies including anti-CD20 antibody (rituximab), the CD19-CD3 bispecific agent (blinatumomab), and the CD22 antibody drug conjugate (inotuzumab) have expanded the armamentarium of strategies for ALL. Incorporation of new-generation oral BCR/ABL kinase inhibitors to routine chemotherapy for Philadelphia chromosome–positive ALL has altered expectations for this subtype. Tailoring of therapy to disease subtype as well as different age groups (pediatric, AYA, and elderly) has led to true personalized therapy. Future directions include moving agents known to be effective in the relapsed/refractory setting to earlier in the treatment course during induction and/or consolidation. Examples include upfront therapy with BiTe and dasatinib for Ph+ disease or inotuzumab plus mini-hyper CVD or CART cells with MRD testing. In AML, the “gold standard” (7+3) for induction chemotherapy since the 1970s has finally been replaced, at least in older unfit individuals, by venetoclax-based therapy. The latter results in overall response rates of 60% to 70% and provides a new backbone regimen on which to potentially add novel experimental agents. Single-agent inhibitors of mutant FLT3, IDH1, and IDH2 have been shown to be superior to conventional chemotherapy in patients with appropriately mutant disease. Newer clinical trials are exploring combinations of targeted agents (FLT3 and IDH inhibitors) with different chemotherapy backbones (i.e., venetoclax plus HMA) or with each other (i.e., venetoclax and gilteritinib). Development

488

SECTION VIII  Hematologic Disease

of reduced intensity and haploidentical alloSCT strategies has permitted specific older AML patients the opportunity to be cured of their disease. Similar approaches may soon provide therapeutic entry points into the treatment of other acute leukemias associated with pathognomonic chromosomal translocations and genetic and molecular aberrations.

SUGGESTED READINGS Arber DA, Orazi A, Hasserjian R, et al: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia, Blood 127(20):2391–2405, 2016. Baxter EJ, Scott LM, Campbell PJ, et al: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders, Lancet 365(9464):1054–1061, 2005. Byrd J, Mrozek K, Dodge R, et al: Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia, Blood 100(13):4325–4336, 2002. Cortes JE, Heidel JH, Hellman A, et al: Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome, Leukemia 33(2):379–389, 2019. DiNardo CD, Pratz K, Pullarkat V, et al: Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia, Blood 133(1):7–17, 2019. DiNardo CD, Stein EM, de Botton S, et al: Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML, N Engl J Med 378(25):2386–2398, 2018. Dohner H, Estey EH, Grimwade D, et al: Diagnosis and management of AML in adults: 2017 ELM recommendations from an international expert panel, Blood 129(4):424–447, 2017. Do¨hner H, Estey EH, Amadori S, et al: Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet, Blood 115(3):453– 474, 2010. Harrison CN, Campbell PJ, Buck G, et al: Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia, N Engl J Med 353(1):33–45, 2005. Harrison CN, Vannucchi AM, Kiladjian JJ, et al: Long-term findings from COMFORT-II, a phase 3 trial of ruxolitinib versus best available therapy for myelofibrosis, Leukemia 30(8):1701–1707, 2016. Hasford J, Pfirrmann M, Hehlmann R, et al: A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon

alfa. Writing Committee 3 for the Collaborative CML Prognostic Factors Project Group, J Natl Cancer Inst 90(11):850–858, 1998. Hughes TP, Mauro MJ, Cortes JE, et al: Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure, N Engl J Med 381(24):2315– 2326, 2019. Kantarjian HM, DeAngelo DJ, Stelljes M, et al: Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia, N Engl J Med 375(8):740–753, 2016. Kantarjian H, Stein A, Gokbuget N, et al: Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia, N Engl J Med 376(9):836–847, 2017. Lambert J, Pautas C, Terre C, et al: Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the openlabel, phase III ALFA-0701 trial, Haematologica 104(1):113–119, 2019. Landolfi R, Marchioli R, Kutti J, et al: Efficacy and safety of low-dose aspirin in polycythemia vera, N Engl J Med 350(2):114–124, 2004. Maude SL, Laetsch TW, Buechner J, et al: Chimeric antigen receptor T cells for sustained remissions in leukemia, N Engl J Med 378(5):439–448, 2018. Perl S, Martinelli G, Cortes JE, et al: Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML, N Engl J Med 381(18):1728–1740, 2019. Pfirrman M, Baccarani M, Saussele S, et al: Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia, Leukemia 30(1):48–56, 2016. Pullarkat V, Slovak ML, Kopecky KJ, et al: Impact of cytogenetics on the outcome of adult acute lymphocytic leukemia: results of the Southwest Oncology Group 9400 study, Blood 111(5):2563–2572, 2008. Sokal J, Cox EB, Baccarani M, et al: Prognostic discrimination in “good-risk” chronic granulocytic leukemia, Blood 63(4):789–799, 1984. Stein EM, DiNardo CD, Pollyea DA, et al: Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia, Blood 130(6):722–731, 2017. Stock W, Luger SM, Advani AS, et al: A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403, Blood 133(14):1548–1559, 2019. Stone RM, Mandrekar SJ, Sanford BL, et al: Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation, N Engl J Med 377(5):454–464, 2017. Vannucchi AM, Kiladjian JJ, Greisshammer M, et al: Ruxolitinib versus standard therapy for treatment of polycythemia vera, N Engl J Med 372(5):426–435, 2015. Wei AH, Strickland SA, Hou JZ, et al: Venetoclax combined with lowDose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study, J Clin Oncol 37(15):1277– 1284, 2019.

48 Disorders of Red Blood Cells Ellice Wong, Michal G. Rose, Nancy Berliner

NORMAL RED BLOOD CELL STRUCTURE AND FUNCTION Erythrocytes, or red blood cells (RBCs), deliver oxygen to all the tissues in the body and carry carbon dioxide back to the lungs for excretion. The erythrocyte is uniquely adapted to these functions. It has a biconcave disk shape that maximizes the membrane surface area for gas exchange, and it has a cytoskeleton and membrane structure that allow it to deform sufficiently to pass through the microvasculature. Passage through capillaries whose diameter may be one fourth the resting diameter of the erythrocyte is made possible by interactions between proteins in the membrane (band 3 and glycophorin) and underlying cytoplasmic proteins that make up the erythrocyte cytoskeleton (spectrin, ankyrin, and protein 4.1). The mature RBC contains no nucleus and is dependent throughout its life span on proteins synthesized before extrusion of the nucleus and release of the cell from the bone marrow into the peripheral circulation. About 98% of the cytoplasmic protein of the mature erythrocyte is hemoglobin. The remainder is mainly enzymatic proteins, such as those required for anaerobic metabolism and the hexose monophosphate shunt. Defects in any of the intrinsic structural features of the erythrocyte can result in hemolytic anemia. Abnormalities of the membrane or cytoskeletal proteins are the causes of alterations in erythrocyte shape and flexibility. Inborn defects in the enzymatic pathways for glucose metabolism decrease the resistance to oxidant stress, and inherited abnormalities of hemoglobin structure and synthesis lead to polymerization of abnormal hemoglobin (sickle cell disease) or to the precipitation of unbalanced hemoglobin chains (thalassemia). All of these changes result in decreased erythrocyte survival. Oxygen is transported by hemoglobin, a tetramer composed of two α chains, two β-like (β, γ, or δ) chains, and four heme molecules, each of which is composed of a protoporphyrin molecule complexed with iron. In fetal life, the main hemoglobin is fetal hemoglobin (HbF: α2, γ2); the switch from HbF to adult hemoglobin (HbA: α2β2) occurs in the perinatal period. By 4 to 6 months of age, the level of HbF has fallen to about 1% of total hemoglobin. HbA2 (α2δ2) is a minor adult hemoglobin, representing about 1% of adult hemoglobin (Table 48.1).

CLINICAL PRESENTATION Anemia, defined as a reduction in RBC mass, is an important sign of disease. It may be caused by decreased production of erythrocytes from nutritional deficiencies, primary hematologic disease, or a response to systemic illness. Alternatively, anemia may be caused by increased blood loss or cellular destruction from hemolysis. Hemolysis may occur as a result of intrinsic abnormalities of the RBC, immune-mediated

RBC destruction, or a systemic vascular process. The investigation of anemia is a critical component of the evaluation of the patient and commonly provides valuable insight into systemic illness. Fig. 48.1 provides an overview of the differential diagnosis of anemia. The symptoms of anemia reflect both the severity and the rapidity with which the reduction in erythrocyte mass has occurred. Patients with acute hemorrhage may exhibit symptoms of hypovolemic shock. Massive hemolysis may result in neurologic impairment or cardiovascular collapse. However, most patients develop anemia more slowly and have few symptoms. Usual complaints are fatigue, decreased exercise tolerance, dyspnea, and palpitations. In patients with coronary artery disease, anemia may precipitate angina. On physical examination, the major sign of anemia is pallor. Patients may be tachycardic and often have significant flow murmurs. Patients with hemolysis often exhibit jaundice and splenomegaly. Patients with iron deficiency may occasionally exhibit signs of pica (i.e., craving for ice or nonfood items such as dirt).

LABORATORY EVALUATION The key components of the laboratory evaluation of anemia are the reticulocyte count, the peripheral blood smear, erythrocyte indices, nutritional studies, and in some cases the bone marrow aspirate and biopsy. The reticulocyte count allows the critical distinction between anemia arising from a primary failure of RBC production and anemia resulting from increased RBC destruction or bleeding. Erythrocytes newly released from the marrow still contain small amounts of RNA; these cells, termed reticulocytes, can be detected with the use of automated counters and fluorescent nucleic acid–binding dyes or manually by staining of the peripheral blood smear with new methylene blue or other supravital stains. In response to anemia, erythropoietin (EPO) production increases, promoting the production and release of increased numbers of reticulocytes. The number of reticulocytes in the peripheral blood therefore reflects the response of the bone marrow to anemia. The reticulocyte count can be expressed either as a percentage of the total number of RBCs or as an absolute number. In patients without anemia, the normal reticulocyte count is 0.5% to 1.5% of RBCs or 20,000 to 75,000/μL. When the anemia is caused by decreased RBC survival, the appropriate marrow response results in a reticulocyte count greater than 2%, with an absolute count of more than 100,000/μL. If the reticulocyte count is not elevated, a cause of failure of RBC production should be sought. Reticulocyte counts that are expressed as a percentage of total RBCs must be corrected for anemia because decreasing the number of circulating cells increases the reticulocyte percentage without any increase in release from the marrow.

489

490

SECTION VIII  Hematologic Disease

The corrected reticulocyte count is calculated by multiplying the reticulocyte count by the ratio of the patient’s hematocrit to a normal hematocrit. An additional calculation, the reticulocyte index or reticulocyte production index (RPI), determines whether the reticulocyte count is appropriate for the degree of anemia. The RPI corrects for both the degree of anemia and release of reticulocytes from the marrow by multiplying the ratio of the patient’s hematocrit to a normal hematocrit by the reticulocyte percentage divided by a maturation term. The maturation term signifies the time in days for RBCs to mature (ranging from 1 for a hematocrit ≥40% to 2.5 for a hematocrit 1500 eosinophils/μL with syndrome no other apparent cause aReactive

forms.

Monocytes Monocytes arise from a common myeloid precursor along with granulocytes under the influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF). Most circulating monocytes are marginated along the walls of blood vessels. They migrate from the vessels into tissues, where they develop into macrophages. The monocyte-macrophage lineage has many diverse functions. These phagocytic cells perform chemotaxis, phagocytosis, and intracellular killing in much the same manner as neutrophils. They are especially important in killing infectious mycobacterial, fungal, and protozoal species. Monocytes interact with other components of the immune system. They are antigen-presenting cells for T lymphocytes, they are capable of cellular cytotoxicity, and they secrete cytokines. The macrophages (i.e., differentiated monocytes) that process antigens and present them to T lymphocytes take on different forms in different tissues such as Langerhans cells in the skin, interdigitating cells in the thymus, and dendritic cells in the lymph nodes. Antigen-presenting cells are nonphagocytic, and the process by which they internalize antigen is not fully understood. Protein antigens are partially digested and expressed on the cell surface in association with major histocompatibility complex class II (Ia) antigens. This feature permits interaction with and activation of helper T cells. Other macrophages, such as Kupffer cells of the liver and alveolar macrophages of the lung, play an important role in removing particulate and cellular debris and senescent erythrocytes from the circulation. Monocytes are capable of antibody-dependent and antibody-independent cytotoxicity against tumor cells. Cytotoxicity is increased by tumor necrosis factor, interleukin-1, and interferon, which are secreted by monocytes. Monocytes secrete large numbers of immunomodulatory proteins (e.g., tumor necrosis factor, interleukin-1, interferon), cytokines (e.g., granulocyte colony-stimulating factor [G-CSF], GM-CSF), coagulation proteins, cell adhesion proteins, and proteases. Monocytosis can be present in inflammatory as well as primary hematologic conditions. Infections such as tuberculosis, endocarditis, and syphilis are commonly associated with a reactive monocytosis. Hematologic malignancies such as chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, and some types of acute myeloid leukemia have clonal monocytosis as a hallmark feature. A reactive monocytosis has also been observed in some lymphomas. Monocytopenia is observed in stress states including severe sepsis and as a result of myelosuppressive chemotherapy. Low monocyte

503

counts can also be found in acquired bone marrow failure states including aplastic anemia and myelodysplastic syndrome (MDS) and in hairy cell leukemia. Monocytopenia associated with natural killer cell deficiency and B-cell lymphoma have been linked to disorders involving GATA2 or SAMD9L mutations.

DETERMINANTS OF PERIPHERAL NEUTROPHIL NUMBERS Most granulocyte precursors are in the bone marrow, where maturation occurs over 6 to 10 days. Marrow precursors represent 20% of the granulocyte mass, and the storage pool represents 75% of the granulocyte mass. Peripheral neutrophils represent only 5% of the total granulocyte mass. Neutrophils circulate in transit between the marrow and peripheral tissues. More than one half of the circulating neutrophils adhere to the vascular endothelium (margination). The half-life of a neutrophil in the circulation was thought to be 6 to 12 hours, but more recent studies suggest it may be as long as 3 to 4 days. After neutrophils migrate into tissues, they survive another 1 to 4 days. The peripheral neutrophil count therefore represents a sampling of less than 5% of the total granulocyte pool and is taken during a very short interval of the total neutrophil lifespan. The peripheral white cell count is a poor reflection of granulocyte kinetics. Abnormalities in neutrophil number can occur rapidly and may reflect a change in marrow granulocyte production or a shift among various cellular compartments. An elevated peripheral white cell count may result from increased marrow production, or it may reflect mobilization of neutrophils from the marginated pool or release from the marrow storage pool. Similarly, a low granulocyte count may reflect decreased marrow production, increased margination or sequestration in the spleen, or increased destruction of peripheral cells. The total peripheral white cell count represents the sum of lymphocytes, monocytes, and granulocytes. The significance of an elevated or depressed leukocyte count depends on the nature of the cellular elements that are increased or decreased. Leukocytosis is a nonspecific term that may denote an increase in lymphocytes (i.e., lymphocytosis) or neutrophils (i.e., neutrophilia). In rare cases, increases may reflect excessive numbers of monocytes, eosinophils, or basophils. Extreme elevation of the white blood cell count to more than 50,000 cells/μL of blood with the premature release of early myeloid precursors is called a leukemoid reaction, which may be associated with inflammation and infection. It requires consideration of a diagnosis of myeloproliferative disease, especially chronic myelogenous leukemia (CML). Evaluation of the peripheral blood smear may reveal characteristic changes that provide clues to the underlying disorder. A leukoerythroblastic smear shows immature granulocytes, teardrop-shaped erythrocytes, nucleated erythrocytes, and increased platelets. These changes reflect marrow infiltration (i.e., myelophthisis) by fibrous tissue, granulomas, or neoplasm. As with leukocytosis, leukopenia may reflect lymphopenia or neutropenia. Neutropenia is generally defined by an absolute neutrophil count of less than 1500 cells/μL, although institutional laboratory reference ranges may vary slightly.

NEUTROPHILIA Neutrophilia usually results from other processes, and it rarely indicates a primary hematologic disorder (Table 49.2). However, patients with a persistently elevated neutrophil count, especially when associated with an elevated hematocrit or platelet count, should be evaluated to rule out a primary myeloproliferative neoplasm. Peripheral blood evaluation for

504

SECTION VIII  Hematologic Disease

TABLE 49.2  Differential Diagnosis of

TABLE 49.3  Differential Diagnosis of

Primary Hematologic Disease Congenital neutrophilia Leukocyte adhesion deficiency Myeloproliferative disorders

Decreased Production of Neutrophils

Neutrophilia

Due to Other Disease Processes Infection (acute or chronic) Acute stress Drugs (e.g., steroids, lithium) Cytokine stimulation (e.g., granulocyte colony-stimulating factor) Chronic inflammation Malignancy Myelophthisis Marrow hyperstimulation Chronic hemolysis, immune thrombocytopenia Recovery from marrow suppression Asplenia Smoking Metabolic and endocrine disorders (e.g., pregnancy, eclampsia, thyroid storm, Cushing disease)

the BCR/ABL fusion product can be performed to consider CML, and assays for JAK2 V617F, JAK2 exon 12, calreticulin, and MPL mutations can help to consider non-CML myeloproliferative neoplasms. Neutrophilia related to acute infection, stress, toxic exposures like smoking, or corticosteroid administration primarily reflects demargination and is usually transient. Persistent neutrophilia usually reflects chronic bone marrow stimulation. Nevertheless, a bone marrow aspirate and biopsy are rarely indicated in the work-up of neutrophilia. The exception is for patients who demonstrate leukoerythroblastic changes, for which a bone marrow examination and culture may be indicated to consider tuberculosis or fungal infection, marrow infiltration with tumor, or marrow fibrosis. Cytogenetic and molecular studies should be performed to help eliminate the diagnosis of marrow malignancies, and the marrow should be cultured for mycobacteria and fungi.

NEUTROPENIA Differential Diagnosis Neutropenia may reflect decreased production, increased sequestration, or peripheral destruction of neutrophils (Table 49.3). Patients should first be evaluated for splenomegaly to consider the possibility of sequestration. For patients who are asymptomatic and for whom previous studies are unavailable, the possibility of constitutional or cyclic neutropenia should be entertained and can be evaluated by serial peripheral blood counts. The normal neutrophil count varies among ethnic groups and is most commonly lower in individuals with African ancestry as compared to white individuals (i.e., constitutional or benign ethnic neutropenia [BEN]). The absence of the red blood cell Duffy antigen has been demonstrated to be associated with BEN. As the Duffy antigen is utilized by the parasite Plasmodium vivax to enter the red blood cell, it is believed that positive selection for the null allele enabled individuals in West Africa to be protected against malaria and have a survival advantage. Cyclic neutropenia is a relatively benign disorder, in which cyclical changes occur in all hematopoietic cell lines but are most dramatic in the neutrophil lineage. At the nadir of the neutrophil counts, patients may have infections, but the condition is often clinically silent.

Neutropenia

Increased Peripheral Destruction

Congenital and/or constitutional cause Sepsis Constitutional neutropenia Immune destruction Benign chronic neutropenia Drug related Kostmann syndrome Associated with collagen vascular Cyclic neutropenia disease Postinfectious cause Isoimmune (in newborns) Nutritional deficiency (B12, folate, Large granular lymphocyte copper) leukemia Drug-induced cause Hypersplenism and/or sequestration Primary marrow failure Aplastic anemia Myelodysplastic syndromes Acute leukemias

In contrast, patients with congenital agranulocytosis or severe congenital neutropenia (SCN) exhibit profound neutropenia and infections in the perinatal period. Kostmann syndrome is a subset of SCN that was described more than 50 years ago as an autosomal recessive disorder; later studies demonstrated that SCN can reflect autosomal dominant, autosomal recessive, X-linked, or sporadic mutations. About 50% of autosomal dominant SCN and almost 100% of cyclic neutropenia cases are associated with inherited mutations in the neutrophil elastase gene. The mutations are thought to produce a misfolded neutrophil elastase protein, which accumulates in the endoplasmic reticulum and activates the unfolded protein response. This complex cellular stress response coordinates the degradation of misfolded protein in the endoplasmic reticulum and can trigger cellular apoptosis if the stress is severe. Later studies have established that autosomal recessive SCN (i.e., Kostmann syndrome) is caused by mutations in the HAX1 gene, which encodes a mitochondrial protein that is required for stabilization of the mitochondrial membrane. Absence of HAX1 results in loss of the mitochondrial membrane potential and induction of apoptosis. Until G-CSF became available, most patients with SCN died in early childhood, but the availability of cytokine therapy has prolonged survival. However, SCN is also associated with a significantly increased incidence of acute leukemia, a complication that has become apparent as patients survive longer. Up to 30% of patients with SCN develop acute myelogenous leukemia over 10 years. Acute myelogenous leukemia in these patients is often associated with truncation mutations in the G-CSF receptor. These acquired somatic mutations may contribute to the pathogenesis of leukemia but do not contribute to the congenital neutropenia. The role of the G-CSF receptor mutations in the pathogenesis of leukemic transformation is controversial, as is the relationship between G-CSF therapy and the acquisition of these mutations. Neutropenia may occur during or after viral, bacterial, or mycobacterial infections. Postviral neutropenia is especially common in children and probably reflects increased neutrophil consumption and a viral suppression of marrow neutrophil production. Neutropenia may be seen as a complication of overwhelming sepsis and is associated with a poor prognosis. Drug-induced neutropenia may reflect dose-dependent marrow suppression or an idiosyncratic immune response. The former is one of the most common complications of chemotherapeutic drugs and is also common with antibiotics such as sulfamethoxazole-trimethoprim.

CHAPTER 49  Clinical Disorders of Granulocytes and Monocytes Chloramphenicol causes dose-dependent marrow suppression, although its more ominous complication is the rare idiosyncratic reaction that gives rise to marrow aplasia. Drugs that are most commonly associated with neutropenia include clozapine, sulfasalazine, ticlopidine, and the thionamide antithyroid agents. Most drug-induced neutropenias respond rapidly to discontinuation of the offending agent. The administration of G-CSF may speed recovery. Autoimmune neutropenia may be seen as a primary disease or as a secondary manifestation of systemic autoimmune disease or lymphoproliferative disease. Primary autoimmune neutropenia is a disorder of infants and young children that resolves spontaneously in more than 90% of patients within 2 years. Secondary autoimmune neutropenia is a common accompaniment to systemic lupus erythematosus. Although not usually clinically severe, neutropenia is often a marker of disease activity. Neutropenia in rheumatoid arthritis may be associated with spleno­ megaly (i.e., Felty syndrome) and is part of the spectrum of large granular lymphocyte (LGL) leukemia. LGL leukemia is a clonal expansion of suppressor T cells. Patients who develop LGL leukemia in association with rheumatoid arthritis share a common HLA-DR4 haplotype with patients with Felty syndrome, suggesting that they are in a common spectrum of disease. LGL leukemia is also a relatively common cause of acquired neutropenia in elderly patients in the absence of rheumatoid arthritis. Recent data have linked LGL leukemia to mutations in the STAT3 gene.

Laboratory Evaluation Unless the diagnosis of benign ethnic or cyclic neutropenia is likely, the evaluation of the patient with neutropenia should include stopping all potentially offending drugs and performing serologic studies to rule out collagen vascular disease. Unlike the evaluation of patients with leukocytosis, bone marrow examination is indicated early for those with neutropenia and is frequently diagnostic. Neutropenia often reflects primary hematologic disease, and bone marrow examination enables the physician to diagnose marrow failure syndromes, leukemia, and MDS. In the absence of bone marrow failure, other causes of neutropenia may give a characteristic bone marrow picture. All patients undergoing bone marrow examination should have cytogenetic and molecular studies performed to aid in the diagnosis of MDS. Sudden onset of agranulocytosis that does not affect platelets or erythrocytes typically is attributable to drug or toxin exposure. Bone marrow examination is rarely necessary. If performed, drug-induced neutropenia produces a characteristic maturation arrest of myeloid cells. Rather than actual inhibition of neutrophil maturation, this feature reflects the immune destruction of myeloid precursors that leaves only the earliest cells behind.

Treatment The therapeutic approach to patients with neutropenia depends on the degree of depression of the neutrophil count. Neutrophil counts between 1000 and 1500 cells/μL are not usually associated with significant impairment of the host response to bacterial infection and require no intervention beyond that demanded for diagnosis and treatment of the underlying cause. Patients with neutrophil counts between 500 and 1000 cells/μL should be alerted to their slightly increased risk of infection, although serious problems are rarely encountered in patients with functional neutrophils and counts higher than 500 cells/μL. Patients with neutrophil counts lower than 500 cells/μL are at significant risk for infection, although this is especially true of patients with acute or chemotherapy-induced neutropenia. In contrast, patients with chronic idiopathic neutropenia may be asymptomatic with absolute neutrophil counts below 100. All patients with neutrophil counts below 500 cells/μL should be instructed to notify the physician at the

505

first sign of infection or fever, and they must be managed aggressively with intravenous antibiotics regardless of the documentation of a source or infecting organism. Patients with a significantly depressed neutrophil count may exhibit few signs of infection because much of the inflammatory response at the site of infection is generated by the neutrophils themselves. In patients with severe immune-mediated neutropenia, corticosteroids and intravenous immunoglobulin may be helpful in elevating the neutrophil count and in preventing infectious complications. G-CSF may increase the peripheral white cell count and may help resolve infections in neutropenia induced by drugs, including chemotherapy. It has been efficacious for some patients with immune-mediated neutropenia and those with MDS. For a deeper discussion of these topics, please see Chapter 158, “Leukocytosis and Leukopenia” in Goldman-Cecil Medicine, 26th Edition.

PROSPECTUS FOR THE FUTURE Significant progress has been made in elucidating the molecular pathogenesis of severe congenital neutropenia and cyclic neutropenia. Compounds that modulate the unfolded protein response may play a role in the treatment of these disorders. Other studies of the molecular basis of myeloid differentiation are establishing the importance of transcription factor function in neutrophil maturation and are providing insights into the pathogenesis of leukemia and myelodysplasia. Their findings may delineate pathways with entry points for therapeutic intervention in myeloid malignancies.

SUGGESTED READINGS Aktari M, Curtis B, Waller EK: Autoimmune neutropenia in adults, Autoimmun Rev 9:62–68, 2009. Andres E, Maloisel F: Idiosyncratic drug-induced agranulocytosis and acute neutropenia, Curr Opin Hematol 15:15–21, 2008. Beekman R: Touw IP: G-CSF and its receptor in myeloid malignancy, Blood 115:5131–5136, 2010. Berliner N: Lessons from congenital neutropenia: 50 years of progress in understanding myelopoiesis, Blood 111:5427–5432, 2008. Berliner N: Leukocytosis and leukopenia. In Goldman L, Schafer AI, editors: Goldman-Cecil Medicine, ed 26, Philadelphia, 2019, Elsevier Saunders. Brinkmann V, Reichard U, Goosmann C, et al: Neutrophil extracellular traps kill bacteria, Science 303:1532–1535, 2004. Dinauer MC, Coates TD: Disorders of phagocyte function. In Hoffman R, Benz EJ, Heslop H, Weitz J, editors: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier, pp 691–709. Glogauer M: Disorders of phagocyte function. In Goldman L, Schafer AI, editors: Goldman-Cecil Medicine, Philadelphia, 2011, Elsevier Saunders, p 24. Mortaz E, Alipoor SD, Adcock IM, Mumby S, Koenderman L: Update on Neutrophil Function in Severe Inflammation, Front Immunol 9:1–14, 2018. Nauseef WM, Borregaard N: Neutrophils at work, Nature Immunology 15:602–611, 2014. Pillay J, den Braber I, Vrisekoop N, et al: In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days, Blood 116:625–627, 2010. Rappoport N, Simon AJ, Amariglio N, Rechavi G: The Duffy antigen receptor for chemokines, ACKR1,- ‘Jeanne DARC’ of benign neutropenia, Br J Haematol 184:497–507, 2019. Xia J, Link DC: Severe congenital neutropenia and the unfolded protein response, Curr Opin Hematol 15:1–7, 2008. Yipp BG, Paul K: NETosis: how vital is it? Blood 122:2784–2794, 2013. Zhang R, Shah MV, Loughran Jr TP: The root of many evils: indolent large granular lymphocyte leukaemia and associated disorders, Hematol Oncol 28:105–117, 2010.

50 Disorders of Lymphocytes Iris Isufi, Stuart Seropian

INTRODUCTION The central cell of the immune system is the lymphocyte. Lymphocytes mediate the adaptive immune response, providing specificity to the immune system by responding to specific pathogens and conferring long-lasting immunity to reinfection. Lymphocytes are derived from hematopoietic stem cells that reside in the bone marrow and give rise to all of the cellular elements of the blood. The two major functional classes of lymphocytes—B lymphocytes (B cells) and T lymphocytes (T cells)—are distinguished by their site of development, antigenic receptors, and function. The major disorders of lymphocytes include neoplastic transformations of specific subsets of lymphocytes that result in an array of lymphomas or leukemias, congenital or acquired defects in lymphocyte development or function with resultant immunodeficiency, and physiologic responses to infection or antigenic stimulation that lead to lymphadenopathy, lymphocytosis, or lymphocytopenia.

LYMPHOCYTE DEVELOPMENT, FUNCTION, AND LOCALIZATION B Cells B cells are characterized by surface immunoglobulins (i.e., antibodies). Their major function is to mount a humoral immune response to antigens by producing antigen-specific antibodies. B cells develop in the bone marrow in a series of highly coordinated steps that involve sequential rearrangement of the heavy- and lightchain immunoglobulin genes and expression of B-cell–specific cell surface proteins (Fig. 50.1). Rearrangement of the immunoglobulin genes results in generation of a large repertoire of B cells that are each characterized by an immunoglobulin molecule with unique antigenic specificity. Mature B cells migrate from the bone marrow to lymphoid tissue throughout the body and are readily identified by cell surface immunoglobulin and antigens that are B cell specific, including CD19, CD20, and CD21. In response to antigen binding to cell surface immunoglobulin, mature B cells are activated to proliferate and undergo differentiation to end-stage plasma cells, which lose most of their B-cell surface markers and produce large quantities of soluble antibodies. Neoplastic disorders of B cells arise from B cells at different stages of development, and B-cell lymphomas can have highly varied morphology and cell surface expression of B-cell antigens (i.e., immunophenotype).

T Cells T cells perform an array of functions in the immune response, including those that are regarded as classic cellular immune responses. T-cell precursors migrate from the bone marrow to the thymus, where they differentiate into mature T-cell subsets and undergo selection to

506

eliminate autoreactive T cells that respond to self-peptides. In the thymus, T-cell precursors undergo a coordinated process of differentiation that involves rearrangement and expression of the T-cell receptor (TCR) genes and acquisition of cell surface proteins that are unique to T cells, including CD3, CD4, and CD8. As T cells mature in the thymus, they ultimately lose the CD4 or CD8 protein. Mature T cells are composed of two major groups: CD4+ and CD8+ cells. After T-cell maturation and selection in the thymus, mature CD4+ and CD8+ T cells migrate to lymph nodes, spleen, and other sites in the peripheral immune system. Mature T cells constitute about 80% of peripheral blood lymphocytes, 40% of lymph node cells, and 25% of splenic lymphoid cells. Mature CD4+ and CD8+ T-cell subsets mediate distinct immune functions. CD8+ cells (cytotoxic T cells) kill virus-infected or foreign cells and suppress immune functions. CD4+ cells (helper T cells) activate other immune cells such as B cells and macrophages by producing cytokines and through direct cell contact. Similar to B cells, T cells express unique TCR molecules that recognize specific peptide antigens. In contrast to B cells, T cells respond only to peptides that are processed intracellularly and bound to (or presented by) specialized cell surface antigen-presenting proteins, designated major histocompatibility complex (MHC) molecules. CD4+ and CD8+ T cells are MHC class restricted in their response to peptide-MHC complexes. CD4+ cells recognize antigenic peptide fragments when they are presented by MHC class II molecules, and CD8+ cells recognize antigenic peptide fragments when they are presented by MHC class I molecules. Binding of the TCR by a specific peptide-MHC complex triggers activation signals that lead to the expression of gene products that mediate the wide diversity of helper functions of CD4+ cells or cytotoxic effector functions of CD8+ cells.

Lymphoid System Lymphocytes localize to peripheral lymphoid tissue, which is the site of antigen-lymphocyte interaction and lymphocyte activation. The peripheral lymphoid tissue is composed of lymph nodes, the spleen, and mucosal lymphoid tissue. Lymphocytes circulate continuously through these tissues through the vascular and lymphatic systems. Lymph nodes are highly organized lymphoid tissues that are sites of convergence of the lymphatic drainage system, which carries antigens from draining lymph to the nodes, where they are trapped. A lymph node consists of an outer cortex and an inner medulla (Fig. 50.2). The cortex is organized into lymphoid follicles composed predominantly of B cells. Some of the follicles contain central areas or germinal centers, where activated B cells proliferate after encountering a specific antigen, that are surrounded by a mantle zone. The T cells are distributed more diffusely in paracortical areas surrounding follicles.

CHAPTER 50  Disorders of Lymphocytes CENTRAL HEMATOPOIETIC TISSUES

507

PERIPHERAL TISSUES Memory cell

Stem cell

Pre-B cells

TdT

B cells

µ

Plasma cell

µ Immature

Mature

Activated

CELL SURFACE MARKERS: CD34 CD19 CD20 CD21 CD24 CD10

CD10 CD38

CD38 CD39 CD23 CD25

PC-1 Fig. 50.1  The maturation of B lymphocytes. Top, The changes in immunoglobulin production and maturation. Bottom, The appearance and disappearance of surface markers. TdT, Terminal deoxynucleotidyl transferase. (Modified from Ferrarini M, Grossi CE, Cooper MD: Cellular and molecular biology of lymphoid cells. In Handin RI, Lux SE, Stossel TP, editors: Blood: Principles and Practice of Hematology, Philadelphia, 1995, JB Lippincott, p 643.)

Cortex Subcapsular sinus

Afferent lymphatics

Germinal center Mantle

Medulla

Efferent lymphatics

The mucosa-associated lymphoid tissues (MALTs) collect antigen from epithelial surfaces and include the gut-associated lymphoid tissue (i.e., tonsils, adenoids, appendix, and Peyer patches of the small intestine) and more diffusely organized aggregates of lymphocytes at other mucosal sites. Lymphocytes circulate in the blood and represent 20% to 40% of peripheral blood leukocytes in adults; the proportion is higher in newborns and children. The majority of peripheral blood lymphocytes are T cells, and the remaining lymphocytes are largely B cells. A small percentage of peripheral blood lymphoid cells represents a third category of lymphoid cells referred to as natural killer (NK) cells. These cells do not bear the characteristic cell surface molecules of B or T cells, and their immunoglobulin or TCR genes have not undergone rearrangement. Morphologically, the cells are large, with abundant cytoplasm containing azurophilic granules, and they are often called large granular lymphocytes. Functionally, they are part of the innate immune system, responding nonspecifically to a wide range of pathogens without requiring prior antigenic exposure.

NEOPLASIA OF LYMPHOID ORIGIN Fig. 50.2  Structure of the normal lymph node. The cortical area contains the follicles, which consist of a germinal center and a mantle zone. The medulla contains a complex of channels that lead to the efferent lymphatics.

The spleen traps antigens from blood rather than from the lymphatic system and is the site of disposal of senescent red cells. Lymphocytes in the spleen reside in the areas described as white pulp, which surround the arterioles entering the organ. As in lymph nodes, the B and T cells are segregated into a periarteriolar lymphoid sheath that is composed of T cells and flanking follicles composed of B cells.

Malignant transformation of lymphocytes leads to a diverse array of lymphoid cancers, including tumors that arise from T cells, B cells, or NK cells. Lymphoid malignancies usually involve lymphoid tissues, but they can arise in or spread to any site. The major clinical groupings of lymphoid malignancies include non-Hodgkin’s lymphomas (NHLs), Hodgkin’s lymphoma, lymphoid leukemias, and plasma cell dyscrasias.

Non-Hodgkin’s Lymphomas Definition and Epidemiology

The NHLs comprise a heterogeneous group of lymphoid malignancies that have different histologic appearances, cells of origin and

508

SECTION VIII  Hematologic Disease

TABLE 50.1  2016 WHO Classification of Mature Lymphoid, Histiocytic, and Dendritic

Neoplasms

Mature B-Cell Neoplasms Chronic lymphocytic leukemia/small lymphocytic lymphoma Monoclonal B-cell lymphocytosisa B-cell prolymphocytic leukemia Splenic marginal zone lymphoma Hairy cell leukemia Lymphoplasmacytic lymphoma Waldenström’s macroglobulinemia Monoclonal gammopathy of undetermined significance (MGUS), IgMa μ Heavy-chain disease γ Heavy-chain disease α Heavy-chain disease Monoclonal gammopathy of undetermined significance (MGUS), IgG/Aa Plasma cell myeloma Solitary plasmacytoma of bone Extraosseous plasmacytoma Monoclonal immunoglobulin deposition diseasesa Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) Nodal marginal zone lymphoma Follicular lymphoma In situ follicular neoplasiaa Duodenal-type follicular lymphomaa Pediatric-type follicular lymphomaa Primary cutaneous follicle center lymphoma Mantle cell lymphoma In situ mantle cell neoplasiaa Diffuse large B-cell lymphoma (DLBCL), NOS Germinal center B-cell typea Activated B-cell typea T-cell/histiocyte-rich large B-cell lymphoma Primary DLBCL of the central nervous system (CNS) Primary cutaneous DLBCL, leg type EBV+ DLBCL, NOSa DLBCL associated with chronic inflammation Lymphomatoid granulomatosis Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma ALK+ large B-cell lymphoma Plasmablastic lymphoma Primary effusion lymphoma Burkitt lymphoma High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangementsa High-grade B-cell lymphoma, NOSa B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma

Mature T and NK Neoplasms T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Aggressive NK-cell leukemia Systemic EBV+ T-cell lymphoma of childhooda Hydroa vacciniforme–like lymphoproliferative disordera Adult T-cell leukemia/lymphoma Extranodal NK-/T-cell lymphoma, nasal type Enteropathy-associated T-cell lymphoma Monomorphic epitheliotropic intestinal T-cell lymphomaa Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides Sézary syndrome Primary cutaneous CD30+ T-cell lymphoproliferative disorders Lymphomatoid papulosis Primary cutaneous anaplastic large cell lymphoma Primary cutaneous γδ T-cell lymphoma Peripheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Anaplastic large-cell lymphoma, ALK+ Anaplastic large-cell lymphoma, ALK−a Hodgkin’s Lymphoma Nodular lymphocyte predominant Hodgkin’s lymphoma Classical Hodgkin’s lymphoma Nodular sclerosis classical Hodgkin’s lymphoma Lymphocyte-rich classical Hodgkin’s lymphoma Mixed cellularity classical Hodgkin’s lymphoma Lymphocyte-depleted classical Hodgkin’s lymphoma Posttransplant Lymphoproliferative Disorders (PTLD) Plasmacytic hyperplasia PTLD Infectious mononucleosis PTLD Florid follicular hyperplasia PTLDa Polymorphic PTLD Monomorphic PTLD (B- and T-/NK-cell types) Classical Hodgkin’s lymphoma PTLD

Provisional entities, histiocytic and dendritic cell entities are not included. aDenotes new entities.

immunophenotypes, molecular biologic factors, clinical features, prognoses, and outcomes with therapy. According to the Surveillance, Epidemiology, and End Results (SEER) database, the NHLs are the seventh most common cancer type, with an estimated 74,200 cases occurring in 2019 and 19,970 patients succumbing to these diseases. The NHLs occur at a median age of 67 and are more common in men and in white individuals. The rate of NHLs increased slowly between 2000 and 2010 but has been decreasing slowly since that time. The annual death rate has fallen an average of 2.2% from 2007 to 2016.

Pathology In view of the heterogeneity of NHLs, classification systems have been devised to identify specific pathologic subtypes that correlate with distinct clinical entities. These systems have evolved steadily over the past 50 years as correlations between histopathologic and biologic behavior have emerged. Pathologic classification schemes have attempted to correlate malignant NHL subtypes with normal cellular counterparts. The World Health Organization (WHO) classification (Table 50.1) is the most current and incorporates morphologic features, immunophenotype, genetic features, and molecular features, with an emphasis on biologic

CHAPTER 50  Disorders of Lymphocytes

TABLE 50.2  Causes of Lymphadenopathy Infectious Diseases Viral: infectious mononucleosis syndromes (cytomegalovirus, Epstein-Barr virus), acquired immunodeficiency syndrome, rubella, herpes simplex, infectious hepatitis Bacterial: localized infection with regional adenopathy (streptococci, staphylococci), cat-scratch disease (Bartonella henselae), brucellosis, tularemia, listeriosis, bubonic plague (Yersinia pestis), chancroid (Haemophilus ducreyi) Fungal: coccidioidomycosis, histoplasmosis Chlamydial: lymphogranuloma venereum, trachoma Mycobacterial: scrofula, tuberculosis, leprosy Protozoan: toxoplasmosis, trypanosomiasis Spirochetal: Lyme disease, syphilis, leptospirosis Immunologic Diseases Rheumatoid arthritis Systemic lupus erythematosus Mixed connective tissue disease Sjögren’s syndrome Dermatomyositis Serum sickness Drug reactions: phenytoin, hydralazine, allopurinol Malignant Diseases Lymphomas Solid tumors metastatic to lymph nodes: melanoma, lung, breast, head and neck, gastrointestinal tract, Kaposi’s sarcoma, unknown primary tumor, renal, prostate Atypical Lymphoid Proliferations Giant follicular lymph node hyperplasia Transformation of germinal centers Castleman disease Miscellaneous Diseases and Diseases of Unknown Cause Dermatopathic lymphadenitis Sarcoidosis Immunoglobulin G4 (IgG4) lymphadenopathy Amyloidosis Mucocutaneous lymph node syndrome (Kawasaki disease) Sinus histiocytosis (Rosai-Dorfman syndrome) Multifocal Langerhans cell (eosinophilic) granulomatosis Lipid storage diseases: Gaucher’s and Niemann-Pick diseases

and therapeutic implications. The most common NHLs encountered in the United States are diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, small lymphocytic lymphoma or leukemia (i.e., chronic lymphocytic leukemia [CLL]), and mantle cell lymphoma.

Etiology The cause of most NHLs is unknown. In most patients no apparent genetic predisposition or epidemiologic or environmental factor can be identified. Many of the NHL subtypes carry pathognomonic chromosomal translocations that often involve an immunoglobulin locus (or TCR locus in T-cell NHLs) and an oncogene or growth regulatory gene. The cause of these aberrant chromosomal rearrangements is unknown. Patients with congenital immunodeficiency syndromes or autoimmune disorders are at increased risk for NHL. Oncogenic human viruses play a causal role in some of the less common NHL variants.

509

Epstein-Barr virus (EBV) is associated with several biologically aggressive NHLs, including acquired immunodeficiency syndrome (AIDS)– related diffuse, aggressive lymphomas, the lymphoproliferative disorders that arise in immunosuppressed patients after organ transplantation, and the form of Burkitt lymphoma that is endemic in Africa. Human T-cell lymphotropic virus type 1 (HTLV-1) is causally linked with adult T-cell leukemia/lymphoma, which is endemic in areas of Japan and the Caribbean basin. The human herpesvirus 8 (HHV-8) of Kaposi’s sarcoma has been implicated in a variant of diffuse, aggressive NHL that arises in serosal cavities and is encountered almost exclusively in patients infected with human immunodeficiency virus (HIV). Several indolent lymphomas have been linked to infectious agents that appear to indirectly promote lymphomagenesis through chronic antigen stimulation, resulting in B-lymphocyte proliferation. Helicobacter pylori infection is linked to gastric MALT lymphomas in this manner; eradication of infection with antibiotics is often associated with regression of the lymphoma.

Clinical Presentation Although numerous subtypes of NHL are recognized, most disease entities may be viewed conceptually as clinically indolent (i.e., low grade) or aggressive (i.e., high grade). Indolent lymphomas typically grow slowly, do not always require therapy, and have a long natural history. A clinical history of recurring and regressing adenopathy may be elicited. Constitutional symptoms such as fever, weight loss, or night sweats occur in about 20% of patients with NHL at the time of onset. These symptoms are more common in patients with aggressive subtypes of NHL. Aggressive lymphomas are associated with limited survival in the absence of therapy. Most patients with NHL exhibit painless lymphadenopathy involving one or more peripheral nodal sites. NHL can involve extranodal sites, and patients can exhibit a variety of symptoms that reflect the site of involvement. Common sites of extranodal disease include the gastrointestinal tract, bone marrow or focal bone lesions, liver, skin, and Waldeyer ring in the nasopharynx and oropharynx, although virtually any site can be involved. Aggressive subtypes of NHL are more likely than indolent lymphomas to involve extranodal sites. Central nervous system involvement, including leptomeningeal spread, rarely occurs with the indolent subtypes but does occur with the aggressive variants. The most aggressive NHLs (i.e., Burkitt and lymphoblastic lymphomas) have a particular propensity to spread to the leptomeninges.

Diagnosis and Differential Diagnosis Many causes of lymphadenopathy exist in addition to lymphoid malignancies (Table 50.2). A thorough history and careful physical examination are important before performing a lymph node biopsy. The investigation of lymphadenopathy can be organized according to the location of the enlarged nodes (i.e., localized or generalized) and clinical symptoms. Cervical lymphadenopathy is most often caused by infections of the upper respiratory tract, including infectious mononucleosis syndromes, viral syndromes, and bacterial pharyngitis. Unilateral axillary, inguinal, or femoral adenopathy may be caused by skin infections involving the extremity, including cat-scratch fever. Generalized lymphadenopathy may be caused by systemic infections (e.g., HIV, cytomegalovirus), drug reactions, autoimmune diseases, or one of the systemic lymphadenopathy syndromes. If the cause of persistent lymphadenopathy is not apparent after a thorough evaluation, an excisional lymph node biopsy should be undertaken. An enlarged supraclavicular lymph node strongly suggests malignancy and should always be sampled. The accurate diagnosis of lymphoma requires excisional biopsy of a lymph node or generous biopsy of involved lymph tissue. Fineneedle aspiration or needle biopsy is rarely sufficient. Analysis of the

510

SECTION VIII  Hematologic Disease

TABLE 50.3  Staging Evaluation for

TABLE 50.4  Staging System for Hodgkin

Required Evaluation Procedures Biopsy of lesion with review by an experienced hematopathologist History with attention to the presence or absence of B symptoms Physical examination with attention to node-bearing areas (including Waldeyer ring) and size of liver and spleen Standard blood work: Complete blood count Lactate dehydrogenase and β2-microglobulin Evaluation of renal function Liver function tests Calcium, uric acid Bone marrow aspirate and biopsy Radiologic studies, including: Chest radiograph (posteroanterior and lateral) Chest, abdomen, and pelvic CT scans PET scan (in Hodgkin’s and aggressive lymphomas)

Stagea

Involvement

I

One node or a group of adjacent Single extranodal lesions nodes without nodal involvement Two or more nodal groups Stage I or II by nodal extent on the same side of the with limited contiguous diaphragm extranodal involvement As above with bulky diseaseb Nodes on both sides of the diaphragm; nodes above the diaphragm with spleen involvement Additional noncontiguous extralymphatic involvement

Lymphomas

Procedures Required Under Certain Circumstances Plain bone radiographs of symptomatic sites or abnormal areas on bone scan Brain or spinal CT or MRI if neurologic signs or symptoms Serum and urine protein electrophoresis Lumbar puncture with cerebrospinal fluid cytology (Burkitt and lymphoblastic lymphoma) B symptoms, Fever, sweats, and weight loss >10% of body weight; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography.

pathologic specimen should include routine histologic examination and immunophenotyping, immunohistochemistry, chromosome analysis, fluorescence in situ hybridization (FISH) testing, and molecular studies. Immunophenotyping can determine the cell of origin (i.e., B cell, T cell, NK cell, or nonlymphoid cell), and the pattern of cell surface antigens aids subclassification. In the case of B-cell NHLs, immunophenotyping can also reveal whether the process is monoclonal in origin (i.e., neoplastic) by determining if surface immunoglobulin is restricted to κ or λ light chain. Immunohistochemistry utilizing stains to assess expression levels of proteins such as MYC and BCL-2 provides prognostic information. In some cases, cytogenetic analysis or molecular studies of immunoglobulin or TCR gene rearrangement may be required to determine the pathologic subtype of lymphoma or to establish a monoclonal process. Chromosome analysis may reveal a complex karyotype often associated with worse prognosis, or deletion of chromosome 17p where the tumor suppressor gene p53 locus is found. FISH probes can identify translocations such as t(8;14) leading to high MYC expression in Burkitt lymphoma, t(14;18) leading to deregulated expression of the BCL-2 gene in follicular B-cell lymphoma, or t(11;14) leading to cyclin D1 (a regulator of the G1-S transition) overexpression in mantle cell lymphoma, among other abnormalities. If a lymph node biopsy is nondiagnostic and unexplained lymph node enlargement persists, biopsy should be repeated. For patients with bone marrow and peripheral blood involvement, such as in small lymphocytic lymphoma or CLL, the diagnosis may be made based on immunophenotyping of peripheral blood lymphocytes by flow cytometry. Care must be taken to exclude the possibility of aggressive lymphoma with involved lymph nodes or extranodal sites in a patient harboring a low-grade or indolent lymphoma such as small lymphocytic lymphoma that is confined to the blood or bone marrow.

and Non-Hodgkin’s Lymphoma

II II bulky

III

IV

Extranodal E Status

aStaging

systems for Hodgkin’s and non-Hodgkin’s lymphomas are similar. For Hodgkin’s lymphoma, the presence or absence of symptoms should be documented with each stage designation: A (asymptomatic) or B (fever, sweats, and weight loss >10% of body weight). bFor Hodgkin’s lymphoma bulky disease includes nodal mass >10 cm or >⅓ of the transthoracic diameter

Treatment After a lymphoma has been diagnosed, patients should undergo complete staging evaluation (Table 50.3). Staging determines the extent of involvement, provides prognostic information, and may influence the choice of therapy. The Lugano modification of the Ann Arbor staging classification is used to stage patients with NHL and Hodgkin’s lymphoma (Table 50.4). A variety of ancillary tests may be performed in specific situations. For example, a test for HTLV-1 and HIV should be performed if adult T-cell leukemia/lymphoma is suspected. Patients with a clinical history suggesting immunodeficiency or behavioral risk factors should be tested for HIV. A gastrointestinal series or endoscopy may be warranted for patients with gastrointestinal symptoms or patients at risk for gastrointestinal involvement (i.e., mantle cell and other lymphomas involving the Waldeyer ring). The choice of therapy is guided by stage, specific subtype, and clinical considerations such as age and the medical condition of the patient. Multiple novel agents are available for therapy of lymphoid neoplasms (Table 50.5). Such agents may be combined or used with traditional chemotherapy.

Lymphoma Subtypes Indolent non-Hodgkin’s lymphomas. The common low-grade or indolent conditions include follicular lymphoma, small lymphocytic lymphoma (which is identical to CLL), and marginal zone lymphomas. Follicular lymphoma (FL) accounts for 20% of adult lymphomas and is the most common indolent lymphoma. It is a mature clonal B-cell neoplasm that histologically retains nodular architecture in the lymph node, which is infiltrated by small, mature-appearing lymphocytes. The immunophenotype is positive for surface markers (CD10, CD19, CD20, CD21) and negative for CD5. Follicular lymphomas are characterized by the t(14;18) translocation that juxtaposes the immunoglobulin heavy chain (IGH) locus with the antiapoptotic B-cell CLL/ lymphoma 2 gene (BCL2); the BCL2 protein is uniformly overexpressed in follicular lymphomas, immortalizing affected cells. Additional gain of function mutations and altered T-cell function in the malignant microenvironment are thought to play a role in pathogenesis.

CHAPTER 50  Disorders of Lymphocytes

511

TABLE 50.5  New Therapeutic Agents in Use for Lymphoma and Plasmacytic Disorders Class

Agents

Target

Mechanism of Action

Indications

Monoclonal Antibodies

Rituximab Obinutuzumab Daratumumab Brentuximab

CD20

Complement-mediated and antibody-dependent cytotoxicity. Apoptosis of tumor cells Antibody bound tubulin inhibitor delivered to tumor cell

Most B-cell lymphomas

Polatuzumab Thalidomide Lenalidomide Pomalidomide

CD79a Cereblon, immune-modulation Bind cereblon, activating E3 ubiquitin ligase complex

Ibrutinib Acalabrutinib Zanubrutinib

Bruton tyrosine kinase

Antibody-Drug Conjugates Imids

Kinase Inhibitors BTK Inhibitors

CD 38 CD 30

NHL subtypes (lenalidomide) Blocks B-cell receptor signaling

Pi3k Inhibitors

BCL-2 Inhibitor Proteosome Inhibitors

CAR-T Cells

Multiple myeloma Hodgkin’s lymphoma and CD30+ lymphomas DLBCL Multiple myeloma

CLL, MCL, MZL, WM

CLL, FL Idelalisib Copanlisib Venetoclax

Phosphatidylinositol-3-kinase

Blocks B-cell receptor signaling

BCL-2

Bortezomib Carfilzomib Ixazomib Axicabtagene ciloleucel Tisagenlecleucel

Proteasome

Blocks antiapoptotic protein BCL-2 CLL leading to programmed cell death Inhibition of toxic protein degradation in Multiple myeloma malignant cells MCL

CD19

Direct binding of genetically engineered DLBCL T cell to malignant B cells ALL

ALL, Acute lymphocytic leukemia; BTK, Bruton tyrosine kinase; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; IMIDS, Immunomodulatory agents; MCL, mantle cell lymphoma; MZL, marginal aone lymphoma; WM, Waldenström’s macroglobulinemia.

Follicular lymphoma is a low-grade, indolent neoplasm with a long natural history (median survival approaches 10 years), but 70% of patients have advanced-stage (III/IV) disease at diagnosis, often with bone marrow involvement, and cure is not considered feasible with standard treatment modalities for most patients. Follicular NHL may eventually transform to a more aggressive lymphoma, characterized pathologically by diffuse large cell infiltrates and clinically by rapidly expanding lymph nodes or tumor masses, rising lactate dehydrogenase (LDH) levels, and the onset of disease-related symptoms. Management of follicular lymphomas is influenced by the stage. For the rare patient with early-stage (I/some non-bulky II) disease after clinical staging, the appropriate treatment is radiation therapy. With the use of locoregional lymphoid irradiation, more than one half of patients with early-stage disease achieve a durable remission or cure. For patients with advanced-stage disease, management is more controversial. Although advanced-stage indolent NHL is responsive to a variety of treatments, incurability and long natural history have led to the practice of deferring treatment until symptoms develop. This strategy is referred to as the watch and wait approach. A prospective study of early intervention compared observation to the anti-CD20 monoclonal antibody rituximab alone and to rituximab followed by maintenance but found no difference in overall survival or histologic transformation rates. Indications for treatment include cosmetic or mechanical problems caused by enlarging lymph nodes, high tumor burden, constitutional symptoms, and evidence of marrow compromise. Multiple treatment options are available, including monoclonal antibody therapies, targeted agents, immunomodulatory agents, chemotherapeutic agents, and radiolabeled antibodies. For most patients appropriate treatment includes the chimeric anti–B-cell monoclonal antibody rituximab, with or without systemic chemotherapy. The addition of rituximab to chemotherapy has increased response rates, duration of remission, and in some studies, overall survival (level I evidence obtained from at least one properly designed, randomized controlled trial).

The choice of chemotherapy to employ in combination with rituximab may be influenced by patient age and medical condition. Multiple options are available, and no regimen has proved superior with regard to overall survival. The combination of bendamustine, a unique agent with properties similar to alkylating agents and purine analogues, plus rituximab appeared advantageous compared with the CHOP regimen (i.e., cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], and prednisone) plus rituximab in a randomized trial with regard to toxicity, response rate, and progression-free survival (level I evidence). Most patients respond to treatment, and at least one third achieve a clinical complete remission. The combination of bendamustine-rituximab results in median time to progression of 5 to 6 years. Treatment with cytotoxic agents is typically discontinued when the maximum response has been achieved, but rituximab may be continued on an intermittent schedule to maintain remission. It has been shown to prolong remission times in randomized studies (level 1 evidence). Risk of recurrence and cost considerations may influence the use of this therapy because rituximab may also be used at the time of recurrence with similar outcomes. After a patient relapses, subsequent remissions may be achieved but are often less durable compared to first remission. Therapeutic options for patients who relapse include retreatment with chemotherapy, often with a different drug or combination than that used initially. Patients in relapse can also be treated with rituximab as a single agent. For patients who are refractory to rituximab, several humanized anti-CD20 antibodies have been developed. Obinutuzumab is a humanized glycoengineered anti-CD20 antibody with enhanced antibody-dependent cellular cytotoxicity function. It has single agent activity in relapsed FL and has shown high response rates in combination with chemotherapy. Immunomodulators such as lenalidomide also have strong activity in combination with anti-CD20 antibodies in the relapsed setting. PI3 kinase inhibitors idelalisib and copanlisib have an overall

512

SECTION VIII  Hematologic Disease

response rate of 56% with median response duration of 12 months. Radioactively labeled anti-CD20 antibodies such as ibritumomab tiuxetan (yttrium labeled) have also been used for patients with relapsed or refractory follicular lymphoma and have been associated with high response rates. Administration of radiolabelled antibodies requires treatment in a specialized center with nuclear medicine expertise and has limited the use of these agents. For patients who have clinical or pathologic evidence of transformation to a higher grade of lymphoma, treatment that is appropriate for a diffuse, aggressive histology should be offered (discussed later). High-dose chemotherapy with autologous or allogeneic stem cell transplantation for follicular NHLs may be appropriate for selected patients with recurrent or refractory disease. Long-term follow-up of patients undergoing allogeneic transplantation suggests that some patients are cured with this modality, but the morbidity associated with allogeneic transplantation has limited its widespread use for indolent lymphomas. In addition to the follicular NHLs, the MALT lymphomas and closely related marginal zone lymphomas are considered low-grade, indolent subtypes. Given the excellent prognosis, localized nature, and long natural history of the MALT lymphomas, they are usually managed conservatively with local treatment modalities (i.e., radiation or surgery) and avoidance of systemic chemotherapy. The monoclonal antibody rituximab has activity against MALT lymphomas and may be used when systemic therapy is desired. The gastric MALT lymphomas are highly associated with H. pylori infection, and remissions may be achieved with eradication of the infection. Antibiotic therapy is therefore first-line treatment for early H. pylori–positive gastric MALT lymphoma. Aggressive non-Hodgkin’s lymphomas. Aggressive NHLs include DLBCL, high-grade lymphoma with C-MYC and BCL-2 and/or BCL-6 rearrangements, B-cell lymphoma unclassifiable with features inter­ mediate between DLBCL and classical Hodgkin’s lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, anaplastic large cell lymphoma, and peripheral T-cell lymphomas. Most of the aggressive lymphomas are B cell in origin; aggressive T-cell lymphomas are managed simi­ larly but have an overall worse prognosis compared with their B-cell counterparts. DLBCL is the most common subtype of NHL, constituting up to 30% of adult NHL in Western countries. Patients present with rapidly enlarged nodal masses; about 30% will have fevers, night sweats or weight loss, and 40% may have involvement of organs outside of lymph nodes. In contrast to patients with low-grade NHLs, all patients with aggressive histology should be offered immediate therapy because these lymphomas are life-threatening and potentially curable. The standard initial therapy for all patients with diffuse, aggressive NHL, regardless of stage, is a multidrug chemotherapy regimen that includes an anthracycline in combination with rituximab. For DLBCL, CHOP plus rituximab (R-CHOP) is the most widely used treatment regimen. Patients with early-stage disease (I/nonbulky II) may be treated with local radiation therapy after a minimum of three cycles of R-CHOP if there is a need to limit exposure to chemotherapy. Patients with advanced-stage disease require six cycles of R-CHOP; the role of local radiation to sites of bulky disease in the setting of advanced-stage disease is not well established. Complete remissions can be achieved with R-CHOP or similar regimens, and more than 50% of patients are cured. Identifying prognostic biomarkers for the subset of patients who respond less well or who suffer early disease relapse is a priority. In the early 2000s, gene expression profiling (GEP) using microarrays shed significant light into the biologic heterogeneity of DLBCL. Three distinct signatures were identified corresponding to potential

cells of origin (COO): germinal center B-cell–like (GCB), activated B-cell–like (ABC), and primary mediastinal large B-cell lymphoma (PMBL), with approximately 15% of cases remaining unclassifiable. The GCB subtype arises from centroblasts, whereas the ABC subtype arises from a plasmablastic cell just prior to germinal center exit. These gene signatures have prognostic implications, with GCB-DLBCLs having a more favorable overall survival than ABC cases. PMBL displays a GEP profile that resembles that of Hodgkin’s lymphoma and has a more favorable prognosis than either DLBCL subtype. In addition to the COO, molecular subtypes of DLBCL have prognostic impact. Up to 15% of DLBCL cases contain translocations involving the MYC gene on chromosome 8q24 in combination with BCL-2 and/or BCL-6 translocations (referred to as “double or triple hit” NHL). C-MYC is a pro-oncogene that encodes a transcription factor that when dysregulated leads to uncontrolled cellular proliferation and survival. BCL-2 is an oncogene on chromosome 8q21 that when translocated leads to dysregulation of the antiapoptotic protein BCL2. BCL-6 is a master regulator of the germinal center reaction and a transcriptional repressor. Double or triple hit NHL has the worst clinical outcome and is insufficiently treated with R-CHOP. Most patients have advanced stage disease, elevated LDH, bone marrow and CNS involvement. In general, more intensive regimens such as dose-adjusted EPOCH-R (etoposide, prednisone vincristine [Oncovin], cyclophosphamide, hydroxydaunorubicin [doxorubicin]-rituximab) or HyperCVAD-R (hyperfractionated doses of cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone-rituximab) are used. MYC and BCL-2 proteins can be overexpressed in DLBCL in the absence of gene translocation. Such “double-expressor” lymphomas have an intermediate prognosis. Most cases of double-hit lymphoma are of GCB origin whereas most cases of double-expresser lymphomas are of ABC origin. Many studies have examined alternatives to R-CHOP therapy, including study of more intensive chemotherapy combinations or with addition of new agents such as ibrutinib or lenalidomide. To date, these approaches have largely failed to show improvements in disease control and survival for standard-risk patients and, therefore, R-CHOP remains the default standard of care for initial treatment of most patients. Published studies of consolidation with high-dose chemotherapy and autologous stem cell transplantation (ASCT) following R-CHOP induction have also been largely negative. In particular, ASCT does not abrogate the negative prognostic impact of C-MYC translocations. In retrospective study, no difference in relapse-free and overall survival with ASCT has been identified in double hit patients who received intensified upfront treatment regimens such as DA-EPOCH-R (dose adjusted EPOCH-R) or HyperCVAD-R. However, a survival benefit for ASCT has been noted in double hit patients treated with R-CHOP, emphasizing the inferior outcomes with R-CHOP in this specific patient population. Patients who relapse after achieving a remission may be cured with high-dose chemotherapy and ASCT, which is standard therapy if relapsed disease remains responsive to regular doses of chemotherapy. In the pre-rituximab era, cure rates with salvage chemotherapy and ASCT approached 50%. However, the large lymphoma CORAL study showed that patients who received rituximab with CHOP as part of upfront therapy had poor PFS (progression-free survival) of 21%. Patients who relapsed within a year of treatment with R-CHOP had very poor outcomes as well. This high-risk relapsed patient population is now the target of clinical trials with chimeric antigen receptor T-cell (CAR-T) therapy. In this type of cellular immunotherapy, patients’ autologous T cells are

CHAPTER 50  Disorders of Lymphocytes collected and genetically modified to express a chimeric T-cell receptor that recognizes one or more surface antigens, such as CD19, on the lymphoma cell. There are two FDA-approved CAR-T products for patients whose disease does not respond adequately to salvage chemotherapy, tisagenlecleucel and axicabtagene ciloleucel. Complete remission rates are in the order of 40% for a group of patients with otherwise poor outcomes. These therapies are being compared to ASCT in randomized trials. Despite promising efficacy, CAR-T cell therapy can result in considerable toxicities, including cytokine release syndrome, neurotoxicity, cytopenias, hypogammaglobulinemia, and infections. Patients are carefully monitored by a multidisciplinary team of physicians with experience in delivering cellular therapies. Mantle cell lymphoma. Mantle cell lymphoma (MCL) accounts for 3% to 10% of adult NHL in Western countries and is most common in older male patients. Caucasians have a higher incidence compared to other ethnicities. The median age at presentation is 68. Mantle cell lymphomas are mature B-cell neoplasms that appear to arise in the mantle zone of the lymphoid follicle and display a highly characteristic immunophenotype, expressing the CD5 antigen and other B-cell markers, but CD23 expression is absent, in contrast to CLL. Mantle cell lymphomas are characterized by a pathognomonic t(11;14) chromosomal translocation that juxtaposes the immunoglobulin heavy chain gene (14q32 locus) with the BCL1 gene, which encodes the growth-promoting protein cyclin D1. Demonstration of the translocation or expression of cyclin D1 protein by immunohistochemistry allows a definitive diagnosis in most cases. Pathologic classification as a blastoid or pleomorphic subtype and a high proliferation rate are features associated with more aggressive behavior and a poor outcome. TP53, Notch-1, and Notch-2 mutations are also associated with an aggressive clinical course. Two MCL subtypes are recognized in the WHO 2016 classification with different clinical manifestations and molecular pathways: Nodal MCL, the most common variant with an aggressive clinical course and multiple oncogenic mutations, and a leukemic, non-nodal subtype of MCL seen in 10% to 20% of patients, who have an indolent clinical course. These latter patients present with lymphocytosis, splenomegaly, and bone marrow involvement. Patients are usually treated with systemic chemotherapy combined with rituximab, but durable remissions are difficult to achieve. High-dose chemotherapy with autologous stem cell transplantation is often applied during first remission for younger patients and has been associated with more durable remissions (level II-1 evidence, which is evidence obtained from well-designed controlled trials without randomization). Patients with TP53 mutations do not benefit from highdose chemotherapy and are preferentially enrolled in clinical trials of new agents. Multiple agents and regimens are available for those who are not candidates for transplantation and patients with recurrent disease. The Bruton tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib and the BCL-2 inhibitor venetoclax have shown remarkable activity in relapsed MCL in combination with anti-CD20 antibodies. They are also being investigated as frontline treatment in combination with immunochemotherapy or in chemotherapy-free combinations. CAR-T cell therapy trials are ongoing in MCL and provide hope for patients who have progressed on the BTK inhibitors. Allogeneic SCT can provide a cure in 30% of patients with MCL and is a considered in relapsed patients and those with TP53 mutations. High-grade non-Hodgkin’s lymphomas. The two high-grade subtypes, Burkitt lymphoma (BL) and lymphoblastic lymphoma, are rare in the adult population. Nonetheless, these subtypes are important because they are potentially curable with appropriate therapy and often require urgent, inpatient treatment at the time of diagnosis due to their

513

highly aggressive nature, rapid growth, and tendency to develop tumor lysis on initiation of therapy. Lymphoblastic lymphoma in adults is an aggressive lymphoma that is considered the lymphomatous counterpart of acute T-cell lymphocytic leukemia. B-cell lymphoblastic lymphoma is less common. Lymphoblastic lymphoma usually afflicts young adult men and involves the mediastinum and bone marrow, with a propensity to relapse in the leptomeninges. Burkitt lymphoma is a rare B-cell lymphoma in adults that is highly aggressive with a propensity to involve the bone marrow and central nervous system. Burkitt lymphoma is characterized cytogenetically by the pathognomonic t(8;14) translocation that moves the MYC oncogene from chromosome 8 to a location close to the enhancers of the antibody heavy-chain genes (IGH locus) on chromosome 14. In central Africa, where Burkitt lymphoma is endemic in children, it is usually associated with EBV. However, in the United States, it is uncommon for sporadic Burkitt lymphoma to be EBV positive. Recently, Burkittlike lymphoma with 11q aberrations has been included in the WHO classification as a provisional entry. The 11q aberrations are particularly frequent in immunocompromised hosts, such as patients after organ transplantation. Recurrent ID3 mutations are found in about 30% of cases of BL, and ID3 has been recently implicated as a tumor suppressor gene with a role in pathogenesis. Burkitt lymphoma and lymphoblastic lymphomas require treatment with intensive multiagent chemotherapy, including intrathecal chemotherapy to prevent leptomeningeal relapse. These lymphomas undergo rapid tumor lysis on initiation of chemotherapy, and all patients must receive prophylaxis against tumor lysis syndrome before and during their first course of chemotherapy. Prophylaxis includes hydration, alkalinization of the urine, allopurinol, and consideration of rasburicase therapy for rapid lowering of elevated uric acid levels.

Prognosis A variety of prognostic variables have been identified for NHL, and specific prognostic schemes have been devised for common diseases, including DLBCL, follicular NHL, and mantle cell lymphomas. The predictors for poor survival for most subtypes include advanced stage (III/IV) at onset, involvement of multiple extranodal sites of disease, elevated LDH, B symptoms (e.g., fever, night sweats, weight loss), and poor performance status. The International Prognostic Index (IPI) stratifies patients based on age, performance status, stage, and number of extranodal sites. The likelihood of cure and long-term, disease-free survival ranges from more than 75% for patients with one or no adverse factors to less than 50% for patients with four or more adverse factors. Factors associated with shortened survival in follicular NHL include older age, advanced stage, anemia, multiple lymph node sites (more than four), and elevated LDH levels. Patients with three or more of these factors have a median survival of 5 years, roughly one half of that of patients with zero or one risk factor. Cytogenetic and molecular abnormalities that result in increased lymphoma cell proliferation and survival are taking center stage as prognostic variables, with some incremental improvement in outcomes with aggressive upfront treatment strategies and cellular therapies. Aggressive T-cell lymphomas usually fare more poorly than B-cell NHL, and patients are typically considered candidates for investigational studies and upfront transplantation. Anaplastic large cell lymphoma (ALCL) ALK+, however, has a favorable outcome with chemotherapy alone. The anti-CD30 antibody-drug conjugate brentuximab vedotin has strong activity in ALCL and other types of T-cell lymphomas that express CD30.

514

SECTION VIII  Hematologic Disease

For a deeper discussion of these topics, please see Chapter 176, “Non-Hodgkin’s Lymphomas,” in Goldman-Cecil Medicine, 26th Edition.

Hodgkin Lymphoma Hodgkin’s lymphoma (HL) is a node-based lymphoid malignancy characterized by the neoplastic Reed-Sternberg (RS) cell in an inflammatory background. Hodgkin’s lymphoma accounts for 10% of lymphomas, with about 8110 new cases diagnosed in the United States in 2019, and it is the most common lymphoma among young adults. The peak incidence of HL occurs between the ages of 20 and 35. The incidence of HL and death rate have declined in the past decade. The cause of Hodgkin’s lymphoma remains enigmatic. Risk factors include a history of infectious mononucleosis, high socioeconomic status, immunosuppression (e.g., HIV infection, allograft transplantation, immunosuppressive drugs), and autoimmune disorders. Although EBV is frequently detected in patients, a direct causal role has not been established.

Pathology Hodgkin’s lymphoma is diagnosed by identifying the malignant RS cell in involved lymphoid tissue. The classic RS cell is large and binucleate, with each nucleus containing a prominent nucleolus, suggesting the appearance of owl eyes. Although the cellular origin of the RS cell was debated for decades, molecular studies have confirmed that RS cells are B cells with clonal rearrangement of the germline IG locus. Unlike NHL, the bulk of the infiltrate in lymph nodes in HL is usually composed of benign reactive inflammatory cells, and the RS cells can be difficult to find. Immunophenotyping of RS cells shows CD30 (Ki-1) and CD15 positivity and negative CD20, CD45, and cytoplasmic or surface immunoglobulin. EBV is identified in the RS cells in about 50% of cases. The pathologic subtypes of classic HL include four variants—nodular sclerosing (NS), mixed cellularity (MC), lymphocyte depleted (LD), and lymphocyte rich (LR)—plus the non-classic variant, nodular lymphocyte-predominant (NLP). The NS form is the most common variant (60% to 80%) and is characterized by fibrous bands separating the node into nodules and by the lacunar type of RS cells. It is the predominant type encountered in adolescents and young adults and typically involves the mediastinum and supradiaphragmatic nodal sites. In the MC type (15%), band-forming sclerosis is absent, and RS cells are easily identified in a diffuse inflammatory infiltrate that is more heterogeneous than that seen in the NS variant. The LR variant (5%) is characterized by classic RS cells in a background of small lymphocytes. LD is a rare variant ( IgD; ± free light chain or light chain alone (κ > λ) IgG > IgA > IgD; ± free light chain or light chain alone (κ > λ) IgA > IgG > IgD; ± free light chain or light chain alone (κ > λ) IgM ± free light chain (κ > λ) γ, α, μ heavy chain or fragment Free light chain (λ > κ) IgG > IgM > IgA, usually without urinary light-chain secretion

Other B-Cell Neoplasms Chronic lymphocytic leukemia B-cell non-Hodgkin’s lymphomas; Hodgkin’s disease

M protein occasionally secreted; IgM > IgG M protein occasionally secreted; IgM > IgG

Nonlymphoid Neoplasms Chronic myelogenous leukemia Carcinomas (e.g., colon, breast, prostate)

No consistent patterns No consistent patterns

Autoimmune or Autoreactive Disorders Cold agglutinin disease Mixed cryoglobulinemia Sjögren’s syndrome

IgM κ most common IgM or IgA IgM

Miscellaneous Inflammatory, Storage, or Infectious Disorders Lichen myxedematosus IgG λ Gaucher’s disease IgG Cirrhosis, sarcoid, parasitic diseases, renal acidosis No consistent pattern Ig, Immunoglobulin. Modified from Salmon SE: Plasma cell disorders. In Wyngaarden JB, Smith LH Jr, editors: Cecil Textbook of Medicine, ed 18, Philadelphia, 1988, WB Saunders, p 1026.

and MRI are considered to further evaluate bone disease and may be necessary for patients with oligosecretory or nonsecretory disease to define disease and evaluate after therapy. Conventional bone scans are less useful due to the osteolytic nature of myeloma. About 20% of patients with multiple myeloma do not have detectable serum M protein by standard electrophoresis but have circulating free light chains that may be detectable by serum free light-chain assays. Free light chains may appear in the urine (i.e., Bence Jones protein) and can also be detected in a 24-hour urine collection by urine protein electrophoresis. Free light-chain assays are quite sensitive and may provide measurement of clonal protein in patients thought to have non-secretory disease by other methods. Free light chains have a relatively short half-life (2 to 6 hours) in the circulation compared with a half-life of weeks for intact immunoglobulin molecules and may therefore be used to obtain a more rapid assessment of disease response once therapy is initiated. In rare cases, patients may have true non-secretory myeloma with no detectable serum or urine M protein by any assay. Clinical presentation. The clinical manifestations of multiple myeloma are the direct effects of bone marrow and bone infiltration by malignant plasma cells, the systemic effects of the M protein, and the effects of the concomitant deficiency in humoral immunity that occurs in this disease. The most common symptom is bone pain. Bone radiographs typically show pure osteolytic punched-out lesions, often in association with generalized osteopenia and pathologic fractures. Bony lesions can show as expansile masses associated with spinal cord compression. Hypercalcemia caused by extensive bony involvement

is common in myeloma and may dominate the clinical picture. Anemia occurs in most patients as a result of marrow infiltration and suppression of hematopoiesis and causes fatigue; granulocytopenia and thrombocytopenia are less common. Patients with myeloma are susceptible to bacterial infections because of impaired production and increased catabolism of normal immunoglobulins. Gram-negative urinary tract infections are common, as are respiratory tract infections caused by Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Klebsiella pneumoniae. Renal insufficiency occurs in about 25% of patients with myeloma. The cause of renal failure is often multifactorial; hypercalcemia, hyperuricemia, infection, and amyloid deposition can contribute. Direct tubular damage from light-chain excretion also occurs. Because of their physicochemical properties, M proteins can cause a host of diverse effects, including cryoglobulinemia, hyperviscosity, amyloidosis, and clotting abnormalities resulting from interaction of the M protein with platelets or clotting factors. Several staging or classification systems exist for myeloma. The Revised International Staging System (R-ISS) for myeloma identifies three stages with distinct prognoses based on β2-microglobulin and albumin levels, LDH, and cytogenetic/FISH abnormalities (Table 50.7). Treatment. Most patients with myeloma exhibit symptomatic, advanced-stage disease and require therapy. Patients with asymptomatic myeloma may have an indolent course and do not always require immediate therapy. Disease progression occurs at a rate of 5% to 10% per year, and patients should be monitored for disease progression

CHAPTER 50  Disorders of Lymphocytes

TABLE 50.7  Revised International Staging

System for Multiple Myeloma

Survival Rate at 5 Years (Months)

Stage

Criteria

I

B2M 5.5 mg/L 40 High-risk chromosomal abnormalities or elevated LDH

II III

Palumbo A et al. Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol, 2015;33:2863. High-risk chromosomal abnormalities include deletion 17p and/or translocation t(4;14) and/or t(14;16). B2M, β2-Microglobulin.

by serial quantification of M protein and serum free light chains and evaluation for disease-related signs or symptoms. For patients with solitary bone or extramedullary plasmacytomas, particularly in the head and neck region, local radiation therapy can induce long-term remissions and is the treatment of choice. Patients with a solitary plasmacytoma of bone are often found on routine MRI of the spine to have asymptomatic bone disease at other sites and should be treated as symptomatic myeloma. Patients with symptomatic myeloma require systemic therapy and meticulous supportive care. Although myeloma is not a curable malignancy, systemic therapy prolongs survival and dramatically improves quality of life. Options for treatment have expanded in the past two decades to include multiple novel compounds in three broad classes of agents, the immunomodulatory drugs (IMIDs), proteasome inhibitors, and monoclonal antibodies. These agents may be used as single agents or in combinations for more intensive therapy. The novel agents are typically administered in combination with high doses of dexamethasone, which is a potent antimyeloma therapy. The IMIDS include thalidomide, lenalidomide, and pomalidomide. Proteasome inhibitors include bortezomib, carfilzomib, and ixazomib. The anti-CD38 monoclonal antibody daratumumab was approved for use in the United States in 2015. These agents have largely supplanted traditional chemotherapeutic agents as the cornerstone of initial and secondary therapies because they are efficacious and well tolerated. Multiple combination regimens have been devised that also incorporate chemotherapeutic agents in modest doses. Thalidomide is the first-in-class IMID and was initially used as a sedative in the United Kingdom in the 1960s, but it was found to cause birth defects (phocomelia) when used to combat nausea during pregnancy. The antiangiogenic properties of thalidomide subsequently led to its development as an anticancer agent. The molecular target of the IMID class was recently elucidated as cereblon, an E3 ligase protein crucial to the activity of B cell–specific transcription factors that influence myeloma cell viability. The IMIDs are typically used in combination with dexamethasone, and when used as initial therapy, they have good tolerability and result in high response rates. Toxicity related to thalidomide includes peripheral neuropathy, constipation, somnolence, and rash. Later-generation IMIDs have a more favorable side effect profile. Myelosuppression is more likely, but neuropathy and constitutional symptoms occur less frequently.

519

The second-generation IMID lenalidomide is more commonly used in North America due to its favorable tolerability. A troublesome and unique side effect of the IMID-steroid combination programs is development of deep vein thrombosis in up to 25% of patients, and some form of preventative therapy is required. Bortezomib is the first-in-class proteasome inhibitor and is an important therapy for patients with adverse cytogenetic risk factors. Bortezomib is typically administered subcutaneously and may cause thrombocytopenia, asthenia, and neuropathy. Most patients respond to initial therapy with a reduction in bone pain, hypercalcemia, and anemia in association with a decline in the M protein level. The selection of initial therapy depends on stage, cytogenetic risk, and candidacy for high-dose chemotherapy and autologous stem cell transplantation. The use of high-dose chemotherapy with alkylating agents followed by autologous peripheral stem cell infusion during first or second remission improves progression-free survival and quality of life compared with conventional therapy. Although this approach is not curative, it does represent an important treatment option for some patients and has an acceptable toxicity profile, even in older patients. Allogenic stem cell or bone marrow transplantation may be associated with durable remission in selected patients, but it carries a high nearterm risk of morbidity and mortality. Patients who experience relapse after standard therapy or transplantation may be treated with alternative chemotherapy regimens or with novel combination therapies, including newer agents and chemotherapy drugs. The first-in-class selective inhibitor of nuclear export, selinexor was recently added to the antimyeloma armamentarium for patients with relapsed or refractory disease as a fifthline therapy. CAR-T cell therapy has shown high response rates in clinic trials and is expected to become available as a standard therapy soon. Supportive care directed toward anticipated complications of myeloma is an important aspect of management. Bone resorption can be reduced with regular injections of the diphosphonates zoledronic acid or pamidronate, reducing pain and pathologic fractures. The monoclonal antibody denosumab targets RANKL, inhibiting osteoclast activity, and may also be used to treat bone disease. Bony lesions, particularly those involving weight-bearing bones, may require palliative irradiation for controlling pain and preventing pathologic fractures. Vertebral bony lesions may lead to spinal cord compression, with increasing back pain and neurologic symptoms. Symptoms suggesting cord compression require prompt evaluation with spinal MRI and, if necessary, local irradiation of involved areas. Avoidance of nephrotoxins, including intravenous contrast media, is important to prevent renal failure. All patients should receive pneumococcal and H. influenzae vaccines, and intravenous gamma globulin may be useful in preventing recurrent infections in patients with profound hypogammaglobulinemia. Use of erythropoietin may alleviate anemia and decrease the need for blood transfusions in patients with treatment-related anemia or concomitant renal insufficiency. Prognosis. Multiple myeloma is considered incurable, but the overall survival of these patients has improved considerably with the use of newer agents and autologous stem cell transplantation. The fiveyear survival as reported by the SEER database is 52.2%. Prognosis depends on stage of disease and cytogenetic profile. Patients with an adverse karyotype, including t(14;16), t(4;14), and 17p deletion, have a less favorable prognosis and are considered for more intensive therapies or clinical investigation. Adverse factors also include advanced stage, impaired renal function, elevated LDH levels, depressed serum albumin levels, and elevated β2-microglobulin levels.

Waldenström’s Macroglobulinemia Waldenström’s macroglobulinemia (WM) is a malignancy of plasmacytoid lymphocytes that secrete large quantities of IgM. It is a chronic

520

SECTION VIII  Hematologic Disease

disorder affecting elderly patients (median age 64 years) that shares features of the low-grade lymphomas and myeloma. Unlike myeloma, Waldenström’s macroglobulinemia is associated with lymphadenopathy and hepatosplenomegaly, and although bone marrow involvement invariably occurs, lytic lesions and hypercalcemia are rare. Diagnostic work-up for WM should include polymerase chain reaction analysis for mutation in the MYD88 gene, which is present in most patients and carries diagnostic and therapeutic relevance. The major clinical manifestations of WM include symptomatic anemia and the hyperviscosity syndrome caused by the physical properties of IgM. In contrast to IgG, IgM remains largely confined to the intravascular space, and as IgM levels rise, plasma viscosity increases. Epistaxis, retinal hemorrhages, dizziness, confusion, and congestive heart failure may occur as a result of the hyperviscosity syndrome. About 10% of IgM proteins have properties of cryoglobulins, and patients show symptoms of cryoglobulinemia or cold agglutinin syndrome demonstrated as acrocyanosis, Raynaud’s phenomenon, and vascular symptoms or hemolytic anemia precipitated by exposure to cold. Some patients with WM may develop a peripheral neuropathy that may antedate the appearance of the neoplastic process. The approach to and treatment of WM is similar to those of other low-grade B-cell lymphomas. The use of fludarabine or an alkylating agent, typically employed in combination with prednisone and rituximab, is effective in decreasing adenopathy and splenomegaly and controlling the M spike but is not curative. Rituximab has activity against WM, as has the proteasome inhibitor bortezomib. The use of rituximab as a single agent may be complicated by initial worsening of hyperviscosity in patients with high IgM burdens. The novel agent ibrutinib, an inhibitor of Bruton tyrosine kinase, is an effective oral therapy for Waldenström’s and may be combined with rituximab. Although complete remissions are rare, patients who respond to therapy have median survivals of 4 years, and some patients survive more than a decade.

Rare Plasma Cell Disorders Heavy-chain disease is a rare lymphoplasmacytoid neoplasm characterized by production of a defective heavy chain of the γ, α, or μ type. The clinical manifestations vary with the type of heavy chain secreted. The γ-type heavy-chain disease is associated with lymphadenopathy, Waldeyer ring involvement with palatal edema, and constitutional symptoms. The α-type heavy-chain disease, also known as Mediterranean lymphoma, is characterized by lymphoid infiltration of the small intestine with associated diarrhea and malabsorption. The μ-type heavy-chain disease is associated with CLL. Primary amyloidosis. Primary AL amyloidosis is a systemic illness characterized by deposition of immunoglobulin light chains in organs and tissue, resulting in an array of symptoms caused by organ dysfunction. Congestive heart failure, bleeding diathesis, nephrotic syndrome, and peripheral neuropathy are common complications. Patients with primary amyloidosis may respond to selected treatments similar to therapy for myeloma. The combination of bortezomib, cyclophosphamide, and dexamethasone is effective in some patients. Selected patients may respond well to high-dose chemotherapy and autologous stem cell support, but there are increased risks of morbidity and mortality if significant end-organ dysfunction such as cardiomyopathy occurs. It is important to note that not all amyloidosis is AL (light chain), and documentation of the source and type of amyloid protein is vital to appropriate management. POEMS syndrome. POEMS syndrome is a rare disorder characterized by polyneuropathy, sclerotic bone lesions, endocrinopathy, monoclonal gammopathy, and skin lesions. The cause of POEMS syndrome is unknown, but the disease may be

progressive, causing severe disability, third spacing of fluid, and elevated vascular endothelial growth factor (VEGF) levels. Monoclonal λ light chains are typically elevated. Limited bone disease may be treated with radiotherapy. High-dose therapy and autologous stem cell transplantation is effective in patients with extensive disease. For a deeper discussion of these topics, please see Chapter 178, “Plasma Cell Disorders,” and Chapter 179, “Amyloidosis,” in Goldman-Cecil Medicine, 26th Edition.

CONGENITAL AND ACQUIRED DISORDERS OF LYMPHOCYTE FUNCTION Several congenital disorders affect lymphocyte maturation or function, resulting in immunodeficiency disorders. Acquired disorders of lymphocyte function are far more common than congenital disorders. HIV infection is the most important infectious cause of acquired immunodeficiency (see Chapter 103). Patients with HIV infection are at increased risk for NHL. NHLs that occur in the setting of HIV have diffuse, aggressive B-cell histology and include DLBCL and Burkitt lymphoma. They are frequently associated with EBV infection and are often advanced stage (III or IV) at diagnosis, with extranodal sites of involvement. Patients with HIV-associated NHL are potentially curable with the multidrug chemotherapy regimens used for treating NHL found in the general population. Treatment of the underlying HIV infection with highly active antiretroviral therapy (ART) has improved the outcome and prognosis of patients with HIV-associated NHL. Patients who have undergone allogeneic organ transplantation require potent immunosuppressive drugs (e.g., cyclosporine, tacrolimus, mycophenolate, corticosteroids, methotrexate) to prevent graft-versushost disease in the case of bone marrow transplantation or allograft rejection in the case of solid organ transplantation. These medications cause defects in T-cell function with an associated immunodeficiency state, which increases risk for a post-transplant lymphoproliferative disorder (PTLD). PTLD is an EBV-associated lymphoproliferative disorder characterized by a polymorphous or monomorphous population of B cells that can be monoclonal or polyclonal. Patients are treated by reducing doses of immunosuppressive drugs whenever possible. Patients with polymorphous disease early after organ transplantation may respond well to this approach. Patients who are not candidates for withdrawal of immunosuppression because of allograft rejection or who develop late monophorphic disease may respond better to treatment with rituximab alone or in combination with chemotherapy.

SUGGESTED READINGS Canellos GP, Anderson JR, Propert KJ, et al: Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD, N Engl J Med 327:1478–1484, 1992. Cheson B, Fisher R, Barrington S, et al: Recommendations for initial evaluation, staging, and response assessment of Hodgkin and nonHodgkin lymphoma: the Lugano classification, J Clin Oncol 32:3059–3068, 2014. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma, N Engl J Med 346:235–242, 2002. Dispenzieri A: POEMS Syndrome: 2019 Update on diagnosis, riskstratification, and management, Am J Hematol 94(7):812–827, 2019. Engert A, Plütschow A, Eich HT, et al: Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma, N Engl J Med 363:640–652, 2010. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced nonHodgkin’s lymphoma, N Engl J Med 328:1002–1006, 1993.

CHAPTER 50  Disorders of Lymphocytes Geisler CH, Kolstad A, Laurell A, et al: Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group, Blood 112:2687–2693, 2008. Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin’s disease. International prognostic factors project on advanced Hodgkin’s disease, N Engl J Med 339:1506–1514, 1998. Howlader N, Noone AM, Krapcho M, et al (eds): SEER Cancer Statistics Review, Bethesda, MD, 1975-2016, National Cancer Institute, based on November 2018 SEER data submission, posted to the SEER web site. https://seer.cancer.gov/csr/1975_2016/. Accessed April 2019. Kyle RA, Therneau TM, Rajkumar SV, et al: A long-term study of prognosis in monoclonal gammopathy of undetermined significance, N Engl J Med 346:564–569, 2002. Maloney DG, Grillo-Lopez AJ, White CA, et al: IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed lowgrade non-Hodgkin’s lymphoma, Blood 90:2188–2195, 1997. McSweeney PA, Niederwieser D, Shizuru JA, et al: Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing

521

high-dose cytotoxic therapy with graft-versus-tumor effects, Blood 97:3390–3400, 2001. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma, N Engl J Med 33:1540–1545, 1995. Rummel MJ, Niederle N, Maschmeyer G, et al: Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial, Lancet 381:1203–1210, 2013. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma, N Engl J Med 341:1565–1571, 1999. Swerdlow SH, Harris NL, Jaffe ES, et al: World Health Organization classification of tumours of hematopoietic and lymphoid tissues, revised ed 4, Lyon, 2017, IARC Press. Wang ML, Rule S, Martin P: Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma, N Engl J Med 369:507–516, 2013.

51 Normal Hemostasis Lauren Shevell, Alfred I. Lee

INTRODUCTION Hemostasis is the physiologic balance of procoagulant and anticoagulant forces that provide structural integrity of vasculature while maintaining circulating blood flow. Vascular damage initiates clotting, which results in a localized platelet-fibrin plug at the site of injury to prevent blood loss. This is followed by clot containment, wound healing, eventual clot dissolution, and tissue regeneration. In healthy individuals, procoagulant and anticoagulant reactions occur continuously and in a balanced fashion so that bleeding is contained while blood vessels simultaneously remain patent to deliver adequate organ blood flow. If any of these processes is disrupted, either from inherited defects or acquired abnormalities, disordered hemostasis may result in either bleeding diatheses or thromboembolic disease. Traditionally, hemostasis has been conceptualized in two parts: primary hemostasis, resulting in adhesion and activation of platelets, and secondary hemostasis, resulting in activation and regulation of the coagulation cascade. More recent studies, however, demonstrate a considerable amount of interplay between primary and secondary hemostatic components. This chapter briefly details the physiologic and interdependent mechanisms of vascular hemostasis, including the normal balance of procoagulant and anticoagulant functions of the blood vessel wall and platelets, receptor-ligand interactions that are critical for hemostasis, as well as the highly complex, interwoven pathways that represent the coagulation cascade.

VASCULATURE PHYSIOLOGY Blood flow in the arterial system differs from that in the venous system and imposes different coagulation requirements. In the pressurized arteries, relatively minor vascular damage can rapidly result in massive exsanguination; therefore, the procoagulant response in the arteries must rapidly arrest bleeding. Platelets are critical to the arterial response; they initially contain the blood loss and then provide an active surface for soluble coagulation factors to both localize and accelerate formation of fibrin for a strong fibrin clot. In contrast, the slower flow rates in the venous circulation produce slower bleeding, a feature that makes platelets less critical; instead, the balance of venous hemostasis is most dependent on the rate of thrombin generation. These differences are underscored clinically by the antithrombotic agents used in these distinct clinical settings: antiplatelet agents such as aspirin and clopidogrel are used to prevent coronary and cerebral artery thrombosis, whereas anticoagulants such as heparins, warfarin, and direct oral anticoagulants (e.g., direct thrombin inhibitors like dabigatran, or Xa inhibitors like rivaroxaban or apixaban) are used for the treatment and prophylaxis of venous disease.

522

Vascular endothelial cells (ECs) that line the luminal surfaces of blood vessels contribute both procoagulant and anticoagulant forces depending on circumstances. When the vasculature is intact, healthy ECs exert anticoagulant activity to maintain blood fluidity. This is done through several mechanisms. First, ECs act as a barrier, separating blood from subendothelial procoagulants such as tissue factor (TF) and collagen (Fig. 51.1A). ECs also contribute to hemostatic balance by secreting several products including prostacyclin, nitric oxide, adenosine diphosphatase, and tissue factor pathway inhibitor (TFPI). Prostacyclin and nitric oxide release by ECs leads to vascular smooth muscle relaxation, reducing shear injury. These chemicals also promote the generation of cyclic adenosine monophosphate (cAMP), thus inhibiting platelet activation and aggregation. Adenosine diphosphatase degrades extracellular platelet-released ADP, inhibiting platelet recruitment into the growing platelet clot. TFPI acts by blunting the initiation of the coagulation cascade (described in more detail in the “Termination of Clotting” section). When ECs are physically damaged or activated, their balance of coagulant properties is shifted to favor a procoagulant state. This is mediated by both the ECs themselves and subendothelial matrix that is exposed when the vascular wall is disrupted. Activated ECs express ligands on their surfaces allowing for platelet adhesion and increased inflammatory responses. These include E-selectin and P-selectin, β1 and β2 integrins, platelet EC adhesion molecule-1 (PECAM-1), and von Willebrand factor (VWF) multimers (Table 51.1). On the activated EC surface, VWF multimers localize and promote platelet adhesion, whereas integrins mediate adhesion and subsequent transendothelial migration of leukocytes into the tissues. After EC damage, the exposed subendothelial matrix also binds VWF multimers to further enhance platelet adhesion. Subendothelial procoagulant proteins such as thrombospondin, fibronectin, and especially collagen function both as ligands to capture platelets and as activators of adherent platelets. Collagen, in particular, is both a platelet ligand and a strong platelet agonist and causes platelets to undergo alpha and dense granule release and to express conformationally active ligands such as glycoprotein IIb/IIIa (GPIIb/IIIa, also known as integrin αIIbβ3) (described in detail later). Another critical procoagulant mediator exposed by EC damage is TF, which is constitutively expressed by subendothelial smooth muscle cells and fibroblasts. As outlined further later, TF is the major initiator of the soluble coagulation system that, along with activated platelets, results in the formation of a definitive platelet-fibrin clot.

VON WILLEBRAND FACTOR VWF is an essential component of coagulation. Produced by ECs and megakaryocytes, the VWF protein is stored within platelets in alpha granules and within ECs in rodlike granules known as Weibel-Palade

CHAPTER 51  Normal Hemostasis

Fluid velocity

Activation

Rolling

Firm adhesion Unactivated GPIIb/IIIa

Torque

Activated GPIIb/IIIa

Shape change

GPIb

Platelet

EC

VWF GPIb binding domain

A

Exposed subendothelial von Willebrand factor

VWF GPIIb/IIIabinding domain

Agonist receptor

Alpha granules

Fibrinogen

Shape change

Dense granules Surface connecting system

se

elea

ule r

Gran

Mitochondria

A A FXIII A A

COX COX

GPIIb/IIIa

Cyclooxygenase enzymes

Microtubules

B

GPIb-V-IX Fig. 51.1  (A) The adhesive interactions that produce stable platelet attachment to subendothelial von Willebrand factor (VWF). The initial attachment between platelet glycoprotein Ib (GPIb) and its binding domain on VWF is rapid but has a short half-life, and the result is a rolling movement caused by torque generated by flowing blood. The VWF-GPIb interaction produces transmembrane signaling that activates the platelet to change shape and simultaneously transforms GPIIb/IIIa into an activated conformation capable of binding to a distinct arginine-glycine-aspartate domain on VWF. This secondary adhesion causes the platelet to firmly adhere to the exposed subendothelial VWF. (B) The internal and external anatomy of a platelet. The platelet consists of several important external, transmembrane, and internal components that help to promote platelet activation, adhesion, aggregation/agglutination, and general coagulation factor–based hemostasis. The most important and most clinically relevant aspects of platelet anatomy are shown. Details regarding the steps leading to platelet activation and release of granules and cytosolic contents are discussed in the text. A, A subunits of factor XIII; COX, cyclooxygenase; EC, endothelial cell; FXIII, factor XIII; GP, glycoprotein complex.

GPIIb/IIIa

523

524

SECTION VIII  Hematologic Disease

TABLE 51.1  Properties of Endothelial Cell

Coagulants Procoagulant

Anticoagulant

Collagen Factor VIII Fibronectin Integrins Platelet-endothelial cell adhesion molecule-1 (PECAM-1) Selectins (E and P) Vasoconstriction von Willebrand factor

Vasodilation Adenosine diphosphatase Heparan sulfates Nitric oxide Prostacyclin Thrombomodulin Tissue factor pathway inhibitor Tissue plasminogen activator

bodies. In both platelets and ECs, VWF proteins multimerize in the Golgi apparatus; about 95% of VWF multimers are constitutively released into the plasma and can be detected on electrophoretic gels as high-, intermediate-, and low-molecular-weight VWF forms. The remaining 5% of VWF multimers are stored either in platelet alpha granules or in EC Weibel-Palade bodies in the form of ultra-large VWF multimers. Following platelet stimulation or EC damage, ultra-large VWF multimers are released into the plasma and have high affinity for platelets and subendothelial collagen, forming string-like structures that must then be cleaved into smaller VWF proteins for proper function. Cleavage of ultra-large VWF multimers is performed by a metalloproteinase, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). In addition to platelet and subendothelial collagen binding, VWF in the plasma serves as a second role in binding and stabilizing coagulation factor VIII and preventing its degradation. The importance of VWF is underscored clinically by von Willebrand disease (VWD), the most common inherited bleeding condition in the world, characterized by defects in either the amount or the activity of VWF protein; and alternatively by thrombotic thrombocytopenic purpura, an inherited or acquired disease arising from defects in ADAMT13 that lead to accumulation of ultralarge VWF multimers, causing microvascular thrombosis, platelet consumption, shearing of red blood cells and multiple end-organ complications.

PLATELET PHYSIOLOGY Platelets are anucleated cells measuring 2 to 4 μm in diameter and are derived from megakaryocyte cytoplasm (Fig. 51.1B). Each megakaryocyte contributes 1000 to 3000 platelets in its lifetime. After platelets are released into the circulation, they survive 7 to 10 days. The normal platelet count ranges between 150,000 to 450,000/μL; only approximately 7100 platelets/μL are required for hemostasis per day if vascular structures are intact (i.e., in the absence of any recent surgeries or trauma) and if there is no increase in normal platelet consumption (e.g., as might occur in sepsis or disseminated intravascular coagulation). The bleeding time, an in vivo measure of hemostasis, is usually less than 8 minutes if the platelet count is within the normal limit. It is used as a screening test for platelet function defects, VWD, and sometimes other bleeding disorders. The bleeding time is dependent on the platelet count and will naturally be prolonged if the platelet count falls to less than 100,000/μL. Therefore, in the setting of thrombocytopenia, a prolonged bleeding time cannot be used to determine whether bleeding is caused by abnormal platelet function, VWD, another bleeding problem, or thrombocytopenia. Because the bleeding time is an

operator-dependent, highly variable in vivo assay that causes trauma to patients, most laboratories now use the Platelet Function Analyzer-100 (PFA-100) (Fig. 52.2), which uses anticoagulated blood to examine the amount of time required for platelets to form a plug in response to either collagen and ADP or collagen and epinephrine (i.e., the “closure time”). The PFA-100 is similar to the bleeding time test in that both may be used to assess platelet function and to screen for VWD but are unable to distinguish between thrombocytopenia and abnormal platelet function when the platelet count is lower than 100,000/μL.

Platelet Activation In the setting of vascular injury, platelets are recruited to the area by exposure to local agonists (collagen, epinephrine and thrombin) and by release of agonists within platelets into the local microenvironment (ADP, thromboxane). The most potent platelet activators, collagen and thrombin, interact with their specific platelet receptors to strongly activate platelets. Epinephrine alone is not a powerful platelet agonist, but stimulation of the α-adrenergic receptor on platelets primes them for synergistic activation by relatively weak agonists such as ADP. Platelets also release activating compounds, including thromboxane A2 (TXA2), which is formed in the platelet cytosol after cyclooxygenase 1 (COX1)mediated cleavage of arachidonic acid, which is then released into the clot milieu. TXA2 is both a platelet agonist and vasoconstrictor and is rapidly degraded to its inert by-product, thromboxane B2. Notably, the exact roles of different platelet agonists depend on a spatial hierarchy within the platelet plug. Thrombin activates platelets within the core of the hemostatic plug, whereas ADP and TXA2 activate platelets in the loosely packed shell surrounding the core. Of particular clinical importance, platelet COX1 activity is irreversibly inhibited by aspirin, which blocks formation of TXA2 for the lifetime of the platelet through a covalent bond causing steric hindrance of the active site. In contrast, nonsteroidal anti-inflammatory drugs (NSAIDs) reversibly and competitively bind at the active site; thus, the antiplatelet effects of NSAIDs are dependent on the continual presence of plasma levels of the NSAID. COX2 is an induced isoform of the cyclooxygenase enzyme that is present within leukocytes and that mediates inflammation and pain. Mature platelets do not possess COX2 activity, providing the rationale for the development of selective COX2 inhibitors to decrease inflammation without increasing the bleeding risk of platelet dysfunction (as well as decreasing risk for gastrointestinal side effects, which will not be addressed here). However, ECs are reliant on COX2 activity to synthesize the antithrombogenic compound prostacyclin. Downregulation of prostacyclin, coupled with preserved platelet function, tips the hemostatic balance in favor of clot formation. In view of this, large-scale clinical trials have shown that highly selective COX2 inhibitors increase the likelihood of hypertension and vascular events including myocardial infarction and stroke.

Platelet Adhesion Platelet activation leads to a functional shape change of the platelet from a disk to an irregular sphere with pseudopod extensions, as well as exposure of platelet binding domains. This enhances platelet adhesion capabilities and maximizes the interaction of coagulation factors with the platelet surface. Initial platelet adhesion is primarily mediated by the glycoprotein 1b-IX-V (GP1b-IX-V) complex on the platelet surface binding to multimeric VWF, which is immobilized by adherence to exposed subendothelial collagen. The weak binding of GP1b-IX-V to VWF contributes to transmembrane signaling with downstream effects that include a change in platelet shape (see Fig. 51.1A) and a change in GPIIb/IIIa (integrin αIIbβ3) from a low-affinity to a highaffinity state, facilitating binding of the latter to fibrinogen and VWF (see Fig. 51.1B). A deficiency of the GP1b-IX-V complex leads to

CHAPTER 51  Normal Hemostasis Bernard-Soulier syndrome, a congenital bleeding disorder characterized by giant platelets that are dysfunctional. GPIIb/IIIa (integrin αIIbβ3) is a member of the integrin superfamily and the most abundant receptor on the platelet surface. Prior to platelet activation, the GPIIb/IIIa (αIIbβ3) receptor sits on the platelet surface and has low affinity for binding. However, upon platelet activation and its consequent conformational changes, the GPIIb/IIIa receptor adopts a high-affinity conformation that facilitates binding both to VWF, securing platelets strongly on the subendothelial surface, and to fibrinogen, linking platelets together and reinforcing the platelet plug. Further, after binding to VWF, the cytosolic side of the GPIIb/IIIa (αIIbβ3) receptor binds to the cytoskeleton of the platelet, fostering further changes to platelet shape change and spreading via cytoskeletal reorganization. These roles of GPIIb/IIIa (αIIbβ3) in platelet adhesion and platelet plug formation provide the rationale for use of GPIIb/IIIa (αIIbβ3) antagonists in treatment of coronary artery disease. Of note, mutations in the gene encoding GPIIb/IIIa (αIIbβ3) lead to Glanzmann thrombocythemia, another congenital bleeding disorder leading to platelet dysfunction.

Platelet Secretion After activation, dense granules and alpha granules within platelets fuse with the canalicular membrane and liberate their procoagulant contents into the extracellular fluid. Dense granules contain serotonin, ADP, ATP, ionized calcium, and histamine. Serotonin and ADP both activate and recruit platelets to sites of vascular injury. Additionally, serotonin, similarly to TXA2, acts as a vasoconstrictor. ADP acts purely as a platelet agonist through the G protein–linked P2RY12 receptor and has no vascoactive properties. The importance of dense-granule release is illustrated by the severe bleeding seen in patients with congenital dense-granule deficiencies such as Hermansky-Pudlak syndrome or Chediak-Higashi syndrome. Alpha granules contain numerous proteins including many adhesive molecules (fibrinogen, VWF, thrombospondin), cellular mitogens (platelet-derived growth factor, transforming growth factor beta), coagulation factors (factor V), and physiologically important receptors (P-selectin, αIIbβ3). The importance of platelet alpha granules is illustrated in patients with gray platelet syndrome, an inherited deficiency of alpha granules leading to bleeding. Other components within platelets, including factor XIII, are also released upon platelet activation and act as clot stabilizers (see Fig. 51.1B).

COAGULATION Coagulation Cascade Model The classical coagulation cascade (Fig. 51.2A), first described over 50 years ago, features two starting points, the intrinsic and extrinsic pathways, that flow in a step-wise waterfall of proteolytic reactions and converge in a common pathway. The common pathway culminates with the generation of thrombin, which converts fibrinogen to fibrin. Fibrin then cross-links platelets and strengthens the platelet plug. In the classical model, coagulation begins with the extrinsic pathway, which is initiated by the exposure of TF and activated factor VIIa, leading to activation of factor X in the common pathway. The intrinsic pathway is initiated by the activation of proteins circulating in plasma—namely, factor XII (Hageman factor), high-molecular-weight kininogen (HMWK, also known as Fitzgerald factor), and prekallikrein (PPK, also known as Fletcher factor). This pathway is also referred to as the contact activation pathway because these proteins are activated by contact with negatively charged surfaces. Factor XIIa and HMWK activate factor XI, leading to the activation of factor IX, which in conjunction with factor VIII activates factor X to initiate the common pathway (see Fig. 51.2AB). The importance of the intrinsic coagulation

525

cascade is demonstrated in patients with hemophilias, which are congenital bleeding disorders due to deficiencies in factor VIII (hemophilia A), factor IX (hemophilia B), or factor X (hemophilia C). Notably, all procoagulants are produced almost exclusively in the liver aside from factor VIII, which is produced in both liver sinusoidal cells and ECs, and VWF, which is produced in ECs and megakaryocytes. The procoagulant factors II, VII, IX, and X, and the anticoagulant proteins C and S, all undergo post-translational modification in the form of vitamin K–dependent g-carboxylation of the amino terminal domains, which is critical for calcium binding and determining the three-dimensional structure of proteins. The importance of vitamin K–dependent g-carboxylation is demonstrated by the anticoagulant warfarin, which acts by blocking vitamin K epoxide reductase, thereby reducing the generation of these specific proteins. In the classical coagulation model, the prothrombin time (PT) serves as a measure of extrinsic pathway activity while the activated partial thrombin time (aPTT) measures activity of the intrinsic pathway. Therapeutically, the PT and aPTT are used to guide warfarin and heparin dosing, respectively. Although the classical model of coagulation is workable for some clinical scenarios, more recent models have made strides to more accurately elucidate and depict the physiology and complex interplay of different components of coagulation.

Cell-Based Model of Coagulation The cell-based coagulation model (see Fig. 51.2B) has largely been established as the most physiologically accurate in vivo model of coagulation. This model proposes that coagulation takes place on the surfaces of different cells in a three-step fashion: initiation, amplification, and propagation. The initiation phase begins as exposed TF on the EC surface binds to picomolar amounts of factor VIIa, present in the circulation at all times. The VIIa-TF complex (termed the extrinsic Xase) activates factors IX and X. The conversion of a small amount of X to Xa produces a tiny amount of thrombin. The nearly trivial amount of thrombin sparks feedback to activate factor XI, leading to amplification of thrombin generation. Factor VIII, conveniently brought to the bleeding site by its carrier VWF, is also activated by thrombin, a step that causes release of VWF. Factor VIIIa then complexes with the picomolar amounts of factor IXa generated by the TF-VIIa complex during the initiation phase to create the VIIIa-IXa complex, known as the intrinsic Xase complex. Notably, IXa generation by the TF-VIIa complex is limited by TFPI, so factor IX is secondarily activated by platelet-bound factor XIa (catalyzed by factor XIIa in conjunction with high molecular weight kininogen), providing sufficient amounts of factor IXa in the intrinsic Xase complex. The formation of this complex on the platelet surface heralds the propagation phase, and the switch of the primary path of Xa generation from the TF-VIIa complex, the extrinsic Xase complex, to the intrinsic Xase. This switch is of significant kinetic advantage, with the intrinsic Xase complex exhibiting a 50-fold higher efficiency than the extrinsic Xase. More than 96% of the total thrombin that is generated during clotting occurs during the propagation phase. The bleeding diathesis associated with hemophilia is a testament to the physiologic importance of the exuberant thrombin generation engendered by the switch from extrinsic to intrinsic Xase. The aPTT, which measures the initiation phase of clotting begun by an artificial in vitro stimulant, is prolonged by severe deficiencies of either VIII or IX, but it is thrombin generation during the propagation phase, a function not evaluated by the aPTT, that is more impaired in hemophilia. Thrombin generated during the initiation phase is a potent platelet activator. The activated platelet expresses receptors for VIIIa and IXa, and binding of these active proteases in complex with membrane phosphatidylserine enhances the binding of the enzyme’s substrate,

526

SECTION VIII  Hematologic Disease Extrinsic pathway

Intrinsic pathway Kallikrein

FVII

FXIIa

FVIIa

Prekallikrein

FXII

Ca2+ FXIa

FXI

Release Tissue damage

Tissue factor

FIXa

FX

FXa

FX

FV Ca FII

2+

Common pathway

FIIa

Fibrinogen

A

FIX

FVIII Ca2+

Ca2+

Fibrin

Initiation phase FVII

FVIIa—TF Ca

Propagation phase

2+

Release Tissue damage

FXI

FXIa

Tissue factor (TF) Ca2+ FX

FIX

FIXa

FXa

FVIII Ca2+ FX

Ca2+ FV

FXa Ca2+

FV FII

FIIa

FII

(Thrombin)

B

Fibrinogen

Fibrin

Fig. 51.2  (A) The classic view of the coagulation cascade. The laboratory-defined extrinsic and intrinsic pathways allow monitoring of anticoagulation by serial measurements of the prothrombin time (PT) and partial thromboplastin time (PTT), respectively. The PT primarily monitors factor VII activity, whereas the PTT is the best measure of XI and the hemophilic factors IX and VIII; both assays will detect deficiency of the common pathway factors (X, V, and II). (B) In the more modern view of the coagulation cascade, initiation of clotting begins with exposure to tissue factor (TF), which combines with small amounts of circulating factor (F) VIIa to form the extrinsic tenase (Xase) complex and generate FXa. FXa forms the prothrombinase complex with FVa and FII, generating small amounts of thrombin (FIIa), which begins to cleave fibrinogen into weak fibrin monomers in the initiation phase of coagulation. Thrombin’s ability to activate factors, especially on the activated platelet surface, is responsible for propagation of the coagulant response. Thrombin generates FXIa, which in turn activates FIX; the TF-VIIa complex (before it is shut down by TFPI) also generates FIXa. Thrombin-activated FVIIIa then combines with IXa to form the intrinsic Xase complex, generating large amounts of FXa and prothrombinase complex on the platelet surface to further amplify thrombin generation. The large amounts of thrombin now generate enough fibrin monomers to form stable polymers and fibrin clot. HMWK, High-molecular-weight kininogen; PK, prekallikrein; TFPI, tissue factor pathway inhibitor.

factor X, increasing the kinetic efficiency of the intrinsic Xase complex. The activated platelet (Table 51.2) also enhances coagulation by supplying the developing clot with an activated platelet surface membrane (i.e., anionic lipids, primarily phosphatidylserine) and abundant factor V, stored in platelet granules. Factor V is then promptly activated to Va by the trace amount of thrombin produced by TF-VIIa complex. In

combination with membrane phospholipids and calcium, activated Xa and its cofactor Va form the prothrombinase complex, which cleaves prothrombin to thrombin. The prothrombinase complex is several hundred thousand times more efficient at converting prothrombin to thrombin than free factor Xa acting on prothrombin alone. The role of the procoagulant effects of activated platelets on thrombosis is

CHAPTER 51  Normal Hemostasis highlighted by Scott syndrome, a condition in which the platelet phospholipid membrane does not change in response to activation, and thus phosphatidylserine is not rearranged from the inner membrane surface to the outer membrane surface, leading to decreased thrombin generation and prolonged bleeding as a result of platelet dysfunction.

Of note, polyphosphate has been shown to have a critical role in coagulation and acts as a procoagulant, initiating clotting through several mechanisms. First, polyphosphate contains numerous negatively anionic charged surfaces leading to activation of plasma factor XII, HMWK, and PPK that set off the intrinsic pathway. Polyphosphate also mitigates the inhibitory effects of TFPI, enhances the activation of factor V and factor IX, and leads to thickened fibrin fibrils by increasing fibrin polymerization.

TABLE 51.2  Procoagulant Properties of

Platelets

Termination of Clotting

Receptor-Ligand Interactions Promoting Adhesion aGPIb-IX-V-VWF bGPIIb/IIIa-fibrinogen and GPIIb/IIIa-VWF cGPIa/IIa-collagen dP-selectin–P-selectin glycoprotein ligand-1

The rapid production of thrombin at a localized site of vascular injury could quickly lead to extensive clotting if left unchecked; thus, there are several mechanisms in place to ensure proper modulation. This includes endogenous inhibitors of the coagulation pathway (Fig. 51.3) that limit coagulation initiation, dilution of procoagulants at the site of injury by flowing blood, and removal and inactivation of activated factors. Endogenous anticoagulants can either prevent thrombin generation or inactivate formed thrombin. Among endogenous anticoagulants that target thrombin generation, the earliest in the coagulation process is TFPI. TFPI acts by both inactivating factor Xa and the TF-VIIa complex. TFPI is constitutively released by ECs into the microvasculature. Nascent TFPI has direct activity only against Xa, but after exposure to Xa, TFPI acquires activity against the TF-VIIa complex. Notably, C1 esterase inhibitor also inhibits factors early in the coagulation cascade, including factor XIIa and PK, although a deficiency of C1 esterase inhibitor, which causes angioedema, does not result in a hypercoagulable state. The most important natural anticoagulant is antithrombin (AT), which inactivates several activated factors in the clotting cascade including factors IIa (thrombin), IXa, Xa, XIa and XIIa. AT is physiologically present at more than twice the concentration of the highest local thrombin concentration that can be reached during clotting. AT activity against thrombin is potentiated 1000-fold by endogenous EC-associated heparin sulfate proteoglycans. This is also the mechanism of anticoagulation employed by the anticoagulant medications

Receptor-Ligand Interactions Mediating Activation GPV-thrombin GPVI-collagen Secreted Alpha-Granule Proteins Ligands (fibrinogen, fibronectin, thrombospondin, vitronectin, von Willebrand factor) Enzymes (α2-antiplasmin; factors V, VIII, and XI) Antiheparin (platelet factor 4) Secreted Dense-Granule Agonists Adenosine diphosphate, serotonin Components and Functions of Platelets That Promote Coagulation Thromboxane A2 formation, phosphatidylserine expression GP, Glycoprotein. aGPIb-IX-V complex is also known as CD42. bGPIIb/IIIa (integrin α β ) complex is also known as CD41. IIb 3 cGPIIa is also known as CD29. dP-selectin is also known as CD62P and P-selectin glycoprotein ligand-1 as CD162.

TISSUE FACTOR

IXa XI

VIIa

XIa IXa

X

VIIIa VIII

TF • VIIa TFPI V

Xa Va•Xa PROTHROMBIN

PS

THROMBIN

Va

MBIN

RO ANTITH

APC FIBRIN MONOMER

FIBRINOGEN

PC

527

Thrombomodulin

Fig. 51.3  Endogenous anticoagulant pathways. Tissue factor pathway inhibitor (TFPI) shuts off tissue factor (TF) stimulation and blocks the TF-VIIa-X complex; in addition, the clotting cascade is further downregulated by the natural anticoagulants. This inhibition is partly generated by thrombin, which activates thrombomodulin. Circulating antithrombin inhibits thrombin activity and Xa generation of thrombin. The complex of thrombin and thrombomodulin activates protein C (PC) to become activated protein C (APC), which combines with protein S (PS) to cleave and inactivate VIIIa and Va, further blocking thrombin generation.

528

SECTION VIII  Hematologic Disease

heparin, low-molecular-weight heparin, and fondaparinux. Platelet surface membranes and platelet factor 4 protect thrombin from inactivation at the clot. However, any thrombin that escapes into the circulation is immediately inhibited by AT, and free thrombin is neutralized instantaneously. Therefore, early thrombin generation is critically dependent on protection by the activated platelet membrane to allow sufficient time to make the transition from initiation to propagation phase. Notably, during the initiation phase, platelet-bound factor Xa is protected from inactivation by both TFPI and AT. Activated protein C (APC) has anticoagulant, anti-inflammatory, and profibrinolytic properties that make it an important regulator of both thrombosis and inflammation. Like TFPI, protein C becomes activated only after coagulation is underway. Formed thrombin binds to thrombomodulin, a proteoglycan associated with endothelial and monocyte cell surfaces. Thrombomodulin-bound thrombin loses its procoagulant abilities such as activating platelets and fibrin clot formation and instead activates protein C. On the EC surface, nascent protein C binds to EC protein C receptor (EPCR), which positions it for activation by the adjacent thrombomodulin-bound thrombin. In a reaction that is enhanced by EPCR and protein S, APC inactivates factors VIIIa and Va (components of the Xase and prothrombinase complexes, respectively), thereby limiting procoagulant self-amplification. Notably, a common mutation in factor V known as factor V Leiden results in the arginine at position 506 being replaced by glutamine, rendering the mutated factor V resistant to cleavage by APC and resulting in a hypercoagulable state. As with other coagulation factors, the activated platelet membrane protects VIIIa and Va from APC inactivation. In addition to its effects on thrombin generation, APC neutralizes plasminogen activator inhibitor-1 (PAI-1, described further in the fibrinolysis section) to enhance clot remodeling. APC has anti-inflammatory properties as well; recombinant APC reduces production of tumor necrosis factor-α after endotoxin challenge, and protein C– deficient mice exhibit higher levels of proinflammatory cytokines. Several other molecules have been identified as contributing to antithrombotic effects. As discussed previously, prostacyclin and nitric oxide, both released from ECs, exert antithrombotic properties through vasodilation and inhibition of platelet aggregation and adhesion. Poly(adenosine 5′-diphosphate [ADP]-ribose) polymerase (PARP) protein regulates TF mRNA levels. Activated macrophages and monocytes express TF on their surfaces, and modulating TF mRNA may prevent some degree of thrombosis in the setting of inflammation. Thrombospondin 5 (also known as cartilage oligomeric matrix

protein), an extracellular matrix protein, has been shown to inhibit thrombin and thrombin-dependent platelet aggregation in mouse models.

Fibrin Clot Architecture The architecture of the fibrin clot is surprisingly variable. Although genetic factors unquestionably play a role in determining clot structure, two dominant factors are the local concentrations of thrombin and fibrinogen, whose reactions yield the fibrin strands. A thrombin-rich microenvironment typically results in thinner, more tightly cross-linked fibers, making the overall fibrin clot virtually impermeable to lytic enzymes. In thrombin-poor locations, the fibrin strands are thicker and the structure more porous, making the clot vulnerable to thrombolysis. Similarly, high fibrinogen concentrations are associated with larger thrombi whose tight, rigid meshwork makes them less deformable and more resistant to lysis. Low fibrinogen concentrations produce a less compact clot that is highly lysis prone. As mentioned previously, one of the major roles of polyphosphate on thrombosis is contributing to thicker fibrin fibrils. Factor XIII plays a critical role in stabilization of the forming clot. Factor XIII circulates in the plasma and is also stored within platelets (see Fig. 51.1B). Notably, 50% of the total fibrin-stabilizing activity in blood resides in the platelet and is released by activation. Thrombinactivated factor XIIIa binds to fibrin and cross-links the fibrin units, thereby rendering them less permeable and more resistant to lysis. Furthermore, factor XIIIa cross-links the major plasmin inhibitor, α2-antiplasmin, directly to fibrin, positioning it for neutralization of any invading plasmin.

Fibrinolysis The fibrinolytic system (Fig. 51.4) operates to restore patency and prevent fibrin from occluding healthy vessels. During clot formation, factor Xa and thrombin stimulate healthy ECs to release tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), both of which activate plasminogen to plasmin. Plasmin then cleaves the fibrin strands of the platelet plug, producing fibrin degradation products, including D-dimer. Additionally, factor XIIIa is also cleaved by plasmin, further destabilizes the platelet plug by reducing fibrin cross-linking. The vast excess of plasminogen in the plasma dictates that under normal circumstances, the concentrations of t-PA and u-PA comprise the rate-limiting step for plasmin formation. The kinetic efficiency of

D-dimer Plasmin Fibrin clot polymer

Plasmin

PAI-1

α2-antiplasmin XIIIa

EC

EC

EC

Plasminogen

EC

t-PA

EC

Fig. 51.4  Balanced fibrinolysis limits the platelet-fibrin clot. The platelet plug and fibrin matrices are strengthened by incorporation of factor XIIIa into the fibrin clot. Factor XIIIa also binds α2-antiplasmin to the clot to protect it from plasmin-mediated fibrinolysis. At the same time, nearby intact endothelial cells (ECs) secrete tissue plasminogen activator (t-PA). t-PA that evades plasminogen activator inhibitor-1 (PAI-1) converts clotbound plasminogen to plasmin and leads to fibrin clot degradation and release of soluble fibrin peptides and D-dimer. Therefore, detection of circulating D-dimer usually indicates active fibrinolysis.

EC

CHAPTER 51  Normal Hemostasis t-PA is improved by at least an order of magnitude in the presence of fibrin. This helps to keep t-PA most active in the microenvironment of the clot. By contrast, u-PA appears to require binding to activated platelets for its ability to liberate plasmin. Acting to contain fibrinolysis are plasma mediators that either inactivate formed plasmin (e.g., α2-antiplasmin and possibly α2-macroglobulin) or block plasmin formation (e.g., PAI-1). α2-Antiplasmin rapidly inactivates plasmin in plasma but is present in lower concentrations than plasminogen and thus can become depleted while plasmin continues to be formed. Additionally, the α2-antiplasmin protein cross-links to the fibrin clot providing resistance to cleavage by plasmin. PAI-1 is present in several-fold molar excess in the plasma and is also released by both ECs and activated platelets, thereby protecting clots from premature lysis. Plasma levels of PAI-1 are highly variable due to a circadian pattern of secretion; polymorphisms of the PAI-1 gene leading to higher PAI-1 levels are associated with a higher risk for thromboembolic disease, whereas rare congenital deficiencies in PAI-1 protein are associated with increased bleeding tendencies. Another mediator that limits fibrinolysis in the vicinity of the clot is thrombin activator fibrinolysis inhibitor (TAFI). TAFI is synthesized in an inactive form by the liver and circulates in the plasma, possibly in a complex with plasminogen. TAFI cleaves specific fibrin lysine residues that would otherwise promote binding of fibrinolytic enzymes (e.g., plasmin). TAFI requires either plasmin or thrombin for activation; however, thrombin activation of TAFI requires extraordinarily large amounts of free thrombin. By contrast, EC-associated thrombomodulin increases thrombin-induced TAFI activation 1250-fold, making this an essential cofactor and one that is predominantly available only at the interface between the blood and the vessel wall. In addition to the EC surface, macrophages are also critical to fibrinolysis. Macrophages degrade the fibrin clot through lysosomal proteolysis by a plasmin-independent mechanism. The macrophage binds to fibrin and fibrinogen through its surface integrin receptor, CD11b/18; this binding is followed by internalization of the complex into the lysosome, where fibrin and fibrinogen are degraded. Tissue repair and regeneration are the physiologic end points of clotting, and they eventually lead to dissolution of the fibrin-based clot. Besides t-PA and u-PA, the intrinsic pathway activators kallikrein, factor XIIa, and factor XIa also generate active plasmin from plasminogen. Plasminogen binding to cell surface receptors promotes its own activation to plasmin by placing it in proximity to t-PA and the fibrin clot and protects plasmin from inactivation by circulating α2-antiplasmin. Plasmin eventually dissolves the fibrin matrix to produce soluble fibrin peptides and D-dimer and also activates metalloproteinases that further degrade damaged tissue. Fibroblasts and leukocytes migrate into the wound, the latter mediated by selectin binding, and these inflammatory cells act in concert with growth factors secreted by leukocytes and activated platelets to enhance vascular repair and tissue regeneration.

Laboratory Testing of Coagulation As described previously, for purposes of laboratory testing, the extrinsic pathway of the classical coagulation cascade is measured by the PT, while the intrinsic pathway is measured by the aPTT. The PT is assessed by measuring the interaction of circulating factor VIIa with exogenously added TF (also known as thromboplastin). The PT is

529

highly sensitive to deficiencies in factors II, V, VII, and X, all of which may be associated with bleeding, but is unaffected by deficiencies in intrinsic pathway factors (i.e., factors XII, XI, IX, or VIII). Because factors II, VII, and X are also vitamin K–dependent factors, with factor VII having the shortest half-life, the PT is also the main lab test used for monitoring warfarin therapy. The degree of prolongation of the PT by warfarin depends on the strength of the particular thromboplastin agent and the specific coagulation instrument used for the assay. A blood test known as the international normalized ratio (INR), calculated by dividing the patient’s PT by a mean control PT, takes these factors into account in order to standardize variations among laboratories in PT measurements and is the preferred test for warfarin monitoring. The aPTT measurement is based on in vitro contact activation (e.g., plasma stimulation with a negatively charged compound such as kaolin). The aPTT is sensitive to deficiencies of factors in the contact (i.e., PK, HMWK, and factor XII), intrinsic (factors XI, IX, and X), and common (factors II, V, and X) pathways but not in the extrinsic pathway (factor VII). As detailed previously, deficiencies of factors VIII, IX, or XI comprise the basis of the congenital hemophilias A, B, and C, respectively, all of which are characterized by bleeding. By contrast, deficiencies of PK, HMWK, and factor XII, while all prolonging the aPTT, do not result in significant bleeding. The aPTT is also highly sensitive to unfractionated heparin and is used to monitor heparin activity although the therapeutic index of the aPTT in patients on heparin is rather wide owing to natural fluctuations in aPTT measurements. Alternatively, heparin, low-molecular-weight heparin, and fondaparinux activity may be measured via an anti-Xa activity, which assesses the level of inhibition of factor Xa. In surgical settings, trauma units, and intensive care units, there may be a need for immediate turnaround in coagulation testing. One specific point-of-care test used for real-time coagulation testing is thromboelastography (TEG), a global test of hemostasis. TEG uses whole blood to monitor all components of hemostasis, including the initiation and termination phases of the coagulation cascade, fibrinolysis, and platelet function. TEG has been demonstrated to improve outcomes in trauma by guiding transfusion therapy and may have roles in surgery and in assessing coagulation status in patients with advanced liver disease, although its utility outside of these indications is uncertain.

SUGGESTED READINGS Büller HR, Bethune C, Bhanot S, et al: Factor XI antisense oligonucleotide for prevention of venous thrombosis, N Engl J Med 372(3):232–240, 2015. Esmon CT: The protein c pathway, Chest 124(26s), 2003. Ho K, Pavey W: Applying the cell-based coagulation model in the management of critical bleeding, Anaesth Intensive Care 45(2):166–176, 2017. Hoffman M, Monroe 3rd DM: A cell-based model of hemostasis, Thromb Haemost 85(6):958–965, 2001. Manly DA, Boles J, Mackman N: Role of tissue factor in venous thrombosis, Annu Rev Physiol 73:515–525, 2011. Morrissey JH, Choi SH, Smith SA: Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation, Blood 119(25):5972–5979, 2012. Shen J, Sampietro S, Wu J, et al: Coordination of platelet agonist signaling during the hemostatic response in vivo, Blood Adv 1(27):2767–2775, 2017.

52 Disorders of Hemostasis: Bleeding Aric Parnes

INTRODUCTION The complex network maintaining a balance between bleeding and clotting functions in fine equilibrium. However, each component of this network can falter. This chapter describes the imbalances that result in bleeding. It covers platelet disorders, vascular abnormalities, and clotting factor deficiencies. In addition to reviewing the pathophysiology and clinical manifestations of these disorders, it covers a general approach to the evaluation of a bleeding patient and how to treat each disease. How the equilibrium shifts to favor coagulation is covered in a separate chapter.

HEMOSTASIS Hemostasis, the ability to stop bleeding, can be simplified into two phases called primary and secondary hemostasis. However, the reality is more complex than this because primary and secondary hemostasis frequently interact and blend together. Primary hemostasis reflects an initial phase of platelet activation, adhesion, and aggregation with help from von Willebrand factor. Secondary hemostasis involves the coagulation factors activating in a cascade to augment and stabilize clotting. The clotting cascade is explained in more detail in Chapter 51. To initiate bleeding, the integrity of the endothelium is disrupted most commonly by trauma or surgery but sometimes through a vascular defect. Regardless of the inciting event, collagen and other platelet activators are released from endothelial tissue triggering primary hemostasis, whereas the release of tissue factor activates the clotting cascade.

CLINICAL EVALUATION OF BLEEDING The evaluation of bleeding requires a careful history and physical examination. The history includes the details of the current bleeding event as well as past bleeding events. Spontaneous bleeding without a traumatic event points to a severe defect in hemostasis. Lifelong recurring bleeding events and a family history of such suggest congenital disease whereas new bleeding despite previous “hemostatic stress tests” such as surgery or dental extraction without bleeding favor an acquired disorder or a medication effect. Disorders of primary hemostasis including causes of thrombocytopenia or platelet dysfunction or diseases of von Willebrand factor lead to mucocutaneous superficial bleeding, but disorders of secondary hemostasis with missing coagulation factors cause deeper bleeding, for example muscle hematomas, hemarthroses, and intracranial hemorrhages. Superficial bleeding can be easy bruising, gum bleeding when brushing teeth, frequent epistaxis, and heavy menstrual bleeding. When uncovering family history, distinguishing between X-linked genetic disease (e.g., hemophilia A and B) and autosomal disease, such as most von Willebrand disease cases, can be vital. The X-linked inheritance pattern for hemophilia A and B

530

means that more severe disease manifests in males than in females and subsequently may appear to skip generations. Similar distinctions appear in the physical examination. Hemarthroses result in joint swelling, tenderness, and moderate warmth, and multiple joint hemorrhages cause arthritis and deformity. Without imaging or laboratory tests, hemarthrosis can be indistinguishable from septic arthritis or other causes of joint pain. Platelet disorders classically result in petechiae, small subcutaneous hemorrhages that typically appear on the legs, a result of gravity dependence. Sometimes vascular anomalies can be seen on physical examination. For example, small ectatic vessels, prone to bleeding, can be seen on oral mucosa in hereditary hemorrhagic telangiectasia. Liver disease can cause bleeding through a decline in production of coagulation factors and a decline in platelet count, due to hypersplenism and decreased thrombopoietin production by the liver. Hallmark features of liver disease can be obvious on examination, such as jaundice and abdominal distension from ascites, but can be overlooked if not searched for. This includes spider angioma, gynecomastia, Dupuytren contracture, and asterixis. Rare causes of aplastic anemia can be determined by physical examination. Fanconi anemia patients have short stature, café au lait spots, hypoplastic thenar eminences, and absent radii. Dyskeratosis congenita, a disease of short telomeres, leads to leukoplakia, nail dystrophy, and hyperpigmented macules. Importantly, the timing of a thorough examination and subsequent laboratory testing must be tempered in order to control rapid bleeding and hemodynamic instability. Airway, breathing, and circulation, the A-B-C’s, take precedence in emergency situations, and recognizing that bleeding can evolve quickly is critical. Life-threatening hemorrhage requires immediate treatment while simultaneously pursuing diagnostic testing. Life-threatening blood loss is not limited to trauma or gastrointestinal sites but also includes small bleeds near the airway or neck and hemorrhages around other vital organs. Heart rate and blood pressure are first steps in assessing volume of blood loss.

LABORATORY EVALUATION OF BLEEDING The initial laboratory assessment of the bleeding patient (Table 52.1) should include complete blood cell counts (CBC), prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen (Fig. 52.1). The CBC marks a critical first step in this evaluation because it includes the platelet count as well as hemoglobin and hematocrit, which are essential for monitoring the rate of blood loss (as are vital signs). The CBC also contains the mean corpuscular volume (MCV), measuring the size of the red blood cell. A low MCV can suggest a slower chronic blood loss resulting in iron deficiency. A peripheral blood smear should be examined to confirm thrombocytopenia. Pseudothrombocytopenia occurs when platelets clump from EDTA

CHAPTER 52  Disorders of Hemostasis: Bleeding

531

TABLE 52.1  Screening Assays for Hemostasis Laboratory Test

Aspect of Hemostasis Tested

Causes of Abnormalities

Blood counts (CBC) and peripheral blood smear

Platelet count and morphologic features

Prothrombin time (PT)

Factor VII–dependent pathways

Partial thromboplastin time (aPTT)

Factor XI–, IX–, and VIII–dependent pathways

Thrombin time Platelet aggregation and platelet function analysis Mixing study

Fibrinogen Platelet and VWF function Factor inhibitors or deficiencies

Thrombocytopenia, thrombocytosis, gray platelet and giant platelet syndromes Vitamin K deficiency and warfarin, liver disease, DIC, factor deficiency (VII, V, X, II), factor inhibitor Heparin, DIC, lupus anticoagulanta, VWD, factor deficiency (XIIa, XI, IX, VIII, V, X, II), factor inhibitor Heparin, hypofibrinogenemia, dysfibrinogenemia, DIC Aspirin, VWD, storage pool disease Abnormal clotting time corrects for a factor deficiency; does not correct for an inhibitor

DIC, Disseminated intravascular coagulation; VWD, von Willebrand disease; VWF, von Willebrand factor. aLupus anticoagulant and factor XII deficiency are not associated with bleeding.

antibodies and are then read as white blood cells instead of platelets by automated counters. Other helpful findings on a peripheral blood smear include schistocytes, suggesting microangiopathic hemolytic anemia. Teardrop cells with immature white and red blood cells characterize the myelophthisic blood smear, indicative of marrow replacement by solid tumor, lymphoma, granuloma, or fibrosis. PT and aPTT are two commonly used broad measures of the coagulation cascade. PT assesses the extrinsic and common pathways, that is clotting factors, in order of activation: VII, X, V, II, and fibrinogen. aPTT covers the intrinsic and common pathways: Clotting factors XII, XI, IX, VIII, X, V, II, and fibrinogen. Both PT and aPTT become abnormal with deficiencies of the common pathway (X, V, II, and fibrinogen) or multiple clotting factor deficiencies involving both the intrinsic and extrinsic pathways. The International Normalized Ratio (INR) represents a standardized correlate of PT so that measurements of vitamin K–dependent anticoagulation can be compared despite interlaboratory variation. Abnormal PT and aPTT should be repeated to verify the elevation was not in error. Specific factor deficiencies may be suspected based on elevations in PT or aPTT and these factor activities can be tested to confirm the diagnosis and monitor effects of treatment. Factor deficiencies can be congenital (e.g., hemophilia A) or acquired (e.g., acquired hemophilia, liver disease, disseminated intravascular coagulopathy [DIC]). A mixing study can distinguish a factor deficiency resulting from a decline in production from a decline due to inhibition from an autoantibody. Mixing studies combine patient plasma with control plasma so that missing factors are replaced and the abnormal clotting times correct (i.e., prolonged PT or PTT becomes normal). A positive mixing study does not correct because of the presence of an inhibitor, blocking the factor from the normal control plasma. Mixing studies can also be useful in finding a lupus anticoagulant, which is important for the diagnosis of antiphospholipid syndrome (see Chapter 53), but a lupus anticoagulant does not affect bleeding and should not be in the differential diagnosis of the bleeding patient. Fibrinogen can be decreased through a decline in production or consumption, as in DIC. The assay is an easy, rapid, and cheap test to run and should be run early in the evaluation of the bleeding patient. Many fibrinogen assays incorporate function into the quantitative measurement, but since this information may not be readily available, thrombin time is able to measure the function of fibrinogen by adding thrombin to plasma and then measuring the conversion of fibrinogen to fibrin. Similarly, platelet function may be helpful if a defect in primary hemostasis is suspected, but platelet count and von Willebrand factor testing are normal. Platelet dysfunction disorders can be induced by

many different medications, although they are often not clinically significant and rarely are congenital. Platelet function can be assessed by platelet aggregation studies or Platelet Function Analyzer-100 (PFA100; Fig. 52.2), which both use platelet activators to trigger platelet activation and aggregation. Different platelet activators such as adenosine diphosphate (ADP), collagen, epinephrine, and ristocetin may detect subtle differences in platelet function. These tests, not surprisingly, fail to work when platelets are absent or low. Bleeding time, a test measuring the time it takes to stop bleeding after making a small incision in the forearm as a gauge of platelet function, should no longer be performed because numerous studies have shown poor sensitivity, specificity, and reproducibility with significant technician variability. Testing for von Willebrand disease (VWD) is as complicated as the disease, which has multiple subtypes, each with different means of diagnosing. A typical von Willebrand factor (VWF) panel includes VWF activity (a functional test measured by ristocetin-mediated binding of VWF to platelets, VWF antigen (the quantitative level), and clotting factor VIII, which declines without the presence of its stabilizer, VWF. Other tests that may be required to determine the subtype of VWD include VWF multimer analysis, VWF-factor VIII binding assay, and a measure of platelet aggregation as induced by ristocetin (RIPA). As with any congenital disorder, gene sequencing may be the only way to confirm the diagnosis, but it adds time and expense and is frequently normal in mild cases of VWD. Additional laboratory tests useful in evaluating bleeding include factor Xa activity for measurement of low-molecular-weight heparin effect, heparin neutralization (with heparinase, hexadimethrine bromide [Polybrene], or protamine), and euglobulin clot lysis time as a measure of fibrinolysis, the time to dissolve a fibrin clot. Currently, the new class of anticoagulants, direct oral anticoagulants (DOACs), do not have readily available methods for measurement of plasma concentrations or activity. Because vitamin C deficiency (scurvy) can cause bleeding, measuring ascorbic acid can be helpful when nutrient deficiency is suspected. Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) use torque to measure clotting of whole blood. These methods have many proponents but remain investigational. A rapid approach to identifying possible causes of bleeding (Fig. 52.3) considers several major disease categories: (1) VWD, thrombocytopenia, or abnormal platelet function; (2) low levels of multiple coagulation factors resulting from vitamin K deficiency, liver disease, or DIC; (3) single-factor deficiency (usually inherited); and, more rarely, (4) an acquired inhibitor to a coagulation factor such as factor VIII. The laboratory evaluation is most efficient when it is performed in this context.

532

SECTION VIII  Hematologic Disease

A

Incubation at 37° C and addition of procoagulants

Plasma without a clotting activator allows substantial light transmission

Initial fibrin stranding occurring after the addition of the procoagulant

Firm clot formation inhibiting light transmission

B Fig. 52.1  Basic methodology underlying measurement of prothrombin (PT) and activated partial thromboplastin time (aPTT). (A) Typical laboratory instrument used to perform basic and complex coagulation assays. (B) Plasma specimens are incubated at 37° C and then mixed with tissue factor and phospholipid (PT) or a surface activator and phospholipid (aPTT). The time it takes for clot formation to block light passage through the specimen is measured and compared with a reference range. Prolongation of the PT or aPTT clotting time can be associated with many congenital or acquired coagulation factor defects. Abnormal PT or aPTT values are typically followed by more specific coagulation factor assays, depending on the type of prolongation and the suspected underlying clinical disease.

BLEEDING CAUSED BY VASCULAR DISORDERS Vascular purpura (i.e., bruising) is defined as bleeding caused by intrinsic structural abnormalities of blood vessels or by inflammatory infiltration of blood vessels (i.e., vasculitis). Although vascular purpura usually causes bleeding in the setting of normal platelet counts and normal coagulation tests, vasculitis and vessel damage may be severe enough to cause secondary consumption of platelets and coagulation factors. Collagen breakdown and thinning of the subcutaneous tissue that overlies blood vessels is often observed in older patients (i.e., senile purpura), and similar atrophic skin changes are a common effect of steroid therapy. Another acquired cause of vascular purpura is scurvy (i.e.,

deficiency of vitamin C [ascorbic acid]). Patients with scurvy have bleeding around individual hair fibers (i.e., perifollicular hemorrhage) and corkscrew-shaped hair. Bruising occurs in a classic saddle pattern over the upper thighs. The bleeding gums are caused by gingivitis and not by the subcutaneous tissue defect. Edentulous patients with scurvy do not have bleeding gums, and scurvy should not be excluded on this basis. Congenital defects of the vessel wall can cause bruising. These rare syndromes include pseudoxanthoma elasticum, a defect of the elastic fibers of the vasculature associated with severe gastrointestinal (GI) and genitourinary bleeding, and Ehlers-Danlos syndrome, which is characterized by abnormal collagen in blood vessels and subcutaneous tissue. Both syndromes cause bruising in the skin, but only patients with pseudoxanthoma elasticum develop significant GI bleeding.

CHAPTER 52  Disorders of Hemostasis: Bleeding

533

A

Collagen-coated membrane with platelet agonist

Direction of whole blood flow

Collagen-coated membrane with platelet agonist

Direction of whole blood flow Collagen-coated membrane with platelet agonist

Collagen-coated membrane with platelet agonist

Direction of whole blood flow Collagen-coated membrane with platelet agonist

Collagen-coated membrane with platelet agonist

B Fig. 52.2  Methodology underlying the Platelet Function Analyzer-100 (PFA-100). (A) Whole blood platelets are streamed toward a collagen-based aperture. The membrane is infused with a potent platelet agonist (i.e., adenosine diphosphate or epinephrine). (B) Streaming the platelets through the instrument channels induces shear-based activation, which in conjunction with the agonists should yield an initial wave of platelet adhesion and aggregation. Over time, activated platelets continue to aggregate, closing off the aperture to whole blood flow. The time it takes for aperture closing is measured in seconds and compared with a reference range. Abnormally prolonged closure times can be associated with von Willebrand disease due to the reliance on adhesion in this assay or with a platelet functional defect due to the reliance on aggregation for complete aperture closure.

534

SECTION VIII  Hematologic Disease

ABNORMAL BLEEDING

Screening test findings normal

Platelet aggregation

Normal platelet aggregation

Platelet dysfunction (abnormal platelet aggregation) Mild VWD

α2-Antiplasmin deficiency Factor XIII deficiency Dysfibrinogenemia ( Thrombin time) Vascular disorder

PT and/or

Low platelet count

PTT

Corrects with mixing study

No correction with mixing study

PT—( V, VII) Liver disease

PTT corrects with polybrene heparin in sample

PT—(Normal V, VII) Warfarin, vitamin K or FVII deficiency) PTT—FVIII, IX, or XI def (hemophilia A, B, or C)

Thrombocytopenia work-up DIC work-up

PTT corrects with phospholipid test for lupus anticoagulant (RVVT, ACA) Factor inhibitor

PT and PTT—common pathway def (I, II, V, X) or combined defect Fig. 52.3  Algorithm for the evaluation of bleeding. Screening laboratory tests for platelet and factor deficiencies are used to narrow the work-up for bleeding, followed by specific factor and other coagulation studies (e.g., mixing studies, D-dimer) to confirm the diagnosis. ACA, Anticardiolipin antibody; DIC, disseminated intravascular coagulation; FVIII, factor VIII; PFA-100, Platelet Function Analyzer-100; PT, prothrombin time; PTT, partial thromboplastin time; RVVT, Russell viper venom time; VWD, von Willebrand disease; ↑, increased; ↓, decreased.

Another inherited vessel wall defect associated with GI bleeding is hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome). This disorder is characterized by degeneration of the blood vessel wall that results in angiomatous lesions resembling blood blisters on mucous membranes, including the lips and GI tract. The frequency of bleeding caused by breakdown of these lesions increases with age, and GI lesions commonly cause significant chronic bleeding, resulting in iron deficiency anemia. The sudden onset of palpable purpura (i.e., localized, raised hemorrhages in the skin) associated with rash and fever may be caused by aseptic or septic vasculitis. Septic vasculitis can be caused by meningococcemia and other bacterial infections and is often accompanied by thrombocytopenia and prolongation of clotting times. One cause of aseptic vasculitis in young children and adolescents is HenochSchönlein purpura, a vasculitis of the skin, GI tract, and kidneys that is usually accompanied by abdominal pain from bleeding into the bowel wall. This syndrome may occur after a viral prodrome and appears to be caused by an immunoglobulin A (IgA) hypersensitivity reaction, as evidenced by serum IgA immune complexes and renal histopathologic features resembling IgA nephropathy. The therapy for bleeding from vascular disorders depends upon the diagnosis. Senile purpura and steroid-induced purpura do not usually require treatment. Scurvy is corrected by vitamin C supplementation. In congenital disorders, including Ehlers-Danlos syndrome, hereditary hemorrhagic telangiectasia, and pseudoxanthoma elasticum, patients should avoid medications (e.g., aspirin) that may aggravate their bleeding tendencies, and they should receive supportive therapy (e.g., iron supplementation, red blood cell transfusion). Systemic administration of estrogen to patients with hereditary hemorrhagic telangiectasia may

help to decrease epistaxis by inducing squamous metaplasia of the nasal mucosa, which protects lesions from trauma. Treatment of septic vasculitis focuses on appropriate antibiotic therapy. In the case of aseptic vasculitis, steroids and immunosuppressive agents are most effective. When vasculitis is severe enough to cause consumption of platelets and coagulation factors (see section on disseminated intravascular coagulation), transfusions of platelets, cryoprecipitate, and fresh-frozen plasma (FFP) may be indicated.

BLEEDING CAUSED BY THROMBOCYTOPENIA With thrombocytopenia, bleeding does not occur until platelets are less than 20,000/μL unless platelet dysfunction accompanies the thrombocytopenia as it frequently does in myelodysplastic syndromes or when aspirin or nonsteroidal anti-inflammatory drugs have been used (Fig. 52.4). Platelets less than 100,000/μL can be problematic after trauma or during surgery. Since most patients do not bleed from mild thrombocytopenia (50,000 to 150,000/μL), treatment is often not required, but thrombocytopenia should be investigated to determine the cause, expected trajectory, and a plan for when treatment is needed. Broadly, thrombocytopenia results from a decline in platelet production, hypersplenism/sequestration, or destruction/consumption. However, determining which category to focus attention on can be challenging. Bone marrow biopsy can help because megakaryocyte hyperplasia implies increased production, a means of compensating for peripheral platelet destruction, whereas megakaryocyte hypoplasia suggests decreased platelet production. Still, bone marrow biopsy is often unnecessary in the evaluation. Hypersplenism is usually associated with an enlarged spleen, but splenic overactivity can be seen when the spleen is normal

CHAPTER 52  Disorders of Hemostasis: Bleeding

535

THROMBOCYTOPENIA

DECREASED PRODUCTION

SEQUESTRATION

INCREASED DESTRUCTION

Splenomegaly Liver disease Malignancy Myelofibrosis

Nutritional B12/folate deficiency

Congenital Alport syndrome Fanconi anemia May-Hegglin anomaly TAR syndrome Wiskott-Aldrich syndrome

Marrow damage Aplastic anemia Cytotoxic chemotherapy Drug-induced Malignancy Myelodysplasia Radiation therapy

HEMODILUTION

Massive transfusion Cardiopulmonary bypass

Immune-mediated ITP Drug-induced Systemic diseases HIV SLE Alloimmune (neonatal, PTP) Heparin

Non–immune-mediated DIC TTP Preeclampsia HELLP syndrome Antiphospholipid syndrome

Fig. 52.4  Differential diagnosis of thrombocytopenia. Disorders resulting in a decreased circulating platelet number can be classified by four main pathophysiologic mechanisms: hypoproduction, sequestration, peripheral destruction, and hemodilution. The history, physical examination, and bone marrow evaluation usually narrow the range of possible causes. DIC, Disseminated intravascular coagulation; HELLP, hemolysis, elevated liver enzymes, and low-platelet count in association with pregnancy; HIV, human immunodeficiency virus; ITP, immune thrombocytopenic purpura; PTP, post-transfusion purpura; SLE, systemic lupus erythematosus; TAR, thrombocytopenia-absent radius syndrome; TTP, thrombotic thrombocytopenic purpura.

in size, as it is in immune thrombocytopenic purpura. Conversely, not all enlarged spleens are associated with hypersplenism (see Fig. 52.4).

Decreased Marrow Production of Platelets Decreased production of platelets in the bone marrow is characterized by decreased or absent megakaryocytes on the bone marrow aspirate and biopsy. Suppression of normal megakaryopoiesis occurs after marrow damage and destruction of stem cells (such as occurs with cytotoxic chemotherapy); destruction of the normal marrow micro-environment and replacement of normal stem cells by invasive malignant disease, aplasia, infection (e.g., miliary tuberculosis), or myelofibrosis; specific but rare intrinsic defects of the megakaryocytic stem cells; and metabolic abnormalities affecting megakaryocyte maturation.

Drug-Associated Thrombocytopenia Many drugs cause immune-mediated thrombocytopenia. However, some can have a direct cytotoxic effect on stem cells and megakaryocytes, causing a decline in platelet production. The classic example of this is cytotoxic chemotherapy used to treat malignancies. These medications are used to stop malignant cells from dividing, but they have the same effect on nonmalignant proliferating cells such as in the bone marrow. This myelosuppression frequently results in thrombocytopenia as well as neutropenia and anemia. Other drugs including thiazide diuretics and alcohol can have similar effects. Diagnostic confirmation comes from recovery of platelets after withdrawal of the medication. Recovery usually occurs within 7 days but can take several weeks. After repeated injury, stem cells may not recover, resulting in chronic thrombocytopenia.

Nutrition-Associated Thrombocytopenia Deficiencies in copper, folate, and vitamin B12 can cause thrombocytopenia. However, they typically will cause other cytopenias prior to

affecting platelet production. Megaloblastic anemia refers to the effects of impaired DNA synthesis on bone marrow causing dyssynchrony between slowed maturation of the nucleus and continued maturation of cytoplasm with unimpaired protein synthesis. This process results in large erythroid precursors called megaloblasts and mature large red blood cells (macrocytes). Certain medications can have this effect: azathioprine, 5-fluorouracil, methotrexate, and others. Folate and vitamin B12 deficiencies are classic causes of megaloblastic anemia and when severe can cause pancytopenia. These deficiencies are most commonly caused by poor absorption either from autoimmune interference of intrinsic factor (pernicious anemia), other causes of atrophic gastritis, celiac disease, or previous gastrointestinal surgery. Less commonly, folate and vitamin B12 deficiency arise from a poor diet (e.g., strict vegans and alcoholics), an inherited defect in transcobalamin, or competition for vitamin B12 absorption from Diphyllobothrium latum parasitic infection. Copper deficiency causes leukopenia and anemia before affecting platelet production. It occurs in two settings, first through malabsorption from celiac disease and past bowel surgeries, and second, through copper transport blockage from zinc excess. Zinc levels should be tested when copper is found to be low. Zinc excess occurs from zinc-containing denture cream and improper use of zinc supplements.

Bone Marrow Invasion When the bone marrow is replaced by non-marrow elements, space for hematopoiesis becomes limited. In addition, the microenvironment necessary to supply proper nutrients, growth factors, and neuroendocrine stimulation is damaged. The prototypic disease of marrow invasion is myelofibrosis, either primary (a chronic myeloproliferative disease) or secondary, from other myeloproliferative

536

SECTION VIII  Hematologic Disease

disease (polycythemia vera, essential thrombocythemia), hematologic malignancy, autoimmune disease, or infection. Rarely, myelofibrosis is associated with systemic mastocytosis and osteogenesis imperfecta. In myelofibrosis, the marrow is replaced by fibrotic strands causing immature erythroid (nucleated red blood cells) and myeloid cells (“left-shift”) to enter the peripheral blood stream. In addition, red blood cells become deformed (teardrop cells) as they squeeze between narrow spaces. This combination of teardrop cells and immature blood cells is called the myelophthisic blood smear. It can be seen when bone marrow is replaced by fibrotic tissue, malignant cells, or granuloma from sarcoidosis or tuberculosis. Confirmation of marrow invasion requires a bone marrow biopsy.

Myelodysplastic Syndrome Myelodysplastic syndrome (MDS) (see also Chapter 47) is a clonal stem cell disorder resulting in ineffective hematopoiesis and cytopenias, either unilineage or multilineage. The diagnosis requires a bone marrow biopsy. Dysplasia (abnormal appearing cells) in the bone marrow and cytopenias fulfill the criteria for diagnosis. Subtypes depend on the number of blasts present in the bone marrow (must be 10% of total circulating number) to restore primary hemostasis. Platelet dysfunction and bleeding caused by other drugs is similarly treated by discontinuing the drug and providing platelet transfusions when needed (Table 52.6).

Uremic Platelet Dysfunction Renal insufficiency can be associated with the accumulation of toxic proteins, which induce high levels of nitric oxide formation by vascular endothelial cells and inhibit platelet function. The uremic state can also suppress platelet secretory pathways and platelet adhesion to exposed endothelium through mechanisms that are not well understood. Nonetheless, the uremic state does put an individual at risk for platelet dysfunction–related bleeding. Because no formal tests are available, the diagnosis should be suspected in individuals with acute or chronic renal failure who demonstrate bleeding. Short-term treatment of uremic platelet dysfunction includes administration of DDAVP. This increases circulating von Willebrand factor, which can help to overcome some of the uremia-associated platelet deficits. Transfusion of red blood cells also seems to help by

increasing volume, thereby pushing platelets to the margins of the blood vessel, where they become easily activated and more likely to plug the gaps between endothelial cells. Conjugated estrogens are of some benefit for long-term treatment. Platelet transfusions may be marginally useful in patients with life-threatening bleeding and acute renal failure, but the effect of this treatment is short lived because the transfused platelets rapidly acquire the uremic defect. Platelet transfusion should not be considered as a first-line therapy for most forms of uremic bleeding. Ultimately, renal replacement therapy, including dialysis or renal transplantation, may be necessary.

Congenital Causes of Platelet Dysfunction Platelet Glycoprotein Defects

Inherited qualitative platelet defects include abnormalities of platelet receptors and granules. Two rare but well-characterized platelet receptor disorders are Bernard-Soulier syndrome and Glanzmann thrombasthenia. Bernard-Soulier syndrome is caused by decreased surface expression of platelet GPIb, a key receptor for von Willebrand factor and less commonly by diminished GPIb function. The syndrome is characterized by mild thrombocytopenia, large platelets, and mild to moderate bleeding symptoms. The diagnosis is usually made in childhood, but some patients may be discovered in adulthood. Laboratory testing for Bernard-Soulier syndrome shows an absent platelet aggregation response to ristocetin (see Table 52.5 and Fig. 52.5) despite adequate VWF activity. Glanzmann thrombasthenia is characterized by an increased bleeding time and abnormally low levels of expression of platelet GPIIb/IIIa (receptor for VWF and fibrinogen) or, less commonly, normal expression but absent GPIIb/IIIa function, while platelet count remains normal. Patients usually exhibit bleeding in childhood. Whereas patients with Bernard-Soulier syndrome have an elevated mean platelet volume (MPV), MPV is normal in Glanzmann thrombasthenia. In cases of Glanzmann thrombasthenia, platelet aggregation testing confirms an absent or diminished response to all agonists except ristocetin (see Table 52.5 and Fig. 52.5). Platelet transfusions correct the bleeding in Bernard-Soulier syndrome and Glanzmann thrombasthenia. However, because of the high risk for alloimmunization with frequent platelet transfusions (particularly because patients lack GPIb or GPIIb/IIIa), this therapy should be used sparingly. Instead, factor VIIa can be used with high efficacy for both diseases. DDAVP has some benefit in Bernard-Soulier syndrome.

Platelet Granule or Secretory Defects Inherited platelet granule disorders are defined by the type of granule that is absent or defective. Storage pool disease is characterized by a relative decrease or absence of dense granules and correspondingly moderate to severe mucosal bleeding. Release of dense granule contents that recruit and activate platelets is impaired. Storage pool disease has a diminished or absent secondary wave of aggregation in response to most agonists (see Table 52.5 and Fig. 52.5). Hermansky-Pudlak syndrome is a dense granule deficiency associated with oculocutaneous albinism, nystagmus, and pulmonary fibrosis. Multiple gene defects have been attributed to Hermansky-Pudlak syndrome and cause lysosome dysfunction. Patients may have spontaneous bleeding, but bleeding more often occurs with surgical procedures or trauma. This can be particularly problematic for the patients who undergo lung transplant for pulmonary fibrosis. Chédiak-Higashi syndrome is a rare dense granule disorder characterized by mild bleeding, partial albinism, and recurrent pyogenic infections. It is caused by a mutation in the LYST gene leading to lysosome dysregulation. Large, irregular, gray-blue inclusions (granules)

CHAPTER 52  Disorders of Hemostasis: Bleeding are seen in neutrophils and other white blood cells. Many patients with Chédiak-Higashi syndrome develop an accelerated phase with HLH. Gray platelet syndrome is characterized by colorless or gray platelets that lack normal staining on the peripheral smear. Electron microscopy confirms the loss of α-granules or their contents. A mutation in the gene NBEAL disrupts vesicle trafficking, leading to a deficiency of the α-granules. Patients with gray platelet syndrome have a history of mild bleeding, and aggregation testing detects diminished responses to epinephrine, ADP, and collagen. Thrombocytopenia with small platelets is characteristic of WiskottAldrich syndrome, an X-linked recessive disorder with eczema and immunodeficiency that can be diagnosed by the lack of CD43 expression on T lymphocytes. A WAS gene mutation results in a defect in the actin cytoskeleton followed by a deficiency in platelet dense granules. Most patients with Wiskott-Aldrich syndrome will not survive without a stem cell transplant. May-Hegglin anomaly and related myosin heavy-chain 9 gene (MYH9) diseases are characterized by giant platelets and Döhle bodies (i.e., basophilic inclusions in leukocytes). Platelet count is low and a family history of bleeding is common because the inheritance pattern is autosomal dominant. Unlike the other diseases in this section, MYH9 diseases have normal granules and normal platelet aggregation, but the MYH9 mutation impairs the platelet cytoskeleton, which affects clot retraction. With thrombopoietin agonists, the additional platelets produced are also dysfunctional, but the quantitative increase in platelets may be enough to stop bleeding. All the platelet dysfunction disorders are treated by avoiding antiplatelet drugs, using hormonal control of menses in women, and transfusing platelets when bleeding occurs.

Platelet Transfusion Therapy Standard Platelet Therapy

Platelet transfusions derived from the whole blood of healthy donors can be used to stop or prevent bleeding. The two broad categories of platelet transfusion support are based on the conditions previously discussed: prophylactic platelet transfusions for thrombocytopenia in nonbleeding patients and platelet transfusion for acute bleeding. For the nonbleeding thrombocytopenic patient, several triggers can prompt platelet transfusion in the absence of frank hemorrhage. Patients receiving chemotherapy may be severely thrombocytopenic and should be transfused when their platelet counts are less than 10,000/μL to prevent spontaneous bleeding. This is a safe and appropriate threshold for patients with relatively uncomplicated clinical pictures without fever, sepsis, or bleeding. The threshold of 10,000/μL, which was rigorously established through several prospective, randomized, controlled trials, significantly decreases the frequency of platelet transfusion and thereby reduces risks associated with multiple blood product exposures. If the patient has complicating circumstances, prophylactic transfusions may be given when platelet counts are lower than 20,000/μL, although this threshold is not rigorously based on clinical trial evidence. For patients undergoing invasive procedures or who suffer trauma, it is reasonable to transfuse platelets when counts are lower than 50,000/μL. Higher platelet counts (>100,000/μL) are recommended for patients undergoing neurologic surgery. The thresholds of 50,000/μL and 100,000/μL are based primarily on experience and published guidelines. Clinical trials are lacking in these settings. For the acutely bleeding patient, the decision to transfuse platelets depends on several factors, of which thrombocytopenia is the most straightforward and useful criterion. Platelet counts higher than 50,000/μL are a reasonable goal for most cases of acute bleeding,

543

whereas counts higher than 100,000/μL may be necessary for neurologic bleeding. Congenital or acquired platelet dysfunction must be considered for acutely bleeding patients. Those with significant bleeding who have taken an antiplatelet drug such as aspirin may benefit from platelet transfusion regardless of baseline counts. Another consideration is the volume of blood products and fluids received. Trauma patients may receive more than 10 units of transfused red blood cells in addition to plasma, volume expanders, and saline solutions. Resuscitation with large fluid volumes (≥10 units transfused) reduces the platelet count to less than 50% of baseline, resulting in a significant dilutional coagulopathy. In these scenarios, repeated platelet counts must be obtained and platelets liberally transfused to maintain adequate hemostasis. Similarly, clotting factors need repletion during massive transfusion (see “Dilutional Coagulopathy” section). Blood banks provide random-donor pooled platelets and apheresis platelets (E-Fig. 52.1). Random-donor pooled platelets consist of platelet concentrates from four to six donors combined (pooled) into one large dose. For the adult patient with uncomplicated thrombocytopenia, a single random-donor platelet concentrate unit typically raises the platelet count by about 8000 to 10,000/μL. Between 4 and 6 units pooled together can be expected to raise counts by 30,000 to 60,000 platelets/μL. Apheresis platelets are collected from one donor using automated apheresis instruments. The dose of these single-donor platelets is almost equivalent to that of a 6-unit platelet pool and is estimated to increase platelet count by up to 50,000/μL in an uncomplicated patient. Based on the expected increments and typical transfusion goals outlined previously, one random-donor platelet pool (6 units pooled together) or one apheresis platelet product should sufficiently raise platelet counts to improve thrombocytopenia and prevent spontaneous bleeding. These doses should also be sufficient to stop or prevent bleeding associated with thrombocytopenia in the setting of invasive procedures, mild to moderate trauma, or bleeding associated with platelet dysfunction. For the complicated patient (e.g., thrombocytopenia with intracranial hemorrhage, massive trauma), additional platelet doses may be necessary to achieve adequate hemostasis.

Platelet Transfusion Failure and Platelet Refractoriness Platelet transfusions in thrombocytopenic patients are not successful in all cases. Uremia causes an acquired dysfunction of transfused platelets, limiting their hemostatic capabilities in vivo. Patients who are thrombocytopenic due to conditions such as ITP usually do not show increased platelet counts after transfusion because circulating autoantibodies cause rapid destruction of both endogenous and infused (exogenous) platelets. This phenomenon, known as platelet transfusion refractoriness, can be caused by many other recipient problems, including fever, sepsis, splenomegaly, and DIC. Although the pathophysiology of refractoriness is well understood for conditions such as ITP or DIC (in which platelets are cleared from the circulation), few data are available to suggest why individuals with conditions such as fever or infection have an inappropriate response to platelet transfusion. When approaching a patient with platelet transfusion refractoriness, the physician should consider whether it is mediated by nonimmune or immune factors. Immune refractoriness indicates antibodymediated clearance. For nonimmune-mediated refractoriness, as in fever or DIC, the underlying conditions usually decrease transfused platelet survival over time but do not affect immediate platelet recovery. A standard diagnostic approach to platelet refractoriness involves measuring the platelet count 10 minutes to 1 hour after completion of the platelet transfusion. The patient with non–immune-mediated

CHAPTER 52  Disorders of Hemostasis: Bleeding

543.e1

E-Fig. 52.1  An apheresis platelet unit. Platelet units, collected from donors by phlebotomy or apheresis instrumentation, contain a total volume of about 250 to 300 mL, usually corresponding to a total platelet count greater than 3.0 × 106 cells/μL in the final unit. Platelets are stored at room temperature and typically have a shelf life of 5 days. They are indicated for the prevention or cessation of bleeding associated with thrombocytopenia or platelet function defects.

544

SECTION VIII  Hematologic Disease

refractoriness typically shows an initial increase at 10 minutes but then a blunted increase in the platelet count 1 hour after transfusion, with a subsequent decline at a steeper rate than expected because of the underlying disorder. For patients with this type of platelet refractoriness, addressing the underlying illness often increases the effectiveness of platelet transfusions. For patients with immune-mediated platelet refractoriness, there is virtually no increase in the platelet count, even minutes after completion of a transfusion. The antiplatelet antibodies are most frequently encountered in individuals who have been recurrently transfused. Repeated exposures to transfused products can induce alloantibodies, most commonly to HLA antigens. Over time and with multiple transfusion exposures, the titer of alloantibodies can increase sharply and cause rapid clearance of incompatible platelets after infusion. For the alloimmunized patient, immunosuppression fails to decrease platelet alloantibodies, and efforts to improve platelet recovery after transfusion are focused on finding compatible platelet units. The first step in managing transfusion of the alloimmunized patient is to provide ABO antigen–matched platelets to minimize clearance caused by naturally occurring ABO antibodies; this is often helpful because platelets express A and B antigens on their surface. If this step fails to yield increases in platelet counts, donor platelets that lack target antigens for the detected alloantibodies should be pursued. One strategy is to use the patient’s serum to crossmatch platelet donor units, with selection of those units demonstrating compatibility for subsequent transfusion. If crossmatch-compatible platelets fail to induce adequate platelet recovery, blood banks should provide platelets that are matched to the recipient’s HLA system in the hope of evading HLA-based antibodies. HLA-matched platelets are collected from compatible donors using apheresis at frequent intervals until the patient’s platelet count recovers and they are no longer transfusion dependent. Many blood banks and transfusion services have attempted to address the problem of platelet HLA alloimmunization through prevention. They provide blood products that have undergone filtration to reduce their white blood cell content, a process called leukoreduction. Because contaminating leukocytes are the primary sources of exposure to HLAs, their removal can be quite effective in preventing subsequent alloimmunization, even in chronically transfused patients.

BLEEDING CAUSED BY VON WILLEBRAND DISEASE Von Willebrand disease is caused by either a deficiency or dysfunction of von Willebrand factor. Because VWF is a key component to primary hemostasis, its deficiency results in easy bleeding, typically superficial (bruising, mucosal). However, VWF is a stabilizer of factor VIII and when VWF is low, factor VIII is rapidly cleared, resulting in declining factor VIII levels and an elevated aPTT. If factor VIII levels are low enough, patients can have deeper bleeding as in hemophilia A and B with muscle hematomas, hemarthroses, and bleeding into the central nervous system. VWF is synthesized in endothelial cells and megakaryocytes and functions in plasma to mediate platelet adhesion to the damaged site. VWF is a large, multimeric protein; the largest multimers contain the greatest number of adhesive sites and confer greater hemostatic ability than smaller VWF molecules. In patients with low VWF levels, platelet adhesion to damaged vessels is delayed. VWD is grouped into three main subtypes (E-Table 52.1). Type 1 VWD results from a decline in VWF antigen. Decline in VWF antigen parallels a decline in VWF activity. Type 2 VWD represents a dysfunctional VWF, leading to a more significant decline in VWF activity than VWF antigen. Type 3 VWD is the most severe type. Patients with type 3 VWD do not make any VWF.

Type 1 von Willebrand Disease Type 1 VWD is the most common type. Although severity can vary significantly, it tends to be mild. The cause is not always clear because many cases of type 1 VWD have a normal VWF gene sequence. Therefore, other factors must be in play such as the rate of VWF secretion, storage, and clearance. Blood type O is associated with a 25% decline in VWF levels. However, this decline does not affect bleeding rates, possibly due to enhanced secretion and decreased clearance of VWF with age. Inheritance of type 1 VWD tends to be autosomal dominant. VWF antigen levels decline in parallel with VWF activity, reported as VWF:ristocetin (RCo), and increasing severity. VWF:RCo measures the ability of the patient’s VWF (plasma) to agglutinate normal platelets in the presence of ristocetin. VWF:RCo 30% to 49% is referred to as “low VWF” but not true VWD. Diagnostic criterion for VWD is VWF:RCo less than 30%. Repeating VWF testing is wise because significant variability occurs within individuals and between labs. VWF levels also increase with age, inflammation, liver disease, and estrogen such as while on oral contraception or during pregnancy. Patients with mild and moderate VWD rarely have bleeding during pregnancy as the baseline VWF levels increase. However, days to weeks after delivery, bleeding becomes more common as levels fall back to the original baseline. Pregnant women should be alerted to this possibility so they contact a provider if postpartum bleeding occurs. Postpartum bleeding should be carefully assessed so it is not dismissed as expected lochia. Treatment for VWD focuses on modalities to increase VWF. DDAVP increases production of VWF and its release from stores in the Weibel-Palade bodies in endothelial cells. It also increases factor VIII levels. Increased VWF levels can be detected within minutes of DDAVP administration, either intravenous or intranasal. Prior to relying on DDAVP for prevention of bleeding with surgeries or treatment of acute bleeds, a DDAVP challenge should be undertaken, where VWF and factor VIII levels are measured at baseline and then at specified timed intervals (e.g., 1 hour, 2 hours, and 6 hours) after administration of DDAVP to confirm an adequate response. Once this is done, intravenous DDAVP 0.3 μg/kg (capped at 20 μg max dose) can be given 30 to 60 minutes prior to surgeries, and intranasal DDAVP can be prescribed so patients can self-treat at home for bleeds or heavy menstrual periods. The drawbacks to DDAVP include common side effects such as flushing, headache, malaise, and nausea, but also importantly hyponatremia, which becomes more severe with every dose. This can be circumvented by instructing patients to incorporate a 1-week drug holiday after every three doses and to limit free water intake during DDAVP days. A drug holiday is also important because tachyphylaxis develops, meaning that subsequent doses have diminishing returns on their ability to raise VWF levels (i.e., the third dose does not work as well as the first dose) as VWF stores become depleted. When DDAVP responses are inadequate or when patients do not tolerate DDAVP, VWF concentrates must be used. VWF concentrates come as plasma-derived or recombinant. Recombinant VWF contains no factor VIII, while plasma-derived VWF has factor VIII attached. This is important for treatment decisions because many patients with VWD also have low factor VIII levels. In that situation, both VWF and factor VIII need to be replaced to effectively treat acute bleeding. Thus, if recombinant VWF is used, a separate infusion of factor VIII concentrate also needs to be infused if factor VIII is low. For severely affected patients who need prophylaxis (regularly infused VWF to prevent spontaneous bleeding), either type of product is adequate because factor VIII levels become normal several hours after VWF is infused since the VWF stabilizes endogenous factor VIII. If baseline VWF levels of zero are assumed, VWF concentrates of 50 U/kg intravenous will bring

CHAPTER 52  Disorders of Hemostasis: Bleeding

544.e1

E-TABLE 52.1  Classification of Von Willebrand Disease Factor

Type 1

Type 2a

Type 2b

Type 2m

Type 2n

Type 3

Pseudo-VWD BSS

Inheritance Platelet count PTT VIII VWF:Ag VWF:Rcof Multimers RIPA

AD NL NL, ↑ NL, ↓ NL, ↓ NL, ↓ NL, ↓ NL, ↓

AD, AR NL ↑, NL NL, ↓ NL, ↓ ↓↓ ↓ H/I ↓↓

AD, AR NL, ↓ ↑, NL ↓, NL ↓, NL ↓, NL ↓↓ H ↑*

AD NL ↑ NL, ↓ NL ↓↓ NL ↓

AR NL ↑↑ ↓↓ NL NL NL NL

AR, AD NL ↑↑ ↓↓ Absent Absent Absent ↓↓

AD ↓, NL ↑, NL ↓, NL ↓, NL ↓, NL ↓↓ H ↑*

AR ↓, NL NL NL NL NL NL ↓↓

AD, Autosomal dominant; AR, autosomal recessive; BSS, Bernard-Soulier syndrome; H, high-molecular-weight multimers; I, intermediate-molecularweight multimers; NL, normal; PTT, partial thromboplastin time; RIPA, ristocetin-induced platelet agglutination; VWD, von Willebrand disease; VWF:Ag, von Willebrand factor antigen level; VWF:Rcof, von Willebrand factor:ristocetin cofactor activity; ↑, increased; ↓, decreased; ↑*, increased agglutination in response to low-dose ristocetin.

CHAPTER 52  Disorders of Hemostasis: Bleeding VWF to 100%. The half-life of these products is about 12 hours, so doses need to be repeated every 12 to 24 hours.

Type 2 von Willebrand Disease Type 2 VWD is characterized by heterozygous mutations that produce a qualitative defect in the VWF molecule. Because the defect causes a dysfunction in VWF, DDAVP, which will increase the dysfunctional endogenous VWF levels, may not work as well as it does for type 1 VWD. A variety of VWF mutations can cause VWD type 2A, which result in decreased VWF secretion or increased clearance through ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin-1-like-domains-13). These patients show disproportionately low VWF:RCo activity compared with the VWF antigen level (VWF RCo:Ag < 0.6) and large or high-molecular-weight VWF multimers are absent (see E-Table 52.1). Platelet aggregation is decreased in response to ristocetin. Patients with type 2A VWD respond to VWF concentrate and less commonly to DDAVP. Type 2B VWD represents a gain-of-function mutation in exon 28 of VWF that augments VWF binding to the platelet GP1b receptor. This leads to mild thrombocytopenia that worsens with exposure to DDAVP. Therefore, DDAVP is contraindicated in type 2B VWD. High-molecular-weight multimers are absent and platelet aggregation is increased by ristocetin (see E-Table 52.1). Patients are treated with VWF concentrate. The same scenario can be found with platelet-type VWD (previously called pseudo-VWD), where the mutation is not on VWF but instead on the GP1b receptor, and this also augments the interaction of VWF with GP1b. GP1b can be sequenced to verify the diagnosis. These patients are treated with platelet transfusions, not VWF, because the VWF is normal. Type 2M VWD has a VWF mutation causing decreased binding to GP1b, the opposite of type 2B VWD. These patients have normal platelet counts and normal VWF multimers. Gastrointestinal bleeding is more common in type 2M VWD than in other types. Some patients with type 2M VWD respond to DDAVP, but most require VWF concentrate. The platelet version of type 2M VWD is called Bernard-Soulier syndrome, which is caused by a mutation in GP1b leading to decreased VWF binding (see “Congenital Causes of Platelet Dysfunction”). In type 2N VWD, the abnormal VWF molecule has decreased binding affinity for factor VIII, which decreases factor VIII survival and produces a bleeding phenotype similar to hemophilia A (e.g., hemarthroses) except that it affects males and females equally because it has an autosomal recessive inheritance pattern, unlike the X-linked hemophilia A and B. The diagnosis of type 2N VWD should be considered in females who have hemophilia A. VWF levels are normal because the mutated region is isolated to the factor VIII binding site and not affecting the other functions of VWF. To confirm the diagnosis, tests for VWF binding to factor VIII are available in reference laboratories. The low factor VIII levels respond poorly to factor VIII infusions because the infused factor is rapidly cleared without functioning VWF to stabilize it. Instead, type 2N VWD is treated with VWF concentrates with or without factor VIII concentrates.

Type 3 von Willebrand Disease Patients with type 3 VWD have a complete deficiency of VWF, often as a result of the inheritance of two abnormal VWF alleles (i.e., compound heterozygous). This VWD type is the most severe and can mimic hemophilia because factor VIII levels are also severely decreased without VWF protection. It does not respond to DDAVP and requires VWF with factor VIII concentrates to treat bleeding. Many patients with type 3 VWD require regular prophylaxis of VWF concentrates infused every 2 to 3 days to prevent spontaneous bleeding.

545

Acquired von Willebrand Disease The acquired form of VWD usually appears as a severe, type 2A–like defect without larger VWF multimers in a patient with no history of bleeding. Acquired VWD is caused by abnormal clearance of the larger VWF multimers and is associated with essential thrombocythemia, monoclonal gammopathies, multiple myeloma, lymphoproliferative disorders, and other malignancies. For some patients, no etiology is apparent. Unlike ITP, acquired VWD is not associated with pregnancy. Acquired VWD has been successfully treated with IVIG and treatment for the underlying disorder. Another cause of abnormal VWF multimer clearance resulting in acquired VWD is critical aortic stenosis (Heyde syndrome). It is corrected with successful surgical repair.

BLEEDING CAUSED BY COAGULATION FACTOR DISORDERS Unlike disorders of platelets and von Willebrand factor, which favor mucocutaneous bleeding, coagulation factor defects generally cause deeper hemorrhages, such as bleeding into muscle and joints. Because the initial platelet plug is not solidified by secondary hemostasis, the effects are clot breakdown and at times delayed bleeding. Most patients with significant factor deficiencies have abnormal screening laboratory test results (E-Table 52.2, Table 52.1, and Fig. 52.1), although patients with mild deficiencies can have bleeding and only borderline-abnormal coagulation factor values. Like other hemostasis abnormalities previously discussed, coagulation factor problems can be classified as congenital deficiencies or acquired.

Congenital Factor Deficiencies Hemophilia A and B After VWD, hemophilia A and B are the two most common factor deficiencies, corresponding to factor VIII and factor IX deficiency, respectively. Hemophilia A, with an incidence of 1:10,000 live male births, is approximately four times more common than hemophilia B. They are both X-linked and clinically indistinguishable from each other. Although more prominent in males, females can also have hemophilia as symptomatic carriers and by skewing of X chromosomal inactivation (i.e., favoring one chromosome over the other). More than 2000 different mutations have been reported to cause hemophilia A and more than 1000 to cause hemophilia B. About 50% of severe hemophilia A patients have an inversion of a major portion of the gene at intron 22 (inversion 22) that results in complete loss of activity. Smaller missense mutations tend to result in mild or moderate disease. One third of cases are de novo, therefore there is no family history. Hemophilia A and B are stratified by severity: Severe hemophilia is defined as a factor activity of less than 1%, moderate hemophilia as a factor activity of 1% to 5%, and mild hemophilia as a factor activity of 6% to 40%. These distinctions appear small, but are not. Severely affected patients bleed often and spontaneously. Moderately affected patients occasionally bleed spontaneously, whereas mildly affected patients typically bleed only after trauma or surgery. The most common locations for hemorrhages are joints and muscles, but bleeding can occur anywhere. They can be life-threatening, particularly when intracranial. Hemarthroses cause intra-articular inflammation and synovial hyperplasia. Subsequent cartilage and bone damage worsens with repeated hemorrhages. Hemophilic arthropathy results in chronic pain and limitations in joint function. Prior to the advent of prophylaxis, patients often needed joint replacement surgery early in life. Currently, patients who bleed frequently take factor prophylaxis by self-infusing factor intravenously every few days to maintain detectable baseline factor levels so that spontaneous bleeding does

546

SECTION VIII  Hematologic Disease

not occur. When acute hemorrhages occur, patients are instructed to infuse factor as early as possible. Most severely affected patients know how to self-infuse intravenously at home. DDAVP, given intravenously or intranasally, can rapidly raise factor VIII levels in mild hemophilia A patients but not in patients who are severely affected. It does not raise factor IX levels in hemophilia B patients either. A newly approved therapy for prophylaxis is emicizumab, a bispecific antibody that mimics the function of factor VIII by binding to factors IXa and X. This has several advantages over traditional factor products. First, administration is subcutaneous, not intravenous like all other previous factor products. Second, the half-life is substantially longer. Traditional factor’s half-life was roughly 12 hours, some extended to nearly 24 hours by the addition of extra moieties such as polyethylene glycol, albumin, or the Fc receptor domain of immunoglobulin, all slowing the metabolism of factor VIII. Emicizumab’s halflife is 30 days. The third advantage of emicizumab is that it is not a clotting factor and, therefore, factor VIII inhibitors do not interfere with its efficacy. The disadvantages of emicizumab are that clotting assays (PTT, factor VIII, and others) no longer provide accurate results and that emicizumab is only used for prophylaxis, so acute bleeds are still treated by infusing factor VIII, although acute bleeds are significantly less common with emicizumab versus traditional factor VIII prophylaxis. Emicizumab works only for factor VIII deficiency, not in hemophilia B. Inhibitors remain the largest problem for hemophilia patients. In up to one third of hemophilia A patients (much less common in hemophilia B), an alloantibody against factor VIII or IX forms, blocking the utility of factor infusions. In this situation, a bypass to work around the inhibitor in the clotting cascade is required to treat hemorrhage. There are two types of bypass agents: activated factor VII and activated 4-factor prothrombin complex concentrates (aPCC), which contain activated factors II, VII, IX, and X. Inhibitor titers can be measured in Bethesda units (BU); 1 BU is defined as the amount of inhibitor that neutralizes 50% of factor activity. High-titer inhibitors (>5 BU) completely neutralize the activity of infused factor concentrates, while low-titer inhibitors can be out-competed by using higher doses of factor, but at the risk of subsequently increasing the titer level. Inhibitors are sometimes transient, sometimes permanent, and sometimes able to be eradicated by immune tolerance induction, by giving frequent high doses of factor infusions to desensitize patients to the factor. Patients with inhibitors have more severe disease and poorly respond to available treatments. Inhibitors make an already costly disease much more expensive. Not just a footnote in history, many hemophilia patients continue to struggle with the sequelae of human immunodeficiency virus (HIV) and viral hepatitis after contracting them from contaminated blood and factor products in the 1980s and 1990s. In fact, a large percentage of hemophilia patients died from complications of these infections. Recombinant factor was developed in the 1990s and most patients switched even though plasma-derived factor products became safe again through viral testing and inactivation procedures. In addition, a large randomized control trial has shown that plasma-derived factor leads to fewer inhibitors than recombinant, yet most patients remain on recombinant products. The future has taken a rapid upward swing for hemophilia patients, with curative therapies for hepatitis C, emicizumab, other novel agents coming soon from development and the imminent arrival of gene therapy through coagulation factor DNA deployed into the liver by a viral vector. Multiple studies for gene therapy have shown early success and are already in phase III trials with approval for wider use expected in the coming years.

Hemophilia C Hemophilia C refers to factor XI deficiency. Although one step prior to factor IX in the clotting cascade, factor XI deficiency is very different than hemophilia A and B. First of all, bleeding tends to be mucocutaneous, similar to platelet and VWF disorders. Second, bleeding risk does not parallel factor activity level and tends to be mild. For example, some patients with zero factor XI activity rarely bleed. Bleeding risk is best determined by a patient’s bleeding history; therefore, the need for presurgical factor replacement depends on whether or not a patient tends to bleed. Factor XI replacement is done with fresh-frozen plasma (FFP) in the United States. Some countries have an available factor XI concentrate. Hemophilia C is inherited autosomal recessively and is common in Ashkenazi Jewish people.

Other Congenital Factor Deficiencies Factor deficiencies can occur in any clotting factor (see E-Table 52.2). Patients with factor V deficiency usually lack plasma factor V and platelet factor V and have joint and muscle bleeding similar to patients with hemophilia. Some patients who are plasma factor V deficient are asymptomatic until they are challenged with the stress of surgery or trauma, and these patients are thought to have normal platelet factor V levels. Rarely, patients inherit combinations of factor deficiencies, such as combined factors V and VIII deficiencies. Some factor deficiencies have specific factor concentrations available for treatment such as factor VIIa, factor X, and factor XIII. However, others do not have specific concentrates available; those would be treated with FFP. In neonates, factor XIII deficiency manifests with late umbilical stump bleeding or intracranial hemorrhage. Bleeding is delayed, but severe. Factor XIII deficiency does not affect PT or aPTT. It is diagnosed by screening for increased clot solubility in urea; if the clot dissolves abnormally quickly, an enzyme-linked immunosorbent assay for the precise factor XIII level should be performed. Factor XIII deficiency is treated with factor XIII concentrate or cryoprecipitate. Because of the long half-life of factor XIII, prophylactic therapy for severe deficiency is provided only in single doses on a 3- to 4-week recurring schedule. Fibrinogen (factor I) functions as a bridging ligand for the platelet receptor GPIIb/IIIa in the platelet-platelet matrix at sites of vascular damage. It also functions in the final steps of the coagulation cascade to form the fibrin clot after activation from thrombin (factor IIa). This dual role leads to a varied phenotype of bleeding with superficial and deeper bleeding when defects in fibrinogen exist. Congenital abnormalities of fibrinogen include low levels (hypofibrinogenemia), absent fibrinogen (afibrinogenemia), and abnormally functioning fibrinogen (dysfibrinogenemia). The diagnosis can be established by screening assays (see E-Table 52.2), laboratory assays to measure fibrinogen levels, and tests such as thrombin time that are designed to measure fibrinogen function. Reptilase time can also confirm dysfibrinogenemia; heparin does not interfere with this assay like it does with thrombin time. PT and aPTT are prolonged in disorders of fibrinogen. Fibrinogen concentrates can be used for replacement, but if not available, cryoprecipitate offers high concentrations of fibrinogen compared to FFP.

Acquired Factor Inhibitors Acquired inhibitors can occur in congenital hemophilia as described above (see “Hemophilia A and B” section), but they can also occur in those born with a normal coagulation system. Acquired factor VIII inhibitors are the most common and are associated with pregnancy, autoimmune disease, and malignancy, especially lymphoproliferative disorders. Some are idiopathic. The mechanisms underlying acquired factor inhibitors remain poorly understood.

CHAPTER 52  Disorders of Hemostasis: Bleeding

546.e1

E-TABLE 52.2  Screening Laboratory Results for Coagulation Factor Deficiencies Deficient Factor

Frequency

PT

PTT

TT

I (fibrinogen) II (prothrombin) V VII VIII IX X XI XIIb or HMWKb or PKb XIII

Rare Rare 1:1,000,000 1:500,000 1:5000 (male patients) 1:30,000 (male patients) 1:500,000 Rarea Rare Rare

↑ ↑ ↑ ↑ NL NL ↑ NL NL NL

↑ ↑ ↑ NL ↑ ↑ ↑ ↑ ↑ NL

↑ ↑ NL NL NL NL NL NL NL NL

HMWK, High-molecular-weight kininogen; NL, normal; PK, prekallikrein; PT, prothrombin time; PTT, partial thromboplastin time; TT, thrombin time; ↑, increased over normal range. aExcept in those of Ashkenazi Jewish descent (about 4% of whom are heterozygous for factor XI deficiency). bNot associated with clinical bleeding.

CHAPTER 52  Disorders of Hemostasis: Bleeding The diagnosis of an acquired inhibitor can be made by laboratory techniques similar to those detailed for patients with congenital hemophilia. A mixing study can be a critical piece to the evaluation. It mixes control plasma with patient plasma, correcting any deficiencies unless an inhibitor is present since the inhibitor will also block the factor in the control plasma. For the treatment of bleeding, patients with acquired inhibitors to factors VIII or IX are administered factor VIIa or aPCC to promote hemostasis by bypassing the inhibitor. Rituximab, an anti-CD20 agent, has become the mainstay for successful treatment along with steroids and should be started as soon as possible to eradicate the inhibitor. Acquired factor X deficiency can occur in patients with amyloidosis, a condition in which the abnormal circulating light chains adsorb and clear factor X, producing low levels and severe bleeding.

Vitamin K Deficiency Bleeding in inpatients and outpatients who are severely ill may be caused by acquired coagulation factor deficiencies from vitamin K deficiency. Because vitamin K is fat-soluble, biliary tract disease can interfere with its absorption. Antibiotics can sterilize the gut and reduce bacterial sources of vitamin K. Other drugs such as cholestyramine directly block vitamin K absorption. Vitamin K deficiency also may reflect poor nutritional status due to malabsorption, chronic disease, or reduced oral intake in patients who are acutely or chronically ill. Factors II, VII, IX, and X are vitamin K–dependent procoagulant factors and proteins C and S are the natural vitamin K-dependent anticoagulants. In addition to disease-associated vitamin K deficiency, the anticoagulant warfarin blocks vitamin K–dependent γ-carboxylation of factors II, VII, IX, and X and causes an acute decrease in functional factor VII levels because factor VII has the shortest half-life (4-6 hours) of all vitamin K–dependent factors in vivo. Individuals who experience bleeding while on warfarin may be treated with vitamin K or, for life-threatening bleeding, a 4-factor PCC or FFP infusion.

Dilutional Coagulopathy As with platelets, coagulation factors can be depleted through the dilutional effects of a pure red blood cell transfusion or with the administration of massive amounts of volume expanders or saline solutions. For every 10 units of red cells acutely transfused, there is a concomitant increase in the international normalized ratio (INR) to greater than 2. Acute bleeding and trauma can also lead to consumption of circulating coagulation factors. In the setting of trauma, it is important to maintain adequate coagulation factor activity through plasma transfusions. Evidence from the trauma literature suggests that transfusion ratios of red cells to plasma should approach 1:1 to optimize hemostasis. However, even this may not fully restore depleted coagulation factors. The effects of dilutional coagulopathy should be monitored by repeated testing of PT and aPTT and supported with a liberal plasma transfusion strategy. As described above (see “Standard Platelet Therapy” section), caregivers must also be vigilant about repletion of platelets.

Liver Disease Unlike patients with vitamin K deficiency or those receiving warfarin, patients with liver disease have low levels of most factors, not just the vitamin K–dependent factors. The exception is factor VIII. Factor VIII levels are usually normal with liver disease because factor VIII is produced in endothelial cells and megakaryocytes. Seemingly in contrast to this, factor VIII levels in hemophilia A patients normalize after liver transplant because factor VIII is synthesized in endothelial cells within the transplanted liver. If factor VIII levels are decreased

547

in patients with liver disease, consideration should be given to superimposed DIC. Evaluating a prolonged PT, measurement of factor VII and a non– vitamin K–dependent factor, such as factor V, is useful. In vitamin K deficiency, the level of factor VII is low, and that of factor V is normal; levels of both factors are low in patients with generalized liver disease. The PT is a sensitive measure of liver function and becomes prolonged in patients with even mild liver disorders; elevation precedes a significant decrease in the albumin or prealbumin levels and is usually coincident with transaminase changes. In patients with mild to moderate liver disease, the PT is prolonged, but the aPTT usually remains within the normal range. In severe liver disease, the PT becomes even more prolonged, and the aPTT also becomes abnormal. Other causes of bleeding in liver disease include associated DIC, inhibition of platelet function and production, removal of platelets from hypersplenism, and increased levels of tissue plasminogen activator. Treatment of bleeding associated with liver disease is based primarily on replacement of coagulation factors by plasma transfusions, although they only temporarily correct abnormalities. Liver transplantation is the only definitive treatment for these synthetic defects.

Acquired Fibrinogen Loss or Defects Congenital fibrinogen disorders were described earlier, but more common are acquired causes such as DIC, causing a consumption of fibrinogen, and liver disease, where defects in post-translational modification of fibrinogen lead to dysfunction or dysfibrinogenemia. The abnormal fibrinogen molecules cannot undergo normal cross-linking or polymerization, resulting in bleeding.

BLEEDING IN PATIENTS WITH NORMAL LABORATORY VALUES Sometimes confirmatory testing of a bleeding disorder can be elusive. Bleeding diathesis from connective tissue disease and vascular causes may have normal coagulation tests. Vitamin C deficiency can lead to bleeding through an acquired connective tissue disease (scurvy). Low VWF and mild deficiencies of clotting factors may not prolong PT and aPTT. Factor XIII deficiency does not affect PT, aPTT, and other tests. Tests of fibrinolysis (plasminogen activator inhibitor-1, alpha-2 antiplasmin, plasminogen, and tissue plasminogen activator) may find rare causes of bleeding. Often cases with significant bleeding histories remain unsolved.

Plasma and Coagulation Factor Transfusion Therapy For patients with one or multiple defects in coagulation proteins, there are several options for replacement therapy. The most widely used product for replacement of coagulation factors is FFP (E-Fig. 52.2). It is collected from the whole blood of healthy donors and is frozen within 8 hours of collection. It contains normal (i.e., therapeutic) levels of all coagulation factors necessary to maintain hemostasis. FFP is an excellent choice for replacement of coagulation factors for many conditions, including liver failure and deficiencies of factors II, V, X, and XI. FFP is commonly used with vitamin K therapy for the reversal of warfarin before invasive procedures or for the onset of bleeding. The appropriate dose of FFP is weight based and does not depend on the extent of prolongation in coagulation studies alone. Administration of FFP at 10 to 15 mL/kg should be sufficient to replace deficient coagulation factors and correct abnormal coagulation values. Assuming a volume of about 200 mL per unit of FFP, a reasonable dose for a 70-kg individual is 4 units of FFP. Administration is time sensitive because coagulation factors degrade at standard half-lives on infusion.

CHAPTER 52  Disorders of Hemostasis: Bleeding

547.e1

E-Fig. 52.2  Single unit of fresh-frozen plasma (FFP). Plasma units, collected from donors by phlebotomy or apheresis instrumentation, contain a total volume of about 200 to 250 mL. FFP possesses all elements found in peripheral blood plasma, including coagulation factors, albumin, complement, and immunoglobulins, although they are primarily administered for coagulation factor defects. FFP is stored in the frozen state (shown) at less than −18° C and must be thawed before issuing and administration. The shelf life while frozen is 1 year.

548

SECTION VIII  Hematologic Disease

FFP should be provided immediately before an intended procedure to ensure adequate hemostasis. In some cases, patients may not be able to tolerate the infusion of the large volume of FFP required to reverse coagulopathic states. Prothrombin complex concentrate (PCC) offers quick reversal of prolonged PT and aPTT without the need for large volumes of FFP. Fourfactor PCC is a concentrated, lyophilized, human-derived concentrate containing factors II, VII, IX, and X that can be reconstituted in small volumes and provided by intravenous bolus injection. A 4-factor PCC was approved for clinical use in 2013 by the U.S. Food and Drug Administration (FDA). A variant PCC (FEIBA) containing activated factors II, VII, IX, and X is used as a bypass agent to treat bleeding in the setting of an inhibitor and is administered in doses of 50 to 100 U/kg every 8 to 12 hours. Vitamin K can be given in addition to plasma infusion or factor concentrates. Oral or parenteral replacement of vitamin K (1 to 10 mg/ day for 1 to 3 days) restores coagulation factor synthesis in patients with normal liver function and vitamin K deficiency. For patients with hemophilia A or B, multiple virally inactivated, human-derived or recombinant factor VIII and IX concentrates are available (see “Hemophilia A and B”). Patients with severe hemophilia often infuse themselves with prophylactic factor on a regular basis (2550 U/kg three times per week for hemophilia A; 50-100 U/kg twice per week for hemophilia B) and boost their dose or frequency of infusion when they sense internal bleeding, sustain trauma, or undergo dental procedures (see E-Table 52.3). Patients with mild hemophilia A may not need factor infusions for minor surgery. Their disease is often managed with DDAVP (0.3 μg/kg) or antifibrinolytic agents such as tranexamic acid 1300 mg three times a day or ε-aminocaproic acid 4 g every 4 to 6 hours. Most patients with hemophilia require factor infusions prophylactically or at times of surgery or trauma. Factor VIII products are infused every 8 to 12 hours, and 1 U/kg of factor VIII concentrate raises plasma factor VIII activity by 2%; 50 U/kg of factor VIII theoretically yields 100% factor VIII activity in a patient with severe hemophilia A. Factor IX has a longer half-life and is infused every 18 to 24 hours; factor IX requires 1 U/kg for a 1% increase in factor IX activity (i.e., 100 U/kg for 100% activity). Major surgery in patients with hemophilia requires intensive factor therapy to achieve normal factor levels (>80%) in the intraoperative period and the early postoperative period to prevent wound hematoma formation. The dose of factors (see E-Table 52.3) is adjusted downward from this intensity, depending on the severity of the insult, the patient’s response to previous factor infusions, and whether factor inhibitors have developed. Hemophilia patients with inhibitors need bypass agents, allowing activation of the extrinsic and common pathways of the clotting cascade. Activated 4-factor PCC is given at doses of 50 to 100 U/kg every 6 to 12 hours. Another widely used bypass agent is activated factor VII (factor VIIa), a recombinant factor protein administered at 90 μg/kg every 2 hours until the bleeding is controlled. This agent is used to control

bleeding in patients with hemophilia inhibitors, acquired hemophilia, congenital factor VII deficiency, and Glanzmann thrombasthenia. It has also been used successfully in Bernard-Soulier syndrome. Several virally inactivated plasma-derived VWF concentrate products and one recombinant VWF are available. The plasma-derived VWF products also contain factor VIII and are particularly useful for bleeding or prophylaxis in moderate to severe VWD when factor VIII levels are low. Recombinant VWF has no factor VIII, so it would need additional factor VIII infused if factor VIII levels were low, as can happen in VWD.

Cryoprecipitate Transfusion Therapy Cryoprecipitate is an often overlooked but important blood product for the treatment of a variety of bleeding disorders. It is prepared by thawing frozen plasma and removing the precipitated portion. It contains a narrow array of coagulation factors, but fibrinogen, factor VIII, VWF, and factor XIII occur in high concentrations. A major advantage of cryoprecipitate is that the average single unit is only 10 to 20 mL (E-Fig. 52.3). Based on its contents and small volume, cryoprecipitate is useful for the replacement of fibrinogen in DIC or in patients with hypofibrinogenemia or dysfibrinogenemia. The product may be helpful for isolated factor XIII deficiency or factor XIII consumption in DIC. Mounting evidence suggests that the VWF and factor VIII in cryoprecipitate can be used to overcome bleeding in uremia by enhancing the adhesive properties of circulating platelets. Cryoprecipitate is most frequently administered for hypofibrinogenemia, and appropriate dosing should take into account a patient’s total plasma volume, baseline fibrinogen levels, and goal fibrinogen levels. For most bleeding associated with hypofibrinogenemia, a goal fibrinogen of more than 100 mg/dL is reasonable. For a 70-kg adult with a fibrinogen level less than 100 mg/dL, a 10-unit pool (total volume of about 150 to 200 mL) should be sufficient to provide adequate fibrinogen. For more complex dosage protocols, such as for children, obese patients, or those with extreme hypofibrinogenemia, consultation with the blood bank is strongly recommended for specific calculations.

PROSPECTUS FOR THE FUTURE Novel modalities continue to be developed for the diagnosis of patients with bleeding disorders. For instance, assays measuring thrombin generation, thromboelastography (TEG), and rotational thromboelastometry (ROTEM) offer a quantitative view of coagulation that may provide greater insight into the source of abnormal bleeding than current tests. Alternatives and improvements in transfusion are also being developed, including cells harvested from induced progenitor cells that can be customized for specific needs. Progress continues to be made in the development and application of novel therapies for hemophilia. Finally, gene therapy and gene editing portend an exciting shift in hematology and medical care, in general.

CHAPTER 52  Disorders of Hemostasis: Bleeding

548.e1

E-TABLE 52.3  Factor Replacement Guidelines for Hemophilia A and B Injury

Factor VIII Initial Dose (U/kg)a

Factor IX Initial Dose (U/kg)b

Dental prophylaxis Hemarthrosis Muscle hematoma Trauma or surgery

15-25 15-50 15-50 50

20-50 30-100 30-100 100

aDosing

intervals should be based on a factor VIII half-life of about 12 hours. Maintenance doses of one half the listed dose may be additionally provided at these intervals. bDosing intervals should be based on a factor IX half-life of about 18 to 24 hours. Maintenance doses of one half the listed dose may be additionally provided at these intervals.

E-Fig. 52.3  A pool of cryoprecipitate. Cryoprecipitate units are prepared by thawing fresh-frozen plasma at cold temperatures to yield a concentrated precipitate containing only fibrinogen, fibronectin, von Willebrand factor, factor VIII, and factor XIII. Individual units of cryoprecipitate typically contain 10 to 20 mL. Cryoprecipitate is stored in the frozen state (shown) at less than −18° C and must be thawed before issuing and administration. The shelf life while frozen is 1 year.

CHAPTER 52  Disorders of Hemostasis: Bleeding

SUGGESTED READINGS Altomare I, Wasser J, Pullarkat V: Bleeding and mortality outcomes in ITP clinical trials: a review of thrombopoietin mimetics data, Am J Hematol 87:984–987, 2012. Hayward CP, Moffat KA, Liu Y: Laboratory investigations for bleeding disorders, Semin Thromb Hemost 38:742–752, 2012. Hod E, Schwartz J: Platelet transfusion refractoriness, Br J Haematol 142:348–360, 2008. Kearon C, Akl EA, Ornelas J, et al: Antithrombotic therapy for VTE disease, ed 10, American College of Chest Physicians Guideline and Expert Panel Report, Chest 149:315–352, 2016. Levy JH, Greenberg C: Biology of factor XIII and clinical manifestations of factor XIII deficiency, Transfusion 53:1120–1131, 2013. Mahlangu J, Oldenburg J, Paz-Priel I, et al: Emicizumab prophylaxis in patients who have hemophilia A without inhibitors, N Engl J Med 379:811–822, 2018. Mannucci PM: New therapies for von Willebrand disease, Hematology Am Soc Hematol Educ Program 590–595, 2019.

549

Menegatti M, Biguzzi E, Peyvandi F: Management of rare acquired bleeding disorders, Hematology Am Soc Hematol Educ Program 80–87, 2019. Roback JD, Caldwell S, Carson J, et al: Evidence-based practice guidelines for plasma transfusion, Transfusion 50:1227–1239, 2010. Rydz N, James PD: Why is my patient bleeding or bruising?, Hematol Oncol Clin North Am 26:321–344, viii, 2012. Seligsohn U: Treatment of inherited platelet disorders, Haemophilia 18(Suppl 4):161–165, 2012. Sharma R, Haberichter SL: New advances in the diagnosis of von Willebrand disease, Hematology Am Soc Hematol Educ Program 596–600, 2019. Wada H, Matsumoto T, Hatada T: Diagnostic criteria and laboratory tests for disseminated intravascular coagulation, Expert Rev Hematol 5:643–652, 2012. Weyand AC, Pipe SW: New therapies in hemophilia, Blood 133:389–398, 2019. Winkelhorst D, Murphy MF, Greinacher A, et al.: Antenatal management in fetal and neonatal alloimmune thrombocytopenia: a systematic review, Blood 129:1538–1547, 2017.

53 Disorders of Hemostasis: Thrombosis Rebecca Zon, Nathan T. Connell

PATHOLOGY OF THROMBOSIS The Virchow triad defines the pathologic mechanisms underlying thrombosis: diminished blood flow, damage to the vascular wall, and an imbalance favoring procoagulant over anticoagulant factors. The first two factors are clearly localized to specific vascular beds; although the last element of the triad may be systemic, data show at least partial regulation of the hemostatic balance by anatomic region. For example, congenital deficiency of antithrombin, protein C, or protein S typically leads to venous thromboembolism (VTE) of the lower extremities. In contrast, the inherited hypercoagulable disorders associated with the factor V Leiden and prothrombin G20210A mutations not only produce lower extremity VTE but also are associated with thrombosis of the cerebral veins and sinuses. This hemostatic regulation in vascular tissues is mediated by multiple factors that include (1) microenvironmental signals, such as shear stress resulting from turbulence in the disrupted flow of damaged vessels, that affect endothelial cell (EC) expression of thrombomodulin, tissue factor, and nitric oxide synthase as well as platelet activation; (2) EC subtype–specific signaling (e.g., shear stress upregulates aortic, but not pulmonary artery, nitric oxide synthase); (3) differences in EC transcriptional regulation of proteins such as von Willebrand factor (VWF) and its cleaving protease, ADAMTS13; and (4) the increasingly appreciated important link between inflammation and thrombosis that is mediated in both physiologies by selectin and integrin ligands.

Atherothrombosis This section briefly discusses hematologic factors that predispose to thrombosis in the setting of atherosclerotic plaque (atherothrombosis); the pathophysiologic mechanisms of atherogenesis are discussed in Chapter 8.

Atherothrombosis and Fibrinolysis In addition to EC-directed regulation of hemostasis, the interaction of EC with the fibrinolytic system is important in the development of atherothrombotic disease because it affects the degree of clot propagation. The breakdown of stable fibrin polymers into fibrin split products, including the D-dimer segments that are routinely measured in the laboratory to detect recent thrombosis, is mediated by plasmin. Plasmin is converted from its inactive form, plasminogen, by tissue-type plasminogen activator (t-PA), the activity of which is regulated by plasminogen activator inhibitor-1 (PAI-1). Abnormal levels of both t-PA and PAI-1 are epidemiologically associated with an increased risk for arterial thrombosis, but the degree to which absolute levels contribute to arterial thrombosis remains controversial. For this reason, the current clinical utility of t-PA and PAI-1 measurements is limited.

550

There is a correlation between higher PAI-1 levels and atherosclerotic disease, which is possibly due to the fact that PAI-1 is markedly increased in generalized inflammation and there is known thrombosis-inflammation interplay. This is especially prominent in patients with type 2 diabetes with acute myocardial infarction and stroke. Elevated PAI-1 levels systemically may prevent thrombi removal from vessels, whereas locally it contributes to increased fibrin deposition in the lumen of the vessels. Currently there are agents that indirectly decrease PAI-1 levels, including angiotensin-converting enzyme (ACE) inhibitors and diabetes medications (including thiazolidinediones and metformin). The first PAI-1 antagonist, tiplaxtinin, has been studied in experimental models and was found to decrease VTE and atherosclerosis, although the clinical trial was discontinued given unfavorable risk-benefit outcomes. Also, meta-analyses have demonstrated PAI-1 4G/5G polymorphisms represent a risk candidate locus for higher VTE risk, which is even further heightened in patients with genetic thrombophilic disorders.

Hyperhomocysteinemia in Arterial Disease Increased levels of plasma homocysteine (HCY) are linked to atherothrombosis. The rare congenital syndromes (e.g., cystathionine β-synthase deficiency) that are characterized by homocystinuria and hyperhomocysteinemia are associated with both VTE and premature atherosclerosis. Elevated HCY induces EC dysfunction and apoptosis, triggering normal coagulation pathways designed to respond to EC damage but without the corresponding upregulation of EC-dependent anticoagulant function (e.g., activated protein C [APC]). Even moderate elevations in HCY may thus contribute to coronary, peripheral, and cerebral arterial disease. Mildly elevated HCY levels are associated with the thermolabile form of the methylene tetrahydrofolate reductase (MTHFR) enzyme, which results from a polymorphism (C677T) in the coding region of the MTHFR binding site. This isoform occurs in 30% to 40% of the general population and introduces a higher set point for regulation of HCY concentration (the substrate for MTHFR), particularly when a relative folate deficiency exists. In fact, deficiency of any of the vitamin cofactors of HCY metabolism (folate, vitamin B6, and vitamin B12) may lead to mild hyperhomocysteinemia. Reduction in HCY levels by supplementation with vitamin B6, vitamin B12, and folate is probably the most effective means of reducing modest HCY elevations, but such supplementation and ultimately lower HCY levels does not decrease atherothrombotic risk, regardless of the cause of hyperhomocysteinemia or the presence of the MTHFR polymorphism. Therefore, the origin of the connection between high HCY and thrombosis remains incomplete, and the search for associated factors that link HCY and hypercoagulability continues.

CHAPTER 53  Disorders of Hemostasis: Thrombosis

TABLE 53.1  Antiplatelet Therapies Inhibitors of Cyclooxygenase Aspirin Nonaspirin NSAIDs (not COX2 selective) P2Y12 Antagonists Prasugrel Ticagrelor Clopidogrel Phosphodiesterase Inhibitors Dipyridamole Prostacyclin GPIIB/IIIA Blockers Abciximab Integrilin Tirofiban COX2, Cyclooxygenase 2; GPIIb/IIIa, glycoprotein IIb/IIIa complex; NSAIDs, nonsteroidal anti-inflammatory drugs.

Role of Platelets in Atherothrombosis Although EC-associated abnormalities clearly influence hemostasis, platelet activation and adhesion are also critical to the development of atherothrombosis, especially in patients with acute coronary syndrome or ischemic stroke. Antiplatelet therapies are the primary modalities for maintaining short- and long-term patency in arteries, especially after coronary revascularization. Antiplatelet therapy can be targeted against specific platelet functions, including cyclooxygenase-mediated formation of thromboxane A2, interaction of adenosine diphosphate (ADP) with its platelet receptor, and binding of the glycoprotein IIb/ IIIa complex (GPIIb/IIIa) to fibrinogen for aggregation (Table 53.1). Aspirin has long been a mainstay in the treatment of myocardial infarction, angina, and stroke because of its irreversible inhibition of platelet cyclooxygenase, a process that blocks the release of thromboxane A2. Aspirin effectively prevents platelet aggregation over the lifetime of a platelet (7 to 10 days); however, aspirin is usually unable to inhibit platelet activation, secretion, and aggregation by thrombin or other strong agonists such as collagen. Therefore, blockade of other platelet activation pathways is important for patients who are at risk for arterial thrombosis. Some drugs used to treat stroke or coronary disease (i.e., clopidogrel and prasugrel) specifically block platelet P2Y12, the ADP receptor, from interaction with ADP in the clot milieu, thereby decreasing platelet recruitment by preventing locally released ADP from activating additional platelets. The CHANCE Trial (2013) and POINT Trial (2018) have shown reduced 90-day stroke risk with the combination of ASA/clopidogrel compared with ASA alone, although results are conflicting between the trials about increased bleeding risk with dual antiplatelet therapy (DAPT). In symptomatic peripheral arterial disease (PAD), where there is poor flow in the extremities due to atherosclerotic plaque, there are benefits with using clopidogrel compared to aspirin (demonstrated by the CAPRIE Trial 1996) but no additional benefit to using both clopidogrel and aspirin together as compared to clopidogrel monotherapy (demonstrated by the MATCH Trial 2004). Antiplatelet therapy with aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) also reduces the risk of stent thrombosis and subsequent cardiovascular events after percutaneous coronary intervention and should be administered for at least 12 months unless

551

the patient is at high risk for bleeding. The PLATO Trial (2009) showed, in acute coronary syndrome, prasugrel and ticagrelor further reduce cardiovascular ischemic events compared with clopidogrel, although they are associated with higher bleeding risk. This effect occurs because drug interactions and variant cytochrome genotypes do not significantly affect production of the active metabolites of prasugrel and ticagrelor; the result is greater and more rapid inhibition of P2Y12 receptor–mediated platelet aggregation in most patients. The EUCLID Trial showed that in PAD, there was no improvement with ticagrelor compared to clopidogrel in terms of cardiovascular death, myocardial infarction, or stroke. Despite its wide use, a significant proportion (up to one third) of patients demonstrate functional platelet resistance to clopidogrel. Under such circumstances, clopidogrel is poorly metabolized to its active form because of the presence of polymorphisms in the cytochrome P-450 gene, CYP2C19, that cause loss of function. The more potent inhibitor, prasugrel, is not affected by cytochrome P-450 genotypes, although nongenetic factors such as platelet turnover, absorption, and compliance also play important roles in response variability. A third avenue for blocking platelet activation targets GPIIb/IIIa, the primary platelet receptor for binding to fibrinogen and VWF. Abciximab, a modified monoclonal antibody, prevents GPIIb/IIIa from binding to fibrinogen and blocks platelet aggregation after angioplasty, stent placement, or pharmacologic thrombolysis. Abciximab has been shown to reduce the incidence of recurrent acute ischemic events after percutaneous coronary revascularization in patients with myocardial infarction or unstable angina, mainly by decreasing the incidence of platelet-mediated thrombosis within the infarct-related vessel during and after the procedure. Other GPIIb/IIIa blockers, including eptifibatide (Integrilin) and tirofiban (Aggrastat), interfere with the GPIIb/IIIa arginine-glycine-aspartate (RGD) binding sites; they are used acutely for parenteral administration in patients with acute coronary syndrome or to maintain coronary patency after percutaneous coronary intervention. Thrombocytopenia is an uncommon (5

1 1 4 (MI in men)

7 8.5 8 ≈1

1 1 1 1.5

Activated protein C resistance (5%)

Heterozygous FVL Homozygous FVL Prothrombin G20210A mutation (1-2%)

Heterozygous Homozygous Platelet GPIIb/IIIa HPA-lb homozygosity (2-3%) Protein C deficiency (0.2-0.5%) Protein S deficiency (0.1%) AT deficiency (0.02-0.05%) Dysfibrinogenemia (rare)

AT, Antithrombin; FVL, factor V Leiden; GPIIb/IIIa, glycoprotein IIb/IIIa complex; HPA-1b, human platelet antigen-1b; MI, myocardial infarction; RR, relative risk. aData on prevalence and relative risk vary widely, often with conflicting results. This information represents an interpretation of data collected from various sources, mainly meta-analyses.

When using platelet inhibitors, physicians and patients must also consider the risk of bleeding if they are on anticoagulation therapy. RE-DUAL (2017) and WOEST (2013) concluded that in patients on anticoagulation prior to percutaneous coronary intervention (PCI) it is recommended to use additionally only clopidogrel rather than ASA/clopidogrel after PCI given the increased bleeding risk with triple therapy.

Venous Thromboembolism: Inherited Risk Factors The balance between thrombin formation and anticoagulant pathways has been extensively studied in patients with inherited deficiencies of naturally occurring anticoagulants (Table 53.2). These patients are predisposed to VTE, which includes deep vein thrombosis (DVT) and pulmonary embolism (PE).

Factor V Leiden The most common inherited disorder leading to VTE is the factor V Leiden (FVL) mutation although it remains a fairly weak risk factor for VTE overall. About 5% of individuals of European ancestry are heterozygous for FVL. The FVL mutation increases VTE risk by decreasing the susceptibility of factor Va to APC-mediated inactivation and by impairing the APC-cofactor activity of factor V in factor VIIIa inactivation, all of which lead to increased thrombin generation. APC resistance can be demonstrated by specialized clotting tests in which the addition of APC fails to inhibit thrombin generation. About one fourth of patients with their first VTE are heterozygous for FVL, and this percentage increases to almost 60% among those with recurrent VTE or a strong family history of VTE. Heterozygous FVL mutation conveys a 7-fold increased risk for VTE. However, at 50 years of age, only 25% of persons with heterozygous FVL mutation have had VTE, compared with much higher percentages in other inherited thrombophilias. It is with concomitant acquired risk factors such as immobilization, pregnancy, or oral contraceptive use that the risk for VTE in persons with FVL mutation becomes more significant. The prothrombin G20210A mutation demonstrates a synergistic effect with FVL mutation, but the MTHFR

mutation does not. Homozygous FVL mutation individuals have a 20- to 80-fold increased risk for VTE. APC resistance without the FVL mutation occurs rarely. Factor V Cambridge mutation, although much less common than FVL mutation, has a similar mutation at an APC cleavage site (Arg306) and is associated with APC resistance and thrombosis. Other minor alleles of factor V, including the 6755 A/G (D2194G) R2 haplotype, may enhance APC resistance. When this haplotype is on a different chromosome than the FVL mutation, it diminishes normal factor V transcription and increases the ratio of FVL to normal factor V.

Prothrombin G20210A Another mutation associated with inherited thrombophilia is the prothrombin G20210A mutation, which occurs in the 3′-untranslated region of the prothrombin gene. This mutation leads to higher than normal prothrombin levels and a 2-fold increased risk for VTE. The heterozygous mutation is present in about 3% of European-derived populations but is identified in about 15% of patients with VTE. Patients homozygous for prothrombin G20210A are rare, but their relative risk for VTE is thought to be about 10-fold. Exactly how the prothrombin mutation affects thrombus development has not been fully defined, but changes in polyadenylation of the prothrombin messenger RNA (mRNA) during transcription appear to be involved. The distribution of circulating prothrombin levels overlaps significantly between those with and without the mutation, so Factor II levels are not helpful in diagnosing the condition. Diagnosis of the G20210A genotype is made by examination of the patient’s DNA for this specific mutation; no screening or functional assays are available.

Inherited Deficiency of Natural Anticoagulants Deficiencies in the natural anticoagulant proteins (antithrombin, protein C, and protein S) are less common than FVL or prothrombin G20210A, but they are more likely to produce symptomatic VTE at an earlier age. Only about one half of the cases of VTE occurring in patients with these deficiencies are associated with acquired risk factors such as pregnancy, surgery, or immobilization. Deficiencies of antithrombin, protein C, or protein S are detected by functional or antigenic assays because some mutations cause a quantitative decrease in the factor, whereas others produce a dysfunctional protein. Many gene mutations have been associated with these deficiencies, but none is predominant. Deficiencies of antithrombin (AT), protein C, and protein S in the aggregate account for fewer than 5% to 10% of all patients with VTE. Antithrombin is a naturally occurring anticoagulant that complexes with endogenous heparin sulfates to inhibit both formed thrombin and factor Xa. Heterozygous antithrombin deficiency leads to antithrombin activity levels less than 70% of normal and a 20-fold increase in the risk for VTE; VTE usually occurs by the age of 25 years in 50% of such patients. More than 200 associated mutations are known. Homozygous mutations are very rare, likely because of lethality in utero. Acquired causes of antithrombin deficiency are more common. Because antithrombin has a low molecular weight, it is lost in the proteinuria of nephrotic syndrome. Acquired antithrombin deficiency is common in patients receiving asparaginase therapy for acute lymphocytic leukemia and may also be associated with severe hepatic veno-occlusive disease after stem cell transplantation; antithrombin and protein C may be excessively consumed in the damaged hepatic microvasculature. Low levels of antithrombin are also associated with poorer outcomes in severely ill patients. Successful treatment of symptomatic patients with heterozygous antithrombin deficiency has included short-term replacement with fresh-frozen plasma or recombinant AT protein, usually coupled with unfractionated heparin (UFH) anticoagulation; long-term therapy for congenitally deficient

CHAPTER 53  Disorders of Hemostasis: Thrombosis patients has consisted primarily of warfarin although the direct oral anticoagulants have become increasingly popular due to their lack of requiring functional antithrombin activity in order to cause an anticoagulant effect. The complex of thrombin and thrombomodulin on the EC surface activates protein C; APC coupled with its cofactor, protein S, cleaves and inactivates factors Va and VIIIa. These actions downregulate the prothrombinase and tenase complexes, respectively, to slow the rate of thrombin generation. Like antithrombin deficiency, heterozygous protein C and protein S deficiencies are observed with venous, and occasionally arterial, thrombosis in younger patients (median age at occurrence, 20 to 40 years). The rare homozygous protein C deficiency manifests in the neonate as purpura fulminans with widespread VTE and skin necrosis. A similar clinical presentation has been reported in heterozygous protein C–deficient adults after institution of warfarin therapy without simultaneous heparinization; this is called warfarin-induced skin necrosis. About one third of these patients are deficient in protein C on a hereditary basis, whereas the rest appear to have acquired protein C deficiency, possibly associated with vitamin K deficiency. Warfarin is a vitamin K antagonist that inhibits production of vitamin K–dependent protein C synthesis; and because of its short half-life, protein C levels rapidly fall before a decline in the levels of the procoagulant factors II, IX, and X. This imbalance shortly after starting warfarin favors a procoagulant state and may result in widespread microvascular thrombosis. Therefore, patients with active VTE should be fully anticoagulated with UFH or low-molecular-weight heparin (LMWH) before concurrent warfarin therapy is begun. UFH/LMWH should be continued for at least 48 hours, warfarin has a full therapeutic effect. Inherited deficiency of protein S has similarly been implicated in warfarin-induced skin necrosis. Protein S deficiency is commonly acquired in acute illness. Protein S circulates in a free form and is bound by complement 4b (C4b)-binding protein; only free protein S is active as a cofactor for protein C. Because C4b-binding protein is an acute phase reactant, its increase with severe illness can decrease the level of free protein S. A similar effect is seen in normal pregnancy. Short-term therapy for homozygous protein C deficiency or for doubly heterozygous protein C or S deficiency, especially in the setting of neonatal purpura fulminans, has included plasma or protein C concentrate with full-dose UFH anticoagulation. Functional and antigenic levels of antithrombin, protein S, and protein C can be assessed to define whether functional deficiency is caused by a dysfunctional protein or by diminished synthesis. As with AT deficiency, initial heparin therapy followed by long-term treatment with warfarin has been successful in heterozygous protein C or S deficiency. As expected, both protein C and protein S levels are decreased during warfarin therapy; therefore, for adequate evaluation of protein C and S, the patient must not be taking warfarin when tested.

Venous Thrombosis: Acquired Risk Factors Surgery and Medical Hospitalization

Medical and surgical illnesses convey increased thrombotic risk; these acquired risk factors are well accepted, even though the pathophysiologic features favoring thrombosis may be uncertain (Table 53.3). Stasis of blood flow is a clear risk factor for thrombus formation (e.g., VTE in immobilized inpatients). Other high-risk situations, including surgery (especially orthopedic) and trauma, are similarly associated with immobilization and stasis of lower extremity blood flow. When evidence of thrombosis is thoroughly sought, both surgery and trauma can be shown to be associated with extremely high (>50%) incidences

553

TABLE 53.3  Acquired Risk Factors for

Thrombosis

Medical and Surgical Illnesses Antiphospholipid antibody, lupus anticoagulant Artificial heart valves Atrial fibrillation (nonvalvular) Congestive heart failure Hemolytic anemias (autoimmune hemolysis, sickle cell, thrombotic thrombocytopenic purpura, paroxysmal nocturnal hemoglobinuria) Hyperlipidemia Immobilization Malignancy Myeloproliferative disorders with thrombocytosis Nephrotic syndrome Orthopedic procedures Pregnancy Trauma, fat embolism Medications Heparin-induced thrombocytopenia Oral contraceptives, hormone replacement therapy Prothrombin complex concentrates

of VTE. Fat embolism and tissue damage may also contribute to the risk for VTE with surgery and trauma, particularly in closed head injuries that result in massive tissue factor release. Prophylactic inferior vena cava (IVC) filters are often placed in trauma patients to protect against PE, especially in high-risk patients for whom anticoagulation is contraindicated because of the increased risk for bleeding, but there remains a high risk for thrombus formation proximal to the filter with subsequent pulmonary embolism. IVC filters should be removed as soon as patients may be safely anticoagulated. All hospitalized medical patients should be considered for venous thromboprophylaxis with UFH or LMWH. Factors that increase bleeding risk that argue against anticoagulation include thrombocytopenia (typically a platelet count 4); gradual downward titration of the DTI as the INR increases is a logical management strategy. Once DTIs are stopped, it is essential to repeat the INR measurement after 4 to 6 hours to confirm that it remains within the therapeutic range. If there is no thrombosis with HIT, the total duration of anticoagulation should be at least 4 weeks; if thrombosis is present, anticoagulation should be continued for 3 to 6 months. Warfarin should never be used as initial therapy to treat HIT, and it should not later be instituted without simultaneous DTI coverage because it may induce acquired protein C deficiency leading to venous limb gangrene. One hallmark of protein C depletion in HIT is a sudden rise in the INR (to >3.5) after a single warfarin dose; in that circumstance, warfarin should be discontinued and the patient repleted with vitamin K. Patients with a history of HIT who need surgery requiring cardiopulmonary bypass can be safely reexposed to brief systemic UFH if ELISA testing is negative for the antibody at least 100 days after the previous UFH exposure.

556

SECTION VIII  Hematologic Disease

Thrombotic Thrombocytopenic Purpura Another cause of thrombocytopenia resulting from platelet activation and clearance is TTP. In patients with congenital or familial TTP, mutations in the VWF-cleaving protease, ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13), abrogate its activity. Patients with acquired TTP usually have an antibody that blocks the normal function of VWF-cleaving protease to less than 10% of normal. Ultralarge VWF multimers released by EC normally anchor to EC through P-selectin and form long strings that adhere and aggregate platelets in the microcirculation. ADAMTS13 downregulates the size of these multimers by docking to the A1/A3 VWF domains and cleaving within the A2 site. Deficient cleaving protease function in TTP leads to an increase in the larger, highest-molecular-weight VWF multimers, which are most effective in anchoring and activating platelets. These, in turn, cause increased platelet adhesion and clearance without activating the coagulation cascade. Therefore, both the prothrombin time (PT) and the PTT are normal in TTP, unlike the case in DIC. TTP after chemotherapy (mitomycin C) or in association with pregnancy, stem cell transplantation, lupus, or HIV infection appears to have a similar pathogenic mechanism of thrombosis. Thrombocytopenia (often severe) is accompanied by microangiopathy with schistocytes on smear and increased serum lactate dehydrogenase. Microvascular occlusions in multiple organs cause symptoms, especially in the kidney and brain. The classic pentad (fever, thrombocytopenia, microangiopathic hemolysis, neurologic symptoms, and renal insufficiency) is present in fewer than 5% of patients with TTP. The diagnosis is typically made based on the clinical assessment of thrombocytopenia and microangiopathic hemolytic anemia; assays for ADAMTS13 activity and inhibitor do not have a rapid turnaround time in most laboratories. Clinical prediction scores (e.g., the PLAMIC score) are helpful as an additional piece of clinical information in the decision to initiate treatment for TTP but cannot be used on their own to exclude TTP. In validation studies, some patients ultimately found to have an ADAMTS13 activity level, less than 10% were noted to have low PLASMIC scores. Treatment of familial TTP is based on replenishment of cleaving protease activity with plasma transfusion; acquired TTP additionally requires removal of the antibody. The latter is accomplished by therapeutic plasma exchange, whereby patient plasma is removed (plasmapheresis) and replaced with fresh-frozen plasma, which often has been made “cryo-poor” to reduce ultralarge VWF multimers in transfused plasma. Corticosteroids are often administered simultaneously, but any added benefit to plasma exchange remains unclear. Platelet transfusions are relatively contraindicated in TTP because of the risk of thrombosis, and they should not be given for thrombocytopenia in the absence of significant bleeding. When plasma exchange fails to remit acquired TTP or when early relapse occurs, immunosuppressive therapy with anti-CD20 may be successful and data suggest that early rituximab will reduce the risk of relapse. The mortality rate associated with severe TTP (defined as undetectable ADAMTS-13 activity) is still significant, almost 10% at 18 months after therapy with plasma exchange. Replacement of ADAMTS-13, which is present in fresh-frozen plasma and in cryoprecipitate, is a potential treatment. Clinical trials have shown the anti-VWF therapy caplacizumab to have benefit in reducing the number of days of plasma exchange needed to achieve a normal platelet count and also reductions in mortality, although with increasing bleeding risk. The ideal subset of patients to receive caplacizumab in conjunction with other therapies for TTP remains to be defined. Caplacizumab does not address the underlying autoantibody causing ADAMTS13

deficiency and use of rituximab for inhibitor eradication is most likely to be beneficial in patients receiving caplacizumab therapy. The hemolytic-uremic syndrome (HUS) is part of the TTP spectrum of disease and also is associated with microvascular platelet thrombi. However, the hemolytic anemia and renal failure of HUS are not usually accompanied by neurologic impairment, and HUS usually does not produce the same degree of thrombocytopenia or microangiopathy as TTP. Moreover, fewer than 3% of HUS cases are associated with any decrease in VWF-cleaving protease activity. Unlike TTP, HUS is usually diagnosed in children (and less commonly in adults) who have hemorrhagic colitis caused by Shiga-like, toxin-producing bacteria, especially the Escherichia coli O157:H7 serotype. Atypical HUS (i.e., without diarrhea or Shiga-like toxin) is rarely associated with other bacterial infections or with complement dysregulation due to mutations or polymorphisms in factors H, I, and B. These mutations increase platelet activation through complement (C3) deposition on the platelet surface. Atypical HUS cases are those that are clinically consistent with HUS but are not associated with toxin-producing bacteria. Some HUS cases, particularly atypical forms, may temporarily respond to plasma exchange along with maintenance hemodialysis until renal function recovers. Data support use of the anti-C5a complement therapy eculizumab to prevent the complement-mediated damage associated with this disease. More recently, a modified form of eculizumab with a longer half-life, ravulizumab, has been approved to treat atypical HUS, allowing patients longer intervals between therapeutic infusions.

CLINICAL EVALUATION OF THROMBOSIS The approach to patients with thromboembolism is defined by the clinical history, results of laboratory studies, and even physical findings. Events that trigger VTE disease include immobilization, orthopedic and other surgical procedures, use of oral contraceptives, and pregnancy. VTE that is recurrent (thrombophilia) may manifest at an early age or at unusual thrombotic sites (e.g., cerebral vessels) and may be accompanied by a family history of VTE, suggesting an inherited disorder. Acquired VTE risk may be associated with systemic disorders such as hemolysis (e.g., PNH, autoimmune hemolytic anemia), collagen vascular disorders (e.g., lupus), or various malignant diseases (e.g., adenocarcinoma). In contrast, arterial thromboembolic disease is more commonly superimposed on ruptured atherosclerotic plaque (e.g., coronary artery disease) or on atheroembolic disorders (e.g., ischemic stroke, peripheral arterial disease). Arterial vascular disease is mainly associated with metabolic risk factors including hypertension, hypercholesterolemia, and diabetes. The clinical approach to thrombotic disease is tailored to the location of the disease (arterial vs. venous and the specific vascular bed) and whether there are abnormalities of the vascular endothelium, platelets, or soluble coagulation factors that predispose the patient to thromboembolic risk.

Laboratory Diagnostics Recurrent VTE is a strong indication for laboratory testing for causes of thrombophilia, especially in patients younger than 50 years of age, in those with unexplained VTE, and in those with a first-degree family history of VTE. Any risk factors that may predispose these individuals to recurrence must be defined, as well as any inherited disorders that may necessitate family counseling or avoidance of additional environmental risks. The current work-up for VTE thrombophilia includes the following: (1) APC resistance, (2) genotyping for prothrombin G20210A, (3) lupus anticoagulant assay and anticardiolipin and anti–β2-glycoprotein I antibody serologies, (4) functional AT and protein C levels, and (5) free protein S (Table 53.4).

CHAPTER 53  Disorders of Hemostasis: Thrombosis

TABLE 53.4  Laboratory Evaluation of

Venous Thrombosis

Activated protein C resistance, factor V Leiden Lupus anticoagulant Anticardiolipin, anti–β2-glycoprotein I antibody serology Homocysteine level: fasting or after methionine load Prothrombin G20210A mutation Antithrombin activity Protein C activity Free protein S level Paroxysmal nocturnal hemoglobinuria (select patients) Myeloproliferative disorders (in select patients)

Genotyping for the FVL mutation can substitute for APC resistance and also determines whether the patient is heterozygous or homozygous, although it may miss rare variants of APC resistance. Patients need to be off of warfarin during these tests and they should not be performed during the acute episode, given the changes in protein levels during these instances. The utility of laboratory testing in the setting of atherothrombosis and arterial thromboembolism is unclear. In the setting of a myeloproliferative disorder, the use of hydroxyurea and/or aspirin therapy may be justified by platelet count and platelet function testing, but typically risk prediction models based on age and prior thrombosis are used to guide management decisions. In patients with unusual or recurrent arterial disease, other assays can be justified, including testing for t-PA and PAI-1 levels and for dysfibrinogenemia (thrombin time and antigen activity ratio), all of which should be performed in consultation with specialists in hemostasis.

THERAPY FOR VENOUS THROMBOEMBOLISM Once VTE has been diagnosed, immediate therapy is required. In most patients, anticoagulation options include heparin, LMWH, or the newer direct oral anticoagulants (DOACs) (i.e., apixaban, rivaroxaban) initially and then warfarin or DOACs thereafter. The DOACs edoxaban and dabigatran require initial parenteral anticoagulation prior to use of the DOAC, but apixaban and rivaroxaban may be started as initial therapy with higher doses. Thrombolytic therapy is indicated for patients with extensive proximal venous clots or PE. IVC filters are used in patients with contraindications to anticoagulation, complications of anticoagulation (usually active bleeding), or failure of anticoagulation (recurrent PE). IVC filters clearly decrease the incidence of early PE, but their use is also associated with thrombosis at the insertion site and late complications of IVC thrombosis as well as a 10% to 20% incidence of postphlebitic syndrome. In patients who may be safely anticoagulated, IVC filters do not reduce the risk of pulmonary embolism and appear to be associated with a higher risk of PE. Temporary IVC filters are often used in trauma patients and appear to be most efficacious when they are placed for fewer than 7 to 10 days. UFH is often the anticoagulation therapy of choice for many inpatients because of its short half-life and reversibility, but LMWH is increasingly used for this indication. UFH is begun as a bolus intravenous infusion of 80 U/kg, followed by a continuous infusion of 18 U/ kg/hour; UFH doses in excess of 30,000 U/day have been shown to be most efficacious at preventing recurrent VTE. UFH is monitored by the PTT, and the therapeutic PTT range determined by each hospital corresponds to anti-Xa levels of 0.3 to 0.7 U/mL. Many hospitals have established protocols for adjustment of UFH infusion based on the patient’s weight and PTT monitoring.

557

UFH should be continued for at least 5 days (longer in patients with extensive clots) and may be discontinued after the patient has been fully anticoagulated with warfarin (INR ≥2 for 2 consecutive days). Some patients receiving large doses of heparin (usually >40,000 U/day) do not develop a therapeutic PTT. This heparin resistance can be caused by a variety of mechanisms, including increased heparin-binding proteins, counteracting medications (e.g., protamine), and decreased antithrombin. An apparent heparin resistance is often seen in patients with coexistent inflammatory disease with high plasma levels of factor VIII and fibrinogen; direct monitoring of anti-Xa levels is indicated. It is important to remember that the anti-Xa level is a measurement of anticoagulant level in the blood but is not a direct measure of the anticoagulant effect present. Some patients may require a higher anti-Xa level in order to achieve therapeutic anticoagulation. LMWH is an excellent alternative to UFH in the treatment of thromboembolism and acute coronary events. The small controlled-size elements of LMWH stimulate antithrombin activity that is more restricted to factor Xa compared with UFH, which has effects on thrombin, factor IX, and factor XI, in addition to others. The practical advantages of LMWH over UFH include increased plasma half-life, more predictable dose response allowing for intermittent fixed dosing, a lower de novo incidence of HIT (10% to 20% of the rate for UFH), and significantly reduced monitoring requirements. LMWH levels are prolonged in renal failure and in those circumstances may need to be monitored and adjusted based on anti-Xa levels. Peak anti-Xa levels (0.5 to 1 U/mL for twicedaily dosing and 1 to 2 U/mL for once-daily dosing) typically occur between 3 and 5 hours after subcutaneous LMWH injection. As with UFH, switching from LMWH to warfarin for long-term management can be accomplished after therapeutic INR values have been present for at least 2 days. Supratherapeutic INR levels commonly occur with warfarin therapy, with or without bleeding. In patients with moderately elevated INR values (>5) and little or no bleeding, temporary discontinuation of warfarin and reinstitution of the drug at a lower maintenance dose may be sufficient. Patients with higher INR values (5 to 9) who are without serious bleeding should have warfarin withheld and should receive low doses (1 to 2.5 mg/day) of oral vitamin K to reach therapeutic INR levels; parenteral vitamin K may be given if gastrointestinal function is problematic. If serious active bleeding occurs with high INR values, especially if surgery is required to correct the bleeding, a combination of vitamin K and transfusion of plasma (see Chapter 52) will rapidly correct the INR. The INR can become elevated as a result of concurrent use of drugs that increase free warfarin levels (Table 53.5). Whenever bleeding occurs as a complication of anticoagulation, serious consideration must be given to future bleeding risks and to whether the patient requires placement of a filter for prophylaxis. Recently, DOACs have been used with increased frequency because their efficacy and safety have now been evaluated in many circumstances. For patients with acute DVT, the initial anticoagulation (within the first week or two) options include: oral factor Xa inhibitors rivaroxaban or apixaban (in addition to the previously mentioned LMWH, subcutaneous fondaparinux, or unfractionated heparin). The decision of which agent to use is based on risk of bleeding, clinician comfort, patient comorbidities, and cost. The doses are: rivaroxaban 15 mg twice daily for 21 days then 20 mg daily; apixaban 10 mg twice daily for 7 days then 5 mg twice daily. For long-term, maintenance therapy, the DOACs approved are: direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban), thrombin inhibitors (dabigatran); as mentioned, warfarin, LMWH and fondaparinux can also be used for

558

SECTION VIII  Hematologic Disease

TABLE 53.5  Guidelines for Duration of

Prophylactic Anticoagulation After VTE Condition

Duration of Therapy

Distal or superficial vein thrombus

3-12 wk

First Proximal VTE No risk factors Correctable risk factor (e.g., surgery, trauma) Malignancy Antiphospholipid syndrome Inherited risk factorc Recurrent VTE/PE

3-6 moa 3-6 mo Long-termb Long-term >6 mo Lifelong

PE, Pulmonary embolism; VTE, venous thromboembolism (includes deep vein thrombosis, pulmonary embolism, and sinus or cerebral thrombosis). aEvaluation of D-dimer after 3-6 mo may assist in the decision to stop prophylaxis. bLong-term therapy must be adjusted individually according to presence of other diseases, risks for bleeding, presence of transient risk factors, and ease of compliance. cInherited risk factors include factor V Leiden; prothrombin 20210A; deficiencies of antithrombin, protein C, or protein S.

long-term therapy. Dosing is as follows: dabigatran 150 mg BID (needs renal dose adjustment 75 mg BID if CrCl 15-30), edoxaban (after acute phase parenteral anticoagulation). DOACs are not recommended with severe renal impairment. However, apixaban can be dose adjusted for renal impairment and other variables. If creatinine is greater than 1.5, age older than 80, or weight 60 kg or less, decrease apixaban dosing to 2.5 mg orally twice daily. RE-COVER (2009) demonstrated, in patients with acute VTE, the oral direct thrombin inhibitor, dabigatran, was found to be as effective as warfarin for reducing recurrence risk and is associated with less bleeding. The benefit is that the DOACs have less variability in therapeutic range compared with warfarin and patients do not need to have blood drawn for INR checks when on the DOACs, as they have to do on warfarin. In summary, based on the most recent American College of Client Physicians (ACCP) Antithrombotic Therapy for VTE Disease Guidelines (2016), DVT of the leg or PE without cancer, dabigatran, rivaroxaban, apixaban, or edoxaban is preferred over vitamin K antagonist therapies as treatment for the 3 months of maintenance therapy. The treatment duration varies based on unprovoked or provoked DVT, location of clot, and initial or recurrent DVT. For most patients with a first episode of DVT (provoked and unprovoked, proximal and distal), treatment should be for 3 months. If proximal DVT or PE and low/moderate bleeding risk, this should be extended beyond 3 months. In patients with recurrent VTE, regardless of bleeding risk, the duration should be greater than 3 months and depending on risk factors of bleeding and patient comorbidities, indefinite anticoagulation may be recommended. The duration of therapy greater than 3 months has not been fully specified and will vary on a case-to-case basis. For patients who have received at least 6 to 12 months of anticoagulant therapy and have clinical equipoise to continue anticoagulation, low-dose rivaroxaban (10 mg once daily) or apixaban (2.5 mg twice daily) is safe and effective to reduce VTE risk with little to no increased bleeding risk as shown in the EINSTEIN Choice and AMPLIFY-EXT trials, respectively. After stopping anticoagulation for unprovoked proximal DVT or PE, guidelines suggest aspirin over no aspirin to prevent recurrent DVT in patients with no contraindication to aspirin but in whom ­anticoagulant is not continued.

Therapy for VTE in Malignancy In patents with malignancy, LMWH is preferred to warfarin. Based on the CLOT trial in 2003, dalteparin (LMWH) had a lower recurrent VTE risk without increasing bleeding risks or deaths compared to warfarin. These were confirmed in the 2006 LITE and ONCENOX trials. The Hokusai VTE Cancer Trial (2018) demonstrated that in patients with VTE and malignancy edoxaban was noninferior to dalteparin for recurrent VTE in an open label study but had higher bleeding risk. For specific malignancies, such as gastrointestinal cancer, LMWH is preferred to edoxaban for long-term anticoagulation (see Raskob 2017). Additionally, some studies recommend not using edoxaban if the CrCl is greater than 95, although the data for avoiding this medication in VTE are not clear. The SELECT-D pilot trial compared rivaroxaban todalteparin in cancer-associated VTE and showed a decreased rate of recurrent VTE in the rivaroxaban group compared to dalteparin but an increased rate of non-major bleeding. There are multiple current trials studying apixaban versus dalteparin for patients with malignancy-associated VTE: the Caravaggio Trial is ongoing, and preliminary results for ADAM-VTE suggest low bleeding risk and low VTE recurrence rates. In summary, based on the most recent ACCP Antithrombotic Therapy for VTE Guidelines (2016), for patients with cancer-associated VTE, as therapy for the first 3 months, LMWH is recommended over other agents whereas ASCO guidelines suggest DOACs may be used as first-line therapy. As mentioned previously, duration of therapy for VTE depends on cancer type (clotting and bleeding risks) and treatment plan for the malignancy. Given known interactions and lack of safety data, DOACs should not be prescribed for patients on dual P-glycoprotein and strong CYP3A inhibitors, including medications such as carbamazepine, phenytoin, ketoconazole, ritonavir, rifampin, and more. Certain antibiotics (i.e., erythromycin or clarithromycin) may increase levels of DOACs, especially in individuals with renal dysfunction.

Prophylaxis of VTE Even with the advent of the DOACs, both warfarin and LMWH are often used for treatment of VTE. Warfarin should be begun during the first 24 hours after presentation with VTE, concurrent with heparin treatment. The PT is prolonged within hours by warfarin because of a rapid decrease in factor VII levels; however, therapeutic warfarin anticoagulation does not occur until other vitamin K–dependent factors (II, IX, and X) also decrease. Therapeutic warfarin anticoagulation is usually achieved within 4 to 5 days with adequate warfarin dosing; UFH or LMWH may be discontinued after the INR has been greater than 2 for at least 2 consecutive days. One long-standing problem with warfarin anticoagulation is the interindividual variability in INR response; at least 50% of this variability in sensitivity to warfarin may be explained by polymorphisms in the CYP2C9 and VKORC1 genes. Although these have been incorporated into models for predicting safe and therapeutic warfarin dosing, most clinicians simply begin dosing and adjust therapy as needed based on periodic monitoring. The therapeutic INR range depends on the condition predisposing the patient to thromboembolism. Prophylaxis after uncomplicated VTE in a patient without known risk factors requires an INR between 2 and 3; in contrast, warfarin prophylaxis for patients with APS and recurrent VTE may require INR values as high as 3 to 4 (Table 53.6). The duration of warfarin or LMWH prophylaxis varies depending on the circumstances of the VTE, the risk for bleeding, and the potential for recurrence. In general, the longer the period of anticoagulation with warfarin, the less the chance of recurrence. Short-term warfarin (6 weeks) is less effective at preventing recurrence than longer courses (6 months). Patients with definite transient risk factors such

CHAPTER 53  Disorders of Hemostasis: Thrombosis

TABLE 53.6  Drugs That Affect Warfarin

TABLE 53.7  Therapeutic International

Increased Warfarin Levels: Prolonged INR ↓ Warfarin clearance Disulfiram Metronidazole Trimethoprim-sulfamethoxazole ↓ Warfarin-protein binding Phenylbutazone ↑ Vitamin K turnover Clofibrate

Patient Subgroup

INR Range

Venous Thrombosis Treatment Prophylaxis

2.0-3.0 1.5-2.5

Artificial Heart Valves Tissue Mechanical

2.0-2.5 3.0-4.0

Levels

Decreased Warfarin Levels: Subtherapeutic INR ↑ Hepatic metabolism of warfarin Barbiturates Rifampin ↓ Warfarin absorption Cholestyramine ↑, Increased; ↓, decreased; INR, international normalized ratio.

as orthopedic surgery have low recurrence rates, even with short-term therapy; still, prolonged thromboprophylaxis (>21 days) after total hip replacement is more efficacious than shorter therapy (7 to 10 days). It is not clear that oral Xa inhibitors and dabigatran provide any additional benefit over LMWH for thromboprophylaxis after total hip or knee replacement (Table 53.7). Additionally, DOACs have been studied as thromboprophylaxis in specific patient settings. The MARINER trial evaluated patients who were discharged after medical illness with increased risk of VTE and showed that rivaroxaban 10 mg by mouth daily for 45 days after discharge did not reduce VTE or VTE mortality compared with placebo. In contrast, patients with “unprovoked” VTE (i.e., outside the setting of trauma, surgery, immobilization, pregnancy, or cancer) have significant recurrence rates, even after 3 to 6 months of warfarin therapy. Because the risk for recurrence in patients with unprovoked proximal VTE or PE is relatively low when D-dimer levels are normal 3 weeks after cessation of anticoagulation, this measure may help providers decide whether anticoagulation past 3 to 6 months is necessary. Given increased risk of recurrence in patients without reversible risk factors for VTE, extended-duration anticoagulation is sometimes warranted. Two studies evaluated using aspirin 100 mg versus placebo after anticoagulation therapy for unprovoked VTE. ASPIRE 2012 found a nonsignificant trend towards fewer recurrent VTE events and a nonsignificant trend towards higher bleeding risk, whereas WARFASA 2012 found statistically significant demonstration of fewer VTE recurrences without differences in major bleeding. There is thought that the trials differ in outcomes due to ASPIRE’s lack of enrollment for prespecified power, differences in inclusion criteria, and that only two thirds of ASPIRE patients had received 6 or more months of anticoagulation prior to initiation of aspirin. Furthermore, the EINSTEIN-CHOICE Trial demonstrated that, in patients with VTE who have completed 6 to 12 months of anticoagulation, there was reduced risk of recurrent VTE without significant bleeding when using both 10 or 20 mg/day of rivaroxaban compared to aspirin 100 mg/day. In AMPLIFY-EXT, another oral factor Xa inhibitor, apixaban, was studied for extended anticoagulation at doses of 5 mg (treatment) or 2.5 mg (prophylactic) and was found to have statistically decreased number of recurrent VTE and no increased bleeding risk compared to placebo.

559

Normalized Ratio (INR) Ranges for Warfarin

Atrial Fibrillation (Nonvalvular) Prophylaxis 1.5-2.5 Lupus Anticoagulant Treatment, prophylaxis Refractory thromboembolism

2.0-3.0 3.0-4.0

Thus, current management for an unprovoked acute VTE includes use of either rivaroxaban or apixaban for the initial 6 months of therapy followed by a dose reduction in either agent. For patients with a provoked VTE, initial anticoagulation practice is the same, but anticoagulation may be stopped 3 months after the provoking risk factor has resolved. Evidence also indicates that inherited hypercoagulable disorders (e.g., FVL mutation) probably confer a lifelong increased risk for VTE or PE, but whether the index VTE was provoked or unprovoked determines length of therapy. Some studies have shown that the bleeding risks incurred by long-term, low-intensity warfarin use are favorably balanced by the decreased incidence of recurrent thrombosis. Therefore, the presence of inherited thrombophilia may warrant continuation of anticoagulation for a longer period, depending on the patient’s other medical illnesses and whether transient circumstances may have predisposed the patient to VTE. Patients who develop recurrent VTE after discontinuation of anticoagulation should receive longterm anticoagulation regardless of whether they have a defined cause of thrombophilia. Patients with APS and a first episode of VTE are at very high risk for recurrent VTE (up to 50% per year) after anticoagulation is discontinued, clearly supporting the rationale of testing for antiphospholipid. Table 53.8 suggests broad guidelines for the duration of warfarin therapy in specific patient subgroups. Because warfarin is a teratogen, effective contraception should be used concurrently in women of childbearing age.

Prophylaxis for VTE in Orthopedic Surgeries RECORD1 and RECORD3 (both published 2008) demonstrated improved efficacy of short-course rivaroxaban over short-course enoxaparin in prevention of VTE after hip and knee replacements, respectively, without increased bleeding risk. RECORD2 (2008) demonstrated that extended-course rivaroxaban was more effective in preventing VTE than short-course enoxaparin without increasing bleeding rates following hip replacement.

Prophylactic Anticoagulation in Hospitalized Medically Ill Patients MEDENOX, PREVENT, and ARTEMIS demonstrated promise of in-hospital thromboprophylaxis with LMWH with a relative risk reduction of 45% to 63% compared to placebo. In acutely medically ill hospitalized patients, MAGELLAN (2013) demonstrated short-course rivaroxaban (10 mg daily for 10 days) is noninferior to short-course

560

SECTION VIII  Hematologic Disease

TABLE 53.8  Direct Oral Anticoagulants

(DOAC) and Their Indications DOAC

Indications

Dabigatran

Direct thrombin inhibitor for nonvalvular atrial fibrillation (to prevent stroke and non-CNS embolism); VTE as maintenance therapy (after initial therapy); VTE prophylaxis of VTE after hip replacement Anti-Xa for nonvalvular atrial fibrillation (to prevent stroke and non-CNS embolism); treatment of VTE and subsequent prophylaxis; and VTE prophylaxis of VTE after hip or knee replacement Anti-Xa for nonvalvular atrial fibrillation (to prevent stroke and non-CNS embolism); VTE as initial therapy or maintenance therapy; VTE prophylaxis of VTE after hip or knee replacement Anti-Xa for prevention of VTE as maintenance therapy (after initial therapy); prevention of embolism in atrial fibrillation; has been studied for treatment of VTE in patients with malignancy and is noninferior to dalteparin (a LMWH) with an increased bleeding risk

Rivaroxaban

Apixaban

Edoxaban

CNS, Central nervous system; VTE, venous thromboembolism; Xa, activated factor X.

enoxaparin (40 mg daily for 10 days) in preventing VTE, although it increases risk of bleeding. Extended rivaroxaban (10 mg daily for 35 ± 4 days) was also found to be superior to short-course enoxaparin for prevention of VTE and its complications but also had increased bleeding risk. The APEX trial studied acutely ill medical patients and showed that extended-duration betrixaban for 35 to 42 days did not reduce the primary end point of asymptomatic proximal clot or symptomatic VTE compared to standard enoxaparin for 6 to 14 days.

Prophylactic Anticoagulation in High-Risk With Malignancy in the Ambulatory Setting

Patients

The CASSINI trial evaluated ambulatory cancer patients at high risk for thromboembolism (Khorana score ≥2) and whether low-dose rivaroxaban (10 mg daily) is more effective than placebo in reducing incidence of venous thromboembolism. Rivaroxaban did not result in statistically significant reduction in incident thromboembolism at 180 days when compared to placebo and had a small, not statistically significant increase in bleeding risk; however, when only time on the drug was considered, there was an absolute reduction in VTE with rivaroxaban compared to placebo. On the other hand, the AVERT trial studied apixaban 2.5 mg twice daily versus placebo in ambulatory cancer patients at intermediate-to-high risk for venous thromboembolism (Khorana score ≥2). Prophylactic apixaban reduced the risk of VTE in these patients but increased the risk of major bleeding episodes. Major bleeding was most common in those with GI or GU malignancy. Of note, the trial populations were different, with AVERT having a significant proportion of patients with lymphoma and CASSINI having a higher proportion of pancreatic cancer.

Antithrombotic Therapy During Pregnancy Heparins, both UFH and LMWH, are the safest therapy for venous thrombosis treatment and prevention during pregnancy. Heparin does not cross the placenta, unlike warfarin, which causes a characteristic fetal embryopathy. Warfarin also causes fetal hemorrhage and placental abruption and should be avoided during pregnancy. VTE or PE during pregnancy should be treated with intravenous UFH for

5 to 10 days, followed by an adjusted-dose regimen of subcutaneous UFH, starting with 20,000 U every 12 hours and adjusted to achieve a PTT higher than 1.5 times baseline at 6 hours after injection. An attractive alternative to UFH during pregnancy is LMWH, which can be given subcutaneously once or twice daily and does not require monitoring. Suprarenal IVC filters have also been used successfully during pregnancy without significant morbidity. In women with APS who become pregnant, therapy is critical to prevent fetal loss; aspirin is combined with prophylactic doses of either subcutaneous UFH (10,000 to 15,000 U/day in divided doses) or LMWH (to achieve an anti-Xa level of 0.1 to 0.3 U/mL). When such women have a history of thromboembolic disease, therapeutic doses of LMWH or UFH plus aspirin are employed. Heparin should be discontinued at the time of labor and delivery, although the risk for hemorrhage is not high during delivery, especially if anti-Xa levels are less than 0.7 U/mL. One concern with residual anticoagulation at delivery is the risk for spinal hematoma with epidural anesthesia; this concern has been reported with both UFH and LMWH. The anti-Xa level that is safe for an epidural procedure is not known. Protamine sulfate can be used to neutralize UFH if the PTT is prolonged during labor and delivery; however, LMWH is only partially (10%) reversed by protamine. Anticoagulation during the postpartum period can be carried out with heparin (either UFH or LMWH) or warfarin; neither drug is contraindicated during breast-feeding. Women receiving long-term warfarin therapy (e.g., for valvular heart disease) who wish to become pregnant need to be switched to a fully anticoagulating dose of UFH or LMWH; warfarin treatment may be restarted after delivery. There is limited evidence to support use of DOACs in pregnancy. There are concerns about a higher incidence of miscarriages and fetal anomalies with DOACs. There is currently not enough data to show safety and suggest use of the DOACs during pregnancy, so they are not recommended.

Perioperative Anticoagulation A common clinical problem is the management of anticoagulation in patients who require surgery. The principles of care in this situation reflect the need for adequate hemostasis during and immediately after surgical procedures as well as the critical importance of restarting anticoagulation as soon as possible postoperatively, especially because surgery itself represents a relative hypercoagulable state. The perceived risk for thromboembolism in patients with atrial fibrillation clearly affects the management of perioperative anticoagulation; in this clinical situation, the CHADS-2 score (cardiac failure, hypertension, age, diabetes, and stroke) may estimate postoperative stroke risk and thus dictate the need for bridging anticoagulation with UFH/LMWH when stopping vitamin K antagonist. For patients with VTE who are anticoagulated on a short-term basis (3 cm but ≤4 cm in greatest dimension T2b Tumor >4 cm but ≤5 cm in greatest dimension T3 Tumor >5 cm or tumor with local invasion to any of the following structures: • Chest wall (including superior sulcus tumors) • Phrenic nerve • Parietal pericardium OR If tumor is associated with a satellite nodule in the same lobe T4 Tumor of any size that invades any of the following: • Mediastinum • Heart or great vessels • Trachea • Recurrent laryngeal nerve • Esophagus • Vertebrae • Carina OR If tumor is associated with an ipsilateral satellite nodule in a different lobe N (Regional Lymph Nodes) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s) M (Distant Metastasis) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural (or pericardial) effusion M1b Single extrathoracic metastasis or involvement of single distant lymph node M1c Multiple extrathoracic metastases

TREATMENT

TABLE 57.4  Staging Using TNM Score

(AJCC 8th Edition) N0

T1a Early (Stage I-II) T1b T1c T2a T2b T3 T4 M1a/b/c Metastatic (Stage IV)

Small Cell Lung Cancer N1

N2 Locally Advanced (Stage IIIa)

Locally Advanced (Stage IIIb)

N3

SCLCs can occasionally be resected if no evidence of metastasis is found, but most SCLCs are treated with chemotherapy for systemic disease. Limited-stage SCLC is treated with combination chemoradiation with curative intent. Extensive-stage SCLC is treated with chemotherapy alone with palliative intent. Carboplatin plus etoposide has the lowest rate of side effects and best survival, making it the chemotherapy of choice for extensive-stage disease. Recent phase 3 data demonstrate an improvement in overall survival with the addition of the immune checkpoint inhibitor (ICPI), atezolizumab, to first-line carboplatin plus etoposide. Previously treated patients can benefit

CHAPTER 57  Lung Cancer

A

B

C

D

E

F

E-Fig. 57.15  Patterns of calcification. Benign patterns of calcification: (A) central, (B) popcorn, (C) diffuse, and (D) lamellated; and patterns concerning for malignancy: (E) eccentric and (F) stippled. (From Abbott G.F., Vlahos I. (2019) CT Diagnosis and management of focal lung disease. In: Hodler J., Kubik-Huch R., von Schulthess G. (eds) Diseases of the chest, breast, heart and vessels 2019-2022. IDKD Springer Series. Springer, Cham.)

587.e1

588

SECTION IX  Oncologic Disease

from re-treatment with carboplatin plus etoposide if they achieve at least 6 months of disease control with initial therapy. Second-line therapies include topotecan or alternative immune checkpoint inhibitors (nivolumab or pembrolizumab) for patients who did not receive firstline atezolizumab. Durable responses to both chemotherapy and radiation therapy and long-term survival are possible. However, relapse with progressive therapeutic resistance is usual despite initial treatment response. Prophylactic cranial irradiation (PCI) improves overall survival in limited-stage disease after completion of chemoradiation. PCI is also favored for patients with extensive-stage disease following good response to primary chemotherapy, but recent evidence allows for active surveillance as a reasonable alternative.

Non–Small Cell Lung Cancer

Early-Stage Disease (Stages I and II) Surgery is potentially curative for early-stage NSCLC and is indicated for patients with stage I or II disease who are eligible as operative candidates. Anatomic resection (lobectomy or pneumonectomy) is favored to remove the primary tumor as well as its draining lymph nodes (N1 disease). Lesser resections (wedge resections or segmentectomies) are favored to spare lung for clinically N0 peripheral tumors that are 2 cm or smaller, radiographically noninvasive cancers (ground glass), in patients with limited pulmonary function, or for multiple primary lung cancers. Stereotactic body radiation therapy (SBRT) or needle-directed thermal ablation may be used to cure stage I NSCLCs that are not amenable to surgery due to medical comorbidities. Once spread to lymph nodes is suspected, patients unable to tolerate anatomic resection are best treated as locally advanced.

Locally Advanced Disease (Stages IIIA and IIIB) Stage III NSCLC is a heterogeneous disease and the optimal treatment strategy is unclear. For stage IIIA/N2 disease, “tri-modality” therapy with neoadjuvant chemotherapy or chemoradiation followed by surgery may be offered. Most patients with stage III NSCLC are not surgical candidates and are treated with chemoradiation followed by immune checkpoint blockade.

Advanced Metastatic Disease (Stage IV) Molecular testing of diagnostic biopsy material is essential for optimal palliative drug selection for patients with stage IV NSCLC. Tumors that do not have any targetable mutations (“wild-type” patients) should be treated with immune checkpoint inhibitor therapy, either alone or in combination with chemotherapy. Prospective, randomized (phase 3) trials have shown that gene-targeted therapy is superior to chemotherapy for stage IV NSCLC with EGFR activating-sensitizing mutations or ALK gene rearrangement. In addition, single-arm (phase 2) studies have shown durable responses to targeted therapy for patients with BRAF V600E, rare EGFR, HER2 mutations, or ROS-1, RET, MET or NTRK gene rearrangements with outcomes superior to chemotherapy (E-Fig. 57.16). These targeted drugs provide durable disease control but do not cure patients. Acquired drug resistance inevitably leads to disease progression and death. A repeat biopsy can be used to determine the molecular mechanism of acquired resistance to targeted therapy, which can be used to inform subsequent drug selection. Patterns of resistance have been used to refine first-line drug selection. For example, the predominant mechanism of gefitinib/erlotinib/afatinib resistance is the emergence of the EGFR T790M mutation (located on exon 20), which accounts for about half of all resistant cases. Patients who have progression of disease despite gefitinib/erlotinib/afatinib therapy are routinely tested for T790M mutation, and, if present, are candidates for osimertinib therapy. First-line osimertinib proved to be superior to gefitinib/erlotinib in a randomized phase 3 trial.

Acquired genetic changes may occur in “off target” genes, shifting oncogenic signal to so-called “bypass tracts.” These include druggable targets such as BRAF, or HER2 mutations, RET rearrangements, and MET amplification. Adenocarcinomas may undergo histologic transformation to squamous histology or SCLC. Patterns of primary sensitivity and acquired resistance may guide multiple lines of therapy in patients with EGFR, ALK, and ROS-1 genetic changes, keeping their management pathway distinct compared to wild-type patients. In wild-type patients, the decision whether or not to use chemotherapy is based on measurement of programmed death-ligand 1 (PDL1) expression. PD-L1 expressed on cancer cells or nearby immune cells binds with the PD-1 receptor on T cells and blocks anticancer immunity. Patients with PD-L1 expression on more than 50% of cancer cells are candidates for single-agent pembrolizumab, an ICPI that is a monoclonal IgG antibody against PD-L1. In a phase 3 trial, pembrolizumab was associated with improved survival and fewer adverse events than chemotherapy in patients with metastatic NSCLC without EGFR or ALK mutations and high PD-L1 expression. Cytotoxic chemotherapy plus pembrolizumab is used for wild-type patients with low PD-L1 expression. Cytotoxic drugs include platinum (carboplatin or cisplatin), which cause DNA double-strand breaks, combined with drugs that block DNA synthesis (pemetrexed, gemcitabine) or cellular mitosis (paclitaxel, docetaxel, nab-paclitaxel, vinorelbine). Cytotoxic chemotherapy lowers the neutrophil count, which can lead to septicemia. ICPIs cause autoimmune side effects, most commonly dermatitis, colitis, or thyroiditis, but also vital organ inflammation (pneumonitis, hepatitis, nephritis), which requires stopping the ICPI and consideration of corticosteroids. Targeted drug therapy is not without difficult or dangerous side effects, including skin rash, diarrhea, gastrointestinal side effects, and rarely cardiac or lung toxicity.

PROGNOSIS The most important prognostic factor in lung cancer is the TNM stage of the disease at the time of initial diagnosis. Poor performance status and weight loss are negative prognostic factors for survival of patients with lung cancer. For a deeper discussion on this topic, please see Chapter 182, “Lung Cancer and Other Pulmonary Neoplasms,” in Goldman-Cecil Medicine, 26th Edition.

SUGGESTED READINGS Gandhi L, Rodriguez-Abreau D, Gadgeel S, et al: Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer, N Engl J Med 378(22):2078–2092, 2018. Hirsch FR, Jänne PA, Eberhardt WE, et al: Epidermal growth factor receptor inhibition in lung cancer: status 2012, J Thorac Oncol 8:373–384, 2013. Imielinski M, Berger AH, Hammerman PS, et al: Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing, Cell 150:1107– 1120, 2012. National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al: Reduced lung-cancer mortality with low-dose computed tomographic screening, N Engl J Med 365:395–409, 2011. Reck M, Rodriguez-Abreu D, Robinson AG, et al: Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer, N Engl J Med 375(19):1823–1833, 2016. Rosell R, Bivona TG, Karachaliou N: Genetics and biomarkers in personalization of lung cancer treatment, Lancet 382:720–731, 2013. Sequist LV, Waltman BA, Dias-Santagata D, et al: Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors, Sci Transl Med 3(75):75ra26, 2011.

CHAPTER 57  Lung Cancer EGFR ALK KRAS AKT1 BRAF HER2 MEK1 MET NRAS PIK3CA PTEN RET ROS1 Unknown E-Fig. 57.16 Molecular-genomic classification in lung adenocarcinoma. Various molecular and genomic driver oncogenic alterations have been identified within non–small cell lung cancer, especially adenocarcinoma, through molecular and genomic tumor profiling. Many of these alterations represent “actionable” or “druggable” therapeutic targets. The pie chart presents the affected genes and the proportions of lung adenocarcinomas containing alterations in them. AKT1, v-akt murine thymoma viral oncogene homolog 1; ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene, serine/threonine kinase; EGFR, epithelial growth factor receptor; HER2, v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2; KRAS, Kirsten rat sarcoma viral oncogene homolog; MEK1, mitogen-activated protein kinase kinase 1; MET, MET proto-oncogene, receptor tyrosine kinase; NRAS, neuroblastoma RAS viral (v-ras) oncogene homolog; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; PTEN, phosphatase and tensin homolog; RET, ret proto-oncogene; ROS1, ROS proto-oncogene 1, receptor tyrosine kinase.

588.e1

58 Gastrointestinal Cancers Khaldoun Almhanna

INTRODUCTION Gastrointestinal (GI) cancers are among the most common cancers worldwide. In the United States, approximately 300,000 new cases of GI cancer were expected in 2018 with an estimated 150,000 deaths. Gastrointestinal cancers are typically epithelial malignancies— carcinomas—with well-defined pathologic patterns of neoplastic transformation. The incidence of GI malignancies is increasing. Screening and early detection have been established for colon cancer and hepatocellular cancer. Asian populations should be screened for gastric and esophageal cancer. Risk factors, presentations, and management of GI malignancies are site specific. Management usually involves advanced diagnostic procedures and multidisciplinary treatment including advanced endoscopy, chemotherapy, radiation, and surgical intervention. Complications of advanced disease including bowel and biliary obstruction, liver failure, bleeding, and impaired nutrition play a significant role in the prognosis and mortality of these diseases. Recent advances in immunotherapy and checkpoint inhibitors, although promising, have not yet significantly improved the overall outcome of these diseases.

ESOPHAGEAL CANCER Epidemiology The incidence rates of esophageal cancer vary by geographic region with the highest incidence in Asia and Eastern Africa and the lowest in Western countries. The incidence of squamous cell carcinoma in the United States is decreasing while the incidence of adenocarcinoma, mostly in the gastroesophageal junction, is increasing in part due to obesity, reflux disease, and Barrett esophagus.

Pathology Squamous cell carcinoma (SCC) is commonly seen in the upper esophagus and is associated with smoking, alcohol use, and dietary intake. Consuming hot beverages in certain areas is thought to be responsible for a higher incidence of SCC (e.g., China, Iran). On the other hand, most adenocarcinomas arise in background of Barrett esophagus. Interestingly, only 50% of patients with Barrett esophagus report a history of chronic reflux. The risk of developing esophageal cancer is increased at least 30-fold in patients with Barrett esophagus and is higher in the presence of high-grade dysplasia.

Clinical Presentation Progressive dysphagia and weight loss are the most common presenting symptoms in patients with esophageal cancer. Chronic blood loss leading to iron deficiency anemia is not an uncommon presentation as well. History of longstanding reflux disease is not as common as expected. Early stage tumors are usually asymptomatic and are diagnosed as part of GI bleeding work-up or Barrett esophagus follow-up.

Diagnosis and Staging Upper endoscopy remains the preferred diagnostic test for esophageal cancer. The diagnosis of cancer will require a histologic examination of the primary tumor or, in case of advanced disease, of metastatic lesions. Endoscopic ultrasound (EUS) provides detailed images of the depth of invasion into the esophagus wall (T stage) and peri-esophageal lymphadenopathy (N stage). EUS also visualizes the left lobe of the liver and can identify metastatic lesions (M stage). Bronchoscopy is recommended in patients with tumors located at or above the carina. Contrast-enhanced computed tomography (CT) and 18-fluorodeoxyglucose positron emission tomography (FDG-PET) scans are helpful in detecting occult metastatic disease.

Treatment Early stage esophageal cancer with negative lymph nodes (T1a: invasion into the mucosa) can be treated with endoscopic mucosal resection. T1b tumors (tumor invades the submucosa) should be treated with upfront surgery. For locally advanced disease, multimodality therapy is recommended. Neoadjuvant concurrent chemotherapy and radiation followed by surgical resection is the standard of care, at least in the United States. Definitive chemotherapy and radiation is an acceptable alternative for patients who are not surgical candidates. The combination of carboplatin and paclitaxel with radiation is currently the most commonly used neoadjuvant (chemotherapy administered before surgery) or definitive therapy. Esophagectomy can be performed with a transthoracic (Ivor-Lewis) or a transhiatal technique, with comparable clinical outcomes. Advanced (stage IV) esophageal cancer is a highly lethal disease with poor outcome. The goals of treatment are to improve survival and quality of life. Several chemotherapeutic agents have shown benefits in patients with advanced esophageal cancer as a single agent or in combination including 5-fluorouracil (5-FU), platinum agents, irinotecan, and taxanes. Two targeted agents, trastuzumab, a monoclonal antibody directed against human epidermal growth factor receptor 2 (HER2), and ramucirumab, a monoclonal antibody against vascular endothelial growth factor receptor 2 (VEGFR 2), have shown activity in metastatic esophageal cancer when combined with chemotherapy. Trastuzumab is indicated in patients who overexpress Her-2 neu. The recently developed PD-1/PDL-1 antibodies are showing some promising activity in this setting for patients with metastatic disease who progressed on first-line therapy. Ongoing studies are currently evaluating these agents alone and in combination with chemotherapy and radiation. Supportive care and localized therapy to the primary tumor might be indicated to help with pain, obstruction, bleeding, and other localized symptoms. Nutritional support in this patient population is always challenging and might require parenteral administration of nutrients.

589

590

SECTION IX  Oncologic Disease

GASTRIC CANCER Epidemiology Gastric adenocarcinoma is one of the most common malignancies worldwide. The disease has shown a remarkable decline in incidence and mortality worldwide secondary in part to refrigeration and the decreased use of food preservatives as well as the recognition of Helicobacter pylori infection as a risk factor. However, this disease remains common in Asian countries (China, Japan, and Korea), in the Middle East, and in Eastern Europe, placing it among the five most common cancers worldwide.

Pathology There are two main histologic subtypes of gastric adenocarcinoma: diffuse and intestinal. The diffuse type (undifferentiated) is increasing in incidence and is associated with younger age, signet ring cells, early metastasis, and worse prognosis. The intestinal type (differentiated) is seen in older patients, is differentiated with a background of intestinal metaplasia, and has a declining incidence and a somewhat better prognosis. The main carcinogenic event in diffuse carcinomas is loss of expression of E-cadherin, the protein responsible for intercellular connections and the organization of epithelial tissues.

Clinical Presentation Weight loss, nausea, and epigastric abdominal pain are the most common symptoms of gastric cancer at initial diagnosis. Early satiety (with the linitis plastica subtype), dysphagia (gastroesophageal junction or cardia tumors), and gastrointestinal bleeding are also commonly seen. Symptoms of distant metastatic disease might be seen at diagnosis. The most common metastatic sites are the liver, peritoneal surfaces (causing ascites), distant lymph nodes, and less commonly, the ovaries (Krukenberg tumor) and lungs.

Diagnosis Upper gastrointestinal endoscopy is the standard diagnostic test to obtain tissue and localize the tumor. Endoscopic ultrasound will help with the TNM staging in combination with CT scans of the chest, abdomen, and pelvis. The role of PET scans is still evolving. The diagnosis of the linitis plastica subtype can be challenging because overt mucosal lesions are often not evident. Radiologic and endoscopic features can guide the diagnosis as well as deep biopsies. Staging laparoscopy can upstage 20% to 30% of patients with gastric cancer with otherwise negative work-up and will spare the patient unnecessary laparotomy. Screening endoscopy is recommended in high-incidence countries as well as high-risk patients.

Treatment Surgery remains the cornerstone of treatment for nonmetastatic disease. The most controversial areas in the surgical management of gastric cancer are whether to perform total gastrectomy for tumors in the upper third of the stomach versus partial gastrectomy for tumors in the lower two thirds. Also controversial is the extent of lymph node dissection. Extended D2 dissection to remove the stomach, all surrounding lymph nodes, and the spleen is superior and recommended compared to D1 dissection (refers to a limited dissection of only the perigastric lymph nodes), but it is associated with excess morbidity and mortality and should be performed by an experienced surgeon. For locally advanced disease, in addition to surgery, either perioperative chemotherapy with a platinum-based regimen or postoperative chemoradiation with 5-FU is an acceptable approach. For metastatic disease, first- and second-line palliative chemotherapy can improve outcomes, including survival. Similar to esophageal cancer (mentioned

previously), trastuzumab and ramucirumab have shown activities in metastatic disease when combined with chemotherapy. The role of immune checkpoint inhibitors in gastric cancer is still evolving as with esophageal cancer.

Prognosis Clinical outcomes depend on the stage at diagnosis. Five-year survival rates are 65%, 40%, 15%, and 5% for stages I, II, III, and IV, respectively. Survival outcomes in Japan and Korea are better than in most Western countries; this disparity may be attributable to routine screening endoscopies or to differences in disease biology.

PANCREATIC CANCER Epidemiology Pancreatic cancer is the eighth leading cause of cancer deaths worldwide and is more common in the Western part of the world (see also Chapter 39). Smoking, obesity and chronic pancreatitis are established clinical risk factors. Pancreatic cancer risk increases with inherited mutations in BRCA1, BRCA2, and PALB2 and with familial syndromes. Intraductal papillary mucinous neoplasms of the pancreas (IPMN) are at risk for malignant degeneration and are commonly managed with surveillance.

Pathology Pancreatic ductal adenocarcinoma is the main histologic type of pancreatic cancer (85% of cases). Adenocarcinoma develops with an accumulation of mutations in the pancreatic duct epithelium. Histologic progression occurs in various stages of pancreatic intraepithelial neoplasia, leading to invasive adenocarcinoma with desmoplastic reaction. Neuroendocrine neoplasms of the pancreas are composed of epithelial neoplastic cells with phenotypic neuroendocrine differentiation. Pancreatic neuroendocrine tumors are uncommon malignancies that originate from the endocrine cells in the pancreas. They may be nonfunctional, or they may secrete hormones such as insulin (insulinoma), gastrin (gastrinoma), glucagon (glucagonoma), or vasoactive intestinal peptide (VIPoma).

Clinical Presentation Pain, jaundice, and weight loss are the most common presenting symptoms in patients with pancreatic ductal adenocarcinoma. New-onset type 2 diabetes mellitus in an adult older than 50 years of age without overt obesity-related risk factors should raise suspicion for pancreatic cancer. Venous thromboembolism is commonly associated with pancreatic cancer and can rarely be a presenting feature. Pancreatic neuroendocrine tumors are usually diagnosed incidentally or can cause symptoms related to excess hormone production including hypoglycemia (insulinoma), Zollinger-Ellison syndrome (gastrinoma), hyperglycemia (glucagonoma), and diarrhea with electrolyte disturbances (VIPoma).

Diagnosis Imaging of the abdomen using ultrasound can be utilized as an initial screening test if pancreatic cancer is suspected. CT or magnetic resonance imaging (MRI) can further identify the lesions and their relation to the surrounding vessels as well as metastatic disease. Endoscopic ultrasound and endoscopic retrograde cholangiopancreatography help visualize the lesions better, relieve any obstruction by stent placement, and obtain histologic confirmation by biopsies with fine-needle aspirations or bile duct brushings. Somatostatinreceptor scintigraphy can be helpful in localizing occult neuroendocrine tumors.

CHAPTER 58  Gastrointestinal Cancers

591

Treatment

Diagnosis

Pancreatic adenocarcinomas are some of the most difficult cancers to treat. Their anatomic locations make them poor candidates for resection. Only 15% to 20% of patients are candidates for surgical resection at the time of diagnosis because the tumor frequently involves the celiac arterial axis and superior mesenteric artery and vein and even the portal vein. Whipple procedure (pancreatoduodenectomy) and distal pancreatectomy are the standard surgeries; however, the 5-year overall survival rate after pancreatic adenocarcinoma resection is less than 20%. The role of adjuvant therapy following resection is not well established. Recent studies with multiagent regimens such as a combination of 5-FU, irinotecan, and oxaliplatin (FOLFIRINOX) or combined gemcitabine and nab-paclitaxel have demonstrated improved overall survival for metastatic pancreatic cancer and following resection as well. Observation only or somatostatin analogues are both acceptable first-line treatment for unresectable pancreatic neuroendocrine tumors. Recent studies in neuroendocrine tumors have also shown improvement in outcomes with targeted agents such as everolimus and sunitinib. Palliation of symptoms is a large component of care. Early referral to palliative care should be considered, especially in symptomatic patients with adenocarcinoma. Referrals to nutrition consultants, opioids, celiac nerve plexus block, biliary drainage, as well palliative surgeries can help improve patients’ quality of life.

Transabdominal ultrasonography can be used to confirm biliary dilation, but to confirm the diagnosis of cholangiocarcinoma, computed tomography scanning or magnetic resonance imaging with magnetic resonance cholangiopancreatography MRCP should be performed. In some patients, an endoscopic retrograde cholangiopancreatography (ERCP) is used as the first test because it allows direct visualization of the suspected area, helps obtain a tissue diagnosis, and allows for therapeutic intervention to alleviate the obstruction. Endoscopic ultrasound can aid in identifying tumor location and extension as well.

Prognosis Pancreatic adenocarcinoma carries a very poor prognosis; the 5-year overall survival rate remains less than 10%. Survival has not improved significantly over the last few decades, in contrast to several other cancers. Neuroendocrine tumor carries a better prognosis, depending on the stage and the grade of the tumor, with survival measured in years.

CHOLANGIOCARCINOMA (BILE DUCT CANCERS) Epidemiology Cholangiocarcinomas (bile duct cancers) arise from the intrahepatic and extrahepatic biliary epithelium of the bile ducts. Cancer of the gallbladder or the ampulla of Vater are sometimes included with cholangiocarcinomas but have different risk factors and clinical behavior. Although uncommon in the United States, the incidence of cholangiocarcinomas has been on the rise for unclear reasons. Established risk factors include sclerosing cholangitis, cholelithiasis, cholecystitis, chronic liver disease, toxin exposure, metabolic syndrome, and infections. Gallbladder cancer is particularly prevalent in South American countries—especially Chile—as well as southeastern Asian countries.

Pathology The majority of cholangiocarcinomas are adenocarcinoma. Immuno­ histochemistry staining might appear similar to other malignancies, in particular pancreatic cancer and upper gastrointestinal malignancies. Imaging and clinical correlation might aid in the differential diagnosis.

Treatment A negative margin surgical resection is the only curative treatment for intrahepatic and extrahepatic cholangiocarcinoma. Distal cholangiocarcinomas have the highest rate of complete resection (R0), compared to proximal and intrahepatic cholangiocarcinoma. Adjuvant chemotherapy (with or without radiation), following curative resection, is recommended in general, and based upon meta-analysis. Gemcitabine, platinum and 5-fluouracil based treatments are usually recommended in the adjuvant setting. Surgical resection with lymph node dissection is the standard treatment for gallbladder cancer and ampullary cancer as well. The role of adjuvant therapy is less clear in this setting. Gallbladder cancer is treated in a similar fashion to cholangiocarcinoma, while recommendations following ampullary cancer resection are less clear. Many clinicians recommend surveillance-only, given the more favorable prognosis of ampullary cancer as compared with other biliary tract cancers and the lack of data supporting a survival advantage with further therapy. However, some oncologists tend to treat these patients as they would resected pancreatic cancer, even for those with the intestinal histology. Enrollment in clinical trials in always preferred. Treatment with gemcitabine and cisplatin is the standard treatment for stage IV cholangiocarcinoma and gallbladder cancer. Stage IV ampullary carcinoma is treated like pancreatic cancer. Tumor profiling and the role of targeted therapy is evolving. The overall prognosis is still poor for all of these stage IV malignancies, with median overall survival less than 12 months.

Prognosis Even following curative resection, cholangiocarcinoma still carries a poor prognosis. Five-year overall survival rate ranges from 30% in patients with negative lymph nodes to 2% in patients with metastatic disease. Enrollment in clinical trials is always recommended. Several new agents and pathways are being evaluated in this patient population.

HEPATOCELLULAR CARCINOMA Epidemiology Hepatocellular carcinoma (HCC), or primary liver cancer, is a common disease around the world. It is the second most common cause of cancer-related death in men worldwide.

Clinical Presentation

Pathology

Painless jaundice, pruritus, dark urine, and light color stool are usually the presenting symptoms of extrahepatic cholangiocarcinoma and are caused by biliary obstruction. Intrahepatic cholangiocarcinoma usually presents with vague right upper quadrant pain or is found incidentally on imaging. Gallbladder cancer can sometimes be an incidental finding during histologic evaluation after cholecystectomy, which is commonly performed for presumed cholelithiasis or cholecystitis.

Most HCCs arise in the setting of underlying cirrhosis, with alcohol use, hepatitis B, and hepatitis C being the most common causes of cirrhosis. Other diseases causing cirrhosis such as hemochromatosis, primary biliary cirrhosis, and α1-antitrypsin deficiency are also contributory. Cirrhosis involves chronic hepatocyte injury and ensuing cell regeneration, which provides the substrate for cancer development: inflammatory cytokine stress, constant cell cycling, and aberrant cell development and differentiation.

592

SECTION IX  Oncologic Disease

DNA hypomethylation Chromosome Alteration Gene

5q mutation or loss APC/ -catenin

Normal epithelium

Hyperproliferative epithelium

Other alterations 12p mutation KRAS

Early adenoma

18q loss DCC/SMAD2/SMAD4

Intermediate adenoma

Late adenoma

17p loss TP53

Carcinoma

Metastasis

DNA mismatch repair (MMR) gene inactivation (e.g., MLH1 hypermethylation) Fig. 58.1  Model of colorectal carcinogenesis. Several genes are involved in the stepwise progression from normal colonic epithelium to adenocarcinoma.

Clinical Presentation

Prognosis

HCC is frequently masked by the underlying liver disease. Abdominal distention from ascites, fatigue, muscle wasting, anorexia, and encephalopathy are features of cirrhosis. Acute hepatic decompensation or right upper quadrant pain may herald the development of HCC. HCC can also be an incidental finding during routine surveillance by screening ultrasound for patients with cirrhosis.

The prognosis in HCC is often determined by the severity of the underlying liver disease. The 5-year survival rate approaches 50% with complete surgical resection or liver transplantation. For advanced HCC, the median overall survival time with therapy is approximately 1 year.

Diagnosis

COLORECTAL CANCER Epidemiology

HCC is one of those rare malignancies for which a diagnosis can be made without histologic confirmation. Nonhistologic criteria for diagnosis include underlying cirrhosis, elevated α-fetoprotein level (>400 ng/mL), and a characteristic appearance on contrast-enhanced CT or MRI (arterial enhancement and rapid washout). In the absence of underlying cirrhosis, however, a tissue diagnosis must be obtained. For patients with cirrhosis, a surveillance program incorporating regular measurements of α-fetoprotein and ultrasound imaging can detect early lesions.

Colorectal cancer is the third most common cancer as well as the third most common cause of cancer-related death in the United States, with approximately 150,000 new cases diagnosed each year. Worldwide, it is a growing problem and one of the most common cancers. There appears to be an increased association between colon cancer and high dietary fat, red meat consumption, low dietary fiber, obesity, and alcohol use. Conversely, increased physical activity and use of supplemental estrogen, folate, vitamin, aspirin, and nonsteroidal anti-inflammatory drugs appear to be protective. A history of inflammatory bowel disease is a risk factor for colorectal cancer.

Treatment

Pathology

For small lesions, surgical resection can be curative. Preoperative assessment of liver function to ensure that the patient is an appropriate candidate for partial liver resection is critical. Liver transplantation is an option that will address HCC as well as the underlying cirrhosis. Strict criteria, such as the Milan criteria (i.e., single tumor ≤5 cm, or up to three tumors each 1 cm. The most common malignancies of the Nodules with papillary carcinoma less thyroid are well-differentiated maligthan 1 cm may not need to be removed nancies with a favorable prognosis. Of and the option of serial ultrasounds (every these, the most common is papillary 6-12 months) should be discussed with thyroid carcinoma. Other malignancies the patient. If the patient feels more include medullary thyroid carcinoma, comfortable with surgery, that can also be poorly differentiated thyroid carcian option. noma, undifferentiated (anaplastic) thyroid carcinoma, squamous cell carcinoma, and malignant lymphoma. Metastases to the thyroid from other malignancies can occur as well

Notes

TABLE 65.7  Characteristics of Thyroid Cancers Type of Cancer

Percentage of Thyroid Cancers

Age at Onset (Yr)

Treatment

Prognosis

Papillary

85

40-80

Good

Follicular

10

45-80

Medullary

3

20-50

Anaplastic

1

50-80

Lymphoma

1

25-70

Lobectomy or thyroidectomy, aggressive cases should receive radioactive iodine ablation Lobectomy or thyroidectomy in aggressive cases Thyroidectomy and central compartment lymph node dissection Isthmusectomy followed by palliative radiograph treatment Radiograph therapy or chemotherapy or both

Fair to good Fair

Poor Fair

644

SECTION X  Endocrine Disease and Metabolic Disease

A rise in serum thyroglobulin levels suggests recurrence of thyroid cancer and should prompt testing for recurrence and/or metastases. These are evaluated by 131I whole body scans carried out under conditions of TSH stimulation, which increases 131I uptake by the thyroid tissue. Elevated TSH levels can be achieved by withdrawal of thyroxine supplementation for 6 weeks or by treatment with recombinant human TSH administered while the patient maintains therapy with thyroid hormone replacement. The latter avoids symptomatic hypothyroidism. Local or metastatic lesions that take up 131I on whole body scanning can be treated with radioactive iodine after the patient has stopped thyroid hormone replacement, whereas those that do not take up 131I can be treated with surgical excision or local radiograph therapy. Conventional chemotherapy has limited efficacy in the treatment of differentiated thyroid cancer, but newer biologic agents targeting the molecular pathogenesis of these tumors appear promising. Medullary carcinoma of the thyroid requires total thyroidectomy with removal of the central lymph nodes in the neck. Completeness of the procedure and monitoring for recurrence are determined by measurements of serum calcitonin. Anaplastic carcinoma is treated with isthmusectomy to confirm the diagnosis and to prevent tracheal compression, followed by palliative radiograph treatment. Thyroid lymphomas are also treated with radiograph therapy, chemotherapy, or both. The prognosis for well-differentiated thyroid carcinomas is good. The patient’s age at the time of diagnosis and sex are the most important prognostic factors. Men older than 40 years of age and women

older than 50 years of age have higher recurrence and death rates than do younger patients. The 5-year survival rate for invasive medullary carcinoma is 50%, whereas the mean survival time for anaplastic carcinoma is 6 months. For a deeper discussion on this topic, please see Chapter 213, “Thyroid,” in Goldman-Cecil Medicine, 26th Edition.

SUGGESTED READINGS Burch HB: Drug effects on the thyroid, N Engl J Med 381(8):749–761, 2019. Cibas ES, Ali SZ: The 2017 Bethesda system for reporting thyroid cytopathology, Thyroid 27:1341–1346, 2017. Gullo D, Latina A, Frasca F, et al: Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients, PloS One 6:e22552, 2011. Haugen BR, Alexander EK, Bible KC, et al: 2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer, Thyroid 26:1–133, 2016. Ross DS, Burch HB, Cooper DS, et al: 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis, Thyroid 26(10):1343–1421, 2016. Welch HG, Doherty GM: Saving thyroids—overtreatment of small papillary cancers, N Engl J Med 379:310–312, 2018. Wiersinga WM: Do we need still more trials on T4 and T3 combination therapy in hypothyroidism? Eur J Endocrinol 161:955–959, 2009.

66 Adrenal Gland Theodore C. Friedman

PHYSIOLOGY The adrenal glands (Fig. 66.1) lie at the superior pole of each kidney and are composed of two distinct regions: the cortex and the medulla. The adrenal cortex comprises three anatomic zones: the outer zona glomerulosa, which secretes the mineralocorticoid aldosterone; the intermediate zona fasciculata, which secretes cortisol; and the inner zona reticularis, which secretes adrenal androgens. The adrenal medulla, lying in the center of the adrenal gland, is functionally related to the sympathetic nervous system and secretes the catecholamines epinephrine and norepinephrine in response to stress. The synthesis of all steroid hormones begins with cholesterol and is catalyzed by a series of regulated, enzyme-mediated reactions (Fig. 66.2). Glucocorticoids affect metabolism, cardiovascular function, behavior, and the inflammatory and immune responses (Table 66.1). Cortisol, the natural human glucocorticoid, is secreted by the adrenal glands in response to adrenocorticotropic hormone (ACTH), a 39-amino-acid neuropeptide that is regulated by corticotropin-releasing hormone (CRH) and vasopressin (AVP) produced in the hypothalamus (see Chapter 64). Glucocorticoids exert negative feedback on CRH and ACTH secretion. The brain hypothalamic-pituitary-adrenal (HPA) axis (Fig. 66.3) interacts with and influences the functions of the reproductive, growth, and thyroid axes at many levels, with major participation of glucocorticoids at all levels. The renin-angiotensin-aldosterone system (Fig. 66.4) is the major regulator of aldosterone secretion. Renal juxtaglomerular cells secrete renin in response to a decrease in circulating volume, a reduction in renal perfusion pressure or both. Renin is the rate-limiting enzyme that cleaves the 60-kD angiotensinogen molecule, synthesized by the liver, to produce the bioinactive decapeptide angiotensin I. Angiotensin I is rapidly converted to the octapeptide angiotensin II by angiotensin-converting enzyme in the lungs and other tissues. Angiotensin II is a potent vasopressor; it stimulates aldosterone production but does not stimulate cortisol production. Angiotensin II is the predominant regulator of aldosterone secretion, but plasma potassium concentration, plasma volume, and ACTH level also influence aldosterone secretion. ACTH also mediates the circadian rhythm of aldosterone, and as a result, the plasma concentration of aldosterone is highest in the morning. Aldosterone binds to the type I mineralocorticoid receptor. In contrast, cortisol binds to both the type I mineralocorticoid and type II glucocorticoid receptors. The intracellular enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) type II, which catabolizes cortisol to inactive cortisone, limits the functional binding to the former receptor. The availability of cortisol to bind to the glucocorticoid receptor is modulated by 11β-HSD type I, which interconverts cortisol and cortisone. Binding of aldosterone to the cytosol mineralocorticoid receptor leads to sodium (Na+) absorption and potassium (K+) and hydrogen (H+) secretion by the renal tubules. The resultant increase in plasma

Na+ and decrease in plasma K+ provide a feedback mechanism for suppressing renin and, subsequently, aldosterone secretion. Adrenal androgen precursors include dehydroepiandrosterone (DHEA) and its sulfate and androstenedione. These are synthesized in the zona reticularis under the influence of ACTH and other adrenal androgen-stimulating factors. Although they have minimal intrinsic androgenic activity, they contribute to androgenicity by their peripheral conversion to testosterone and dihydrotestosterone. In adult men, excessive levels of adrenal androgens have negligible clinical consequences, but in women they result in acne, hirsutism, and virilization. Because of gonadal production of androgens and estrogens and the secretion of norepinephrine by sympathetic ganglia, deficiencies of adrenal androgens and catecholamines are not clinically recognized.

SYNDROMES OF ADRENOCORTICAL HYPOFUNCTION Adrenal Insufficiency Glucocorticoid insufficiency can be primary, resulting from destruction or dysfunction of the adrenal cortex, or secondary, resulting from ACTH hyposecretion (Table 66.2). Medications and supplements affecting cortisol levels are shown in Table 66.3. Autoimmune destruction of the adrenal glands (Addison’s disease) is the most common cause of primary adrenal insufficiency in the industrialized world, accounting for about 65% of cases. Usually, both glucocorticoid and mineralocorticoid secretions are diminished in this condition that, if left untreated, can be fatal. Isolated glucocorticoid or mineralocorticoid deficiency may also occur, and it is becoming apparent that mild adrenal insufficiency (similar to subclinical hypothyroidism, discussed in Chapter 65) should also be diagnosed and, in some cases, treated. Adrenal medulla function is usually spared. About 80% of patients with Addison’s disease have antiadrenal antibodies directed at 21α-­ hydroxylase (CYP21A2), though in clinical practice this may be lower due to poor quality of commercial autoantibody testing. Tuberculosis used to be the most common cause of adrenal insufficiency. However, its incidence in the industrialized world has decreased since the 1960s, and it now accounts for only 15% to 20% of patients with adrenal insufficiency; calcified adrenal glands can be observed in 50% of these patients. Rare causes of adrenal insufficiency are listed in Table 66.2. Many patients with human immunodeficiency virus (HIV) infection have decreased adrenal reserve without overt adrenal insufficiency. Addison’s disease may be part of two distinct autoimmune polyglandular syndromes. The triad of hypoparathyroidism, adrenal insufficiency, and mucocutaneous candidiasis characterizes type I polyglandular autoimmune syndrome, also called autoimmune polyendocrinopathy 1 (APECED), which usually manifests in childhood. Other, less common manifestations include hypothyroidism, gonadal failure,

645

646

SECTION X  Endocrine Disease and Metabolic Disease

Adrenal medulla (center)

A

Adrenal cortex (outer)

B Zona Glomerulosa–mineralocorticoids Zona Fasciculata–glucocorticoids Zona Reticularis–androgens

Cortex

C

D Fig. 66.1  (A) Anatomic location of the adrenal glands. (B) Distribution of adrenal cortex and medulla. (C) Zones of the adrenal cortex. (D) Magnetic resonance images of the abdomen showing the position and relative size of the normal adrenal glands (arrows). (D, From Nieman LK: Adrenal cortex. In Goldman L, Schafer AI, editors: Goldman-Cecil medicine, ed 24, Philadelphia, 2012, Saunders, Figure 234-1.)

gastrointestinal malabsorption, insulin-dependent diabetes mellitus, alopecia areata and totalis, pernicious anemia, vitiligo, chronic active hepatitis, keratopathy, hypoplasia of dental enamel and nails, hypophysitis, asplenism, and cholelithiasis. Type II polyglandular autoimmune syndrome, also called Schmidt syndrome, is characterized by Addison’s disease, autoimmune thyroid disease (Graves’ disease or Hashimoto thyroiditis), and insulin-dependent diabetes mellitus. Other associated diseases include pernicious anemia, vitiligo, gonadal failure, hypophysitis, celiac disease, myasthenia gravis, primary biliary cirrhosis, Sjögren’s syndrome, lupus erythematosus, and Parkinson’s disease. This syndrome usually develops in adults. Common manifestations of adrenal insufficiency are anorexia, weight loss, increasing fatigue, occasional vomiting, diarrhea, and salt craving. Muscle and joint pain, abdominal pain, and postural dizziness may also occur. Signs of increased pigmentation (initially most significant on the extensor surfaces, palmar creases, and buccal mucosa) often occur secondary to the increased production of ACTH and other related peptides by the pituitary gland (E-Fig. 66.1). Laboratory abnormalities may include hyponatremia, hyperkalemia, mild metabolic acidosis, azotemia, hypercalcemia, anemia, lymphocytosis, and eosinophilia. Hypoglycemia may also occur, especially in children. Acute adrenal insufficiency is a medical emergency, and treatment should not be delayed pending laboratory results. In a critically ill patient with hypovolemia, a plasma sample for cortisol, ACTH, aldosterone, and renin should be obtained, and then treatment with

hydrocortisone (100 mg IV bolus) and parenteral saline administration should be initiated. Sepsis-induced adrenal insufficiency is recognized by a basal cortisol level lower than 10 μg/dL or a change in cortisol of less than 9 μg/dL after administration of 0.25 mg ACTH (1-24) (cosyntropin). In severe illness, albumin and cortisol-binding globulin (CBG) are low, resulting in a low level of total cortisol but not free cortisol; therefore, a low total cortisol level may not be diagnostic of adrenal insufficiency in this setting. In a patient with chronic symptoms suggestive of adrenal insufficiency described previously, a basal early morning plasma cortisol measurement, a 1-hour cosyntropin test, or both, should be performed. These tests are not recommended in patients without symptoms of adrenal insufficiency. In the latter test, 0.25 mg of cosyntropin is given intravenously or intramuscularly, and plasma cortisol is measured after 0, 30, and 60 minutes. A normal response is a plasma cortisol concentration higher than 18 μg/dL at any time during the test. A patient with a basal morning plasma cortisol concentration lower than 5 μg/dL and a stimulated cortisol concentration lower than 18 μg/dL probably has adrenal insufficiency and should receive treatment. A basal plasma morning cortisol concentration between 10 and 18 μg/dL in association with a stimulated cortisol concentration lower than 18 μg/dL probably indicates impaired adrenal reserve and a requirement for receiving cortisol replacement under stress conditions (see later discussion). Birth control pills and oral estrogens increase CBG levels; therefore, a patient on those agents may have a normal basal or cosyntropin-stimulated cortisol level and have a low free cortisol level, making interpretation of the test difficult for these patients. Once the diagnosis of adrenal insufficiency is made, the distinction between primary and secondary adrenal insufficiency needs to be established. Secondary adrenal insufficiency results from inadequate stimulation of the adrenal cortex by ACTH (see Chapter 64). Hyperpigmentation does not occur. In addition, because mineralocorticoid levels are normal in secondary adrenal insufficiency, symptoms of salt craving, as well as the laboratory abnormalities of hyperkalemia and metabolic acidosis, are not present, although hyponatremia may be observed. Hypothyroidism, hypogonadism, and growth hormone deficiency may also be present. To distinguish primary from secondary adrenal insufficiency, a basal morning plasma ACTH value should be obtained, along with a serum aldosterone level and a measurement of plasma renin activity (PRA). A plasma ACTH value greater than 20 pg/mL (normal, 5 to 30 pg/mL) is consistent with primary adrenal insufficiency, whereas a value lower than 20 pg/mL probably represents secondary adrenal insufficiency. A PRA value greater than 3 ng/mL/hour in the setting of a suppressed aldosterone level is consistent with primary adrenal insufficiency, whereas a value lower than 3 ng/mL/hour probably represents secondary adrenal insufficiency. The 1-hour cosyntropin test is suppressed in both primary and secondary chronic adrenal insufficiency. Secondary adrenal insufficiency occurs commonly after the discontinuation of exogenous glucocorticoids. Alternate-day glucocorticoid treatment, if feasible, results in less suppression of the HPA axis than does daily glucocorticoid therapy. Complete recovery of the HPA axis can take 1 year or more, and the rate-limiting step appears to be recovery of the CRH-producing neurons. Under stress, cortisol secretion is increased. Therefore, the concept of adrenal fatigue, proposed by some alternative providers, has no biologic validity. After stabilization of acute adrenal insufficiency, patients with Addison’s disease require lifelong replacement therapy with both glucocorticoids and mineralocorticoids. Many patients are overtreated with glucocorticoids and undertreated with mineralocorticoids. Because overtreatment with glucocorticoids results in insidious weight

CHAPTER 66  Adrenal Gland

Cholesterol 1 2 Pregnenolone

3

Progesterone

7 17-Hydroxypregnenolone

4

7 3

17-Hydroxyprogesterone

7

4

6 5 11-DeoxyCorticosterone Aldosterone Mineralocorticoids corticosterone (DOC) 11-Deoxycortisol

5

Cortisol

Glucocorticoids

7

3 9 Dehydroepian∆4-Androstenedrosterone (DHEA) dione

Estrone

8

8

Testosterone

Enzyme Number 1 2 3 4 5 6 7 8 9

Sex Steroids

9

Estradiol

Sex Steroids

Enzyme (Current and Trivial Name) StAR; Steroidogenic acute regulatory protein CYP11A1; Cholesterol side-chain cleavage enzyme/desmolase 3β-HSD II; 3β-Hydroxylase dehydrogenase CYP21A2; 21α-Hydroxylase CYP11B1; 11β-Hydroxylase CYP11B2; Corticosterone methyloxidase CYP17; 17α-Hydroxylase/17, 20 lyase 17β-HSD; 17β-Hydroxysteroid dehydrogenase CYP19; Aromatase Fig. 66.2  Pathways of steroid biosynthesis.

TABLE 66.1  Actions of Glucocorticoids Metabolic Homeostasis Regulate blood glucose level (permissive effects on gluconeogenesis) Increase glycogen synthesis Raise insulin levels (permissive effects on lipolytic hormones) Increase catabolism, decrease anabolism (except fat), inhibit growth hormone axis Inhibit reproductive axis Stimulate mineralocorticoid receptor by cortisol Connective Tissues Cause loss of collagen and connective tissue Calcium Homeostasis Stimulate osteoclasts, inhibit osteoblasts Reduce intestinal calcium absorption, stimulate parathyroid hormone release, increase urinary calcium excretion, decrease reabsorption of phosphate Cardiovascular Function Increase cardiac output Increase vascular tone (permissive effects on pressor hormones) Increase sodium retention Behavior and Cognitive Function Daytime fatigue Nocturnal hyperarousal Decreased short-term memory Decreased cognition Euphoria or Depression Immune System Increase intravascular leukocyte concentration Decrease migration of inflammatory cells to sites of injury Suppress immune system (thymolysis; suppression of cytokines, prostanoids, kinins, serotonin, histamine, collagenase, and plasminogen activator)

647

648

SECTION X  Endocrine Disease and Metabolic Disease

Site

Catecholamines, cytokines, growth factors

Brain

Hypothalamus

– CRH

AVP

–

–

– ACTH

Pituitary

Adrenal

Cortisol

Fig. 66.3  Brain hypothalamic-pituitary-adrenal axis. Minus signs ­indicate negative feedback. ACTH, Adrenocorticotropic hormone; AVP, arginine vasopressin; CRH, corticotropin-releasing hormone.

hypoaldosteronism with hyperkalemia and hyperchloremic metabolic acidosis. The plasma sodium concentration is usually normal, but total plasma volume is often deficient. PRA and aldosterone levels are low and unresponsive to stimuli, including hypokalemia. Diabetes mellitus and chronic tubulointerstitial diseases of the kidney are the most common underlying conditions leading to impairment of the juxtaglomerular apparatus. A subset of hyporeninemic hypoaldosteronism is caused by autonomic insufficiency and is a frequent cause of orthostatic hypotension. Stimuli such as upright posture or volume depletion, mediated by baroreceptors, do not cause a normal renin response. Administration of pharmacologic agents such as nonsteroidal anti-inflammatory agents, angiotensin-converting enzyme inhibitors, and β-adrenergic antagonists can also produce conditions of hypoaldosteronism. Salt administration often with fludrocortisone and the α1-receptor agonist midodrine are effective in correcting the orthostatic hypotension and electrolyte abnormalities caused by hypoaldosteronism.

Congenital Adrenal Hyperplasia Site Liver Kidney

Angiotensinogen (452 A.A.) Prorenin

Renin Angiotensin I (10 A.A.)

Lung, plasma

Angiotensin-converting enzyme Angiotensin II (8 A.A.)

Adrenal, vascular

Angiotensin II receptor

Adrenal

Aldosterone

Fig. 66.4  Renin-angiotensin-aldosterone axis. A.A., Amino acids.

gain and osteoporosis, the minimal cortisol dose that can be tolerated without symptoms of glucocorticoid insufficiency (usually joint pain, abdominal pain, or diarrhea) is recommended. An initial regimen of 10 to 15 mg hydrocortisone first thing in the morning plus 5 mg hydrocortisone at about 3:00 pm mimics the physiologic dose and is recommended; a third dose is occasionally needed. Whereas glucocorticoid replacement is fairly uniform in most patients, the requirement for mineralocorticoid replacement varies greatly. The initial dose of the synthetic mineralocorticoid fludrocortisone should be 100 μg/day (often in divided doses), and the dosage should be adjusted to keep the standing PRA value between 1 and 3 ng/mL/hr. Under the stress of a minor illness (e.g., nausea, vomiting, fever >100.5° F), the hydrocortisone dose should be doubled for as short a period as possible. An inability to ingest hydrocortisone pills may necessitate parenteral hydrocortisone administration. Patients undergoing a major stressful event (e.g., surgery necessitating general anesthesia, major trauma) should receive 150 to 300 mg parenteral hydrocortisone daily (in divided doses) with a rapid taper to normal replacement during recovery. All patients should wear a medical information bracelet and should be instructed in the use of intramuscular emergency hydrocortisone injections or alternatively hydrocortisone suppositories as another option.

Hyporeninemic Hypoaldosteronism Mineralocorticoid deficiency can result from decreased renin secretion by the kidneys. Resultant hypoangiotensinemia leads to

Congenital adrenal hyperplasia (CAH) refers to autosomal recessive disorders of adrenal steroid biosynthesis that result in glucocorticoid and mineralocorticoid deficiencies and compensatory increase in ACTH secretion (see Fig. 66.2). Five major types of CAH exist, and the clinical manifestations of each type depend on which steroids are in excess and which are deficient. CYP21A2 deficiency is the most common of these disorders and accounts for about 95% of patients with CAH. In this condition, there is a failure of 21-hydroxylation of 17-hydroxyprogesterone and progesterone to 11-deoxycortisol and 11-deoxycorticosterone, respectively, with deficient cortisol and aldosterone production. Cortisol deficiency leads to increased ACTH release, resulting in adrenal hyperplasia and overproduction of 17-hydroxyprogesterone and progesterone. Increased ACTH production also leads to increased biosynthesis of androstenedione and DHEA, which can be converted to testosterone. Patients with CYP21A2 deficiencies can be divided into two clinical phenotypes: classic 21-hydroxylase deficiency, which usually is diagnosed at birth or during childhood, and late-onset 21-hydroxylase deficiency, which develops during or after puberty. Two thirds of patients with classic CYP21A2 deficiency have various degrees of mineralocorticoid deficiency (salt-losing form); the remaining one third have the non–salt-losing type (simple virilizing form). Both decreased aldosterone production and increased concentrations of precursors that are mineralocorticoid antagonists (progesterone and 17-hydroxyprogesterone) contribute to salt loss. Late-onset 21-hydroxylase deficiency represents an allelic variant of classic 21-hydroxylase deficiency and is characterized by a mild enzymatic defect. This deficiency is the most common autosomal recessive disorder in humans and is present at high frequency in Ashkenazi Jews. The syndrome usually develops at the time of puberty with signs of virilization (hirsutism and acne) and amenorrhea or oligomenorrhea. This diagnosis should be considered in women who have unexplained hirsutism and menstrual abnormalities or infertility. The most useful initial measurement for the diagnosis of classic 21-hydroxylase deficiency is that of plasma 17-hydroxyprogesterone. A value greater than 200 ng/dL is consistent with the diagnosis. The diagnosis of late-onset 21-hydroxylase deficiency is based on the ­finding of an elevated level of plasma 17-hydroxyprogesterone (>1500 ng/dL) 30 minutes after administration of 0.25 mg of synthetic ACTH (1-24). The aim of treatment for classic 21-hydroxylase deficiency is to replace glucocorticoids and mineralocorticoids, suppress ACTH and androgen overproduction, and allow for normal growth and

CHAPTER 66  Adrenal Gland

TABLE 66.2  Syndromes of Adrenocortical

Hypofunction

Primary Adrenal Disorders Combined Glucocorticoid and Mineralocorticoid Deficiency Autoimmune Isolated autoimmune disease (Addison’s disease) Polyglandular autoimmune syndrome, type I Polyglandular autoimmune syndrome, type II Infectious Tuberculosis Fungal Cytomegalovirus Human immunodeficiency virus Vascular Bilateral adrenal hemorrhage Sepsis Coagulopathy Thrombosis, embolism Adrenal infarction Infiltration Metastatic carcinoma and lymphoma Sarcoidosis Amyloidosis Hemochromatosis Congenital Congenital adrenal hyperplasia 21-Hydroxylase deficiency 3β-ol Dehydrogenase deficiency 20,22-Desmolase deficiency Adrenal unresponsiveness to ACTH Congenital adrenal hypoplasia Adrenoleukodystrophy Adrenomyeloneuropathy Iatrogenic Bilateral adrenalectomy Drugs and supplements: See Table 66.3 Mineralocorticoid Deficiency Without Glucocorticoid Deficiency Corticosterone methyl oxidase deficiency Isolated zona glomerulosa defect Heparin therapy Critical illness Angiotensin-converting enzyme inhibitors Secondary Adrenal Disorders Secondary Adrenal Insufficiency Hypothalamic-pituitary dysfunction Exogenous glucocorticoids After removal of an ACTH-secreting tumor Hyporeninemic Hypoaldosteronism Diabetic nephropathy Tubulointerstitial diseases Obstructive uropathy Autonomic neuropathy Nonsteroidal anti-inflammatory drugs β-Adrenergic drugs ACTH, Adrenocorticotropic hormone.

sexual maturation in children. A proposed approach to treating classic 21-hydroxylase deficiency recommends physiologic replacement with hydrocortisone and fludrocortisone in all affected patients. Virilizing

649

effects can be prevented by the use of an antiandrogen (spironolactone or flutamide). Although the traditional treatment for late-onset 21-hydroxylase deficiency is dexamethasone (0.5 mg/day), the use of an antiandrogen such as spironolactone (100 to 200 mg/day) or flutamide (125 mg/day) is probably equally effective and has fewer side effects. Mineralocorticoid replacement is not needed in late-onset 21-hydroxylase deficiency. 11β-Hydroxylase (CYP11B1) deficiency accounts for about 5% of patients with CAH. In this condition, the conversions of 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone (the precursor to aldosterone) are blocked. Affected patients usually have hypertension and hypokalemia because of increased amounts of precursors with mineralocorticoid activity. Virilization occurs, as with 21-hydroxylase deficiency, and a late-onset form manifesting as androgen excess also occurs. The diagnosis is made from the finding of elevated plasma 11-deoxycortisol levels, either basally or after ACTH stimulation. Rare forms of CAH are 3β-HSD type II deficiency, 17α-hydroxylase (CYP17) deficiency, and steroidogenic acute regulatory protein (StAR) deficiency. Patients previously diagnosed with 3β-HSD type II deficiency most likely had polycystic ovarian syndrome (PCOS), which is associated with high DHEAS levels.

SYNDROMES OF ADRENOCORTICAL HYPERFUNCTION Hypersecretion of the glucocorticoid hormone cortisol results in Cushing’s syndrome, a metabolic disorder that affects carbohydrate, protein, and lipid metabolism (see Table 66.1). Hypersecretion of mineralocorticoids such as aldosterone results in a syndrome of hypertension and electrolyte disturbances.

Cushing’s Syndrome Pathophysiology

Cushing’s syndrome refers to any condition of endogenous glucocorticoid excess, while Cushing’s disease refers to an ACTH-secreting pituitary tumor leading to glucocorticoid excess. Increased production of cortisol is seen in both physiologic and pathologic states (Table 66.4). Physiologic hypercortisolism occurs with stress, during the last trimester of pregnancy, and in persons who regularly perform strenuous exercise. Pathologic conditions of elevated cortisol levels include exogenous or endogenous Cushing’s syndrome and several psychiatric states, such as depression, alcoholism, anorexia nervosa, panic disorder, and alcohol or narcotic withdrawal. Cushing’s syndrome may be caused by exogenous administration of ACTH or glucocorticoid or by endogenous overproduction of these hormones. Endogenous Cushing’s syndrome is either ACTH dependent or ACTH independent. ACTH dependency accounts for 85% of patients and includes pituitary sources of ACTH (Cushing’s disease) and ectopic sources of ACTH. Pituitary Cushing’s disease accounts for 90% of patients with ACTH-dependent Cushing’s syndrome. Ectopic secretion of ACTH occurs most commonly in patients with small cell lung carcinoma. These patients are older, usually have a history of smoking, and primarily exhibit signs and symptoms of lung cancer rather than those of Cushing’s syndrome. Patients with the clinically apparent ectopic ACTH syndrome, in contrast, have mostly lung, thymic or pancreatic carcinoid tumors. ACTH-independent causes account for 15% of patients with Cushing’s syndrome and include adrenal adenomas, adrenal carcinomas, micronodular adrenal disease, and autonomous macronodular adrenal disease. The female-to-male ratio for noncancerous forms of Cushing’s syndrome is 4:1.

650

SECTION X  Endocrine Disease and Metabolic Disease

TABLE 66.3  Medications and Supplements Affecting Cortisol Levels Type of Drugs

Generic Name

Brand Name

Effect on Cortisol

Comments

Cushing’s drugs

Ketoconazole Mifepristone Somatostatin analogues (octreotide, lanreotide, pasireotide) Metyrapone

Nizoral Korlym Sandostatin, Somatuline, Signifor

↓ ↑ ↓

Decreases cortisol biosynthesis Blocks cortisol at the receptor Lowers cortisol mildly

Metopirone

↓

Etomidate Mitotane Citalopram Sertraline Fluoxetine Imipramine Desipramine Trazodone Mirtazapine Olanzapine Quetiapine Temazepam Alprazolam Lorazepam

Amidate Lysodren Celexa Zoloft Prozac Tofranil Norpramin Desyrel Remeron Zyprexa Seroquel Restoril Xanax Ativan

↓ ↓ ↑ ↑ − ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓/−

High rate of adrenal insufficiency Can be given IV Adrenolytic

Cabergoline Bromocriptine Metoclopramide Methylphenidate

Dostinex Parlodel Reglan Ritalin

↓ ↓ ↑ ↑

Clonidine Loperamide Morphine, Methadone, Codeine Buprenorphine Naloxone Naltrexone

Catapres Imodium Various

↓ ↓ ↓

Buprenex Narcan Revia

↓ ↑ ↑

Provera, Prometrium

↓ ↑ ↑ ↑ ↓

Antidepressant

Antipsychotic Anti-anxiety

Dopamine agents

Antihypertensives Opioids/anti-opioids

Drugs of abuse

Hormones

Heroin Cocaine Alcohol Tobacco/nicotine Progesterone

Megestrol Growth hormone Thyroid hormone Raloxifene Estrogens, birth control pills

DHEA Desmopressin Oxytocin

Megace Various Synthroid, Levoxyl, Cytomel Armour, etc. Evista

DDAVP

↓ ↓ ↓ ↓ −

↓ ↑ ↓

Anecdotal-lowers cortisol, literature no effect Variable effect Variable effect Found in one study but not another study

Unclear if low-dose naltrexone (LDN) has the same effect

Binds to the cortisol receptor, so Cushingoid features could occur, even though cortisol levels are decreased Used for weight gain Increase catabolism of cortisol Increase catabolism of cortisol Used for osteoporosis Raises cortisol-binding protein and raises total cortisol, does not affect free cortisol

Anecdotal reports of lowering cortisol

CHAPTER 66  Adrenal Gland

651

TABLE 66.3  Medications and Supplements Affecting Cortisol Levels—cont’d Type of Drugs

Generic Name

Brand Name

Effect on Cortisol

Comments

Diabetes medications

Rosiglitazone

Avandia

↓/−

Supplements

Pioglitazone Phosphatidyl serine

Actos Seriphos

↓/− ↓

Initial studies found a reduction in cortisol, not confirmed by additional studies

Gingko biloba St. John’s wort Rhodiola

↓ ↑ ↓

Effective at night, Seriphos and phosphatidyl serine are slightly different

Bold indicates substantial effect.

Clinical Presentation The clinical signs, symptoms, and common laboratory findings of hypercortisolism observed in patients with Cushing’s syndrome are listed in Table 66.5. Patients with Cushing’s syndrome often have some, but not all, of the signs and symptoms discussed here. Typically, the obesity is centripetal, with a wasting of the arms and legs, which is distinct from the generalized weight gain observed in idiopathic obesity. Rounding of the face (called moon facies) and a dorsocervical fat pad (buffalo hump) may occur in obesity not related to Cushing’s syndrome, whereas facial plethora and supraclavicular filling are more specific for Cushing’s syndrome. Patients with Cushing’s syndrome may have proximal muscle weakness; consequently, the inability to stand up from a squat or to comb their own hair can be revealing. Sleep disturbances and insomnia, hyperarousal in the evening and night, mood swings, and other psychological abnormalities are frequently seen. Cognitive dysfunction and severe fatigue are often present. Menstrual irregularities often precede other Cushingoid symptoms in affected women. Patients of both sexes complain of a loss of libido, and affected men frequently complain of erectile dysfunction. Adult-onset acne or hirsutism in women could also suggest Cushing’s syndrome. The skin striae observed in patients with Cushing’s syndrome are often violaceous (i.e., purple or dark red, from hemorrhage into the striae) depending on the level of hypercortisolism. Thinning of the skin on the top of the hands is a specific sign in younger adults with Cushing’s syndrome. Old pictures of patients are extremely helpful for evaluating the progression of the physical stigmata of Cushing’s syndrome. Associated laboratory findings in Cushing’s syndrome include elevated plasma alkaline phosphatase levels, granulocytosis, thrombocytosis, hypercholesterolemia, hypertriglyceridemia, and glucose intolerance, and/or diabetes mellitus. Hypokalemia or alkalosis usually occurs in patients with severe hypercortisolism as a result of the ectopic ACTH syndrome.

Diagnosis If the history and physical examination findings are suggestive of hypercortisolism, then the diagnosis of Cushing’s syndrome can usually be established by collecting urine for 24 hours and measuring the urinary free cortisol (UFC). This test is extremely sensitive for diagnosis of Cushing’s syndrome because in 90% of affected patients the initial UFC level is greater than 50 μg/24 hours (Fig. 66.5). Cortisol is normally secreted in a diurnal manner: The plasma concentration is highest in the early morning (between 6:00 and 8:00 am) and lowest around midnight. Most patients with Cushing’s syndrome have blunted diurnal variation. Nighttime plasma cortisol values greater than 50% of the morning values are considered to be consistent with Cushing’s syndrome. Because of the difficulty

of obtaining nighttime plasma cortisol levels, measurement of latenight salivary cortisol has been developed to assess hypercortisolism. This test has a high degree of sensitivity and specificity for the diagnosis of Cushing’s syndrome and is convenient for patients. Multiple measurements of UFC or salivary cortisol may be needed to either diagnose or exclude Cushing’s syndrome, especially in subjects with convincing and progressive signs and symptoms of hypercortisolism. The overnight dexamethasone suppression test has been widely used as a screening tool to evaluate patients who may have hypercortisolism. Dexamethasone, 1 mg, is given orally at 11:00 pm or midnight, and plasma cortisol is measured the following morning at 8:00 am. A morning plasma cortisol level greater than 1.8 μg/dL suggests hypercortisolism. This test produces a significant number of both false-­ positive and false-negative results, but it is recommended in the 2008 Endocrine Society consensus guidelines.

Differential Diagnosis Once the diagnosis of Cushing’s syndrome is established, the cause of the hypercortisolism needs to be ascertained by biochemical studies that evaluate the HPA axis; this should be accompanied by imaging procedures and at times, venous sampling. The initial approach is to measure basal ACTH levels, which are normal or elevated in Cushing’s disease and the ectopic ACTH syndrome but are suppressed in primary adrenal Cushing’s syndrome. Patients with a suppressed ACTH level can proceed to adrenal imaging studies. To distinguish between Cushing’s disease and the ectopic ACTH syndrome, the 2-day dexamethasone suppression test or 8-mg overnight dexamethasone suppression test and bilateral simultaneous inferior petrosal sinus sampling (IPSS) may be used. In the dexamethasone suppression test (Liddle test), 0.5 mg of dexamethasone is given orally every 6 hours for 2 days (low dose), followed by 2 mg of dexamethasone every 6 hours for another 2 days (high dose). On the second day of high-dose dexamethasone, the UFC level will be suppressed to less than 10% of the baseline collection value in patients with pituitary adenomas but not in patients with the ectopic ACTH syndrome or adrenal cortisol-secreting tumors. The Liddle test has some methodologic drawbacks, and results should be interpreted cautiously; other confirmatory tests should be performed before surgery is recommended. An overnight high-dose dexamethasone suppression test can be helpful in establishing the cause of Cushing’s syndrome. In this test, a baseline cortisol level is measured at 8:00 am, and then 8 mg of dexamethasone is given orally at 11:00 pm. At 8:00 am the following morning, a plasma cortisol measurement is obtained. Suppression, which occurs in patients with pituitary Cushing’s disease, is defined as a decrease in plasma cortisol to less than 50% of the baseline level.

CHAPTER 66  Adrenal Gland

A

B

651.e1

C

D

E-Fig. 66.1  Pigmentation in Addison’s disease. (A) Hands of an 18-year-old woman with autoimmune polyendocrine syndrome and Addison’s disease. Pigmentation in a patient with Addison’s disease before (B) and after (C) treatment with hydrocortisone and fluorocortisone. Notice the additional presence of vitiligo. (D) Similar changes are also seen in a 60-year-old man with tuberculous Addison’s disease before and after corticosteroid therapy. (B and C, Courtesy Professor C.R.W. Edwards. From Larsen PR, Kronenberg HM, Melmed S, et al, editors: Williams Textbook of Endocrinology, ed 10, Philadelphia, 2002, Saunders.)

652

SECTION X  Endocrine Disease and Metabolic Disease

TABLE 66.4  Syndromes of Adrenocortical

Hyperfunction

States of Glucocorticoid Excess Physiologic States Stress Strenuous exercise Last trimester of pregnancy Pathologic States Psychiatric conditions (pseudo-Cushing’s disorders) Depression Alcoholism Anorexia nervosa Panic disorders Alcohol and drug withdrawal ACTH-dependent states Pituitary adenoma (Cushing’s disease) Ectopic ACTH syndrome Bronchial carcinoid Thymic carcinoid Islet cell tumor Small cell lung carcinoma Ectopic CRH secretion ACTH-independent states Adrenal adenoma Adrenal carcinoma Micronodular adrenal disease Exogenous Sources Glucocorticoid intake ACTH intake States of Mineralocorticoid Excess Primary Aldosteronism Aldosterone-secreting adenoma Bilateral adrenal hyperplasia Aldosterone-secreting carcinoma Glucocorticoid-suppressible hyperaldosteronism Adrenal Enzyme Deficiencies 11β-Hydroxylase deficiency 17α-Hydroxylase deficiency 11β-Hydroxysteroid dehydrogenase type II deficiency Exogenous Mineralocorticoids Licorice Carbenoxolone Fludrocortisone Secondary Hyperaldosteronism Associated with hypertension Accelerated hypertension Renovascular hypertension Estrogen administration Renin-secreting tumors Without hypertension Bartter syndrome Sodium-wasting nephropathy Renal tubular acidosis Diuretic and laxative abuse Edematous states (cirrhosis, nephrosis, congestive heart failure) ACTH, Adrenocorticotropin hormone; CRH, corticotropin-releasing hormone.

Bilateral IPSS is an accurate and safe procedure for distinguishing pituitary Cushing’s disease from the ectopic ACTH syndrome.

Venous blood from the anterior lobe of the pituitary gland empties into the cavernous sinuses and then into the superior and inferior petrosal sinuses. Venous plasma samples for ACTH determination are obtained from both inferior petrosal sinuses, along with a simultaneous peripheral sample, both before and after intravenous bolus administration of ovine corticotropin-releasing hormone (oCRH). Significant gradients at baseline and after oCRH stimulation between petrosal sinus and peripheral samples suggest pituitary Cushing’s disease. In baseline measurements, an ACTH concentration gradient of 1.6 or more between a sample from either of the petrosal sinuses and the peripheral sample is strongly suggestive of pituitary Cushing’s disease, whereas patients with the ectopic ACTH syndrome or adrenal adenomas have no ACTH gradient between their petrosal and peripheral samples. After oCRH administration, a central-to-peripheral gradient of more than 3.2 is consistent with pituitary Cushing’s disease. An ACTH gradient ipsilateral to the side of the tumor is found in 70% to 80% of pituitary Cushing’s disease patients sampled. Although this procedure requires a radiologist who is experienced in IPSS, it is available at many tertiary care facilities. The test cannot be done to distinguish patients with Cushing’s syndrome from those without the condition, and the test needs to be done when the patient is hypercortisolemic, making it less helpful in those with episodic cortisol secretion. Magnetic resonance imaging (MRI) with gadolinium is the preferred procedure for localizing a pituitary adenoma. In many centers, a dynamic MRI is performed; the pituitary is visualized as the gadolinium enters and leaves the gland. Because about 10% of normal individuals are found to have a nonfunctioning pituitary adenoma on pituitary MRI, pituitary imaging should not be the sole criterion for the diagnosis of pituitary Cushing’s disease.

Treatment The preferred treatment for all forms of Cushing’s syndrome is appropriate surgery or, in some cases, radiation therapy (see Chapter 64). A more appealing option for many patients with Cushing’s disease who remain hypercortisolemic after pituitary surgery is bilateral adrenalectomy followed by lifelong glucocorticoid and mineralocorticoid replacement therapy. In patients with the ectopic ACTH syndrome, the goal is to localize the tumor by appropriate scans so it can be removed surgically. A unilateral adrenalectomy is the treatment of choice in patients with a cortisol-secreting adrenal adenoma. Cortisol-secreting adrenal carcinomas initially should also be managed surgically; however, the prognosis is poor, with only 20% of patients surviving more than 1 year after diagnosis. Medical treatment for hypercortisolism may be needed to prepare patients who are undergoing or have undergone pituitary irradiation and are awaiting its effects before surgery; it may also be needed for those who are not surgical candidates or elect not to have surgery. Ketoconazole, o,p′-DDD (mitotane), metyrapone, aminoglutethimide, mifepristone (FDA approved for Cushing’s syndrome if accompanied by hypertension or glucose intolerance/diabetes), and trilostane are the most commonly used agents for adrenal blockade and can be used alone or in combination. The somatostatin analogue, pasireotide, which decreases ACTH and may decrease tumor size, is an FDAapproved drug for treating Cushing’s disease.

Primary Mineralocorticoid Excess Pathophysiology

The causes of primary aldosteronism (see Table 66.4) are aldosterone-producing adenoma (75%), bilateral adrenal hyperplasia (25%), adrenal carcinoma (1%), and glucocorticoid-remediable hyperaldosteronism ( ng/mL/hr and serum aldosterone > 15 ng/dL

Confirm with either oral sodium loading, saline infusion, fludrocortisone suppression, or captopril challenge

Adrenal imaging (CT or MRI)

Bilateral adenoma or bilateral hyperplasia

Adrenal adenoma

Confirm with adrenal venous sampling

Medical Treatment (Spironolactone or Epleronone)

Unilateral Adrenalectomy

Fig. 66.6 Flowchart for evaluation of a patient with probable primary hyperaldosteronism. Plasma aldosterone is measured in ng/dL, and plasma renin activity (PRA) is measured in ng/mL/hour. CT, Computed tomography; MRI, magnetic resonance imaging.

tumors secrete a small amount of excess cortisol, leading to a condition that used to be called subclinical Cushing’s syndrome and is now called mild autonomous cortisol excess (MACE) or autonomous cortisol secretion, a condition associated with comorbidities including hypertension, glucose intolerance/diabetes, obesity, dyslipidemia, osteoporosis, and increased cardiovascular events. This condition does not progress to overt Cushing’s syndrome. An overnight 1-mg dexamethasone test is recommended for all patients with an adrenal mass seen on imaging. A morning cortisol post-dexamethasone of between 1.8 and 5 μg/dL suggests possible autonomous cortisol secretion that usually does not need surgery, whereas values greater than 5 μg/dL should be worked up for Cushing’s syndrome as described previously. Under certain circumstances, surgical removal should be performed. Patients with hypertension should also undergo measurement of serum potassium, plasma aldosterone concentration, PRA, and plasma free metanephrines (only if the unenhanced CT attenuation value is greater than 10 Hounsfield units). Surgery should be considered for all patients with functional adrenal cortical tumors that are hormonally active or larger than 4 cm. Tumors not associated with hormonal secretion that are smaller than 4 cm and have benign imaging characteristics do not need follow-up.

Primary Adrenal Cancer Primary adrenal carcinomas are rare, with an incidence of 1 to 5 per 1 million persons. The female-to-male ratio is 2.5:1, and the mean age at onset is 40 to 50 years. About 25% of patients have symptoms,

656

SECTION X  Endocrine Disease and Metabolic Disease

including abdominal pain, weight loss, anorexia, and fever. Eighty percent of primary adrenal carcinomas are functional, with secretion of glucocorticoid alone (45%) or glucocorticoid plus androgens (45%) being most common. At presentation, metastatic spread is evident in 75% of cases. An incidentally discovered adrenal mass that is large is more likely to be malignant. Resection is recommended for tumors larger than 6 cm and often for those larger than 4 cm. In patients who do not have a known cancer, most adrenal masses that turn out to be malignant are primary adrenocortical carcinomas, whereas in patients with a known malignancy, an adrenal mass is likely to be a metastasis in about 75% of cases. The treatment of adrenocortical carcinomas is surgery. These cancers are usually resistant to radiation and chemotherapy, but the adrenolytic compound mitotane has been shown to improve survival. Adrenocortical carcinomas carry a poor prognosis, with overall 5-year survival rates of less than 20%. For a deeper discussion on this topic, please see Chapter 214, “Adrenal Cortex,” in Goldman-Cecil Medicine, 26th Edition.

SUGGESTED READINGS Annane D, Pastores SM, Rochwerg B, et al: Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017, Intensive Care Med 43:1751–1763, 2017. Bornstein SR, Allolio B, Arlt W, et al: Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab 101:364–389, 2016. Fassnacht M, Arlt W, Bancos I, et al: Management of adrenal incidentalomas: European Society of Endocrinology clinical practice guideline in collaboration with the European Network for the Study of Adrenal Tumors, Eur J Endocrinol 175:G1–G34, 2016. Nieman LK, Biller BM, Findling JW, et al: The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab 93:1526–1540, 2008. Rushworth RL, Torpy DJ, Falhammar H: Adrenal crisis, N Engl J Med 381:852–861, 2019. Speiser PW, Arlt W, Auchus RJ, et al: Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab 103:4043–4088, 2018.

CHAPTER 66  Adrenal Gland

A

656.e1

B

E-Fig. 66.2  (A) Adrenal incidentaloma discovered in a woman undergoing investigation for abdominal pain. (B) Incidentally discovered right adrenal myolipoma. (From Larsen PR, Kronenberg HM, Melmed S, et al, editors: Williams textbook of endocrinology, ed 10, Philadelphia, 2002, Saunders.)

67 Male Reproductive Endocrinology Glenn D. Braunstein

INTRODUCTION The testes are composed of Leydig (interstitial) cells, which secrete testosterone and estradiol, and the seminiferous tubules, which produce sperm. They are regulated by the luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are secreted by the anterior pituitary under the influence of the hypothalamic decapeptide gonadotropin-releasing hormone (GnRH) (Fig. 67.1). LH stimulates the Leydig cells to secrete testosterone, which feeds back in a negative fashion at the level of the pituitary and hypothalamus to inhibit further LH production. FSH stimulates sperm production through interaction with the Sertoli cells in the seminiferous tubules. Feedback inhibition of FSH is through gonadal steroids, as well as through inhibin, a glycoprotein produced by Sertoli cells. Biochemical evaluation of the hypothalamic-pituitary-Leydig axis is carried out by measurement of serum LH and testosterone concentrations, whereas a semen analysis and serum FSH determination provide an assessment of the hypothalamic-pituitary-seminiferous tubular axis. The ability of the pituitary to release gonadotropins can be tested dynamically through GnRH stimulation, and the ability of the testes to secrete testosterone can be evaluated through injections of human chorionic gonadotropin (HCG), a glycoprotein hormone that has biologic activity similar to that of LH.

HYPOGONADISM Either testosterone deficiency or defective spermatogenesis constitutes hypogonadism. Often both disorders coexist. The clinical manifestations of androgen deficiency depend on the time of onset and the degree of deficiency. Testosterone is required for development of the Wolffian duct into the epididymis, vas deferens, seminal vesicles, and ejaculatory ducts, as well as for virilization of the external genitalia through the major intracellular testosterone metabolite, dihydrotestosterone (DHT). Consequently, early prenatal androgen deficiency leads to the formation of ambiguous genitalia and to male pseudohermaphroditism. Androgen deficiency occurring later during gestation may result in micropenis or cryptorchidism, the unilateral or bilateral absence of testes in the scrotum resulting from the failure of normal testicular descent. During puberty, androgens are responsible for male sexual differentiation, which includes growth of the scrotum, epididymis, vas deferens, seminal vesicles, prostate, penis, skeletal muscle, and larynx. Additionally, androgens stimulate the growth of axillary, pubic, facial, and body hair and increase sebaceous gland activity. They are also responsible through conversion to estrogens for the growth and fusion of the epiphyseal cartilaginous plates, clinically seen as the pubertal growth spurt. Prepubertal androgen deficiency leads to poor muscle development, decreased strength and endurance, a

high-pitched voice, sparse axillary and pubic hair, and the absence of facial and body hair. The long bones of the lower extremities and arms may continue to grow under the influence of growth hormone; this condition leads to eunuchoid proportions (i.e., arm span exceeding total height by ≥5 cm) and greater growth of the lower extremities relative to total height. Postpubertal androgen deficiency may result in a decrease in libido, impotence, low energy, fine wrinkling around the corners of the eyes and mouth, and diminished facial and body hair. Male hypogonadism may be classified into three categories according to the level of the defect (Table 67.1). Diseases directly affecting the testes result in primary or hypergonadotropic hypogonadism, which is characterized by oligospermia or azoospermia and low testosterone levels but exhibits elevations of LH and FSH because of a decrease in the negative feedback regulation on the pituitary and hypothalamus by androgens, estrogens, and inhibin. In contrast, hypogonadism from lesions in the hypothalamus or pituitary gives rise to secondary or hypogonadotropic hypogonadism; the low testosterone level or ineffective spermatogenesis results from inadequate concentrations of the gonadotropins. The third category of hypogonadism is the result of defects in androgen action.

Hypothalamic-Pituitary Disorders Panhypopituitarism occurs congenitally from structural defects or from inadequate production or release of the hypothalamic-releasing factors. The condition may also be acquired through replacement by tumors, infarction from vascular insufficiency, infiltrative disorders, autoimmune diseases, trauma, and infections. Kallmann syndrome is a form of hypogonadotropic hypogonadism that is associated with problems in the ability to discriminate odors, either incompletely (hyposmia) or completely (anosmia). This syndrome results from a defect in the migration of the GnRH neurons from the olfactory placode into the hypothalamus. Therefore, it represents a GnRH deficiency. Patients remain prepubertal, with small, rubbery testes, and they develop eunuchoidism (E-Fig. 67.1). Hyperprolactinemia may result in hypogonadotropic hypogonadism because prolactin elevation inhibits normal release of GnRH, decreases the effectiveness of LH at the Leydig cell level, and also inhibits some of the actions of testosterone at the level of the target organ. Normalization of prolactin levels through withdrawal of an offending drug, by surgical removal of the pituitary adenoma, or with the use of dopamine agonists reverses this form of hypogonadism. Weight loss or systemic illness in male patients can cause another form of secondary hypogonadism, hypothalamic dysfunction. Weight loss or illness induces a defect in the hypothalamic release of GnRH and results in low levels of gonadotropin and testosterone. This condition is commonly observed in patients with cancer, AIDS, or chronic

657

658

SECTION X  Endocrine Disease and Metabolic Disease

–

+ –

Testosterone Estradiol

TABLE 67.1  Classification of Male

Hypothalamus

Hypogonadism

GnRH

Pituitary gonadotrophs

LH

+

FSH

Leydig cell

Inhibin Testosterone Estradiol

+

Testicle Testosterone

–

Hypothalamic-Pituitary Disorders (Secondary Hypogonadism) Panhypopituitarism Isolated gonadotropin deficiency Complex congenital syndromes Hyperprolactinemia Hypothalamic dysfunction Gonadal Disorders (Primary Hypogonadism) Klinefelter’s syndrome and associated chromosomal defects Myotonic dystrophy Cryptorchidism Bilateral anorchia Seminiferous tubular failure Adult Leydig cell failure Androgen biosynthesis enzyme deficiency Defects in Androgen Action Testicular feminization (complete androgen insensitivity) Incomplete androgen insensitivity 5α-Reductase deficiency

+ Seminiferous tubule

Sperm

Fig. 67.1 Regulation of the hypothalamic-pituitary-testicular axis. The plus (+) and minus (−) symbols indicate positive and negative feedback, respectively. FSH, Follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.

inflammatory processes. Prolonged use of opioids and therapeutic doses of glucocorticoids may suppress gonadotropin production and cause secondary hypogonadism.

Primary Gonadal Abnormalities The most common congenital cause of primary testicular failure is Klinefelter’s syndrome, which occurs in about 1 of every 600 live male births and is usually caused by a maternal meiotic chromosomal nondisjunction that results in an XXY genotype. At puberty, clinical findings include the following: a variable degree of hypogonadism; gynecomastia; small, firm testes measuring less than 2 cm in the longest axis (normal testes, 3.5 cm or greater); azoospermia; eunuchoid skeletal proportions; and elevations of FSH and LH (E-Fig. 67.2). Primary gonadal failure is also found in patients with another congenital condition, myotonic dystrophy, which is characterized by progressive weakness; atrophy of the facial, neck, hand, and lower extremity muscles; frontal baldness; and myotonia. About 3% of full-term male infants have cryptorchidism, which spontaneously corrects during the first year of life in most cases; consequently, by 1 year of age, the incidence of this condition is about 0.8%. When the testes are maintained in the intra-abdominal position, the increased temperature leads to defective spermatogenesis and oligospermia. Leydig cell function usually remains normal, resulting in normal levels of adult testosterone. Bilateral anorchia, also known as the vanishing testicle syndrome, is a rare condition in which the external genitalia are fully formed, indicating that ample quantities of testosterone and DHT were produced during early embryogenesis. However, the testicular tissue disappears before or shortly after birth, and the result is an empty scrotum. This condition is differentiated from cryptorchidism by an

HCG stimulation test. Patients with cryptorchidism have an increase in serum testosterone level after an injection of HCG, whereas patients with bilateral anorchia do not. Acquired gonadal failure has numerous causes. The adult seminiferous tubules are susceptible to a variety of injuries, and seminiferous tubular failure is found after infections such as mumps, gonococcal or lepromatous orchitis, irradiation, vascular injury, trauma, alcohol ingestion, and use of chemotherapeutic drugs, especially alkylating agents. The serum FSH concentration may be normal or elevated, depending on the degree of damage to the seminiferous tubules. The Leydig cell compartment may also be damaged by these same conditions. In addition, some men experience a gradual decline in testicular function as they age, possibly because of microvascular insufficiency. Patients with decreased testosterone production may clinically exhibit lowered libido and potency, emotional lability, fatigue, and vasomotor symptoms such as hot flashes. The serum LH concentration is usually elevated in this situation.

Defects in Androgen Action When either testosterone or its metabolite, DHT, binds to the androgen receptor in target cells, the receptor is activated and binds DNA; the resulting stimulation of transcription, protein synthesis, and cell growth collectively constitutes androgen action. An absence of androgen receptors causes the syndrome of testicular feminization, a form of male pseudohermaphroditism. These genetic males have cryptorchid testes but appear to be phenotypic females. Because androgens are inactive during embryogenesis, the labial-scrotal folds fail to fuse, and a short vagina results. The fallopian tubes, uterus, and upper portion of the vagina are absent because the fetal testicular Sertoli cells secrete Anti-Müllerian duct hormone (Müllerian duct inhibitory factor) during early fetal development. At puberty, these patients have breast enlargement because the testes secrete a small amount of estradiol and the peripheral tissues convert testosterone and adrenal androgens to estrogens. Axillary and pubic hair does not grow because androgen action is required for their development. The serum testosterone concentrations are elevated as a result of continuous stimulation by elevated concentrations of LH. LH is high because of the inability of the testosterone to act in a negative feedback fashion at

CHAPTER 67  Male Reproductive Endocrinology

658.e1

E-Fig. 67.1  A boy aged 15 years, 10 months, with isolated gonadotropin deficiency and anosmia (Kallmann syndrome). He had undescended testes, but after administration of 10,000 U of human chorionic gonadotropin (HCG), the testes descended and were palpable in the scrotum. Height was 163.9 cm (−1.5 standard deviation); the upper-to-lower body ratio was 0.86, which is eunuchoid. The phallus measured 6.3 × 1.8 cm, and the testes were 1.2 × 0.8 cm. The concentration of plasma luteinizing hormone (FSH) was 1.2 ng/mL, and that of testosterone was 16 ng/mL. After administration of 100 μg of LH-releasing hormone (LHRH), the plasma LH (LER-960) was 0.7 ng/mL, and the FSH (LER-869) was 2.4 ng/mL. (From Styne DM, Grumbach MM: Puberty in the male and female: its physiology and disorders. In Yen SCC, Jaffee RB, editors: Reproductive endocrinology, ed 2, Philadelphia, 1986, Saunders, p. 313-384.)

658.e2

SECTION X  Endocrine Disease and Metabolic Disease

B

A

C

D

E-Fig. 67.2  (A) A 19-year-old phenotypic male with chromatin-positive seminiferous tubule dysgenesis (Klinefelter’s syndrome). The karyotype was 47,XXY, gonadotropin levels were elevated, and testosterone levels were low-normal. Notice normal virilization with long legs and gynecomastia (B). (C) The testes were small and firm and measured 1.8 × 0.9 cm. Testicular biopsy revealed a severe degree of hyalinization of the seminiferous tubules and clumping of Leydig cells. (D) A 48-year-old male with 47, XXY Klinefelter’s syndrome with severe leg varicosities. (From Larsen PR, Kronenberg HM, Melred S, et al, editors: Williams textbook of endocrinology, ed 10, Philadelphia, 2002, Saunders.)

659

CHAPTER 67  Male Reproductive Endocrinology

LH, FSH, testosterone (T), semen analysis

↓Sperm count ↓LH ↓FSH, ↓T

↓Sperm count ↑LH or FSH, ↓or NL T

↓Sperm count NL T & LH; NL or ↑FSH

Hypothalamic-pituitary abnormality

Primary testicular abnormality

Are sperm present?

Yes

Are testes present in scrotum?

Measure PRL; MRI of hypothalamicpituitary region

No

Seminal fluid fructose No

Yes

HCG stimulation

Size and consistency

↑T Cryptorchidism

No ↑T

Small and firm

Postpubertal size, NL or soft

Probable Klinefelter’s syndrome

Acquired primary hypogonadism

Present

Absent

Testicular biopsy

Congenital absence of seminal vesicles and vas deferens

Abnormal

Anorchia Spermatogenic failure

Perform karyotype

NL

Ductal obstruction

Fig. 67.2  Laboratory evaluation of hypogonadism. ↑, Elevated; ↓, decreased or low; FSH, follicle-stimulating hormone; HCG, human chorionic gonadotropin; LH, luteinizing hormone; MRI, magnetic resonance imaging; NL, normal; PRL, prolactin.

the hypothalamus. Patients may have incomplete forms of androgen insensitivity caused by point mutations affecting the androgen receptor gene, and clinically these patients show varying degrees of male pseudohermaphroditism. Patients who lack the 5α-reductase enzyme that is required to convert testosterone to DHT are born with a bifid scrotum, which reflects abnormal fusion of the labial-scrotal folds, and hypospadias, in which the urethral opening is in the perineal area or in the shaft of the penis. At puberty, androgen production is sufficient to partially overcome the defect; the scrotum, phallus, and muscle mass enlarge, and these patients appear to develop into physiologically normal men.

Diagnosis Fig. 67.2 illustrates an algorithm for the laboratory evaluation of hypogonadism in a phenotypic man. Serum concentrations of LH, FSH, and testosterone should be obtained, and a semen analysis should be performed. A low testosterone level with low concentrations of gonadotropins indicates a hypothalamic-pituitary abnormality, which needs to be evaluated with serum prolactin determination and radiographic examination. Elevated concentrations of gonadotropins with a normal or low testosterone level reflect a primary testicular abnormality. If no testes are palpable in the scrotum and careful milking of the patient’s

lower abdomen does not bring retractile testes into the scrotum, an HCG stimulation test should be performed. A rise in serum testosterone concentrations indicates the presence of functional testicular tissue, and a diagnosis of cryptorchidism can be made. Absence of a rise in testosterone suggests bilateral anorchia. Small, firm testes in the scrotum are highly suggestive of Klinefelter’s syndrome; this diagnosis needs to be confirmed with a chromosomal karyotype. Testes that are more than 3.5 cm in longest diameter and that are either of normal consistency or are soft indicate postpubertal acquired primary hypogonadism. If the major abnormality is a deficient sperm count with or without an elevation of FSH, differentiation between a ductal problem and acquired primary hypogonadism must be made. If spermatozoa are present, at least the ducts emanating from one testicle are patent; this condition indicates an acquired testicular defect. If the patient has no sperm in the ejaculate, a primary testicular or ductal problem may be responsible. The seminal vesicles secrete fructose into the seminal fluid. Therefore, the presence of fructose in the ejaculate should be followed by a testicular biopsy to determine whether the defect results from spermatogenic failure or from an obstruction of the ducts leading from the testes to the seminal vesicles. Absence of seminal fluid fructose indicates a congenital absence of the seminal vesicles and vas deferens.

660

SECTION X  Endocrine Disease and Metabolic Disease

Male Infertility The inability to conceive after 1 year of unprotected sexual intercourse affects about 15% of couples, and male factors appear to be responsible in about 20% of cases. Female factors account for close to 40%, and a couple factor is present in about 25% of cases with about 15% being undefined. In addition to the defects in spermatogenesis that occur in patients with hypothalamic, pituitary, testicular, or androgen action disorders, hyperthyroidism, hypothyroidism, adrenal abnormalities, and systemic illnesses can result in defective spermatogenesis, as can microdeletions of genetic material on the Y chromosome. Disorders of the vas deferens, seminal vesicles, and prostate may also lead to infertility, as may diseases affecting the bladder sphincter that result in retrograde ejaculation, in which the sperm passes into the bladder rather than through the penis. Anatomic defects of the penis (as observed in patients with hypospadias), poor coital technique, and the presence of antisperm antibodies in the male or female genital tract also are associated with infertility.

Therapy for Hypogonadism and Infertility Treatment of androgen deficiency in patients who have hypothalamic-pituitary or primary testicular abnormalities is best accomplished with exogenous testosterone administration—either intramuscular injection of intermediate (1-3 weeks)- or long (3 months)-acting testosterone esters or transdermal testosterone patches or gel. Buccal, nasal, and subcutaneous testosterone pellets are also available but are less often used. Testosterone therapy increases libido, potency, muscle mass, strength, athletic endurance, hair growth on the face and body, and bone density. The most common side effect is erythrocytosis. Other side effects include acne, fluid retention, benign prostate hyperplasia, and, rarely, sleep apnea. This therapy is contraindicated in patients with cancer of the prostate. If fertility is desired, patients with hypothalamic abnormalities may develop virilization and spermatogenesis with the use of GnRH delivered in a pulsatile fashion subcutaneously by an external pump. Direct stimulation of the testes in patients with hypothalamic or pituitary abnormalities may be accomplished with the use of exogenous gonadotropins, which increase testosterone and sperm production. If primary testicular failure is present and the patient has oligospermia, an attempt can be made to concentrate the sperm for intrauterine insemination or in vitro fertilization. If the azoospermia is caused by ductal obstruction, repair of the obstruction may be undertaken or aspiration of sperm from the epididymis may be accomplished for in vitro fertilization.

GYNECOMASTIA Gynecomastia refers to a benign enlargement of the male breast that results from proliferation of the glandular component. This common condition is found in close to 70% of pubertal boys and in about one third of adults 50 to 80 years old. Estrogens stimulate and androgens inhibit breast glandular development; gynecomastia results from an imbalance between estrogen and androgen actions at the breast tissue level. This condition may result from an absolute increase in free estrogens, a decrease in endogenous free androgens, androgen insensitivity of the tissues, or enhanced sensitivity of the breast tissue to estrogens. Table 67.2 lists the common conditions associated with gynecomastia. Gynecomastia must be differentiated from fatty enlargement of the breasts without glandular proliferation and from other disorders of the breasts, especially breast carcinoma. Male breast cancer usually manifests as a unilateral, eccentric, hard or firm mass that is fixed to the underlying tissues. It may be associated with skin dimpling or

TABLE 67.2  Conditions Associated With

Gynecomastia

Physiologic Conditions Neonatal Pubertal Involutional Pathologic Conditions Neoplasms Testicular Adrenal Ectopic production of human chorionic gonadotropin Primary gonadal failure Secondary hypogonadism Enzyme defects in testosterone production Androgen insensitivity syndromes Liver disease Malnutrition with refeeding Dialysis Hyperthyroidism Excessive extraglandular aromatase activity Drugs Estrogens and estrogen agonists Gonadotropins Antiandrogens or inhibitors of androgen synthesis Cytotoxic agents Highly active antiretroviral therapy (ART) Spironolactone Cimetidine Growth hormone Alcohol Human immunodeficiency virus infection Idiopathic

retraction or with crusting of the nipple or nipple discharge. In contrast, gynecomastia occurs concentrically around the nipple and is not fixed to the underlying structures. Although physical examination is usually sufficient to differentiate gynecomastia from breast carcinoma, mammography or ultrasonography may be required. Painful and tender gynecomastia in a pubertal adolescent should be monitored with periodic examinations because, in most patients, pubertal gynecomastia disappears within 1 year. Incidentally discovered, asymptomatic gynecomastia in an adult requires a careful assessment for alcohol, drug, or medication use; liver, lung, or kidney dysfunction; and signs and symptoms of hypogonadism or hyperthyroidism. If these conditions are not present, only follow-up is required. In contrast, in an adult with recent onset of progressive painful gynecomastia, thyroid, liver, and renal function should be determined. If test results are normal, serum concentrations of HCG, LH, testosterone, and estradiol should be measured. Further evaluation should be carried out according to the schema outlined in Fig. 67.3. Removal of the offending drug or correction of the underlying condition causing the gynecomastia may result in regression of the breast glandular tissue. If the gynecomastia persists, an off-label trial of antiestrogens (e.g., tamoxifen) may be given for 3 months to see whether regression occurs. Gynecomastia that has been present for longer than 1 year usually contains a fibrotic component that does not respond to medications. In these cases, correction usually requires surgical removal of the tissue. For a deeper discussion on this topic, please see Chapter 223, “Reproductive Endocrinology and Infertility,” in Goldman-Cecil Medicine, 26th Edition.

661

CHAPTER 67  Male Reproductive Endocrinology

Measure serum HCG, LH, T, E2

↑HCG

↑LH, ↓T

↓or normal LH, ↓T

↑LH, ↑T

↑E2, ↓or normal LH

Normal

Testicular ultrasonography

Primary hypogonadism

Measure serum prolactin

Measure T4, TSH

Testicular ultrasonography

Idiopathic gynecomastia

Mass

Normal ↑T4, ↓TSH

Testicular germ cell tumor

Extragonadal germ cell tumor or HCG-secreting nontrophoblastic neoplasm

Chest film Abdominal CT

Elevated

Probable prolactinsecreting pituitary tumor

Secondary hypogonadism

Normal

Leydig or Sertoli cell tumor

Adrenal CT or MRI

Normal

Normal

Hyperthyroidism

Mass

Androgen resistance

Mass

Normal

Adrenal neoplasm

Increased extraglandular aromatase activity

Fig. 67.3  Diagnostic evaluation for causes of gynecomastia based on measurements of serum human chorionic gonadotropin (HCG), luteinizing hormone (LH), testosterone (T), and estradiol (E2). ↑, Increased; ↓, decreased; CT, computed tomography; MRI, magnetic resonance imaging; T4, thyroxine; TSH, thyroid-stimulating hormone. (From Braunstein GD: Gynecomastia, N Engl J Med 328:490-495, 1993.)

SUGGESTED READINGS Bhasin S, Brito J, Cunningham GR, et al: Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab 103:1715–1744, 2018. Gravholt CH, Chang S, Wallentin M, Fedder J, Moore P, Skakkebaek A: Klinefelter syndrome: integrating genetics, neuropsychology, and endocrinology, Endocr Rev 39:389–423, 2018. Irwin GM: Erectile dysfunction, Clinics in Office Practice 46:249–255, 2019.

Pan MM, HGockenberry MS, Kirby EW, Lipshultz LI: Male infertility diagnosis and treatment in the era of in vitro fertilization and intracytoplasmic sperm injection, Med Clin N Amer 102:337–347, 2018. Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society for Male Reproduction and Urology: Evaluation of the azoospermic male: a committee opinion, Fertil Steril 109:777–782, 2018. Sansone A, Romanelli F, Sansone M, Lenzi A, Luigi LD: Gynecomastia and hormones, Endocrine 55:37–44, 2017. Shepard CL, Kraft KH: The nonpalpable testis: a narrative review, J Urol 198:1410–1417, 2017.

68 Diabetes Mellitus, Hypoglycemia Robert J. Smith

DIABETES MELLITUS Definition and Diagnostic Criteria Diabetes mellitus is not a single disease but a group of disorders that develop as a consequence of absolute or relative deficiency of the hormone insulin. Inadequate actions of insulin in stimulating the uptake of glucose by body tissues and regulating the metabolism of carbohydrate, fat, and protein result in hyperglycemia. Other metabolic disturbances in addition to hyperglycemia typically occur in uncontrolled diabetes, including altered lipoprotein dynamics and elevated free fatty acid levels. These abnormalities contribute to the acute and chronic clinical consequences of diabetes. The criteria used to diagnose diabetes mellitus in nonpregnant individuals are summarized in Table 68.1. The diagnosis can be made on the basis of a fasting blood glucose level of 126 mg/dL or higher, a random blood glucose concentration (i.e., determined at any time in association with meals or fasting) of 200 mg/dL or higher, or a 2-hour glucose level of 200 mg/dL or higher as part of a 75-g oral glucose tolerance test. Alternatively, diabetes can be diagnosed if the hemoglobin A1c (HbA1c) level is 6.5% or higher. HbA1c, a measure of the percentage of hemoglobin in circulating erythrocytes that is glycosylated, correlates with mean circulating glucose levels. HbA1c provides an index of the average blood glucose level over the preceding 2 to 3 months. Because HbA1c accumulates progressively throughout the lifespan of an erythrocyte, spurious values may occur in states of altered erythrocyte turnover (e.g., with various anemias) or with certain hemoglobinopathies that increase or decrease the susceptibility of hemoglobin to glycosylation. In patients with marked elevations in blood glucose or HbA1c and coincident symptoms typical for hyperglycemia (e.g., polyuria and polydipsia), the diagnosis can be made based on a single test result. With less marked glucose elevations in the absence of symptoms, the diagnosis should be confirmed by repeat testing on a separate day. Patients who have mild elevations in plasma glucose levels that do not reach the threshold for diagnosis of diabetes (e.g., HbA1c levels between 5.7% and 6.4%) are at increased risk for progression to diabetes and therefore are considered to have prediabetes. Prediabetes patients with fasting blood glucose levels between 100 and 125 mg/ dL are more specifically labeled as having impaired fasting glucose, and those with 2-hour postprandial plasma glucose levels between 140 and 199 mg/dL (most reliably measured after a standardized 75-g oral glucose load) have impaired glucose tolerance (see Table 68.1). Although not all individuals with prediabetes will become diabetic, the mean progression rate to overt diabetes is approximately 6% per year. There also is evidence from observational studies that the prediabetic state is associated with an increased risk of cardiovascular disease. Gestational diabetes mellitus (GDM) is a term applied to diabetes first recognized during pregnancy. The most widely accepted

662

thresholds for diagnosis of GDM are a fasting plasma glucose level of 92 mg/dL or higher at any gestational stage and values on a 75-g oral glucose tolerance test at 24 to 28 weeks’ gestation of 92 mg/dL or higher fasting, 180 mg/dL or higher at 1 hour, or 153 mg/dL or higher at 2 hours after glucose loading (Table 68.2). Untreated diabetes in pregnancy is associated with increased fetal malformations, problems in delivery, and possibly more frequent diabetes complications in the mother.

Etiologic Classification Once the diagnosis is made based on elevated blood glucose or HbA1c values, it is important to establish the specific subtype of diabetes based on a combination of clinical and molecular pathophysiologic features Table 68.3. Type 1 diabetes (T1DM) is characterized by extensive destruction of the insulin-producing beta cells within the islets of Langerhans in the pancreas and dependence on insulin therapy for survival. In previous medical literature, the terms juvenile-onset diabetes or insulin-dependent diabetes were used for T1DM. This terminology is no longer used, because T1DM not uncommonly has its onset in adulthood, and multiple other forms of diabetes often require treatment with insulin. T1DM accounts for 5% to 10% of all diabetes in the United States. In most patients, it involves autoimmune mechanisms leading to beta cell destruction (the type 1A form). Rare individuals have no markers for autoimmunity and are classified as having type 1B (idiopathic) diabetes. Most patients with T1DM progress to marked insulin deficiency over a period of several weeks to months after initial presentation. A smaller number of individuals with evidence of beta-cell autoimmunity but much slower disease progression have a variant form of T1DM that has been designated latent autoimmune diabetes of adulthood (LADA). In patients with marked elevations in glucose and accompanying ketoacidosis, particularly if they are young and nonobese, the diagnosis of T1DM is highly probable. This can be confirmed by measuring autoantibodies against glutamic acid decarboxylase (GAD65), insulin, tyrosine phosphatases (IA-2 and IA2-beta), and zinc transporter 8 (ZnT8), with several of these often obtained as a panel, and also by a clinical course demonstrating an ongoing need for insulin to control hyperglycemia. A fasting C-peptide level can be measured later in the disease to confirm marked deficiency in insulin secretion. C-peptide is a fragment of the insulin precursor proinsulin, which is cleaved during the synthesis of insulin. It is secreted and circulates in proportion to endogenous insulin production but is absent from injected exogenous insulin preparations. Type 2 diabetes (T2DM) is a heterogeneous, clinically defined subtype that accounts for more than 90% of all diabetes in the United States. It typically has a gradual onset with progression over multiple years or even decades. There is often prolonged preservation of at least partial insulin secretory capacity together with evidence

CHAPTER 68  Diabetes Mellitus, Hypoglycemia

TABLE 68.1  Criteria for the Diagnosis of

Diabetes Mellitus Measurement

Normal

Plasma glucose (mg/dL) Fastinga 2000 white blood cells per microliter), usually in the 10,000 to 100,000 white blood cells per microliter range. Serum uric acid is not a diagnostically reliable test during acute flares since serum urate level may be normal or even low. Laboratory testing may reveal leukocytosis and elevated inflammatory markers, both of which are nonspecific. Between attacks, MSU crystals can often be demonstrated in previously inflamed joints, providing support to the diagnosis.

Radiologic Features During an acute attack, a plain radiograph may only show soft tissue swelling. In chronic advanced gout, well-defined, “punched out” juxtaarticular erosions characterized by a sclerotic rim and overhanging

“Activating” signal

canakinumab rilonacept MSU crystals

Ca

2+

K+ + K + K+ K

PRRs

Extracellular

Mitochondrial dysfunction

Intracellular Ruptured lysosome

NF-KB

ASC

Pro-caspase 1

Inactive NLRP3

K+

BHB

colchicine

Cathespins

Ca2+ Ca2+ 2+ Ca Ca2+

antioxidants Inflammasome assembly

ROS mtDNA

colchicine BAPTA-AM CP-456,773 (MCC950) NLRP3 Inflammasome

NF-KB

Nucleus

NLRP3 Pro- IL-18 Pro- IL-1β

Cleavage by caspase 1

IL-18 IL-1β

Secretion of active cytokines

VX-765 α-antitrypsin-Fc (AAT-Fc)

Fig. 84.2  NLRP3 inflammasome activation and potential targets in gout. ASC, Apoptosis-associated specklike protein containing a CARD; mtDNA, mitochondrial DNA; NF-kB, nuclear factor kappa light-chain-enhancer of activated B cells; PRRs, pattern recognition receptors; ROS, reactive oxygen species. (From Szekanecz Z, Szamosi S, Kovács GE, et al: The NLRP3 inflammasome–interleukin 1 pathway as a therapeutic target in gout, Arch Biochem Biophys 670:82-93, 2019.)

810

SECTION XIV  Musculoskeletal and Connective Tissue Disease

A

B

MSU CPPD Fig. 84.3  Polarized microscopy image of (A) strongly negative birefringent monosodium urate crystals and (B) weakly positive calcium pyrophosphate dihydrate crystals. Arrows indicate axis of polarization. (A, Modified from the ACR Slide Collection on the Rheumatic Diseases. Available at http://images.rheumatology. org/. Accessed January 2015; B, Modified from Saadeh C, Diamond HS: Calcium pyrophosphate deposition disease. Available at: http://emedicine.medscape.com/article/330936-overview#showall.)

edges may be seen. The joint space is preserved until late in the course of the disease. Soft tissue masses may be detected in patients with tophi. Dual-energy CT is a useful noninvasive imaging modality that can identify and color-code urate deposits in patients with gout. Ultrasound is a promising noninvasive tool in the diagnosis and management of gout.

Gout in Transplantation Patients Hyperuricemia occurs much more frequently in transplantation patients using cyclosporine than in the normal population. Compared to patients with classic gout, transplant patients exhibit a significantly shorter period of asymptomatic hyperuricemia (0.5 to 4 years vs. 20 to 30 years), a shorter stage of acute intermittent gout (1 to 4 years vs. 10 to 15 years), and rapid development of tophi as early as 1 year after transplantation. Gouty attacks can be atypical and less severe, in part because of the concomitant use of prednisone.

Differential Diagnosis Acute gouty arthropathy should be distinguished from septic arthritis and other crystal-induced arthropathies such as calcium pyrophosphate dihydrate (CPPD) deposition disease. The onset of acute CPPD arthropathy is usually less abrupt, and attacks tend to last longer, up to 1 month or more. Attacks occur more often in large joints such as the knee and wrist. Forms of spondyloarthropathies including reactive arthritis, psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel–related arthritis can also present with monoarticular arthritis. In these disorders, synovial fluid is inflammatory, with a leukocyte count usually in the range of 10,000 to 50,000/μL, but crystals are absent and fluid culture is negative. The diffuse and symmetric involvement of small joints in the hands and feet seen in chronic tophaceous gout can sometimes be confused with the symmetrical polyarthritis of rheumatoid arthritis and rheumatoid nodules. Aspiration of chronically inflamed joints or a tophus can help in distinguishing the two entities.

Treatment Management strategies should focus on treating acute attacks, longterm management of hyperuricemia, patient education, and lifestyle modification.

Management of Acute Gouty Attack Nonsteroidal anti-inflammatory drugs (NSAIDs) (such as naproxen and indomethacin) are typically used, and all seem to be equally

effective. A full dose should be immediately initiated. Therapy should be continued for 7 to 10 days to ensure complete resolution of symptoms. NSAIDs are inappropriate in patients with peptic ulcer disease, inflammatory bowel disease, or renal insufficiency, and they must be used with caution in patients at risk for cardiovascular events. Oral colchicine can be effective if used within the first 24 to 48 hours of an acute attack. A commonly prescribed dose is 1.2 mg, followed by 0.6 mg 1 hour later in the first day, followed by dose tapering until the attack is resolved. Colchicine can cause nausea and diarrhea and therapy should be stopped if symptoms are severe. Use of intravenous colchicine is discouraged due to high risk of bone marrow suppression. Intra-articular corticosteroid administration is a very effective therapy for patients with monoarticular or oligoarticular disease in whom other systemic therapies are contraindicated. Enteral or parenteral glucocorticosteroids are effective in patients with renal insufficiency, intolerance to NSAIDs or colchicine, or treatment resistance. This approach is usually reserved for polyarticular flares when intra-articular injection is not practical (i.e., too many involved joints). Prednisone, 30 to 50 mg daily, is commonly used. Urate-lowering therapy (ULT) should not be interrupted during acute attacks. Prompt initiation of anti-inflammatory therapy at the onset of symptoms may shorten the duration of attacks.

Management of Intercritical and Chronic Gout Urate-lowering therapy. The aim of chronic treatment is to prevent recurrent attacks and to minimize joint damage by depleting tophaceous deposits in joints and soft tissue. This is achieved by lowering uric acid level below 6 mg/dL. A target level of less than 5 mg/ dL should be considered in patients with chronic tophaceous gout as this may result in a faster, more effective reduction in tophus size and flare frequency. Indications for ULT include two or more attacks in a single year, presence of tophi, chronic kidney disease CKD stage 2 or more, chronic gouty arthritis, or recurrent nephrolithiasis. Three categories of urate-lowering therapies are available: uricostatic agents that decrease uric acid production, uricosuric agents that increase renal excretion of uric acid, and uricolytic agents that break up uric acid into other metabolites. The optimal duration of ULT is not known, and lifelong therapy is usually recommended. ULT is typically started after resolution of an acute attack. Uricostatic therapy. Allopurinol and febuxostat are xanthine oxidase inhibitors (XOI) that prevent urate formation. They are effective in managing gout in both overproducers and undersecretors of uric acid.

CHAPTER 84  Crystal Arthropathies Allopurinol remains the first-line and most commonly used ULT agent, particularly in patients with chronic renal insufficiency, uric acid stones, or uric acid overproduction. If renal function is normal, a starting dose of 100 mg daily is recommended because higher doses may increase the risk of allopurinol-associated hypersensitivity, a potentially lethal complication. The risk of early flares may also be increased with higher doses. The dose should be titrated up by 100 mg increments every 2 to 5 weeks until the target uric acid level is reached. The maximal dose is 800 mg/day. Doses above 300 mg per day can be safely used in patients with renal impairment. Adverse events include rash (2%), hepatitis, vasculitis, eosinophilia, and bone marrow suppression. Allopurinol-associated hypersensitivity is a serious side effect. Risk factors include concomitant use of thiazides and penicillin allergy. Fever, severe exfoliative dermatitis, eosinophilia, and hepatic and renal failure can occur. Febuxostat may be used in patients who do not achieve target uric acid levels despite adequate allopurinol dose titration or in patients with side effects to allopurinol. Uricosuric therapy. Probenecid may be used as first-line ULT in uric acid undersecretors ( MCPs and wrists), whereas rheumatoid arthritis more commonly affects proximal small joints in the hands (MCPs and wrists > PIPs > DIPs).

TREATMENT The natural history of osteoarthritis includes periods of relative stability interspersed with rapid deterioration. Management should be individually tailored and may include a combination of nonpharmacologic, pharmacologic, and surgical approaches. The primary goal of treatment is to improve pain and function and reduce disability. Patients should be educated regarding the objectives of treatment and the importance of lifestyle changes, exercise, pacing of activities, and other measures to unload the damaged joints. The initial focus should be on self-help and patient-driven treatments rather than on passive therapies. Patients should be encouraged to adhere to nonpharmacologic and pharmacologic therapies. Physical therapists may be helpful in providing instruction in appropriate exercises to reduce pain and preserve functional capacity. For knee and hip osteoarthritis, assistive devices such as walking aids may be useful. In patients with first carpometacarpal joint osteoarthritis, hand orthoses are recommended. Graded regular aerobic, aquatic exercise, muscle-strengthening, and range-of-motion exercises are beneficial. Tai chi has been shown to have beneficial effects not only in the treatment of knee and hip osteoarthritis, but also in improving quality of life and depression. Overweight patients should be encouraged to lose weight. A combination of dietary weight loss in conjunction with exercise results in improvement of both pain and function compared to either intervention alone, though long-term weight management may be challenging for patients. A knee brace can reduce pain, improve stability, and diminish the risk of falling for patients with knee osteoarthritis and mild or moderate varus or valgus instability. Advice concerning appropriate footwear is also important. Spinal orthoses may provide benefit to patients with significant cervical or lumbar involvement. Local applications of heat, ultrasound, or transcutaneous electrical nerve

stimulation (TENS) may provide short-term benefit in these patients. In patients with knee and hip osteoarthritis, TENS is not recommended as there have been limited studies and lack of benefit. Acupuncture may also offer symptomatic benefit for patients with osteoarthritis, but its efficacy in knee, hip, and hand osteoarthritis is still debatable as studies have shown variable results. Pharmacologic therapy provides symptomatic relief but does not alter the course of the disease. Pharmacologic therapy should therefore be selected based on its relative efficacy and safety. The use of concomitant medications in the setting of comorbidities should be taken into account. Acetaminophen (up to 3 g/day with caution) may be an effective initial oral analgesic for mild to moderate pain, though it may not provide sufficient benefit on its own. In patients with symptomatic osteoarthritis, nonsteroidal anti-inflammatory drugs (NSAIDs) should be used at the lowest effective dose, although their long-term use should be avoided if possible. If patients are at risk for increased gastrointestinal toxicity, a cyclooxygenase-2 (COX2)–selective agent or a nonselective NSAID with co-prescription of a proton pump inhibitor or misoprostol for gastroprotection should be considered. All NSAIDs, including nonselective and COX2-selective agents, should be used with caution in patients with cardiovascular risk factors and chronic kidney disease. Topical NSAIDs and capsaicin may be effective alternatives to oral analgesic or anti-inflammatory agents in knee and hand osteoarthritis and may be used as adjunctive agents, particularly in elderly patients. If patients fail the aforementioned, find other therapies ineffective, and are not surgical candidates, then tramadol, a weak opioid receptor agonist, may also be used in these select cases. Non-tramadol opiates are discouraged as they pose risk for an increase of adverse effects that typically outweighs their benefits. In select patients that have exhausted other therapies and medications, non-tramadol opioids may be used for the shortest possible length of time, given the limited pain control with longer duration of these medications. Despite the popularity of these products, meta-analyses have shown that oral glucosamine and chondroitin sulfate have limited benefit in patients with knee osteoarthritis and are currently not recommended in knee, hip or hand osteoarthritis. Other agents, such as duloxetine, when compared to placebo, were shown to reduce pain and improve function in a meta-analysis. Duloxetine can be used in pain management and studies have shown efficacy in the treatment of osteoarthritis. Occasional injection of intra-articular corticosteroids (usually no more than once every 4 months) may provide modest short-term symptomatic benefit with minimal toxicity, especially in the knee. Studies have shown that patients given more frequent corticosteroid injections (i.e., every 3 months) lose greater cartilage volume than those given a corticosteroid injection every 4 months, but the significance of this cartilage loss is unclear. Patients with moderate to severe pain and effusion or other local signs of inflammation may be more responsive to these injections. Intra-articular hyaluronate appears to have little or no benefit based on current evidence. Recent trials evaluated platelet-rich plasma injections and mesenchymal stem cell injections in osteoarthritis, but these are not currently recommended because there is a concern in the techniques used for these injections as well as the heterogeneity and lack of standardization of available preparations. Surgical management includes total joint replacement, which is extremely effective in relieving pain, decreasing disability, and improving function. With improvements in surgical technique and technology, the indications for total joint replacement have expanded to include younger and older age groups. Other surgical options include osteotomy and uni-compartmental knee replacement.

CHAPTER 85  Osteoarthritis Referral to an orthopedic surgeon should be considered in cases where other treatment options have been exhausted and quality of life is greatly reduced, including joint pain disrupting sleep, restriction of walking distance, and limiting participation in daily activities. Arthroscopy is not recommended for the management of knee osteoarthritis.

PROGNOSIS Given the obesity epidemic and the marked contact loads that increased weight places on the knee, obesity is likely the most important modifiable risk factor for the development and progression of knee osteoarthritis. One kilogram of weight loss decreases the load on the knee by 4 kg. Varus and valgus malalignments have also been identified as important risk factors for the progression of knee osteoarthritis.

SUGGESTED READINGS Blagojevic M, Jinks C, Jeffery A, et al: Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis, Osteoarthritis Cartilage 18:24–33, 2013. Helmick CG, Felson DT, Kwoh CK, et al: Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I, Arthritis Rheum 58:15–25, 2008. Hochberg MC, Altman RD, April KT, et al: American College of Rheumatology 2012 recommendations for the use of nonpharmacologic

817

and pharmacologic therapies in osteoarthritis of the hand, hip, and knee, Arthritis Care Res 64:465–474, 2012. Hunter DJ, Bierma-Zeinstra S: Osteoarthritis, Lancet 393(10182): 1745–1759, 2019. Kolasinski SL, Neogi T, Hochberg MC, et al: 2019 American College of Rheumatology/Arthritis Foundation guidelines for the management of osteoarthritis of the hand, hip and knee, Art Rheum 72(2):220–233, 2019. Litwic A, Edwards MH, Dennison EM, et al: Epidemiology and burden of osteoarthritis, Br Med Bull 105:185–199, 2013. McAlindon TE, LaValley MP, Harvey WF, et al: Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial, J Am Med Assoc 317:1967– 1975, 2017. Okano T, Mamoto K, Di Carlo M, et al: Clinical utility and potential of ultrasound in osteoarthritis, Radiol Med 124:1101–1111, 2019. Wang ZY, Shi SY, Li SJ, et al: Efficacy and safety of duloxetine on osteoarthritis knee pain: a meta-analysis of randomized controlled trials, Pain Med 16(7):1373–1385, 2015. Zhang W, Moskowitz RW, Kwoh CK, et al: OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence, Osteoarthritis Cartilage 15:981–1000, 2007. Zhang W, Moskovitz RW, Nuki G, et al: OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines, Osteoarthritis Cartilage 16:137–162, 2008.

86 Nonarticular Soft Tissue Disorders Niveditha Mohan

INTRODUCTION The nonarticular soft tissue disorders account for most musculoskeletal complaints in the general population. These disorders include a large number of anatomically localized conditions (e.g., bursitis, tendinitis) and fibromyalgia syndrome, a generalized pain disorder. For most nonarticular soft tissue conditions, the etiologic factors and pathogenesis are poorly understood. Once the location of the symptom is defined, (e.g., shoulder pain), the specific structure that is involved should be identified (e.g., supraspinatus tendon, subacromial bursa) using a careful history and physical examination. In the case of back pain, precise anatomic delineation of the structure involved (e.g., intervertebral disk, facet joint, ligament, paraspinal muscle) is more likely to require advanced imaging. When the patient complains of diffuse pain, it is imperative to evaluate for contribution of local pain that may be driving the diffuse pain, with a thorough physical examination.

EPIDEMIOLOGY Precise data for prevalence or incidence of most nonarticular soft tissue syndromes are not available, but these conditions account for up to 30% of all outpatient visits. Fibromyalgia is considered to be the most common cause of generalized musculoskeletal pain in women between the ages of 20 and 55 years. The global mean prevalence is 2.7%.

ETIOLOGIC FACTORS AND PATHOGENESIS The precise pathophysiology of most nonarticular soft tissue disorders remains unknown, although predisposing factors, such as trauma, overuse, repetitive activities (e.g., tennis elbow, lateral epicondylitis) or biomechanical factors (e.g., leg-length discrepancy in trochanteric bursitis), can be identified in many cases. The term tendinitis implies tendon sheath inflammation, but small tendon tears, periostitis, and nerve entrapment have been proposed as potential mechanisms. Similarly, although the term bursitis implies bursal inflammation, demonstrable inflammation is difficult to find. In some cases (e.g., acute bursitis of the olecranon or prepatellar bursa), the mechanism is an acute inflammatory response to sodium urate crystals deposited in the soft tissue, an extra-articular manifestation of gout. The favorable response of tendinitis and bursitis to anti-inflammatory agents, including corticosteroids, supports the view that at least one component of these syndromes is the result of an inflammatory process. Fibromyalgia is the current term for chronic widespread musculoskeletal pain for which no alternative cause can be identified. The underlying pathology is due to alterations in central nervous system

818

(CNS) function leading to augmented nociceptive (caused by pain) processing that leads to the development of CNS-mediated somatic symptoms of fatigue, sleep, memory and mood difficulties in addition to the chronic widespread pain. There may also be alterations in the immune system leading to an enhanced inflammatory state with emerging evidence that some of the pathobiology of fibromyalgia may involve altered nociceptor sensitivity. This disorder often begins in childhood or adolescence, and individuals who eventually go on to develop FM are more likely to experience headaches, dysmenorrhea, temporomandibular joint disorder, chronic fatigue, irritable bowel syndrome and other functional gastrointestinal tract disorders, interstitial cystitis/painful bladder syndrome, endometriosis, and other regional pain syndromes (especially back and neck pain).

CLINICAL PRESENTATION Many of the soft tissue rheumatic syndromes involve bursae, tendons, ligaments, and muscles. Bursae are closed sacs lined with mesenchymal cells that are similar to synovial cells; the sacs are strategically located to facilitate tissue gliding. Subcutaneous bursae (e.g., olecranon, prepatellar) form after birth in response to normal external friction. Deep bursae (e.g., subacromial bursa) usually form before birth in response to movement between muscles and bones and may or may not communicate with adjacent joint cavities. Adventitious bursae (e.g., over the first metatarsal head) form in response to abnormal shearing stresses and are not uniformly found. Although most forms of bursitis involve isolated, local conditions, some may be the result of systemic conditions such as gout. Tendinitis, bursitis, and myofascial disorders should be distinguished from articular disorders. In most cases, this can be accomplished by a careful examination of the involved structure (Table 86.1). General principles of the musculoskeletal examination are as follows: 1. Observation: If deformity or soft tissue swelling is detected, is it fusiform (i.e., surrounding the entire joint in a symmetrical fashion) or is it localized? Local rather than fusiform deformity distinguishes nonarticular disorders from articular disorders. 2. Palpation: Is tenderness localized or in a fusiform distribution? Is there an effusion? Local (not fusiform or joint line) tenderness distinguishes nonarticular disorders from articular disorders. An effusion typically indicates an articular disorder. 3.  Assessing range of motion: The musculoskeletal examination includes the assessment of active range of motion (i.e., patient attempts to move the symptomatic structure) and passive range of motion (i.e., examiner moves the symptomatic structure). Articular disorders usually are characterized by equal impairment in active and passive movements as a result of the mechanical limitation

CHAPTER 86  Nonarticular Soft Tissue Disorders

TABLE 86.1  Differentiating Nonarticular

Soft Tissue Disorders From Articular Disease Manifestation Limitation of motion Crepitus of articular surfaces (structural damage) Tenderness Synovial (fusiform pattern) Local Swelling Synovial (fusiform pattern) Local +,

819

TABLE 86.2  Bursitis Syndromes Location

Symptom

Finding

Subacromial Olecranon Iliopectineal Trochanteric Prepatellar Infrapatellar

Shoulder pain Elbow pain Groin pain Lateral hip pain Anterior knee pain Anterior knee pain

+ 0

Anserine

Medial knee pain

+ 0

Ischiogluteal Retrocalcaneal

Buttock pain Heel pain

Calcaneal

Heel pain

Tender subacromial space Tender olecranon swelling Tender inguinal region Tender at greater trochanter Tender swelling over patella Tender swelling lateral or medial to patellar tendon Tender medioproximal tibia (below joint line of knee) Tender ischial spine (at gluteal fold) Tender swelling between Achilles tendon insertion and calcaneus Tender central heel pad

Nonarticular Soft Tissue Disorders

Articular Disease

Active > passive 0

Active = passive +/0

0 + 0 +/0

Present; 0, absent.

of joint motion resulting from proliferation of the synovial membrane, an effusion, or derangement of intra-articular structures. Impairment of active movement characterizes nonarticular disorders to a much greater degree than passive movement. Clinical symptoms include pain, warmth, and swelling over the site of the bursa that are worse with activity and better with rest. Bursitis can be distinguished from tendinitis by the pain during active and passive range of movement; in tendinitis, pain is elicited only during active range of movement. However, for many patients there is concomitant bursitis and tendinitis. Muscle sprains or strains are typically diagnosed based on a history of preceding activity causing the symptom along with pain and limitation of movement when the muscle is contracted against resistance. The clinical signs and symptoms of chronic myofascial pain are more nonspecific and characterized by a distribution that is frequently nonanatomic and associated with hyperalgesia in the involved area. Fibromyalgia syndrome is characterized by widespread pain and a host of other symptoms, including insomnia, cognitive dysfunction, depression, anxiety, recurrent headaches, dizziness, fatigue, morning stiffness, extremity dysesthesia, irritable bowel syndrome, and irritable bladder syndrome.

DIAGNOSIS AND TREATMENT Septic Bursitis Superficial forms of bursitis, particularly olecranon bursitis and prepatellar and occasionally infrapatellar bursitis, are more frequently infected or involved with crystal deposition than are deep forms of bursitis, presumably due to direct extension of organisms through subcutaneous tissues. Most commonly, Staphylococcus aureus is isolated from infected superficial bursae. Septic bursitis should be suspected when there is cellulitis, erythema, fever, and peripheral leukocytosis. Definitive diagnosis and exclusion of infection of subcutaneous bursae usually require aspiration of the distended bursa. The bursal fluid should be assessed for cell count, Gram stain, and culture and examined for crystals.

Nonseptic Bursitis Nonseptic bursitis frequently appears as an overuse condition associated with sudden or unaccustomed repetitive activity of the associated extremity. The two most common types of bursitis are subacromial and trochanteric bursitis (Table 86.2). Subacromial bursitis is the most common overall cause of shoulder pain over the lateral upper arm or deltoid muscle that is exacerbated

with abduction of the arm. It occurs as a result of compression of the inflamed rotator cuff tendon between the acromion and humeral head. Because the rotator cuff forms the floor of the subacromial bursa, bursitis in this location often results from tendinitis of the rotator cuff. Occasionally, subacromial bursitis or rotator cuff tendinitis results from osteophyte compression of the rotator cuff tendon originating from the acromioclavicular joint. The differential diagnosis includes tears of the rotator cuff, intra-articular pathologic mechanisms of the glenohumeral joint, bicipital tendinitis, cervical radiculopathy, and referred pain from the chest. Trochanteric bursitis is the result of inflammation at the insertion of the gluteal muscles at the greater trochanter. It produces lateral thigh pain, which is often worse when the patient lies on the affected side. Women seem to be more prone to develop this condition, perhaps because of increased traction of the gluteal muscles as a result of the relatively broader female pelvis. Other potential risk factors include weight gain, local trauma, overuse activities such as jogging, and leglength discrepancies (primarily on the side with the longer leg). These factors are thought to lead to increased tension of the gluteus maximus on the iliotibial band, producing bursal inflammation. The differential diagnosis of trochanteric bursitis includes lumbar radiculopathy (particularly of the L1 and L2 nerve roots), meralgia paresthetica (i.e., entrapment of the lateral cutaneous nerve of the thigh as it passes under the inguinal ligament), true hip joint disease, and intra-abdominal pathologic processes. Other bursitis syndromes are less common and listed in Table 86.2. Septic bursitis is treated with a combination of serial aspirations of the infected bursa and antibiotics, initially directed against S. aureus and then adjusted depending on the results of bursal fluid cultures. Recurrent septic bursitis may need surgical excision of the bursa. The approach to nonseptic bursitis should include rest, local heat, and unless contraindicated by peptic ulcer disease, renal disease, or advanced age, nonsteroidal anti-inflammatory drugs (NSAIDs). The most effective approach usually is local injection of a corticosteroid. Superficial bursae with obvious swelling should be aspirated before the corticosteroid is injected. For deep bursae, such as the subacromial or trochanteric bursae, aspiration yields little or no fluid, and direct injection of a corticosteroid without attempted aspiration is reasonable. Caution is advised in attempted aspiration or injection of the iliopsoas bursa, the ischiogluteal bursa, and the gastrocnemius-semimembranosus bursa (i.e., Baker cyst). These bursae lie close to important neural and vascular structures, and aspiration under ultrasound guidance is recommended.

820

SECTION XIV  Musculoskeletal and Connective Tissue Disease

TABLE 86.3  Tendinitis Syndromes Location

Symptom

Extensor pollicis brevis and abductor pollicis longus (de Quervain tenosynovitis) Flexor tendons of fingers

Wrist pain

Medial epicondyle Lateral epicondyle Bicipital tendon Patella Achilles Tibialis posterior

Peroneal

Finding

Pain on ulnar deviation of the wrist, with the thumb grasped by the remaining four fingers (i.e., Finkelstein test) Triggering or locking of Tender nodule on flexor fingers in flexion tendon on palm over metacarpal joint Elbow pain Tenderness of medial epicondyle Elbow pain Tenderness of lateral epicondyle Shoulder pain Tenderness along bicipital groove Knee pain Tenderness at insertion of patellar tendon Heel pain Tender Achilles tendon Medial ankle pain Tenderness under medial malleolus with resisted inversion of ankle Lateral midfoot or ankle Tenderness under lateral pain malleolus with passive inversion

Tendinitis Most tendinitis syndromes are the result of inflammation in the tendon sheath. Overuse with microscopic tearing of the tendon is the most common risk factor for tendinitis. Tendon compression by an osteophyte may occur, such as in the rotator cuff tendon compressed by an osteophyte originating from the acromioclavicular joint. A common form of tendinitis is lateral epicondylitis, also known as tennis elbow (Table 86.3). This is a common overuse syndrome among tennis players, but it can be seen in many other settings requiring repetitive extension of the forearm (e.g., painting overhead). The diagnosis is confirmed by exclusion of elbow joint pathology and the finding of local tenderness at the lateral epicondyle, which is typically exacerbated by forearm extension against resistance. Enthesopathies such as Achilles tendinitis and peroneal and posterior tibial tendinitis may occur in the setting of an underlying seronegative arthropathy such as Reiter disease or psoriatic arthritis. A history and clinical evaluation for these disorders should be pursued for the appropriate patient. Therapy for tendinitis—NSAIDs, local heat, and corticosteroid injection—is similar to that for bursitis. Rest, physical therapy, occupational therapy, and occasionally ergonomic modification are useful adjuncts. The goal of corticosteroid injection in tendinitis is to infiltrate the tendon sheath rather than the tendon itself because direct injection into a tendon may result in rupture of the tendon. Corticosteroid injection of the Achilles tendon should be avoided because of the propensity of this tendon to rupture. Surgical management of tendinitis is indicated only after failure of conservative treatment. For example, chronic impingement of the supraspinatus tendon that is refractory to conservative treatment may require subacromial decompression.

Fibromyalgia Syndrome Descriptions of fibromyalgia syndrome exist far back in the medical literature, but it remains a diagnosis of exclusion due to the lack of objective diagnostic or pathologic findings. Fibromyalgia syndrome as

TABLE 86.4  2011 American College of

Rheumatology Fibromyalgia Diagnostic Criteria Modification

Criteria 1. 0 to 19 pain locations on the widespread pain index (WPI) 2. 6 self-reported symptoms, including difficulty sleeping, fatigue, poor cognition, headache, depression and abdominal pain. 0–3 points for fatigue, cognition, and sleep; 1 point for abdominal pain, headache, and depression 3. Symptoms are present for at least 3 months 4. Exclusion of other explanation for the pain Total score is calculated by adding WPI and self-reported symptom score; 12–13 is generally indicative of fibromyalgia. There has been a 2016 modification to this score to minimize misclassification of regional pain disorders. Somatic symptoms may include muscle pain or weakness, irritable bowel syndrome, fatigue or tiredness, cognitive or memory problems, headache, numbness or tingling, dizziness, insomnia, depression, nervousness, seizures, abdominal pain or cramps (especially upper abdomen), constipation, diarrhea, nausea, vomiting, fever, dry mouth, itching, chest pain, wheezing, Raynaud’s phenomenon, hives or welts, tinnitus, hearing difficulties, heartburn, oral ulcers, loss of or change in taste, dry eyes, blurred vision, shortness of breath, loss of appetite, rash, sun sensitivity, easy bruising, hair loss, frequent or painful urination, and bladder spasms.

defined by the American College of Rheumatology (ACR) 1990 definition for use in clinical trials is a chronic, widespread pain condition with characteristic tender points on physical examination, often associated with a constellation of symptoms such as fatigue, sleep disturbance, headache, irritable bowel syndrome, and mood disorders. In 2010, the ACR developed preliminary diagnostic criteria based only on symptoms because of well-documented issues with the tender point examination (Table 86.4). These criteria do not require a tender point examination, but they provide a scale for measuring the severity of symptoms that are characteristic of fibromyalgia and show good correlation with the 1990 ACR criteria. The clinical presentation of fibromyalgia syndrome is an insidious onset of chronic, diffuse, poorly localized musculoskeletal pain, typically accompanied by fatigue and sleep disturbance. The physical examination reveals a normal musculoskeletal system, with no deformity or synovitis. However, widespread tenderness occurs, especially at tendon insertion sites, indicating a general reduction in the pain threshold. Approximately one third of the patients identify antecedent trauma as a precipitant for their symptoms, one third of patients describe a viral prodrome, and one third have no clear precipitant. A variety of less typical presentations has been described, including a predominantly neuropathic presentation with paresthesias (i.e., numbness and tingling) in a nondermatomal distribution, an arthralgic rather than myalgic presentation, and an axial skeletal manifestation resembling degenerative disk disease. Many patients may have undergone invasive diagnostic tests and, in some cases, inappropriate procedures such as carpal tunnel release or cervical or lumbar laminectomies. Conditions that should be considered in the differential diagnosis of fibromyalgia syndrome include polymyalgia rheumatica (in older patients), hypothyroidism, polymyositis, and early systemic lupus erythematosus or rheumatoid arthritis. However, symptoms are exhibited for many months or years without evidence of other signs or symptoms of an underlying connective tissue disease, making other possible diagnoses unlikely.

CHAPTER 86  Nonarticular Soft Tissue Disorders Results of laboratory and radiographic studies are usually normal for patients with fibromyalgia syndrome. Exclusion of other conditions, such as osteoarthritis, rheumatoid arthritis, and systemic lupus erythematosus, by radiography, erythrocyte sedimentation rate, assays for rheumatoid factor or antinuclear antibody, and other tests is no longer considered necessary for the diagnosis of fibromyalgia syndrome. Fibromyalgia should be diagnosed on the basis of positive criteria. The treatment of fibromyalgia includes reassurance that the condition is not a progressive, crippling, or life-threatening entity. A combination of treatment options, including medication and physical measures, is helpful for most patients. Medications found to be helpful in short-term, double-blind, placebo-controlled trials include amitriptyline and cyclobenzaprine. Low doses of these medications (e.g., 10 to 30 mg of amitriptyline, 10 to 30 mg of cyclobenzaprine) are moderately effective and generally well tolerated. Studies have shown that newer antidepressants of the serotonin-norepinephrine reuptake inhibitor group (e.g., duloxetine, venlafaxine, bupropion) and α2δ ligands (e.g., gabapentin, pregabalin) are also effective, particularly in combination with low doses of tricyclic agents. There is currently significant interest among patients regarding the use of cannabinoids for the management

821

of chronic pain but very little data to support their use. However, there is evidence that chronic opioids are not indicated in these patients due to the high risk of dependence, tolerance, and possible worsening of hyperalgesia in these patients. Patients should be encouraged to take an active role in the management of their condition. If possible, they should begin a progressive, low-level aerobic exercise program to improve muscular fitness and provide a sense of well-being. Cognitive behavioral therapy has been shown to improved function significantly. Adherence, compliance, and access to these modalities are limitations in patients. A combination approach is effective for most patients in alleviating symptoms, although a small minority of patients requires more intensive treatment strategies, such as psychiatric treatment or referral to a pain center.

SUGGESTED READINGS Goldenberg DL, Burkhardt C, Crofford L: Management of fibromyalgia syndrome, J Am Med Assoc 292:2388–2395, 2004. Littlejohn GO: Balanced treatments for fibromyalgia, Arthritis Rheum 50:2725–2729, 2004.

87 Rheumatic Manifestations of Systemic Disorders and Sjögren’s Syndrome Andreea Coca, Ghaith Noaiseh

INTRODUCTION Rheumatologic manifestations may herald a variety of systemic conditions, including malignancy, endocrinopathy, and hematologic disorders (Tables 87.1 and 87.2). Musculoskeletal symptoms can precede or follow the diagnosis of these diseases. Patients may complain of joint or muscle pain, joint swelling, rashes, and many other symptoms.

RHEUMATOLOGIC PARANEOPLASTIC MANIFESTATIONS Cancer has a myriad of presentations, and paraneoplastic rheumatologic manifestations are not uncommon. They can vary from musculoskeletal conditions to vascular involvement (leukocytoclastic vasculitis), myositis, systemic lupus erythematosus (SLE)–like symptoms, and scleroderma. The pathophysiologic mechanisms of musculoskeletal symptoms in a patient with cancer are often unknown and remain speculative. The association is presumed if there is a close temporal relationship between the diagnosis of a malignancy and the onset of musculoskeletal symptoms or the rheumatic syndrome resolves after successful treatment of the malignancy. In many cases, however, the association may be coincidental. Cancer may directly invade articular or periarticular structures and mimic rheumatic syndromes, as in chondrosarcoma, giant cell tumor, and osteogenic sarcoma. Musculoskeletal symptoms can occur as paraneoplastic phenomena without direct involvement by the tumor, as in dermatomyositis (DM) in patients with ovarian cancer. The incidence of malignancy with rheumatic manifestations is unclear, but musculoskeletal symptoms occur more frequently with hematologic malignancies than with solid tumors. No single laboratory test can confirm the diagnosis of a rheumatic illness in a patient with cancer. All patients with rheumatologic syndromes should be evaluated with a thorough history, physical examination, and age-­ appropriate malignancy screening.

Hypertrophic Osteoarthropathy Hypertrophic osteoarthropathy (HOA) is characterized by digital clubbing, periostitis of the long bones, and arthritis. Arthritis is most prominent in large joints, and periostitis develops mostly at the distal ends of the femur, tibia, and radius. The primary form of HOA (primary pachydermoperiostosis) is usually a self-limited disease of childhood. The secondary form may be generalized or localized and is mainly associated with lung cancer and suppurative lung disease. HOA is also associated with cardiovascular disease (e.g., cyanotic congenital heart disease, infective endocarditis), hepatobiliary disorders (e.g., liver cirrhosis, primary biliary cirrhosis), and gastrointestinal disease (e.g., inflammatory bowel disease, celiac disease). Periostitis without digital clubbing can be seen in thyroid acropachy,

822

hypervitaminosis A, fluorosis, venous stasis, hyperphosphatemia, and sarcoidosis. Isolated chronic digital clubbing, which is mainly associated with pleuropulmonary disease, does not seem to cause HOA. The pathogenesis of HOA remains elusive, although several possible mechanisms have been proposed, including platelet derived growth factor and vascular derived growth factor. HOA is usually accompanied by bone and joint pain associated with periarticular periostitis. The pain is usually exacerbated by dependency and relieved with limb elevation. Typical signs of periostitis include periosteal new bone along the distal ends of long bones, which can be seen on plain radiographs. When periostitis is not obvious on plain radiography, a bone scan is useful to demonstrate early evidence of disease. Radiologic evaluation of the thorax is important because of the association between HOA and lung neoplasms. In many cases, symptomatic management with nonsteroidal anti-inflammatory drugs or other analgesics while treating the underlying disorder provides significant relief of symptoms. In refractory cases, bisphosphonates such as pamidronate and zoledronic acid have been reported to be effective.

Rheumatoid Arthritis–like Polyarthritis Inflammatory rheumatoid arthritis–like syndrome has been associated with solid neoplasms and hematologic malignancies. Clinical characteristics associated with this paraneoplastic syndrome include acute onset, asymmetrical disease frequently involving the lower extremities, synovitis in large joints that spares the wrists and hands without bony erosion, and negative results for rheumatoid factor and cyclic citrullinated peptide antibody. However, these features are not specific and may be confused with elder-onset rheumatoid arthritis, seronegative rheumatoid arthritis, spondyloarthropathy, and remitting seronegative symmetrical synovitis with pitting edema (RS3PE).

Remitting Seronegative Symmetrical Synovitis With Pitting Edema RS3PE manifests with sudden onset of polyarthritis, pitting edema, and prominent constitutional symptoms. More than one half of the RS3PE cases are associated with malignancy, including hematologic and solid tumors. The evaluation of the patient presenting with RS3PE should prompt an age-appropriate malignancy work-up.

Eosinophilic Fasciitis Eosinophilic fasciitis can be easily mistaken for scleroderma, presenting with puffy skin, sometimes indurated, progressing towards significant subcutaneous thickening, with characteristic peripheral eosinophilia. It can be seen in the setting of a variety of hematologic malignant disorders.

CHAPTER 87  Rheumatic Manifestations of Systemic Disorders and Sjögren’s Syndrome

TABLE 87.1  Systemic Conditions

TABLE 87.2 Musculoskeletal

Malignancies Myelodysplasia Lymphoma Leukemia

Endocrine Disease

Musculoskeletal Manifestations

Diabetes mellitus

Carpal tunnel syndrome Charcot arthropathy Adhesive capsulitis Cheiroarthropathy Diabetic amyotrophy Diabetic muscle infarction Proximal myopathy Joint effusions Carpal tunnel syndrome Chondrocalcinosis Myopathy Osteoporosis Thyroid acropachy Myopathy Erosive arthritis Chondrocalcinosis Muscle cramps Soft tissue calcifications Spondyloarthropathy Carpal tunnel syndrome Myopathy Raynaud’s phenomenon Premature osteoarthritis Myopathy Osteoporosis Avascular necrosis

Associated With Rheumatic Manifestations

Paraneoplastic Rheumatologic Disorders RS3PE Eosinophilic fasciitis Hypertrophic osteoarthropathy

Hyperthyroidism

Hyperparathyroidism

Endocrinopathies Diabetes Hypothyroidism Hyperthyroidism Hyperparathyroidism Acromegaly

Hypoparathyroidism

Acromegaly

Gastrointestinal Disorders Whipple disease Hemochromatosis Primary biliary cirrhosis

Cushing syndrome

Miscellaneous Multiple myeloma Amyloidosis HIV-related rheumatologic disorders Sarcoidosis

Rheumatologic Complications Immunotherapy

Manifestations of Endocrine Disease

Hypothyroidism

Hematologic Disorders Hemophilia Sickle cell disease Thalassemia

of

Checkpoint

Inhibitor

Immune checkpoint inhibitors (ICIs) are the most commonly used type of cancer immunotherapy. They work by blocking inhibitory molecules on the T cells, resulting in heightened T-cell mediated immune response against malignancy. Unfortunately, they have a variety of side effects, the musculoskeletal ones being among the predominant ones. Inflammatory arthritis can present in a pattern similar to rheumatoid arthritis or a seronegative spondyloarthropathy. Joint damage can be severe and erosions are common. For the most part, the work-up is normal, although inflammatory markers can be elevated. Mild inflammatory arthritis responds to NSAIDs. In cases of severe arthritis, oral corticosteroids are warranted as well as anti-tumor necrosis factor (TNF) agents. Sjögren’s syndrome (SS)–like presentation manifests primarily with significant ocular and mucosal dryness. Most patients do not exhibit autoantibodies. The distinction from SS is based on minor salivary gland biopsy, which demonstrates a diffuse T cell lymphocytic infiltrate and acinar injury, a pattern distinct from SS. Polymyalgia rheumatica and giant cell arthritis have been described following treatment with ICIs. PMR symptoms are typical, and temporal artery biopsy pathology is under distinguishable between users or nonusers of ICIs. DM and polymyositis (PM) have also been described, with proximal muscle weakness, elevated muscle enzymes and pathognomonic abnormalities of the electromyography (EMG) and MRI images. Monotherapy with oral steroids has generally been very effective.

823

Immune checkpoint inhibitors can also modulate the underlying systemic autoimmune diseases. In patients with rheumatoid arthritis or psoriasis, up to 30% of them can flare during treatment. However, discontinuation of systemic immunosuppression is not recommended, and patients should continue the treatment.

Systemic Autoimmune Diseases and Malignancy Lupus-like Syndrome

Antinuclear antibodies (ANAs) can be seen in patients with solid neoplasms (e.g., gastric, cervical, and breast carcinomas, testicular seminoma), lymphomas, or myelodysplastic disorders, but the significance of these autoantibodies is poorly understood. It is not clinically indicated to search for an underlying malignancy in a patient with typical SLE. However, lupus-like autoantibodies and unexplained Coombspositive hemolytic anemia or thrombocytopenia without clinical signs of rheumatic disease warrant further investigation for an occult neoplasm.

Raynaud’s Phenomenon and Scleroderma-like Syndrome The sudden onset of Raynaud’s phenomenon and scleroderma-like syndrome can herald an underlying tumor such as hematologic malignancies and carcinomas of the liver, ovary, testis, bladder, breast, or stomach. Scleroderma-like skin changes may also occur in patients with osteosclerotic myeloma with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin abnormalities (i.e., POEMS syndrome) and in those with carcinoid tumors. Characteristics that suggest secondary Raynaud’s phenomenon include age at onset older than 50 years, symptom asymmetry, symptoms that persist year-round, and rapid digital ulceration and necrosis. Secondary Raynaud’s is also suggested by scleroderma-like syndromes

824

SECTION XIV  Musculoskeletal and Connective Tissue Disease

in patients older than 50 years, rapid progression of skin sclerosis, or a poor response to therapy. The lack of Raynaud’s phenomenon can be another distinguishing characteristic of paraneoplastic scleroderma-like syndrome because Raynaud’s phenomenon occurs in approximately 95% of cases of systemic sclerosis.

Vasculitides Vasculitis is rarely associated with malignancy and is most commonly seen in patients with lymphoproliferative disorders and myelodysplastic syndrome. Cutaneous leukocytoclastic vasculitis is the most common manifestation of paraneoplastic vasculitis. Although clinical presentations of paraneoplastic vasculitides are indistinguishable from those of the idiopathic condition, a chronic, relapsing disease with cytopenias and poor response to conventional treatment suggests a hidden malignancy.

Inflammatory Myopathies The association between inflammatory myopathies and malignancies has been well established. DM and PM have an increased risk for malignancy, primarily solid tumors. Most malignancies are ovarian, lung, and stomach, primarily seen in the Western population. Differentiating between malignancy or not-­ malignancy-associated DM or PM can be very challenging, because CPK levels and muscle biopsy findings are similar. Immediately after diagnosis, all patients should undergo age-appropriate malignancy screening. This screening should be repeated every 3 to 5 years, regardless of disease activity. The suspicion for malignancy should be significantly increased in treatment-resistant myositis. The association of anti-P1 55/P1 40 antibodies has been described as highly predictive of cancer-associated DM.

Malignancies Associated With TNF Inhibitors Adalimumab and etanercept have been on the market since the late 1990s and widely used in a variety of systemic and organ-specific autoimmune diseases. The most common malignancy reported was Hodgkin’s and non-Hodgkin’s lymphomas. There is an increased risk for nonmelanoma skin cancer but no evidence of other malignancies.

HEMATOLOGIC DISORDERS WITH RHEUMATIC MANIFESTATIONS Hemophilia Acute, painful hemophilic arthropathy of the knees, elbows, and ankles is the most common manifestation of hemophilia. Repeated episodes of hemarthrosis result in synovial proliferation and chronic inflammation, causing chronic hemophilic arthropathy. This is characterized by joint deformity, fibrous ankylosis, and osteophyte overgrowth. Radiography typically shows degenerative arthritis. Besides prompt administration of factor concentrate replacement, acute hemarthrosis must be treated conservatively with cold applications and joint immobilization followed by a structured physical therapy program. Aspiration (after factor replacement) is needed only if concomitant septic arthritis is suspected or the joint is very tense.

Sickle Cell Disease Musculoskeletal complications of sickle cell disease include painful crises, arthropathy, dactylitis, osteonecrosis, and osteomyelitis. Sickle cell crisis is the most common musculoskeletal feature, and it can produce painful arthritis of the large joints and noninflammatory joint effusions adjacent to areas of bony crisis. Osteonecrosis of the femoral head, shoulder, and tibial plateau may result from repeated local bone ischemia or infarct.

Dactylitis manifesting as bilateral, painful, swollen hands or feet (i.e., hand-foot syndrome) may be the first manifestation of the disease in infants and young children. It can be associated with fever and leukocytosis, believed to be secondary to local bone marrow ischemia. Treatment is supportive. Increased risk of septic arthritis and osteomyelitis, most often due to Salmonella species, has been associated with hemoglobinopathies.

Endocrine Disorders Endocrine diseases usually manifest with diffuse, poorly defined musculoskeletal symptoms and joint pain that is more often periarticular. Clinical suspicion of endocrinopathy is by far the most important diagnostic step. Routine clinical laboratory tests such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ANA, rheumatoid factor, and uric acid level are usually not helpful. Radiographs often raise the suspicion of an endocrinopathy and are pathognomonic in advanced disease.

Diabetes One of the most common musculoskeletal complications of diabetes is diabetic cheiroarthropathy (i.e., diabetic hand syndrome). It is characterized by insidious development of waxy thickening of the skin of the fingers and hands and by flexion contractures of the metacarpophalangeal joints and interphalangeal joints. Patients cannot press the palms together completely without a gap with the wrists fully flexed (i.e., prayer sign). Although this syndrome is associated with long duration of diabetes and poor glycemic control, it may develop before the onset of overt diabetes and mimic sclerodactyly. Dupuytren contracture and stenosing flexor tenosynovitis (i.e., trigger finger) may be identified. People with diabetes are more prone to develop carpal tunnel syndrome. Diabetic periarthritis of the shoulders (i.e., adhesive capsulitis or frozen shoulder) is more common in patients with diabetes, especially in women with a long history of diabetes. Capsulitis is characterized by staged progression of pain and restriction of shoulder motion. Patients with long-standing, poorly controlled diabetes may develop a painless, swollen, deformed joint known as a Charcot joint or neuropathic arthropathy. Tarsal, metatarsophalangeal, and tarsometatarsal joints are most commonly involved, and it can be confused with osteomyelitis on radiographs. Diffuse idiopathic skeletal hyperostosis (DISH) is seen in up to 20% of diabetic patients, who are typically obese and older than 50 years. It is associated with neck and back stiffness rather than pain. Lateral radiographic views of the spine show four or more contiguously fused vertebrae, the result of flowing ossification of the anterior longitudinal ligament without involvement of apophyseal (facet) joints. Diabetic amyotrophy (i.e., diabetic lumbosacral radiculoplexus neuropathy) is remarkable for acute or subacute onset of severe hip, buttock, or thigh pain followed by progressive weakness of the affected extremity. It occurs typically in older male patients who have relatively well-controlled diabetes. Diabetic muscle infarction occurs in long-standing insulindependent diabetes. It presents with sudden onset of pain and swelling in the calf, mimicking deep venous thrombosis. CK levels might be elevated. A biopsy is often necessary to rule out other possible etiologies.

Thyroid Disease Hypothyroidism is primarily associated with myxedematous arthropathy, primarily affecting the large joints with swelling and stiffness. Synovial fluid analysis reveals a noninflammatory fluid and radiographs are generally normal. Other common rheumatologic manifestations are carpal tunnel, nonspecific arthralgia, and a myositis-like picture with proximal muscle weakness and elevated CK.

CHAPTER 87  Rheumatic Manifestations of Systemic Disorders and Sjögren’s Syndrome Hyperthyroidism is associated with pain and proximal muscle weakness in up to 70% of hyperthyroid patients. Osteoporosis is likely the most common musculoskeletal manifestation of thyroid disease. Thyroid acropachy is a rare manifestation of Graves’ disease presenting with swelling of the hands, digital cramping, and periostitis. It is more likely to occur in patients already having other complications of Graves’ disease, primarily ophthalmopathy.

Parathyroid Disease The most common rheumatologic manifestations of primary hyperparathyroidism include pain, proximal muscle weakness, chondrocalcinosis, tendon ruptures, and osteoporosis. Longstanding uncontrolled hyperparathyroidism leads to osteitis fibrosis cystica, primarily seen in end-stage renal disease. Radiographs are characteristic, with subperiosteal resorption and resorption of the tuft of the distal phalanx. Occasionally, erosions can be seen, making it easy to confuse it with rheumatoid arthritis. Secondary hyperparathyroidism is the leading cause of renal osteodystrophy in chronic kidney disease.

Acromegaly Acromegaly is often associated with joint pain, mostly secondary to degenerative disease affecting the weight-bearing joints, including the spine. Radiographs are characteristic and include periosteal apposition of tubular bones, deformation of the epiphysis, and chondrocalcinosis. In addition, acromegaly can also be associated with carpal tunnel and proximal muscle weakness. Overgrowth of cartilage initially produces joint space widening, but it may eventually lead to severe osteoarthritis with pain, limited range of motion, and deformity.

GASTROINTESTINAL DISEASES WITH RHEUMATIC MANIFESTATIONS Whipple Disease Whipple disease is a rare, multisystem disease that most often affects the gastrointestinal tract, caused by an infection with Tropheryma whippelii. Musculoskeletal symptoms can precede the diagnosis by years. Intermittent migratory oligoarthritis of large joints is typical, but some patients may have a florid polyarthritis. Synovial fluid is usually inflammatory with predominant mononuclear cells. Radiographs are often normal.

Hemochromatosis Hemochromatosis is one of the most common genetic diseases among people of northern European ancestry, and it is frequently associated with osteoarthritis-like arthropathy, chondrocalcinosis, and osteoporosis. The second and third metacarpophalangeal joints of both hands are typically involved, and hook-like osteophytes on the radial side of the metacarpal are characteristic in radiographs, the “iron-fist” sign. Chondrocalcinosis of the wrist and knee is very common in patients with hemochromatosis. Acute attacks of pseudogout can be a predominant clinical manifestation. There is no effective treatment, and regular phlebotomies are not effective.

MISCELLANEOUS DISORDERS Multiple Myeloma Rheumatologic manifestations of multiple myeloma include bone pain resulting from lytic bone lesions, pathologic fractures, and osteoporosis. Thoracolumbar pain in the setting of hypercalcemia, renal insufficiency, and anemia suggest the possibility of multiple myeloma.

825

Multiple myeloma can manifest atypically and mimic specific autoimmune disorders such as SS and SLE.

Amyloidosis Amyloidosis is a disorder of protein folding in which insoluble fibrillar proteins are deposited in the extracellular space in one or more organs, disrupting tissue structure and function. The clinical manifestations and prevalence depend on the type of amyloidosis. The amyloid protein can be identified as apple green birefringence on Congo red staining of an abdominal fat pad aspiration or rectal mucosal biopsy specimen. Systemic light-chain (AL) amyloidosis is one of the most common forms of systemic amyloidosis. Amyloid proteins derived from monoclonal light chains can invade the synovium, producing rheumatoid arthritis–like symptoms. Joint stiffness is more pronounced in amyloid arthropathy, and deposition of amyloid protein at the glenohumeral joint produces enlargement of the anterior shoulder, called the shoulder pad sign. Amyloid deposition in the blood vessels can manifest as claudication and symptoms similar to those of temporal arteritis. Deposition in the muscles may also lead to weakness or pain, presenting with a myositis-like picture or muscle pseudohypertrophy. Systemic AA amyloidosis (formerly known as secondary amyloidosis) can complicate any chronic inflammatory disorder. The most common rheumatologic diseases complicated by a systemic AA amyloidosis are rheumatoid arthritis, juvenile idiopathic arthritis and ankylosing spondylitis.

Human Immunodeficiency Virus Infection There are a plethora of muscular skeletal manifestations associated with human immunodeficiency (HIV), either disease specific or secondary to highly active antiretroviral therapy (ART). They range from arthralgias and arthritis to inflammatory myositis, sarcoidosis, rheumatoid arthritis, SLE, SS, zidovudine-associated myopathy, osteopenia, osteomalacia, and osteomyelitis. HIV-associated arthritis is seronegative polyarticular noninflammatory arthritis, primarily affecting the weight-bearing joints. It is a self-limiting condition, responding to conservative management. Rarely, it requires NSAIDs or low-dose corticosteroids for symptoms relief. The incidence of reactive arthritis has been drastically reduced since introduction of ART. The presentation is classical, with enthesopathy, plantar fasciitis, dactylitis, and inflammatory synovial fluid. However, it can be associated with severe erosive arthritis, which is generally not seen in non-HIV-related reactive arthritis. Muscle involvement in HIV is common. It can present with inflammatory or noninflammatory myopathy. Prior to ART, the patient was more likely to develop PM, nemaline rod (rod like structures in muscle cells) myopathy and HIV wasting syndrome. Posttreatment, mitochondrial myopathy and rhabdomyolysis are more commonly seen. The most common bone diseases seen in HIV patients are osteoporosis and avascular necrosis, especially in patients that have a very low CD4 count.

Sarcoidosis Clinical features of sarcoidosis can mimic those of many acute and chronic rheumatic diseases. Acute sarcoidosis (also called Löfgren syndrome) manifests with fever, erythema nodosum, hilar lymphadenopathy, and acute polyarthritis, almost invariably involving the ankles and knees. The arthritis is usually self-limited and tends to be nondeforming and nonerosive. Chronic sarcoid arthropathy is less common and usually associated with active multisystemic disease. Osseous involvement can be focal or

826

SECTION XIV  Musculoskeletal and Connective Tissue Disease

generalized and occurs in about 5% of patients with sarcoidosis. Bone cysts are usually asymptomatic, but they can manifest in the phalanges with sausage-like fingers or pseudoclubbing. Focal osteolytic changes can lead to pathologic fractures. Sarcoid muscle involvement is often asymptomatic, but it may manifest with proximal pain, progressive weakness, or atrophy

SJÖGREN’S SYNDROME Definition and Epidemiology SS is a chronic systemic autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands that leads to mucosal dryness and salivary gland enlargement, and by autoantibody production. Extra-glandular manifestations occur in 25% to 30% of patients and may occur as the presenting feature or during the evolution of the disease. Prevalence is approximately 0.1% to 0.6% of the general population. SS is mostly a disease of middle-aged women, but it can affect people of all ages. The female-to-male ratio is at least 9:1. SS can occur as a primary disorder or can be associated with other autoimmune diseases such as rheumatoid arthritis and SLE.

Pathogenesis The pathogenesis of SS is not fully understood. Autoimmune epithelitis is the most widely accepted model of autoimmunity in SS, in which the glandular epithelial cells (EC) act as a main orchestrator of the inflammatory response and not just an innocent bystander that is damaged by surrounding inflammation. In a genetically predisposed subject (e.g., HLA-DR3-DQ1-positive), outside triggers, such as sialotropic viruses or hormonal factors, activate EC, which then act as nonprofessional antigen presenting cells by expressing MHC I and II molecules and toll-like receptors, secreting cytokines and chemokines necessary to attract other inflammatory cells and activating both innate and adaptive immunity. Altogether, these steps promote a vicious cycle perpetuating immune system activation. Activated macrophages and dendritic cells produce type I interferon, leading to local tissue damage. Inflammatory milieu attracts and activates T and B lymphocytes to form lymphocytic foci. In fact, the presence of lymphocytic infiltration around the epithelial structures of salivary glands and other affected tissues is the histopathologic hallmark of SS. Additionally, EC are among inflammatory cells that produce B-cell activating factor (BAFF or BLyS), a pivotal molecule that promotes B-cell maturation, proliferation, and survival. B-cell hyperactivity in SS is a key feature of the disease highlighted by presence of specific autoantibodies such as anti-Ro/SSA and anti-La/SSB antibodies, nonspecific hypergammaglobulinemia, presence of monoclonal gammopathy, and development of non-Hodgkin’s lymphoma. Moreover, antibody production is essential for the formation of immune complexes (IC), which can lead to complement activation and tissue damage, or vasculitis, when deposited in the capillaries of certain organs such as the skin, kidneys, and peripheral nerves. To summarize, immunopathogenesis of SS is thought to result from either lymphocytic infiltration of target tissue epithelia leading to progressive functional impairment or IC-mediated complement activation and tissue damage.

Clinical Presentation Patients typically present with insidious onset of sicca syndrome (persistent dry eyes and dry mouth). Decreased tear flow leads to epithelial damage of cornea and conjunctiva, a condition known as keratoconjunctivitis sicca. Grittiness, foreign body sensation, photophobia, and formation of thick secretions in the inner canthus can occur. Untreated

cases can lead to corneal ulcerations, scarring, bacterial infections, and visual impairment. Occasionally, patients may deny dry mouth but report difficulty swallowing dry food. Exam may reveal absence of a normal salivary pool under the tongue, dry and sticky mucosa, gingival recession. and dental caries. Atrophic oral candidiasis is a less recognized complication and usually presents with burning mouth syndrome and atrophied papillae on the tongue surface with or without angular cheilitis in the absence of classic whitish exudate. Upper respiratory tract involvement may lead to nasal dryness, recurrent nonallergic rhinitis and sinusitis, and dry cough. Vaginal dryness associated with dyspareunia and dry skin may also occur. Salivary gland enlargement is seen in about 30% to 40% of patients, classically presenting as painless unilateral or bilateral parotid gland enlargement, which spontaneously resolves 2 to 3 weeks later. Other common presentations include arthralgia, myalgia, fatigue, and malaise. SS can overlap with several nonrheumatic autoimmune diseases, such as Hashimoto thyroiditis and celiac disease. In addition to SS-specific symptoms, patients may have a plethora of extraglandular manifestations, summarized in Table 87.3. Placental transmission of maternal anti-SSA/Ro and anti-SSB/La may lead to neonatal disease. Female patients with SS or SLE planning a family who have anti-Ro/La antibodies should be counselled about this risk to the neonate, which occurs in approximately 2% to 5% of cases.

Sjögren’s Syndrome and Non-Hodgkin Lymphomas Compared to the general population, SS patients have a 15- to 20-fold increased risk of developing lymphomas, usually mucosa-associated lymphoid tissue (MALT) B-cell lymphoma. Interestingly, lymphoma typically develops in organs where the disease is active, such as salivary glands. Persistent unilateral parotid gland enlargement in SS is alarming and requires additional work-up. Other risk factors associated with lymphoma development include palpable purpura, splenomegaly, lymphadenopathy, positive rheumatoid factor, positive serum cryoglobulins, C4 hypocomplementemia, lymphopenia, and monoclonal gammopathy. Patients who exhibit one or several risk factors need to be closely monitored.

Laboratory Findings Antinuclear antibodies and rheumatoid factor are seen in up to 80% and 50% of cases, respectively. When present, patients may be erroneously diagnosed with SLE or RA. Anti-SSA/Ro, and anti-SSB/La antibodies are present in 60% to 80% and 30% to 40% of SS patients, respectively. Hypergammaglobulinemia, anemia of chronic disease, and elevated ESR (related to hypergammaglobulinemia) are commonly encountered. CRP is usually normal. Lymphopenia, neutropenia, and thrombocytopenia may also occur. Serum cryoglobulins and monoclonal gammopathy are present in 10% and 15%, respectively. Complement levels C3 and C4 may be decreased as markers of disease activity but low C4 may occasionally be congenital.

Diagnosis In the clinically appropriate context, such as presence of sicca symptoms or an extraglandular manifestation, the diagnosis is made based on objective demonstration of glandular dysfunction and presence of autoimmunity as assessed by elevated serum anti SSA/Ro or a positive minor salivary gland biopsy. Importantly, absence of sicca symptoms does not rule out SS. Various tests are used to assess for glandular dysfunction. To confirm keratoconjunctivitis sicca, the Schirmer test measures tear flow over a 5-minute period using standardized paper strips; 5 mm or less

CHAPTER 87  Rheumatic Manifestations of Systemic Disorders and Sjögren’s Syndrome

TABLE 87.3  Systemic Manifestations of

Sjögren’s Syndrome System

Clinical Manifestations

Constitutional

Fever Fatigue Purpura: hypergammaglobulinemic or cryoglobulinemia-associated leukocytoclastic vasculitis Annular erythema (photosensitive, indistinguishable from subacute cutaneous lupus erythematosus) Urticaria Xeroderma Arthralgia and myalgia Nonerosive arthritis (mimicking rheumatoid arthritis) Inflammatory myopathy Obstructive pattern on pulmonary function testing Interstitial lung disease (nonspecific, usual and lymphocytic interstitial pneumonia) Cryptogenic organizing pneumonia Bronchiectasis Interstitial nephritis Renal tubular acidosis (typically type I, less commonly type II) Cryoglobulin-mediated membranoproliferative glomerulonephritis Multiple sclerosis-like syndrome Transverse myelitis Cognitive dysfunction Axonal sensory polyneuropathy Sensorimotor polyneuropathy Small fiber neuropathy Autonomic neuropathy Ganglionopathy Chronic inflammatory demyelinating polyneuropathy Cranial neuropathies (usually trigeminal neuralgia) Mononeuritis multiplex (vasculitis-associated) Autoimmune cholangitis Raynaud’s phenomenon (without digital tip ulcerations) Vasculitis (affecting small vessels, usually in skin, kidney, and nerves) Lymphadenopathy Splenomegaly Non-Hodgkin’s lymphoma, usually marginal-zone histologic type, particularly mucosa-associated lymphoid tissue (MALT)-related lymphoma

Cutaneous

Musculoskeletal

Pulmonary

Renal

Central nervous system Peripheral nervous system

Hepatobiliary Vascular

Reticuloendothelial Lymphoproliferative

of wetting confirms objective dryness. It is a simple test that can be performed routinely in the clinic. A normal Schirmer test does not rule out dry eyes. Slit-lamp examination of the ocular surface, using vital dye drops such as Lissamine green and fluorescein, assesses severity of ocular damage by staining devitalized spots. Unstimulated salivary flow can be measured by asking the patient to spit into a container for 5 to 15 minutes; a saliva flow rate of 0.1 mL/min or less confirms objective dryness. Diagnostic labial salivary gland biopsy is usually performed by harvesting four to six minor glands from the inner mucosa of the lower lip. The classical histological feature is

827

focal lymphocytic sialadenitis, which is foci of 50 or more lymphocytes clustered around normal appearing salivary tissue (periepithelial infiltrates) (Fig. 87.1).

Classification Criteria 2016 ACR/EULAR classification criteria are listed in Table 87.4. Although designed for research purposes and not considered diagnostic criteria, they can be helpful as a diagnostic framework in patients suspected to have SS. These classification criteria are applicable to any patient with at least one item of the following: 1.  A symptom of ocular or oral dryness (persistent dry eyes >3 months, recurrent sensation of sand or gravel in the eyes, using tear substitutes >3 times daily, persistent dry mouth >3 months, or need to drink liquids to aid in swallowing dry food) 2. Suspicion of SS based on presence of a suggestive body organ involvement or abnormal laboratory testing as listed in the ESSDAI (European League Against Rheumatism SS Disease Activity Index) tool. Examples include prominent parotid swelling, recent diagnosis of axonal sensory polyneuropathy, significant neutropenia, hypergammaglobulinemia, and hypocomplementemia. Objective dryness testing should be performed after holding anticholinergic medications for adequate period of time. Exclusion criteria include history of head and neck radiation therapy, polymerase chain reaction (PCR)–confirmed active hepatitis C infection, AIDS, sarcoidosis, amyloidosis, graft-versus-host disease, and IgG4-related disease.

Differential Diagnosis The differential diagnosis of SS includes etiologies that can cause sicca symptoms and or lacrimal/salivary gland enlargement. Numerous medications with anticholinergic properties, including over-thecounter products, may lead to dry eyes and mouth. Anxiety, depression or aging may also lead to sicca symptoms. Diffuse infiltrative lymphadenopathy syndrome associated with HIV and infiltrative diseases such as sarcoidosis can cause dry mouth and parotid swelling. IgG4-related disease is associated with sicca complaints and persistent lacrimal and salivary gland swelling. Sialadenosis (or sialosis) is a persistent, usually painless, bilateral swelling of parotid glands, associated with alcoholism, obesity, diabetes mellitus, chronic liver disease, and eating disorders. Histologic findings include fatty infiltrates and minimal inflammatory cells. Fibromyalgia syndrome may lead to sicca symptoms, along with fatigue and musculoskeletal pain.

Management The goal of therapy in SS is to prevent complications and alleviate symptoms. Topical and systemic pharmacologic therapies can improve sicca symptoms, but therapeutic agents able to induce remission or alter the course of the disease are not yet available. Immunosuppressive medications are usually used in patients with severe systemic involvement. Treatment of sicca syndrome is summarized in Table 87.5. Oral disease-modifying antirheumatic drugs (such as azathioprine and methotrexate) do not appear to be effective, although hydroxychloroquine is frequently used to treat arthralgia, rashes, and fatigue. Cyclophosphamide may be used with severe body organ involvement such as vasculitic neuropathies or glomerulonephritis. Currently, use of biologic therapies in SS is experimental; however, rituximab has been used in severe thrombocytopenia, interstitial lung disease, vasculitic neuropathies, and non-Hodgkin’s lymphoma.

828

SECTION XIV  Musculoskeletal and Connective Tissue Disease

A

B Fig. 87.1  (A) Low magnification. Cross-section of a labial minor salivary gland in SS patient revealing focal lymphocytic sialadenitis. Three lymphocytic foci, each (triangles) with >50 lymphocytes adjacent to normal-appearing glandular tissue. (B) High magnification. Several hundred lymphocytes forming a lymphocytic focus.

SUGGESTED READINGS

TABLE 87.4  2016 ACR/EULAR

Classification Criteria of Primary Sjögren’s Syndrome Item

Score

Labial salivary gland with focal lymphocytic sialadenitis and focus score of ≥1 foci/4 mm2 Positive anti-SSA/Ro Ocular staining score ≥5 in any eye Schirmer test ≤5 mm/5 min in any eye Unstimulated salivary flow rate ≤0.1 mL/min

3 3 1 1 1

A score ≥4 points classifies a patient as having SS.

TABLE 87.5  Management of Sicca

Syndrome in Patients With Sjögren’s Syndrome Treatment of dry eyes

Treatment of dry mouth

Avoid dry environment Moisture chamber goggles/glasses Artificial tears (preservative free if used more than four times daily) Lubricating gels (at bedtime) Tear drainage duct plugging (reversible) or cautery (irreversible) Topical anti-inflammatory therapy (cyclosporine, lifitegrast, corticosteroids) Avoid or discontinue medications with anticholinergic properties, when possible Optimize oral hygiene (regular brushing, flossing) Sugar-free lozenges (to stimulate saliva) Artificial saliva Fluoride-based topical products Oral secretagogues (pilocarpine, cevimeline)

Brito-Zerón P, Baldini C, Bootsma H, et al: Sjögren syndrome, Nat Rev Dis Primers 2:16047, 2016. Chakravarty SD, Markenson JA: Rheumatic manifestations of endocrine disease, Curr Opin Rheumatol 25(1):37–43, 2013. Cordner S, De Ceulaer K: Musculoskeletal manifestations of hemoglobinopathies, Curr Opin Rheumatol 15:44–47, 2003. Goules AV, Tzioufas AG: Lymphomagenesis in Sjögren’s syndrome: predictive biomarkers towards precision medicine, Autoimmun Rev 18(2):137–143, 2019. Ravindran V, Anoop P: Rheumatologic manifestations of benign and malignant haematological disorders, Clin Rheumatol 30:1143–1149, 2011. Vivino FB, Bunya VY, Massaro-Giordano G, et al: Sjogren’s syndrome: an update on disease pathogenesis, clinical manifestations and treatment, Clin Immunol 203:81–121, 2019.

SECTION

XV

Infectious Disease 88 Host Defenses Against Infection, 830

  97  Intraabdominal Infections, 910

89 Laboratory Diagnosis of Infectious Diseases, 842

  98 Infectious Diarrhea, 916   99 

Infections Involving Bone and Joints, 922

91 Bacteremia and Sepsis, 858

100 

Urinary Tract Infections, 925

92 Infections of the Central Nervous System, 865

101  Health Care−Associated Infections, 929

90 Fever and Febrile Syndromes, 848

102 

Sexually Transmitted Infections, 935

103 

Human Immunodeficiency Virus Infection, 944

93  Infections of the Head and Neck, 882 94 Infections of the Lower Respiratory Tract, 887 95 Infections of the Heart and Blood Vessels, 895

104  I nfections in the Immunocompromised Host, 963 105 

96 

 cute Bacterial Skin and Skin Structure A Infections, 903

Infectious Diseases of Travelers: Protozoal and Helminthic Infections, 973

829

88 Host Defenses Against Infection Richard Bungiro, Edward J. Wing

HOST VERSUS PATHOGEN: VICTORY, DEATH, OR COEXISTENCE

CATEGORIES OF HOST DEFENSES AND RISKS OF INFECTION

Many factors determine whether we coexist peacefully with our normal microbial flora and also whether we live or die in an environment filled with a wide spectrum of potentially pathogenic microbes. Factors such as age, nutritional status, underlying medical conditions (e.g., diabetes mellitus, chronic pulmonary disease), and the nature of the exposure (e.g., microbial virulence, inoculum size) may affect our response to infectious disease, with the outcome ultimately determined by our host defenses, which include anatomic (e.g., skin) and physiologic barriers (e.g., stomach acid), innate immune responses (e.g., phagocytes, microbial pattern receptors), and adaptive responses that include specific antibodies and cell–mediated immunity. Humans are equipped with a multilayered host defense system to counter infectious organisms, and the interaction between a potential pathogen and a human can lead to one of three basic outcomes: death of the human host, elimination of the pathogen (with or without clinical symptoms), or an ongoing symbiotic relationship whose nature may change with time and under additional biologic pressures. For example, while some healthy humans are colonized by Streptococcus pneumoniae, pneumonia or meningitis may be caused by virulent strains, leading to death if the host’s defenses cannot eliminate the pathogen in time. Most individuals exposed to Mycobacterium tuberculosis are asymptomatic because the adaptive immune response contains the organism in a live but nonreplicating (latent) state. Almost one third of the world’s population is so infected, but only about 10% progress to active disease. Immunologic impairment (e.g., as a result of human immunodeficiency virus [HIV] infection) and factors such as age-associated immune senescence increase the risk of progressing from latent to active disease. The asymptomatic nature of an infection should not automatically be equated with latency or dormancy of the pathogen. For example, chronic HIV infection was initially incorrectly characterized as having a prolonged latent or silent stage before the host developed immunodeficiency and opportunistic infections. However, most untreated HIV-infected individuals harbor actively replicating virus that kill CD4+ T lymphocytes on a daily basis, although the aggregate effects are not appreciated until CD4+ T lymphocyte levels are reduced to below 200 cells/mL, typically after 8 to 10 years of infection without antiretroviral treatment. Infected individuals are contagious to others despite their relatively asymptomatic state, thus treatment (when available) is recommended regardless of CD4+ T lymphocyte levels. Treatment halts viral immune destruction and reduces viral burden in blood and genital secretions, thus decreasing an infected individual’s risk of transmitting HIV.

The relative importance of the innate and adaptive immune defenses is best illustrated by individuals who are deficient in a particular immunological component. For example, cancer chemotherapy may lead to the depletion of innate cells such as neutrophils, rendering the host more susceptible to bacterial and fungal infections. Congenital deficiency of immunoglobulins increases the risk of infections that are usually thwarted by antibody responses such as those associated with Streptococcus pneumoniae and Haemophilus influenzae. Pharmacologic inhibition of tumor necrosis factor-α (TNF-α) for the treatment of chronic inflammatory disease such as Crohn’s or psoriasis increases the risk of developing active tuberculosis among those with latent infection. In 1981 astute clinicians, recognizing the increased incidence of an atypical pneumonia caused by Pneumocystis jirovecii (formerly P. carinii) among young men, sounded the alarm that a novel acquired immunodeficiency syndrome (eventually shown to primarily affect CD4+ T lymphocytes) had appeared that was later ascribed to HIV. Host defenses to infection can be classified as nonimmunologic barriers, innate immunity, and specific or adaptive immunity. Immune defenses against microbial pathogens are composed of cells and molecules located in the blood, peripheral sites such as the skin and submucosal regions, and in secondary lymphoid tissues such as the lymph nodes, tonsils, spleen, and Peyer patches. For a deeper discussion of these topics, please see Chapters 39 through 44 in Section VII, “Principles of Immunology and Inflammation,” in Goldman-Cecil Medicine, 26th Edition.

830

Nonimmunologic Host Defenses Nonimmunologic host defenses include anatomic and physiologic barriers that prevent the entry of pathogens into the body. Injuries or devices that damage or bypass anatomic barriers frequently lead to infection. Examples include burns, intravenous catheters, intubation, urinary tract catheters, surgery, and trauma. The respiratory tract defenses depend on mucus that entraps pathogens and on ciliary action and cough that continuously clear the mucus and organisms from the lungs and upper airways. Respiratory viruses, including influenza, may inhibit ciliary action or denude the mucous membrane completely, allowing bacteria to colonize and cause secondary infection. Stroke, medications, or other causes of reduced cough reflex may lead to poor clearance of secretions, mucus, and pathogens, leading to lung infection. Smoking and exposure to industrial toxins such as silica may similarly reduce lung host defenses, such as by reducing ciliary action and inhibiting alveolar macrophage function respectively. Alveolar macrophages located in the lung parenchyma play an essential role in the initial clearance and killing of pathogens.

CHAPTER 88  Host Defenses Against Infection Nonimmune gastrointestinal defenses include gastric acidity, which kills many microorganisms, and vomiting and diarrhea, which help to clear pathogens from the gut. Bacteria vary greatly in their susceptibility to gastrointestinal host defenses. For example, as few as 10 Shigella sp bacteria can cause infection, whereas 105 to 108 Vibrio cholera bacteria are required for infection. The urinary tract is protected physically by regular urine flow, the acidity of the urine, and antimicrobial peptides. Conditions that interfere with these factors (e.g., prostatic hypertrophy, renal stones) may lead to stasis and infection. Mechanical injection of bacteria through the urethra into the bladder, as may occur in women during sexual intercourse, can lead to colonization of the bladder and infection. Urinary tract catheters bypass normal mechanical barriers allowing bacteria to enter the bladder retrograde resulting in urinary tract infections. The normal microbiologic flora on the skin and in the respiratory and gastrointestinal tracts is an important component of host defenses. Normal florae compete with pathogens for nutrients and have antimicrobial activity of their own. To illustrate, certain commensal bacteria

of the skin secrete acid that prevents colonization by species more likely to cause disease. Disruption of the normal flora, such as by antibiotic treatment, allows opportunistic organisms such as Clostridioides difficile in the gut and Candida sp in the mouth or vagina to colonize and cause disease. Organs that clear organisms from the bloodstream and lymph, including the liver, spleen, and lymph nodes, play an essential role after a pathogen has breached the primary anatomic barriers. Lack of a spleen increases a person’s susceptibility to overwhelming sepsis caused by encapsulated bacteria including S. pneumoniae, Neisseria meningitidis, and H. influenzae. Cirrhosis of the liver allows portal vein blood to bypass the liver, increasing susceptibility to infection by gut flora.

Innate Immunity Innate immunity refers to inborn resistance mechanisms that rapidly recognize pathogens and promote inflammation at the site of infection, thus comprising a critical first line of defense against pathogens. Fig. 88.1 compares the major features of innate and adaptive immunity.

FEATURE

INNATE IMMUNITY

ADAPTIVE IMMUNITY

Specificity

For structures shared by classes of microbes (pathogen-associated molecular patterns)

For structural detail of microbial molecules (antigens); may recognize nonmicrobial antigens

Different microbes

Different microbes

PAMPs

Antigens

Identical Toll-like receptors

Distinct antigen-specific antibodies

Number of microbial molecules recognized

About 1,000 molecular patterns (estimated)

>107 antigens

Receptors

Encoded in germline; limited diversity (pattern recognition receptors)

Encoded by genes produced by somatic recombination of gene segments; greater diversity

lg

TCR Toll-like receptor

N-Formyl methionyl Mannose receptor receptor

831

Scavenger receptor

Number and types of receptors

38.3° C or 100.9° F), some conditions can increase the body temperature by overriding or bypassing the normal homeostatic mechanism and may even produce body temperatures in excess of 41° C or 105.8° F (i.e., hyperthermia), which can be rapidly fatal and does not respond to antipyretics. Rapid cooling is critical to the patient’s survival in hyperthermic conditions such as heat stroke. Even in otherwise healthy individuals, heat stroke can occur after vigorous exercise and prolonged exposure to high environmental temperatures and humidity. Heat stroke is marked by temperatures greater than 40.6° C (105.1° F), altered sensorium or coma, and cessation of sweating. Treatment includes covering the patient with wet compresses followed by intravenous infusion of fluids appropriate to correct fluid and electrolyte losses. Severe hyperthermia may be a heritable reaction to anesthetics (i.e., malignant hyperthermia) or a response to phenothiazines (i.e., neuroleptic malignant syndrome). Serotonin syndrome, which often includes fever, is classically associated with the simultaneous administration of two serotonergic agents (e.g., selective serotonin reuptake inhibitors plus tramadol). It can also occur after initiation of a single serotonergic drug that increases the serotonin level of individuals who are particularly sensitive to serotonin. Occasionally, persons with CNS disorders such as paraplegia and persons with severe dermatologic conditions are unable to dissipate heat and can experience hyperthermia. Hyperpyrexia is the term for extraordinarily high fever (>41.5° C or 106.7° F), which can occur in patients with severe infections but is most commonly observed in persons with CNS hemorrhages.

CHAPTER 90  Fever and Febrile Syndromes

DIAGNOSTIC APPROACH TO THE ACUTELY ILL PATIENT WITH FEVER Patterns of fever should be considered when assessing acutely ill, febrile persons. Evaluation includes determining the normal diurnal variation in body temperature, which often persists when patients have fever. Normally, body temperature peaks in the late afternoon or early evening. Rigors (i.e., bed-shaking chills) often mark the onset of bacterial infection, typically bacteremia, although they may occur in other clinical situations, such as drug-induced fever or transfusion reactions. Wide swings in temperature may indicate an abscess. Malaria should be considered for anyone with fever who has visited or lived in malarious regions or who has relapsing fever accompanied by episodes of shaking chills and high fever separated by 1 to 3 days of normal body temperature and relative well-being. The timing of administration of anti-inflammatory drugs should be assessed because they may alter or blunt the febrile response. Most infectious diseases manifest with fever as an early finding and with subclinical and eventual clinical involvement of specific organ systems. If fever occurs as the sole complaint or is associated with localized symptoms and signs, the diagnostic approach includes taking a thorough history, including an extensive review of systems, medical and surgical histories, and immunizations, including those from childhood. Antipyretics may be withheld to allow assessment of the fever trajectory. Elderly individuals, persons taking corticosteroids, and patients with chronic liver or renal disease may be less likely to mount a fever. All likely sources of disease, including travel, exposure to Mycobacterium tuberculosis, and occupational, hobby, animal, insect, and sexual contacts, should be assessed. Previous itineraries and activities, geographic risks of diseases, and the seasonality and incubation periods of possible disease exposures should be considered in returning travelers.

Viral Infection Acute febrile illnesses in young healthy adults usually are caused by viral infections, which do not require precise diagnosis because they are self-limited and seldom have therapeutic options. Upper respiratory tract symptoms of rhinorrhea, sore throat, cough, and hoarseness most often result from rhinovirus, coronavirus, parainfluenza virus, and adenoviruses. Adenovirus outbreaks occur among persons living in close quarters such as military barracks or college dormitories. Respiratory syncytial virus, human metapneumovirus, and human bocavirus infections occur in similar conditions and sometimes manifest with pneumonia. A coronavirus causes the potentially fatal upper respiratory viral infection called Middle East respiratory syndrome (MERS). It has caused pneumonia with acute respiratory distress syndrome (ARDS) and death in one half of infected individuals, and it is highly contagious. See Appendix for discussion of COVID-19. Meningitis symptoms occur predominantly from enterovirus infections during summer months, although the symptom complex warrants urgent treatment of bacterial causes while the diagnostic process occurs. Febrile syndromes without meningitis are more common manifestations of enteroviral infections. Arthropod-borne viruses such as California encephalitis virus; eastern, western, and Venezuelan equine encephalitis viruses; St. Louis encephalitis virus; and West Nile virus can produce self-limited febrile illnesses and encephalitis. Colorado tick fever is a biphasic illness seen after northwestern and southwestern tick exposures. It is characterized by high fevers and leukopenia. A deer tick virus—Powassan virus—has

849

been associated with numerous cases of fever and encephalitis in New England and the Upper Midwest. Influenza causes sore throat, cough, myalgias, arthralgias, and headache in addition to fever, and it most often manifests in an epidemic pattern during winter months. It is unusual for fever to persist beyond 5 days in uncomplicated influenza. Prolonged fever in persons with diagnosed influenza warrants investigation and treatment of bacterial superinfection. The epidemics of avian influenza and H1N1 pandemic strains in recent years are sobering reminders that influenza viruses have a remarkable ability to mutate, producing new immune-resistant strains on a regular basis. Preventive yearly influenza vaccination is important. Mononucleosis syndromes of fever with detectable lymph node enlargement typify infections with Epstein-Barr virus (EBV), cytomegalovirus (CMV), primary human immunodeficiency virus (HIV), and Toxoplasma gondii (i.e., toxoplasmosis). Other manifestations of these infections include abnormal liver function test results, respiratory tract symptoms, and neurologic symptoms. Diagnosis of acute HIV infection, which can produce a mononucleosis-like syndrome, is an urgent issue.

Bacterial Infections Pathogenic bacteria can infect all body parts and can cause a spectrum of localized illness warranting antibiotic therapy. For example, Staphylococcus aureus may cause skin abscesses or cellulitis. Highly pathogenic organisms may colonize individuals who have had contact with the health care system. Most concerning is the event of bacteria entering the bloodstream. Obtaining timely blood cultures before administering the antibiotics indicated for presumed bacterial infections in persons with common clinical syndromes can help to identify bloodstream pathogens and define the required course of treatment. Fever may be the predominant clinical manifestation of S. aureus illness. This organism and the methicillin-resistant form (i.e., MRSA) frequently cause sepsis without an obvious primary site of infection. It should be considered in patients undergoing intravenous therapy or hemodialysis and in those who use intravenous drugs or who have severe chronic dermatitis. Bacteremia with staphylococci may cause hematogenous seeding of bones leading to osteomyelitis and heart valves leading to endocarditis in individuals; the bacteremia may also reflect these underlying processes. Other common causes of bacteremia and their sources include Streptococcus pneumoniae (i.e., pneumonia), Escherichia coli (i.e., urinary tract and gastrointestinal sources), streptococci (i.e., skin), and anaerobes (i.e., gastrointestinal tract). Listeria monocytogenes bacteremia is seen predominantly in persons with depressed cell-mediated immunity and pregnant women. Although bacteremia is the most common manifestation of listeriosis in these hosts, many with listeriosis may have meningitis and warrant lumbar puncture for cerebrospinal fluid culture. Most cases occur in individuals over age 50. Typhoid and paratyphoid fever (i.e., enteric fever) are common in many low-income countries. Patients may have fever alone as the primary clinical manifestation. Travelers to six countries account for 80% of US cases: India, Mexico, Philippines, Pakistan, El Salvador, and Haiti. Fever with headache and an insidious onset with an unremarkable physical examination is common, although a faint and transient rash (i.e., rose spots) may appear by the second week of illness. Symptoms may include diarrhea, constipation, vague abdominal discomfort, and sometimes dry cough. Diagnosis depends on the culture of blood or stool.

Fever With Localized Symptoms and Signs Localized bacterial infection can be apparent, as in cases of abscess, cellulitis, or otitis media, or can be clinically occult. It can develop as

850

SECTION XV  Infectious Disease

TABLE 90.1  Infections Exhibiting Fever as the Sole or Dominant Feature Infectious Agent or Source

Epidemiologic Exposure and History

Distinctive Clinical and Laboratory Findings

Viruses Rhinovirus, adenovirus, parainfluenza

None (adenovirus in epidemics)

Often URI symptoms; throat and rectal cultures; rapid viral antigen testing Pneumonia with ARDS; viral antigen testing of sputum; PCR of normally sterile sites (CDC) Occasionally aseptic meningitis, rash, pleurodynia, herpangina; serologic or nucleic acid testing (PCR) Headache, myalgias, arthralgias; nasopharyngeal culture, rapid viral antigen testing Monospot test, EBV specific antibodies; EBV PCR in immunocompromised; CMV IgM shell vial assay; CMV antigenemia assay; CMV DNA of CSF; culture and histopathology of tissues Biphasic illness, leukopenia; blood, CSF cultures, serologic or PCR Altered mentation or encephalitis; serum and CSF IgM (CDC)

Middle East respiratory syndrome (MERS) Enteroviruses (non-polioviruses: coxsackieviruses, echovirus) Influenza

Travel to Arabian Peninsula or contact from Middle East Summer, epidemic Winter, epidemic

EBV, CMV

Close personal contact; blood or tissue exposure; occupational or perinatal exposure

Colorado tick fever

Southwest and Northwest regions, tick exposure

Powassan virus

New England and Upper Midwest exposure

Bacteria Staphylococcus aureus Listeria monocytogenes Salmonella typhi, Salmonella paratyphi

IV drug users, IV catheters, hemodialysis, dermatitis Depressed cell-meditated immunity Food or water contaminated by carrier or patient

Streptococci

Valvular heart disease

Animal Exposure Coxiella burnetii (Q fever)

Exposure to infected livestock, parturient animals

Leptospira interrogans

Water contaminated by urine From dogs, cats, rodents, small mammals

Must exclude endocarditis; blood cultures Meningitis may also be present; blood, CSF cultures Headache, myalgias, diarrhea, or constipation, transient rose spots; blood, marrow, or stool cultures Low-grade fever, fatigue; blood cultures Headache, occasionally pneumonitis, hepatitis, culture-negative endocarditis; serologic testing Headache, myalgias, conjunctival suffusion, biphasic illness, aseptic meningitis; serologic testing

ARDS, Acute respiratory disease syndrome; CDC, Centers for Disease Control and Prevention case definition; CMV, cytomegalovirus; CSF, cerebrospinal fluid; EBV, Epstein-Barr virus; IgM, immunoglobulin M; IV, intravenous; PCR, polymerase chain reaction; URI, upper respiratory infection.

an undifferentiated febrile syndrome. Careful inspection of mucous membranes and conjunctiva may reveal petechiae, which are clues to meningococcemia or infective endocarditis. Finding heart murmurs in the setting of fever may suggest endocarditis and warrant additional blood cultures. Pulmonary signs in pneumonia include rales and evidence of consolidation, but persons with cryptococcosis, coccidioidomycosis, histoplasmosis, psittacosis, legionellosis, or pneumocystis pneumonia may show few signs. Pyelonephritis and renal abscesses can occur with few localizing signs. These infections should be suspected based on exposure history and the host’s immune status. It is important to assess the size of the liver, spleen, and lymph nodes, particularly in cases of viral infection. A swollen joint may indicate septic arthritis. A complete neurologic examination, including cranial nerves and testing for meningeal signs, may indicate CNS infection. Malaria, bacterial sepsis, and bacterial infections of the lung, urinary tract, CNS, and intestines with resultant bacteremia warrant urgent initiation of empirical treatment while awaiting final identification and sensitivities. For febrile patients with features suggesting a bacterial infection, evaluation should include complete blood counts with differential and platelet counts, blood smears for those at risk for malaria or babesiosis, urinalysis, throat and blood cultures, and a chest radiograph. Fevers with rash as a prominent feature warrant exclusion of life-threatening infectious diseases, including meningococcemia, toxic shock syndrome (TSS), and Rocky Mountain spotted fever (RMSF).

Characterization of the rash can help. Clues to some of the common infections exhibiting fever as the sole feature and those causing fever with rash are provided in Tables 90.1, 90.2, and 90.3. Tables 90.4 and 90.5 list common syndromes associated with imported fevers when assessing travelers.

FEVER OF UNKNOWN ORIGIN Most febrile conditions resolve or are readily diagnosed and treated, but some fevers can persist and remain unexplained. Table 90.6 shows the most common causes of unexplained fevers. The term fever of unknown origin (FUO) identifies a pattern of fever with temperatures greater than 38.3° C (101° F) on several occasions over more than 3 weeks after an initial diagnostic work-up for which the diagnosis remains uncertain. Verifying the presence or absence of fever is important; up to 35% of 347 patients admitted to the National Institutes of Health (NIH) for evaluation of prolonged fever were determined not to have significant fever or had fever of factitious origin. Cases of FUO are categorized as classic FUO, health care–associated FUO, neutropenic (immune-deficient) FUO, and HIV-related FUO. Each of these FUO subtypes can have unique causes.

Classic Fever of Unknown Origin The most common causes of classic FUO are infections, malignancies, and noninfectious inflammatory disorders; miscellaneous causes and undiagnosed cases account for the remaining categories. Historically,

CHAPTER 90  Fever and Febrile Syndromes

TABLE 90.2  Differential Diagnosis of

Infectious Agents Producing Fever and Rash Maculopapular, Erythematous Lesions Enterovirus EBV, CMV, Toxoplasma gondii Acute HIV infection Colorado tick fever virus Salmonella typhi Leptospira interrogans Measles virus Rubella virus Hepatitis B virus Treponema pallidum Parvovirus B19 Human herpesvirus 6 Vesicular Lesions Varicella-zoster virus Herpes simplex virus Coxsackievirus A Vibrio vulnificus Cutaneous Petechiae Neisseria gonorrhoeae Neisseria meningitidis Rickettsia rickettsii (Rocky Mountain spotted fever) Rickettsia typhi (murine typhus) Ehrlichia chaffeensis Echoviruses Streptococcus viridans (endocarditis) Diffuse Erythroderma Group A streptococci (scarlet fever, toxic shock syndrome) Staphylococcus aureus (toxic shock syndrome) Distinctive Rash Ecthyma gangrenosum: Pseudomonas aeruginosa Erythema migrans: Lyme disease Mucous Membrane Lesions Vesicular pharyngitis: coxsackievirus A Palatal petechiae: rubella, EBV, scarlet fever (group A streptococci) Erythema: toxic shock syndrome (Staphylococcus aureus and group A streptococci) Oral ulceronodular lesion: Histoplasma capsulatum Koplik spots: measles virus CMV, Cytomegalovirus; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus.

infections have made up the largest category, representing 25% to 50% of cases. Abscesses, endocarditis, tuberculosis, complicated urinary tract infections, and biliary tract diseases have consistently been among the most important. Abscesses account for almost one third of infectious causes, and most are intra-abdominal or pelvic in origin. Perforation of a colonic diverticulum or appendicitis can sometimes lead to large, walled-off abdominal abscesses with few localizing signs. During the past 50 years, the improvement of imaging studies and their greater accessibility have made abdominal or pelvic abscesses and malignancies more easily detected and less likely to be the cause of prolonged, undiagnosed fever. Malignant neoplasms can induce fever directly through the production and release of pyrogenic cytokines and

851

indirectly by undergoing spontaneous or induced necrosis or creating conditions conducive to secondary infections. Endovascular infections are usually detectable by blood cultures, although slow-growing or fastidious organisms may make detection difficult. Infections, including tuberculosis, typhoid fever, malaria, and amebic liver abscesses, remain the most frequent causes of FUO in developing countries. The incidence of some FUOs varies according to geographic location. Classic FUO may occur as familial Mediterranean fever among Ashkenazi Jews; as Kikuchi disease, which is an unusual form of necrotizing lymphadenitis seen primarily in Japan; and as TNF receptor–associated periodic fever (TRAPS), formerly called familial Hibernian fever, which is an inherited periodic fever syndrome described originally in Ireland. The proportion of FUOs due to noninfectious inflammatory diseases and undiagnosed conditions has risen. Of the connective tissue diseases, juvenile rheumatoid arthritis (i.e., Still disease), other variants of rheumatoid arthritis, and systemic lupus erythematosus predominate among younger patients. Temporal arteritis and polymyalgia rheumatica syndromes are more common among elderly patients. Fever may be blunted or absent in up to one third of elderly individuals with serious conditions. Older people may more often have atypical clinical presentations of common infectious and noninfectious diseases. For example, elderly persons may have tuberculosis without cough or fever, infective endocarditis with fatigue and weight loss but without fever, and abdominal abscesses with little abdominal tenderness found on physical examination. Leukocytosis and increased band forms are more likely to be associated with a serious infection. HIV should be considered as a possible cause of FUO in older patients, although it is not usually suspected early in the course of FUO. Fever in returned travelers is most often caused by common infections, such as malaria and respiratory or urinary tract infections. However, fever caused by dengue, typhoid fever, or amebic liver abscess is increasingly identified, especially among international travelers returning from the tropics. Katayama fever is a febrile syndrome occurring after exposure to fresh water schistosomes in endemic areas. It may resolve spontaneously or may require treatment with antiparasitic agents to prevent sequelae that carry severe morbidity. A travel history should be obtained, and it may redirect the entire work-up.

Health Care–Associated Fever of Unknown Origin Some FUOs are associated with health care practices, including surgical procedures, urinary and respiratory tract instrumentation, intravascular devices, drug therapy, and immobilization. Quality control measures are set up to minimize and avoid bloodstream infections and decubitus ulcers. Drug-related fever, septic thrombophlebitis, recurrent pulmonary emboli, and Clostridioides difficile colitis must be considered in the work-up of hospitalized patients who develop fever greater than 38° C (100.4° F) for more than 3 days if it was not present on admission.

Immune Deficiency–Associated Fever of Unknown Origin Immunosuppressed individuals have the highest incidence of FUO of any group of patients. Due to impaired immune responses, signs of inflammation other than fever are notoriously absent or diminished, producing atypical clinical manifestations and an absence of radiologic abnormalities for what otherwise would be readily diagnosed infections. In patients with impaired cell-mediated immunity, FUO often results from conditions other than pyogenic bacterial infections (e.g., fungi, CMV). Neutropenia is a dangerous condition that can be considered a subclass of immunodeficiency. Persons with profound neutropenia are at high risk for bacterial and fungal infections. Episodes of fever

TABLE 90.3  Fever and Rash in Viral Infection Virus

Disease Features

Incubation and Early Symptoms

Coxsackie, ECHO virus

Maculopapular rubelliform, 1–3 mm, faint pink, begins on face, spreading to chest and extremities Herpetiform vesicular stomatitis with peripheral exanthema (papules and clear vesicles on an erythematous base), including palms and soles (hand, foot, and mouth disease) Erythematous, maculopapular rash begins on upper face and spreads down to involve extremities, including palms and soles. Koplik spots are bluegray specks on a red base found on buccal mucosa near second molars. Atypical measles occurs in individuals who received killed vaccine and then are exposed to measles. The rash begins peripherally and is urticarial, vascular, or hemorrhagic. Maculopapular rash beginning on face and moving down; petechiae on soft palate

Summertime No itching or lymphadenopathy Multiple cases in household or community-wide epidemic Mostly diseases of children Incubation period 10–14 days First, severe upper respiratory symptoms, coryza, cough, and conjunctivitis; then Koplik spots, then rash

Measles

Rubella

Varicella

Herpes simplex virus

Hepatitis B and C virus Epstein-Barr virus Human immunodeficiency virus

Generalized vesicular eruption; pruritic lesions in different stages from erythematous macules to vesicles to crusted; spread from trunk centrifugally; zoster lesions are painful and often dermatomal Oral primary: small vesicles on pharynx, oral mucosa that ulcerates; painful and tender Recurrent: vermilion border, one or few lesions, genital; may be asymptomatic or appear similar to oral lesions on genital mucosa Prodrome in one fifth; erythematous, maculopapular rash, urticaria Leukocytoclastic vasculitis occurs in hepatitis C Erythematous, maculopapular rash on trunk and proximal extremities Occasionally urticarial or hemorrhagic Maculopapular truncal rash may occur as early manifestation of infection

Incubation 12–23 days Adenopathy; posterior auricular, posterior cervical, and suboccipital Incubation 14–15 days; late winter, early spring Herpes zoster is a reactivation, occurs any season Incubation 2–12 days

Arthralgias, arthritis; abnormal liver function test results; hepatitis B antigenemia Transiently occurs in 5–10% of patients during first week of illness Associated fever, sore throat, and lymph node enlargement may persist for 2 or more weeks

TABLE 90.4  Common Syndromes and Diseases Associated With Fever in Returned Travelers Sore Throat

Cough

Abdominal Pain

Arthralgia or Myalgia

Diarrhea

Bacterial pharyngitis Diphtheria Infectious mononucleosis HIV seroconversion Lyme disease Poliomyelitis Psittacosis Tularemia Viral hemorrhagic fever (Lassa) Nonspecific viral URTI

Amebiasis (hepatic) Anthrax Bacterial pneumonia Filarial fever TPE Histoplasmosis Legionnaires disease Leishmaniasis (visceral) Loeffler syndrome Malaria Measles Melioidosis Plague Q fever Relapsing fever Schistosomiasis (acute) Toxocariasis Trichinosis Tuberculosis Tularemia Typhoid and paratyphoid Typhus Viral hemorrhagic fevers Nonspecific viral URTIs

Amebiasis (intestinal) Anthrax Campylobacter enteritis Legionnaires disease Malaria Measles Melioidosis Plague Relapsing fevers Salmonellosis Schistosomiasis (acute) Shigellosis Typhoid fever Viral hemorrhagic fevers Yersiniosis

Arboviruses Dengue Yellow fever Babesiosis Bartonellosis Brucellosis Erythema nodosum leprosum Hepatitis (viral) Histoplasmosis HIV seroconversion Legionnaires disease Leptospirosis Lyme disease Malaria Plague Poliomyelitis Q fever Relapsing fevers Secondary syphilis Toxoplasmosis Trichinosis Trypanosomiasis (African) Tularemia Typhoid and paratyphoid Typhus Viral hemorrhagic fevers

Amebiasis (intestinal) Anthrax Campylobacter enteritis HIV seroconversion Legionnaires disease Malaria melioidosis Plague Relapsing fever Salmonellosis Schistosomiasis (acute) Shigellosis Typhoid in children Viral hemorrhagic fevers Yersiniosis

HIV, Human immunodeficiency virus; TPE, tropical pulmonary eosinophilia; URTI, upper respiratory tract infection. From Beeching N, Fletcher T, Wijaya L: Returned travelers. In Zuckerman JN, editor: Principles and practice of travel medicine, ed 2, Boston, 2013, Wiley-Blackwell, p 271.

CHAPTER 90  Fever and Febrile Syndromes

853

TABLE 90.5  Common Clinical Findings and Associated Infections After Tropical Travel Clinical Findings

Infections

Fever and rash

Dengue, chikungunya, rickettsial infections, enteric fever (skin lesions may be sparse or absent), acute HIV infection, measles, acute schistosomiasis Enteric fever, amebic liver abscess Dengue, malaria, rickettsial infection, enteric fever, chikungunya Viral hemorrhagic fevers (dengue and others), meningococcemia, leptospirosis, rickettsial infections Acute schistosomiasis; drug hypersensitivity reaction; fascioliasis and other parasitic infections (rare) Common bacterial and viral pathogens; legionellosis, acute schistosomiasis, Q fever, melioidosis Cerebral malaria, viral or bacterial meningoencephalitis, African trypanosomiasis Epstein-Barr virus, cytomegalovirus, toxoplasmosis, acute HIV infection Malaria, enteric fever, Epstein-Barr virus, cytomegalovirus, toxoplasmosis, acute HIV, acute schistosomiasis, brucellosis, tuberculosis, Q fever, visceral leishmaniasis (rare) Vivax malaria, acute hepatitis (B, C, or E), tuberculosis, amebic liver abscess

Fever and abdominal pain Undifferentiated fever and normal or low white blood cell count Fever and hemorrhage Fever and eosinophilia Fever and pulmonary infiltrates Fever and altered mental status Mononucleosis syndrome Fever persisting >2 weeks Fever with onset >6 weeks after travel

HIV, Human immunodeficiency virus. Modified from Centers for Disease Control and Prevention: CDC health information for international travel 2012, New York, 2012, Oxford University Press.

are common in patients with neutropenia. Many episodes are short lived because they respond quickly to treatment or are manifestations of rapidly fatal infections. Bacteremia and sepsis can cause rapid deterioration in neutropenic patients, and empirical, broad-spectrum antibiotics should be administered promptly without waiting for the results of cultures. However, only about 35% of prolonged episodes of febrile neutropenia respond to broad-spectrum antibiotic therapy. If fevers persist after 3 days of treatment with broad-spectrum antibiotics, diagnostic tests to explore fungal causes should be considered along with empirical antifungal treatment.

Human Immunodeficiency Virus–Related Fever of Unknown Origin The advent of highly active antiretroviral therapy (ART) with the achievable suppression of the HIV viral load has greatly reduced the frequency of FUO in HIV-infected patients. High vigilance is warranted to test for new HIV in a matter-of-fact manner in the primary care setting. The primary phase of HIV infection can be asymptomatic or sometimes be characterized by a mononucleosis-like illness in which fever is a prominent feature (see Chapter 103). After symptoms of the primary phase of HIV infection resolve, patients enter a long period of subclinical infection during which they are usually afebrile. In the later phases of untreated HIV infection, episodes of fever become common, often signifying a superimposed illness. Many of these are potentially devastating opportunistic infections, which tend to manifest in atypical fashion because of the severe immunodeficiency. Patients with untreated acquired immunodeficiency syndrome (AIDS) can have multiple infections simultaneously, which highlights the importance of treating and documenting adherence with ART. After initiating effective ART the HIV viral load is effectively suppressed and the frequency of FUO in HIV-infected patients falls markedly.

Approach to the Patient With Fever of Unknown Origin Evaluation of a patient with FUO typically includes verification that the patient has fever, consideration of the fever pattern, a comprehensive history, repeated physical examinations, appropriate laboratory investigations, key imaging studies, and invasive diagnostic procedures. The physical examination should scrutinize the patient more closely than usual because key physical abnormalities in patients with FUO are subtle and require repeated examinations to be appreciated.

Work-up of a patient with an FUO should focus on the history, physical examination, and initial laboratory data. In place of rational diagnostic thinking, there is a temptation to order multiple comprehensive laboratory and imaging studies. Rather than leading to a diagnosis, this shotgun approach may result in enormous expense, false-positive results, and unnecessary additional investigations that may obfuscate the true diagnosis. A fundamental principle in the management of classic FUO is that therapy should be withheld, whenever possible, until the cause of the fever has been determined, so that treatment can be tailored to a specific diagnosis. The exception is in the setting of the immunocompromised host because rapid empirical treatment is most often needed. If fevers persist after an exhaustive work-up there may be a role for fluorodeoxyglucose positron emission tomography (18 FDG-PET/CT) imaging, if available. This allows enhancement of acute and chronic inflammatory processes by uptake of FDG in all activated leukocytes and provides the necessary spatial resolution that may substantially contribute to finding the cause of FUO. The radiation exposure and cost and the degree of incremental improvement in detection over other methods must be carefully considered. Cardiac ECHO can be helpful if culture-negative endocarditis or atrial myxoma is suspected in patients with cardiac murmurs. The most invasive tests such as lymph node biopsies, bone marrow biopsies, and temporal artery biopsies should be undertaken only with strong clinical suspicion and based on physical findings or those found on imaging. Persons who reside in the southeastern part of the United States and immigrants from world regions endemic for Strongyloides stercoralis should have a S. stercoralis titre—whether or not they have a fever—to identify and eradicate risk for overwhelming strongyloidiasis.

SPECIFIC CONDITIONS AND EXPOSURES CAUSING FEVER Fever After Animal Exposures Q Fever Q fever is a widespread zoonotic infection caused by the pathogen Coxiella burnetii that has acute and chronic manifestations. The primary source of infection is infected cattle, sheep, and goats. The organism can exist for months in soil and can become airborne. The onset of disease is typically abrupt, and high-grade fever (40° C or 104° F),

854

SECTION XV  Infectious Disease

TABLE 90.6  Common Causes of Fever of

Unknown Origin

Infections Abscesses Brucellosis Catheter infections Cytomegalovirus Coccidioidomycosis Histoplasmosis Human immunodeficiency virus (HIV) infection Infective endocarditis Intra-abdominal, subdiaphragmatic, and pelvic disease Liver and biliary tract disease Lyme disease Mycobacterium tuberculosis Osteomyelitis Sinusitis Toxoplasmosis Urinary tract infection Autoimmune Conditions Adult Still disease Familial Mediterranean sarcoidosis Rheumatoid arthritis Systemic lupus erythematosus Temporal arteritis Malignancy Hepatocellular carcinoma Leukemia Metastatic cancers Pancreatic cancer Renal cell carcinoma Miscellaneous Causes Deep vein thrombosis, pulmonary embolism Hyperthyroidism Kikuchi disease Periodic fever (tumor necrosis factor receptor associated)

fatigue, headache, and myalgias are the most common symptoms. Acute Q fever is usually a mild disease that resolves spontaneously within 2 weeks. Q fever endocarditis usually occurs in patients with previous valvular damage or immunocompromise, and it is often the predominant manifestation of chronic infection. An immunofluorescence assay is the reference method for the serodiagnosis of Q fever. Consideration of doxycycline therapy is warranted only for patients who are symptomatic.

Leptospirosis Leptospirosis is a zoonotic infection with protean manifestations caused by the spirochete Leptospira interrogans. It is distributed worldwide, but most clinical cases occur in the tropics. The organism infects rodents, cattle, swine, dogs, horses, sheep, and goats, and it is shed in the urine. Humans most often become infected after exposure to environmental sources, such as contaminated water. Leptospirosis may manifest as a subclinical illness followed by seroconversion, a self-limited systemic infection, or a severe, potentially fatal illness accompanied by multiorgan failure. Acute illness manifests with the abrupt onset of fever, rigors, myalgias, and headache in 75%

to 100% of patients. Conjunctival suffusion in a patient with a nonspecific febrile illness accompanied by lymphadenopathy, hepatomegaly, and splenomegaly points to a diagnosis of leptospirosis. During the second phase of illness, fever is less pronounced, but headache and myalgias can be severe, and aseptic meningitis is an important manifestation. In some patients with leptospirosis, the clinical course may be complicated by jaundice (although liver failure is rare), renal failure, uveitis, hemorrhage, ARDS, myocarditis, and rhabdomyolysis (i.e., Weil syndrome). Because the clinical features and routine laboratory findings of leptospirosis are not specific, a high index of suspicion must be maintained. The diagnosis is usually made by serologic testing for L. interrogans. Symptomatic individuals warrant treatment with doxycycline.

Brucellosis Brucellosis is a zoonotic infection caused by Brucella melitensis. It is transmitted to humans by contact with fluids from infected animals (e.g., sheep, cattle, goats, pigs) or derived food products such as unpasteurized milk and cheese. Clinical manifestations of brucellosis include fever, night sweats, malaise, anorexia, arthralgias, fatigue, weight loss, and depression. Patients may have fever and a multitude of complaints but no other objective findings. The onset of symptoms may be abrupt or insidious, developing over several days to weeks. The musculoskeletal and genitourinary systems are the most common sites of involvement. Neurobrucellosis, endocarditis, and hepatic abscesses occur in 1% to 2% of cases. The diagnosis of brucellosis should be considered for an individual with otherwise unexplained fever and nonspecific complaints who has had a possible exposure. Ideally, the diagnosis is made by culture of the organism from blood or other sites, such as bone marrow. Serologic tests include tube agglutination and enzyme-linked immunosorbent assay (ELISA). For adults with nonfocal disease, treatment with doxycycline and rifampin is suggested.

Fever and Rash The most concerning diseases associated with fever and rash are meningococcemia, staphylococcal TSS, and RMSF.

Bacterial Meningitis Neisseria meningitidis is the leading cause of bacterial meningitis in children and young adults in the United States. Recent experience in New York City identified HIV patients as being at increased risk for meningococcal disease. Manifestations of meningococcal disease can range from transient fever and bacteremia to fulminant disease, with death ensuing within hours of the onset of clinical symptoms. Acute systemic meningococcal disease may manifest as one of three syndromes: meningitis alone, meningitis with accompanying meningococcemia, and meningococcemia without clinical evidence of meningitis. The typical initial symptoms of meningitis due to N. meningitidis consists of the sudden onset of fever, nausea, vomiting, headache, decreased ability to concentrate, and myalgias in an otherwise healthy patient. A petechial rash appears as discrete lesions 1 to 2 mm in diameter, most frequently occurring on the trunk and lower portions of the body. More than 50% of patients have petechiae at clinical presentation. Petechiae can coalesce into larger purpuric and ecchymotic lesions.

Staphylococcal Toxic Shock Syndrome S. aureus strains produce exotoxins that cause three syndromes: food poisoning, caused by ingestion of S. aureus enterotoxin; scalded skin syndrome, caused by exfoliative toxin; and TSS, caused by toxic shock syndrome toxin 1 (TSST-1) and other enterotoxins. About one half

CHAPTER 90  Fever and Febrile Syndromes

855

of reported TSS cases are menstrual, associated with bacterial growth on highly absorbent tampons. Non-menstrual TSS has been associated with surgical and postpartum wound infections, mastitis, septorhinoplasty, sinusitis, osteomyelitis, arthritis, burns, cutaneous and subcutaneous lesions (especially of the extremities, perianal area, and axillae), and respiratory infections after influenza. Some MRSA strains can produce TSST-1, and patients infected with these strains may develop TSS. The Centers for Disease Control and Prevention (CDC) case definition for a confirmed case includes several criteria. Patients must have fever greater than 38.9° C, hypotension, diffuse erythroderma, desquamation (unless the patient dies before desquamation can occur), and involvement of at least three organ systems. Although 80% to 90% of TSS patients have S. aureus isolated from mucosal or wound sites, the isolation of S. aureus is not required for the diagnosis of staphylococcal TSS.

americanum). Patients typically have an acute illness that has an incubation period of 1 to 2 weeks. Most patients are febrile and have nonspecific symptoms such as malaise, myalgia, headache, and chills. One feature that may distinguish HME from human granulocytic anaplasmosis (HGA), another tick-borne illness caused by Anaplasma phagocytophilum, is a rash (macular, maculopapular, or petechial). This rash occurs in about 30% of patients with HME but is rare in patients with HGA. The preferred and most widely available diagnostic method for ehrlichiosis is the indirect fluorescent antibody test. The diagnosis should be considered in all patients with Lyme disease or babesiosis. Treatment with doxycycline should be initiated for all patients suspected of having ehrlichiosis or anaplasmosis.

Rickettsial Infections

The typical manifestations of viral infections associated with rash may unequivocally establish the cause of a febrile syndrome. For example, varicella-zoster virus infection manifests with distinctive lesions of chickenpox or herpes zoster (i.e., shingles). The resurgence of measles mandates the ability to recognize its rash. Acute onset of high fever characterizes viral hemorrhagic fevers, along with bleeding complications and high mortality rates in some cases. Arthropods often transmit viral infections, including dengue, which is one of the most common causes of fever in returned travelers.

RMSF is a potentially lethal but usually curable tick-borne disease. Most cases of RMSF occur in the spring and early summer in endemic areas, particularly in the south central and southeastern states, when outdoor activity is most common. The etiologic agent, Rickettsia rickettsii, is a gram-negative, obligate intracellular bacterium that is usually transmitted through a tick bite. Up to one third of patients with proven RMSF do not recall a recent tick bite or recent tick contact. In the early phases of illness, most patients have nonspecific signs and symptoms such as fever, headache, malaise, myalgias, arthralgias, and nausea with or without vomiting. Most patients with RMSF develop a rash between the third and fifth days of illness. The rash typically begins with pink, blanching macules that evolve to a deep red color and then become hemorrhagic. The lesions begin at the wrists, forearms, and ankles and then spread to the arms, thighs, trunk, and face. The diagnosis of RMSF is based on a constellation of symptoms and signs in an appropriate epidemiologic setting (e.g., endemic area in the spring or early summer). In later illness, the diagnosis can be made by skin biopsy and confirmed serologically. Murine typhus is a worldwide illness caused by Rickettsia typhi organisms that are transmitted by fleas. It produces a moderately severe illness characterized by fever, rash, and headache. Disease in the United States has been reported in Texas and Southern California. Rickettsia africae, the cause of African tick-bite fever, occurs in travelers returning from East Africa. It produces a large eschar with a febrile syndrome similar to RMSF. Rickettsial infections respond to treatment with doxycycline and warrant rapid initiation of treatment.

Viral Infections Associated With Rash

Fever With Lymphadenopathy

Lyme disease is a tick-borne illness caused by pathogenic species of the spirochete Borrelia burgdorferi in the United States. Other species in Europe and Asia can cause more aggressive presentations. Localized disease includes erythema migrans in 80% of patients and nonspecific findings that resemble a viral syndrome. Erythema migrans is an expanding macule that forms an annular lesion with a clearing middle. Early disseminated Lyme disease with acute neurologic or cardiac involvement usually occurs weeks to several months after the tick bite and may be the first manifestation of the disease. Nonspecific symptoms (e.g., headache, fatigue, arthralgias) may persist for months after treatment of Lyme disease. There is no evidence that these persistent subjective complaints represent ongoing active infection. Co-infection with Babesia and Ehrlichia is common, and these infections should be considered in persons diagnosed with Lyme disease.

Generalized and localized lymphadenopathy can be major manifestations of some infectious diseases, such as in mononucleosis syndromes, tuberculosis, HIV infection, and pyogenic infections. Infectious mononucleosis is characterized by a triad of fever, tonsillar pharyngitis, and lymphadenopathy. EBV is a widely disseminated herpesvirus that is spread by intimate contact between susceptible persons and EBV shedders. Lymph node involvement in infectious mononucleosis is typically symmetrical and more commonly involves the posterior cervical than the anterior chains. The posterior cervical nodes are deep beneath the sternocleidomastoid muscles and must be carefully palpated. The nodes may be large and moderately tender. Lymphadenopathy may also become more generalized including enlargement of the spleen, which distinguishes infectious mononucleosis from other causes of pharyngitis. Lymphadenopathy peaks in the first week and then gradually subsides over 2 to 3 weeks. Splenomegaly is seen in 50% of patients with infectious mononucleosis and usually begins to recede by the third week of the illness. Patients with a clinical picture of infectious mononucleosis should have a white blood cell count with differential and a heterophile (Monospot) test. If the heterophile test result is positive, no further testing is necessary when the clinical scenario is compatible with typical infectious mononucleosis. If the heterophile test result is negative but there is still a strong clinical suspicion of EBV infection, the Monospot test can be repeated because results can be negative early in clinical illness. If the clinical syndrome is prolonged or the patient does not have a classic EBV syndrome, immunoglobulin M (IgM) and immunoglobulin G (IgG) viral capsule antigen (VCA) and Epstein-Barr nuclear antigen (EBNA) antibodies should be measured. IgG EBNA detected within 4 weeks of symptom onset excludes acute primary EBV infection as an explanation and should prompt consideration of EBVnegative causes of mononucleosis.

Human Ehrlichiosis

Cytomegalovirus

The principal vector of Ehrlichia chaffeensis, the agent that causes human monocytic ehrlichiosis (HME), is the Lone Star tick (Amblyomma

The spectrum of human illness caused by CMV is diverse and mostly depends on the host. CMV infection in the immunocompetent host

Lyme Disease

856

SECTION XV  Infectious Disease

usually is asymptomatic or may manifest as a mononucleosis-like syndrome. Transmission occurs through multiple routes. The mononucleosis syndrome associated with CMV infection has been described as typhoidal because systemic symptoms and fever predominate, and signs of enlarged cervical nodes and splenomegaly are not as commonly seen as they are in EBV infection. Diarrhea, fever, fatigue, abdominal pain, and mildly abnormal liver enzymes are common findings. Immunocompromised patients, such as those who have received transplants, may have serious, life-threatening infections such as pneumonitis, hepatitis, colitis, and retinitis. Serology provides indirect evidence of recent CMV infection based on changes in antibody titers at different time points during the clinical illness. Serologies are also helpful in determining past exposure to CMV. This information is particularly relevant for monitoring immunosuppressed hosts at risk for CMV reactivation syndromes.

to cats or fleas. Laboratory testing that supports the diagnosis includes a positive B. henselae antibody titer or biopsy of a lymph node with a positive Warthin-Starry stain or polymerase chain reaction (PCR) analysis of tissue.

Pyogenic Infection S. aureus and group A streptococcal (GAS) infections can produce acute, suppurative lymphadenitis. Enlarged and tender lymph nodes usually are found in the submandibular, cervical, axillary, or inguinal areas. Patients have fever and leukocytosis. Pyoderma, pharyngitis, and periodontal infections are usually the primary sites of infection. Management includes drainage and antibiotics.

Plague

Most cases of new HIV infection are passed asymptomatically, and routine testing of sexually active persons should be performed as part of good primary care. All patients with mononucleosis syndromes should undergo HIV testing. Published series consistently report that the most common findings of acute HIV are fever, generalized lymphadenopathy, sore throat, rash, myalgia or arthralgia, and headache when symptomatic.

Bubonic plague is a bacterial syndrome caused by Yersinia pestis that usually consists of fever, headache, and a large mat of inguinal, axillary, or cervical lymph nodes. Lymph nodes suppurate and drain spontaneously. The diagnosis should be considered for acutely ill patients in the southwestern United States with possible exposure to fleas and rodents. Gram-negative coccobacilli can be seen in lymph node aspirates. The characteristic safety-pin appearance of Y. pestis with dark blue staining of polar bodies is seen with Wayson stain.

Toxoplasmosis

Sexually Transmitted Diseases

Toxoplasmosis, an infection with a worldwide distribution, is caused by the intracellular protozoan parasite T. gondii. Humans can acquire Toxoplasma organisms through ingestion of contaminated meat, vertical transmission, blood transfusion, exposure to oocysts from cat feces, or organ transplantation. Immunocompetent persons with primary infection are usually asymptomatic, but latent infection can persist for the life of the host. When symptomatic infection does occur, the most common manifestation is bilateral, symmetrical, nontender cervical adenopathy. Patients may have headache, fever, and fatigue. Symptoms usually resolve within several weeks. In AIDS patients or other immunocompromised hosts who have been previously infected, T. gondii infection may reactivate in the brain, causing abscesses and encephalitis.

Inguinal lymphadenopathy associated with sexually transmitted diseases can be unilateral or bilateral. In primary syphilis, enlarged nodes are discrete, firm, and nontender. Tender lymphadenopathies with matting are seen in lymphogranuloma venereum. The lymphadenopathy of chancroid is most often unilateral and manifests with pain and fused lymph nodes. Primary genital herpes infection also causes tender inguinal lymphadenopathy.

Primary Human Immunodeficiency Virus Infection

Infections Causing Regional Lymphadenopathy Scrofula (i.e., tuberculous cervical adenitis) develops in a subacute to chronic pattern. Low-grade fever is usually associated with a large mass of matted cervical lymph nodes. In children, M. tuberculosis is the etiologic agent, but in adults, Mycobacterium avium complex and Mycobacterium scrofulaceum are more commonly found. Surgical excision is the treatment of choice.

Cat-Scratch Disease Cat-scratch disease, a condition caused by Bartonella henselae, is characterized by self-limited regional lymphadenopathy after a cat scratch or transmission from another vector. Other manifestations can include visceral organ, neurologic, and ocular involvement. In 85% to 90% of children, cat-scratch disease manifests as a localized cutaneous and lymph node disorder near the site of organism inoculation. In some individuals, the organisms disseminate and infect the liver, spleen, eye, bone, or CNS. Patients with localized disease usually have a self-limited illness, whereas those with disseminated disease can have life-threatening complications. B. henselae infection should be considered in the initial evaluation of FUO in children. The diagnosis of cat-scratch disease is based on typical clinical findings (i.e., lymphadenopathy) associated with probable exposure

FACTITIOUS FEVER AND SELF-INDUCED ILLNESS In most case series, factitious fever or self-induced illness is a relatively uncommon cause of FUO, but it may occur more often than generally appreciated. Patients with these conditions are often young women, and 50% have had training in some aspect of health care. They are often well educated, cooperative, articulate, and manipulative of family and caregivers. Patients can no longer manipulate thermometers because electronic or infrared thermometry is used, and causing factitious fever is difficult. Clues to the factitious fever diagnosis include absence of a toxic appearance despite high temperature readings, lack of tachycardia, and absent diurnal variation. Patients may appear well between episodes of fever. Genuine fever can be induced if an individual injects or ingests pyrogenic substances such as bacterial suspensions, urine, or feces. Although intermittent polymicrobial bacteremia may suggest a diagnosis of intra-abdominal abscess, it represents self-induced infection. The discovery of needles and substances for injection in the patient’s belongings may help in the diagnosis. In most cases, a psychogenic basis for the behavior is assumed. However, one study with detailed psychological patient analyses found no evidence of major psychiatric diagnoses among individuals with self-induced or simulated illnesses. Munchausen syndrome and Munchausen by proxy are the most extreme forms of factitious fever. Patients often agree stoically to numerous highly invasive procedures to diagnose and treat themselves or their children (i.e., proxy). All of these individuals require objective but complete, tactful, and compassionate assessments and considerable psychiatric care.

CHAPTER 90  Fever and Febrile Syndromes

SUGGESTED READINGS Aduan RP, Fauci AS, Dale DC, et al: Factitious fever and self-induced infection: a report of 32 cases and review of the literature, Ann Intern Med 90:230–242, 1979. Aduan RP, Fauci AS, Dale DC, et al: Prolonged fever of unknown origin (FUO): a prospective study of 347 patients, Clin Res 26:558A, 1978. Brown I, Finnigan NA: Fever of unknown origin (FUO). In StatPearls [Internet], Treasure Island (FL), 2019, StatPearls Publishing. [Updated 2018 Nov 18]. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK532265.

857

Cannon J: Perspective on fever: the basic science and conventional medicine, Complement Ther Med 21(Suppl 1):S54–S60, 2013. Osilla EV, Sharma S: Physiology, temperature regulation. In StatPearls [Internet], Treasure Island (FL), 2019, StatPearls Publishing. [Updated 2019 Mar 16]. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK507838. Weber D, Cohen M, Rutala W: The acutely ill patient with fever and rash. In Bennett JE, Dolin R, Blaser M, editors: MandellDouglas and Bennett’s principles and practice of infectious diseases, ed 8, Elsevier, 2015, pp 732–747.

91 Bacteremia and Sepsis Russell J. McCulloh, Steven M. Opal

DEFINITION

EPIDEMIOLOGY

Sepsis is a leading cause of morbidity and death among hospitalized patients. The disease process results from a complex interplay of host immune responses and infectious microorganisms. In 2016 an international panel of experts released an updated definition of sepsis, specifying it as life-threatening organ dysfunction caused by a dysregulated host response to infection. Manifestations can include fever, altered mental status, and abnormalities in inflammation and coagulation. Severe cases can progress to multiple organ system dysfunction followed by organ failure and death. Diagnostic criteria for sepsis are provided in Table 91.1. The term “severe sepsis,” once recognized as a separate entity defined by more severe organ dysfunction, is now synonymous with the current definition of sepsis and should no longer be used. Septic shock is a combination of sepsis and persistent hypotension and tissue hypoperfusion despite adequate fluid resuscitation or the need to use vasopressors to maintain a mean arterial pressure (MAP) at 65 mm Hg or greater and in addition an elevated serum lactate greater than 2 mmol/L. The continuum of disease manifestations from localized infection to multiorgan failure and refractory septic shock is depicted in Fig. 91.1. Sepsis is a situation in which the infection-induced systemic inflammatory and coagulopathic responses have become injurious to the host. Sepsis is an infectious process characterized by tissue injury from hypoperfusion and immune dysregulation. Severe infection should be used to describe an infection that is accompanied by systemic inflammation but without evidence of organ dysfunction remote from the site of infection (i.e., the former definition of sepsis). Whether these revised definitions can resolve the current confusion in terminology remains to be seen. Understanding the pathophysiology of sepsis syndrome has proved helpful in differentiating and treating severe inflammatory processes that manifest with symptoms similar to sepsis, including pancreatitis, severe trauma, thermal burns, and certain toxin or environmental exposures. These processes can produce a systemic inflammatory response syndrome (SIRS), but they lack the component of infection needed to establish a diagnosis of sepsis. The remarkable clinical similarity between these severe “sterile” inflammations and septic shock reflects their molecular profiles. Identical signaling pathways for the immune response are activated by highly conserved pathogen-associated molecular patterns (PAMPs), which are molecular motifs recognized by cells of the host’s innate immune system. Damage-associated molecular patterns (DAMPs) are molecules released by injured host cells that act as endogenous danger signals to promote the inflammatory response (see “Pathophysiology of Septic Shock” later in this chapter).

The worldwide incidence of sepsis is difficult to assess due to limited data from developing countries. In industrialized countries, reported rates of sepsis range from 22 to 300 cases per 100,000 people. Sepsis may account for up to 6% of adult deaths. In the United States, more than 750,000 cases of sepsis and 200,000 sepsis-related deaths occur annually. The risk of mortality depends on the severity of illness and multiple host factors (discussed later). Overall, estimates of death from sepsis range from 20% of mild to moderate cases to more than 60% of patients with septic shock. The financial impact of sepsis cases is immense. Each episode of sepsis costs approximately $50,000 in health care expenditures, for a total of more than $24 billion dollars in 2016 in the United States alone. Bacterial infections are the most common cause of sepsis. Bloodstream infections due to bacteria account for the largest proportion of hospitalizations. The rates are highest for premature infants, the advanced elderly (especially those older than 85 years of age), and patients with intravenous catheters, implanted devices, or severe medical morbidities such as severe burns or hematologic malignancies. Pathogens most commonly identified in bloodstream infections include staphylococci (e.g., Staphylococcus aureus), group A streptococci, Escherichia coli, Klebsiella species, Enterobacter species, and Pseudomonas aeruginosa. Immunocompromised patients and patients with long-term intravascular catheters are at increased risk for fungal bloodstream infections from Candida species, and some species may be resistant to commonly used antifungal medications. Given the broad variety of potential pathogens, clinicians face the dual challenges of an accurate and timely diagnosis and choice of appropriate empirical therapy. Several epidemiologic factors can guide the clinician in cases of sepsis when a source has not been identified. Table 91.2 lists microorganisms that are associated with certain host factors that predispose a patient to infection and sepsis. Host factors associated with worse outcomes include extremes of age, use of immunomodulating medications, and concomitant chronic medical conditions. Several diagnostic and treatment factors are associated with severity of illness and clinical outcome. Delay in effective antimicrobial therapy correlates with worse outcomes. Infection with multidrug-resistant organisms may cause a delay in effective therapy, and for some organisms, particularly gram-negative enteric rods, the delay may be independently related to worse outcomes. Certain organisms (e.g., P. aeruginosa, Staphylococcus aureus) are more virulent. The primary infection site also is important; respiratory sites are the most common, and the central nervous system often is the most lethal site of infection. The number of organ systems involved plays a role, with mortality increasing as the number of dysfunctional organ systems increases.

858

859

CHAPTER 91  Bacteremia and Sepsis

TABLE 91.1  Diagnostic Criteria for Sepsisa General Criteria Life-threatening organ dysfunction caused by a dysregulated response to infection

Organ Dysfunction Criteria Change in Sequential (Sepsis-related) Organ Failure Assessment (SOFA)b score of ≥2 points. It can be used to measure the severity of organ dysfunction.

SOFA Scoring (Range 0–4 Per Category, 0–24 Total Score Range) Criterion 0 1 2 Respiration; Pao2/Fio2 (torr) >400 ≤400 ≤300 Platelets (×103/mm3) Bilirubin (mg/dL) Glasgow Coma Scale Hypotensionc

>150 0.1 (or phenylephrine>300 mcg bolus >5.0 2 mmol/L [>18 mg/dL]) From Singer M, Deutschman CS, Seymour CW, et al: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), JAMA 315(8):801-10, 2016. Fio2, Fraction of inspired oxygen; INR, international normalized ratio; MAP, mean arterial pressure; Pao2, partial pressure of oxygen. aThe criteria include documented or suspected infection and some of the variables listed. bAssuming baseline SOFA of 0 in most cases. cAdrenergic agents must be administered for at least 1 hour to count; doses are in mcg/kg/min.

Pathophysiology

Renal dysfunction

Cardiovascular insufficiency

Pathogenic microorganism

Local Systemic inflammatory inflammatory response response

Hepatic dysfunction Endothelial dysfunction Metabolic dysfunction

Evidence of inadequate organ perfusion

Gastrointestinal dysfunction

Death

Immune system dysfunction Central nervous Respiratory insufficiency system dysfunction Hematologic dysfunction

Clinical entity

Local infection

Systemic infection

Acute respiratory Multiorgan distress dysfunction syndrome Fig. 91.1  The spectrum of illness and nomenclature for sepsis pathophysiology.

PATHOLOGY AND IMMUNOPATHOGENESIS The pathologic findings of fatal septic shock are often rather bland on gross examination and even histologic examination of tissue samples.

Sepsis

Septic shock

The most common finding is increased tissue edema in the interstitial spaces and excess lung fluid and pleural fluid. Signs of hyaline membrane formation and fibrin deposition in the alveoli are common and

860

SECTION XV  Infectious Disease

TABLE 91.2  Microorganisms Commonly Identified in Septic Patients Based on Host Factors Host Factor

Organisms to Consider

Asplenia

Encapsulated organisms, particularly Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Capnocytophaga canimorsus Vibrio, Salmonella, and Yersinia species; encapsulated organisms, other gram-negative rods Klebsiella species, S. pneumoniae Mucormycosis, Pseudomonas species, Escherichia coli, group B streptococci Enteric gram-negative rods, Pseudomonas, Aspergillus, Candida, Mucor species, Staphylococcus aureus, streptococcal species Listeria, Salmonella, and Mycobacterium species, herpesviruses (including herpes simplex, cytomegalovirus, varicella-zoster virus) Salmonella species, S. aureus, Mycobacterium avium complex, S. pneumoniae, group B streptococci

Cirrhosis Alcohol abuse Diabetes Neutropenia T-cell dysfunction Acquired immunodeficiency syndrome

indicate the fibroproliferative stage of acute respiratory distress syndrome (ARDS). Occasionally, punctate or macroscopic evidence can be detected in the adrenal tissues. Diffuse petechiae in tissues and mucosal surfaces may indicate disseminated intravascular coagulation (DIC). The kidneys usually appear normal, and necrosis of kidney tissues is distinctly uncommon. The term acute tubular necrosis is a misnomer, and the term acute kidney injury (AKI) is more appropriate for describing the functional and usually reversible loss of kidney function found in septic shock without accompanying evidence of glomerular or tubular necrosis. An important finding at autopsy is identification of the infectious focus that caused septic shock. The focal infection that precipitated sepsis is readily identifiable in most deceased patients despite days to weeks of seemingly appropriate antimicrobial therapy directed against the pathogens. If careful histochemical studies are performed shortly after a patient succumbs to sepsis, excessive apoptosis (but not necrosis) of immune effector cells is identifiable in lung, spleen, lymph nodes, and hepatic tissues. Electron microscopy of tissues after death from sepsis often reveals loss of tight junctions along epithelial and endothelial surfaces. Electron microscopy also demonstrates diffuse mitochondrial swelling and degradation and clearance of intracellular organelles (i.e., autophagy).

PATHOPHYSIOLOGY OF SEPTIC SHOCK The molecular mechanisms that underlie the basic pathophysiology of septic shock have been determined. Sepsis is triggered when a pathogen or cluster of pathogens breaches the epithelial barriers at a tissue site, evades clearance by humoral and cellular innate immune defenses, and causes an invasive infection. On entry into the host tissues, microbial pathogens are first sensed by myeloid cells of the innate immune system by pattern recognition receptors (e.g., toll-like receptors [TLRs]) on the cell surface and in endosomal compartments. TLRs detect highly conserved molecular motifs of microbes. Examples include lipopolysaccharide (LPS), the endotoxin produced by gram-negative bacteria; bacterial lipopeptides from gram-positive bacteria; β-glucans of the cell wall of fungi; viral RNA genomes and proteins; bacterial flagella; and DAMPs released from injured host cells, including intracellular structures such as histone proteins, mitochondrial DNA, and high-mobility group box 1 (Fig. 91.2). TLRs and related intracellular pattern recognition receptors, including the inflammasome elements, retinoic acid–inducible gene 1 (RIG1)–like helicases, and cytoplasmic microbial TLR4, alert the host to infection. TLR4 is the long-sought-after LPS receptor of the human innate immune system. LPS is released from the cell membrane of gram-negative bacteria on their destruction. LPS is first bound to a

carrier protein, LPS-binding protein, and the LPS monomer is then delivered to a membrane-associated, multiligand, pattern recognition receptor, CD14. LPS monomers are then passed to a soluble protein (i.e., myeloid differentiation factor 2 [MD2]) and bind to the ectodomain of TLR4. After this LPS/MD2/TLR4 complex is completed and dimerized, intracellular signaling alerts the host to the invasive infectious challenge. The pathway induces a series of phosphorylation events of adaptor proteins and signaling molecules that terminate in the activation and translocation of transcriptional activating factors such as nuclear factor-κB (NF-κB) into the nucleus. The transcription factors bind to promoter sites of the acute phase protein network, resulting in an acute outpouring of inflammatory, host defense, and coagulation components. Other TLRs, such as TLR5 (i.e., bacterial flagella) and the TLR2/ TLR1 and TLR2/TLR6 heterodimers (i.e., bacterial lipopeptides, lipoteichoic acid, and other elements of bacteria and fungi), are expressed on the cell surface of immune effector cells that recognize different molecular patterns. Nucleic acid recognition–specific TLRs reside in endosomal vacuoles, where they detect microbial DNA (TLR9), single-stranded RNA (TLR7 and TLR8), and double-stranded RNA (TLR3). An array of complement elements, cytokines, chemokines, prostaglandins, vasoactive peptides, platelet-activating factor, and proteases are generated, resulting in activation of neutrophils, neutrophil extracellular traps (NETs), monocytes, macrophages, dendritic cells, lymphocytes, and endothelial cells in a combined effort to wall off the infectious process, clear the pathogens, and begin the process of tissue repair. This defense system efficiently clears pathogens from the host after local injury and the inevitable minor breaches of the epithelial barriers by microorganisms that occur over a lifetime. If the inflammatory process is unchecked and accompanied by large numbers of pathogens or even a few highly virulent organisms (e.g., plague, tularemia, anthrax, and hemorrhagic fever viruses) to which the host has no preexisting immunity, a generalized, inflammatory, and injurious process known as sepsis evolves over a short time, and it can be deleterious or lethal to the host. The same inflammatory response that can be life-saving in localized infection can become life-threatening if it becomes sustained and generalized. Endothelial membranes throughout the body are activated and become pro-adherent and pro-coagulant surfaces that promote neutrophil and platelet adherence. Neutrophils release proteases, cytokines, NETs, reactive oxygen radicals, and vasoactive prostanoids that damage endothelial cells and their function. Cytokine-inducible nitric oxide synthase is upregulated, resulting in massive generation of nitric oxide (NO). NO is a potent vasodilator, and in combination with other vasoactive peptides and phospholipid mediators, it promotes diffuse opening of capillary beds and increased permeability, with loss of

CHAPTER 91  Bacteremia and Sepsis

Endothelium

Binding of lipopolysaccharide of gram-negative bacilli Binding of lipopeptides and MD2 lipoteichoic acid of CDI4 TLR2 gram-positive bacteria TLR4

Transcription of immunomodulatory cytokines, complement and procoagulants

TLR1 NF-κB

Release of NF-κB and transfer to nucleus

861

Prostaglandins Leukotrienes Proteases Oxidants

Sepsis Activation and binding of myeloid cells

Increased activity of iNOS

Increased NO NO

Vasodilation Fig. 91.2  Immunopathogenesis of sepsis. Early recognition of bloodstream infection begins with sensing by pattern recognition receptors: toll-like receptor 4 (TLR4); cluster determinant 14 (CD14); myeloid differentiation factor 2 (MD2) for gram-negative bacterial lipopolysaccharide and TLR2 for lipoteichoic acid and other elements from gram-positive bacteria. Engagement of the TLRs by their ligands signals transcription of the acute phase response genes by nuclear factor-κB (NF-κB). Septic shock is initiated by systemic release of an array of vasoactive mediators, including nitric oxide (NO) produced by cytokine-inducible NO synthase (iNOS).

intravascular fluids into the interstitial spaces. Reactive oxygen species combine with NO to generate highly injurious reactive nitrogen intermediates (e.g., peroxynitrite) that damage mitochondrial function and induce apoptosis. Systemic hypotension rapidly develops, and septic shock ensues. Immediate action by the clinician is mandatory to correct the hemodynamic status and resolve the underlying infection.

CLINICAL PRESENTATION Despite the vast improvements in understanding the pathophysiologic basis of sepsis, clinical diagnosis remains limited to the medical history, symptomatic assessment, and nonspecific laboratory and hemodynamic criteria. Compounding the problem is the need for prompt institution of appropriate antimicrobial therapy, making early recognition of sepsis critically important. Patients with clinical findings as outlined in Table 91.1 should undergo thorough and prompt evaluation for a possible infectious cause, including bacterial cultures of blood and (when indicated) other body fluids. Localizing signs and symptoms should prompt a thorough physical examination and directed imaging to identify a nidus of infection. Defects of natural defensive barriers, such as transcutaneous devices or intravascular catheters, should be assessed for infection and removed if suspected to be the origin of the septic process. To minimize the potential delay in prompt recognition and management of sepsis resulting from obtaining laboratory data, the Sepsis-3 recommendations included a bedside quick SOFA (qSOFA) scoring system. The qSOFA allows for repeated bedside evaluations of patients at risk for developing sepsis and relies on three clinical criteria, each worth 1 point: (a) Respiratory rate 22/ min or greater; (b) altered mentation; and (c) systolic blood pressure

less than 100 mm Hg. A qSOFA score of 2 or greater should prompt further investigation into infectious causes and organ dysfunction as well as initiation or escalation of therapy, as appropriate. Despite its clinical logic and its simplicity, the experience thus far with its predictive value has been mixed. General clinical presentation of sepsis varies widely. Many patients have fever or chills, but older patients and those on immunomodulating medications may not mount a fever. Hypothermia portends a worse prognosis or more severe illness. Tachypnea may be an indicator of respiratory compensation for underlying metabolic acidosis or the early signs and symptoms of ARDS. Mental status changes can result from metabolic derangements caused by sepsis, hypoglycemia, the underlying infectious process, or concomitant hypotension. This symptom can be difficult to identify in the elderly patient with dementia, and caution should be exercised in the evaluation and treatment of the otherwise stable elderly patient with possible mental status changes. Skin findings (e.g., cellulitis, abscess) can provide clues to the cause of sepsis and may indicate the state of peripheral systemic perfusion. Several microorganisms can cause specific skin manifestations in systemic infection. S. aureus and streptococci can cause diffuse erythro­ derma, bullous lesions, or generalized desquamation. Bacteremia caused by several gram-negative organisms, including P. aeruginosa and enteric organisms, can result in ecthyma gangrenosum, particularly in immunocompromised patients. These lesions are round and 1 to 15 cm in diameter, and they have a central area of necrosis and peripheral erythema. Infection with Neisseria meningitidis can result initially in lower extremity petechiae progressing to diffuse purpura, which likely portends septic shock and a high risk of death. A similar clinical presentation can be observed in other unusual infectious diseases, such as

862

SECTION XV  Infectious Disease

overwhelming pneumococcal sepsis in the asplenic host or disseminated neisserial infections in patients with late complement deficiencies. Hemodynamic instability, particularly hypotension with or without accompanying oliguria, is commonly associated with sepsis. Instability can result from poor cardiac output, intravascular fluid depletion, or low systemic vascular resistance. Hypotension can initially respond to intravenous fluid resuscitation, but in cases of severe sepsis and septic shock, it may require additional support with vasopressors. Intensive cardiac monitoring may be necessary to gauge the relative need for intravenous fluids or vasopressors after initial fluid resuscitation measures are attempted. Patients in septic shock can be tachycardic and hypotensive. They may have relatively warm extremities (i.e., warm shock or distributive shock), or they may be peripherally vasoconstricted, with mottled and cool extremities (i.e., cold shock). Warm shock is the predominant finding in most adult patients at the onset of septic shock, with evidence of diffuse vasodilation, bounding pulses, and a compensatory high cardiac output despite evidence of diminished myocardial performance. Increased cardiac output is accomplished primarily by increased heart rate in an attempt to maintain blood pressure and perfuse vital organs. If shock is not promptly corrected, myocardial dysfunction ensues and cold shock evolves over the next several hours. Older patients with limited cardiac reserves tolerate shock poorly and are more likely to develop cold shock. Evidence of septic shock at presentation that is refractory to early resuscitation portends a poor prognosis, with mortality rates exceeding 70%. Besides hypotension, oliguria can represent developing AKI. It can arise from a combination of the disease process, infecting organism, and medications. Inflammatory cytokines, microbial toxins, systemic hypotension, and iatrogenic renal injury from medications can result in AKI. Other causes of renal injury include interstitial injury from infection or medications and immune complex–mediated injury, as seen in cases of endocarditis. Besides tachypnea, pulmonary symptoms seen in septic patients include marked hypoxia due to interstitial edema, inflammation, or hemodynamic instability. ARDS is defined as an arterial partial pressure of oxygen less than 50 mm Hg despite fractional inspired oxygen of greater than 50%, together with diffuse alveolar infiltrates and a pulmonary capillary wedge pressure of less than 18 mm Hg. ARDS occurs in up to 40% of septic patients. The diffuse pulmonary inflammation in ARDS results in increased pulmonary vascular permeability, which complicates fluid resuscitation efforts because excessive fluid can exacerbate pulmonary edema and hypoxia. Altered mental status and sepsis-related myopathy also result in airway compromise and weak respiratory effort, necessitating invasive ventilatory support. Patients with sepsis can have marked hematologic changes. They may have neutrophilic leukocytosis, which is often accompanied by increased immature cell counts, or they can be markedly leukopenic (particularly lymphopenic), often in cases of severe septic shock. Transient neutropenia is often seen in the early phase of septic shock and results from activation and adherence of neutrophils along endothelial surfaces in the microcirculation. This is rapidly followed by prolonged neutrophilia as sepsis-induced inflammatory cytokines stimulate bone marrow synthesis of new white blood cells. Thrombocytopenia and coagulopathy can occur, and patients have petechiae or purpura at presentation. Severe derangements in coagulation can produce DIC, which can lead to thrombin deposition throughout the microcirculation. Excessive activation and degradation of clotting factors can deplete coagulation factors, resulting in diffuse hemorrhage. Excessive mucosal bleeding around airway tubes and prolonged bleeding from venipuncture sites presage internal bleeding events. Massive gastrointestinal hemorrhage can occur, which can cause or exacerbate hypotension and shock.

Derangements in glucose homeostasis can be seen at presentation. This can take the form of hyperglycemia in diabetics receiving glucose-containing fluids or acute metabolic derangement due to infection. Hypoglycemia is more common in patients with underlying liver disease. Increased anaerobic metabolism due to poor tissue oxygenation and coupled with mitochondrial dysfunction and impaired hepatic clearance of lactic acid may result in increased serum lactate levels and metabolic acidosis.

DIAGNOSIS Accurate diagnosis of sepsis relies on the history, physical examination, and general laboratory investigation. Diagnostic criteria for sepsis in adults based on the Sepsis-3 criteria are listed in Table 91.1. Accurate and timely identification of the underlying infectious cause is essential. For patients able to provide a history, an assessment of medical comorbidities, potential exposures, prior infections, and immune system abnormalities may help to guide empirical antimicrobial therapy and the laboratory investigation, particularly microbial cultures. Two sets of blood cultures drawn from a fresh venipuncture and from existing indwelling intravascular lines (before initiation of empirical antimicrobial therapy when possible) help to identify the causative organism in many cases. A recent study in over 3000 patients reinforces the value of obtaining diagnostic, pre-antibiotic treatment, blood cultures. The diagnostic yield was nearly 50% higher for blood cultures obtained in the pre-antibiotic treatment group compared to the post-antibiotic treatment blood cultures (sampled up to 120 minutes after the start of antibiotic therapy). Symptomatic assessment and physical examination should suggest a location of focal infection that can help to guide radiologic studies and interventions to drain pus. Beyond microbial cultures, several other laboratory studies can help to define the severity of illness and provide baseline data for monitoring the response to therapy. Basic laboratory testing, including a complete blood count with differential, chemistries, and creatinine and aminotransferase levels, can help to identify significant organ dysfunction. Oxygen saturation by pulse oximetry should be measured promptly to identify gas exchange capacity and the need for ventilatory support. Coagulation studies should be obtained, particularly for patients with evidence of DIC and those who are thrombocytopenic. For patients with altered mental status or marked respiratory difficulty, arterial blood gas sampling can help define the underlying derangement and physiologic compensation and can indirectly gauge the severity of illness. Levels of inflammatory markers, including C-reactive protein and procalcitonin, usually are elevated. An elevated procalcitonin level can help to differentiate septic shock from other causes of shock and provide some prognostic data and a measure of response to therapy. In cases of sepsis due to pneumonia, serial measurement of procalcitonin can help to guide the duration of antibiotic therapy. Other testing should be directed toward identifying the potential cause. Patients with severe diarrhea should undergo testing for antibiotic-associated Clostridioides difficile infection. Imaging studies should focus on identifying infectious sources and facilitate drainage of fluid collections or abscesses. Computed tomography may be of use in such circumstances, although for the critically ill patient who is not stable for transport, bedside radiographic studies, especially ultrasound, should be considered. Multiple tests of physiologic function and advanced microbiologic diagnostic tests are increasingly used in clinical practice. They include polymerase chain reaction (PCR)–based assays for identifying bacteria and viruses and various assays of inflammatory cytokines and other biomarkers alone and in combination as potential diagnostic and prognostic aids.

CHAPTER 91  Bacteremia and Sepsis

863

TABLE 91.3  Recommended Initial Management of Sepsis in Adults • • • • • • •

• • • • • • •

S tart resuscitation immediately in patients with hypotension or serum lactate level >2 mmol/L. Obtain appropriate cultures before starting antibiotics if doing so does not significantly delay therapy. Evaluate for a focus of infection amenable to source control (e.g., abscess drainage). Remove intravascular catheters if potentially infected. Begin broad-spectrum antibiotics within the first hour of severe sepsis and septic shock. Initial antibiotic regimen is based on likely source of sepsis, likely pathogens, and local antibiotic susceptibility patterns of common pathogens. Begin fluid resuscitation using crystalloids as the first choice. If colloids are used, avoid starches and consider albumin in selected patients who have hypoalbuminemia or require large-volume fluid resuscitation. Give fluid challenge of up to 30 mL/kg of crystalloids over 15–30 min in septic patients with suspected volume depletion; larger volumes of fluids may be needed in some patients. The goals for resuscitation should be a central venous pressure of 8–12 mm Hg, a mean arterial pressure (MAP) ≥65 mm Hg, and a superior vena cava oxygen saturation ≥70% or mixed venous oxygen saturation ≥65%. Maintain targeted MAP of ≥65 mm Hg; if fluids are not effective in reestablishing adequate blood pressure, begin vasopressors. After hemodynamic parameters are stabilized, limit fluid therapy to prevent pulmonary fluid accumulation and exacerbation of hypoxemia. Use norepinephrine, centrally administered, as the vasopressor of choice. Epinephrine is the second choice, followed by vasopressin as salvage therapy. Dobutamine may be useful if an inotrope is needed. Avoid dopamine except for special situations (i.e., low risk of tachyarrhythmia and persistent bradycardia). Give red blood cells when the hemoglobin concentration decreases to 1–2 cm should probably be excluded from short-course therapy. Ampicillin and gentamicin for Ceftriaxone for 6 wk 4 wk is an alternative regimen, but some isolates may produce β-lactamase, thereby reducing the efficacy of this regimen.

Ampicillin and gentamicin for 6 wk is an alternative regimen, but some isolates may produce β-lactamase, thereby reducing the efficacy of this regimen.

Modified from Mylonakis E, Calderwood SB: Infective endocarditis in adults, N Engl J Med 345:1318-1330, 2001. HIV, Human immunodeficiency virus; IE, infective endocarditis; NVE, native valve endocarditis; PVE, prosthetic valve endocarditis. aVancomycin therapy is indicated for patients with confirmed immediate hypersensitivity reactions to β-lactam antibiotics. bFor patients who have IE due to methicillin-susceptible staphylococci and are allergic to penicillin, a first-generation cephalosporin or vancomycin may be substituted for nafcillin or oxacillin. Cephalosporins should be avoided in patients with confirmed immediate-type hypersensitivity reactions to β-lactam antibiotics. cHACEK organisms: Haemophilus spp, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae.

902

SECTION XV  Infectious Disease

TABLE 95.8  Echocardiographic Indications

for Surgical Intervention in Infective Endocarditis

Vegetation Persistent vegetation after systemic embolization Anterior mitral valve leaflet vegetation (particularly if ≥1 embolic events occur during the first 2 wk of antimicrobial therapy)a Increase in vegetation size despite appropriate antimicrobial therapya,b Valvular Dysfunction Acute aortic or mitral insufficiency with signs of ventricular failureb Heart failure unresponsive to medical therapyb Valve perforation or ruptureb Large abscess or extension of abscess despite appropriate antimicrobial therapyb Paravalvular Extension Valvular dehiscence, rupture, or fistulab New heart blockb Large abscess or extension of abscess despite appropriate antimicrobial therapyb Modified from Baddour LM, Wilson WR, Bayer AS, et al: Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association; endorsed by the Infectious Diseases Society of America, Circulation 111:e394-e433, 2005. aSurgery may be required because of risk of embolization. bSurgery may be required because of failure of medical therapy or heart failure.

SUGGESTED READINGS Baddour LM, Cha YM, Wilson WR: Clinical practice: infections of cardiovascular implantable electronic devices, N Engl J Med 367:842–849, 2012. Blauwkamp TA, Thair S, Rosen MJ, et al: Analytical and clinical validation of a microbial cell-free DNA sequencing test for infectious disease, Nat Microbiol 4:663–674, 2019. Bor DH, Woolhandler S, Nardin R, et al: Infective endocarditis in the U.S., 1998–2009: a nationwide study, PloS One 8(e60033):2013.

Brouqt P, Raoult D: Endocarditis due to rare and fastidious bacteria, Clin Microbiol Rev 14:177–207, 2001. Fernández-Hidalgo N, Almirante B, Gavaldà J, et al: Ampicillin plus ceftriaxone is as effective as ampicillin plus gentamicin for treating Enterococcus faecalis infective endocarditis, Clin Infect Dis 56:1261–1268, 2013. Fournier PE, Thuny F, Richet H, et al: Comprehensive diagnostic strategy for blood culture-negative endocarditis: a prospective study of 819 new cases, Clin Infect Dis 51:131–140, 2010. Garcia-Cabera E, Fernandez-Hidalgo N, Almirante B, et al: Neurological complications of infective endocarditis: risk factors, outcome, and impact of cardiac surgery: a multicenter observational study, Circulation 127:2272–2284, 2013. Iversen K1, Ihlemann N1, Gill SU1, et al: Partial oral versus intravenous antibiotic treatment of endocarditis, N Engl J Med 380(5):415–424, 2019. Kadri AN, Wilner B, Hernandez AV, et al: Geographic trends, patient characteristics, and outcomes of infective endocarditis associated with drug abuse in the United States from 2002 to 2016, JAHA 8:e12969, 2019. Kang DH, Kim YJ, Kim SH, et al: Early surgery versus conventional treatment for infective endocarditis, N Engl J Med 366:2466–2473, 2012. Kiefer T, Park L, Tribouilloy C, et al: Association between valvular surgery and mortality among patients with infective endocarditis complicated by heart failure, J Am Med Assoc 306:2239–2247, 2011. Li JS, Sexton DJ, Mick N, et al: Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis, Clin Infect Dis 30:633–638, 2000. Mermel LA, Allon M, Bouza E, et al: Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Disease Society of America, Clin Infect Dis 49:1–45, 2009. Morrisette T, Miller MA, Montague BT, et al: Long-acting lipoglycopeptides: “Lineless Antibiotics” for serious infections in persons who use drugs, Open Forum Infect Dis 6(7):ofz274, 2019, Published 2019 Jun 5. Mylonakis E, Calderwood SB: Infective endocarditis in adults, N Engl J Med 345:1318–1330, 2001. Steele JM, Seabury RW, Hale CM, et al: Unsuccessful treatment of methicillinresistant Staphylococcus aureus endocarditis with dalbavancin, J Clin Pharm Ther 43:101–103, 2018. Wilson W, Taubert KA, Gewitz M, et al: Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group, Circulation 116:1736–1754, 2007.

96 Acute Bacterial Skin and Skin Structure Infections Sajeev Handa

DEFINITION Acute bacterial skin and skin structure infections (ABSSSIs) comprise infections of the skin, subcutaneous tissue, fascia, and muscle by a multitude of organisms. The focus of this chapter is on bacterial causes; however, references will be made to select viruses and fungi.

EPIDEMIOLOGY ABSSSIs are among the most common infections found in all age groups. Although the exact incidence is unknown, several factors predispose to development of ABSSSIs: • Epidermal breaks caused by trauma, surgical wounds, human or animal bites, or dry and irritated skin with concomitant tinea infection • Immunosuppressed states caused by malnutrition, diabetes mellitus, or acquired immunodeficiency syndrome (AIDS) • Chronic venous or lymphatic insufficiency

PATHOLOGY Infectious Mechanisms Microbes penetrate the integument after entering through a cut, bite, or hair follicle. Components of the host’s defense system, including oxygen radicals, complement, immunoglobulins, macrophages, lymphocytes, and granulocytes, are recruited to the site of invasion through a vast plexus of dermal capillaries. Bacteria contain proteins whose N-terminal amino acid sequence begins with an N-formyl-methionine group that is chemoattractive to phagocytes, including macrophages and granulocytes. Other microbial cell wall components, such as the zymosan of yeast, endotoxins of gram-negative bacteria, and the peptidoglycans of gram-positive bacteria, activate the alternative complement pathways, producing serum-derived chemotactic factors. Efflux of phagocytes occurs from the capillary through endothelial cell interstices and follows the gradient of chemotactic factors derived from bacteria and serum to the site of active infection. Activated endothelial cells also produce chemotactic cytokines such as interleukin-8 (IL-8). Activated granulocytes synthesize leukotriene B4 from arachidonic acid, a potent chemoattractant for leukocytes. Production of proinflammatory cytokines such as IL-1, IL-6, and tumor necrosis factor augments immune function, inducing fever, priming neutrophils, and increasing antibody production and synthesis of acute phase reactants such as C-reactive protein. Cytokine-driven stimulation of endothelial cells generates nitric oxide and prostaglandins, both of which cause vasodilatation. The net physiologic effect is greater blood flow to the tissue, causing acute inflammation. As described by Celsus (30 bc to 38 ad), acute

inflammation is characterized by rubor (i.e., redness), calor (i.e., increased heat), tumor (i.e., swelling), dolor (i.e., pain), and, as added by Virchow in the 19th century, function laesa (i.e., loss of function). Chapter 88 discusses host defenses against infection in more depth.

Pathologic Manifestations Impetigo is characterized by thick, crusted lesions with rounded or irregular margins that typically occur on the face. Most cases are caused by Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), or by group A streptococci (e.g., Streptococcus pyogenes). Certain strains of streptococci causing impetigo have been implicated in the development of poststreptococcal glomerulonephritis. Folliculitis is a superficial bacterial infection of the hair follicles. Purulent material is found in the epidermis. It manifests as clusters of multiple, small, raised, pruritic, erythematous lesions that are typically less than 5 mm in diameter. Furuncles (i.e., boils) are infections of the hair follicle. Purulent material extends through the dermis into the subcutaneous tissue, where small abscesses may form. A carbuncle is coalescence of several inflamed follicles into a single inflammatory mass. Purulent drainage exudes from multiple follicles. Cellulitis is superficial inflammation of the skin and underlying tissues. It is characterized by erythema, warmth, and tenderness of the involved area (Fig. 96.1). Erysipelas (“red skin”) is a variant of cellulitis that is predominantly caused by toxin-producing S. pyogenes. It manifests as a superficial, spreading, warm, erythematous (fiery red) lesion distinguished by its indurated and elevated margin. Lymphatic involvement and vesicle formation are common. Groups B, C, and D streptococci may also be implicated (Fig. 96.2). Necrotizing fasciitis is a progressive and rapidly spreading inflammatory reaction deep in the fascia associated with secondary necrosis of the subcutaneous tissues. Thrombosis of the dermal vessels is responsible for tissue necrosis. Necrotizing fasciitis may be polymicrobial (type I), involving aerobic microbes (e.g., streptococci, staphylococci, gram-negative bacilli) and anaerobes (e.g., Peptostreptococcus, Bacteroides, Clostridioides spp), or it may be monomicrobial (type II) and caused by S. pyogenes (Fig. 96.3). When involving the scrotum and perineal area, it is known as Fournier gangrene. Pyomyositis is a less serious infection involving the musculature that results from direct inoculation of bacteria. For example, infection can result from injection drug use or from secondary seeding by S. aureus or group A β-hemolytic streptococci from an incidental bacteremia or a hematoma caused by non-penetrating trauma. Ecthyma is an ulcerative pyoderma of the skin that extends into the dermis (unlike impetigo). It is caused by group A streptococci and Pseudomonas species.

903

904

SECTION XV  Infectious Disease

ETIOLOGY AND CLINICAL PRESENTATION Causative Organisms

Fig. 96.1  Ill-defined erythema and edema with bullae formation is characteristic of lower extremity cellulitis. (From Pride HB: Cellulitis and erysipelas. In Zaoutis LB, Chiang VW, editors: Comprehensive pediatric hospital medicine, Philadelphia, 2007, Mosby, Fig. 156-1.)

Fig. 96.2  Sharply defined erythema and edema is characteristic of erysipelas. (From Pride HB: Cellulitis and erysipelas. In Zaoutis LB, Chiang VW, editors: Comprehensive pediatric hospital medicine, Philadelphia, 2007, Mosby, Fig. 156-2.)

A multitude of organisms can cause ABSSSIs. However, three are most common: S. pyogenes, S. aureus, and Streptococcus agalactiae. S. pyogenes (i.e., group A β-hemolytic streptococci) is a gram-positive coccus that may cause erysipelas, streptococcal cellulitis, necrotizing fasciitis, myositis, myonecrosis, and streptococcal toxic shock syndrome. Streptococcal cellulitis arises from infection of wounds, burns, or surgical incisions and may progress to involve large areas. Injection drug users and individuals with impaired lymphatic drainage are at high risk. Systemic manifestations include fever, chills, malaise with or without associated lymphangitis, and bacteremia. In contrast to erysipelas, the affected area is not raised, and the demarcation between involved skin and uninvolved skin is indistinct. The lesions tend to be more pink than fiery red. Streptococcal toxic shock syndrome manifests with hypotension and is associated with acute kidney injury, elevated aminotransferases, rash or soft tissue necrosis, and coagulopathy. It may be complicated by the acute respiratory distress syndrome. Isolation of the organism from a sterile site provides a definite diagnosis. S. aureus is a gram-positive coccus that is found in the anterior nares of up to 30% of healthy people. It is responsible for a variety of invasive and suppurative infections. Localized ABSSSIs include furuncles, carbuncles, bullous and nonbullous impetigo, mastitis, ecthyma, cellulitis, and wound and foreign body infections. Bacteremia may be complicated by septicemia, endocarditis, pericarditis, pneumonia, empyema, osteomyelitis, and abscesses of the soft tissue, muscle, and viscera. Staphylococcal toxic shock syndrome is typically associated with tampon use but may occur after childbirth or surgery and can be associated with cutaneous lesions. It manifests with the acute onset of fever, erythroderma, hypotension, and multisystem involvement (e.g., acute kidney injury, elevated levels of aminotransferases, coagulopathy, nausea, vomiting, diarrhea). Community-associated MRSA is the most common identifiable cause of ABSSSIs in the emergency department. Isolates contain genes encoding for multiple toxins, including cytotoxins that result in leukocyte destruction and tissue necrosis. S. agalactiae (a group B streptococcus) is a gram-positive diplococcus. It may account for up to one third of ABSSSIs among adults. Cellulitis, foot ulcers, and infection of decubitus ulcers are common manifestations. Cellulitis has been associated with foreign bodies such as breast or penile implants. Less commonly, polymyositis, blistering dactylitis, and necrotizing fasciitis may occur.

Other Organisms

Fig. 96.3 Spontaneous necrotizing fasciitis due to Clostridioides septicum. The patient developed sudden onset of severe pain in the forearm. Swelling rapidly ensued, and he sought medical treatment. Crepitus was found on physical examination, and gas in the soft tissue was verified with routine radiographs. Immediate surgical débridement revealed necrotizing fasciitis but sparing of the muscle. Notice the purple-violaceous appearance of the skin. (From Stevens DL, Aldape MJ, Bryant AE. Necrotizing fasciitis, gas gangrene, myositis and myonecrosis. In Cohen J, Powderly WG, Opal SM, editors: Infectious diseases, ed 3, London, 2010, Mosby, Fig. 10-11.)

Aeromonas hydrophila, Aeromonas veronii, and Aeromonas schubertii are gram-negative rods found in salt and fresh water. They may cause mild to severe wound infections after injury, producing cellulitis, myonecrosis, and rhabdomyolysis. Necrotizing fasciitis has been reported with A. veronii and A. schubertii infections. Aeromonas wound infections have also been reported as a result of the medicinal use of leeches. Arcanobacterium haemolyticum is a gram-positive, weakly acidfast bacillus. It has been isolated from soft tissue infections, including chronic ulcers, cellulitis, and paronychia. Bacillus anthracis is a gram-positive bacillus that forms spores. Transdermal inoculation of the spores from even incidental trauma can result in cutaneous anthrax. It manifests initially as a small, pruritic papule that becomes surrounded by painless, nonpurulent vesicles that easily rupture, leaving a black eschar at the base of the ulceration.

CHAPTER 96  Acute Bacterial Skin and Skin Structure Infections

905

Fig. 96.4  Cutaneous anthrax lesion on the skin of the forearm caused by the bacterium Bacillus anthracis. (From Centers for Disease Control and Prevention: Public health image library. Available at http://phil.cdc. gov/Phil/home.asp. Accessed October 31, 2014.)

Fig. 96.5 Tularemic ulcer with eschar formation after percutaneous inoculation of Francisella tularensis. (From Beard CB, Dennis DT: Tularemia. In Cohen J, Powderly WG, Opal SM, editors: Infectious diseases, ed 3, London, 2010, Mosby.)

Uncomplicated disease heals without scar formation in 1 to 3 weeks. Serious cutaneous disease is marked by extensive edema, worsening inflammation, and toxemia (Fig. 96.4). Bartonella henselae is a gram-negative bacillus that causes cat-scratch disease. Between 3 and 10 days after a bite or scratch from a cat or other vector, a tender, erythematous papule appears. Lymphadenopathy ipsilateral to the site of inoculation occurs 1 to 3 weeks later, and the patient typically experiences constitutional symptoms. The lymphadenopathy may take months to resolve. Capnocytophaga canimorsus is a thin, gram-negative bacillus with tapered ends. It is strongly associated with dog (primarily) and cat bites and scratches. Asplenic patients are at particular risk for sepsis due to this organism. Clostridioides perfringens is an anaerobic, large, gram-positive rod. It can cause cellulitis or life-threatening necrotizing infections of skin, muscle, and other soft tissues. The latter is characterized by rapidly progressive tissue destruction, gas in tissues, shock, and death. Conditions such as trauma or illicit drug injection produce anaerobic tissue conditions that favor the organism. The condition can also develop in patients with bowel carcinoma or neutropenia. Gram stain of tissue or exudate reveals large, gram-positive rods and no inflammatory cells. Edwardsiella tarda is a gram-negative rod found in fresh water environments. It is associated with wound infections, abscesses, and bacteremia. The mortality rate is high among patients with liver disease and iron overload. Eikenella corrodens is a gram-negative bacillus that is part of the normal human oral flora. It is an important pathogen in human bite wounds, closed-fist injuries, and infections seen in chronic finger or nail biters. Severe soft tissue infection may occur, leading to septic arthritis and osteomyelitis. Erysipelothrix rhusiopathiae is a gram-positive rod, but it may appear as gram-negative because of rapid decolorization. Its major reservoir is in domestic swine, and infection occurs by direct cutaneous contact through a cut or abrasion. Disease is characterized as erysipeloid (i.e., subacute cellulitis with vesiculation), as a diffuse cutaneous eruption with systemic symptoms, or as bacteremia that is often associated with endocarditis. Francisella tularensis is a gram-negative coccobacillus found in rabbits, hares, hamsters, and rodents. Ulceroglandular tularemia occurs 3 to 5 days after humans are inoculated cutaneously during contact with any of these species. A papule is formed initially, followed by ulceration

with enlargement of the regional lymph nodes. Vesicles may be seen. If left untreated, the ulcer remains for weeks before healing, leaving a residual scar. Suppuration of the affected lymph nodes is the most common complication, occurring despite appropriate treatment (Fig. 96.5). B. anthracis and F. tularensis have been used as agents in bioterrorism. Mycobacterium marinum is an atypical, acid-fast bacillus; it is the most common atypical mycobacterium that causes infection in humans. After inoculation of a skin abrasion or puncture wound in salt or fresh water (nonchlorinated), lesions appear as papules on an extremity. Lesions progress to shallow ulcers and form scars. Typically, lesions are solitary, but they may take on the appearance of ascending, sporotrichoid-like, nodular lymphangitis that may involve the local joint or tendons. Mycobacterium leprae is a slow-growing, acid-fast bacillus that cannot be grown in vitro. It is the cause of leprosy (Hansen disease). It is primarily transmitted by the airborne route and causes chronic disfiguring skin lesions and nerve damage. For a deeper discussion of this topic, please see Chapter 310, “Leprosy (Hansen Disease)” in Goldman-Cecil Medicine, 26th Edition. Pasteurella multocida is a gram-negative coccobacillus that may occur at the site of a scratch or bite from a dog or cat. Cellulitis results within 24 hours of the injury, producing swelling, erythema, tenderness, serous or purulent discharge with or without regional lymphadenopathy, chills, and fever. Pseudomonas aeruginosa is a gram-negative rod and primarily a nosocomial pathogen. In the community, serogroup 0:11 may cause folliculitis related to the use of hot tubs, whirlpools, and swimming pools. Typically, the eruption occurs 48 hours after exposure and consists of tender, pruritic papules, papulopustules, or nodules. It is an important pathogen in burn wound infections, which may progress to sepsis. Vibrio vulnificus is a gram-negative bacillus that is spread by contamination of a superficial wound with warm seawater. It can cause rapidly developing and intense cellulitis, necrotizing fasciitis, and ulcer formation. Aggressive soft tissue infection may occur with necrosis, fever, sepsis, and bullae formation. Ingestion of raw oysters, particularly by immunocompromised patients (e.g., liver cirrhosis, iron overload) may be followed 1 to 3 days later by septicemia associated with necrotizing cutaneous lesions.

Select Fungi and Viruses Cryptococcus neoformans, Candida albicans, Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, and

906

SECTION XV  Infectious Disease

opportunistic fungi can have skin manifestations. Opportunistic fungi, including Aspergillus species, fungi in the order Mucorales, and Fusarium species, can infect the skin of immunocompromised patients. Skin manifestations of fungal infections include papules, nodules, circumscribed erythematous lesions, ulcers, verrucous lesions, and eschars. Sporothrix schenckii is a dimorphic fungus ubiquitous primarily in the tropical parts of North and South America. Cutaneous inoculation from thorny plants (e.g., rose bushes) is followed by development of a painless papule that enlarges slowly to become a nodular lesion with a violaceous hue or ulceration. Secondary lesions may form along the lymphatic drainage distribution. Exposure to herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) at abraded skin sites allows entry into the epidermis and dermis. Infection typically occurs from sexual contact, but it occasionally occurs at extraoral or extragenital sites, such as the hands of health care workers, producing a painful erythema primarily at the junction of the nail bed and skin (i.e., whitlow). This progresses to a vesicopustular lesion that can mimic a bacterial infection (i.e., paronychia). Sexually transmitted diseases are discussed in Chapter 100.

Primary varicella-zoster virus (VZV) infection occurs by the respiratory route but may occur through contact with infected lesions. Viremia results in crops of papules that primarily occur on the trunk and progress to vesicles and then to pustules, followed by crusting. Zoster or shingles represents reactivation of the latent virus in the sensory neurons of the dorsal root ganglion, resulting in pain that proceeds to a rash in the distribution of the affected dermatome in a few days. The appearance of papules and vesicles in a unilateral dermatomal distribution confirms the diagnosis. Ramsay Hunt syndrome occurs when the VZV infection involves the geniculate ganglia and causes a painful eruption in the ear canal and tympanic membrane that is associated with ipsilateral seventh cranial nerve palsy. Vesicles that appear on the tip of the nose (i.e., Hutchinson sign) may be preceded by development of ophthalmic zoster and involvement of the cornea. Immunosuppressed individuals are at higher risk for disseminated disease. Table 96.1 provides a classification for the spectrum of skin involvement by bacteria and fungi.

TABLE 96.1  Classification of Bacterial and Mycotic Infections of the Skin Disease or Disorder Primary Pyodermas Impetigo Folliculitis Furuncles and carbuncles Paronychia Ecthyma Erysipelas Chancriform lesions Membranous ulcers Cellulitis Infectious Gangrene and Gangrenous Cellulitis Streptococcal gangrene and necrotizing fasciitis Progressive bacterial synergistic gangrene Gangrenous balanitis and perineal phlegmon Gas gangrene, crepitant cellulitis Gangrenous cellulitis in immunosuppressed patients Preexisting Skin Lesions With Secondary Bacterial Infections Burns Eczematous dermatitis and exfoliative erythrodermas Chronic ulcers (varicose, decubitus) Dermatophytosis Traumatic lesions (abrasions, animal bites, insect bites) Vesicular or bullous eruptions (varicella, pemphigus) Acne conglobata Hidradenitis suppurativa Intertrigo Pilonidal and sebaceous cysts Pyoderma gangrenosa

Microorganisms Staphylococcus aureus, group A streptococci S. aureus, Candida spp, Pseudomonas aeruginosa (diffuse folliculitis), Malassezia furfur, Pityrosporum ovale S. aureus S. aureus, group A streptococci, Candida, P. aeruginosa Group A streptococci, Pseudomonas spp Group A streptococci Treponema pallidum, Haemophilus ducreyi, Sporothrix, Bacillus anthracis, Francisella tularensis, Mycobacterium ulcerans, Mycobacterium marinum Corynebacterium diphtheriae Group A or other streptococci, S. aureus; rarely, various other organisms Group A streptococci, mixed infections with Enterobacteriaceae and anaerobes Anaerobic streptococci plus a second organism (S. aureus, Proteus spp) Group A streptococci, mixed infections with enteric bacteria (Escherichia coli, Klebsiella spp), anaerobes Clostridioides perfringens and other clostridial species; Bacteroides spp, peptostreptococci, Klebsiella spp, E. coli Pseudomonas, Aspergillus spp, agents of mucormycosis P. aeruginosa, Enterobacter spp, various other gram-negative bacilli, various streptococci, S. aureus, Candida spp, Aspergillus spp S. aureus, group A streptococci S. aureus, streptococci, coliform bacteria, P. aeruginosa, peptostreptococci, enterococci, Bacteroides spp., C. perfringens S. aureus, group A streptococci Pasteurella multocida, C. diphtheriae, S. aureus, group A streptococci S. aureus, group A streptococci Cutibacterium (formerly Propionibacterium) acnes S. aureus, Proteus spp. and other coliforms, streptococci, peptostreptococci, P. aeruginosa, Bacteroides spp. S. aureus, coliforms, Candida spp Peptostreptococci, Bacteroides sp, coliforms, S. aureus S. aureus, peptostreptococci, Proteus spp and other coliforms, P. aeruginosa

CHAPTER 96  Acute Bacterial Skin and Skin Structure Infections

907

TABLE 96.1  Classification of Bacterial and Mycotic Infections of the Skin—cont’d Disease or Disorder

Microorganisms

Cutaneous Involvement in Systemic Infections Bacteremias

Infective endocarditis Fungemias Listeriosis Leptospirosis (Weil disease and pretibial fever) Rat-bite fever Melioidosis Glanders Carrión’s disease (verruga peruana)

S. aureus, group A streptococci (and other groups such as D), Neisseria meningitidis, Neisseria gonorrhoeae, P. aeruginosa, Salmonella typhi, Haemophilus influenzae Viridans streptococci, S. aureus, group D streptococci, and others Candida spp, Cryptococcus spp, Blastomyces dermatitidis, Fusarium Listeria monocytogenes Leptospira interrogans serotypes Streptobacillus moniliformis, Spirillum minus Burkholderia pseudomallei Burkholderia mallei Bartonella bacilliformis

Scarlet Fever Syndromes Scarlet fever Scalded skin syndrome Toxic shock syndrome

Group A streptococci, rarely S. aureus S. aureus (phage group II) Group A streptococci, S. aureus (pyrogenic toxin–producing strains)

Parainfectious and Postinfectious Nonsuppurative Complications Purpura fulminans (manifestation of disseminated intravascular coagulation) Group A streptococci, N. meningitidis, S. aureus, pneumococcus Erythema nodosum Group A streptococci, Mycobacterium tuberculosis, Mycobacterium leprae, Coccidioides immitis, Leptospira autumnalis, Yersinia enterocolitica, Legionella pneumophila Erythema multiforme–like lesions (rarely), guttate psoriasis Group A streptococci Other Lesions Erythrasma Nodular lesions

Corynebacterium minutissimum Candida, Sporothrix, S. aureus (botryomycosis), M. marinum, Leishmania brasiliensis; leprosy due to M. leprae can cause popular lesions, nodular, and ulcerative lesions Hyperplastic (pseudoepitheliomatous) and proliferative lesions (e.g., mycetomas) Nocardia spp, Scedosporium apiospermum (formerly Pseudallescheria boydii), Blastomyces dermatitidis, Paracoccidioides brasiliensis, Phialophora, Cladosporium Vascular papules/nodules (bacillary angiomatosis, epithelioid angiomatosis) Bartonella henselae, Bartonella quintana Annular erythema (erythema chronicum migrans) Borrelia burgdorferi Modified from Mandell GL, Bennett JE, Dolin R, editors: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 9, Philadelphia, 2020, Elsevier.

DIAGNOSIS A thorough medical history is critical; it should assess the specific risk factors, such as travel history, animal contacts, marine exposures, occupational and avocational hazards (e.g., farming, gardening), and immune status. If an animal bite has occurred, the timing of the bite, circumstances of injury, and health status of the animal should be determined. Human bites are classified as self-inflicted, occlusal (i.e., intentional), or closed-fist injuries. In addition to wound assessment, evaluation for other transmissible pathogens, including human immunodeficiency virus (HIV), HSV, Treponema pallidum (the etiologic agent of syphilis), and hepatitis B and C viruses, should be pursued. A thorough clinical examination should follow. Initial antimicrobial management, if indicated, is directed by the history and physical examination findings. Evaluation of hospitalized patients should include a complete blood count and a basic metabolic panel. The C-reactive protein level may be useful as a marker for inflammation and guidance

for treatment. The creatine phosphokinase concentration may be helpful, but it is not specific for cases of compartment syndrome and necrotizing fasciitis involving the musculature. Cultures are not indicated for uncomplicated common forms of ABSSSIs managed in the outpatient setting. The benefit of blood cultures for cellulitis in hospitalized patients is uncertain because the yield is low. Cultures are indicated for patients who require incision and drainage because of the risk of deep structure and underlying tissue involvement. The most sensitive and specific test for the diagnosis of HSV and VZV cutaneous lesions is nucleic acid amplification. A sample is scraped from the base of an active dermal lesion with a swab. Direct fluorescent antibody testing is less sensitive. Incision and drainage of these lesions is contraindicated.

Special Diagnostic Considerations Animal Bites

Blood cultures, tissue biopsy, and aspirates for culture of aerobic or anaerobic organisms are preferred methods in cases of animal bites.

908

SECTION XV  Infectious Disease • R  uptured Baker cyst • Mixed cryoglobulinemia due to immune complex disease from chronic hepatitis C or B infection (may have an erythematous rash) • Pyoderma gangrenosum • Sweet syndrome (acute febrile neutrophilic dermatosis) • Venous stasis

TREATMENT Pharmacologic and Supportive Care Fig. 96.6  Radiograph of patient with clostridial myonecrosis shows gas in the tissues. (Courtesy J.W. Tomford, MD.)

Human Bites Wounds swabs may produce misleading information in cases of human bites. A Gram stain should be performed to assess organisms, neutrophils (i.e., inflammation), and squamous epithelial cells (i.e., superficial contamination). If feasible, tissue biopsy or aspiration of the infected site can provide specimens for aerobic and anaerobic culture.

Traumatic Wounds The optimal time to acquire specimens for cultures is immediately after débridement of the wound site and not within the first 48 hours post-trauma. Analysis of initial cultures should focus on common pathogens, and additional testing should be reserved for uncommon or rare infections associated with unusual circumstances, such as Vibrio species after salt water exposure. Tissue biopsy and special stains may be required in certain situations, such as suspected infection with M. marinum.

Burn Wounds Before sampling, the burn area must be clean and devoid of topical antimicrobial agents. Sampling of the burn wound by either surface swab or tissue biopsy for culture is recommended for monitoring the presence and extent of infection. Quantitative evaluation of swab or culture specimens is recommended twice weekly to monitor colonization. Evidence of systemic infection related to the wound should prompt blood cultures.

Diabetic Foot Infections Superficial swab cultures of ulcerations can be misleading and should be avoided. If surgical débridement is performed, deep tissue specimens should be sent to the microbiology laboratory for evaluation. Radiographs should be obtained if bone involvement is suspected, and they may also be useful in demonstrating soft tissue gas before crepitus is detected (Fig. 96.6). Magnetic resonance imaging is the most sensitive modality. Chapter 89 discusses the laboratory diagnosis of infectious diseases in more detail.

Differential Diagnosis Many noninfectious conditions can mimic SSTIs: • Brown recluse spider bite • Contact dermatitis • Gout • Psoriatic arthritis with distal dactylitis • Reactive arthritis • Relapsing polychondritis

Mild cases of cellulitis may be managed on an outpatient basis with penicillin VK, amoxicillin, or if the patient has a history of a penicillin skin rash and nothing to suggest an IgE-mediated reaction, cephalexin. If clinically unclear whether the infection is due to S. pyogenes or S. aureus, get cultures and start empiric therapy with amoxicillin or penicillin VK or cephalexin and trimethoprim-sulfamethoxazole (TMP-SMX). Azithromycin, linezolid, tedizolid or delafloxacin may be used in patients with a past history of IgE-mediated allergic reaction to β-lactam antibiotics. Severe cellulitis should be managed with parenteral penicillin, cefazolin or ceftriaxone. Vancomycin may be used in patients with allergies to penicillin. Concomitant tinea infection should be treated with a topical antifungal agent such as clotrimazole or terbinafine. For suspected methicillin-susceptible S. aureus (MSSA) (fluctuance or positive Gram stain) dicloxacillin may be used as an outpatient, nafcillin or oxacillin as an inpatient. For MRSA, doxycycline or TMPSMX may be used as an outpatient, vancomycin as an inpatient. Other inpatient options include daptomycin, telavancin, ceftaroline, clindamycin (watch for inducible resistance), or linezolid. Dalbavancin and oritavancin may be used as alternatives in ABSSSIs for those who are moderately ill and who refuse hospitalization. Note that neither doxycycline nor TMP-SMX provides adequate streptococcal coverage. A β-lactam antibiotic may be considered for hospitalized patients with nonpurulent cellulitis, with modification to MRSA-active treatment if there is no clinical response. Cellulitis associated with an abscess requires surgical drainage. In addition to supportive care, urgent surgical consultation should be obtained in the event that crepitus, bullae, rapidly evolving cellulitis, or pain disproportional to physical examination findings suggests necrotizing fasciitis. Initial parenteral therapy with vancomycin, daptomycin, or linezolid combined with piperacillin-tazobactam or a carbapenem (either meropenem or ertapenem) is appropriate. Type II necrotizing fasciitis due to S. pyogenes or clostridial myonecrosis should prompt combined therapy with parenteral penicillin and clindamycin. Clindamycin by virtue of its mechanism of action suppresses streptococcal toxin and cytokine production. The use of intravenous immune globulin in cases of necrotizing fasciitis remains controversial. Compartment syndrome requires emergent surgical decompression to prevent muscle necrosis and irreversible neuronal damage.

Special Treatment Considerations Animal Bites

Mild cases of animal bites (dog or cat) may be treated with amoxicillin-clavulanate. Inpatient parenteral agents including ampicillin-sulbactam or piperacillin-tazobactam may be used for those who require hospitalization. For patients with a penicillin allergy, a fluoroquinolone plus clindamycin may be used in dog bites, doxycycline in cat bites. As with all animal bites, rabies postexposure prophylaxis and vaccination should be considered.

CHAPTER 96  Acute Bacterial Skin and Skin Structure Infections

Human Bites Patients who have human bite wounds without evidence of infection should receive prophylactic treatment with amoxicillin-clavulanate for 3 to 5 days. Closed-fist injuries require radiographic evaluation and consultation with a hand surgeon for possible wound exploration. Parenteral treatment with ampicillin-sulbactam or moxifloxacin is recommended.

Burn Wounds Systemic therapy with antibiotics and antifungals is reserved for burn patients demonstrating signs of sepsis or septic shock. Infection due to mucormycoses requires liposomal amphotericin B.

Diabetic Foot Infections Simple infections such as cellulitis are most often caused by group A streptococci or S. aureus and should be managed accordingly. If ulcers do not have purulence or inflammation, antimicrobials are not indicated. Severe limb-threatening infections require surgical evaluation and broad-spectrum antibiotic coverage because infection tends to include aerobic and anaerobic organisms. Empirical therapy directed at P. aeruginosa is not usually necessary unless the patient has other risk factors. MRSA-active treatment is recommended for patients with a history of MRSA, when the local prevalence of MRSA is high in the community, or if the infection is severe. All wounds require adequate wound irrigation and débridement.

Marine Lacerations and Punctures The treatment regimen for marine lacerations and punctures should include doxycycline and ceftazidime or a fluoroquinolone to provide adequate coverage for V. vulnificus. Treatment of fresh water injuries should also include a third- or fourth-generation cephalosporin (i.e., ceftazidime or cefepime) or a fluoroquinolone. If M. marinum is suspected, treatment with clarithromycin, minocycline, doxycycline, sulfamethoxazole-trimethoprim, or rifampin plus ethambutol is appropriate. Aeromonas wound infections may be treated with either ciprofloxacin or levofloxacin.

Others Cellulitis or wound infections attributed to A. hemolyticum may be treated with clindamycin, erythromycin, vancomycin, or tetracycline. Animal handlers with cutaneous anthrax infection (naturally acquired) require treatment with amoxicillin or penicillin. Cases of suspected bioterrorism, however, must be treated with ciprofloxacin or levofloxacin and must be reported immediately.

909

Tularemia is treated with streptomycin or gentamicin/tobramycin. Mild cases may be treated with ciprofloxacin or doxycycline. Azithromycin is the drug of choice for cat-scratch disease. For individuals at risk for E. rhusiopathiae infection, the treatment of choice is penicillin or amoxicillin for localized skin infection and parenteral penicillin or ceftriaxone for widespread skin infection. Lymphocutaneous/cutaneous sporotrichosis (S. schenkii) may be treated with itraconazole. HSV and VZV infections are susceptible to acyclovir, famciclovir, or valacyclovir if treatment is indicated.

PROGNOSIS Full recovery is expected for patients with simple ABSSSIs provided they receive appropriate treatment. For those who develop complications such as necrotizing fasciitis, the estimated mortality rate is between 30% and 70%. The prognosis is guarded for patients with multiple comorbidities and those who are immunosuppressed.

SUGGESTED READINGS Cohen J, Powderly WG, Opal SM, editors: Infectious diseases, ed 3, London, 2010, Mosby. Golstein EJ: Bite wounds and infectious, Clin Infect Dis 14:633–640, 1992. Herchline T: Cellulitis treatment and management. Available at http:// emedicine.medscape.com/article/214222-overview. Accessed October 31, 2014. Lipsky BA, Berendt AR, Cornia PB, et al: Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections, Clin Infect Dis 54:132–173, 2012, 2012. Liu C, Bayer A, Cosgrove SE, et al: Clinical practice guidelines by the Infectious Diseases Society of America for the treatment if methicillinresistant Staphylococcus aureus infectious in adults and children, Clin Infect Dis 52:e18–e55, 2011. Miller JM, Binnicker MJ, et al: A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2018 update by the Infectious Diseases Society of America (IDSA) and the American Society of Microbiology (ASM). Available at http://www.idsociety.org/practiceguideline/laboratory-diagnosis-of-infectious-diseases/. Spelman D: Cellulitis and skin abscess: clinical manifestations and diagnosis. UpToDate. Available at http://www.uptodate.com/contents/cellulitis-andskin-abscess-clinical-manifestations-and diagnosis. Accessed September 16, 2019. Stevens DL, Bisno AL, Chambers HF, et al: Practice guidelines for the diagnosis and management of skin and soft-tissue infections, Clin Infect Dis 59(2):e10–e52, 2014.

97 Intraabdominal Infections Eric Benoit

Intraabdominal infections are common in hospitalized patients, both as a primary indication for admission and as a complication. Although antibiotics play a central role in treatment, many of these patients require source control and warrant surgical consultation to manage complications such as perforation and peritonitis. Intraabdominal infections are usually polymicrobial and are caused by components of bowel flora most commonly including aerobic Escherichia coli and other Enterobacteriaceae and anaerobic Bacteroides fragilis and streptococci.

may progress from localized to diffuse peritonitis. Patients with peritonitis are tachycardic, tachypneic, and acutely uncomfortable. They avoid movement, and merely jostling the bed exacerbates the pain. The patient’s abdomen may be rigid due to involuntary tightening of the muscles of the abdominal wall (guarding). The onset of peritonitis is ominous as it may herald the progression to sepsis and septic shock. These cases mandate emergent surgical consultation prior to imaging and almost always require operative exploration. Elderly patients or those with diabetes or on steroids may have a blunted response to peritonitis, and they should therefore be approached with a high degree of suspicion regarding complications of intraabdominal infections.

SOURCE CONTROL AND TIMING OF ANTIBIOTICS

APPENDICITIS

Early administration of broad-spectrum antibiotics has become standard of care in patients with suspected infection. Mortality increases with every hour delay to antibiotic therapy in septic patients. However, antibiotics alone are not sufficient for most intraabdominal infections, which require an intervention to control the source of infection. Purulence must be drained. This may be surgical removal of the infected tissue as in appendectomy, percutaneous drainage of an abscess by interventional radiology, or endoscopic retrograde cholangiopancreatography (ERCP) to remove obstructing stones in cases of cholangitis. Appropriate source control has been shown to be as important to outcomes as early antibiotics. The Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial demonstrated that most intraabdominal infections may be treated for 4 days after achieving source control, and this is true even for complicated intraabdominal infections. Furthermore, prolonged antibiotic administration in the setting of intraabdominal infection has been shown to increase the risk of further infections including bacteremia and Clostridioides difficile infections as well as increase the rate of in-hospital mortality. Source control and limited duration of antibiotic therapy, therefore, are critical considerations in management of intraabdominal infections.

When the lumen of the appendix is occluded either by a lymphatic tissue or a fecalith, mucosal fluid secretion and bacterial overgrowth cause an increase in pressure within the appendix. This eventually leads to venous outflow obstruction and further increases in pressure until arterial inflow is compromised, and the resulting ischemia leads to perforation. The classic presentation is periumbilical pain that migrates to the right lower quadrant, frequently associated with anorexia and nausea. Patients in whom the appendix has perforated often describe a sudden relief of localized pain followed several hours later by the onset of diffuse peritonitis. Leukocytosis, if present, is often not severe. CT scan of the abdomen has become the diagnostic tool of choice with both sensitivity and specificity over 90% for detection of acute appendicitis. Findings of dilated appendix, fecalith, and stranding of the fat around the appendix are suggestive of acute appendicitis. CT scan may also detect a phlegmon (inflamed infected tissue) or abscess associated with perforated appendicitis (Fig. 97.1). Ultrasound may be useful in children, and MRI is an alternative imaging modality in pregnant women. Clinical diagnosis of appendicitis can be challenging, but the prevalence of CT scanning has markedly decreased the negative appendectomy rate. Management of appendicitis is appendectomy, most often performed laparoscopically. Although there is active research into antibiotic therapy alone for appendicitis, this is not standard of care. Those patients who do not undergo appendectomy at initial presentation are often brought back for an interval appendectomy 6 to 8 weeks later. More advanced appendicitis may present with a phlegmon. These patients may be treated with antibiotics until an abscess develops, at which time drainage by interventional radiology is appropriate. Patients who develop signs of physiologic compromise (tachycardia, tachypnea, peritonitis) should instead proceed urgently to the operating room. Patients with perforated appendicitis may require more extensive surgery (e.g., ileo-cecectomy) and have a higher risk of intraabdominal abscess. Appendicitis is a polymicrobial infection with colonic bacteria E. coli and Bacteroides species being common. Antibiotics should be

INTRODUCTION

PERITONITIS Peritonitis is a disseminated infection of the peritoneal cavity and typically presents with diffuse, rather than localized, tenderness. Primary peritonitis is most often seen in patients with ascites from cirrhosis. It may be managed with antibiotics alone and after therapy may require suppressive antibiotics. Diagnosis is made by sampling peritoneal fluid; the diagnosis is likely if the number of neutrophils is greater than 250/microliter. Cultures may be negative. Secondary peritonitis is due to an inciting event, such as hollow viscus perforation, ischemia, or a localized abscess that has spread, and is more common than primary peritonitis. Any intraabdominal infection

910

CHAPTER 97  Intraabdominal Infections

A

911

B Fig. 97.1  CT scan may detect (A) a phlegmon (inflamed infected tissue) or (B) an abscess associated with perforated appendicitis.

administered until time of operation and may be stopped thereafter in uncomplicated cases. Perforated appendicitis should be treated with antibiotics for 4 days after surgery. Uncomplicated appendicitis has a mortality rate less than 1%, but perforation, particularly in pediatric or elderly patients, increases the risk significantly. Other complications after appendicitis include intraabdominal abscess and wound infection.

DIVERTICULITIS Diverticula are herniations of the colonic mucosa through naturally occurring openings in the taenia coli through which vessels run (Fig. 97.2). They are most commonly found in the sigmoid colon but may also be present in the right colon. The presence of diverticula (diverticulosis) increases with age, and diet influences their development. Low dietary fiber present in the Western diet contributes to rates of diverticulosis as high as 50% in Americans over the age of 80. Dietary fiber is thought to protect against the development of diverticulosis as demonstrated by lower rates of disease in countries in Asia and Africa. While right-sided diverticular disease is prone to bleeding, sigmoid diverticulosis risks development of diverticulitis, the infection of diverticula. Approximately 10% to 25% of patients with diverticula will develop diverticulosis in their lifetime. The pathophysiology of diverticulitis is similar to appendicitis: occlusion of a diverticulum results in bacterial overgrowth, vascular compromise, ischemia, and perforation. Diverticulitis can present with varying degrees of severity that are enumerated by the Hinchey classification (Table 97.1). Local infection and inflammation may be self-limited or managed by outpatient antibiotics. More severe cases result in microperforation of diverticula with contained air or abscess within the bowel wall. Complicated diverticulitis results in a distant abscess in the abdomen, pelvis, or retroperitoneum. The most severe cases present with free intraabdominal air and purulent or feculent peritonitis. Patients with diverticulitis most often present with left lower quadrant pain and tenderness. More severe cases may develop fever and leukocytosis whereas the most critical cases have frank peritonitis and physiologic compromise such as acidosis, acute kidney injury, and hypotension. Imaging with IV contrast CT scan is standard of care, both to diagnose the presence and severity of diverticulitis and to identify complications such as abscess. However, patients with peritonitis due to suspected diverticulitis should not undergo CT imaging but instead belong in the operating room. An upright chest radiograph may demonstrate free air under the diaphragm in cases of perforation.

Simple diverticulitis may be managed with outpatient antibiotics. More severe cases require admission for intravenous antibiotics, bowel rest, and IV hydration. As the pain and tenderness resolve, the diet may be advanced. Complicated diverticulitis with uncontained abscess requires source control, and these patients should be evaluated for drainage by interventional radiology or laparoscopic drainage by surgery. Patients with free perforation require urgent surgery for control of contamination and resection of perforated bowel. The most common procedure is sigmoid resection with colostomy, although there is increasing evidence to support primary anastomosis with or without a diverting loop ileostomy. Delayed complications of diverticulitis include abscess, colonic stricture, and fistulae (colovesical, colovaginal or coloenteric). Patients should undergo colonoscopy 6 to 8 weeks after diverticulitis to assess for colorectal cancer. Diverticulitis may recur in up to 20% of patients over 10 years. Although recurrence does make patients more prone to future episodes, the risk of complications such as free perforation does not increase with recurrence. Recurrent diverticulitis does not mandate surgery, but for those patients who wish to avoid future episodes elective sigmoid resection removes the burden of left-sided diverticulosis, effectively eliminating the source of disease. Regardless of treatment plan, patients should be encouraged to pursue a high-fiber diet. Former teaching suggested eliminating such foods as seeds and nuts, but this has not been shown to influence the recurrence of diverticulitis. Like appendicitis, diverticulitis is a polymicrobial infection with colonic flora such as E. coli and bacteroides predominating. Accordingly, broad-spectrum antibiotics such as piperacillin/tazobactam are appropriate, and the duration of therapy is 7 to 10 days. Patients who have resolution of pain while on IV antibiotics may be transitioned to oral agents (such as amoxicillin/clavunate) and complete their course as outpatients.

INFECTIOUS BOWEL DISEASE Infectious Colitis Infectious colitis is an infection of the bowel that may be caused by bacteria (E. coli, Campylobacter, Shigella), viruses (norovirus, rotavirus, cytomegalovirus) or parasites (Entamoeba histolytica) (see Chapter 98). These patients present with abdominal pain that is frequently crampy in nature and diarrhea. In older patients particularly, infectious colitis may be difficult to distinguish from ischemic colitis. CT scan with IV contrast demonstrates inflammation of the bowel wall, in contrast to the lack of enhancement seen in ischemic disease. The presence of free fluid is ominous. For many patients with infectious colitis either symptomatic relief or a course of antibiotics directed at potential bacterial

912

SECTION XV  Infectious Disease

Peritoneum Circular muscle Taenia coli Epiploic appendix

Diverticulum

Mucosa

Concentration in diverticulum Blood vessel piercing musculature

Relationship of diverticula to blood vessels and taeniae (schematic)

Fig. 97.2  Diverticulosis. (From the Netter Collection of Medical Illustrations. Available at www.netterimages. com. Accessed October 31, 2014.)

pathogens may be sufficient. Stool samples may aid in diagnosis and treatment of different pathogens. Regardless of etiology these patients require frequent abdominal exams, and in rare cases, should they progress to worsening pain, fever, tachycardia, hypotension or peritonitis, they belong in the operating room for colectomy.

Cytomegalovirus Colitis Cytomegalovirus is a common, self-limited viral infection, but it may cause colitis in immunocompromised patients, such as transplant patients, those who undergo frequent steroid therapy for ulcerative

colitis or as a complication of acquired immunodeficiency syndrome (AIDS). Diagnosis of CMV colitis requires a high degree of suspicion in the correct clinical context. Colonoscopy may demonstrate ulcerated lesions and CMV immunohistochemistry on biopsy specimens. Antimicrobial therapy is with an antiretroviral agent such as ganciclovir. Surgery is reserved for complications such as perforation.

Clostridioides difficile Colitis Clostridioides difficile colitis is most often a complication of antibiotic therapy. It occurs when healthy intraluminal bacteria are depleted,

CHAPTER 97  Intraabdominal Infections

TABLE 97.1  Hinchey Classification of

Diverticulitis Class

Description

Treatment

0 Ia

Mild clinical diverticulitis Contained pericolic inflammation or phlegmon Contained pericolic abscess Pelvic, distant intraabdominal or retroperitoneal abscess Purulent peritonitis Feculent peritonitis

Oral antibiotics IV antibiotics, bowel rest

Ib II III IV

IV antibiotics, bowel rest Percutaneous drainage, IV antibiotics Operative drainage/resection Operative drainage/resection

allowing pathogenic species to predominate. Agents such as cephalosporins, fluoroquinolones, and clindamycin are commonly implicated, but any antibiotic in the preceding several months—even a single dose—increases the risk of C. difficile colitis. Hospitalized patients are at greater risk due to exposure, although community strains of C. difficile have been identified. Patients most often present with frequent diarrhea as well as abdominal pain. The disease is associated with leukocytosis sometimes as high as 30,000 to 40,000. Diagnosis is ideally sought in those with greater than or equal to three unformed stools in 24 hours. The diagnosis is confirmed by stool studies with PCR for toxin. Infectious Disease Society Guidelines recommend oral vancomycin or fidaxomicin for 10 days for an initial episode of C. difficile colitis. Metronidazole is an alternative if vancomycin or fidaxomicin are not available. Fulminant cases may be treated with oral vancomycin and, if ileus is present, vancomycin enema. Intravenous metronidazole should also be given. First recurrent infection should be treated with oral vancomycin as a tapered and pulsed regimen or a course of fidaxomicin. Fecal microbiota transplant, which aims to repopulate the gut with healthy bacteria, should be considered investigational; while studies have demonstrated utility in patients with recurrent or refractory disease, it carries the risk of disease transmission. Patients with C. difficile colitis remain at high risk of bowel perforation as well as progression to toxic megacolon. Those patients with signs of unremitting inflammation, such as fevers, tachycardia, and tenderness despite antibiotic therapy should be considered for surgery. Patients who progress to perforation often present in shock with hypotension and altered mental state. These patients have a high mortality, and surgery mandates subtotal colectomy, often with vancomycin enemas to the rectal stump.

BILIARY INFECTIONS Cholecystitis The gallbladder, like the appendix, is an anatomic cul-de-sac, and the narrow neck of the cystic duct is prone to occlusion by gallstones or edema, preventing drainage of bile and leading to bacterial overgrowth. The undrained, infected fluid present in cholecystitis leads to an increase in pressure that may progress to ischemia of the gallbladder wall, gangrene, and perforation. Cholecystitis may be distinguished from biliary colic by its duration; biliary colic typically resolves spontaneously and patients are able to eat. Cholecystitis, on the other hand, is marked by prolonged pain and tenderness and is frequently associated with leukocytosis. Patients report right-sided or epigastric pain, often associated with a recent meal. On examination, tenderness is usually localized to the right upper quadrant. However, in cases of gallbladder perforation, infected

913

bile may flow down the right paracolic gutter, leading to right-sided abdominal or even pelvic tenderness. The classic finding of Murphy’s sign is the abrupt cessation of inspiration when palpating the right upper quadrant; the excursion of the diaphragm during inspiration displaces the gallbladder inferiorly to the examiner’s hand, resulting in sudden, exquisite pain that interrupts the patient’s breathing. Right upper quadrant ultrasound is the imaging modality of choice in which gallbladder wall thickening, a distended, fluid-filled gallbladder, and pericholecystic fluid are findings consistent with acute cholecystitis. Occasionally the ultrasound will demonstrate air within the gallbladder wall; emphysematous cholecystitis carries a high mortality and these patients warrant urgent surgery. Although CT scan is sensitive and specific for diagnosis of cholecystitis, it exposes patients to radiation and may miss non-cholesterol stones. Laboratory values include leukocytosis and elevated total bilirubin from the blockage of bile drainage. Treatment of acute cholecystitis is cholecystectomy, most often performed laparoscopically. In patients who are too sick to tolerate operation, percutaneous drainage with a cholecystostomy tube is appropriate to decompress the infected gallbladder. Some of these patients will recover sufficiently to undergo surgery 6 weeks later. Other patients, particularly those who are elderly and frail, may require prolonged cholecystotomy tube drainage.

Acalculous Cholecystitis Acalculous cholecystitis occurs in critically ill patients, particularly those who have not been receiving enteral nutrition. Diagnosis requires a high index of suspicion, especially in intubated patients. Patients with unexplained fever or leukocytosis without an obvious source should undergo a right upper quadrant ultrasound, which demonstrates a distended gallbladder with a thickened wall. These patients are frequently too sick to tolerate surgical cholecystectomy and instead are referred to interventional radiology for a cholecystostomy tube to decompress the infected bile. Tube drainage is often continued until the patient recovers sufficiently to tolerate cholecystectomy, although for some chronically debilitated patients tube drainage may suffice.

Cholangitis Cholangitis is an infection due to the blockage of the bile ducts, most commonly from gallstones. These patients present with right upper quadrant or epigastric pain. The classic findings are right upper quadrant pain, fever and jaundice (Charcot’s triad) that may progress to include altered mental status and shock (Reynold pentad). These patients have infected bile or pus within the biliary tree, and this is best drained by ERCP with sphincterotomy and stenting. Ascending cholangitis can be an aggressive infection, with patients rapidly progressing to septic shock. Antibiotics alone are not sufficient and source control is mandated. Suspicion of cholangitis should prompt urgent consultation with a gastroenterologist and a surgeon, and these patients often require fluid resuscitation and admission to a critical care unit. Right upper quadrant ultrasound in cases of cholangitis may demonstrate cholelithiasis without findings of cholecystitis, but a dilated common bile duct as evidence of a stone that has passed out of the gallbladder. Important laboratory values include hyperbilirubinemia, leukocytosis, and an elevated alkaline phosphatase as evidence of bile duct irritation. Patients who undergo ERCP with sphincterotomy may have pneumobilia on subsequent imaging; this is due to retrograde passage of air from the duodenum into the biliary tree and may not indicate infection. Bacteria associated with biliary infections include E. coli, Klebsiella, and Pseudomonas but may also include Enterobacter and Bacteroides. Biliary cultures are rarely used to guide therapy and therefore

914

SECTION XV  Infectious Disease

antimicrobial therapy uses broad-spectrum agents such as piperacillin/tazobactam. For patients with uncomplicated acute cholecystitis, antibiotics may be stopped after surgery. For those too sick to undergo surgery, antibiotics are continued for 7 to 10 days, depending on clinical improvement. Patients with cholangitis require broad-spectrum antibiotics and source control in addition to fluid resuscitation.

PANCREATITIS AND PANCREATIC INFECTION Pancreatitis is usually a self-limited inflammation of the pancreas. A small percentage progress to pancreatic necrosis, which is a risk factor for infected pancreatitis. Percutaneous aspiration of pancreatic fluid collections is not advised due to the risk of seeding sterile collections. The question of prophylactic antibiotics in cases of pancreatic necrosis has been actively debated for decades. In the interest of limiting antibiotic exposure and selecting resistant organisms, we defer antibiotics until there is evidence of infected pancreatic necrosis such as air within the fluid collections. Antibiotic therapy consists of a carba­ penem and the duration is dictated by clinical improvement. Patients with infected pancreatic necrosis may undergo percutaneous drainage, but the infected material is often too thick to allow drainage. However, drain placement may be preliminary to creating a tract for videoscopic-assisted retroperitoneal dissection (VARDS) of the necrotic pancreas. Patients with unremitting signs of infection and inflammation may require surgery for drain placement and lavage.

INTRAABDOMINAL ABSCESS Solid Organ Abscesses Solid organ abscesses may form in the liver, spleen, and less commonly, the kidneys. The most common causes of hepatic abscess in the United States are biliary tract infection and portal vein bacteremia from diverticulitis, appendicitis or inflammatory bowel disease. Colonic bacteria predominate, including Klebsiella pneumoniae as well as anaerobes such as Bacteroides spp, Fusobacterium, and streptococcal species. Hepatic abscesses present with fevers as well as right upper quadrant pain. Laboratory data may show leukocytosis and an elevated alkaline phosphatase. CT scan is the imaging modality of choice for solid organ abscesses. Hepatic abscesses may be multifocal. Multiple, small abscesses are best treated with antibiotics whereas large, persistent abscesses may require percutaneous drainage. An important but less common cause of liver abscess is due to Entamoeba histolytica found frequently in patients from developing countries (see Chapter 105). Splenic abscesses are seen in patients with infected endocarditis resulting from septic emboli or those who have undergone splenic artery embolization. The resulting ischemia and necrosis of splenic parenchyma serves as a nidus of infection. The presence of a splenic abscess should prompt a search for the source, including an echocardiogram. Patients may be treated with antibiotics and percutaneous drainage. Splenic abscesses may prove difficult to eradicate, in which case splenectomy is an option. Renal abscesses may occur with recurrent pyelonephritis, particularly in the setting of urinary tract obstruction such as staghorn renal calculi. Source control may require percutaneous nephrostomy tubes to drain infected urine that cannot drain distally, and nephrectomy is indicated in cases of recurrent, fistulizing disease.

Intraabdominal and Intrapelvic Intraabdominal and intrapelvic abscesses may form as a result of other infections, such as perforated appendicitis or diverticulitis, or after surgery for perforation of the alimentary tract. The omentum may

form adhesions around the site of infection, walling it off from the remainder of the peritoneal cavity and allowing an abscess to form. This appears as a rim-enhancing fluid collection on CT scan (with IV contrast). Small abscesses (≈2 cm) in an otherwise healthy patient with a functional immune system may be treated with antibiotics alone. Larger abscesses, however, may require drainage because antibiotics may not penetrate the infected area. Source control may be accomplished with percutaneous drainage, although this warrants a conversation with the interventional radiologist as the location may preclude safe drainage due to surrounding structures. Operative source control may be accomplished by laparoscopic washout and drain placement, although this carries the risk of bowel injury due to the friable nature of the inflamed bowel. Small bowel often forms the wall of deep abscesses and surgical source control often requires bowel resection in these cases.

CONCLUSIONS Although early administration of broad-spectrum antibiotics remains a mainstay of treatment of intraabdominal infections, source control and early identification of complications such as peritonitis from free perforation or disseminated infection are critical concepts for the clinician to understand. CT scan with intravenous contrast is the imaging modality of choice for most intraabdominal infections. Elderly patients, those with diabetes, those taking steroids, or immunocompromised patients may not mount the same exuberant response of peritonitis, and therefore they must be approached with a high degree of suspicion regarding complications.

SUGGESTED READINGS Ahmed M: Acute cholangitis—an update, World J Gastrointest Pathophysiol 9(1):1–7, 2018. Broad JB, Wu Z, Ng J, et al: Diverticular disease management in primary care: how do estimates from community-dispensed antibiotics inform provision of care? PloS One 14(7):e0219818, 2019. Eid AI, Mueller P, Thabet A, Castillo CF, Fagenholz P: A step-up approach to infected abdominal fluid collections: not just for pancreatitis, Surg Infect (Larchmt) 21(1):54–61, 2020. Kumar A, Roberts D, Wood KE, et al: Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock, Crit Care Med 34(6):1589–1596, 2006. Kumar V, Fischer M: Expert opinion on fecal microbiota transplantation for the treatment of clostridioides difficile infection and beyond, Expert Opin Biol Ther 20(1):73–81, 2020. Maconi G, Barbara G, Bosetti C, Cuomo R, Annibale B: Treatment of diverticular disease of the colon and prevention of acute diverticulitis: a systematic review, Dis Colon Rectum 54(10):1326–1338, 2011. Martinez ML, Ferrer R, Torrents E, et al: Impact of source control in patients with severe sepsis and septic shock, Crit Care Med 45(1):11–19, 2017. Mazuski JE, Tessier JM, May AK, et al: The surgical infection society revised Guidelines on the management of intra-abdominal infection, Surg Infect (Larchmt) 18(1):1–76, 2017. McDonald LC, Gerding DN, Johnson S, et al: Clinical practice guidelines for clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and society for Healthcare Epidemiology of America (SHEA), Clin Infect Dis 66(7):987–994, 2018. Mourad MM, Evans R, Kalidindi V, Navaratnam R, Dvorkin L, Bramhall SR: Prophylactic antibiotics in acute pancreatitis: endless debate, Ann R Coll Surg Engl 99(2):107–112, 2017. Podda M, Cillara N, Di Saverio S, et al: Antibiotics-first strategy for uncomplicated acute appendicitis in adults is associated with increased rates of peritonitis at surgery. A systematic review with meta-analysis of randomized controlled trials comparing appendectomy and non-operative management with antibiotics, Surgeon 15(5):303–314, 2017.

CHAPTER 97  Intraabdominal Infections Riccio LM, Popovsky KA, Hranjec T, et al: Association of excessive duration of antibiotic therapy for intra-abdominal infection with subsequent extraabdominal infection and death: a study of 2,552 consecutive infections, Surg Infect (Larchmt) 15(4):417–424, 2014. Sawyer RG, Claridge JA, Nathens AB, et al: Trial of short-course antimicrobial therapy for intraabdominal infection, N Engl J Med 372(21):1996–2005, 2015.

915

Schlottmann F, Gaber C, Strassle PD, Patti MG, Charles AG: Cholecystectomy vs. Cholecystostomy for the management of acute cholecystitis in elderly patients, J Gastrointest Surg 23(3):503–509, 2019.

98 Infectious Diarrhea Awewura Kwara

DEFINITION AND EPIDEMIOLOGY Diarrhea is defined as the passage of three or more unformed stools or more than 250 g of unformed stools per day. Based on duration, diarrhea can be classified as acute (less than 14 days), persistent (14 to 29 days), or chronic (30 or more days). Infectious diarrhea is diarrhea that has an infectious etiology and is often associated with symptoms and signs of enteric involvement, such as nausea, vomiting, abdominal cramps, passage of bloody stool (dysentery), or systemic symptoms. Organisms responsible for infectious diarrhea include bacteria, viruses, and parasites. In the United States (US), acute diarrhea is common, with an estimated annual burden of 179 million outpatient visits, nearly 500,000 hospitalizations, and more than 5000 deaths. The Foodborne Diseases Active Surveillance Network (FoodNet) maintained by the Centers for Disease Control and Prevention (CDC) provides data on pathogen-specific burden of diarrheal diseases in the United States by monitoring cases of laboratory-diagnosed infections caused by eight enteric pathogens transmitted through food in 10 US sites. During 2018, FoodNet identified 25,606 infections, 5893 hospitalizations, and 120 deaths. Campylobacter, Salmonella, and Shiga toxin–producing Escherichia coli (STEC) were the most common identified infections.

PATHOLOGY Diarrhea is an alteration of movement of ions and water that leads to an increase in water content, volume, or frequency of stools. Under normal conditions, up to 9 L of fluid is passed through the adult gastrointestinal tract daily. Almost 98% of this fluid is absorbed, and only 100 to 200 mL is excreted in stools. Enteric pathogens or microbial toxins that are ingested can overcome host defenses and alter this balance toward a net secretion, leading to diarrhea. A large number of microorganisms are normally ingested with every meal. Host defense mechanisms against enteric pathogens include low gastric pH, rapid transit of bacteria through the proximal small intestine, cellular immune responses, and antibody production. In addition, large numbers of normal bacterial flora inhabit the intestines and prevent colonization by enteric pathogens. Alteration of the normal defense mechanisms can put individuals at risk for infectious diarrhea. Individuals with gastric resection or achlorhydric states have increased frequency of infection due to Salmonella, Giardia lamblia, and helminths, whereas some organisms, such as Shigella or rotavirus, survive the extreme acidity of the gastric environment. Some viral, bacterial, and parasitic infections are more common in patients with impaired cellular or humoral immunity. More than 99% of the normal colonic flora is made up of anaerobic bacteria; they produce fatty acids and cause acidic pH,

916

which is important for resistance to colonization. Alteration of the bacterial flora due to broad-spectrum antibiotic therapy predisposes some individuals to the development of Clostridioides difficile infection (CDI). The virulence factors employed by enteric pathogens include inoculum size, adherence factors, toxin production, and invasion. Organisms such as Shigella, enterohemorrhagic Escherichia coli (EHEC), G. lamblia, and Entamoeba histolytica need as few as 10 to 100 organisms to produce infection, whereas Vibrio cholerae needs 105 to 108 organisms to cause disease. Infectious diarrhea can be classified as noninflammatory or inflammatory based on pathogenesis. Noninflammatory diarrhea is caused by pathogens that adhere to the mucosa of small intestine, disrupting the absorptive and/or secretory processes without causing inflammation or destruction. Pathogens that cause noninflammatory diarrhea include viruses, enterotoxin-producing organisms, G. lamblia, and Cryptosporidium parvum. Inflammatory diarrhea is cause by pathogens that target the distal ileum or the colon and cause acute inflammatory reaction by secreting cytotoxins or invading the intestinal epithelium. Cytotoxin-producing bacteria include enteroaggregative E. coli (EAEC), EHEC, and C. difficile and invasive organisms include Salmonella, Shigella, and Campylobacter.

Enterotoxin-Induced Secretory Diarrhea Ingested enterotoxin-producing bacteria colonize the small bowel, and then produce enterotoxin, which binds to the mucosa and causes watery diarrhea through hypersecretion of isotonic fluid that overwhelms the absorptive capacity of the colon. V. cholerae produces the cholera toxin, a heterodimeric protein composed of a single toxic active A subunit (CTA) and a B subunit pentamer (CTB), which is responsible for binding of the toxin to the intestinal mucosa. The bound toxin through a series of processes activates adenylate cyclase to produce cyclic adenosine monophosphate (cAMP), which causes increased chloride secretion and decreased sodium absorption, leading to hypersecretion of fluid. Enterotoxigenic E. coli (ETEC) produces both a heat-labile enterotoxin that acts by the same mechanism as the cholera toxin and a heat-stable enterotoxin that causes secretory diarrhea through activation of guanylate cyclase to produce cyclic guanosine monophosphate (cGMP).

Cytotoxin-Induced Diarrhea In contrast to enterotoxins, cytotoxins elaborated by enteric pathogens destroy mucosal epithelial cells, causing acute inflammatory reaction and bloody diarrhea (dysentery). Shigella dysenteriae produces the Shiga toxin, which causes dysenteric diarrhea in patients with shigellosis. Other toxin-producing bacteria include Vibrio parahaemolyticus, C. difficile, and STEC.

CHAPTER 98  Infectious Diarrhea

917

TABLE 98.1  Epidemiologic and Clinical Characteristics of Common Enteric Pathogens Organism

Epidemiologic Features

Common Clinical Features

Campylobacter jejuni

Consumption of undercooked poultry, travel to tropical and semitropical regions

Vibrio cholerae Clostridioides difficile Enterotoxigenic Escherichia coli

Inadequately cooked seafood, travel to endemic regions Antibiotic use, recent hospitalization, elderly patients with coexisting conditions Travel to tropical and semitropical regions

Nontyphoidal Salmonella

Food-borne outbreaks, exposure to animals

Shigella

Person-to-person transmission, daycare center contact

Shiga toxin–producing E. coli

Food-borne outbreaks, undercooked hamburgers, raw seed sprouts, water and wading pool exposure Ingestion of shellfish and undercooked seafood

Acute watery diarrhea, fever, abdominal pain, fecal evidence of inflammation (positive fecal leukocytes or lactoferrin) Acute dehydrating watery diarrhea; fever is usually absent Diarrhea with fever, fecal evidence of inflammation, marked leukocytosis Watery diarrhea, abdominal cramps, nausea and vomiting; leukocytes absent in stools Acute watery diarrhea, fever, abdominal pain, evidence of inflammation Severe diarrhea with fever, abdominal pain, bloody diarrhea, fecal evidence of inflammation Abdominal pain, bloody stools, absence of fever, fecal evidence of inflammation Watery diarrhea, abdominal cramps, nausea; fever and vomiting are less frequent Acute watery diarrhea, fever, abdominal pain, bloody diarrhea Watery diarrhea, nausea, vomiting, abdominal pain

Noncholeraic Vibrio Yersinia enterocolitica Norovirus Cyclospora Cryptosporidium Entamoeba histolytica Giardia lamblia

Contaminated food or water, inadequately cooked meats, unpasteurized milk Winter outbreaks in congregate settings, outbreaks on cruise ships Food-borne outbreaks, travel to tropical and subtropical regions (especially Nepal) Waterborne outbreaks, travel to tropical and subtropical regions Travel to tropical regions, recent immigration from endemic regions Waterborne outbreaks, travel to mountainous areas of North America, Russia

Persistent noninflammatory diarrhea Persistent noninflammatory diarrhea Bloody diarrhea, extraintestinal involvement (liver abscess) Abdominal pain, persistent watery diarrhea, flatulence, steatorrhea, nausea and vomiting

Invasive Diarrhea

SPECIFIC PATHOGENS

Some bacteria cause dysentery through direct invasion and destruction of intestinal mucosa. Shigella and enteroinvasive E. coli (EIEC) invade and multiply in epithelial cells and spread to adjacent cells. Diarrhea is often accompanied by fever, abdominal cramps, and small amounts of bloody mucoid stools. Other bacteria, such as Salmonella typhi and Yersinia enterocolitica, penetrate the mucosa before disseminating into the bloodstream to cause a systemic illness.

The epidemiologic and clinical features of common enteric pathogens and the recommended methods for diagnosis and treatment are summarized in Tables 98.1 and 98.2.

Bacterial Food Poisoning Bacterial food poisoning is caused by ingestion of preformed toxins in food that results in a toxic illness. The toxins may include cytotoxins, enterotoxins, and neurotoxins. Pathogens that cause bacterial food poisoning include Staphylococcus aureus, Clostridioides perfringens, and Bacillus cereus. These organisms grow in food and produce toxins that are ingested directly in the food. Symptoms occur soon after food ingestion, with incubation periods of 1 to 16 hours. The illness is rarely associated with fever, and symptoms usually resolve within 12 to 24 hours after onset. The staphylococcal and B. cereus toxins act on the nervous system to cause vomiting. S. aureus causes vomiting and diarrhea within 2 to 7 hours after ingestion of improperly cooked or stored food containing its heat-stable enterotoxin. C. perfringens produces secretory and cytotoxin-induced watery diarrhea within 8 to 14 hours after ingestion of contaminated vegetables, meat, or poultry. B. cereus often contaminates fried rice, vegetables, or sprouts; it produces one of two toxins that cause disease resembling that of S. aureus or C. perfringens infection within 1 to 6 hours after ingestion.

Shigella Diarrhea due to Shigella spp (shigellosis) occurs after ingestion of fecally contaminated food or water. The main strains include S. dysenteriae, S. flexneri, S. boydii, and S. sonnei. Ingestion of as few as 10 to 100 microorganisms can lead to infection because the bacteria are relatively resistant to gastric acid. Person-to-person transmission is common, and the attack rate is highest among infants and young children in child-care centers. The incubation period is 6 to 72 hours. Illness may initially manifest as noninflammatory watery diarrhea caused by enterotoxin production or multiplication of bacteria in the small intestines. Invasion of the colonic epithelium and mucosa often manifests as dysentery. Complications of S. dysenteriae type 1 shigellosis include hemolytic-uremic syndrome (HUS). Reactive arthritis is associated with S. flexneri infection.

Salmonella Salmonella enterica serovars typhi and paratyphi cause enteric fever whereas nontyphoidal Salmonella spp cause diarrhea. Nontyphoidal salmonellosis results from ingestion of contaminated meat, dairy, or poultry products or from direct contact with animals such as birds, pet turtles, snakes, and other reptiles. An oral inoculum of 105 to 108 organisms is needed but smaller inocula can cause disease in patients

918

SECTION XV  Infectious Disease

TABLE 98.2  Diagnosis and Recommended Antimicrobial Treatment for Diarrhea With Specific

Pathogens in Adults Organism

Diagnosis

Recommendations

Campylobacter jejuni

Routine stool culture

Vibrio cholerae O1

Stool culture in special salt-containing media (TCBS), test isolate for O1 serotype

Clostridioides difficile

Stool test for C. difficile toxin A or B by EIA, or PCR for the B toxin gene

Enterotoxigenic Escherichia coli

Stool culture for E. coli, with assay for enterotoxin

Nontyphoidal Salmonella

Routine stool culture

Shigella

Routine stool culture

Shiga toxin–producing E. coli

Stool culture with sorbitol-MacConkey agar, followed by serotyping for O157, then H7, with EIA for Shiga toxins Stool culture in special salt-containing media (TCBS)

Azithromycin 500 mg PO daily for 3 days. Alternative ciprofloxacin 500 mg PO bid for 3 days Doxycycline 300 mg or azithromycin 1000 mg PO single dose, or tetracycline 500 mg PO qid or TMP-SMZ 160/800 mg PO bid or ceftriaxone 1–2 g IV/IM q24h for 3 days Stop implicated antibiotic. Vancomycin 125 mg PO qid or fidaxomicin 200 mg PO bid for 10 days. For fulminant CDI, vancomycin 500 mg four times daily orally or by NGT is recommended. Azithromycin 1000 mg PO single dose or 500 mg PO daily for 3 days or ciprofloxacin 500 mg PO bid for 3 days Antimicrobials not recommended except for groups at risk of invasive disease. Ciprofloxacin 500 mg bid for 5 to 7 days or ceftriaxone 100 mg/kg/day in one or two divided doses for 5 to 7 days, or longer if endovascular infection or relapsing Ciprofloxacin 500 mg bid for 3 days or ceftriaxone 1–2 g IV/IM for 3 days or azithromycin 500 mg PO daily for 3 days Antibiotics and antimotility drugs should be avoided

Noncholeraic Vibrio Yersinia enterocolitica

Stool culture on MacConkey media incubated at 25° to 28° C

Cyclospora Cryptosporidium

Stool trichrome or acid-fast stain for parasites Stool trichrome or acid-fast stain for parasites, EIA for Cryptosporidium species

Isospora Entamoeba histolytica

Stool trichrome or acid-fast stain for parasites Stool examination for ova and parasites, EIA for E. histolytica Stool examination for ova and parasites, EIA for Giardia species

Giardia

Ceftriaxone 1–2 g IV/IM q24h plus doxycycline 100 mg PO bid for 3 days Antibiotics usually not required. For severe infection or bacteremia, treat with TMP-SMZ or fluoroquinolone or doxycycline plus aminoglycoside TMP-SMZ 160/800 mg bid for 7–10 days Self-limited in immunocompetent persons. If severe or if patient is immunocompromised, nitazoxanide 500 mg PO bid for 3 to 14 days TMP-SMZ 160/800 mg PO bid for 7–10 days Metronidazole 750 mg tid for 5–10 days, plus iodoquinol 650 mg tid for 20 days or paromomycin 500 mg tid for 7 days Single dose tinidazole 2 g or nitazoxanide 500 mg bid for 3 days. Metronidazole 250 to 750 mg tid for 5 to 10 days

EIA, Enzyme immunoassay; PCR, polymerase chain reaction; PO, per oral; bid, twice a day; qid, four times a day; TCBS, thiosulfate-citrate-bile salts-sucrose agar; tid, three times a day; TMP-SMZ, trimethoprim-sulfamethoxazole.

with impaired gastric acidity or compromised immunity. The organisms invade the distal ileum and cause diarrhea with fever, nausea, or vomiting. Diarrhea usually resolves in 2 to 3 days. Complications include bacteremia and metastatic seeding of atherosclerotic plaques and prostheses. Antibiotic treatment does not shorten the duration of diarrhea and may prolong intestinal carriage in stools. Antibiotics are indicated only for cases of severe disease or extraintestinal involvement.

Campylobacter Disease caused by Campylobacter jejuni usually results from ingestion of undercooked poultry or direct contact with animals. The infective dose is 104 to 106 organisms, with an incubation period of 1 to 5 days. Acute watery, noninflammatory diarrhea is the most common presentation. Less frequently, acute inflammatory enterocolitis with systemic symptoms may occur. Prodromal symptoms such as fever, myalgia, headache, and malaise may precede diarrhea. Complications include postinfectious irritable bowel syndrome, reactive arthritis, especially associated with the human leukocyte antigen B27 (HLA-B27), and Guillain-Barré syndrome, which can occur 2 to 3 weeks after diarrhea has resolved. Antibiotic therapy shortens the carriage state.

Vibrio V. cholerae can be divided by the O-antigen of lipopolysaccharide into more than 150 strains. The toxigenic strains V. cholerae O1 and O139 produce cholera toxin and are associated with clinical illness. The infectious oral inoculum is about 105 to 108 organisms, with an incubation period of 6 hours to 5 days. Classic cholera starts with vomiting, abdominal pain, and diarrhea. Diarrhea progresses to voluminous watery stools that have been described as “rice water” because they are clear with flecks of mucus. Massive diarrhea can lead to dehydration and shock within a few hours. The illness may be fulminant, with death occurring 3 to 4 hours after onset. Fever and bacteremia are rare. In endemic areas, the diagnosis is usually made on clinical grounds. Toxigenic V. cholerae non-O1, non-O139 produces cholera toxin and has caused sporadic cases of diarrhea or small outbreaks in some parts of the United States through consumption of contaminated seafood or water. V. parahaemolyticus has also been reported to cause acute gastroenteritis from consumption of contaminated seafood. The characteristics of noncholeraic Vibrio species are covered in Tables 98.1 and 98.2.

Listeria Listeria monocytogenes is an uncommon cause of diarrhea in the United States. The two major clinical syndromes of Listeria infection are

CHAPTER 98  Infectious Diarrhea gastroenteritis and listeriosis. Outbreaks may be due to ingestion of contaminated ready-to-eat foods such as unpasteurized milk, cheeses, meats, vegetables, and unwashed raw produce. Gastroenteritis is usually mild, noninvasive, and generally self-limiting. Symptoms including diarrhea, fever, chills, headache, joint pains, and myalgia that may occur 9 to 32 (median, 20) hours after ingestion of contaminated food. The diagnosis of gastroenteritis is often missed, as stool is not routinely cultured. In febrile gastroenteritis where traditional pathogens are not isolated using standard media, culture of stools with selective media for L. monocytogenes may demonstrate the organism. If diagnosed in a susceptible host, Listeria gastroenteritis may be treated with amoxicillin 500 mg orally three times a day or TMP/SMX 160/800 mg for 7 days. Listeriosis is a more severe invasive illness, which may manifest as bacteremia, central nervous system disease, or sepsis in pregnant women with fetal loss. Risk factors for listeriosis include extremes of age, pregnancy, and immunocompromised state. In 2019, the FoodNet reported 134 laboratory-diagnosed cases of listeriosis in the United States, of which 131 (98%) were hospitalized and 21 (16%) died. The overall incidence was 0.3 per 100,000 population.

Diarrhea-Causing Escherichia coli There are several types of diarrheagenic E. coli, each with a different pathogenesis leading to diarrhea. These include ETEC, STEC, enteropathogenic (EPEC), EIEC, EAEC, and diffusely adherent E. coli. ETEC is the most common cause of traveler’s diarrhea. EPEC has been associated with epidemic diarrhea in neonates. EHEC is acquired by eating contaminated food or water. The oral inoculum is 10 to 100 organisms, with an incubation period of 3 to 4 days. Most disease in the United States is caused by E. coli O157:H7. Infection with EHEC, including E. coli O157:H7 and other STEC serotypes can cause hemorrhagic colitis. It is classically associated with bloody diarrhea, abdominal pain, and fecal leukocytes. Systemic complications include HUS in children and thrombotic thrombocytopenia purpura in adults. Antibiotic therapy may increase the risk of HUS.

Clostridioides difficile C. difficile infection is the main cause of nosocomial diarrhea among adults in the United States. The main risk factor for CDI is antibiotic use. Advanced age and severe underlying disease contribute to susceptibility. Virtually all antibiotics have been implicated in the development of CDI, but the most common agents are clindamycin, cephalosporins, fluoroquinolones, ampicillin, and amoxicillin. Infection is transmitted by spores, which occur in the environment and are resistant to alcohol-based handwashing solutions. The spores of toxigenic C. difficile are ingested, survive gastric acidity, geminate, and colonize the lower intestinal tract, where they elaborate two exotoxins, toxin A (an enterotoxin) and toxin B (a cytotoxin). The toxins disrupt cell and tight junctions, leading to fluid leakage. The cellular toxicity results in neutrophilic colitis and formation of a pseudomembrane in some cases. The hypervirulent strain referred to as the North American pulsedfield gel electrophoresis type 1 (NAP1/027) strain is associated with a severe course, higher mortality, and increased risk of relapse. Bacterial factors implicated in outbreaks of CDI caused by the NAP1/027 strain include increased production of toxins A and B, fluoroquinolone resistance, and production of a binary toxin. Patients often have abdominal pain and watery diarrhea but may also have bloody stools. Markers of severe or fulminant CDI include pseudomembranous colitis, acute renal failure, marked leukocytosis, hypotension, and toxic megacolon. The indigenous intestinal microbiota is important for colonization resistance and for recovery from antibiotic-associated CDI.

919

Yersinia enterocolitica Y. enterocolitica is a zoonosis caused by ingestion of contaminated food or water or undercooked meats. Oral inoculation requires 109 organisms for infection, with an incubation period of 3 to 7 days. The illness may mimic acute appendicitis and may be complicated by ileal perforation, mesenteric adenitis, or terminal ileitis. Postinfectious reactive arthritis may occur.

Viral Causes of Diarrhea Viruses cause diarrhea by adhering to the intestinal mucosa and disrupting the absorptive and secretory processes without causing inflammation. They may invade intestinal villous epithelial cells and cause sloughing of villi. Rotavirus is a common cause of severe diarrhea in children younger than 5 years of age. The incidence of rotavirus disease has fallen in many countries following the introduction of the rotavirus vaccine. Rotavirus still results in greater than 200,000 deaths annually, mostly in low-income countries. Norovirus is highly contagious and is a very common cause of food-borne gastroenteritis in adults and children in the United States. It has been the cause of epidemic diarrhea on cruise ships. Other viruses that cause diarrhea are adenoviruses, sapoviruses, and astroviruses. The incubation period is usually longer than 14 hours, and vomiting may be a prominent feature of diarrheal disease caused by viral agents.

Protozoan Causes of Diarrhea Important parasitic causes of diarrhea include G. lamblia, C. parvum, and E. histolytica. Contaminated water sources tend to be the cause of outbreaks. G. lamblia trophozoites adhere to the epithelium of the upper small intestine and damage the mucosal brush border without invasion. Ingestion of a few organisms can lead to disease. C. parvum, Isospora belli, and Cyclospora cayetanensis occasionally cause self-limited diarrhea in immunocompetent individuals but may cause severe disease in patients with advanced acquired immunodeficiency syndrome (AIDS). E. histolytica causes a syndrome ranging from mild diarrhea to fulminant amebic colitis and extraintestinal amebic abscesses.

Traveler’s Diarrhea Traveler’s diarrhea affects 10% to 40% of travelers from industrialized countries who visit tropical and semitropical developing countries. The causative agent is identified in about 85% of cases, and 90% of those identified are bacterial pathogens, most often ETEC or EAEC. Less common bacterial causes include EIEC, diffusely adherent E. coli, Shigella spp, Salmonella spp, Campylobacter spp, Aeromonas, V. cholerae, noncholeraic Vibrio, and Plesiomonas. The viral etiologies include rotavirus and norovirus. Protozoal causes are rare. Travelers to highrisk areas should be counseled to wash hands, avoid uncooked food, and drink bottled water. Patients with traveler’s diarrhea should be treated empirically with antibiotics without stool examination.

CLINICAL PRESENTATION The epidemiologic and clinical characteristics are important to identify the potential etiologic agent and to guide management (see Table 98.1). The initial evaluation should consider the severity of illness, signs of dehydration, and intestinal inflammation indicated by the fever, abdominal pain, blood in stools (dysentery), or tenesmus. Important epidemiologic clues in the history include age, travel history, ingestion of undercooked or raw food and meat, antibiotic use, sexual activity, daycare attendance, and outbreaks involving others with similar exposure (see Table 98.1). Fever (temperature 38.5° C or 101.3° F or higher) is associated with invasive pathogens that cause

920

SECTION XV  Infectious Disease

intestinal inflammation. The examination should determine the severity of dehydration and need for rehydration as well as the likely cause. Signs of dehydration or hypovolemia include lax skin turgor and tenting, dry mucus membranes, decreased urination, tachycardia, and hypotension.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS The approach to diagnosis and management of infectious diarrhea is shown in Fig. 98.1. Most cases of diarrheal illnesses are self-limiting with almost half resolving within 1 day. Therefore, microbiologic investigation is usually not necessary for patients who are seen within 24 hours of the onset of illness unless certain conditions are present. The indications for stool culture include severe diarrhea (six or more stools per day), diarrhea lasting longer than 1 week, fever, dysentery, hospitalization, inflammatory diarrhea, and multiple cases in a suspected outbreak. Routine stool culture will identify Shigella, Salmonella, Campylobacter, and Aeromonas. Polymerase chain reaction (PCR)–based diagnostic tests are now available and include a multiplex approach that allows several bacterial, viral, and parasitic enteropathogens to be detected in a single test simultaneously. The Luminex xTAG Gastrointestinal Pathogens Panel tests for 14 viruses, bacteria, and parasites and the FilmArray Gastrointestinal

panel (Biofire Diagnostics) tests for 22 viruses, bacteria, and parasites. These methods are faster and have higher sensitivity than culture-based methods but they do not distinguish pathogenic and nonpathogenic organisms. If the patient has bloody diarrhea or HUS, stool culture for E. coli O157:H7 and tests for Shiga-like toxin (or the genes that encode them) should be performed. If there is a history of recent antibiotic use, hospitalization, or age greater than 65 years with coexisting conditions, immunosuppression, or neutropenia, stool samples should be tested for C. difficile toxin. Available tests for C. difficile toxin include enzyme immunoassay (EIA), nucleic acid amplification test (NAAT) and glutamate dehydrogenase (GDH plus toxin) test. No single test is suitable as a stand-alone test and often a multistep algorithm testing is used. Consider protozoa, and check stools for ova and parasites (e.g., trophozoites) and/or for Giardia antigen test if diarrhea duration is greater than 7 days. If a patient has AIDS, stools should be checked for Cryptosporidium, Microsporidium, and Mycobacterium avium complex.

TREATMENT Initial therapy should include fluid and electrolyte repletion with or without antimicrobial therapy. Oral rehydration is often adequate unless the patient is comatose or severely dehydrated. Nutritional support with continued feeding improves outcomes in children. Acute Diarrhea

ASSESS FOR DEHYDRATION Mild to moderate: ORS Severe: IV hydration; admit to hospital, especially if elderly

Traveler, food outside home, daycare worker, water park, peripartum, sexually active

Fever, bloody

Stool culture†, O&P E. coli strain typing C. difficile toxin

Medications* Stop if possible If antibiotic, stool C. difficile toxin

Afebrile, watery

Other Fecal impaction Appendicitis Ischemia

Immunosuppressed

Stool CX, O&P, C. difficile toxin ? Viral/fungal Admit if ill

Antimotility agent‡ No improvement

Antibiotic Antimotility agent

Antibiotic§ Antimotility agent Report to Public Health and save blood/stool.

Fig. 98.1  Approach to the diagnosis and management of acute infectious diarrhea. *More than 700 medications cause diarrhea, including furosemide, caffeine, protease inhibitors, thyroid preparations, metformin, mycophenolate mofetil, sirolimus, cholinergic drugs, colchicine, theophylline, selective serotonin reuptake inhibitors, proton pump inhibitors, histamine-2 blockers, 5-ASA derivatives, angiotensin-converting enzyme inhibitors, bisacodyl, senna, aloe, anthraquinones, and magnesium- or phosphorus-containing medications. †Specifically request culture for Yersinia, Plesiomonas, enterohemorrhagic Escherichia coli serotype O157:H7, and Aeromonas if suspected. ‡If high suspicion for Clostridioides difficile or invasive bacterial infection, wait for stool culture and toxin studies before starting. Racecadotril has antisecretory effects without paralyzing intestinal motility and can be used if available. §Not recommended for patients with bloody diarrhea due to E. coli O157:H7. CX, Culture; IV therapy, intravenous rehydration; O&P, ova and parasites; ORS, oral rehydration solution. (From Goldman L, Schaefer AI: Goldman-Cecil Medicine, 25th ed. Philadelphia, Elsevier, 2016, Fig. 140-1.)

CHAPTER 98  Infectious Diarrhea

Oral Fluid Therapy In most patients with diarrhea, fluid repletion can be achieved with oral rehydration therapy using isotonic fluids containing glucose and electrolytes. An effective solution can be prepared by the addition of 2 tablespoons of sugar, one fourth of a teaspoon of salt (NaCl), and onefourth of a teaspoon of baking soda (NaHCO3) to 1 L of boiled drinking water. In the United States, fluids such as Pedialyte or Rehydrolyte solutions are recommended. Fluid should be administered in large quantities until there is clinical evidence that fluid balance is restored and then as maintenance therapy. Oral rehydration therapy can be life-saving for patients in developing countries with severe diarrhea.

Intravenous Fluid Therapy Massive fluid loss due to diarrhea should be rapidly replaced by the administration of intravenous fluids. Lactated Ringer’s solution is the fluid of choice because the composition is similar to electrolyte loss during diarrhea. The rate of fluid administration and maintenance should be guided by clinical signs including vital signs, appearance of the mucosa, neck veins, and skin turgor.

Antimicrobial Therapy Most cases of infectious diarrhea do not require antimicrobial therapy. However, antibiotics may decrease the volume of diarrhea (e.g., in cholera) or the duration and severity of the illness. Antibiotics are effective in the treatment of shigellosis, traveler’s diarrhea, and Campylobacter infection. In uncomplicated salmonellosis, antibiotics may prolong the shedding of Salmonella. The choice and dose of antimicrobials for specific pathogens are described in Table 98.2. For traveler’s diarrhea in adults, empiric therapy with azithromycin 500 mg daily, or ciprofloxacin 500 mg twice a day, or trimethoprim-sulfamethoxazole (TMP-SMZ) 160/800 mg twice a day, for 3 days is adequate. For antibiotic-associated C. difficile colitis, broad-spectrum antibiotics should be discontinued, if possible. Preferred therapy for an initial episode of CDI is oral vancomycin 125 mg four times a day or fidaxomicin 200 mg twice daily for 10 days. If those antibiotics are not available, metronidazole 500 mg three times daily for 10 days is an alternative therapy. Fecal microbiota transplantation may be indicated for patients with multiple recurrences of CDI who have failed appropriate antibiotic

921

treatments. Antibiotics must be avoided in patients with STEC O157 or other STEC that produce Shiga toxin.

Symptomatic Therapy Antidiarrheal agents such as loperamide and bismuth subsalicylate can be used in some instances for symptomatic relief. Loperamide inhibits intestinal peristalsis and has some antisecretory properties. When used with or without antibiotics in cases of traveler’s diarrhea, it may reduce the duration of diarrhea by about 1 day. Antimotility agents should be avoided in patients with bloody or suspected inflammatory diarrhea. The use of these agents has been implicated in prolonging the duration of fever in shigellosis, development of toxic megacolon in CDI, and development of HUS in children with STEC infection.

PROGNOSIS The prognosis is generally good but is variable depending on the etiology and the severity of illness. Most patients recover completely within 3 to 5 days. However, serious complications, including death, can be seen in individuals who become severely dehydrated, infants, elderly patients, and those with underlying medical conditions or immunosuppression. Untreated severe dehydration may lead to shock, renal failure, and death. Postinfectious reactive polyarthritis can complicate cases due to Yersinia, Campylobacter, and Shigella, and Guillain-Barré syndrome may occur after diarrhea caused by Campylobacter.

SUGGESTED READINGS DuPont HL: Acute infectious diarrhea in immunocompetent adults, N Engl J Med 370:1532–1540, 2014. DuPont HL: Persistent diarrhea: a clinical review, J Am Med Assoc 315:2712– 2723, 2016. McDonald LC, Gerding DN, Johnson S, et al: Clinical practice guidelines for clostridium difficile infection in adults and children: 2017 update by Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 66:987-994. Shane AL, Mody RK, Crump JA, et al: 2017 infectious Diseases Society of America clinical practice guidelines for diagnosis and management of infectious diarrhea, Clin Infect Dis 65:e45–e79, 2017.

99 Infections Involving Bone and Joints Jerome Larkin

DEFINITION Osteomyelitis refers to infection of any component of the bony skeleton, whereas septic arthritis refers to that of native or prosthetic joints. Tendons, ligaments, and bursae can also become infected, especially if they involve prosthetic or bio-grafted material. Osteomyelitis and septic arthritis can occur by seeding during bacteremia, due to extension from a contiguous focus of infection in an adjacent tissue or structure, as a consequence of vascular insufficiency or as a complication of trauma. In the case of hematogenous infection, the bacteremia itself may be relatively transient and of little clinical consequence. Hematogenous osteomyelitis is common in children but accounts for only 20% of osteomyelitis in adults. The vertebrae and pelvis are the most commonly involved sites of hematogenous osteomyelitis in adults. Peripheral vascular disease leading to tissue hypoxia and related to diabetes, hypertension, hyperlipidemia, and smoking is the biggest risk factor for the development of osteomyelitis in adults older than 50. There is often preceding soft tissue infection or destruction as a result of vascular insufficiency and neuropathy. It is most common in the lower extremities, particularly in the feet, and often occurs in diabetics. Trauma, especially when it involves open fracture with its attendant disruption of the bony architecture and vascular supply, is a second major risk factor for the development of osteomyelitis and septic arthritis. This is particularly true when an open fracture, as may be experienced in a fall or motor vehicle accident, is heavily contaminated with soil or other environmental materials. Such fractures often require internal fixation (i.e., the placement of rods, screws, and other metal devices to stabilize the bone). The presence of such internal fixation provides a nidus for bacteria and other microorganisms including fungi to elude the immune system and incubate. Chronic osteomyelitis is a possible complication of such injuries and is often a result of multiple or unusual organisms. It may occur despite aggressive débridement and prophylactic antibiotic treatment at the time of injury and can arise months or even years afterwards. Individuals who experience prolonged periods of immobility such as those suffering from paraplegia are also at risk for osteomyelitis. Infection typically involves the pelvis, sacrum, and lower spine corresponding to areas of unrelieved pressure as a result of the immobility. Osteomyelitis may be conceptualized as acute or chronic. The former is typically hematogenous, associated with signs of inflammation in the overlying soft tissue and with an onset over the course of days to a week. Radiographs are usually normal at presentation. Chronic osteomyelitis is more indolent with onset over the course of months, is more likely to exhibit bony destruction on plain radiograph at the time of presentation, and is often associated with a draining sinus tract. Sequestra (areas of dead bone) and involucra (new bone formed around sequestra) may also be seen. Whereas acute osteomyelitis may require a 6-week course of antibiotics alone to effect cure, chronic

922

osteomyelitis more typically requires surgical intervention and a prolonged (3 or more months) course of antibiotic therapy.

PATHOPHYSIOLOGY Aspects of the vascular supply of the bone as well as properties of the most common pathogen, Staphylococcus aureus, may combine to lead to infection. Although bone is generally resistant to infection, the vasculature of the metaphysis contains capillary loops composed of a single layer of discontinuous endothelial cells, which may allow bacteria to enter the extracellular matrix. These capillary beds lack functionally active phagocytes. S. aureus can elaborate proteins expressed on its surface that promote adherence to tissues of the extracellular matrix. When engulfed by osteoblasts, S. aureus can survive for prolonged periods of time in an almost spore-like state leading to potential recurrences of infection. Finally, many bacteria can elaborate biofilms that allow them to elude clearance by the immune system. Prosthetic material such as in joint replacements and other grafts can serve as a platform for the formation of such biofilms. In the case of septic arthritis there is usually some underlying abnormality in the joint, but this abnormality may be as mundane as osteoarthritis. It is hypothesized that relatively trivial injury, which may in fact go unnoticed or unremembered by the patient, leads to minor bleeding into the joint, which in turn provides a hospitable environment for bacteria to incubate.

CLINICAL PRESENTATION AND DIAGNOSIS Patients with osteomyelitis will often present with pain at the site of infection. The overlying soft tissue may have signs of inflammation or tissue destruction, the latter often seen in diabetics with soft tissue ulceration. Historically, the diagnosis of osteomyelitis relied on the presence of lucency on plain radiograph of the affected area. Diagnosis could be confirmed histologically by bone biopsy with culture to identify the pathogenic organism. Currently, diagnosis is typically made by MRI with gadolinium, which demonstrates marrow edema with or without bony destruction. Alternatively, diagnosis may be made by three-phase bone scan or CT. These may be especially helpful in patients with renal insufficiency who cannot undergo gadolinium-enhanced studies due to the risk of nephrogenic systemic fibrosis. An elevated C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) supports the diagnosis. Microbiologic diagnosis is made either by positive blood cultures or bone biopsy and culture. Culture of cutaneous ulcers is typically not helpful because results of such studies usually demonstrate multiple colonizing organisms and do not correlate with organisms isolated on bone culture. An exception is the isolation of S. aureus or Salmonella from a draining fistula or on occasion Pseudomonas from an ulcer. In the former case, the bacterium can then

CHAPTER 99  Infections Involving Bone and Joints be presumed to be the pathogen; in the latter, a decision would then need to be made to include coverage for this organism in an empiric antibiotic regimen. If cultures of bone obtained by noninvasive techniques under radiographic guidance are negative, either the procedure should be repeated or an open biopsy with culture performed. Septic arthritis of native joints typically will present with the cardinal features of inflammation (i.e., erythema, swelling, warmth, and pain) when involving joints of the extremities. Fever may often be present and septic arthritis is more likely to present with an associated bacteremia. Septic arthritis of the spine, pelvis, and hip may require imaging, usually MRI, because these may be difficult to assess by examination alone. Persistent back, pelvic or hip pain that is otherwise unexplained should prompt radiographic evaluation even in the absence of fever. Diagnosis ultimately relies on joint aspiration with débridement. Such procedures should occur prior to the administration of antibiotics. Fluid should be sent for cell count with differential, crystal analysis, Gram stain, anaerobic culture, and fungal and acid-fast stains and cultures. Positive stains and/or cultures are taken as evidence of infection in most cases in which an appropriate clinical syndrome is also present. White blood cell (WBC) counts higher than 50,000 cells/mL are suggestive of infection. In cases that are difficult to diagnose or instances where antibiotics have been given prior to aspiration, it may be appropriate to have cultures held for up to 14 days. Specialized culture techniques for fastidious organisms such as anaerobes and nutritionally deficient streptococci may be required. Ultimately, tagged WBC scans may help to clarify the presence or absence of septic arthritis in difficult cases. Evolving molecular technologies such as PCR, especially microarray assays that detect multiple pathogens, and 16-S ribosomal sequencing may offer alternative and more rapid and precise diagnosis in the future. Prosthetic joint infections (PJI) are defined by their timing following implantation: acute (less than 3 months), delayed (3 to 12 months) or late (12 months). Early PJI presents similarly to native joint infections. Delayed and late infections are more indolent, presenting with pain, decreased function, and evidence of loosening of the prosthesis on plain films. More overt signs of inflammation or systemic infection may be subtle or absent altogether. Diagnosis relies on the presence of either a draining sinus tract that communicates with the prosthesis or two or more periprosthetic cultures harboring the same organism. Minor criteria have been proposed with three or more of the following used to diagnose PJI: elevated CRP or ESR, synovial fluid WBC greater than 3000, elevated synovial polymorphonuclear cells (PMNs), a single positive culture or greater than five PMNs per high-power field on examination of periprosthetic tissue. A point scoring system as advanced by Parvizi and colleagues may increase the sensitivity of the use of minor criteria or be used as a tool in more diagnostically obscure cases. Most cases of osteomyelitis and septic arthritis are due to Staphylococcus, Streptococcus, and aerobic gram-negative bacilli, although virtually any pathogenic microorganism can cause such infections in the appropriate circumstance. Infecting staphylococci include both S. aureus and coagulase-negative staphylococci. Coagulasenegative staphylococci are often implicated in prosthetic joint infections or infections associated with orthopedic hardware. Streptococcus spp causing bone and joint infections include groups A, B, C, G and F as well as Abiotrophia and Gemella (formerly termed nutritionally deficient streptococci). Gram-negative organisms account for as much as 30% of hematogenous infections. Gram-negative infections are seen more commonly in the elderly as a result of urinary tract infections with associated bacteremia. Isolated species include Escherichia coli, Haemophilus influenza, and H. parainfluenza. Infections with Serratia marcescens and Pseudomonas are associated with exposure to water and are usually nosocomial or related to intravenous drug use. Fungi such

923

as Candida, Aspergillus, and Zygomycetes may cause bone and joint infections, particularly in immune-compromised patients, diabetics or those who have suffered trauma. Nocardia and other acid-fast organisms may be seen following trauma or in association with prosthetic joints and may require several attempts at débridement before being isolated. Cutibacterium acnes is often isolated from shoulder infections, especially those involving prosthetic joints. The variety of potential pathogens underscores the need to obtain appropriate specimens for culture prior to the administration of antibiotics. Infection with Borrelia burgdorferi, the causative agent of Lyme disease, can lead to a multifocal or monoarticular septic arthritis. Fluid analysis is consistent with bacterial septic arthritis but is negative for typical organisms on culture. Associated findings of erythema migrans, diffuse myalgias and arthralgias, cranial nerve palsies, fever, and aseptic meningitis may also be present. Polymerase chain reaction of joint fluid has a reported sensitivity of between 30% and 75%. Diagnosis relies on serology and associated findings in patients who reside in endemic areas. Later-stage disease may present with a less inflammatory-appearing effusion, often without any other symptoms. Treatment is with either doxycycline or ceftriaxone depending on the stage of disease. Neisseria gonorrhea may cause a solitary or multifocal septic arthritis. It is usually seen in sexually active younger adults. Culture of the joint fluid may be negative but testing of specimens from the pharynx, urethra or rectum are usually positive by nucleic acid amplification. The treatment of choice is ceftriaxone.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of both osteomyelitis and septic arthritis includes other noninfectious inflammatory disorders such as gout, pseudogout, rheumatoid arthritis, inflammatory bowel disease, and other inflammatory and autoimmune disorders. Occasionally, neoplasms such as sarcomas or metastatic lesions may present similarly to osteomyelitis. Several viruses such as rubella, parvovirus B19, Chikungunya and hepatitis B can cause arthritis. Chronic recurrent multifocal osteomyelitis is a noninfectious inflammatory lesion of bone thought to be autoimmune in nature and characterized by findings on MRI similar to osteomyelitis. It is culture-negative and unresponsive to antibiotics. It is a diagnosis of exclusion often made only after several attempts at diagnosing and treating presumed bacterial osteomyelitis. Although typically seen in children, with peak incidence between 7 and 12 years of age, it can also occur in adults.

TREATMENT Treatment of osteomyelitis involves débridement of appropriate infected and/or necrotic tissue as well as the administration of antibiotics. It is critically important to remove all necrotic or devitalized tissue, which may serve as a nidus of chronic or recurrent infection if not removed. In this regard, it is often necessary to remove any fixating hardware, plastic devices, bone grafts or other donor tissue if infection has been present for greater than one month or is recurrent. Cadaveric donor tissue infections often are caused by atypical organisms such as Clostridioides spp. Historically, sequestra developed in the site of chronically infected bone. These are produced by the action of the immune system and histologically are characterized by granulomatous tissue that serves to isolate the infection. While effective in containing infection, they also represented a risk for recurrence as well as an area of bone weakening. When present, they should be surgically excised. Infection that occurs in the immediate postoperative period (i.e., within 1 month after placement of hardware and grafts)

924

SECTION XV  Infectious Disease

and that appears to only involve the soft tissue may be treated with débridement and antibiotics alone with a reasonable chance of success. Occasionally, infected hardware must be left in place in order to stabilize the bone while a fracture is healing. In this instance, it may be necessary to continue antibiotic treatment until hardware removal can be accomplished. Infected spine hardware that must remain in place may require prolonged antibiotic treatment, at times indefinitely. The addition of rifampin for staphylococcal infections with retained hardware to which the infecting organism is susceptible improves overall cure rates. Septic arthritis requires serial débridement of the joint until active purulence has resolved. This is indicated by decreasing cell count and sterilization of joint fluid cultures. Prosthetic joint infection typically requires removal of the infected prosthesis with placement of an antibiotic spacer for 4 to 6 weeks while antibiotics are administered. This is followed by placement of a new prosthesis once all signs and symptoms of infection have resolved. Selected infections with coagulase-negative staphylococci and Streptococcus infections may be treated with débridement, joint retention, and a 6-week or longer course of antibiotics. Consideration should then be given to chronic suppressive antibiotic therapy, assuming an appropriate agent is available. Antibiotic treatment should be with agents active against the infecting organism if culture and susceptibility data are available. β-Lactams are the preferred agent in most cases. Therapy with quinolones for Enterobacteriaceae and in combination with rifampin for staphylococci may be considered. These drugs have the advantage of high oral bioavailability that approaches or equals tissue levels when given intravenously. Care should be taken regarding drug interactions with rifampin and the risk of Clostridioides difficile colitis and Achilles tendon rupture with quinolones. Recent literature also indicates a small increased risk of aortic aneurysm or dissection with this class of antibiotics. In the face of negative cultures, empiric therapy with an agent active against typical pathogens, including methicillin-resistant S. aureus, is reasonable. Vancomycin remains the standard agent for empiric therapy. Prior administration of antibiotics may lead to negative cultures even in cases of unequivocal infection. In this situation, empiric therapy should be based on the activity of the agents previously administered, as well as on potential pathogens based on exposure history. In all cases, the clinical response to infection should be monitored and should inform subsequent decision making regarding the need for additional débridement or changes in antibiotic therapy. Monitoring inflammatory markers such as CRP or ESR is helpful in determining the adequacy of response to treatment. If elevated at the start of treatment they should fall to normal or near normal by the time treatment is finished. Signs and symptoms of inflammation at the site of infection should have also resolved at the cessation of treatment. There are few randomized, controlled trials comparing different durations of antimicrobial therapy. Acute osteomyelitis should be treated for 4 to 6 weeks. Continuing treatment in a patient who is improved but who has failed to resolve elevated inflammatory markers or local signs of inflammation is reasonable. Such patients should be closely monitored and evaluated for the need for additional débridement or other measures aimed at diagnosis and source control. Chronic osteomyelitis may require 12 or more weeks of therapy, and treatment is usually individualized based on the clinical situation. Patients on therapy should also be monitored weekly for toxicity to antibiotics. Assessment of renal and hepatic function, complete blood count, and drug levels are typically followed depending on the specific agent used. In the case of aminoglycosides, renal function and peak and trough levels should be followed twice weekly. Long-acting glycopeptides such as dalbavancin and oritavancin are promising alternatives to daily antibiotic dosing.

A recent open-label study of the treatment of osteomyelitis that included over 1000 randomized patients demonstrated a lack of inferiority of oral therapy when compared with intravenous therapy. Costs were reduced and patient satisfaction was higher in the orally treated group. The incidence of serious side effects and adverse reactions was similar between the two groups. Oral therapy was largely with quinolones. The study encompassed a heterogenous population so, although promising, application of the findings to particular patients should be done thoughtfully. Adjunctive therapies such as bone grafting, revascularization procedures, and the placement of muscle flaps to cover and protect exposed bone may be utilized in the appropriate clinical situation. Native joint septic arthritis may be treated with a 4-week course of antibiotics; prosthetic joint infections are typically treated for 6 or more weeks. Monitoring for toxicity and response to treatment is similar to that for osteomyelitis.

PROGNOSIS The prognosis for osteomyelitis and septic arthritis is excellent, assuming adequate diagnosis, débridement, and antimicrobial therapy. The most common complication is residual pain and/or decreased function of the affected bone or joint. These are relatively rare and relatively minor. An exception involves prosthetic joint infections, in which 25% to 50% of patients experience some loss of function as a result of the infection. Recurrence rates for chronic osteomyelitis, especially in diabetics, may be as high as 30%. In more complex cases such as open contaminated fractures or infected hardware that requires retention, complications include nonunion, prosthesis failure, and chronic osteomyelitis. Infections that cannot be controlled may lead to the need for amputation and its attendant loss of function and mobility. Occasionally, bone or joint infections can lead to dissemination to other joints or the bloodstream. Such cases usually involve infection with S. aureus and fortunately remain the exception.

SUGGESTED READINGS American Academy of Orthopedic Surgeons: Diagnosis and prevention of periprosthetic joint infections clinical practice guidelines. March, 2019. Lew DP, Waldvogel FA: Osteomyelitis, Lancet 364:369–379, 2004. Li HK, Rombach I, Zambellas R, et al: Oral versus intravenous antibiotics for bone and joint infection, N Engl J Med 380:425, 2019. Parvizi J, Tan TL, Goswami K, et al: The 2018 definition of periprosthetic hip and knee infection: an evidence-based and validated criteria, J Arthroplasty 33:1309, 2018. Rappo U, Puttagunta S, Shevchenko V, et al: Dalbavancin for the treatment of osteomyelitis in adult patients: a randomized clinical trial of efficacy and safety, Open Forum Infect Dis 6:331, 2018. Shuford JA, Steckelberg JM: Role of oral antimicrobial therapy in the management of osteomyelitis, Curr Opin Infect Dis 16:515–519, 2003. Spielberg B, Lipsky BA: Systemic antibiotic therapy for chronic osteomyelitis in adults, Clin Infect Dis 54:393, 2012. Stengel D, Bauwens K, Sehouli J, et al: Systematic review and meta-analysis of antibiotic therapy for bone and joint infections. Lancet Infect Dis 201 1: 175-188. Tande AJ, Steckelberg JM, Osmon DR, Berbari EF: Osteomyelitis. In Bennett JE, Dolin R, Blaser MJ, editors: Principles and practice of infectious diseases, 9th ed, Philadelphia, 2020, Elsevier. Tice AD, Hoaglund PA, Shoultz DA: Outcomes of osteomyelitis among patients treated with outpatient parenteral antimicrobial therapy, Am J Med 114:723–728, 2003. Waldvogel FA, Medoff G, Swartz MN: Osteomyelitis: a review of clinical features, therapeutic consideration and unusual aspects, N Eng J Med 282:316–322, 1970. Wunsch S, Krause R, Valentin T, et al: Multicenter clinical experience of real life dalbavancin use in gram-positive infection, Int J Infect Dis 81:210, 2019.

100 Urinary Tract Infections Abdullah Chahin, Steven M. Opal

DEFINITION AND DIAGNOSIS The term urinary tract infection (UTI) refers to significant bacteriuria in a patient with symptoms or signs attributable to the urinary tract and no alternative diagnosis. UTI includes asymptomatic bacteriuria, urethritis, cystitis, pyelonephritis, catheter-associated UTI, prostatitis, and urosepsis. This chapter focuses primarily on the two major forms of UTI, cystitis and pyelonephritis. A practical classification divides these infections into uncomplicated and complicated UTI. Uncomplicated UTIs are episodes of cystitis and mild pyelonephritis occurring in healthy, premenopausal, sexually active, nonpregnant women with no history suggestive of abnormalities in the urinary tract. All other episodes of UTI are deemed to be potentially complicated and deserving of further evaluation. The term asymptomatic bacteriuria refers to isolation of bacteria in an appropriately collected urine specimen from an individual who describes no symptoms for urinary tract infection. In women, asymptomatic bacteriuria is defined as two consecutive voided midstream urine specimens with isolation of the same bacterial strain at levels of at least 105 colony-forming units (CFU) per milliliter from patients without genitourinary symptoms. In men, a single clean-catch, midstream voided urine specimen with one bacterial species at a concentration greater than 105 CFU/mL defines asymptomatic bacteriuria. The diagnosis of asymptomatic bacteriuria is also established in both women and men from a single catheterized urine specimen (not an indwelling catheter) with one bacterial species isolated at concentrations greater than 102 CFU/mL. Although infants and toddlers infrequently have asymptomatic bacteriuria, the incidence increases with age, owing to the incomplete bladder emptying from various obstructive urologic conditions that develop with advanced age, reaching up to 15% or greater in women and men age 65 to 80 years and as high as 50% after age 80. Asymptomatic bacteriuria is therefore commonly encountered in clinical practice, and it frequently poses a challenge in determining the exact source of infection in elderly patients presenting with sepsis. Asymptomatic bacteriuria is a common cause for unnecessary use of antibiotics and the array of complications that can result from antibiotic misuse, ranging from mild adverse reactions to devastating complications such as antibiotic-associated Clostridioides difficile infections. The presence of asymptomatic bacteriuria therefore should not be considered as equivalent to UTI except in neutropenic patients and individuals with anatomic or functional defects in the urinary tract. Asymptomatic bacteriuria in pregnancy has been an indication for treatment. However, the most recent Systematic Review for the US Preventive Services Task Force in September of 2019 showed that screening and treatment for asymptomatic bacteriuria during pregnancy was associated with reduced rates of pyelonephritis and low birth weights, but the available evidence was not current, with only one study conducted in the past 30 years. It is difficult to define

asymptomatic bacteriuria in the patient who has undergone renal transplantation, and bacteriuria in such patients often indicates the need to treat for UTI. To increase the sensitivity of urinalysis and culture, significant bacteriuria is defined as greater than 102 CFU/mL of urine in a woman with symptoms of uncomplicated cystitis and pyuria (≥5 white blood cells per milliliter of urine per high-power field). Among women with symptoms of uncomplicated pyelonephritis and men with UTI, significant bacteriuria is defined as greater than 104 CFU/mL plus pyuria. In patients with complicated UTI, a concentration of 105 CFU/mL or higher is required for the definition of significant bacteriuria independently of pyuria. In order for these definitions to be valid, the urine must remain in the bladder for at least 2 hours, and after urine collection the sample should be incubated immediately. If urine is not incubated immediately, it can be refrigerated for up to 8 hours before proper incubation. Although the presence of bacteriuria is vital for the establishment of the diagnosis of UTI, clinical symptomatology is the hallmark of UTI. The presence of dysuria, increased frequency of urination, suprapubic tenderness, and hematuria associated with bacteriuria or pyuria on urinalysis is unequivocally consistent with the diagnosis of cystitis. Back or flank pain, nausea, vomiting, and the presence of fever or rigors suggest infection of the upper urinary tract, although it is not easy to distinguish cystitis from pyelonephritis on clinical grounds alone. The diagnosis of UTI gets more difficult when patients cannot ascribe symptoms to the urinary tract (e.g., patients with paraplegia or neurogenic bladder, confused elderly or sedated patients) or when they have atypical symptoms, such as changes in mental status, agitation, or hypotension. Sometimes patients have urinary symptoms without bacteriuria (the pyuria-dysuria or “urethral syndrome” commonly caused by Chlamydia trachomatis or other difficult-to-culture genitourinary pathogens). With the widespread utilization of indwelling catheters, catheterassociated urinary tract infection (CAUTI) remains a challenge in health care and one of the most common nosocomial infections. Essentially, CAUTI has similar symptoms to a typical UTI but requires the presence of an indwelling urinary catheter for the term to apply. The standard Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN) CAUTI definition is complex and subjective. Moreover, it can be difficult to diagnose in patients who are already hospitalized due to the resemblance of the potential signs and symptoms of CAUTI with many other acute disorders that were part of the original reason for hospitalization.

LABORATORY FINDINGS Young, sexually active women with typical symptoms of UTI have a high pretest probability for UTI. Therefore, no laboratory test is indicated. In this population, pretreatment urine analysis and culture are

925

926

SECTION XV  Infectious Disease

indicated only if the diagnosis is not straightforward or if an antibiotic-resistant organism is suspected. Urinalysis and culture are indicated in all cases of suspected complicated UTI. The presence of white blood cell casts in urinalysis indicates pyelonephritis, and this finding suggests a complicated UTI with possible obstructive lesions within the kidney or collecting system (e.g., papillary necrosis). Blood cultures are mandatory for patients with suspected pyelonephritis. Staphylococcus aureus bacteriuria should prompt work-up for S. aureus bacteremia and for renal abscesses in non-catheter-related UTIs, particularly in those who are hospitalized and have laboratory evidence of infection. S. aureus UTI may also occur without hematogenous seeding in cases of indwelling catheters, with frequent instrumentation, or in the presence of hardware in the genitourinary tract. Candida is a commonly isolated organism on urine cultures (candiduria). Yeasts can be detected in contaminated samples during collection, in patients who have bladder or indwelling catheter colonization, and rarely in patients who have upper urinary tract infection that developed either from retrograde spread from the bladder or hematogenous spread from a distant source. The presence of pyuria and quantitative cultures of urine in cases of candiduria have proved to be of little use in separating infection from colonization. Therefore, clinical symptoms are of great importance, because diagnosing UTI with Candida might necessitate an extensive work-up to assess for invasive fungal infections (Candidemia or perinephric abscesses). Imaging studies are indicated if kidney stones, malignancy, obstructive uropathy, and urologic malformations are suspected.

EPIDEMIOLOGY At the extremes of age, men are more prone to UTI than women. In young boys, urethral malformation is commonly the cause, and in older men, UTI is usually caused by bladder neck obstruction secondary to prostatic hypertrophy. Homosexual men are at increased risk for acquiring UTIs. Teenage girls and sexually active women have more UTIs than their male counterparts. A higher than expected incidence of UTI among young girls might suggest sexual abuse. Sexually active women have the highest rate of UTI. Postmenopausal women have increased prevalence of UTI due to estrogen deficiency and age-related pelvic relaxation with poor bladder emptying. The most common etiologic agent in patients with uncomplicated UTI is Escherichia coli (90% of cases), followed by Staphylococcus saprophyticus. Other agents include Klebsiella spp, Enterococcus faecalis, Enterococcus faecium, Proteus spp, Providencia stuartii, and Morganella morganii. In patients with complicated UTI, E. coli is still the most frequent uropathogen, but at a lower rate than in uncomplicated UTI. Other causative organisms are Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacter spp, Serratia marcescens, Stenotrophomonas maltophilia, Enterococcus spp, and Candida spp. Anaerobic agents are infrequent causes of UTI; when present, they represent fistulae between the digestive tract and the urinary tract. Staphylococcus aureus UTI most often represents bacteremia with bacteriuria resulting from clearance of bloodstream bacteria by the kidney. Whereas 1% of individuals with a UTI get pyelonephritis, 20% to 40% of pregnant women with a UTI develop pyelonephritis, and 30% of patients with pyelonephritis have bacteremia. In diabetic and transplanted patients with UTI, the incidence of bacteremia is higher.

PATHOGENESIS There are at least three routes by which bacteria can enter the bladder or kidney: ascending, hematogenous, and lymphatic. Lymphatic spread is the least common route. The hematogenous route is important for gram-positive organisms such as S. aureus or Candida spp but unimportant for gram-negative bacilli. The ascending route is the most

important for enteric bacteria, and this mechanism is supported by higher frequency of UTI in women, given the shorter length of the female urethra, and in individuals with an indwelling Foley catheter. Before reaching the urinary bladder or kidney, the microorganism must colonize the external part of the urinary tract. Probably the most important aspect in the establishment of UTI is the interaction between host factors (e.g., secretor phenotype, P1 blood group, uroplakin I and II) and bacterial virulence factors (the adhesins, P fimbriae, and type I fimbriae [pili]). The urinary bladder is normally covered by a glycosaminoglycan surface that prevents binding of bacteria that transiently enter the bladder. P-fimbriated uropathogenic E. coli bind to alpha 1-4 linked, galactose-galactose disaccharide moieties found on uroepithelial cells, and these gal-gal glycolipids are also expressed on the P1 blood group. People with P1 blood group are overrepresented among individuals with either recurrent UTI or pyelonephritis. Also, people who lack P1 blood group are less prone to complicated UTI. Studies have shown that P-fimbriated E. coli is present in 60% to 100% of isolates from patients with UTI. Ascending UTI infection can be inhibited experimentally by epithelial cell surface receptor analogues. Type I fimbriae bind to glycoprotein uroplakin I and II. E. coli expressing type I fimbriae are responsible for most cases of cystitis. Once E. coli is attached to uroepithelial cells, both mechanical and biochemical factors facilitate the development of full-blown UTI. The local trauma and mechanical massage of the urethra during sexual intercourse help deliver bacteria into the bladder and, if vesicoureteral reflux or another ureteral anatomic defect is present, into the kidney. Urinary catheter placement also helps to propel bacteria into the bladder, and all patients with a long-term indwelling catheter in place will eventually develop asymptomatic UTI. All uropathogenic organisms have the ability to multiply in the urine. From the standpoint of the host, other factors associated with the development of UTI are a new sex partner (within 1 year), use of diaphragms and spermicides, family history of UTI in a first-degree relative, and lower expression of CXCR1, an interleukin 8 receptor. Pathogenic factors associated with the development of UTI are flagellae, diverse adhesins, siderophores, toxins, polysaccharide coating, and the ability to cause a deleterious inflammatory response. Patient behaviors that are not associated with UTI include precoital or postcoital voiding patterns, daily beverage consumption, frequency of urination, delayed voiding habits, wiping patterns, tampon use, douching, use of hot tubs, and type of underwear.

TREATMENT The goal of treatment in uncomplicated UTI is to decrease symptoms and prevent complications. Treatment should be guided by two important principles: the prevalence of resistant genitourinary pathogens in the community and collateral damage to ecologic microbiota (i.e., the risk of propagation of resistant organisms). First-line agents for uncomplicated UTI are nitrofurantoin, trimethoprim-sulfamethoxazole (TMP-SMX), and fosfomycin trometamol; alternative agents are the fluoroquinolones (except moxifloxacin) and the β-lactams (Table 100.1). Treatment of complicated UTI should be based on culture results and the other comorbidities that are present. Recurrent UTI in sexually active women can be prevented with postcoital TMP-SMX 40/200 mg single dose (if the patient has more than two UTIs per year related to coitus) or with daily, every other day, or weekly antibiotic. If the patient has a UTI unrelated to coitus or there are fewer than two UTIs per year related to coitus, the prevention of the UTI recurrence can be achieved with patient-initiated therapy. Daily topical application of intravaginal estriol can be helpful in postmenopausal women. After completion of the treatment, urine culture is indicated for pregnant women and on an individualized basis for other patients with complicated UTI.

927

CHAPTER 100  Urinary Tract Infections For a deeper discussion on this topic, please see Chapter 268, “Approach to the Patient with Urinary Tract Infection,” in GoldmanCecil Medicine, 26th Edition.

in untreated UTI cases. Serious complications include renal abscesses which usually present with fever, back and abdominal pain and may include urinary tract symptoms. Abscesses are usually due to ascending urinary tract infection often with an obstructive process. E. coli or other enteric aerobic rods are typical organisms. Renal abscess can also be due to hematogenous spread of S. aureus. Prolonged antibiotic therapy directed at the offending organism is usually curative. Perinephric abscess results from rupture of an intrarenal abscess into the perinephric space between the renal capsule and Gerota’s fascia. Treatment is drainage and antibiotics. Some other serious complications of urinary tract infections are listed in Table 100.2.

COMPLICATIONS Unrecognized and untreated UTIs can quickly develop grave complications. Recurrent infections, structural damage of the urinary tract and scar tissue formation, loss of renal function, increased risk of delivering low-birthweight or premature infants in pregnant women, and septic shock could all develop

TABLE 100.1  Therapy for Uncomplicated Urinary Tract Infections CYSTITIS

PYELONEPHRITIS

Antimicrobial Agent

Useful Therapeutically

Dose and Duration

Nitrofurantoin monohydrate macrocrystals

aYes,

first line

No

NA

Reduced renal tissue penetration

Trimethoprimsulfamethoxazole

aYes,

first line

100 mg bid for 5 days Cheap, well tolerated SE: N, H Low impact on microbiome 160/800 mg bid for If resistance is known 3 days to be 4 days after admission) compared with early HAP may be the most useful factor when determining empirical antimicrobial therapy. Although bacteria play the largest role in HAP, fungi and viruses also must be considered in immunosuppressed patients. One definition of HAP or VAP includes clinical, radiographic, and microbiologic criteria. Signs and symptoms indicating an infection include fever (≥38° C), peripheral leukocytosis, purulent sputum, and worsening respiratory status. A tracheal aspirate for Gram stain and culture provides the last piece of diagnostic information. When several of these signs and symptoms exist in the absence of a pulmonary infiltrate, alternative diagnoses should be considered, including ventilator-associated tracheobronchitis. The greatest risk factor for the prediction of MDRO-related pneumonia is prior intravenous antibiotic therapy, whether for HAP or VAP (see Table 101.2). Longer duration of hospitalization increases the risk for acquisition of multidrug resistant pathogens, though the concept of early- and late-onset pneumonia has been challenged by more recent studies. Prior intravenous antibiotic therapy within the last 90 days is an independent risk factor for both MRSA and MDR Pseudomonas aeruginosa. Additional risk factors in VAP include septic shock, acute respiratory distress syndrome (ARDS), 5 or more days prior to occurrence, and prior receipt of acute renal replacement therapy.

INFECTIONS ASSOCIATED WITH VASCULAR CATHETERS The NHSN collects data on CLABSIs, and public reporting is required for CLABSIs in ICUs and certain non-ICU inpatient units. In 2011, the incidence of CLABSIs ranged from 0 to 3.7 cases per 1000 catheter days. In 2015, CLABSIs made up a smaller percentage of HAIs (16.9%) than in 2011 (18.8%). Although CLABSIs have the lowest prevalence

CHAPTER 101  Health Care–Associated Infections

E-TABLE 101.1  Risk Factors for

Developing a Health Care–Acquired Infection Catheter-Associated Urinary Tract Infection Duration Female gender Age >50 years Not maintaining an unobstructed, closed drainage system Ventilator-Associated Pneumonia Endotracheal tube Underlying chronic lung disease Age >70 years Depressed levels of consciousness Gastric alkalinization Nasogastric or enteral feeding tube Previous antibiotic exposure Central Line–Associated Bloodstream Infection Prolonged hospitalization before insertion Duration of catheterization Site of catheterization (femoral > subclavian) Heavy colonization at the site of insertion and on the hub Neutropenia Total parenteral nutrition Substandard maintenance of the catheter Surgical Site Infection Increased age Perioperative hyperglycemia Obesity Smoking Immunosuppressive medications Infections present at time of surgery Malnutrition Operative characteristics: inadequate surgical scrub and skin preparation have been implicated, along with poor timing and dosing of antimicrobial prophylaxis, lower-skilled surgeon, longer operative time, inappropriate tissue oxygenation, and not maintaining normothermia Clostridioides difficile Infection Age >65 years Antimicrobial exposure Health care exposure Gastric acid suppression (controversial whether this is an independent risk factor)

930.e1

CHAPTER 101  Health Care–Associated Infections

931

TABLE 101.1  Strategies for Preventing Health Care–Associated Infections Horizontal Strategies (to Prevent All or Many Types of HAIs) 1. Standard precautions • Hand hygiene • Use of appropriate PPE • Respiratory hygiene and cough etiquette • Appropriate environmental cleaning and waste disposal 2. Chlorhexidine bathing in all ICU patients and in non-ICU acute inpatients with central linesa 3. Isolation precautions appropriate for pathogen 4. Steps to prevent needlestick injuries 5. Education of health care workers on IC/IP protocols Vertical Strategies (Specific to HAI Type) CAUTI Urinary catheter placed only for appropriate indications: Urinary retention or obstruction Need for accurate UOP measurement in critical illness Incontinence and perineal or sacral wounds Comfort care use for terminal illness Consider alternatives: Condom catheters Intermittent catheterization Proper insertion and maintenance: Maintain aseptic technique Properly secure catheter to patient Maintain closed drainage system Maintain unobstructed flow Urinary catheter premeditated stop order or RN-initiated discontinuation policy Anti-infective catheters if infection rates remain high Reflexive culture testing algorithms to reduce false diagnosis of urinary tract infection VAP Use noninvasive ventilation when able On intubation: Semirecumbent position (30–45 degrees) unless contraindicated Hypopharyngeal suctioning Avoid gastric overdistention Use cuffed ET tube Oral care, tooth brushing Keep ventilatory circuit closed unless changing for soiling or malfunctioning Daily targeted sedation management Spontaneous breathing trial if screening finds applicable Use weaning protocols to minimize duration of ventilation

CLABSI Use checklist for device insertion: Bundle supplies All present use at least face mask, then proceduralist uses sterile gown and gloves, mask, and head cap Avoid femoral line placement if possible Skin antisepsis with alcohol and >0.5% chlorhexidine Use of chlorhexidine-impregnated dressing or sponge at insertion site Empower personnel to stop nonemergent insertion if improper technique is followed Maintenance: Access as infrequently as feasible Scrub the access hub or port with antiseptic Daily bathing with chlorhexidine and intranasal antiseptic with mupirocin or povidone-iodine Daily audits for assessment of device need and potential discontinuation Interventions to reduce blood culture contamination that may be falsely assessed as true bacteremia SSI Preoperative strategies: Nonirritative hair removal with clippers on the day of surgery (not razors) Eradicate remote infection Decolonization of Staphylococcus aureus CHG bathing Smoking cessation Glucose control, hemoglobin A1c 100 for >3 mo

CD4 150 for >6 mo

Toxoplasma gondii

Mycobacterium avium complex

Mycobacterium tuberculosis

Histoplasmosis

Isoniazid (INH) 300 mg daily × 9 months Alt: Rifapentine + INH 900 mg once weekly for 12 weeks Alt: Rifampin 10 mg/kg/day (600 mg max) × 4 months Itraconazole 200 mg daily

Cryptococcosis

Fluconazole

Pneumocystis Pneumonia Pneumocystis jirovecii is a ubiquitous yeast in the environment. It is not associated with disease except in the setting of immunocompromise. Before the widespread use of ART and prophylactic medications, Pneumocystis jirovecii pneumonia (PJP or PCP; both abbreviations are still used) occurred in 70% of patients with AIDS, and the course of treated PCP was still associated with 20% to 40% mortality. The typical presentation is subacute, with progressive fever, shortness of breath, and weight loss over weeks. Profound desaturation with exertion is a common clinical sign, as is a substernal catch on inspiration. Hypoxemia is the most common laboratory abnormality. A serum LDH greater than 500 is common, and a serum 1,3-β-D-glucan is commonly elevated as well. Both of these can be helpful diagnostically. Definitive diagnosis can be made on sputum sample; induced sputum may be positive, though often bronchoscopic sampling for DFA and/or PCR testing is needed. Radiographic findings are classically described as diffuse, bilateral, symmetrical “ground-glass” interstitial infiltrates emanating from the hila in a “butterfly” pattern. However, it is important to remember that 10% of patients will have a normal radiograph, and 30% will have nonspecific findings. Atypical findings such as nodules, blebs, or cysts, can occur, as can spontaneous pneumothorax. Early initiation of treatment is crucial, and treatment should not be delayed while waiting for diagnostic results in patients with a high index of suspicion. First-line therapy is trimethoprim-sulfamethoxazole 15 to 20 mg/kg/day in divided doses over a 21-day course. Steroids should be added in patients with moderate or severe disease, generally defined as a PO2 of less than 70 or an Aa gradient of 35 mm Hg or greater. Alternative treatments for mild-to-moderate disease include primaquine with clindamycin, dapsone with trimethoprim, or atovaquone. Alternative treatments for moderate-to-severe disease include primaquine with clindamycin or intravenous pentamidine. Due to the high prevalence of Pneumocystis, prophylaxis with trimethoprim-sulfamethoxazole is recommended for all patients with a CD4 count less than 200. Alternatives include dapsone, atovaquone, or

Stop after completion of recommended LTBI treatment duration

inhaled pentamidine. In patients with a CD4 count between 100 and 200, prophylaxis can be discontinued once the serum HIV viral load is undetectable for 3 to 6 months. See Table 103.3 for prophylaxis guidelines.

Cryptococcal Disease Cryptococcus neoformans is a yeast that generally affects immunocompromised individuals. It enters the body through the lungs, though pulmonary disease is often asymptomatic. Meningitis is the most common clinical presentation of cryptococcal disease, but cutaneous manifestations, classically presenting as umbilicated papules, may be present in 10% of patients. Cryptococcal meningitis occurs in about 1 million cases per year worldwide, with an estimated 600,000 deaths annually. Classic meningeal symptoms occur in only 25% of patients; more commonly, patients present with progressive headache, lethargy progressive to encephalopathy, personality changes, memory loss, coma, and death. A serum cryptococcal antigen test is generally positive, but a lumbar puncture must be performed both for diagnosis and for therapeutic purposes to evaluate CSF pressure (and relieve it, if elevated). CSF studies will generally show an elevated total protein and low glucose, and CSF cryptococcal antigen testing will be positive. India ink staining of the CSF, though uncommon now in the United States, will show encapsulated yeast forms. CSF lymphocyte counts may be elevated or may be normal. A minimal inflammatory response is common; in fact, 55% of patients with AIDS-related cryptococcal meningitis have a CSF lymphocyte count of less than 10 cells/mL. This lack of immunologic response is associated with a poorer prognosis. Treatment is focused on (1) management of CSF pressures through serial lumbar puncture with removal of CSF until pressures return to normal range and (2) antifungal therapy. Therapy is generally divided into three phases: induction, consolidation, and maintenance. Induction therapy is with amphotericin B and flucytosine. Once CSF cultures have cleared and patients have completed at least 2 weeks of therapy, consolidation with high-dose oral fluconazole is continued

CHAPTER 103  Human Immunodeficiency Virus Infection for 8 additional weeks. Maintenance therapy is with oral fluconazole 200 mg daily for a minimum of 1 year.

Toxoplasma Encephalitis Toxoplasma gondii is an obligate intracellular protozoan that most commonly causes encephalitis in patients with AIDS, though it may also present with retinitis or in skeletal muscle or myocardium. Primary infection occurs from eating undercooked meat containing tissue cysts or ingesting oocysts that have been shed in cat feces and sporulated into the environment. Clinical disease in PLWH is usually due to reactivation. Patients present with a focal encephalitis with headache, confusion, motor weakness, and fever. In the absence of treatment, disease will progress to seizures, stupor, coma, and death. Imaging is usually the means of diagnosis, with contrast-enhanced MRI showing multiple contrast-enhancing lesions in the gray matter of the cortex or basal ganglia, often associated with edema. Because disease is usually due to reactivation of latent disease, patients may have a positive serum anti-toxoplasma IgG. CSF testing for toxoplasma PCR may be positive as well. Treatment is initiated based on high clinical suspicion rather than definitive diagnosis. If repeat imaging in 1 to 3 weeks does not show response to treatment in all visualized lesions, brain biopsy may be necessary. In this scenario, biopsy is important to rule out alternative diagnoses such as CNS lymphoma, progressive multifocal leukoencephalopathy (PML), or tuberculosis, among others. Treatment consists of pyrimethamine and sulfadiazine with leucovorin to reduce hematologic toxicity. Treatment is for a minimum of 6 weeks; then patients should be put on chronic maintenance therapy until the CD4 has been greater than 200 for over 6 months. Primary prophylaxis for Toxoplasma with trimethoprim-sulfamethoxazole should be initiated in any patient with a CD4 count less than 100, with atovaquone as an alternative. See Table 103.3 for prophylaxis guidelines.

Mycobacterium Tuberculosis Tuberculosis is the most common opportunistic infection seen worldwide in people living with HIV disease and in fact is the leading cause of death due to infectious disease worldwide. PLWH may either acquire acute disease through inhaling droplet nuclei or suffer reactivation disease due to impaired cellular immunity. The annual risk of reactivation tuberculosis disease in people living with HIV is estimated to be 3% to 16% per year. Reactivation can occur at any CD4 count but is higher risk the more significant the immunodeficiency. The greatest risk in people living in the United States is birth or residence outside the United States because global rates of tuberculosis are much higher than in the United States itself. Clinical presentations of people living with HIV are generally not different than in people who do not have HIV, but presentations of severe systemic disease and disseminated disease are more common. Clinical manifestations can be protean, but classic symptoms of fever, cachexia, and night sweats remain common. Pulmonary disease is still the most common presentation. Chest radiographs in patients may show features of primary tuberculosis, including hilar adenopathy, lower or middle lobe infiltrates, miliary pattern, or pleural effusions, as well as classic patterns of reactivation with upper lobe disease. Less common presentations include pericarditis, pericardial effusions, meningitis, CNS lesions, and bony disease. Diagnosis is determined in the same manner as in HIV-negative patients, and treatment does not differ, though careful review of medications is important to avoid significant drug/drug interactions that can occur between antiretrovirals and antituberculous medications. See Chapter 94 for more details.

Nontuberculous Mycobacterial Disease A number of different nontuberculous mycobacteria are associated with advanced HIV disease, though far and away the most common is Mycobacterium avium complex (MAC). The incidence of MAC in

951

patients with severe AIDS-associated immunosuppression is 20% to 40% in the absence of effective ART or chemoprophylaxis. Disease tends to occur with a CD4 count less than 50 and a high HIV viral load (usually greater than 100,000). MAC often presents as a disseminated disease with fever, night sweats, weight loss, diarrhea, and abdominal pain. On physical examination, hepatosplenomegaly and lymphadenopathy are common. Laboratory testing is often initially nonspecific, though anemia and an increased alkaline phosphatase are common. Diagnosis is usually made on a compatible clinical syndrome and isolation of MAC on culture or AFB stain on tissue with confirmation on culture. Cultures can be sent from blood, lymph node biopsy, bone marrow, or other tissues or fluids felt to be infected. Treatment is with two or more drugs, usually clarithromycin or azithromycin with ethambutol. Rifabutin may be added as a third agent in some cases. Treatment is for a minimum of 12 months and may then be discontinued when patients are asymptomatic and have a CD4 count greater than 100 for over 6 months. Prophylaxis against MAC is no longer recommended routinely for those who are immediately initiating ART, based on literature demonstrating no added benefit when ART is initiated promptly. Prophylaxis is therefore only recommended in those with a CD4 count less than 50 who are not receiving ART or who are not on fully suppressive ART, and only once active MAC disease has been ruled out based on clinical assessment, including a baseline AFB blood culture. Prophylaxis is generally with azithromycin 1200 mg once weekly.

Progressive Multifocal Leukoencephalopathy PML is an opportunistic infection of the CNS caused by JC virus, a polyoma virus that causes focal demyelination. JC virus is common throughout the world and demonstrates a seroprevalence of 39% in healthy adults. PML is a disease that occurs with profound immunosuppression in people with HIV (CD4 20,000 IU/mL), those with a family history of hepatocellular carcinoma, Asian males over 40, Asian females over 50, and all Africans and African Americans.

Cardiovascular Disease Before ART, patients with HIV with low CD4 counts were at risk for myocarditis, pericardial effusion, and dilated cardiomyopathy, but at present these conditions are markedly less common. What has become apparent, however, is an increased risk for cardiovascular disease, including both myocardial infarction and stroke. In a landmark study from the US Veteran Affairs system in 2013, PLWH were found to have a 50% increase in acute myocardial infarction compared to HIV-uninfected patients, even after controlling for traditional risk factors such as smoking and diabetes. In a more recent review in 2018, a relative risk of 2.16 for cardiovascular (CV) disease in PLWH was noted. Unlike HIV-negative patients, there is an increased rate (up to 50%) of type II myocardial infarction (vasospasm, endothelial dysfunction) compared to type I (thromboembolic) infarction, suggesting different etiologic processes. Longitudinal studies have shown that the risk for stroke and, more recently, congestive heart failure are similarly elevated.

955

Several additional features of CV disease are worth noting. Longterm studies from the Kaiser Permanente system in California and from Europe initially demonstrated increased rates of CV disease in PLWH but found that more recent data in selected populations saw a convergence of rates with HIV-negative patients, perhaps due to improvements in CV prevention, such as the widespread use of HMG co-A reductase inhibitors (“statins”). It is also worth noting that PLWH do have a higher prevalence of some risk factors for CV disease, particularly smoking, diabetes mellitus, renal disease, metabolic syndrome, and hypertension. The risk conveyed by these factors in total is of a much larger magnitude than that contributed by HIV itself. Thus, addressing these risk factors is particularly important in this population that has a baseline elevated CV risk due to HIV. Proven interventions include smoking cessation and the use of antihypertensives and statins, which should be prescribed following American College of Cardiology/American Heart Association guidelines. Improving diet and exercise also are important, especially for patients as they age. The effect of certain antiretrovirals on CV risk remains an area of controversy. Protease inhibitors (PIs) are known to have an adverse effect on the metabolic profile, including inducing hyperlipidemia, when compared to newer classes of ART drugs such as integrase inhibitors. Risk is not necessarily uniform across the class; a recent cohort analysis specifically identified darunavir to be associated with increased risk when compared to atazanavir. In addition, several studies have shown that abacavir increases CV risk, but these findings have not been confirmed in others. Integrase inhibitors and newer reverse transcriptase inhibitors have a lesser effect on patients’ lipid profiles, although integrase inhibitors have been associated with more weight gain than other classes, which itself may raise the risk of other diseases that raise CV risk (e.g., diabetes, hypertension).

Renal Disease In the early years of the HIV epidemic, a new form of progressive renal disease was identified, termed HIV-associated nephropathy (HIVAN). It was characterized by rapidly progressive renal failure and nephrotic-range proteinuria. This disease was found to be more common in African Americans. The incidence of HIVAN rose until the mid-1990s and then fell with the advent of effective ART. Although HIVAN has become uncommon, the incidence of chronic renal disease in PWHV remains significantly higher than in the general population. The prevalence of stage III chronic kidney disease (glomerular filtration rate of 30 to 59 mL/min) has ranged from 3.5% to 9.7%. PLWH are more than 16 times more likely to need renal replacement therapy. The etiology of renal disease in PLWH is multifactorial; risk factors include low CD4 counts, high viral loads, hypertension, diabetes mellitus, cardiovascular disease, African American race, hepatitis C coinfection, and prior exposure to certain ART drugs such as tenofovir. Patients are also at risk of acute kidney injury, particularly in the setting of dehydration, infection, and polypharmacy. In addition, patients may develop immune complex kidney disease and thrombotic microangiopathy. Most important in prevention and treatment of renal disease is the use of effective ART and consistent monitoring of renal function. Controlling both hypertension and diabetes are also essential in preventing the progression of renal disease.

Osteoporosis and Bone Disease PLWH have increased rates of osteopenia and osteoporosis and consequently longitudinal controlled studies have shown an almost 3-fold rate of fractures compared to that of the general population. Risk factors for decreased bone density are usually multiple and include effects of ART, particularly protease inhibitor– and tenofovir disoproxil fumarate–containing regimens; low body weight; vitamin D deficiency;

956

SECTION XV  Infectious Disease

alcohol use; hypogonadism; opiate exposure; smoking; and effects of HIV itself. Patients should be assessed for vitamin D deficiency and other risk factors and treated and counseled appropriately. Bone density assessment by dual-energy x-ray absorptiometry (DXA) is recommended for all men with HIV who are over 50, all postmenopausal women, those with a history of fragility fractures, patients on chronic corticosteroids, and patients at high risk for fall. Risk of fragility fracture should be assessed primarily using the Fracture Risk Assessment Tool (FRAX). ART regimens should be reviewed for osteopenia and osteoporosis risk. Patients diagnosed with osteopenia or osteoporosis should be treated following established guidelines.

Endocrine Disorders Metabolic Syndrome

PLWH are at increased risk for metabolic syndrome, which includes central obesity, insulin resistance, hypertension, and hypertriglyceridemia. Some classes of ART such as protease inhibitors seem to increase the risk for metabolic syndrome, and this risk translates into increased risk for CV disease. Treatment with weight loss and exercise, anti-hypertensives, and diabetic medications if diabetes is diagnosed, are recommended.

Diabetes Mellitus The risk for diabetes mellitus (DM) in PLWH patients was not initially appreciated but has become apparent in more recent years. One estimate is that the relative risk for DM in PLWH is 2.4 when compared to the general population. This risk is compounded by the rates of metabolic syndrome, obesity, and adverse lifestyle (such as poor diet and low rates of exercise). In addition, a diagnosis of DM markedly increases the risk for CV disease, including stroke and peripheral vascular disease, as well as renal disease. Screening PLWH with a hemoglobin A1c or fasting blood sugar on an annual basis is important, particularly as the population ages. Treatment for patients at risk for DM and those with DM should follow established guidelines for management of diabetes.

Other Endocrine Disorders Other endocrine disorders that disproportionately affect PLWH, particularly those with low CD4 counts, include adrenal insufficiency (AI), hypogonadism, and male gynecomastia. In the pre-ART era, adrenal gland pathology caused by CMV and mycobacteria was frequent, but clinical AI characterized by malaise, orthostatic hypotension, weight loss, hyponatremia, and hypoglycemia, was uncommon. Clinical AI remains rare. Hypogonadism is common in men with HIV and may manifest as erectile dysfunction and loss of libido but may also occur more subtly with low energy, depression, or inability to gain muscle mass. Screening with serum testosterone may indicate hypogonadism that can be treated with androgen replacement therapy. Gynecomastia in men with HIV may also occur and be due to hypoandrogenism, liver disease, medication side effects, or as a part of normal aging.

Nonalcoholic Fatty Liver Disease Nonalcoholic fatty liver disease (NFLD) ranges from simple hepatic steatosis (or fatty liver) to NASH and hepatic fibrosis that can lead to cirrhosis. The rates of steatosis and NASH in PLWH are increasing and appear to be greater than in the general population, perhaps because of the increased rates of obesity, metabolic syndrome, and diabetes mellitus. NASH and subsequent cirrhosis pose a significant risk for PLWH and emphasize the importance of preventative measures including weight control.

Obesity In the early years of the HIV epidemic, advanced AIDS was associated with low weight, and in fact one of the characteristics of the disease

was wasting and inanition. Effective ART prevented and even reversed this manifestation of infection, even in end-stage AIDS. Now with PLWH on ART, a new problem has arisen—obesity. In countries like the United States, the rates of obesity in PLWH (20% to 31%) match the rates in the general population. Rates of complications related to obesity in PLWH, such as diabetes mellitus and cardiovascular disease, are nearly twice the rates in uninfected patients. Rates of obesity in PLWH may be related to a combination of factors including poor diet quality, greater food insecurity, lack of exercise, and genetics. Perhaps most important, however, has been the lack of awareness of the consequences of obesity and also the best approaches to losing weight. Although there has been a dearth of research in the treatment of obesity in PLWH, behavioral weight loss programs focusing on behavior change, diet, and exercise have been shown to be effective for this population. In addition, bariatric surgery for morbidly obese patients has been an effective strategy in individual cases.

Aging and HIV The average age of the first 1000 cases of HIV reported in 1983 was 34 years. With the advent of effective ART, the age of PLWH has steadily increased so that by the year 2015, it was estimated that 50% of PLWH were over the age of 50, and by the year 2030 it is estimated that 70% will be over the age of 50. Similar trends, although delayed, are being observed worldwide in low- to medium-income countries. Despite this increase in the age of PLWH, mortality remains elevated compared to the general population, although there is great heterogeneity. Individuals with risk factors such as low CD4 count, elevated viral loads, drug use, hepatitis coinfections, and other comorbidities have increased mortality rates, whereas subgroup analysis of population studies have shown that individuals with CD4 counts greater than 350 cells/microliter at diagnosis, consistent viral suppression, and an absence of other risk factors have a life expectancy similar to uninfected individuals. Nonetheless, most population studies comparing PLWH to the general population, controlling for risk factors, have shown a decrease in life expectancy of anywhere from 2 to 13 years depending on the subpopulation. Whether HIV infection accelerates the aging process has been a controversial subject and continues to be investigated. It is known, however, that HIV is associated with chronic inflammation at levels that are similar to older individuals. Inflammation is presumed to be driven by ongoing low-level viral replication, even in virally suppressed individuals, and by the effect of the initial damage to the immune system during acute HIV infection (e.g., injury to gut immune tissue). Elevated markers of inflammation include elevated levels of IL-6, elevated markers of microbial translocation, and elevated levels of macrophage activation. In addition, immune dysregulation and immune senescence as evidenced by decreased pools of CD4 T cells, increased senescent CD8 T cells that secrete cytokines, and an inability to respond robustly to new antigens, all occur in PLWH as well as elderly noninfected people. Increased inflammation and immune dysregulation are part of the normal aging process but appear to occur earlier in PLWH. In addition, as discussed previously, PLWH are at increased risk for a variety of comorbidities, some of which are associated with increased inflammation, such as cardiovascular disease. Compared to age-matched controls, PLWH have higher rates of geriatric syndromes including falls, urinary incontinence, difficulty with activities of daily living, slow gait, decreased vision and hearing, and frailty. As a result, they are at increased risk for associated morbidity. In addition, PLWH are more likely to develop frailty early. Frailty is defined several ways, but Fried’s criteria are commonly used and include decreased strength, endurance, activity, and walking speed, as well as weight loss. Patients with frailty are at significant risk for poor outcomes including hospitalization and death. Risks for frailty

CHAPTER 103  Human Immunodeficiency Virus Infection

957

in PLWH include low current and nadir CD4 counts as well as other comorbidities and geriatric syndromes. As the population of PLWH ages, recognizing and addressing both geriatric syndromes and frailty will be increasingly important in their care. Finally, aging patients in general face a number of challenges to their health and well-being including comorbidities, increasing physical impairments, loss of partners, and family and social isolation. PLWH are particularly at risk for some of these challenges and in addition many face challenges such as poverty, housing and/or food insecurity, and concern for safety. The loss of friends and community is particularly stressful and has been described by one aging PLWH as “a shrinking kind of life.” It is important for physicians caring for PLWH to be aware of these issues.

off in the coming years. The presence of STIs increases the risk of HIV transmission from partner to partner, particularly syphilis and herpes simplex disease. In people living with HIV, rates of STIs have also increased. As “undetectable = untransmittable” becomes a more commonly understood concept among patients, education about protecting themselves from acquiring STIs is important as patients make informed decisions about condom use. Annual STI screening, or more frequent depending on risk behavior, is important in sexually active patients. Treatment of these STIs is the same in HIV-negative as in HIV-positive persons and the response to treatment is good.

Mental Health

Initial Counseling and Ambulatory Evaluation

As HIV has changed to a chronic and manageable illness, the emphasis of mental health treatment has shifted from managing acute syndromes to helping patients live well. Depression and anxiety, as well as other mental illnesses, are very common among PLWH. Often patients will not feel comfortable acknowledging the need for mental health care. For many PLWH, their HIV physician may be their only health care provider, and therefore it is crucial for providers to offer routine screenings for mental health concerns such as depression and anxiety. Screenings will also offer opportunities for physicians to facilitate referrals for additional mental health evaluation and appropriate behavioral and psychiatric care. Trauma is not uncommon and treatment of PTSD can be very helpful.

Once HIV is diagnosed, the health care provider should talk to the patient about the clinical course and treatment of HIV infection and the use of immunologic and virologic studies (e.g., CD4 counts, PVL assays) to guide therapy. Stigma related to HIV remains an important concern and a key barrier to engagement in care. Addressing this as part of post-test counseling and intake to care is key to retention in care for persons newly diagnosed. The patient should be educated about modes of HIV transmission through unprotected sex or sharing of needles. The benefit of “U=U” (undetectable = untransmittable) should be discussed with patients so they understand that initiating treatment and achieving an undetectable viral load is both important for their own health as well as their partners. The initial evaluation should include both an HIV-oriented review of systems and a complete physical examination. In particular, the skin must be examined for HIV-associated rashes and Kaposi’s sarcoma. Examination of the oral cavity may reveal thrush, gingivitis, hairy leukoplakia, superficial ulcers caused by HSV, aphthous ulcers, or lesions characteristic of Kaposi’s sarcoma. In persons with very advanced disease, the optic fundi may have hemorrhagic lesions characteristic of CMV retinitis. Lymph node enlargement, hepatomegaly, splenomegaly, and any genital lesions should be carefully noted. Neurologic examination for both peripheral neuropathy and decreased global cognition deserves close attention.

Substance Use Disorder Substance/alcohol use and substance/alcohol use disorders are common among PLWH. Alcohol use (e.g., problematic and binge drinking) may also co-occur with the use of substances (e.g., cocaine, methamphetamine). Both alcohol use and substance use have been associated with higher rates of risk-taking behaviors (e.g., condomless sex with multiple partners) and have also been associated with decreased adherence to ART. It is also important to note that many individuals who use substances maintain high levels of adherence to ART; thus, the existence of substance or alcohol use should not prevent physicians from prescribing ART. There are many factors that contribute to or exacerbate substance and alcohol use. For instance, among methamphetamine users, there exists a high correlation between methamphetamine use and chemsex behaviors. Other common factors that may perpetuate continued use include co-occurring mental health diagnoses (e.g., PTSD, anxiety, ADHD), minority stress, and environmental instability. Many studies have shown that treatment of opiate use disorders with medication assisted therapy, such as buprenorphine, can be done in conjunction with HIV treatment. Likewise, treatment of alcohol use disorders can be done in conjunction with HIV treatment. Whereas pharmacotherapy for stimulant use disorders is lacking, the patient-physician relationship can still play an important role in facilitating referral for evidence-based behavioral care for stimulant use. Importantly, patient-centered HIV care cannot focus solely on HIV viral suppression but must proactively address mental health and substance use concerns to promote the goal of patients living meaningful lives with the chronic disease of HIV. Routine screening for substance abuse treatment (i.e., at regular follow-up visits) is recommended. Co-locating substance abuse treatment with HIV care (i.e., one stop shopping) is preferred.

Sexually Transmitted Infections Rates of sexually transmitted infections (STIs) continue to rise in the United States, reaching an all-time high in 2018 (the last available reported data at the time of this publishing), with no sign of leveling

HIV MANAGEMENT AND TREATMENT

Laboratory Monitoring The CD4 count and the PVL should be measured at the first visit, and the patient should be shown the results. Graphic illustrations of the interaction between PVL and CD4 can be useful to increase patient understanding. HIV genotyping to assess for drug resistance should also be performed. The PVL is a key measure of treatment adherence and is repeated at regular intervals, generally 2 to 8 weeks after initiation of therapy and every 3 to 6 months once patients are stably on treatment. Once a patient is stable on treatment with suppressed virus (500,000 copies/mL, HBV coinfection, or in whom ART is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available

Raltegravir (Isentress) plus emtricitabine or lamivudine plus tenofovir alafenamide or tenofovir disoproxil fumarate

AI

BI for TDF BII for TAF

TABLE 103.7B  Generally Recommended Initial Regimens (IAS-USA) Drug Combination Bictegravir/tenofovir alafenamide/emtricitabine (Biktarvy) Dolutegravir/abacavir/lamivudine (Triumeq)

Dolutegravir (Tivicay) plus emtricitabine/tenofovir alafenamide (Descovy)

Details

Strength AIa

Testing for HLA-B*5701 allele should be performed before abacavir use (evidence rating AIa); patients who test positive should not be given abacavir (evidence rating AIa). Because it typically takes several days or longer to obtain results for HLA-B*5701 testing, tenofovir-containing regimens should be used when starting ART on the same day as HIV diagnosis or until HLA-B*5701 testing results are available. In patients with or at high risk for cardiovascular disease, a tenofovir-containing regimen, rather than an abacavir-containing regimen, should be used if possible. In settings in which TAF/emtricitabine is not available or if there is a substantial cost difference, TDF (with emtricitabine or lamivudine) is effective and generally well tolerated, particularly if the patient does not have, or is not at high risk for, kidney or bone disease

Because of this, baseline resistance testing is recommended prior to initiation of ART. Treatment does not necessarily need to be delayed until results are available, as resistance testing can take several weeks to result. If treatment is initiated empirically, adjustments should be made promptly if resistance is discovered. Repeat resistance testing should be considered in the setting of treatment failure to help determine whether the patient’s virus has developed resistance to the current regimen, or whether medication adherence, drug/drug interactions, absorption, or another issue is the reason for virologic failure. Resistance testing can be performed in three major ways. The most common method is HIV-1 RNA genotyping. This involves direct sequencing of viral genes that encode the drug target proteins (i.e., reverse transcriptase, protease, and integrase). Genes are sequenced and compared to the wild-type genotype and previously determined resistance mutations. A second method for identifying resistance is by performing HIV-1 phenotype testing. This involves replication of the virus in culture when exposed to various antivirals. This provides a direct measure of viral resistance in vitro; growth would be expected to occur in the presence of a drug if the virus harbors resistance mutations to that agent. Finally, cellular-associated DNA genotyping allows for resistance testing even in the setting of patients with undetectable PVLs. This testing involves sequencing of archived HIV-1 proviral DNA that has been integrated into infected host cells during virus replication. The choice of a resistance test depends on the patient’s viral load and the desired information. In patients determined to have resistance, several resources are available to help choose a new regimen. The IAS-USA has developed a useful catalog of resistance mutations that is available online at https://

AIa

AIa

www.iasusa.org/resources/hiv-drug-resistance-mutations/. Stanford University also maintains an interactive web-based database of known HIV resistance mutations, which is also freely available online at https://hivdb.stanford.edu. Its interactive format allows the user to input specific mutations and it will generate a predicted susceptibility profile of all available drugs. Use of these resources and expert consultation with an HIV specialist experienced in treatment of resistant virus is recommended.

Future Directions of Antiretroviral Treatment Current antiretroviral therapy has made leaps and bounds from the early regimens, which involved multiple drugs with high toxicity given multiple times per day. Today, most patients can be treated with a small number of pills—usually one—dosed once or twice a day. Still, treatment is advancing. Several new regimens are challenging the “triple-therapy” paradigm, including two-drug combinations that demonstrate noninferiority when compared to traditional threedrug first-line regimens. More are sure to come. A few other treatment options that are likely close on the horizon include the following: 1. Injectable regimens: Clinical trials of injectable therapy have been completed, showing high efficacy and patient acceptance of oncemonthly injectable treatments. Some issues of concern with these regimens include the need for more frequent appointments, how to provide oral “bridge” therapy to patients missing an appointment, how to deal with adverse reactions of medications with long half-lives, and concern over the subtherapeutic tail that follows discontinuation of an injectable depot-type regimen. Even so, these regimens present an exciting new direction for therapy.

CHAPTER 103  Human Immunodeficiency Virus Infection 2. Implantable slow-release medications: Similar to implantable contraceptive devices, implantable antiretroviral-delivery devices offer an attractive approach to infrequent (once-monthly or even longer) dosing. The minor surgery needed for placement of the device is a concern, as is any complication of removal. 3. Oral agents with longer half-lives: Several oral agents are in development that might be able to be dosed once weekly or longer. As with injectable regimens, concerns remain about how to deal with adverse reactions of medications with long half-lives and the subtherapeutic tail that follows discontinuation. 4. New drug classes: Several new drug classes with novel mechanisms of action are in development and provide hope for patients with complex resistance patterns, patients who struggle with side effects of current regimens, and those seeking new delivery methods or dosing intervals. Classes currently in development include attachment inhibitors, nucleoside reverse transcriptase translocation inhibitors (NRTTIs), maturation inhibitors, monoclonal antibodies to CCR5, capsid inhibitors, and broadly neutralizing antibodies.

HIV CURE RESEARCH Thus far, there have only been two documented cases of HIV cure. The first case, described as the “Berlin patient,” was reported in 2009. He was a man with refractory AML who had HIV infection with a CCR5tropic virus. He received two hematopoietic stem cell transplants, the second from a CCR5-negative donor. He also received total body irradiation and anti-thymocyte globulin. The second case, the “London patient,” was reported in 2019. This patient had refractory Hodgkin’s lymphoma and HIV with CCR5-tropic virus and received a stem cell transplant from a CCR5-negative donor. The patient did not receive irradiation, and T-cell depletion was achieved with an anti-CD52 agent. Both patients had mild graft-versus-host disease (GVHD). Both patients have had no recurrence of HIV viremia and no isolation of active virus from any tissue samples despite remaining off of antiretroviral therapy. These cases both illustrate extreme examples of potential routes to a cure—stem cell transplants carry a very high mortality, and GVHD is a lifelong disease that can have significant morbidity. However, the cases do demonstrate that the possibility of a cure is more than just theoretical, and ongoing studies for a cure to HIV is an area of intense research. As a retrovirus, HIV integrates into the host genome, and latently infected cells are the primary reason that ART is not curative. All current ART targets viral proteins involved in viral replication; therefore, they are ineffective at removing the viral reservoir of latent disease, as the target viral proteins are not active in latently infected cells. Stopping ART always results in a recurrence of viremia over time in PLWH, as latent cells awaken and replication resumes. Thus the problem of finding a cure for HIV is largely a problem of determining how to cure latently infected cells. Further, currently ART is highly effective and very well tolerated, resulting in an essentially normal life expectancy. Ethically, the “cure” cannot be worse than treatment; this poses a high bar for researchers. A safe, effective, scalable, well-tolerated, and cost-effective intervention that is fully curative, or that allows for longterm viral control without the use of ART, is still many years away, but the groundwork has now been laid.

HIV PREVENTION, PEP AND PREP Three broad approaches have had a major impact on reducing HIV transmission: harm reduction and behavioral modification, ART for “treatment as prevention,” and the use of medications for pre- and

961

postexposure prophylaxis. All of these activities are supported by expanded testing and improved linkage to care. Harm reduction and behavior modification are broad categories of public health interventions to prevent HIV transmission. An example is the adoption of safer sexual practices, especially the use of condoms during sexual activity to prevent HIV transmission. Other interventions, such as those targeted toward people who inject drugs, including syringe exchange programs, safe injection facilities, and community methadone and buprenorphine programs, have also had a marked effect on reducing risk of HIV transmission. Many other approaches in the appropriate clinical and societal context can also have significant impact, such as male circumcision in highly impacted communities. Treatment as prevention is the cornerstone of efforts to control the worldwide HIV epidemic, and widespread access to ART is a key goal of HIV prevention efforts today. Antiretroviral treatment of HIVinfected pregnant women and their infants in the peripartum period has decreased maternal-child transmission from 25% to less than 5% in North America. If a pregnant woman maintains viral suppression during pregnancy and during breast-feeding, the risk of transmission to her infant is less than 1%. Among sexually active individuals, a number of studies across thousands of individuals have demonstrated that patients who are on treatment and undetectable cannot transmit HIV to their sexual partners, regardless of condom use. The strength of these data are robust and results are consistent across multiple large studies in different populations across multiple countries, including in both heterosexual and MSM populations. In fact, none of the studies demonstrated a single case of transmission from an undetectable patient to their partner. The power of treatment as prevention has led to the popular educational campaign of “U=U” or “undetectable = untransmittable.” The use of ART has also been shown to be an effective tool for HIV prevention as postexposure prophylaxis after both occupational exposures to HIV (termed “PEP”) and after unprotected sexual exposures (termed “nPEP”). Guidelines for PEP and nPEP recommend treatment as early as possible, within 72 hours at the most after an exposure. The treatment regimen should be based on the source patient’s resistance pattern, if known, or if unknown, is generally with two NRTIs (tenofovir disoproxil fumarate and emtricitabine) and an integrase inhibitor (either raltegravir or dolutegravir) for 28 days. Occupational PEP is highly effective, and post exposure seroconversion of health care workers is virtually nonexistent since implementation of PEP. Guidelines for both PEP and nPEP are available through the CDC at: https://www. cdc.gov/hiv/risk/pep/index.html. The use of ART for PrEP in HIV-negative individuals at high risk for HIV exposure has demonstrated excellent efficacy across multiple studies and populations. In individuals at high risk for sexual exposure, including MSM, individuals in serodiscordant relationships, sex workers, and individuals with multiple sexual partners, the daily use of either tenofovir disoproxil fumarate with emtricitabine (the combination tablet Truvada) or tenofovir alafenamide with emtricitabine (Descovy) has been shown to reduce risk of HIV transmission by 99% if taken with consistent adherence. PrEP has also been shown to be effective in people who inject drugs, with a 74% reduction with consistent daily use. Studies have been performed and others are ongoing to evaluate more risk-based, intermittent dosing. Additionally, studies are underway to look at other potential medications and delivery methods (e.g., injectable drugs, implantable devices). Universal linkage, retention, and access to high-quality, culturally appropriate, and affordable HIV treatment should be the central goals of both HIV treatment and prevention, because effective treatment is effective prevention. Individuals should also be supported to protect themselves, and harm reduction techniques and behavior modification

962

SECTION XV  Infectious Disease

interventions play an ongoing important role in HIV prevention for at-risk populations, with both PEP and PrEP offering additional pharmacologic aids to the universal goal of bringing an end to new HIV infections.

SUGGESTED READINGS Aberg JA, Gallant JE, Ghanem KG, et al: Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV Medicine Association of the Infectious Diseases Society of America, Clin Infect Dis 58:e1–34, 2014. International Antiviral Society–USA: Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2018 Recommendations of the International Antiviral Society–USA Panel. Available at: https://www. iasusa.org/resources/guidelines/. Accessed January 2020.

International Antiviral Society–USA: HIV Drug Resistance Mutations. Available at: https://www.iasusa.org/resources/hiv-drug-resistancemutations/. Accessed January 2020. Stanford University: HIV Drug Resistance Database. Available at: https:// hivdb.stanford.edu. Accessed January 2020. U.S. Center for Disease Control and Prevention: Post-Exposure Prophylaxis. Available at: https://www.cdc.gov/hiv/risk/pep/index.html. Accessed January 2020. U.S. Department of Health and Human Services: Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Available at: https://aidsinfo.nih.gov/guidelines/html/4/adult-andadolescent-opportunistic-infection/0. Accessed January 2020. U.S. Department of Health and Human Services: Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Available at: https://aidsinfo.nih.gov/guidelines. Accessed January 2020.

104 Infections in the Immunocompromised Host Dimitrios Farmakiotis, Ralph Rogers

INTRODUCTION Individuals with an impaired immune system are at risk for infections due to typical pathogens and less virulent organisms that usually do not cause illness. Diagnosis can be challenging due to atypical disease manifestations. The pace and severity of illness in tenuous patients demands that complicated treatment decisions are made early, despite lack of diagnostic certainty. This chapter aims to provide a clinically oriented framework for diagnosis and management of infections in immunocompromised hosts, excluding patients with HIV/AIDS (Figs. 104.1 and 104.2).

EPIDEMIOLOGY The population of immunocompromised individuals is rapidly growing and becoming more diverse, including patients with primary (congenital) immunodeficiencies, some of which are newly recognized; individuals with hematologic malignancies (HM), who are now surviving longer; solid organ (SOT) and hematopoietic cell transplant (HCT) recipients; and finally, patients being treated with newly developed immunomodulatory medications (TNF-α inhibitors, monoclonal antibodies, ibrutinib) that expose more and more individuals to potential infectious complications.

PATHOGENESIS Not all immunocompromised individuals are at equal risk for every possible infection. Instead, “immunocompromised hosts” are a heterogenous group, in which specific immune deficits come with distinct risks (see Fig. 104.1 and Tables 104.1 and 104.2).

Neutropenia Neutrophils are the primary defense against bacterial and fungal infections. Neutropenia associated with increased risk for infection is defined as absolute neutrophil count less than 500/μL. Primary immunodeficiency syndromes such as congenital neutropenia (inadequate production), chronic granulomatous disease (ineffective microbial killing), and leukocyte adhesion deficiency (ineffective recruitment to sites of infection) are associated with increased number and severity of infections, usually caused by typical bacterial (e.g., Staphylococcus, Streptococcus, Enterobacteriaceae) and fungal (e.g., Candida) colonizers of skin, gastrointestinal, genitourinary, and respiratory tracts. Neutropenia is common with HM, due to decreased neutrophil production from both bone marrow infiltration and cytotoxic chemotherapy. Cytotoxic chemotherapy acts primarily on rapidly dividing

cells, thus in addition to its desired effect it also has negative impact on the rapidly dividing cells of the gastrointestinal tract lining (mucositis). This decrease in an anatomic barrier in combination with decreased neutrophil defense can lead to rapidly progressive infections from microbial translocation. Therefore, “neutropenic fever” is a medical emergency, and such patients need prompt and broad antimicrobial therapy against typical enteric pathogens and Pseudomonas (which is associated with high mortality).

Cell-Mediated and Humoral Immune Deficits The adaptive immune response provided by the cell-mediated and humoral components of the immune system allows for effective intracellular and extracellular microbial killing and is critical against viral infections, while also contributing to antibacterial and antifungal defenses. Many primary immunodeficiency syndromes affect cellular and humoral immunity, each causing increased susceptibility to various bacterial, fungal, and viral infections. Severe combined immunodeficiency (underdevelopment of both T cells and B cells) predisposes infants to serious infections from common viruses (e.g., Herpesviridae), bacteria, and fungi (e.g., Pneumocystis). DiGeorge syndrome (thymic hypoplasia leading to underdevelopment of T cells) and hyperimmunoglobulin-E syndrome (impaired T cell differentiation and function) predispose individuals to recurrent bacterial skin or sinopulmonary infections. X-linked agammaglobulinemia (underdevelopment of B cells) predisposes patients to bacterial infections with encapsulated organisms (pneumococcus, Haemophilus influenza, Neisseria meningitidis) and common viral pathogens (e.g., Enteroviridae). Secondary causes of hypogammaglobulinemia (e.g., chronic lymphocytic leukemia [CLL], protein-losing enteropathy, nephrotic syndrome) may also lead to increased risk for viral and bacterial infections.

Asplenia and Complement Deficits Functional or anatomic asplenia leads to increased risk for severe infections due to encapsulated bacteria and blood-borne parasites (e.g., Plasmodium, Babesia) since the spleen is the primary site that filters out parasitized red blood cells. The complement system acts by opsonization of pathogens allowing for subsequent phagocytosis and can also act on its own to eliminate pathogens via the membrane attack complex. Complement deficiencies lead to an increased risk for infections due to encapsulated bacteria, especially N. meningitidis. They can be congenital or from eculizumab, a monoclonal antibody that is effective treatment for atypical hemolytic uremic syndrome by inhibiting terminal complement.

963

964

SECTION XV  Infectious Disease

• Fever • Skin lesions • Pulmonary manifestations • Abdominal pain, diarrhea • CNS manifestations • Other

Host

• lmmunosuppression - e.g., SOT, HCT, prior immunosuppression - Induction, maintenance, neutropenia - Rejection, GVHD • Timeframe • Prophylaxis and other OI

Syndrome

Infectious Noninfectious • Bacterial • Disease - Common, Mycobacteria, Nocardia - Recurrence of malignancy • Viral - GVHD - Respiratory viruses - Surgical complications - CMV, EBV, HHV6, BK, JC • Drugs • Fungal - lmmunosuppression - Candida, Cryptococcus, Aspergillus, • Other Mucorales, Pneumocystis • Parasitic - Toxoplasma, Strongyloides Fig. 104.1 Algorithmic approach to the diagnosis of syndromes suspicious for infection in the immunocompromised host. Continuous reassessment is paramount. For a discussion of abbreviations and specific pathogens see “Specific Pathogens” section below. Drug toxicities and interactions

TABLE 104.1  Primary Immunodeficiency

Syndromes

Likelihood

Threshold for clinical failure

Fig. 104.2 Management decisions should be based on the balance between the likelihood of a diagnosis and the clinical consequences of not treating immediately, given the toxicities and drug-drug interactions of antimicrobials.

Hematologic Malignancies Neutropenia is the main risk factor for infection in patients with acute leukemia. At the time of diagnosis, an individual may have already been neutropenic for an extended time and thus at risk for infection by environmental molds, such as Aspergillus or the Mucorales. After induction chemotherapy, patients stay profoundly neutropenic for several weeks, leading to increased risk for infection as outlined previously. Lymphoma patients usually do not experience extended periods of neutropenia from chemotherapy, which is, nonetheless, profoundly lymphocyte-depleting. Risk for infection sometimes depends on dosing (e.g., there is increased risk for Pneumocystis with R-CHOP-14, i.e., bi-weekly, due to more frequent administration of steroids). CLL is a chronic leukemia that is often monitored but not treated given its indolent course. However, these patients frequently have hypogammaglobulinemia and may be at increased risk for bacterial or viral sinopulmonary infections.

Syndrome

Description

Defects in Phagocytes Congenital neutropenia Chronic granulomatous disease Leukocyte adhesion ­deficiency

Inadequate neutrophil production Ineffective microbial killing by phagocytes due to decreased NADPH oxidase activity Ineffective recruitment of phagocytes to sites of infection

Defects in Cellular and Humoral Immunity Severe combined T- and/or B-cell deficiency or absence immunodeficiency ZAP-70 deficiency Defects in T-cell proliferation and activation DiGeorge syndrome Thymic hypoplasia leading to defects in T-cell maturation Idiopathic CD4 lymphopenia Inadequate CD4+ T-cell production Hyper-IgE syndrome Defect in JAK/STAT signaling pathway leading to multiple immune deficits Hyper-IgM syndrome Defect in class-switch recombination leading to inadequate IgG/IgA/IgE production X-linked agammaglobulinemia Defect in B-cell maturation leading to decreased or absent immunoglobulin production Common variable immunode- Defective immunoglobulin production ficiency Defects in Innate Immunity NK cell deficiency Absent or defective NK cells Complement deficiencies Absent or defective complement components

Solid Organ Transplantation SOT is a life-saving procedure, but unless the transplanted organ (allograft) is coming from the recipient’s identical twin, the transplant recipient must take immunosuppressive medications in order to prevent their immune system from rejecting the allograft as “nonself.”

CHAPTER 104  Infections in the Immunocompromised Host

965

TABLE 104.2 Immunosuppressive

TABLE 104.3  Infections After Solid Organ

Class

Examples

Risk Category

Cytotoxic agents

Bleomycin Cisplatin Cyclophosphamide Cytarabine Doxorubicin Etoposide Fluorouracil Methotrexate Paclitaxel Vincristine Alemtuzumab Anti-thymocyte globulin Basiliximab Belatacept Rituximab Adalimumab Etanercept Infliximab Prednisone Azathioprine Cyclosporine Mycophenolate Sirolimus Tacrolimus Eculizumab Ibrutinib Idelalisib Natalizumab Ruxolitinib Tocilizumab

Early Infections Anatomic disruption

Medications

Lymphocyte depleting agents

TNF-α inhibitors

Corticosteroids Common antirejection medications

Other monoclonal antibodies and signal transduction inhibitors associated with increased risk for infection

Transplantation

Donor derived

Hospital acquired

Middle Infections Reactivation of latent pathogens

Opportunistic infections

Late Infections Community acquired Post-prophylaxis reactivation

Examples Anastomotic leak Surgical site infection Bacterial: Mycobacterium tuberculosis Fungal: Aspergillus Viral: CMV, EBV, HBV, HCV, HIV, HSV, LCMV, VZV Parasite: Toxoplasma Catheter-related infection Clostridioides difficile colitis Ventilator-associated pneumonia Bacterial: M. tuberculosis Fungal: Candida Viral: BKPyV, CMV, HBV, HCV, HSV, VZV Parasite: Strongyloides, Toxoplasma Bacterial: Nocardia Fungal: Aspergillus, Pneumocystis Parasite: Microsporidia Pneumonia Urinary tract infection CMV HSV VZV

SOT recipients are given potent immunosuppressive medications to prevent acute rejection at the time of their transplant (induction) and thereafter stay on two to three immunosuppressants (maintenance). The risks for specific types of infection differ, depending on the time since transplantation (Table 104.3). Infections early on are related to the transplant surgery itself (anastomotic leak, surgical site infection) or are hospital acquired (catheter infection, C. difficile colitis); early infections can also be donor derived (i.e., present in the donor at the time of transplant, then transferred to the recipient with the allograft). Infections in the “middle period” are often due to reactivation of preexisting latent infections (CMV, hepatitis B or C, Toxoplasma) or to opportunistic pathogens (Pneumocystis, Aspergillus). Late infections are usually community acquired (e.g., pneumonia) and organ specific (recurrent urinary tract infections in kidney transplant recipients, cholangitis in liver transplant recipients, late aspergillosis in lung transplant recipients). Augmented immunosuppression for rejection increases the risk for infection. So does “immunosenescence,” and elderly SOT recipients sometimes present with opportunistic infections many years after transplantation.

are given high doses of cytotoxic medications and/or radiation therapy to destroy their old immune system (conditioning) and thus are at risk for many infections while waiting for their new hematopoietic cells to populate the bone marrow and begin functioning (engraftment). A common complication after HCT is graft-versus-host disease (GVHD), where the donor immune system recognizes recipient organs (mostly the skin and gastrointestinal tract) as “nonself” and mounts a potentially devastating immune response. Additional immunosuppressive medications are given to prevent or treat GVHD, adding to the risk for infection. Further, GVHD is itself an immunosuppressive condition given that it acts to slow immune expansion after HCT. As in individuals receiving SOT, risks for specific types of infection differ depending on the time since transplantation and presence of GVHD (Table 104.4). Early on, infections are related to profound neutropenia and mucositis from the conditioning regimen. Functional neutrophils are newly present after engraftment, but other arms of adaptive and innate immunity are slowly reconstituted thereafter, first NK-cells, then CD8+ T cells, and finally B cells and CD4+ T cells, sometimes years later. This process can be delayed by both GVHD and immunosuppressive medications for it (see Table 104.4).

Hematopoietic Cell Transplantation

Novel Immunomodulatory Medications

Hematopoietic (stem) cell transplantation (HCT) involves replacing the bone marrow and immune system with a new, healthier one. This life-saving procedure is associated with many infectious and noninfectious post-transplantation complications. HCT recipients

The number and variety of immunomodulatory medications has dramatically increased in recent years, leading to newly recognized syndromes. Examples are invasive fungal infections with ibrutinib (a tyrosine kinase inhibitor used to treat lymphoid malignancies),

966

SECTION XV  Infectious Disease

TABLE 104.4  Infections After

Hematopoietic Cell Transplant Risk Category Pre-engraftment Neutropenia Mucositis Hospital acquired

Early Post-engraftment Reactivation of latent pathogens

Opportunistic infections

Late Post-engraftment Community acquired

Post-prophylaxis reactivation

Examples Bacterial: skin/GI/GU flora Fungal: Candida, Aspergillus Viral: HSV, VZV Catheter-related infection Clostridioides difficile colitis Ventilator-associated pneumonia Bacterial: Mycobacterium tuberculosis Fungal: Candida Viral: adenovirus, BKPyV, CMV, HBV, HCV, HHV-6, HHV-8, HSV, JCPyV, VZV Parasite: Strongyloides, Toxoplasma Bacterial: Nocardia Fungal: Aspergillus, Mucorales, Pneumocystis Parasite: Microsporidia Pneumonia Sinusitis Urinary tract infection CMV HSV VZV

progressive multifocal encephalopathy (PML) with natalizumab (selective adhesion molecule inhibitor used to treat multiple sclerosis), hepatitis B reactivation or rituximab (anti-CD20+ monoclonal antibody used for treatment of B-cell lymphomas), and mycobacterial infections and histoplasmosis with TNF-α inhibitors (see Table 104.2).

CLINICAL PRESENTATION Central Nervous System Infection Headache, neck stiffness, photophobia, encephalopathy, or new focal neurologic deficits, with or without fever, may be indicative of central nervous system (CNS) infection. Clinical symptoms of meningitis and cerebrospinal fluid (CSF) pleocytosis may be dampened in the setting of immunosuppression. In addition to typical pathogens (pneumococcus, enterovirus, herpes simplex virus [HSV]), one should consider other bacterial (Listeria, Nocardia), viral (e.g., arbovirus, astrovirus, CMV, Epstein-Barr virus [EBV], lymphocytic choriomeningitis [LCMV], varicella zoster virus [VZV]), fungal (e.g., Cryptococcus), and parasitic (Toxoplasma) etiologies. CNS infection can be part of a systemic syndrome, and dysfunction of other organs may give a clue to the etiology (e.g., severe pneumonia with adenovirus meningitis, Nocardia lung nodules). CNS imaging is paramount and can aid in diagnosis (e.g., multiple ring-enhancing lesions with Toxoplasma encephalitis, multifocal white matter changes with PML [Fig. 104.3]).

Pneumonia Although fever and productive cough are the hallmark sign and symptom of pneumonia, both may be muted in immunocompromised hosts. Alternatively, pneumonia may be rapidly progressive and fulminant.

Beyond typical bacterial and viral etiologies, pneumonia in immunocompromised patients can be caused by atypical bacterial (Legionella, Nocardia, Mycobacterium tuberculosis or nontuberculous mycobacteria), viral (adenovirus, CMV, HSV, VZV), fungal (Aspergillus, Cryptococcus, dimorphic fungi, non-Aspergillus molds, Pneumocystis), and parasitic (Toxoplasma, Strongyloides hyperinfection) etiologies. Associated nonpulmonary manifestations (e.g., cryptococcal meningitis) can help make the diagnosis. Computed tomography (CT) and bronchoscopy are often necessary to better define the infectious process.

Diarrhea Clinicians should consider bacterial (Clostridioides difficile, Salmonella), viral (adenovirus, CMV, enterovirus, norovirus), and parasitic (Cryptosporidium, Giardia) etiologies. Stool PCR panels can be useful but sometimes cannot differentiate between colonization and infection for some organisms, such as enteropathogenic E. coli. A careful exposure history can help narrow the possible diagnoses, especially for infections with regional endemicity. Colonoscopy with tissue biopsy may be necessary to make a definite diagnosis. At our institution, multiplex PCR, C. difficile toxin in the stool, and CMV viral load in the blood are standard protocol for SOT recipients with diarrhea. Leading noninfectious causes are medications, especially mycophenolate (an antimetabolite used for maintenance immunosuppression), and GVHD.

Skin Manifestations Skin lesions in the immunocompromised patient can be a sign of localized (“outside-in”) or disseminated (“inside-out”) infection. Necrotic lesions raise concern for angioinvasive mold, although they can also be seen with severe bacterial infections and neutropenia, due to toxin effect with minimal inflammation. The most classic lesion is ecthyma gangrenosum, a painful eschar in neutropenic sepsis caused by Pseudomonas, but also other gram-negative or gram-positive (S. aureus) bacteria. Disseminated candidiasis can present with diffuse maculopapular rash and Fusarium sepsis with painful nodules. Vesicular lesions always raise concern for herpetic infection, although HSV (especially resistant or HSV2) can also cause large ulcerated lesions. “Sporotrichoid lesions” (cordlike clusters of inflammatory nodules) can be due to Sporothrix, S. aureus, Nocardia or atypical mycobacteria. Noninfectious causes are very common, such as drug rash, primary skin cancer (the most common malignancy after SOT), skin metastases and leukemia cutis, GVHD, neutrophilic eccrine hidradenitis, and Sweet syndrome (febrile neutrophilic dermatosis, an inflammatory reaction to tumors and chemotherapy that is best treated with corticosteroids). For accurate diagnosis, a skin biopsy with cultures is often necessary.

Fever of Unknown Origin Persistent fever in an immunocompromised host without a clear etiology or any focal signs or symptoms is a relatively common clinical scenario. History and physical examination will often reveal subtle signs or symptoms integral to steering further diagnostic efforts. Careful attention to the mouth (Fig. 104.4), skin, and perineal area is imperative, because each may provide easily overlooked clues. Perineal infection can manifest with rectal pain alone. Beyond typical screening studies such as blood and urine cultures and a chest radiograph, an algorithmic approach to further investigation may involve stepwise additional testing including fungal markers, PCRbased testing for viruses (CMV, EBV, HHV-6), and cross-sectional imaging of the chest, abdomen, and pelvis. Advanced laboratory tests (e.g., cell-free DNA sequencing, an emerging technology that detects and identifies nonhuman DNA fragments in a clinical sample) and

CHAPTER 104  Infections in the Immunocompromised Host

967

Fig. 104.3  Progressive multifocal encephalopathy (PML) in an immunocompromised patient with severe combined immunodeficiency (SCID) and autoimmune hemolytic anemia requiring many cycles of rituximab and high-dose corticosteroids. MRI shows significant progression of white matter abnormalities after 3 months.

imaging studies (positron emission tomography-PET) may be useful adjuncts depending on the clinical scenario.

DIAGNOSIS The pace and breadth of diagnostic testing is best driven by the pace and severity of a patient’s underlying illness. Although there is a vast number of potential pathogens that may be the cause of an individual’s presenting illness, the history the patient gives along with their physical examination is usually enough to dramatically narrow the differential diagnosis. Although most patients present with a single unifying diagnosis, it is not uncommon for immunocompromised patients to present with multiple ongoing processes. Therefore, we favor a structured approach, frequently revisiting the initial or new clinical manifestations (see Fig. 104.1).

Host Considerations Fig. 104.4  Oral lesions in an HCT recipient with GVHD on high-dose steroids who developed disseminated HSV1 infection with fulminant hepatitis.

First, one should understand the host, mainly the immune deficits specific to the individual patient: How long has the patient been

968

SECTION XV  Infectious Disease

neutropenic and what potential pathogens has the patient been exposed to while neutropenic? How long has it been since SOT and what is the immunosuppression? For HCT recipients, are they pre- or post-engraftment, do they have GVHD, and what immunosuppressive medications are they on? What prophylactic antimicrobials are they taking, and for how long? What previous chemotherapy have they received? Previous and concomitant opportunistic infections often speak for the host.

Syndrome Considerations Next, one identifies the syndrome using presenting complaints. Often there is a single clinical syndrome such as pneumonia or diarrhea. At other times, the signs and symptoms are less focal, and instead the presenting syndrome may simply be fever and fatigue; more than one clinical syndrome can be present. One structured way to construct a broad differential diagnosis for the host and the syndrome is to first consider infectious versus noninfectious causes and then build a differential diagnosis by pathogen kingdom (bacterial, fungal, viral, parasitic) and noninfectious causes (underlying disease, GVHD, medication toxicities, unusual causes) (see Fig. 104.1).

Laboratory Testing In immunocompromised hosts, direct tests for pathogens (antigen or PCR-based testing) are much more useful than antibody assays, which mainly indicate past exposure, and because the measured immune response may be absent. Fungal markers are components of the fungal cell wall that can be detected in blood or other body fluids and help make the diagnosis of fungal infections. The most commonly used are serum and CSF cryptococcal antigen, serum, bronchoalveolar lavage (BAL) or CSF Aspergillus galactomannan, and serum or CSF 1,3-β-D-glucan, which is a broad fungal marker that can aid in the diagnosis of invasive aspergillosis, candidiasis, and pneumocystis pneumonia. However, fungal markers can be falsely elevated (e.g., false-positive 1,3-β-D-glucan in patients receiving hemodialysis or intravenous immunoglobulin [IVIG]) and should be interpreted in context. Peripheral blood cultures (including standard bacterial cultures and those facilitating growth of acid-fast bacilli and fungi) and cultures from more invasive procedures (BAL) may provide a diagnosis and also give a measure of antimicrobial susceptibility. Invasive tissue biopsy may at times be necessary for a definitive diagnosis and to help differentiate between colonization and infection.

Diagnostic Imaging Imaging studies are also important in the diagnostic process. As with laboratory testing, the lack of inflammation can lead to misleading imaging findings (e.g., relatively normal abdominal imaging despite ongoing acalculous cholecystitis). Some findings can be suggestive of specific diagnoses when interpreted in the context of a specific syndrome in an at-risk immunocompromised host (e.g., the halo sign [ground-glass opacities surrounding a pulmonary nodule] suggestive of invasive pulmonary aspergillosis [Fig. 104.5] versus the reversed halo sign [ground-glass opacity surrounded by a ring of consolidation] suggestive of mucormycosis).

TREATMENT General Principles Choosing an appropriate empiric treatment regimen for an immunocompromised patient can be challenging. Waiting for test results may not be wise given the potentially rapid progression of infection in this population. Medication toxicities and drug-drug interactions

Fig. 104.5 Invasive aspergillosis in a patient receiving high-dose corticosteroids. Chest CT shows dense consolidation and surrounding “halo sign” (i.e., hazy, ground-glass-like opacities surrounding a nodule or mass), which represents hemorrhage and is typically seen in invasive aspergillosis. Blood and BAL cultures grew A. fumigatus; the value of Aspergillus antigen (galactomannan) in the blood was great than the assay cut off.

(DDI) are often a determining factor in the clinical outcome. Early and aggressive treatment is often necessary, though given the breadth of potential infectious etiologies, treating every possible pathogen is not feasible. Instead, when considering empiric treatment, the unlikeliness of a specific diagnosis should be balanced against the potential consequences of not treating. As a rule, broad coverage is in order while the patient’s clinical presentation is unfolding, with de-escalation of therapy to prevent toxicities after further diagnoses are ruled out and as the patient improves (see Fig. 104.2).

Source Control Control of the source of infection is imperative. In immunosuppressed patients, antimicrobials alone are often insufficient to combat infection. Given the diminished clinical reserve and lack of expected immune response, an undrained abscess or an infection due to a biofilm-forming agent on a blood stream or unremoved intravascular catheter or urinary catheter can be devastating.

Adjusting Immunosuppression Reducing immunosuppression can be life-saving. With neutropenia in particular, granulocyte colony-stimulating factor (G-CSF) administration can help early ANC recovery. In SOT, acute rejection can develop after reducing immunosuppression, but it is very unusual to have simultaneous acute rejection and overwhelming infection given the polarization of an already impaired immune system towards fighting infection. There is also the possibility of developing immune reconstitution inflammatory syndrome (IRIS) (i.e., increased inflammation from reduction of immunosuppression), which often needs to be treated with corticosteroids. Further, some immunosuppressive medications have desirable adjuvant properties (e.g., antifungal effect of calcineurin inhibitors [CNI]). Specifically, in cryptococcal infections, CNI discontinuation leads to increased risk for IRIS and unfavorable outcomes. Immunosuppression adjustments are thus individualized. Reinstitution of immunosuppressive therapy may be indicated as infection resolves.

CHAPTER 104  Infections in the Immunocompromised Host

969

Drug-Drug Interactions

CMV

It is imperative to check for DDI with immunosuppressive or other medications every time any antimicrobial is started and stopped (see Fig. 104.2). For instance, triazole antifungal medications predictably increase the serum concentration of CNI (via triazole-mediated inhibition of their metabolism by cytochrome P-450), and thus empiric dose adjustments of CNI are usually indicated when stopping or starting a triazole.

Similar to other herpesviruses, CMV remains dormant after primary infection and can reactivate, causing disease. The highest-risk patients are SOT recipients who are not immune to CMV and receive it from the donor (D+/R−), as well as lymphocyte-depleted and D−/R+ HCT recipients (because they adopt the immune system of their donor). CMV causes fever and infectious mononucleosis-like symptoms and signs, gastrointestinal disease (esophagitis, gastritis, colitis) and pneumonia (mostly in lung and HC transplant recipients). Retinitis is rare in HIV-negative patients. Treatment of choice is (val)ganciclovir and foscarnet for resistant CMV. Multidrug-resistant CMV is rare but an emerging threat. Prophylaxis with (val)ganciclovir is used in most SOT recipients for the first few months after transplant. The main toxicity of (val)ganciclovir is bone marrow suppression, whereas foscarnet can cause nephrotoxicity and electrolyte abnormalities.

PREVENTION Lifestyle Precautions While in the hospital, neutropenic patients often have specific measures in place to reduce the risk of acquisition of new infections by ingestion (bottled water, avoidance of foods with potential for bacterial or fungal colonization), inhalation (air filtration and positive pressure ventilation, no flowers or plants, avoidance of nearby heavy construction or remodeling activities), or mucosal translocation (avoidance of hard food that can cause oral trauma). Many of these commonsense precautions can also be implemented at home. For immunocompromised patients, close contact with other individuals with viral infection should be avoided, and thorough evaluations before travel are advised.

Immunizations The best time to give immunizations is prior to the onset of immunosuppression, which allows for the most robust immune response. Otherwise, most vaccines are administered 1 year post-transplant. Live vaccines are generally contraindicated in immunocompromised individuals, out of concern for clinical illness caused by the vaccine strain. Immunization of household contacts and health care workers is mandated.

Antimicrobial Prophylaxis At many centers, individuals with acute leukemia undergoing induction chemotherapy and patients receiving HCT are given a fluoroquinolone (levofloxacin) and a yeast-only (fluconazole) or mold-active (voriconazole, posaconazole) triazole. Antiviral prophylaxis with acyclovir protects against reactivation of latent herpesviruses (e.g., HSV, VZV). Fluconazole is used sometimes in liver transplant recipients and anti-Aspergillus prophylaxis in lung transplant recipients. Antiviral prophylaxis active against CMV ([val]ganciclovir) is given to many SOT patients. Given the potential myelotoxicity of (val)ganciclovir, alternative strategies are used to prevent CMV infection in HCT (close monitoring of viral load or alternative antivirals such as letermovir). Prophylaxis against Pneumocystis is indicated in SOT and HCT recipients for 6 to 12 months after transplant and in patients receiving prolonged high-dose corticosteroids. Some HCT recipients with severe GVHD receive antibacterial prophylaxis active against encapsulated bacteria and antifungal prophylaxis.

SPECIFIC PATHOGENS HSV and VZV HSV1/2 cause mainly mucocutaneous disease (oral or genital lesions), but in immunocompromised patients they can more frequently disseminate, cause CNS infection, multiorgan failure, predominantly fulminant hepatitis, and protean manifestations (e.g., pneumonia) (see Fig. 104.4). VZV can also cause disseminated disease and various CNS syndromes, including vasculitis. The treatment of choice for severe infections is intravenous acyclovir. (Val)acyclovir and (val)ganciclovir are effective prophylaxis; (val)acyclovir administration in very immunosuppressed patients can lead to resistance, mostly in HSV1. Resistant herpetic infections are treated with foscarnet.

Other Herpesviruses EBV can manifest as lytic infection (directly caused by proliferating virus, such as infectious mononucleosis or CNS infection). However, it is mainly associated with post-transplant lymphoproliferative disorder (PTLD) (progressive transformation of EBV-infected B-lymphocytes to lymphoma). Treatment is reduction of immunosuppression to allow for cytotoxic T-cell surveillance of the abnormal EBV-infected B cells. For the same reason, rituximab is often used early on, even preemptively with rising EBV viremia in HCT recipients. Other pathogenic human herpesviruses include HHV-6, which typically causes CNS infection in HCT recipients (PALE: Post-transplant acute limbic encephalopathy) treated with ganciclovir or foscarnet, and HHV-8, which causes Kaposi’s sarcoma.

Polyomaviruses In addition to patients with AIDS, JC virus causes PML in a variety of hosts (SOT, HCT recipients, and patients with HM) (see Fig. 104.3). PML manifests with progressive cognitive decline, focal neurologic deficits, and characteristic MRI findings; it overall has poor prognosis. BK virus causes renal allograft dysfunction in kidney transplant recipients, hemorrhagic cystitis in HCT or (less commonly) other severely T-cell depleted individuals; BK can rarely cause PML and disseminated infection. The cornerstone of management for polyomavirus infections is decrease in immunosuppression. A promising recent approach to the management of PML and other refractory viral infections is infusion of virus-specific active T cells (adoptive immunity). As a rule, laboratory diagnosis of viral infections in immunocompromised patients is based on detection of the virus by quantitative PCR and, sometimes, histopathology.

Candida Candida albicans is the most common fungal pathogen in the Western world and an important commensal of the normal skin, oral, gastrointestinal, and vaginal flora. Non-albicans Candida species can be resistant to antifungal drugs, therefore an important threat with rising frequency in patients receiving antifungal prophylaxis. Candida auris has recently emerged as the first virulent fungus that exhibits multidrug resistance and the potential for nosocomial transmission, which is considered a public health emergency. Candida species cause mucocutaneous (dermatitis, thrush, esophagitis or vaginitis) and invasive candidiasis. Neutropenia, corticosteroids, and abdominal pathology are the main risk factors. Indwelling catheters are an important source of candidemia, given the strong propensity of this organism to form biofilms (Fig. 104.6). Therefore, central line removal is strongly advised for the successful management of candidemia. Echinocandins (caspo/mica/anidulafungin) are the

970

SECTION XV  Infectious Disease

treatment of choice for severe invasive candidiasis, except for urinary, eye or CNS infections given their poor penetration in these compartments. Amphotericin-B and azoles have activity against most Candida species; the latter can be used for mild infections and as step-down oral therapy.

Cryptococcus Cryptococcus can cause meningitis, encephalitis, pneumonia, sepsis-like syndrome, and atypical infections (such as cellulitis) in patients with significant T-cell immunosuppression (SOT or HCT recipients, lymphoma patients). Diagnosis is made by culture, detection of cryptococcal antigen in blood or CSF, and histopathology. Severe infections, including meningitis, are treated with amphotericin-B and flucytosine, followed by many months of fluconazole. Decrease in immunosuppression without discontinuation of CNI should be individualized. Fluconazole and other azoles, often used as antifungal prophylaxis in immunosuppressed patients, decrease the risk for cryptococcosis.

Aspergillus

transplant recipients are the highest risk groups, especially with exposure to high inocula (e.g., construction). Aspergillus can often be a colonizer (saprophytic aspergillosis), without causing invasive disease, such as in the absence of radiographic abnormalities, or as an isolated aspergilloma (Fig. 104.7). Fungal markers (Aspergillus galactomannan, 1,3-β-D-glucan), with careful review of imaging findings (see Fig. 104.5), host factors, and clinical presentation, can help differentiate between colonization and infection. An interesting entity at the intersection of saprophytic and invasive disease is chronic necrotizing (also known as cavitary or semi-invasive) aspergillosis. It affects “immunomodulated” patients, such as elderly patients with chronic obstructive pulmonary disease (COPD), often with negative fungal markers but positive anti-Aspergillus antibodies, and warrants antifungal treatment (Fig. 104.8). The treatment for the majority of aspergilloses is voriconazole, with close follow-up of drug levels and dose adjustments of other medications that have significant DDI. Alternative agents include isavuconazole, amphotericin, or the echinocandins; the latter are static and not preferred as monotherapy.

Unlike Candida, molds such as Aspergillus and the Mucorales are not part of normal flora but inhaled from the environment. In the setting of impaired immune (especially neutrophil) defenses, they grow and invade tissues, causing invasive sinopulmonary or even disseminated mold infections. Individuals with prolonged neutropenia, those receiving high-dose corticosteroids, and lung

Other

Candidemia

Abdominal Fig. 104.8 Chronic cavitary aspergillosis of the left lung in a patient with severe COPD. A. fumigatus antibodies were positive, galactomannan negative, BAL cultures grew A. fumigatus. The lesions on CT progressed over months.

Central venous catheter-related Fig. 104.6  Spectrum of invasive candidiasis.

R

L

R

Fig. 104.7  Aspergilloma (saprophytic aspergillosis) in a patient with emphysema. Chest CT shows a mobile mass (Left: supine, right: prone) within a small cavity.

L

CHAPTER 104  Infections in the Immunocompromised Host

Mucorales and Other Fungi Clinical syndromes caused by molds of the order Mucorales (e.g., Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, and Apophysomyces spp) are rare, aggressive infections with the potential for rapid progression and high mortality. The most common manifestations are sinus and pulmonary infections in neutropenic patients, those receiving high-dose corticosteroids, diabetics, and even immunocompetent individuals when there is high inoculum exposure (e.g., in natural disasters and trauma with significant soil inhalation or contamination of deep wounds). These organisms are highly angioinvasive, and necrotic tissue is an important clue on physical exam. The “reversed halo” sign on CT is considered suggestive of pulmonary mucormycosis. The Mucorales do not have significant amounts of 1,3-β-D-glucan or galactomannan, therefore fungal markers will typically be negative. In vitro culture can be challenging. Therefore, the diagnosis of mucormycoses is elusive and often made by tissue histopathology with visualization of aseptate, broad-angled hyphae. In contrast, Aspergillus hyphae are narrow branching at 45° angles and septate (Fig. 104.9). Surgical débridement, when possible, and timely initiation of appropriate treatment with amphotericin-B are paramount. Posaconazole and isavuconazole have activity against the Mucorales, but voriconazole and the echinocandins do not. Immunocompromised patients are at risk for endemic infections from dimorphic fungi (histoplasmosis, blastomycosis, and coccidiomycosis); preemptive testing and/or prophylaxis might be indicated in certain geographic areas. Histoplasmosis in particular has been associated with TNF-α inhibition. Pneumocystis infection can manifest as typical interstitial or focal (“granulomatous”) pneumonia, almost exclusively in patients not receiving prophylaxis. Treatment is similar to patients with AIDS (first line: trimethoprim/sulfamethoxazole [TMP/SMX]). Microsporidia, now classified as fungi, can cause diarrhea, CNS, and multiorgan infections (including donor-derived outbreaks), for which albendazole is the treatment of choice.

Nocardia Nocardia species are abundant in soil and cause subacute pulmonary, CNS or skin infections in patients with impaired cellular immunity, mainly SOT/HCT recipients and those on high-dose corticosteroids. Most species are sensitive to TMP/SMX. Initial combination of at least two antibiotics (TMP/SMX with a carbapenem, linezolid or minocycline)

971

is usually indicated given distinct susceptibilities of different Nocardia species. Targeted treatment should be continued for many months.

Mycobacteria Individuals with latent tuberculosis (LTB) are at high risk for reactivation after TNF-α inhibition or T-cell immunosuppression, such as SOT/HCT. In immunosuppressed patients, active TB is often disseminated and its treatment challenging due to medication toxicities and DDI. Therefore, candidates for SOT, HCT, or TNF-α inhibitors are tested for LTB by protocol and if positive treated with isoniazid or an alternative regimen, prior to or shortly after onset of immunosuppression. Atypical (nontuberculous) mycobacteria (NTM) cause diverse clinical syndromes, mainly pulmonary, skin, and catheter-related infections. The immune deficits predisposing to such infections are similar to TB. NTM are frequent colonizers of the respiratory tract. Treatment regimens are often complicated, with multiple toxicities and DDI; therefore, it is important to differentiate infection from colonization and treat, when indicated, in a timely manner, especially lung transplant candidates and recipients.

Parasites Immunocompromised patients (especially heart transplant recipients) are at risk for donor-derived or reactivation of toxoplasmosis. TMP/ SMX is effective prophylaxis. Toxoplasmosis can manifest as CNS lesions, pneumonia, or fever of unknown origin (FUO) and severe sepsis, the latter mainly in HCT recipients who are not on prophylaxis prior to engraftment, given concern for bone marrow suppression from TMP/SMX. Sulfamethoxazole with pyrimethamine or high-dose TMP/SMX are effective treatments. Strongyloides hyperinfection is rare but devastating and can be recipient- or donor-derived. It develops usually weeks after onset of T-cell immunosuppression (e.g., transplant, high-dose steroids) with diarrhea, and, as the larvae translocate from the bowel and disseminate to different organs, ileus, pulmonary infiltrates, skin lesions, and gram-negative sepsis from intestinal bacterial co-translocation. Diagnosis is made by visualization of Strongyloides larvae in the stool, BAL or tissue. The treatment for hyperinfection is oral or parenteral veterinary ivermectin for days. Mortality is very high. Transplant candidates and donors from endemic areas are typically screened by serology (antibody) and, if positive, receive 1 to 2 days of ivermectin.

Fig. 104.9  Aspergillus (left: narrow-angled, septate) and Lichtheimia (right: wide-angled, aseptate) hyphae on Gomori-methenamine silver (GMS) stains of lung and heart tissue, respectively, from the autopsy of a patient with CLL on high-dose steroids. In immunocompromised patients, Ockham’s razor doesn’t always apply and multiple infections can coexist. (Tsikala-Vafea M, Weibiao C, Olszewski AJ, et al. Fatal mucormycosis and aspergillosis in an atypical host: What do we know about mixed invasive mold infections? Case Rep Infect Dis 2020:8812528, 2020.)

972

SECTION XV  Infectious Disease

Intestinal parasites (Giardia lamblia, Entamoeba histolytica, Crypto­ sporidium parvum) can cause acute or chronic diarrhea in immunocompromised patients. Giardia in particular affects patients with IgA deficiency. Free-living amoebas can cause severe meningoencephalitis with almost 100% mortality.

SUGGESTED READINGS Bousfiha A, Jeddane L, Picard C, et al: The 2017 IUIS phenotypic classification for primary immunodeficiencies, J Clin Immunol (38):129–143, 2018. Denning DW, Cadranel J, Beigelman-Aubry C, et al: Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management, Eur Respir J 47(1):45–68, 2016. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biologic therapies: an infectious diseases perspective, Clin Microbiol Infect (24), 2018, Supplement 2. Farmakiotis D, Kontoyiannis DP: Emerging issues with diagnosis and management of fungal infections in solid organ transplant recipients, Am J Transplant 15(5):1141–1147, 2015. Farmakiotis D, Ross J, Koo S: Chapter 201: Candida and Aspergillus. In McKean SC, Ross JJ, Dressler DD, Scheurer DB, editors: Principles and practice of hospital medicine, ed 2, McGraw-Hill, 2017, pp 1618–1624.

GarciaCadenas I, Rivera I, Martino R, et al: Patterns of infection and infection-related mortality in patients with steroid-refractory acute graft versus host disease, Bone Marrow Transplant 52(1):107–113, 2017. Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice, Clin Transplant, 2019. Li X, Jevnikar A: Transplant immunology, West Sussex, 2016, John Wiley & Sons. Mehta H, Malandra M, Corey S: G-CSF and GM-CSF in neutropenia, J Immunol 195(4):1341–1349, 2015. Pizzo P: Management of patients with fever and neutropenia through the arc of time: a narrative review, Ann Intern Med 170(6):389–397, 2019. Qian C, Wang Y, Reppel L, et al: Viral-specific T-cell transfer from HSCT donor for the treatment of viral infections or diseases after HSCT, Bone Marrow Transplant 53(2):114–122, 2018. Simner P, Miller S, Carroll K: Understanding the promises and hurdles of metagenomic next-generation sequencing as a diagnostic tool for infectious diseases, Clin Infect Dis 66(5):778–788, 2018. Taplitz R, Kennedy E, Bow E, et al: Antimicrobial prophylaxis for adult patients with cancer related immunosuppression: ASCO and IDSA clinical practice guideline update, J Clin Oncol 36(30):3043–3054, 2018.

105 Infectious Diseases of Travelers: Protozoal and Helminthic Infections Jessica E. Johnson, Rebecca Reece

INTRODUCTION Medical advice for overseas travelers, recommended protective measures, and the diagnosis and treatment of common parasitic diseases endemic in the United States and abroad are reviewed in this chapter.

PREPARATION OF TRAVELERS Americans made more than 70 million international trips in 2015, and this number continues to increase every year. If we look at a breakdown of where these travels occur, 75% were to a malaria-endemic country. Increases in international travel are associated with exposures to infectious diseases worldwide and bring the issues of prevention and management of health problems in travelers into the office of every physician. The risk of becoming ill while traveling internationally depends on the destination and duration of the trip, the underlying health and age of the traveler, and activities/exposures that occur while abroad. Major issues to be addressed before traveling include required and recommended immunizations, malaria prophylaxis, and traveler’s diarrhea, as well as measures to prevent tick and mosquito bites. Information about health risks in specific geographic areas, updated weekly, can be obtained from the US Centers for Disease Control and Prevention (CDC) through its publications or website (www.cdc.gov/ travel/destinations/list).

Immunizations All international travelers should ensure they are up-to-date on routine vaccinations. Only yellow fever vaccination may be required by law for international travel, but other immunizations are often strongly recommended, depending on the destination, type, and duration of travel. Before immunization, a thorough history should be obtained to determine the safety of immunizations and any allergies to eggs or chick embryo cells. Pregnant women and individuals who are immunocompromised by human immunodeficiency virus (HIV), malignancy, or chemotherapy pose specific and important concerns requiring review before receiving vaccinations.

Hepatitis A In the United States, one of the most frequently identified risks for hepatitis A infection is travel. The risk varies with living conditions, length of stay, and incidence of hepatitis A in the area visited. In some areas, the disease affects an estimated 1 of every 500 to 1000 travelers on a 2- to 3-week trip. Therefore, hepatitis A vaccination is recommended for all susceptible persons traveling to or working in countries with intermediate or high endemicity of infection. Hepatitis A vaccine should be given at least 2 weeks before departure but remains effective if given up until the time of travel. A single dose provides protection

for 1 to 2 years; a booster 6 to 18 months later is required for long-lasting immunity (at least 20 years and possibly lifelong).

Influenza Although influenza is not necessarily considered a travel-related illness, it is the most common vaccine-preventable disease in travelers. The influenza vaccine should be considered in the panel of vaccines offered to the traveler. Influenza seasons can occur at different times of the year in different parts of the world. If a patient cannot be immunized, a course of the antiviral medication oseltamivir can be provided to take at the first sign of a flu-like illness.

Japanese Encephalitis Japanese encephalitis (JE) virus is closely related to the West Nile and Saint Louis encephalitis viruses and is transmitted to humans through the bite of an infected mosquito. JE virus is the most common vaccine-preventable cause of encephalitis in Asia. It occurs throughout most of Asia and parts of the western Pacific. The overall incidence of JE among people from non-endemic countries traveling to Asia is estimated to be less than 1 case per 1 million travelers. However, expatriates and travelers who stay for prolonged periods in rural areas with active JE virus transmission are likely to be at similar risk as the susceptible resident population (i.e., 5 to 50 cases per 100,000 children per year). Even during brief trips, travelers might be at increased risk if they have extensive outdoor or nighttime exposure in rural areas during periods of active transmission. Short-term (5%) or both. It should be treated with intravenous quinidine for 7 days with close monitoring of the QTc interval. In many parts of the world, intravenous artesunate is used, but it may be associated with high rates of relapse. Other important causes of fever after travel include viral hepatitis (hepatitis A and E), typhoid fever, bacterial enteritis, arboviral infections (e.g., dengue, chikungunya, Zika), rickettsial infections, and, in rare instances, leptospirosis, acute HIV infection, and amebic liver abscess (see also Chapter 90).

Acquired Immunodeficiency Syndrome

Skin Diseases

Several countries continue to have policies that bar entry to persons with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Several countries require serologic testing for HIV from all travelers applying for visas lasting longer than 3 months; official documentation is required well in advance of travel. Patients with HIV infection need special preparation before travel to developing countries because of their increased susceptibility to certain illnesses (e.g., pneumococcal infection, tuberculosis). Risk of HIV infection and other sexually transmitted diseases should be discussed, especially with young, sexually active adults.

Sunburn, insect bites, skin ulcers, and cutaneous larva migrans are the most common skin conditions affecting travelers after their return home. Persistent skin ulcers should prompt a work-up for cutaneous leishmaniasis, mycobacterial infection, or fungal infection. Careful, complete inspection of the skin is important in detecting the rickettsial eschar in a febrile patient or the central breathing hole in a “boil” caused by myiasis.

Pregnant Women

The Returning Traveler The most common medical problems encountered by travelers after their return home are diarrhea, fever, respiratory illnesses, and skin lesions. A detailed history should focus on the traveler’s exact itinerary, including dates of travel, exposure history (e.g., food indiscretions, drinking-water sources, freshwater contact, sexual activity, animal contact, insect bites), style of travel (urban vs. rural), immunization history, and use of antimalarial chemoprophylaxis.

Diarrhea Traveler’s diarrhea is an acute condition that usually resolves within 2 weeks. If the traveler’s diarrhea is not responsive to empiric antibiotic treatment, a work-up should be performed to evaluate for Giardia lamblia (see later discussion). Three stool specimens for ova and parasites and a stool culture are indicated (E-Fig. 105.1). If Giardia tests are

Fever

PROTOZOAL INFECTIONS Protozoal infections, though endemic to certain regions, can be encountered all around the world, partly because of the increase in travel and migration (Table 105.1). They cause a tremendous burden of disease in the tropics and subtropics as well as more temperate climates. Immunosuppression associated with various conditions, particularly HIV infection, leads to more severe manifestations. Of all protozoal diseases, malaria causes the most deaths globally, approximately 1 million people each year.

Protozoal Infections in the United States Giardiasis

Giardiasis is a common cause of nonbloody diarrhea in returning travelers. G. lamblia and G. intestinalis are found worldwide, including in the United States. However, giardiasis is most commonly diagnosed in travelers returning from Latin America, Southeast Asia, or the Middle East. Transmission is by the fecal-oral route in the setting of contaminated

CHAPTER 105  Infectious Diseases of Travelers: Protozoal and Helminthic Infections

E-Fig. 105.1  Giardia wet preparation.

975.e1

976

SECTION XV  Infectious Disease

TABLE 105.1  Protozoal Infections Protozoan

Setting

Endemic in the United States Babesia microti New England Giardia lamblia

Mountain states

Toxoplasma gondii

Ubiquitous

Entamoeba histolytica

Southeast

Vectors

Diagnosis

Special Considerations

Treatment

Ixodid ticks, transfusions Humans, small mammals

Thick or thin blood smear

Severe disease in asplenic persons Common in homosexual men, travelers, children in daycare centers Pregnant women, immunosuppressed host (AIDS) Common in homosexual men, travelers, institutionalized persons

Quinine and clindamycin

Severe in immunosuppressed hosts (AIDS) Common cause of vaginitis

Nitazoxanide

Consider in returning travelers with fever

Dependent on regional resistance pattern (see text) Sodium stibogluconate

Domestic cats, raw meat Human

Cryptosporidium species Ubiquitous

Human

Trichomonas vaginalis

Human

Ubiquitous

Microscopic examination of stool or duodenal fluid Clinical; serologic confirmation Microscopic examination of stool or touch preparation from ulcer Acid-fast stain of stool Wet preparation of genital secretions

Primarily Seen in Travelers and Immigrants Plasmodium species Africa, Asia, South Anopheles mosquito Thick and thin blood America smears Leishmania donovani

Middle East

Sandfly

Tissue biopsy

Trypanosoma species

Africa, South America

Reduviid bugs, transfusion

Direct examination of blood or CSF

Consider in immigrants with fever and splenomegaly Very rare in travelers, transfusion associated

Quinacrine, nitazoxanide, or metronidazole Pyrimethamine and sulfadiazine Metronidazole

Metronidazole

Dependent on species and stage of disease

AIDS, Acquired immunodeficiency syndrome; CSF, cerebrospinal fluid.

food or water or public swimming areas, or by person-to-person contact in certain risk populations such as men who have sex with men. It is usually a self-limited diarrheal illness that lasts 2 to 4 weeks but may persist longer. Rarely, individuals have associated fevers, nausea, or vomiting. The diagnosis is made by microscopic examination of stool for cysts or trophozoites or by an antigen detection test. Treatment options include metronidazole, tinidazole, or nitazoxanide.

Amebiasis Amebiasis is another diarrheal illness that occurs in travelers. Like Giardia, Entamoeba histolytica is found worldwide, and transmission is by the fecal-oral route. However, most infected individuals (80%) are asymptomatic. The presentation in those acutely infected includes bloody or watery diarrhea with abdominal cramping lasting up to 4 weeks. In immunocompromised individuals, a severe invasive infection can occur with risk of necrotizing colitis or bowel perforation. Extraintestinal amebiasis can occur as well, particularly liver abscesses. The diagnosis can be made by microscopic examination of stool for ova and parasites or by antigen detection tests of stool or serum. Treatment is with metronidazole or tinidazole in symptomatic individuals, followed by paromomycin or iodoquinol. Asymptomatic patients should also be treated with iodoquinol or paromomycin to prevent spread or later disease development.

Protozoal Infections Common in Travelers and Immigrants Leishmaniasis

Leishmaniasis is transmitted by the sandfly and can manifest with cutaneous, mucocutaneous, or visceral involvement. The skin finding is a persistent ulcer with raised edges in a traveler returning from the Middle East (Old World: Leishmania major, Leishmania tropica) or Latin America (New World: Leishmania braziliensis, Leishmania

peruviana, others). Diagnosis is by tissue biopsy. Visceral leishmaniasis can have hepatic, splenic, or bone marrow involvement and is more commonly identified in immigrants from Asia (Leishmania donovani) or South America (Leishmania chagasi). Diagnosis is by tissue biopsy or culture of the involved organ. Treatment varies based on severity of presentation and resistance characteristics. Most cutaneous lesions are self-limited, but treatment options include sodium stibogluconate (Pentostam) or paromomycin. For visceral involvement, treatment includes sodium stibogluconate, amphotericin B, or a combination of these two agents.

African Trypanosomiasis African trypanosomiasis, or African sleeping sickness, is a protozoal infection caused by Trypanosoma rhodesiense (East Africa) or Trypanosoma gambiense (Central and West Africa), which is transmitted by the tsetse fly. Presenting symptoms include fever, headache, and central nervous system involvement. The disease is rarely reported in travelers returning from sub-Saharan Africa but should be considered in immigrants from these areas. Frequently, the patient remembers a chancre at the site of the insect bite (E-Fig. 105.2). The diagnosis is made by microscopic examination of blood, lymph, or cerebrospinal fluid for the parasite (E-Figs. 105.3 and 105.4). Treatment varies by species and is highly toxic. Consultation with an expert in infectious disease or tropical medicine is recommended.

American Trypanosomiasis American trypanosomiasis, or Chagas’ disease, is caused by Trypanosoma cruzi and is endemic in Central and South America. Transmitted by contact with feces of reduviid bugs (kissing bugs) (E-Fig. 105.5), it can also be acquired through blood transfusion or organ transplantation from an infected individual. The risk to travelers is extremely low but increases with prolonged stays in poor-quality

CHAPTER 105  Infectious Diseases of Travelers: Protozoal and Helminthic Infections

976.e1

E-Fig. 105.4  African trypanosomiasis morula in cerebrospinal fluid.

E-Fig. 105.2  African trypanosomiasis chancre.

E-Fig. 105.3  African trypanosomiasis blood smear.

E-Fig. 105.5  Reduviid bug (“kissing bug”) on the skin.

CHAPTER 105  Infectious Diseases of Travelers: Protozoal and Helminthic Infections housing. The presentation has an acute phase of 3 months followed by a chronic infection for life. The classic acute presentation involves swelling and erythema of the eyelid and ocular tissue at the entry site of infection, known as the Romaña sign. However, most individuals are asymptomatic throughout the infection and are identified only at the time of blood donation. Between 20% and 30% of individuals develop manifestations of chronic infection decades later that can include cardiomegaly and heart failure, megaesophagus, or megacolon. Diagnosis in the acute phase is by microscopic examination of peripheral blood (E-Fig. 105.6). In the chronic phase, various serologic analyses are available to aid in diagnosis. Treatment is recommended early because it may prevent chronic manifestations. In the United States, antitrypanosomal drugs are available through the CDC in consultation with an expert in the field. For most chronic manifestations, however, treatment is supportive.

HELMINTHIC INFECTIONS Infestation by nematodes, or roundworms, is the most common parasitic infection in the world. The intestinal nematodes Ascaris and Trichuris are the two most prevalent types. Other important helminths include Strongyloides, Enterobius, schistosomes, and tapeworms (see later discussion). Although most helminths are found worldwide, they disproportionately affect the developing world and pose potential risk to travelers to those areas (Table 105.2).

Helminthic Infections Common in the United States Pinworm

Enterobiasis is common in the United States and worldwide. Children are predominantly infected, and transmission is by the fecal-oral route. The clinical presentation is perianal pruritus. Diagnosis is made by the tape test, in which transparent tape is applied to the perianal skin overnight and then examined microscopically for ova on the tape. Treatment is with mebendazole or albendazole.

Roundworm Ascaris lumbricoides is found worldwide, including in the United States, but mostly affects people in the developing world. Although affected individuals are usually asymptomatic, some develop pulmonary infiltrates during the migration phase of the worm or obstruction of the biliary, pancreatic, or intestinal tract. These manifestations usually occur in the setting of high worm burden. Diagnosis is by stool examination for ova and parasites (E-Fig. 105.7). Treatment is with mebendazole or albendazole.

Whipworm Trichuris trichiura are called whipworms because of their characteristic shape in the adult form. Like Ascaris, this is an intestinal nematode that infects mostly children. It is usually asymptomatic except in the setting of heavy worm burden, which can lead to rectal prolapse and bloody diarrhea among children in the developing world. Diagnosis is made by stool examination for ova and parasites or by endoscopy revealing colitis and the presence of adult worms. The treatment of choice is mebendazole or albendazole.

Hookworm Ancylostoma duodenale and Necator americanus (hookworms) are similar to roundworms in their worldwide distribution and are common among immigrants from Asia and sub-Saharan Africa. Infection occurs through direct penetration of the skin by the larvae, which travel through the lymphatics and the bloodstream to the lungs and are then swallowed. Infected individuals may be asymptomatic, or they

977

may develop pruritic dermatitis at the site of entry. As with the roundworm, pulmonary infiltrates can occur during the migration phase; this is known as Löffler syndrome. Chronic iron deficiency anemia associated with heavy hookworm infection can be severe and debilitating. Eosinophilia is common. The diagnosis is made by stool examination for ova and parasites (E-Fig. 105.8). The treatment is mebendazole or albendazole.

Helminth Infections Common in Travelers and Immigrants Strongyloidosis

Strongyloides stercoralis is a helminthic parasite that is found worldwide, although more commonly in the tropics. Infection occurs from contact with contaminated soil; the larva penetrates the skin, migrates to the lungs, and is then swallowed by the individual. The infection is usually asymptomatic, but infection can persist into the chronic phase decades later. Those with symptoms usually have gastrointestinal complaints of bloating, diarrhea, and abdominal pain. Eosinophilia is a common finding in these individuals. In immunocompromised individuals, a hyperinfection syndrome with dissemination of the organism can occur. Hyperinfection syndrome has a higher mortality rate and occurs usually in immigrants who become immunosuppressed as a result of chemotherapy, use of steroids, or illness. Diagnosis is made by stool examination (approximately 30% to 50% sensitivity) (E-Fig. 105.9) or by serology but this does not distinguish between chronic and acute disease. Treatment is with ivermectin for 2 days; in the setting of hyperinfection, a longer course is required.

Schistosomiasis Schistosomiasis is found throughout the tropics and the developing world. Also known as blood flukes, schistosomes use freshwater mollusks as their intermediate host and penetrate the skin of individuals, leading to infection. The three major species are: Schistosoma mansoni (Africa, Middle East, South America), Schistosoma haematobium (Africa, Middle East), and Schistosoma japonicum (China, Philippines, and Southeast Asia). Acute infection can manifest with dermatitis, although most cases are asymptomatic. Chronic infection develops from the immune response to egg deposition. S. haematobium can lead to urinary obstruction or hematuria and is associated with an increased risk of bladder cancer. S. mansoni and S. japonicum can lead to hepatosplenomegaly, hepatic fibrosis, obstruction of portal blood flow, and varices. S. japonicum can infect the central nervous system causing ring enhancing lesions and seizures. Diagnosis is by examination of stool or urine for schistosome eggs in individuals from endemic areas, who have a high egg burden; among travelers, in whom the egg burden is usually low, serology is used for diagnosis. The treatment of choice is praziquantel.

Lymphatic Filariasis (Elephantiasis) Wuchereria bancrofti and Brugia malayi are found throughout the tropics; they are lymph-dwelling filariae that cause elephantiasis. The presentation can vary from acute lymphadenitis, to asymptomatic microfilaremia, filarial fevers, or tropical pulmonary eosinophilia. Lymphadenitis can involve both upper and lower extremities with both of these filarial species, but scrotal involvement only occurs with W. bancrofti. The diagnosis is made by examination of a peripheral blood smear for microfilariae obtained between 10 pm and 4 am because these organisms are nocturnally periodic. Diethylcarbamazine is used for lymphatic filariasis to eradicate the microfilariae and the adult worms. However, the management of chronic lymphatic obstruction remains a challenge because it is not fully reversible and requires supportive therapy.

CHAPTER 105  Infectious Diseases of Travelers: Protozoal and Helminthic Infections

E-Fig. 105.6  Chagas’ disease blood smear.

977.e1

978

SECTION XV  Infectious Disease

TABLE 105.2  Helminthic Infections Helminth

Vectors

Diagnosis

Treatment

Endemic in the United States Pinworm (enterobiasis) Ubiquitous Ascaris lumbricoides Southeast Trichuris trichiura Southeast Hookworm Southeast

Setting

Human Human Human Human

Direct examination for ova Stool examination for ova Stool examination for ova Stool examination for ova

Mebendazole, albendazole Mebendazole, albendazole Mebendazole, albendazole Mebendazole, albendazole

Common in Travelers and Immigrants Strongyloides stercoralis Developing world Schistosoma species Developing world

Human Snails

Thiabendazole, ivermectin Praziquantel

Asia, some parts of Africa

Mosquitoes

Stool examination for larvae Stool or urine examination for ova Nocturnal blood examination

Black flies

Biopsy

Ivermectin

Loa loa

Africa, South and Central America Africa

Tabanid flies

Clonorchis sinensis

Asia

Undercooked fish and snails

Diethylcarbamazine or ivermectin Praziquantel

Echinococcus species Taenia solium (cysticercosis) T. solium, Taenia saginata, Diphyllobothrium latum (tapeworms)

Worldwide Developing world Worldwide

Canines and livestock Humans, pigs Pigs, bovine, fish

Blood examination, clinical setting Stool examination for ova, radiology Radiology, serology, biopsy Radiology, serology Stool examination for ova or proglottids

Wuchereria and Brugia species Onchocerca volvulus

Loa loa (Eyeworm)

Ivermectin

Surgery, supportive therapy Surgery, albendazole Praziquantel

Loiasis is caused by the eyeworm (Loa loa) and is found in West and Central Africa. Presentation can vary and may include pruritus, subcutaneous swellings, joint manifestations, or neurologic symptoms. In the rarest presentation, the adult worm can be seen in the anterior chamber of the individual’s eye. Diagnosis is confirmed by the presence of microfilariae in blood samples or isolation of the adult worm. Treatment is as for lymphatic filariasis, with diethylcarbamazine.

tomographic (CT) scans show ring enhancing lesions. The diagnosis is usually based on the history and imaging findings, and confirmation can be made by immunoblot assay. Treatment depends on the site of infection and symptoms. It may include antiparasitic treatment, antiseizure medications, and surgical removal. The antiparasitic drug of choice is praziquantel or albendazole. Expert consultation before treatment is recommended because of the risk of increasing focal cerebral edema and seizure activity.

River Blindness

Intestinal Tapeworms

Onchocerca volvulus infection mostly occurs in regions of West and Central Africa but also in South and Central America. Pruritic dermatitis is the most common presentation; but involvement of the eye is the most serious presentation. Ocular involvement occurs in endemic areas in individuals with heavy worm burden. The complications can begin with conjunctivitis and photophobia. Corneal involvement with the microfilariae causes an inflammatory reaction leading to sclerosing keratitis and blindness. River blindness is the most common cause of blindness in Africa. The diagnosis is made by examination of skin snips for microfilariae. Ivermectin is the drug of choice; an initial single dose is followed by a repeat dose at 3 or 6 months to suppress any further microfilariae because this does not eliminate the adult worm.

Tapeworms that commonly infect humans include Taenia solium (from raw pork), Taenia saginata (raw beef), and Diphyllobothrium latum (raw fish). Most infections are asymptomatic except in the case of invasive disease with T. solium, as discussed earlier (see Cysticercosis). Praziquantel is the treatment of choice for all three tapeworms.

Clonorchiasis Clonorchis sinensis is the Chinese liver fluke. This is an important infection to consider in Asian immigrants who have symptoms consistent with biliary tract disease, including right upper quadrant pain, anorexia, and weight loss. Though the disease is uncommon, untreated infections can lead to cholangiocarcinoma. Treatment is curative with praziquantel in 85% of cases.

Cysticercosis Cysticercosis is caused by the pork tapeworm, Taenia solium. Individuals report new-onset seizures or headaches. Head computed

Echinococcus The tapeworm Echinococcus granulosus causes hydatid disease with production of a cystic liver mass. This occurs in immigrants from sheep-raising parts of the world such as South America, Central Asia, and the Middle East. The characteristic appearance of the cyst includes a calcified wall with a dependent hydatid on CT scans. This appearance and the supporting history help to make the diagnosis; the serologic testing available can be falsely negative. Treatment often includes percutaneous drainage or surgical removal. Care must be taken to avoid rupture or spillage of the contents, which can result in life threatening anaphylaxis. Albendazole is usually given before surgical removal. Less common is Echinococcus multilocularis, which causes alveolar cyst disease. This more aggressive infection leads to liver lesions as well as brain and lung involvement. Treatment includes resection of liver lesions in combination with antiparasitic therapy with mebendazole or albendazole. However, these agents are not parasiticidal, so the mortality rate remains high. Other potential therapies, such as amphotericin B and nitazoxanide, are being explored.

CHAPTER 105  Infectious Diseases of Travelers: Protozoal and Helminthic Infections

E-Fig. 105.8  Hookworm egg.

E-Fig. 105.7  Ascaris egg from wet preparation.

E-Fig. 105.9  Strongyloides stool wet preparation.

978.e1

CHAPTER 105  Infectious Diseases of Travelers: Protozoal and Helminthic Infections

FUTURE DIRECTIONS The field of travel medicine is constantly changing as infectious diseases do not always follow a historical pattern. With the increasing globalization of travel, we can see outbreaks and epidemics develop in new areas such as the West Africa Ebola outbreak in 2014-2015, the Zika epidemic 2015-2016, and the ongoing MERS-CoV outbreak in the Middle East that alter our guidance to patients and our management of returning travelers from these areas. As a physician caring for travelers, we must stay informed of the changing landscape of infectious diseases across the world.

SUGGESTED READINGS Arguin P: Approach to the patient before and after travel. In Goldman L, Schafer A, editors: Cecil textbook of medicine, ed 24, Philadelphia, 2012, Saunders, pp 1800–1803.

979

Centers for Disease Control and Prevention: CDC health information for international travel 2018, New York, 2017, Oxford University Press2017. Freedman DO, Chen LH, Kzoarsky PE: Medical considerations before international travel, N Eng J Med 375:247–260, 2016. Jeronimo S, de Queiroz Sousa A, Pearson R: Leishmaniasis. In Guerrant RL, Walker DH, Weller PF, editors: Tropical infectious diseases: principles, pathogens, and practices, ed 3, Philadelphia, 2011, Saunders, pp 696–706. Kirchoff L: Trypanosoma species (American trypanosomiasis, Chagas’ disease): biology of trypanosomes. In Mandell GL, Bennett JE, Dolin R, editors: Principles and practice of infectious diseases, ed 7, Philadelphia, 2010, Churchill Livingstone, pp 3481–3488. Leder K, Torresi J, Libman M, et al: GeoSentinel surveillance of illness in returned travelers, 2007-2011, Ann Intern Med 158:456–468, 2013.

SECTION

XVI

Neurologic Disease 106  Neurologic Evaluation of the Patient, 981

116  Disorders of the Motor System, 1037

107  Disorders of Consciousness, 986

117 Congenital, Developmental, and Neurocutaneous Disorders, 1048

108  Disorders of Sleep, 992 118  Cerebrovascular Disease, 1056 109  Cortical Syndromes, 997 110 Dementia and Memory Disturbances, 1001

119 Traumatic Brain Injury and Spinal Cord Injury, 1069 120  Epilepsy, 1073

111 Major Disorders of Mood, Thoughts, and Behavior, 1007

121  Central Nervous System Tumors, 1087

112 Autonomic Nervous System Disorders, 1013

122 Demyelinating and Inflammatory Disorders, 1092

113 Headache, Neck and Back Pain, and Cranial Neuralgias, 1017

123 Neuromuscular Diseases: Disorders of the Motor Neuron and Plexus and Peripheral Nerve Disease, 1101

114  Disorders of Vision and Hearing, 1025 124  Muscle Diseases, 1111 115  Dizziness and Vertigo, 1033 125  Neuromuscular Junction Disease, 1122

980

106 Neurologic Evaluation of the Patient Frederick J. Marshall

INTRODUCTION To arrive at an accurate neurologic diagnosis, the clinician generates and tests hypotheses about the location and the mechanism of injury to the nervous system. Hypotheses are refined as the clinician progresses from the interview to the physical examination to the laboratory assessment of the patient. The focus is first placed on entities that are common, serious, and treatable. Common presentations of common diseases account for roughly 80% of cases, rare presentations of common diseases account for roughly 15%, typical presentations of rare diseases roughly 5%, and rare presentations of rare diseases less than 1% of cases. Focus your energy on common diseases but learn the rare disorders too.

TAKING A NEUROLOGIC HISTORY The clinician should strive to determine the location, quality, and timing of symptoms. Encourage the patient to report the progression of symptoms rather than a list of diagnostic procedures and specialty evaluations. Establish when the patient last felt normal, whether the progression has been relentless or remitting, and whether it has been chronic, subacute or acute. This information substantially constrains the differential diagnosis. Ambiguous descriptors such as dizzy should be rejected in favor of evocative descriptors such as light-headed (which may implicate cardiovascular insufficiency) or off balance (which may implicate cerebellar or posterior column dysfunction). Family members and other witnesses should corroborate historical information when appropriate. Historical information should include the medical and surgical histories; current medications; prior responses to efforts at treatment; allergies; family history; review of systems; and social history, including the patient’s level of education, work history, possible toxin exposures, substance use, sexual history, current life circumstance, and overall function. Clues to localization are sought during the interview. For example, pain is usually caused by a lesion of the peripheral nervous system, whereas aphasia (i.e., disordered language processing) indicates an abnormality of the central nervous system. Because sensory and motor functions are anatomically relatively distant in the cerebral cortex but progressively closer together as fibers converge in the brain stem, spinal cord, roots, and peripheral nerves, the coexistence of sensory loss and motor dysfunction in a limb implies a large lesion at the level of the cortex or a smaller lesion lower down in the neuraxis. Small lesions in areas of high traffic such as the spinal cord or brain stem can result in widespread neurologic dysfunction, whereas small lesions elsewhere may be asymptomatic. Table 106.1 lists the potential localizing values of common neurologic symptoms to help address the issue of lesion localization. Tables 106.2 and 106.3 list symptoms that are commonly associated

with lesions at specific locations in the nervous system. Some symptoms can result from a lesion at any of several levels of the nervous system. For example, double vision can result from a focal lesion in the brain stem, peripheral nerves (cranial nerve III, IV, or VI), neuromuscular junction, or extraocular muscles; or it can be nonfocal and result from an increase in intracranial pressure. Associated symptoms (or their lack) may lead the interviewer to reject certain hypotheses that at first seemed most likely. Table 106.4 lists the most important types of neuropathologic conditions and provides examples of diseases in each category. Some neuroanatomic locations point to a specific diagnosis or a limited number of diagnoses. For example, disease of the neuromuscular junction is usually caused by an autoimmune process such as myasthenia gravis (common) or Eaton-Lambert myasthenic syndrome (uncommon). The exceptions—botulism and congenital myasthenic disorders—are rare. Alternatively, some areas of the nervous system (e.g., the cerebral hemispheres) are vulnerable to practically any of the categories of disease outlined in Table 106.4. The pace and temporal order of symptoms are important. Degenerative diseases usually progress gradually, whereas vascular diseases (e.g., stroke, aneurysmal subarachnoid hemorrhage) progress rapidly. Certain symptoms such as double vision almost invariably develop abruptly, even if the underlying disorder has been developing gradually over days to weeks.

NEUROLOGIC EXAMINATION Performance of the main elements of a general screening neurologic examination is imperative (Table 106.5), but the examination should be tailored to confirm or disprove the clinical hypotheses generated from the patient’s history. Unexpected signs must be explained, often with a return to the history for further clarification. The goal of the exam is to determine whether the cause is diffuse, focal or multifocal. The examination is approached as if only one of two possible injuries has occurred—the final common pathway to a structure is disrupted, or the input to that pathway is disrupted (Fig. 106.1). In the case of the motor system, the final common pathway is the motor unit and includes the anterior horn cells giving rise to axons in a nerve, the nerve itself, the neuromuscular junction, and the muscle. Injury to any of these structures results in dysfunction of the muscle. Conversely, if these structures are intact, observing the muscle function may be possible under the right circumstances. If all modes of engaging the final common pathway fail to elicit a response, the clinician can conclude that the lesion is located somewhere within the final common pathway. For example, a man with paralysis of facial movement on one side that is caused by a lesion of cranial nerve VII cannot smile voluntarily, close his eye, or wrinkle his forehead on the affected side. Spontaneous laughter or smiling as an automatic response to a joke also fails to

981

982

SECTION XVI  Neurologic Disease

move the paretic side. If the problem is central, however, facial movement with involuntary (spontaneous) smiling may be preserved or increased. This observation is common in patients with facial weakness caused by a stroke. Central input to a final common pathway in the nervous system is usually tonically inhibitory. Damage to this input typically results in overactivity of the involved muscle group. Signs of damage to central inhibitory systems include spasticity and hyperreflexia (i.e., motor cortex, subcortical white matter, or corticospinal pathways in the brain stem and spinal cord); dystonia, rigidity, tremor, and tic (i.e., basal ganglia or extrapyramidal systems); and ataxia and dysmetria (i.e., cerebellum). An exception is hypotonia, which may be seen in cerebellar disease.

Recording the opening and closing pressures is important. Tissue infection in the region of the puncture site is an absolute contraindication to lumbar puncture. Relative contraindications include known or probable intracranial or spinal mass lesion, increased intracranial pressure as a result of mass lesions, coagulopathy caused by thrombocytopenia (usually correctable), anticoagulant therapy, and bleeding disorders. Rare but severe complications of lumbar puncture include transtentorial or foramen magnum herniation, spinal epidural hematoma, spinal abscess, herniated or infected disk, meningitis, and adverse reaction to a local anesthetic agent. More common and relatively benign complications include headache and backache.

TECHNOLOGIC ASSESSMENT

In selected specialty centers, a diagnostic biopsy is performed on various tissues, including brain, peripheral nerve (see Chapter 123),

Laboratory investigations and special testing should be used to confirm a clinical suggestion and to finalize the diagnosis. Testing should be selectively performed because of expense, risk, and discomfort to the patient. Frequently helpful tests are discussed in subsequent sections. Diagnostic tests should never be ordered without a specific differential diagnosis firmly in mind. Many neurodiagnostic tests disclose incidental abnormalities unrelated to a patient’s symptomatic disease process.

Lumbar Puncture Investigation of the cerebrospinal fluid (CSF) is indicated in a small number of specific circumstances, usually infections, malignancy, or inflammatory/immune mediated conditions (Table 106.6). When taken, a CSF specimen should be routinely sent for laboratory testing to determine cell and differential counts, protein and glucose levels, and bacterial cultures. The CSF should also be examined for its color and clarity. Cloudy or discolored CSF should be centrifuged and examined for xanthochromia in comparison with water. Additional, special studies may be obtained as appropriate, including Gram stain; fungal, viral, and tuberculous cultures; cryptococcal and other antigens; tests for syphilis; Lyme titers; malignant cytologic patterns; paraneoplastic and other specific protein antibodies; and oligoclonal bands. Polymerase chain reaction for specific viruses may also be appropriate. Assessment of specific CSF proteins such as tau, phosphorylated tau, and amyloid-β in selected patients at risk for dementia may be considered. The 14-3-3 protein, found in Creutzfeldt-Jakob disease, may be found in patients with rapid-onset dementia.

TABLE 106.1  Potential Localizing Value of

Common Neurologic Symptoms Potential Localizing Value

Sign or Symptom

High

Focal weakness, sensory loss, or pain Focal visual loss Language disturbance Neglect or anosognosia Vertigo Dysarthria Clumsiness Fatigue Headache Insomnia Dizziness Anxiety, confusion, or psychosis

Medium

Low

Tissue Biopsies

TABLE 106.2  Symptom Localization in the

Central Nervous System Sign or Symptom Cerebral Hemispheres Unilateral weakness or sensory complaints Language dysfunction Spatial disorientation Anosognosia (lack of insight into deficit) Hemivisual loss

Location Contralateral cerebral hemisphere

Left hemisphere (frontal and temporal) Right hemisphere (parietal and occipital) Right hemisphere (parietal) Contralateral hemisphere (occipital, temporal, and parietal) Flattening of affect or social disinhibition Bihemispheric (frontal and limbic) Alteration of consciousness Bihemispheric (diffuse) Alteration of memory Bihemispheric (hippocampus, fornix, amygdala, and mammillary bodies) Cerebellum Limb clumsiness Unsteadiness of gait or posture

Ipsilateral cerebellar hemisphere Midline cerebellar structures

Basal Ganglia Slowness of voluntary movement Involuntary movement

Substantia nigra and striatum Striatum, thalamus, and subthalamus

Brain Stem Contralateral weakness or sensory complaints in the body with ipsilateral weakness or sensory complaints in the face Double vision Vertigo Alteration of consciousness Spinal Cord Weakness and spasticity (ipsilateral) and anesthesia (contralateral) below a specified level Unsteadiness of gait Bilateral (can be asymmetrical) weakness and sensory complaints in multiple contiguous radicular distributions

Midbrain, pons, and medulla

Midbrain and pons Pons and medulla Midbrain, pons, medulla (reticular formation) Corticospinal and spinothalamic tracts

Posterior columns Central cord

CHAPTER 106  Neurologic Evaluation of the Patient

983

TABLE 106.3  Symptom Localization in the

TABLE 106.4  Categories of Neurologic

Sign or Symptom

Disease Category

Example

Genetic Autosomal dominant Autosomal recessive X-linked recessive Mitochondrial Sporadic

Huntington’s disease Friedreich’s ataxia Duchenne muscular dystrophy Progressive external ophthalmoplegia Down syndrome

Neoplastic Intrinsic Extrinsic Paraneoplastic

Glioblastoma Metastatic melanoma Cerebellar degeneration

Motor Unita

Anterior Horn Cell Weakness and wasting with muscle twitching (fasciculation) but no sensory complaints Spinal Root Weakness and sensory loss confined to a known radicular distribution (pain, a common feature, may spread) Plexus Pain, weakness, and sensory loss in a limb; not limited to a single radicular or peripheral nerve distribution Nerve Pain, distal weakness, and/or sensory changes confined to a single peripheral nerve distribution Pain, distal weakness, and/or sensory changes affecting both sides symmetrically (usually starting in feet) Pain, distal weakness, and/or sensory changes affecting scattered single peripheral nerve distributions Unilateral special sensory loss

Location Anterior horn of spinal cord (diffuse or segmental) Cervical, thoracic, lumbar, and sacral

Brachial and lumbosacral (may also be caused by polyradiculopathy) Peripheral nerves (mononeuropathy)

Structural Inflammatory

Peripheral nerves (polyneuropathy)

Infectious Bacterial Viral Protozoal Fungal Helminthic Prion

Meningococcal meningitis Herpes encephalitis Toxoplasmosis Cryptococcal meningitis Cysticercosis Creutzfeldt-Jakob disease

Degenerative Central Central and peripheral

Parkinson’s disease Amyotrophic lateral sclerosis

Autoimmune Central demyelinating Peripheral demyelinating Neuromuscular junction

Multiple sclerosis Guillain-Barré syndrome Myasthenia gravis

Toxic and Metabolic Endogenous Exogenous

Uremic encephalopathy Alcoholic neuropathy

Other Structural Trauma Hydrodynamic Psychogenic

Spinal cord injury Normal pressure hydrocephalus Hysterical paraparesis

Unilateral facial weakness involving entire one half of face Neuromuscular Junction Progressive weakness with repeated use of a muscle; no sensory complaints

Ocular, pharyngeal, and skeletal

aAnterior

Vascular Stroke

Thrombotic, embolic, lacunar, hemorrhagic Arteriovenous malformation Cranial arteritis

Peripheral nerves (mononeuropathy multiplex) Cranial nerves I, II, V, VII, VIII, and IX Cranial nerve VII (ipsilateral)

Muscle Proximal weakness; no sensory complaints

Disease

Diffuse and various patterns

horn cell and the peripheral nervous system.

muscle (see Chapter 124), and skin. Occasionally, biopsy provides the only means of arriving at a definitive diagnosis.

Electrophysiologic Studies Electrophysiologic studies include electroencephalography, electromyography, nerve conduction studies, and evoked potentials. These studies are helpful in situations in which the patient cannot be examined or interviewed adequately. Electroencephalography is most often used to investigate seizures (see Chapter 120). It can document encephalopathy, in which case the background electrical activity of the brain is slowed, and it is also used in the evaluation of brain death. Electromyography is useful in the differential diagnosis of muscle disease, neuromuscular junction disease, peripheral nerve disease, and anterior horn cell disease. Nerve conduction studies (see Chapters 123 and 124) may show decreased amplitude (characteristic of axonal neuropathy) or decreased velocity (characteristic of demyelinating neuropathy). Visual-evoked potential studies are commonly used in the evaluation of possible multiple sclerosis (see Chapter 122). Asymmetrical

slowing of the cortical response to visual pattern stimulation suggests demyelination in the optic nerve or central optic pathways. Brain stem auditory-evoked potential studies are useful in the diagnosis of diseases affecting cranial nerve VIII or its central projections. Lesions at the cerebellopontine angle and the brain stem cause abnormal delay in conduction. Brain stem auditory-evoked potentials are helpful in the diagnosis of deafness in infants. Somatosensory-evoked potentials are used to identify a slowing of central sensory conduction that results from demyelinating disease, compression, or metabolic derangements. They are also used to evaluate spinal cord–mediated sensory abnormalities.

Imaging Studies Magnetic resonance imaging (MRI) and computed tomography (CT) are high-resolution imaging techniques that provide extraordinary

984

SECTION XVI  Neurologic Disease

TABLE 106.5  Elements of a General Screening Neurologic Examination Systemic Physical Examination Head (trauma, dysmorphism, and bruits) Neck (tone, bruits, and thyromegaly) Cardiovascular (heart rate, rhythm, and murmurs; peripheral pulses and jugular venous distention) Pulmonary (breathing pattern, cough and cyanosis) Abdomen (hepatosplenomegaly) Back and extremities (skeletal abnormalities, peripheral edema, and straight-leg raising) Skin (neurocutaneous stigmata and hepatic stigmata) Mental Status Level of consciousness (awake, drowsy, and comatose) Attention (coherent stream of thought, serial 7s) Orientation (temporal and spatial) Memory (short and long term) Language (naming, repetition, comprehension, fluency, reading, and writing) Visuospatial skills (clock drawing and figure copying) Judgment, insight, thought content (psychotic) Mood (depressed, manic, and anxious) Cranial Nerves Olfactory (smell in each nostril) Optic (afferent pupillary function, funduscopic examination, visual acuity, visual fields, and structural eye findings) Oculomotor, trochlear, and abducens (smooth pursuit and saccadic eye movements, nystagmus, efferent pupillary function, and eyelid opening) Trigeminal (jaw jerk, facial sensation, afferent corneal reflex, and muscles of mastication) Facial (efferent corneal reflex, facial expression, eyelid closure, nasolabial folds, and power and bulk) Vestibulocochlear (nystagmus, speech discrimination, Weber test, and Rinne test) Glossopharyngeal and vagus (afferent and efferent gag reflex and uvula position) Spinal accessory (power and bulk of sternocleidomastoid and trapezii muscles) Hypoglossal (position, bulk, and fasciculations of tongue) Motor Examination Pronator drift (subtle corticospinal lesion) Tone and bulk of muscles (basal ganglia lesion yields rigidity, cerebellar lesion yields hypotonia, corticospinal lesion yields spasticity, nonspecific bihemispheric disease yields paratonia [inability to relax muscles], hypertrophy indicates dystonia, pseudohypertrophy indicates muscle disease, and atrophy indicates lower motor neuron disease) Adventitious movements (tremor, tic, dystonia, and chorea indicate disease of the basal ganglia; asterixis and myoclonus may indicate toxic metabolic process) Power of major muscle groups (scale 0-5) Upper extremities: deltoids, biceps, triceps, wrist extension and flexion, finger extension and flexion, and interossei Lower extremities: hip flexion, extension, abduction, and adduction; knee extension and flexion; ankle dorsiflexion, plantar flexion, inversion, and eversion; toe extension and flexion

diagnostic precision for central nervous system lesions. Most neurologic diseases, however, can have normal CT and MRI findings. Moreover, many abnormal findings on CT and MRI bear no relation to the diagnosis responsible for the patient’s symptoms. Table 106.7 compares CT with MRI. MRI is used for most purposes, although CT has the advantage of wider accessibility, greater speed of acquisition, and better tolerability by the patient. CT detects acute hemorrhage and is preferred for emergencies. MRI provides more detail and simultaneously obtains images in the horizontal,

Sensory Examination Light touch (posterior columns) Pinprick (spinothalamic tract) Temperature (spinothalamic tract) Joint position sense (posterior columns) Vibration (posterior columns) Graphesthesia (cortical sensory) Double simultaneous stimulation (cortical sensory) Two-point discrimination (posterior columns and cortical sensory) Reflex Examination Standard reflexes (grades 0-4) Biceps Triceps Brachioradialis Knee jerk Ankle jerk Pathologic reflexes Babinski sign (if present) Myerson sign (glabellar sign) (if present) Snout (if present) Jaw jerk (if brisk) Palmomental (twitch of chin muscles when palm is stroked) (if present) Hoffmann sign (thumb or index finger flexion when nail of middle finger is flicked) (if brisk) Coordination and Gait Finger-nose-finger (action tremor suggesting cerebellar disease) Rapid alternating movements (dysdiadochokinesia suggesting cerebellar disease) Fine motor movements (slowness and small amplitude suggesting basal ganglia or corticospinal tract abnormalities) Heel-to-shin (ataxia suggesting cerebellar disease) Arising from chair with arms folded across chest (inability in advanced basal ganglia, cerebellar, corticospinal, or muscle disease) Walking naturally (look for decreased arm swing, spasticity, broad base, festination (quickening and shortening of normal gait), waddle, footdrop, start hesitation, and dystonia) Tandem gait (look for ataxia) Walking with feet everted or inverted (look for latent dystonia) Hopping on each foot separately (look for latent dystonia) Stand with feet together and eyes open, eyes closed (sensory ataxia and cerebellar disease) Response to retropulsive stress (loss of postural righting mechanisms)

vertical, and coronal planes. Contrast media for CT or MRI are useful in the diagnosis of tumors, abscesses, and other processes that derange the blood-brain barrier. MRI can be used for functional imaging and spectroscopy; both techniques have great promise for the evaluation of cognitive and metabolic disorders, epilepsy, multiple sclerosis, and many other conditions. MR- and CT-angiography allow noninvasive visualization of the major vessels of the head and neck. Conventional angiography with an intra-arterial injection of contrast agent is used for evaluation of

CHAPTER 106  Neurologic Evaluation of the Patient

985

TABLE 106.8  Some Neurologic Conditions

for Which Genetic Tests Are Commercially Available Upper motor neuron Lower motor neuron Effector (muscle) Central connections Peripheral nerve Fig. 106.1  The nervous system can be conceptually reduced to a series of higher-order inputs that converge on final common pathways. For example, upper motor neurons converge on lower motor neurons, whose axons form the final common pathway to an effector muscle.

TABLE 106.6  Indications for Lumbar

Puncture

Urgent (Do Not Wait for Brain Imaging) Acute central nervous system infection in the absence of focal neurologic signs Less Urgent (Wait for Brain Imaging) Vasculitis, subarachnoid hemorrhage, or cryptic process Increased intracranial pressure in the absence of mass lesion on magnetic resonance imaging or computed tomography Intrathecal therapy for fungal or carcinomatous meningitis Symptomatic treatment for headache from idiopathic intracranial hypertension or subarachnoid hemorrhage

TABLE 106.7  Magnetic Resonance

Imaging Versus Computed Tomography Magnetic Resonance Imaging (MRI) Resolution 1-2 mm (higher with newer 3-Tesla magnets) Gadolinium contrast relatively safe, except in severe renal insufficiency Unaffected by bone; multiple planes of imaging available; functional (physiologic) imaging capacity Computed Tomography Resolution >5 mm Iodine contrast associated with anaphylaxis and rash Faster acquisition than MRI Metallic objects such as pacemaker or aneurysm clip preclude MRI Acute hemorrhage well visualized Better tolerated by patients who are severely ill or claustrophobic

• N  euromuscular diseases: nerve (Charcot-Marie-Tooth disease); muscle (myotonic dystrophy, Duchenne-Becker muscular dystrophy); spinal muscular atrophy, familial amyotrophic lateral sclerosis • Movement disorders: ataxia (spinal cerebellar ataxias, Friedreich ataxia); dystonia, parkinsonism, chorea • Dementias: Alzheimer’s disease, frontotemporal dementia, hereditary prion disease • Mental retardation (fragile X syndrome) • Mitochondrial diseases: mitochondrial encephalomyelopathy, lactic acidosis, and stroke-like symptoms (MELAS syndrome); myoclonus epilepsy with ragged red fibers (MERRF syndrome)

Single-photon emission CT (SPECT) is useful for the evaluation of intracranial blood flow. The development of iodine-123 ioflupane injection (DaTscan) makes it possible to visualize the dopamine transporter to follow cell loss in patients with Parkinson’s disease. Positron-emission tomography (PET) is a functional imaging technology that can demonstrate specific metabolic derangements. It is useful for evaluating local abnormalities of glucose and oxygen metabolism. PET is of particular value in defining the site of origin of focal seizures. Customized ligands can be used to identify specific pathologic processes. Examples include three FDA-approved agents for estimating β-amyloid neuritic plaque density in Alzheimer’s disease and fluorodopa F18 in Parkinson’s disease.

Genetic and Molecular Testing There are more neurologic diseases than diseases of all other systems combined. Discoveries have revolutionized the diagnostic approach to many of these diseases, and new genetic tests are discovered every year. Table 106.8 outlines the tests that are commercially available. Genetic testing for a disorder requires the clinician to perform a thoughtful and caring evaluation of the patient, usually with input from and evaluation of the patient’s family. Important ethical issues surround the use of genetic tests, including the ability to ensure privacy, to ensure adequate psychological and social support for patients who may be given devastating news, and to address adequately the appropriateness of prenatal screening or presymptomatic testing when no treatment is available.

PROSPECTS FOR THE FUTURE Novel imaging techniques and molecular diagnostic studies are beginning to shed light on the pathogenesis of neurologic conditions that have been identifiable only by clinical phenomenology. Studies of previously untreatable neurodegenerative disorders are now targeting presymptomatic individuals in the hope that earlier intervention can modify disease outcomes. Despite these and foreseeable future advances, the clinical aspects of neurologic disease remain fundamentally important in understanding the impact of disease on patients and their families.

SUGGESTED READINGS many intracranial vascular abnormalities, including small aneurysms and arteriovenous malformations, and inflammation of small blood vessels. Noninvasive ultrasonography of the carotid and vertebral arteries can define stenotic vessels. It has been supplemented by transcranial Doppler technology, which allows characterization of blood flow in intracranial arteries.

Biller J, editor: Practical neurology, ed 4, Philadelphia, 2012, Lippincott Williams & Wilkins. DeLuca GC, Griggs RC: Approach to the patient with neurologic disease. In Goldman L, Schafer AI, editors: Goldman-Cecil medicine, ed 26, 2020, pp 2298–2304, (Philadelphia.. Ropper, AH, Samuels MA, Leine JP, Prasad S, editors: Adams and victor’s principles of neurology, ed 11, New York, McGraw Hill.

107 Disorders of Consciousness Leah Dickstein, Paul M. Vespa

INTRODUCTION Coma is a state in which the patient is unresponsive and the eyes remain closed even with vigorous stimulation. A poorly responsive state in which the eyes are spontaneously open, or an agitated and confused state, or delirium is not coma but may represent early stages of the same disease processes and should be investigated in the same manner. Consciousness requires that the brain stem reticular activating system and its cortical projections be intact and functioning. The reticular formation begins in the mid pons and ascends through the dorsal midbrain to synapse in the thalamus; it then innervates higher centers through thalamocortical connections. Knowledge of this anatomic substrate provides the short list of regions to be investigated in the search for a structural cause of coma: Brain stem or bihemispheric dysfunction, be it medication or lesion-related, is typically needed to impede consciousness, whereas structural lesions elsewhere are not the cause of the patient’s unconsciousness. In addition to structural lesions, meningeal inflammation, metabolic encephalopathy, sedation, and seizures diffusely affect the brain and complete the differential diagnosis for the patient in coma.

PATHOPHYSIOLOGIC FACTORS Meningeal irritation caused by infection or blood in the subarachnoid space is an essential early consideration in coma evaluation because its cause requires immediate attention (especially with purulent meningitis) and may not be diagnosed by computed tomography (CT). Hemispheric mass lesions result in coma either by expanding across the midline laterally to compromise both cerebral hemispheres or by impinging on the brain stem to compress the rostral reticular formation. These processes—lateral herniation (lateral movement of the brain) and transtentorial herniation (vertical movement of the brain)— most commonly occur together. At the bedside, clinical signs of an expanding hemispheric mass evolve in a level-by-level, rostral-caudal manner (Fig. 107.1). Hemispheric lesions of adequate size to produce coma are readily seen on CT. Brain stem mass lesions produce coma by directly affecting the reticular formation. Because the pathways for lateral eye movements—the pontine gaze center, medial longitudinal fasciculus, and oculomotor (third nerve) nucleus—traverse the reticular activating system, impairment of reflex eye movements is often the critical element of diagnosis of a brain stem lesion. A comatose patient without impaired reflex lateral eye movements does not have a mass lesion compromising brain stem structures in the posterior fossa. CT is not able to show some lesions in this region. Posterior fossa lesions may block the flow of cerebrospinal fluid from the lateral ventricles, resulting in the dangerous situation of noncommunicating hydrocephalus.

986

Metabolic abnormalities are caused by deficiency states (e.g., thiamine, glucose), by derangements of metabolism (e.g., hyponatremia), or by the presence of exogenous toxins (e.g., drugs) or endogenous toxins (e.g., organ system failure). Metabolic abnormalities result in diffuse dysfunction of the nervous system; therefore, with rare exceptions, they produce no localized signs such as hemiparesis or unilateral papillary dilation. The diagnosis of metabolic encephalopathy means that the examiner has found no focal anatomic features on examination or neuroimaging studies to explain coma but that a specific metabolic cause has not been established. Drugs have a predilection for affecting the reticular formation in the brain stem and for producing paralysis of reflex eye movement on examination. Multifocal structural disorders may simulate metabolic coma (Table 107.1). In the late stages of status epilepticus, motor movements may be subtle even though seizure activity is continuing throughout the brain (nonconvulsive status epilepticus). Once seizures stop, the so-called postictal state can also cause unexplained coma.

DIAGNOSTIC APPROACH The history and examination are essential in the diagnosis and are not replaced by brain imaging (Table 107.2). A history of a premonitory headache supports a diagnosis of meningitis, encephalitis, or intracerebral or subarachnoid hemorrhage. A preceding period of intoxication, confusion, or delirium points to a diffuse process such as meningitis or endogenous or exogenous toxins. The sudden apoplectic onset of coma is particularly suggestive of ischemic or hemorrhagic stroke affecting the brain stem or of subarachnoid hemorrhage or intracerebral hemorrhage with intraventricular rupture. Lateralized symptoms of hemiparesis or aphasia before coma occur in patients with hemispheric masses or infarctions. The physical examination is critical, quickly accomplished, and diagnostic. The issues are three: (1) Does the patient have meningitis? (2) Are signs of a mass lesion present? and (3) Is this condition a diffuse syndrome of exogenous or endogenous metabolic etiology? Emergency management should then be instituted accordingly (Table 107.3).

Identification of Meningitis Signs of meningeal irritation are not invariably present and have differing sensitivities depending on the cause: They are extremely common with acute pyogenic meningitis and subarachnoid hemorrhage and less common with indolent, fungal meningitis. Nevertheless, the presence of these signs on examination is the central clue to the diagnosis. Missing these signs results in time-consuming additional tests such as brain imaging and the potential loss of a narrow window of opportunity for directed therapy.

CHAPTER 107  Disorders of Consciousness

Pupillary light response

Reflex eye movements

987

Motor response to pain

Early diencephalic

Late diencephalic

Midbrain

Pons of upper medulla Fig. 107.1  The evolution of neurologic signs in coma from a hemispheric mass lesion as the brain becomes functionally impaired in a rostral-caudal manner. The terms early diencephalic and late diencephalic refer to levels of dysfunction just above and just below the thalamus, respectively. (From Aminoff MJ, Greenberg DA, Simon RP: Clinical neurology, Stamford, Conn., 1996, Appleton and Lange.)

TABLE 107.1  Multifocal Disorders

Indicating Metabolic Coma Disseminated intravascular coagulopathy Sepsis Pancreatitis Vasculitis Thrombotic thrombocytopenic purpura Fat emboli Hypertensive encephalopathy Diffuse micrometastases

Separation of Structural From Metabolic Causes of Coma The goal of this differential diagnosis is achieved by neurologic examination. Because the evaluation and potential treatments for structural and metabolic coma are widely divergent and the disease processes in both categories are often rapidly progressive, initiating prompt medical and surgical evaluation may be life-saving. Identification of a structural versus a metabolic cause is accomplished by focusing on three features of the neurologic examination: the motor response to a painful stimulus, pupillary function, and reflex eye movements.

Motor Response Passive neck flexion should be tested (Fig. 107.2) in all comatose patients unless a history of head trauma exists. When the neck is passively flexed by attempting to bring the chin within a few fingerbreadths of the chest, patients with irritated meninges reflexively flex one or both knees. This sign, called the Brudzinski reflex, is usually asymmetrical and not dramatic, but any evidence of knee flexion during passive neck flexion mandates that the cerebrospinal fluid be examined. Is CT required before lumbar puncture in this setting? In the absence of lateralized signs (e.g., hemiparesis) supporting a superimposed mass lesion, a spinal puncture should be performed immediately. Although rare cases of herniation after lumbar puncture have been reported in children with bacterial meningitis, the urgency of diagnosis and treatment at the point of coma is paramount. The time required for CT may result in a fatal therapeutic delay. An alternative approach involves obtaining blood cultures and immediately initiating antibiotic therapy with subsequent lumbar puncture. With this approach, the cerebrospinal fluid cell count, glucose determination, and protein content are unchanged, and Gram stain and culture often remain positive despite a short period of antibiotic treatment. Bacterial antigens in the cerebrospinal fluid or blood can also be detected.

Asymmetrical or reflex function of the motor system provides the clearest indication of a mass lesion. Elicitation of a motor response requires that a painful stimulus be applied, to which the patient will react. The patient’s arms should be placed in a semiflexed posture, and a painful stimulus should be applied to the head or trunk. Strong pressure on the supraorbital ridge or pinching of the skin on the anterior chest or inner arm is the most useful method; finger nail bed pressure is also used, but it makes the interpretation of upper limb movement difficult. The neurologic examination of a patient with an expanding hemispheric mass lesion is shown in Fig. 107.1. Hemispheric masses in their early diencephalic stage (i.e., compromising the brain above the thalamus) produce appropriate movement of one upper extremity—that is, movement toward the painful stimulus. The attenuated contralateral arm movement reflects a hemiparesis. This lateralized motor response in a comatose patient establishes the working diagnosis of a hemispheric mass. As the mass expands to involve the thalamus (late diencephalic stage), the response to pain becomes reflex arm flexion associated with extension and internal rotation of the legs (decorticate posturing); asymmetry of the response in the upper extremities is seen. With further brain compromise at the midbrain level, the reflex posturing in the arms changes such that both arms and legs respond by extension (decerebrate posturing); at that level, the asymmetry tends to

988

SECTION XVI  Neurologic Disease

TABLE 107.2  Causes of Coma With

Normal Computed Tomography Scan Meningeal disorders Subarachnoid hemorrhage (uncommon) Bacterial meningitis Encephalitis Subdural empyema Exogenous toxins Sedative drugs and barbiturates Anesthetics and γ-hydroxybutyratea Alcohol Stimulants Phencyclidineb Cocaine and amphetaminec Psychotropic drugs Cyclic antidepressants Phenothiazines Lithium Anticonvulsants Opioids Clonidined Penicillins Salicylates Anticholinergics Carbon monoxide, cyanide, and methemoglobinemia Endogenous toxins, deficiencies, derangements Hypoxia and ischemia Hypoglycemia Hypercalcemia Osmolar causes Hyperglycemia Hyponatremia Hypernatremia Organ system failure Hepatic encephalopathy Uremic encephalopathy Pulmonary insufficiency (carbon dioxide narcosis) Seizures Prolonged postictal state Spike-wave stupor Hypothermia or hyperthermia Brain stem ischemia Basilar artery stroke Pituitary apoplexy Conversion or malingering

anesthetic, similar to γ-aminobutyric acid; used as a recreational drug and body building aid. It has a rapid onset and rapid recovery, often with myoclonic jerking and confusion. It causes deep coma lasting 2 to 3 hours (Glasgow Coma Scale score = 3) with maintenance of vital signs. bComa associated with cholinergic signs: lacrimation, salivation, bronchorrhea, and hyperthermia. cComa after seizures or status epilepticus (i.e., a prolonged postictal state). dAn antihypertensive agent that is active through the opiate receptor system; overdose is frequent when used to treat narcotic withdrawal. aGeneral

be lost. At this point, the pupils become mid-position in size, and the light reflex is lost, first unilaterally and then bilaterally. With further progression to the level of the pons, the most frequent finding is no response to painful stimulation, although spinal-mediated movements of leg flexion may occur.

TABLE 107.3  Emergency Management 1. Ensure airway adequacy. 2. Support ventilation and circulation. 3. Obtain blood for glucose, electrolytes, hepatic and renal function, prothrombin and partial thromboplastin times, complete blood count, and drug screen. 4. Administer 100 mg of thiamine intravenously (IV). 5. Administer 25 g of dextrose IV (typically 50 mL of 50% dextrose) to treat possible hypoglycemic coma.a 6. Treat opiate overdose with naloxone (0.4-2 mg IV repeated every 2-3 minutes as needed). 7. The specific benzodiazepine antagonist flumazenil (0.2 mg IV every 1 min, ×1-5 doses; max is 1 mg) should be given for reversal of benzodiazepine-induced coma or conscious sedation.b aThe

glucose level is poorly correlated with the level of consciousness in hypoglycemia; stupor, coma, and confusion are reported with blood glucose concentrations ranging from 2 to 60 mg/dL. bNot recommended in coma of unknown origin because seizures may be precipitated in patients with polydrug overdoses that include benzodiazepines with tricyclic antidepressants or cocaine.

Fig. 107.2  Elicitation of Brudzinski sign of meningeal irritation, as seen in infectious meningitis or subarachnoid hemorrhage. (From Aminoff MJ, Greenberg DA, Simon RP: Clinical neurology, Stamford, Conn., 1996, Appleton and Lange.)

The classic postures illustrated in Fig. 107.1, and particularly their asymmetry, strongly support the presence of a mass lesion. However, these motor movements, especially early in coma, are most frequently seen as fragments of the fully developed, asymmetrical flexion or extension of the arms (illustrated as decorticate and decerebrate postures in Fig. 107.1). A small amount of asymmetrical flexion or extension of the arms in response to a painful stimulus carries the same implications as the full-blown postures of decortication or decerebration. Metabolic lesions do not compromise the brain in a progressive, level-by-level manner as do hemispheric masses, and they rarely produce the asymmetrical motor signs typical of masses. Reflex posturing may be seen, but it lacks the asymmetry of decortication seen with a hemispheric mass, and it is not associated with the loss of pupillary reactivity at the stage of decerebration.

Pupillary Reactivity In metabolic coma, one feature is central to the examination: Pupillary reactivity is present. This reactivity is seen both early in metabolic coma, when an appropriate motor response to pain may be retained, and late in coma, when no motor responses can be elicited. The pupillary reaction in metabolic coma is lost only when coma is so deep that the patient requires ventilatory and blood pressure support.

CHAPTER 107  Disorders of Consciousness

Reflex Eye Movements The presence of inducible lateral eye movements reflects the integrity of the pons and midbrain. These reflex eye movements (see Fig. 107.1) are brought about with the use of passive head rotation to stimulate the semicircular canal input to the vestibular system (so-called doll’s eyes maneuver) or by inhibiting the function of one semicircular canal by infusing ice water against the tympanic membrane (caloric testing). In metabolic coma, reflex eye movements may be lost or retained. Lack of inducible eye movements with the doll’s eyes maneuver, in the setting of preserved pupillary reactivity, is virtually diagnostic of drug toxicity. With metabolic coma of non–drug-induced origin, such as organ system failure, electrolyte disorders, or osmolar disorders, reflex eye movements are preserved. Brain stem mass lesions are most commonly caused by hemorrhage or infarction. Reflex lateral eye movements, the pathways for which traverse the pons and midbrain, are particularly affected, and the reflex postures of decortication and decerebration typical of brain stem injury are common. Lesions restricted to the midbrain (e.g., embolization from the heart to the top of the basilar artery) cause sluggish pupillary reflexes or their absence, with or without impaired medial eye movements; both are controlled by the third cranial nerve. With lesions restricted to the pons (e.g., intrapontine hypertensive hemorrhage), pupils are reactive but very small (pinpoint or pontine pupils), reflecting focal impairment of sympathetic innervations; pinpoint pupils are rare. Ocular bobbing (spontaneous symmetrical or asymmetrical rhythmic vertical ocular oscillations) is most often a manifestation of a pontine lesion. Seizures occurring in a patient with acute brain injury (such as that resulting from encephalitis, hypertensive encephalopathy, hyponatremia, hypernatremia, hypoglycemia, or hyperglycemia) or chronic brain injury (such as dementia or mental retardation) often result in prolonged postictal coma. The examination shows reactive pupils and inducible eye movements (in the absence of overtreatment with anticonvulsants), and often up-going toes or focal signs are observed (Todd paresis). Nonconvulsive status epilepticus should be considered as a diagnosis even if there are no obvious seizure movements. Nonconvulsive seizures can cause coma and also can complicate other etiologies of coma, including infectious and metabolic disorders. Nonconvulsive seizures should be suspected in patients with (1) a seemingly prolonged “postictal state” after generalized convulsive seizures or prolonged alteration of alertness after an operative procedure or neurologic insult; (2) acute onset of impaired consciousness or fluctuating mentation interspersed with episodes of normal awareness; (3) altered mental status or consciousness associated with facial myoclonus or nystagmoid eye movements; or (4) episodic blank staring, aphasia, automatisms (e.g., lip-smacking, fumbling with fingers), or acute-onset aphasia without an acute structural lesion. The diagnosis is made by electroencephalography (EEG) (see Chapter 120). EEG provides information about brain electrical activity even when brain function is depressed and cannot be evaluated otherwise, as in comatose patients. EEG is essential to detect electrical seizures and document their duration as well as the response to therapy and to improve coma prognostication. Current evidence suggests that the presence of nonconvulsive seizures or periodic discharges, delay to diagnosis, and duration of nonconvulsive status in patients with or without acute brain injury are independent predictors of worse outcome.

PROGNOSIS IN COMA AFTER CARDIAC ARREST Historically, prognostication after cardiac arrest was solely based on neurologic examination. Pupillary, corneal, and motor responses are

989

Coma Exclude major confounders No brain stem reflexes at any time Yes (pupil, cornea, oculocephalic, cough)

Brain death testing

Or Day 1 Myoclonus Status epilepticus Or Day 1–3 SSEP absent N20 responses

Yes

Poor outcome

FPR 0% (0–8.8)

Yes

Poor outcome

FPR 0.7% (0–3.7)

Yes

Poor outcome

FPR 0% (0–3)

Poor outcome

FPR 0% (0–3)

Or Day 1–3 Serum NSE 33 µg/L Or

Day 3 Yes Absent pupil or corneal reflexes; extensor or absent motor response No Indeterminate outcome

Fig. 107.3  Decision algorithm for use in prognostication of comatose survivors after cardiopulmonary resuscitation (CPR). The numbers in parentheses show the exact 95% confidence intervals. FPR, False-positive rate; N20, a negative peak at 20 ms on SSEP; NSE, neuron-specific enolase; SSEP, somatosensory evoked potential. (Data from Wijdicks EFM, Hijdra A, Young GB, et al: Practice parameter: prediction of outcome in comatose survivors after CPR [an evidence-based review]: report of the Quality Standards Subcommittee of the American Academy of Neurology, Neurology 67:203-210, 2006.)

the best clinical indicators of prognosis that can be assessed at bedside. Such responses reflect the functionality of the brain stem, which is the most resilient portion of central nervous system (Fig. 107.3). Although the neurologic exam is still the cornerstone of prognostication, there has been extensive work using other modalities to better predict prognosis. Current guidelines endorse using EEG to guide prognostication in comatose survivors of cardiac arrest. The absence of normal background activity or reactivity predicts a poor prognosis. Conversely, continuous background activity and the presence of reactivity are among the few reliable predictors of good neurologic recovery. Somatosensory evoked potentials (SSEPs), another electrophysiologic marker of cortical responsiveness, are most helpful for predicting which patients will remain in a persistent coma. By 24 hours after cardiac arrest, bilateral absence of the N20 cortical response (a negative peak at 20 ms) to median nerve stimulation predicts a grave outcome. The early onset of generalized myoclonic status is an ominous sign. Neuron-specific enolase (NSE) is the most promising of several serum biomarkers that have been evaluated. NSE level greater than 30 ng/mL predicts persistent coma. Despite tremendous potential, the role of neuroimaging as a prognostic tool after hypoxic-ischemic injury from cardiac arrest has yet to be clearly defined. Severe reductions in the apparent diffusion coefficient (ADC), as well as bilateral hippocampal hyperintensities on magnetic resonance imaging (MRI), suggest severe global damage and extensive ischemic injury and are predictive of poor neurologic recovery. Therapeutic hypothermia has been demonstrated to improve neurologic outcomes in patients who have return of spontaneous circulation

990

SECTION XVI  Neurologic Disease

TABLE 107.4  Locked-In Syndrome Clinical features Eye opening Reactive pupils Volitional vertical eye movements in response to command Muteness Quadriparesis Sleep-wake cycles Causes Pontine vascular lesions (common) Head injury, brain stem tumor, pontine myelinolysis (rare) Recovery possible Onset over 1-12 wk (vascular)a or Onset over 4-6 mo (nonvascular)a Prognosis favorable Normal CT scana Early recovery of lateral eye movementsa CT, Computed tomography. aImplications for care.

but remain comatose after cardiac arrest. The use of therapeutic hypothermia quite likely influences the clinical examination and ancillary test findings. There are a scarcity of data about the utility of physical examination, EEG, and evoked potentials in predicting outcomes among cardiac arrest patients with induced hypothermia. It is well accepted that one should consider observation for longer than 72 hours before prognosticating outcome in patients treated with hypothermia.

COMA-LIKE STATES Patients with locked-in syndrome have a lesion (usually a hemorrhage or an infarct) that transects the brain stem at a point below the reticular formation (thereby sparing consciousness) but above the ventilatory nuclei of the medulla (thereby maintaining cardiopulmonary function) (Table 107.4). Such patients are awake, with eye opening and sleep-wake cycles, but the descending pathways through the brain stem that are necessary for volitional vocalization or limb movement have been transected. Voluntary eye movement, especially vertically, is preserved, and patients can open and close their eyes or produce appropriate numbers of blinking movements in answer to questions. The EEG is usually normal, reflecting normal cortical function. Psychogenic unresponsiveness is a diagnosis of exclusion. The neurologic examination shows reactive pupils and no reflex posturing in response to pain. Eye movements during the doll’s eyes maneuver show volitional override rather than the smooth, uninhibited reflex lateral eye movements of coma. Ice water caloric testing either arouses the patient because of the discomfort produced or induces cortically mediated nystagmus rather than the tonic deviation typical of coma. The slow, conjugate roving eye movements of metabolic coma cannot be imitated and therefore rule out psychogenic unresponsiveness. Likewise, the slow, often asymmetrical, and incomplete eye closure seen after passive eye opening in a comatose patient cannot be feigned. In contrast, conscious patients usually exhibit some voluntary muscle tone in the eyelids during passive eye opening. The EEG in psychogenic unresponsiveness is that of normal wakefulness, with reactive posterior rhythms on eye opening and eye closing. In patients with catatonic stupor, lorazepam administration may produce awakening. Unresponsive wakefulness syndrome, previously called vegetative state (VS), is exhibited by patients with eye opening and sleep-wake cycles. The reticular activating system of the brain stem is intact to

produce wakefulness, but the connections to the cortical mantle are interrupted, precluding awareness. A VS is termed persistent after 3 months if the brain injury was ischemic in nature or after 12 months if the brain injury was traumatic in nature. The determination as to when persistent equals permanent cannot be stated absolutely. Prediction early in VS of which patients will remain persistently vegetative is particularly difficult in cases of trauma. Lesions of the corpus callosum and dorsolateral brain stem seen on MRI 6 to 8 weeks after trauma correlated with persistence of VS at 1 year. A combined analysis of morphologic MRI studies and post-traumatic brain stem spectroscopy can be a predictor of persistent vegetative states (PVS) and minimally conscious states (MVS). In rare cases, patients show late improvement, but they do not return to normal. Bilateral absence of SSEPs in the first week predicts death or VS. Patients in a PVS open their eyes diurnally and in response to loud sounds; blinking occurs with bright lights. Pupils react and eye movements occur both spontaneously and with the doll’s eyes maneuver. Yawning, chewing, swallowing, and, uncommonly, guttural vocalizations and lacrimation may be preserved. Spontaneous roving eye movements (very slow, with constant velocity) are particularly characteristic and distressing to the patient’s visitors because the patient appears to be looking about the room. The brain stem origin of the eye movements is documented by their being readily redirected by the oculocephalic (doll’s eyes) reflex. The limbs may move, but motor responses are only primitive; pain usually produces decorticate or decerebrate postures or fragments of these movements. Minimally conscious state (MCS) is a newly described entity in which patients do not meet criteria for PVS. Both patients in PVS and those in MCS demonstrate severe alteration in consciousness. In contrast to PVS, subjects with MCS exhibit evidence of limited interaction with the environment by visually tracking, following simple commands, answering yes or no (not necessarily reliably), or having intelligible verbalization or restricted purposeful behavior. It is estimated that the rate of misdiagnosis between the VS and MCS is about 40%. Novel applications of functional neuroimaging in patients with disorders of consciousness may aid in differential diagnosis, prognostic assessment, and identification of pathophysiologic mechanisms. In one study, authors prospectively evaluated cortical activation in response to a familiar voice in seven patients in VS and four subjects in MCS. All four of the MCS patients and only two of the VS patients showed activation that extended beyond the primary auditory cortex to hierarchically higher-order associative temporal areas. Over the course of 3 months, these two VS patients improved clinically to MCS. Brain death characterizes the irreversible cessation of brain function. Therefore, death of the organism can be determined based on death of the brain. Although local laws may dictate some details, the standard definition permits a diagnosis of brain death based on documentation of irreversible cessation of all brain function, including function of the brain stem (Table 107.5). Documentation of irreversibility requires that the cause of the coma is known, that the cause is adequate to explain the clinical findings of brain death, and that exclusionary criteria are absent (Table 107.6). Confirmatory tests are sometimes used but are not required for diagnosis (Table 107.7). Brain death results in asystole, usually within days (mean, 4 days), even if ventilatory support is continued. Recovery after appropriate documentation of brain death has never been reported. Removal of the ventilator results in terminal rhythms (most often complete heart block without ventricular response), junctional rhythms, or ventricular tachycardia. Purely spinal motor movements may occur in the moments of terminal apnea (or during apnea testing in the absence of passive administration of oxygen); these may include arching of the back, neck turning, stiffening of the legs, and upper extremity flexion.

CHAPTER 107  Disorders of Consciousness

TABLE 107.5  Criteria for Cessation of

Brain Functiona

Anatomic Region Tested

Confirmatory Sign

Hemispheres

Unresponsive and unreceptive to sensory stimuli including painb Unreactive pupilsc Absent reflex eye movementsd Apneae

Midbrain Pons Medulla

CO2, Carbon dioxide; Pco2, partial pressure of carbon dioxide. aSequential testing is necessary for a clinical diagnosis of brain death; it should be done at least every 6 hours in all cases and at least every 24 hours in the setting of anoxic-ischemic brain injury. bThe patient does not rouse, groan, grimace, or withdraw limbs. Purely spinal reflexes (deep tendon reflexes, plantar flexion reflex, plantar withdrawal, and tonic neck reflexes) may be maintained. cMost easily assessed by the bright light of an ophthalmoscope viewed through its magnifying lens when focused on the iris. Unreactive pupils may be either midposition, as they will be in death, or dilated, as they often are in the setting of a dopamine infusion. dNo eye movement toward the side of irrigation of the tympanic membrane with 50 mL of ice water. The oculocephalic response (doll’s eyes maneuver) is always absent in the setting of absent oculovestibular testing. eNo ventilatory movements in the setting of maximum CO stimulation 2 (≥60 mm Hg); with apnea, Pco2 passively rises 2 to 3 mm Hg/min). Disconnect the ventilator from the endotracheal tube and insert a cannula with 6 L of oxygen per minute.

TABLE 107.6  Exclusionary Criteria for

Brain Death

Seizures Decorticate or decerebrate posturing Sedative drugs Hypothermia (50%) to cause symptoms. However, recent pathologic and radiologic studies provide evidence that substenotic lesions can also cause strokes due to plaque rupture and acute thrombosis, as is the case elsewhere in the body. Small-­vessel disease refers to the occlusion of a penetrant branch of a larger artery, usually due to microatheroma or to lipohyalinosis, a degenerative disorder of the vessel characterized by deposition of fatty and proteinaceous material. Hematologic disorders and coagulopathies, including leukemia, Waldenström’s macroglobulinemia, polycythemia, primary and secondary antiphospholipid antibody syndrome, and genetic defects of the coagulation cascade, may also lead to occlusive thrombi and emboli. The cerebral circulation differs from the systemic circulation in some important ways. The brain is protected by the anastomoses described previously. In addition, cerebral autoregulation maintains a constant cerebral perfusion pressure over a range of systemic blood pressures (Fig. 118.3). Cerebral arterioles have a well-­developed muscular coat that allows constriction in response to increased blood pressure and dilation with hypotension. The arterioles are also exquisitely sensitive to changes in peripheral arterial concentrations of carbon dioxide (Paco2) and oxygen (Pao2). When the partial pressure of CO2 decreases, such as during hyperventilation, the arterioles constrict and blood flow is reduced. In healthy individuals, cerebral autoregulation maintains a constant cerebral blood flow over mean arterial pressures of 60 to 140 mm Hg. In patients with chronic hypertension, the autoregulatory curve is shifted to the right, so that even minor reductions in blood pressure may not be tolerated. At blood pressures above these limits, moreover, as in severe hypertension, autoregulatory capacity may be overwhelmed, leading to breakthrough edema and hemorrhage.

1060

SECTION XVI  Neurologic Disease

ACA

Anterior communicating artery

MCA

Posterior communicating artery

PCA Basilar artery

ICA

CCA Vertebral artery

Subclavian artery

Artery arch

Fig. 118.2  Sites of predilection for atheromatous plaque. ACA, Anterior cerebral artery; CCA, common carotid artery; ICA, internal carotid artery; MCA, middle cerebral artery; PCA, posterior cerebral artery. (From Caplan LR: Stroke: a clinical approach, ed 2, Boston, 1993, Butterworth-­ Heinemann.)

Injury to Brain Tissue

70

CBF (mL/100 g/min)

60 50

Specific disorders may originate from autoregulatory dysfunction: posterior reversible encephalopathy syndrome (PRES) and the reversible cerebral vasoconstriction syndrome (RCVS). In posterior reversible encephalopathy syndrome, there is loss of autoregulatory control with leakage of fluid across the blood-­brain barrier, primarily in the posterior regions of the brain. Patients present with elevated blood pressures, headaches, seizures, and loss of visual function. Reversible cerebral vasoconstriction syndrome, a recently recognized syndrome, remains incompletely characterized, and shares features with posterior reversible encephalopathy syndrome. The two disorders overlap in 10% or more of cases. Patients with RCVS are typically young women who present with acute, severe headache, have minimal or no neurologic deficits, and may have evidence of non-­ aneurysmal, superficial SAH as well as vasospasm of the cerebral arteries. Sympathetic innervation of the vessels is also less in the posterior circulation than anteriorly, leading to a reduced ability of the posterior circulation to adapt to changes in blood pressure, and may contribute to the propensity for edema to form in the occipital lobes during hypertensive crises. In addition, focal cerebral activity, such as occurs when activating brain regions responsible for moving a limb, is accompanied by increased metabolic activity in the appropriate region, and is accommodated by slight increases in local blood flow and oxygen delivery. Exploitation of this increased local energy demand and delivery is what allows imaging of functional brain activity using MRI, which can detect subtle changes in regional cerebral blood flow. These changes in blood flow are mediated by the neurovascular unit, a complex structure characterized by the local interaction of neural, glial, and vascular elements in the brain. Intracerebral capillaries also lack adventitia, with astrocytes serving as the vascular component of the neurovascular unit. Tight junctions at the capillary level play an important role in the blood-­brain barrier, which limits permeability between the vascular compartment and the brain tissue.

Normal Chronic hypertension

40 30 20 10 0

50 100 150 200 Mean arterial blood pressure (mm Hg) Fig. 118.3 Autoregulatory cerebral blood flow (CBF) response to changes in mean arterial pressure in normotensive and chronically hypertensive persons. Note the shift of the curve toward higher mean pressures with chronic hypertension. (From Pulsinelli WA: Cerebrovascular diseases-­principles. In Goldman L, Bennett JC, editors: Cecil textbook of medicine, ed 21, Philadelphia, 2000, Saunders, p 2097.)

In the setting of infarction or hemorrhage, cerebral autoregulation is also impaired, resulting in cerebral dependence on systemic blood pressure to maintain adequate perfusion. Thus, decreasing the blood pressure in the setting of acute ischemia may be hazardous.

The adult brain weighs about 1500 g, or 2% of total body weight, but accounts for 20% of the total body oxygen consumption. Because the brain cannot store much energy, dysfunction results after only a few minutes of deprivation when either oxygen or glucose content is reduced below critical levels. In the resting state, normal total cerebral blood flow is 50 mL/min per 100 g of brain tissue. Neuronal dysfunction occurs at cerebral blood flow levels below 50 mg/dL, and irreversible neuronal injury begins at levels below 30 mg/dL. Both the degree and duration of reductions in cerebral blood flow are related to the likelihood of permanent neuronal injury. When blood supply is completely interrupted for 30 seconds, brain metabolism is altered; after 1 minute, neuronal function may cease. After 5 minutes, anoxia initiates a chain of events that may result in cerebral infarction; however, if oxygenated blood flow is restored quickly enough, the damage may be reversible, as with a TIA. Research into the cellular basis of cerebral ischemia has led to the concept of the “ischemic cascade.” As perfusion of the brain decreases, a chain of events at the neuronal level begins with failure of the membrane sodium/potassium (Na/K) pump, the depolarization of the neuronal membrane, the release of excitatory neurotransmitters such as glutamate and glycine that hyperstimulate their receptors, and the opening of calcium channels. Calcium enters the neuron through various voltage-­sensitive and receptor-­mediated channels (e.g., the N-­methyl-­d-­aspartate receptor). The influx of calcium is at the root of further neuronal injury, leading to damage to organelles and further destabilization of neuronal metabolism and function. These events may lead to neuronal death, which may be delayed, even after

CHAPTER 118  Cerebrovascular Disease restoration of blood flow, and are a target of experimental neuroprotective strategies. Recent research has distinguished between the “core” infarct and an “ischemic penumbra,” or shadow. The core represents a central region of necrosis, or tissue that dies very quickly after blood flow ceases. The penumbra represents the surrounding region of brain tissue, in which neurons are dysfunctional but potentially salvageable. Recanalization of occluded vessels with blood flow into infarcted tissue, particularly when delayed, results in “reperfusion injury.” Increased use of MRI has shown that petechial hemorrhagic infarction is very common, occurring in the majority of strokes, even when not suspected clinically.

TABLE 118.3  Clinical Manifestations of

CLINICAL PRESENTATION

VA or PICA

The signs and symptoms of strokes are varied and depend on the type of stroke, the region of the nervous system affected by the lack of flow or hemorrhage, and the patient’s handedness (Table 118.3). In general, embolic ischemic strokes are characterized by the sudden onset of a neurologic deficit, usually painless. Thrombotic strokes may have a stuttering or progressive course due to fluctuating hypoperfusion and gradual occlusion. Arterial dissections, as well as hemorrhages, are more often associated with headaches than ischemic stroke of other causes. Hemorrhagic strokes and large hemispheric infarcts can lead to decrease in consciousness due to increased intracranial pressure. Most emboli occur in the territory of the MCAs. Lesions of the dominant (almost always left) hemisphere are characterized by variable combinations of right hemiparesis, right hemisensory loss, right visual loss, impaired gaze to the right side of space, and language disturbance. When the superior division of the MCA is affected, the language impairment is predominantly motor: the patient either cannot speak or produces sparse, agrammatic speech, despite an ability to fully comprehend spoken and written material. When the inferior division is affected, the patient may produce fluent, prosodic (normal stress and intonation), but nonsensical speech and be unable to follow instructions. Larger infarcts of the dominant hemisphere produce a total loss of language function, leaving the patient mute and uncomprehending. Lesions of the nondominant (right) hemisphere produce deficits of the left side of the body. Language is preserved but the patient may demonstrate impaired attention, particularly to the left side of space; fail to appreciate the presence of people or objects to their left; and may even fail to recognize the left side of their own body (asomatognosia). This neglect phenomenon may extend even to a lack of awareness of any deficit of function on their part (anosognosia). These patients may thus be found at home, lying on the floor paralyzed yet unaware that anything is the matter; their unawareness can delay their presentation to the hospital for treatment and similarly limit their participation in rehabilitation. Lesions in the right hemisphere may also cause dysprosody, the nondominant equivalent of aphasia, which is characterized by a lack of the emotional and gestural components of speech, despite preservation of its semantic content; many of these patients have a flat affect or appear to be depressed. Infarcts in the territory of the anterior cerebral arteries often cause weakness limited to the legs, due to location of the representation of the legs in the medial part of the hemispheres. They may have incontinence, lack initiative (abulia), and have gaze palsies. In some cases their deficits may be more extensive and mimic those of MCA infarctions. Posterior cerebral artery infarcts lead to visual loss, often without any motor deficit. With involvement of the medial temporal lobes supplied by the PCAs, there may also be behavioral disturbances, including delirium and amnesia. Brain stem infarcts cause specific syndromes due to the affected neural pathways and nuclei. Midbrain infarcts often produce vertical gaze deficits and impaired consciousness if the reticular activating system is involved.

1061

Ischemic Stroke Occluded Vessel

Clinical Signs

ICA MCA

Ipsilateral blindness (variable), MCA syndrome Contralateral hemiparesis, hemisensory loss (face or arm more than leg) Aphasia (dominant) or anosognosia (nondominant) Homonymous hemianopsia (variable) Contralateral hemiparesis, hemisensory loss (leg more than arm) Abulia (especially if bilateral) Ipsilateral facial sensory loss, hemiataxia, nystagmus, Horner syndrome Contralateral loss of temperature or pain sensation Dysphagia Gait ataxia, nausea, vertigo, dysarthria Quadriparesis, dysarthria, dysphagia, diplopia, somnolence, amnesia Contralateral homonymous hemianopsia, amnesia, sensory loss

ACA

SCA BA PCA

ACA, Anterior cerebral artery; BA, basilar artery; ICA, internal carotid artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; PICA, posterior inferior cerebellar artery; SCA, superior cerebellar artery; VA, vertebral artery.

Many cerebral infarctions do not cause weakness and may therefore be missed by the less astute clinician who assumes that a stroke always leads to paralysis. These syndromes include fluent (or Wernicke) aphasia, cortical visual loss, and Wallenberg syndrome (lateral medullary syndrome caused by occlusion of the vertebral or posterior inferior cerebellar artery). Because the inferior division of the MCA supplies the lateral temporal lobe and parietal lobes, including the Wernicke area, occlusion of that vessel may cause a prosodic, fluent speech with multiple paraphasic errors and poor comprehension, while sparing the motor strip in the frontal lobe. Emboli traveling up the basilar artery may lead to significant infarction in the territory of both PCAs, causing complete blindness, sometimes without awareness of the deficit on the part of the patient, due to infarction of both occipital lobes (the “top of the basilar syndrome”). Behavioral abnormalities, memory loss, and eye movement abnormalities may also occur, due to involvement of the medial temporal lobe structures and the midbrain eye movement centers. Small emboli to branches of the superior division of the MCA may cause focal weakness of the hand, particularly fine finger movements, simulating a peripheral compression neuropathy. In patients presenting with dizziness, it is particularly difficult to distinguish stroke from vestibular neuronitis or Meniere’s disease (see Chapter 115). The presence of a normal head-­thrust test, skew deviation, or direction-­changing nystagmus are all signs of stroke, rather than a peripheral cause. Patients in the emergency ward should not be discharged until they can walk without imbalance; patients with nausea and vomiting due to cerebellar infarction may develop fatal brain stem compression due to swelling (so-­called “fatal gastroenteritis”). The signs and symptoms of subarachnoid hemorrhage differ from other stroke types due to the absence of focal deficits. Instead, patients present with abrupt onset of severe headache (i.e., “the worst headache of my life”), vomiting, altered consciousness, and sometimes coma, typically without localizing signs. Thrombosis of cerebral veins or the larger draining dural sinuses present with a combination of headache due to elevated intracranial pressure, seizures, and focal deficits due to hemorrhage. Rarely the

1062

SECTION XVI  Neurologic Disease

A

B

Fig. 118.4  Early signs of infarction on computed tomography of the brain. (A) Hyperdense middle cerebral artery sign (red arrow), and (B) hypoattenuation of the left caudate and lentiform nuclei, loss of the insular ribbon, and sulcal effacement (outlined in red).

syndrome of thunderclap headache, or sudden severe headache without any focal signs similar to that occurring in SAH, may be due to venous thrombosis. Occlusion of the cerebral venous sinuses may occur in association with hyperviscosity or a hypercoagulable state, including pregnancy or hormonal contraceptive use. Imaging findings include bilateral hemorrhagic infarctions in a parasagittal distribution and extensive white matter edema. Contrast-­enhanced CT may demonstrate the empty delta sign, indicating a filling defect in the sagittal sinus. Magnetic resonance venography (MRV) and T1-­weighted MRI images confirm the presence of thrombus; cerebral angiography is seldom needed to confirm the diagnosis.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS The potential benefit of thrombolytic therapy within 4.5 hours of onset of acute ischemic stroke requires urgent differentiation of ischemic stroke from hemorrhage and other causes of sudden neurologic symptoms. Headache, vomiting, seizures, and coma are more common in hemorrhagic stroke, though these are never reliable enough to preclude imaging. The distinction is straightforward in most cases once a head CT is performed. The hyperdense signal of blood in the parenchyma on CT almost invariably distinguishes hemorrhage from ischemia. In exceptional cases the typical hyperdensity of ICH is absent owing to severe anemia or to its subacute state, during which blood may be indistinguishable from brain tissue. Certain imaging findings on initial CT further support a presumed diagnosis of infarction, such as a hyperdense vessel sign indicative of thrombus in the vessel, or loss of the gray-­white junction and sulci in the cortex, and loss of the demarcation of the insular cortex and deep gray nuclei, both of which are early indicators of ischemia and edema (Fig. 118.4). CT angiography often identifies the site of vascular occlusion. Imaging in the setting of suspected acute ischemia does not definitively diagnose ischemia but rather excludes hemorrhage; if clinical symptoms are consistent with cerebral ischemia, then thrombolytic treatment is indicated within the appropriate time window. Primary stroke centers must perform and interpret CT scans within 30 minutes of the arrival of a patient with suspected stroke. MRI can also effectively

exclude acute hemorrhage, and diffusion-­weighted imaging sequences are more sensitive to the earliest changes of ischemia (Fig. 118.5), but the speed and availability of CT make it the initial imaging modality of choice at most centers. MRI scanning may then be used to provide additional information. Specific MRI sequences have greater sensitivity to blood than CT and may identify hemorrhagic infarction missed by CT. Clinical features at stroke onset may suggest a subtype of cerebral infarction but require confirmatory laboratory data. Cerebral embolism is suggested by sudden onset and a syndrome of circumscribed focal signs attributable to cerebral surface infarction, such as pure aphasia or pure hemianopia. Unless the source of embolization is obvious on hospital admission, blood cultures, electrocardiographic monitoring, and echocardiography are indicated. A diagnosis of atherosclerotic infarction is suggested if there were previous TIAs, particularly when the symptoms are stereotypical. Doppler ultrasonography, CT angiography or magnetic resonance angiography can usually identify the stenosis. In equivocal cases, conventional angiography may be needed. Small penetrating vessel infarcts, or lacunar infarcts, usually spare cortical functions, such as language and cognition, but cause loss of elementary neurologic function, such as strength, sensation, and coordination. Up to 25% of patients with lacunar infarcts have large-­vessel disease or a cardioembolic source, so it is important to carry out a complete etiologic evaluation in all stroke patients. Up to 50% of patients with transient deficits lasting less than 24 hours have evidence of infarction on imaging, and the risk of stroke and other vascular events is as high after TIA as after completed stroke. In the acute setting, when decisions about thrombolysis must be made, it is virtually impossible to know which patients with ischemia will have symptoms resolve without infarction (thus, having a TIA) and which will have a completed infarction. Patients with either stroke or TIA need immediate attention to secondary prevention strategies. In terms of choosing treatments, the important issue is to identify the cause of the cerebral ischemia, rather than its duration. Entities other than cerebral ischemia can masquerade as strokes and TIAs. Among patients diagnosed with stroke in emergency departments, 20% or

CHAPTER 118  Cerebrovascular Disease

A

1063

B

Fig. 118.5 Magnetic resonance imaging scan of the brain of the same patient shown in Fig. 118.4. (A) Diffusion-­weighted image shows bright signal in the left middle cerebral artery territory. (B) Apparent diffusion coefficient shows dark signal in the same area, confirming acute infarction.

more have a stroke mimic, including seizure, migraine, systemic infection, brain tumor, and toxic-­metabolic encephalopathy. Other sources of misdiagnosis are listed in Table 118.4. In patients with a prior history of cerebral infarct or hemorrhage, new metabolic derangements, including infections, may precipitate a recrudescence of the original stroke syndrome. Hypoglycemia, hyponatremia, urinary tract infection, pneumonia, and initiation of a psychotropic medication can each precipitate this phenomenon. The patient returns to normal over hours to days when the new insult is treated or reversed. Such metabolic and infectious causes of neurologic deterioration should be excluded in patients with a history of earlier brain injury before diagnosing a new stroke. Focal signs may also occur with metabolic disturbances in patients without prior history of stroke. External signs of injury are usually present in brain trauma, but they need not be present after acceleration-­deceleration injury, such as from a motor vehicle accident. The most frequent sites of brain contusions are the frontal and temporal poles, which are not typical locations for strokes. Seizures may occasionally complicate acute stroke, but they may also mimic stroke. Unlike stroke, seizures are often characterized by obtundation, an amnestic state, clonic activity, incontinence, or tongue biting. The postictal deficit, often called a Todd paralysis, resembles stroke because weakness or language and other cortical deficits may occur. The deficits after seizure usually resolve within hours after the seizure but occasionally persist for up to a week, making the distinction from stroke difficult. Seizures may also develop months or years after an infarct or hemorrhage, and the postictal state in these patients may recapitulate the initial stroke syndrome. Migraine with persistent aura often mimics stroke or TIA. Aura alone, without headache (i.e., acephalgic migraine), is sometimes experienced by those who previously suffered from migraine with aura. Migraine aura typically produces a visual disturbance that marches across the vision of both eyes as an advancing, enlarging blind spot that takes 20 to 30 minutes to resolve. Subsequent unilateral, pounding headache suggests the diagnosis but may not occur. Less often, migrainous auras take the form of sensory symptoms. The speed of the march is generally slower than the rapid spread of symptoms in stroke. As many as 10% of brain tumors present with acute transient symptoms reflecting intratumoral hemorrhage or focal seizures. Seizures

TABLE 118.4  Stroke Mimics and

Differential Diagnosis

Common Mimics Metabolic encephalopathy (e.g., hypoglycemia, hyponatremia) Systemic infection Seizure Migraine Brain tumors Other Mimics Transient focal neurologic symptoms associated with amyloid angiopathy Positional vertigo Cardiac events Syncope Trauma (especially acceleration-­deceleration without evidence of external injury) Subdural hematoma Herpes simplex virus encephalitis Transient global amnesia Dementia Demyelinating disease Cervical spine disease/radiculopathy/fracture Myasthenia gravis Parkinsonism Hypertensive encephalopathy Conversion disorder Intoxication/substance abuse

often precede focal signs. Imaging usually demonstrates an enhancing mass even when symptoms are mild.

TREATMENT Stroke prevention and treatment are directed toward: (1) preventing the first stroke (primary prevention); (2) limiting damage from the stroke; (3) optimizing functional recovery following stroke; and (4)

1064

SECTION XVI  Neurologic Disease

avoiding recurrence (secondary prevention). Specific measures for treatment and prevention depend on the patient’s risk factors and stroke mechanism. The diagnostic evaluation of the stroke patient dictates optimal therapy.

TABLE 118.5  Risk Factor

Treatment

Primary Prevention of Stroke

Hypertension Myocardial infarction Hyperlipidemia Atrial fibrillation

Anti-­hypertensives HMG-­CoA reductase inhibitors HMG-­CoA reductase inhibitors Anticoagulation (warfarin, other agents) Left atrial exclusion (selected patients) ACE inhibitor Metformin Bariatric surgery Carotid endarterectomy

Randomized trials have demonstrated that specific interventions prevent first stroke among patients with specific risk factors (Table 118.5). Treatment of hypertension, for example, is associated with up to a 45% reduction in the risk of stroke. Among patients with atrial fibrillation, the use of warfarin is associated with a 60% to 70% relative reduction in risk of stroke, though younger patients without any accompanying heart disease, hypertension, or diabetes may be managed with antiplatelet agents alone. Hydroxymethylglutaryl-­coenzyme A (HMG-­CoA) reductase inhibitors, or statins, have been shown in some primary prevention studies, and in studies of patients with heart disease, to reduce the risk of a first stroke as well as that of heart disease. The effects on stroke risk are more modest than the effects on heart disease, possibly reflecting the greater heterogeneity among causes of stroke compared to heart disease. For patients with asymptomatic carotid stenosis of at least 60%, carotid endarterectomy reduces the risk of stroke, though the effect is much more modest than in symptomatic patients, and the number of patients needed to treat to prevent one stroke is greater. Because many of the large randomized trials of endarterectomy for asymptomatic patients were conducted in the era before the current recommended use of statins and antiplatelet agents, it is no longer clear that surgery is superior to medical therapy. New trials are therefore addressing medical versus surgical and endovascular treatment in patients with asymptomatic stenosis. Antiplatelet therapy is not of established benefit for prevention of a first stroke. In a large primary prevention study, for example, aspirin use was associated with an increased risk of both ischemic and hemorrhagic stroke, despite reducing the risk of ischemic heart disease. However, other studies have shown that aspirin reduces the risk of ischemic stroke among women over the age of 45. The Mediterranean diet also protects against cardiovascular disease, including stroke. It is characterized by high intake of fruits, vegetables, and legumes; olive oil as the principal source of fat; moderate consumption of fish and poultry, with minimal intake of red meat and dairy; and an option of mild to moderate consumption of red wine, mostly with meals. Compared to a low-­fat diet, this combination of nutrients decreased 5-­year stroke risk by approximately 30% in a randomized trial. Observational studies provide evidence that certain behaviors prevent stroke. Smoking cessation leads to a reduction by 5 years in stroke risk to levels similar to nonsmokers. Consumption of alcohol in moderation, up to two drinks daily for men and one daily for women, is associated with a lower level of stroke risk than in those who do not drink. Physical activity, weight loss when appropriate, and management of diabetes are also recommended.

Acute Treatment of Ischemic Stroke For patients with ischemic stroke evaluated within 3 hours of symptom onset with no evidence of hemorrhage on a brain CT or MRI, recombinant tissue plasminogen activator (rt-­ PA), a thrombolytic agent, improves functional outcomes at 3 months compared to placebo. Among the 624 ischemic stroke patients treated within 3 hours in the original landmark study, the proportion of patients achieving normal or near-­normal neurologic and functional status by 3 months was significantly higher among those receiving rt-­PA, though there was no definite benefit at 24 hours. The proportion of patients who achieved independence in their performance of activities of daily living was

Evidence-­Based Primary Prevention of Ischemic Stroke

Diabetes mellitus/vascular disease Diabetes mellitus type II, obesity Asymptomatic carotid stenosis (60-­99%) Diet High vascular risk populations

Mediterranean diet Antiplatelet therapy HMG-­CoA reductase inhibitors

HMG-­CoA, Hydroxymethylglutaryl-­coenzyme A.

increased from 38% to 50%, an absolute benefit of 12%. The absence of an immediate (24-­hour) benefit, coupled with the finding of a benefit at 3 months, is consistent with the hypothesis that thrombolytic treatment works to reduce the size of the infarct penumbra by reperfusing tissue before permanent infarction of the entire territory occurs, despite some irreversible injury to a core component. Patients treated with rt-­PA had a 10-fold increase in incidence of hemorrhagic conversion of the infarction (from 0.6% in placebo-­ treated patients to 6.0% in rt-­PA–treated patients). Overall, however, the rates of neurologic deterioration and mortality within the first day after stroke were similar between the groups. Rt-­PA was approved for patient use by the US Food and Drug Administration (FDA) in 1996, and it is now considered standard of care for ischemic stroke patients presenting within 3 hours. Specific guidelines for eligibility and exclusion must be met when using rt-­PA to reduce the risk of complications (Table 118.6). Because of the potential to reduce cerebral perfusion below the limits permitted by autoregulation in the setting of acute brain injury, current guidelines recommend that blood pressure not be reduced acutely after ischemic stroke, and systolic blood pressure levels as high as 220 mm Hg are allowed. Before and following thrombolytic treatment, however, systolic blood pressure should be kept below 180 mm Hg to reduce the risk of hemorrhagic conversion. In addition, antiplatelet and anticoagulant medications must be withheld for 24 hours after rt-­PA. Subsequent meta-­analyses and individual trials have demonstrated that the benefit of thrombolytic therapy decreases as the time interval between symptom onset (the presumed beginning of ischemia) and treatment increases, but that the therapeutic time window persists as long as 4.5 hours after stroke in selected patients (i.e., those under age 80 years without a combined history of prior ischemic stroke and diabetes mellitus). In considering the duration of stroke symptoms, neurologists use the time that the patient was last known to be well as the time of onset of the stroke, rather than the time that the patient was discovered to have stroke symptoms. Because stroke is usually painless, patients may not be aware of the onset of symptoms. In patients with aphasia, anosognosia, or diminished consciousness, the patient may not be able to provide details regarding the time of onset of their symptoms, and a witness is required. In patients who wake with stroke,

CHAPTER 118  Cerebrovascular Disease

TABLE 118.6  Eligibility and Exclusion

Criteria for Treatment of Acute Ischemic Stroke With Intravenous Rt-­PA

Eligibility Age ≥18 years Diagnosis of ischemic stroke causing measurable neurologic deficit Well-­documented onset of symptoms 185 mm Hg Diastolic blood pressure >110 mm Hg Rapidly improving or minor neurologic symptoms and signs Symptoms suggestive of subarachnoid hemorrhage Gastrointestinal or urinary tract bleeding within 3 weeks Arterial puncture at a noncompressible site within 1 week Platelet count 1.7 Relative Exclusion Criteria (Must Weigh Risks and Benefits) Seizure at stroke onset Myocardial infarction within 6 weeks Infective endocarditis Hemorrhagic eye disorder Blood glucose 400 mg/dL (21.6 mmol/L) Patients requiring very aggressive therapy for blood pressure reduction

moreover, it is difficult if not impossible to determine the time at which the symptoms started, and so the time that the patient went to bed is usually considered the starting point of the time window to decide eligibility for thrombolytic therapy. Recent clinical trials, however, provide evidence that when advanced imaging techniques are used, patients can be selected for treatment with intravenous rt-­PA up to 9 hours after last known well. In one study, when the MR DWI showed changes consistent with ischemia but the fluid attenuated inversion recovery (FLAIR) sequences did not, the duration of ischemia was presumed to be less than 4.5 hours, and patients were considered eligible for randomization to rt-­PA or placebo; among those treated with IV rt-­PA, outcomes were significantly better. Another trial used the mismatch between areas of permanent injury and those of diminished perfusion, representing “at risk” tissue, from CT or MRI, to establish an ischemic penumbra that could be salvaged up to 9 hours after onset. Interventional techniques to revascularize occluded vessels have also been demonstrated to benefit selected patients with ischemic stroke. For patients with MCA occlusions presenting up to 6 hours after symptom onset, there is evidence that intra-­arterial thrombolytic agents delivered via catheter into the face of the occluding thrombus can improve functional outcomes, despite an increase in risk of hemorrhage similar to that seen with intravenous rt-­PA. More recently, the FDA has approved the use of mechanical devices called stent-­retrievers specifically engineered to facilitate clot extraction in the setting of ischemic stroke in the middle cerebral artery in selected patients. These devices, used during an angiographic procedure, provide a wire mesh that can surround the thrombus in the vessel and then be used to pull the clot out. They may be used up to 24 hours after stroke onset and

1065

can achieve a recanalization rate of up to 80%. Patients are selected for the procedure by using infarction-­perfusion mismatch imaging to identify those with areas of uninfarcted, salvageable brain tissue. Meta-­ analyses of several randomized trials in these patients have shown marked benefits, with about two to three patients needed to treat to achieve clinically significant functional improvement. Treatment with heparin and various heparinoids for acute stroke are not of benefit and are not recommended in acute stroke. In some patients with massive hemispheric strokes, surgical decompression (hemicraniectomy) can be life-­saving with acceptable functional outcomes, particularly for younger patients. Since stroke is characterized by a cascade of events that can cause further neuronal injury for hours or days after stroke, experimental animal stroke studies have tested strategies that might limit this injury (i.e., neuroprotection), including drugs targeting N-­methyl-­ d-­aspartate (NMDA) receptors, glycine receptors, calcium channels, adhesion molecules, free radicals, albumin, inflammation, and membrane constituents. However, none of these have been of benefit in human clinical trials.

Treatment of Intracerebral Hemorrhage Treatment of ICH is primarily supportive. Many patients require management in the intensive care setting to manage elevated blood pressure and secondary complications, such as respiratory failure, aspiration, and hemodynamic instability in severely neurologically compromised patients. In many cases, patients also require management of intracranial pressure using osmotic agents, such as mannitol or hypertonic saline, or therapeutic hyperventilation. In some patients, surgical evacuation of hematomas may be life-­saving, although trials have thus far failed to show that most ICH patients benefit from surgical decompression. Among more than 1000 participants randomized in a large international study, there was no evidence of benefit of surgical over medical therapy, apart from a potential benefit in the subgroup of patients with small superficial hemorrhages. Most hemorrhages that occur deep within the hemispheres probably cause the majority of their damage immediately after the ictal hemorrhage, so that evacuation does not save tissue and may introduce further damage. One of the major recent insights into the pathogenesis of cerebral injury associated with ICH has been the recognition that a large proportion of hemorrhages continue to expand during the early hours after onset. As a result, there has been increased interest in the use of prothrombotic agents to reduce this expansion and to limit secondary cerebral injury. Though preliminary studies on the potential benefits of infusing factor VII as a prothrombogenic agent showed promise, subsequent and more definitive studies did not confirm a benefit in the majority of patients, although it remains possible that subgroups of patients, including those with warfarin-­associated hemorrhage, may benefit. For cerebellar hemorrhages, surgical decompression may be life-­ saving, and it is essential to recognize the signs and symptoms of incipient brain stem compression and herniation (i.e., headache, vertigo, nausea, vomiting, and truncal ataxia without focal weakness, declining sensorium, and gaze-­palsy). Neuroimaging studies that support the need for surgical decompression include hematoma greater than 3 cm, fourth ventricular shift, cisternal obliteration, and ventricular enlargement. Lumbar puncture is contraindicated with ICH, particularly with cerebellar hemorrhages, because life-­ threatening tonsillar herniation and midbrain compression may occur. Great caution must be taken in these patients subjected to ventriculostomy for the purposes of reducing intracranial pressure because upward cerebellar herniation may occur. The management of aneurysmal SAH is complicated, and recurrent bleeding risks and mortality are high. Antifibrinolytic agents, such as ε-­aminocaproic acid, used to preserve the thrombus around

1066

SECTION XVI  Neurologic Disease

an aneurysm and thereby prevent rebleeding, have been unsuccessful. Therefore, definitive therapy is elimination of the ruptured aneurysm. This may be accomplished surgically or with interventional embolization techniques, such as with coils deposited in the aneurysm. Even after securing the aneurysmal site of bleeding, however, several other complications may ensue, of which vasospasm leading to cerebral infarction is one of the most common. Vasospasm appears to represent a reaction of the blood vessels to the blood in the surrounding subarachnoid space. Transcranial Doppler screening may be used daily to detect early changes of vasospasm; continuous EEG monitoring and multimodality monitoring of vital signs are other emerging ways to detect cerebral dysfunction while still reversible. The calcium-­ channel antagonist nimodipine, which crosses the blood-­brain barrier, has become standard of care in SAH patients for up to 3 weeks after hemorrhage. It improves outcomes, although it is not clear that this is through a reduction in vasospasm, as originally hypothesized. Hydration, hyperosmolar therapy, hypertensive therapy, and angioplasty of vascular spasm may also be used to reduce risk of infarction. Other complications of SAH include cerebral edema, seizures, ventricular dilatation, the syndrome of inappropriate ADH secretion (SIADH), and cardiac failure. Hydrocephalus may require ventricular shunting.

Rehabilitation and Recovery A team approach to stroke rehabilitation, starting with a stroke recovery unit with experienced physiatrists and physical therapists, has proven beneficial for the optimum recovery of patients. A specialized stroke unit is particularly helpful in avoiding complications such as infections, contractures, and decubiti, and in maximizing independence for patients. Speech and occupational therapists help patients improve their swallowing, communication, and daily living skills. Constraint-­induced therapy is a specific type of physical therapy that involves having a hemiparetic patient wear a large mitt to prevent use of the unaffected limb for several hours daily, forcing the patient to use the affected limb for most tasks. In a randomized trial, constraint-­ induced therapy with intensive task-­directed therapy was associated with functional improvement compared to standard physical therapy. It remains unclear, however, whether the use of constraints or the intensive nature of the therapy itself was responsible for the improvements in function. Intensive task-­directed therapy is both difficult for the patient and expensive, however, and may not be practical for large numbers of patients. Recent studies have suggested that home therapy, guided by therapists using videoconferencing with patients (i.e., “telerehabilitation”) may be more feasible for patients. Depression is a frequent accompaniment of stroke, reflecting both the physical disability and altered brain chemistry. Depression may respond to selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants. Escitalopram administered prophylactically to stroke patients was effective in preventing the development of depression, though other studies have not confirmed this. There is also evidence from other trials that SSRI treatment facilitates functional recovery after stroke.

Secondary Stroke Prevention The optimal secondary prevention strategy for an individual patient depends on the stroke mechanism. For stroke or TIA caused by carotid stenosis of 70% or more of the vessel diameter, carotid endarterectomy (CEA) by a skilled surgeon with an acceptable complication rate (310 mOsm/L) Hypocalcemia ( 450 mg/ dL as in nonketotic hyperglycemic states) and in Rasmussen encephalitis, a very rare, usually pediatric epilepsy syndrome. Status epilepticus related to profound hyperglycemia can produce refractory focal status epilepticus that often resolves once hyperglycemia is corrected. Postanoxic myoclonic status epilepticus is often accompanied by generalized polyspike and slow wave epileptiform discharges on EEG but may be less responsive to common AED treatments for status epilepticus. It typically reflects significant and extensive cortical injury, often associated with a poor prognosis. Once status epilepticus is diagnosed, treatment is urgent. The longer status epilepticus lasts, the more difficult it is to terminate and the more likely it is to cause brain damage. Aggressive therapy is mandatory for convulsive status epilepticus (Table 120.5). If initial therapy is

not rapidly effective, anesthetic agents requiring intubation and ventilation should be used within an hour of onset. Focal status epilepticus can also result in permanent neuronal injury and should also be treated expeditiously, although therapeutic choices are often made to try to stop focal status epilepticus with agents that do not cause respiratory depression to avoid intubation. Absence status is unlikely to result in permanent sequelae and usually responds promptly to benzodiazepine treatment. Investigation into the cause of status epilepticus should be undertaken during its treatment and continued after seizures stop.

GENETIC COUNSELING AND PREGNANCY Heredity Patients with epilepsy should be advised about the hereditary risks to their children, although in most people with epilepsy, it does not influence their decision about having children. The most common genetic generalized epilepsies have complex inheritance patterns with about 10% of children of an affected parent developing seizures. There are over 200 mendelian-­inherited syndromes with epilepsy, all rare. Screening for genetic causes of epilepsy has become more useful for certain subgroups of patients, particularly those with unknown etiology under the age of 2 years. Gene microarray assays have become more effective tools and have added to older less precise genetic assays such as karyotype or FISH assays. Genetics counselors provide valuable diagnostic and educational assistance in the care of patients who may have a genetic form of epilepsy or who may have specific concerns about the potential risk for their children.

TABLE 120.5  Treatment of Convulsive Status Epilepticus Time (Min)

Steps

0-­5 (Stabilize, ABCs)

Give O2; ensure adequate ventilation Monitor: vital signs, ECG, oximetry, seizure duration Establish intravenous access; Obtain finger stick blood glucose level, If 10 mL) lumbar puncture is frequently

CHAPTER 121  Central Nervous System Tumors

Fig. 121.3  Contrast-enhanced T1-weighted MRI shows a large enhancing tumor in the midline of the cerebellum with compression of the fourth ventricle.

required in order to make the diagnosis. If the initial cytology is negative and suspicion is high, additional lumbar puncture can be considered. Findings of elevated CSF protein and white blood cell count or low glucose should raise suspicion. In the majority of cases, biopsy or resection is the preferred method to establish the histology and grade of primary brain tumors. Exceptions include patients suspected to have PCNSL; a search for malignant cells in the CSF or by vitreous biopsy can be attempted to avoid surgery. Additionally, surgery is typically avoided in brain stem gliomas because the MRI appearance is characteristic and biopsy is considered dangerous.

TREATMENT Surgical resection is the initial goal for most patients with benign and malignant primary brain tumors. Surgical resection provides tissue for analysis and often relieves neurologic symptoms; maximal surgical resection, when feasible, improves outcome. One exception is PCNSL, in which clinical deterioration can result from resection. Biopsy alone is adequate unless significant symptoms of mass effect from the tumor are present. In addition, small meningiomas can often be observed. Standard therapy for newly diagnosed glioblastoma is maximal resection and focal external beam radiation of 60 Gy in combination with temozolomide followed by adjuvant temozolomide for 6 months. In a prospective randomized trial of newly diagnosed glioblastoma patients, the median survival with radiation and temozolomide was 14.6 months versus 12.1 months with radiation alone. In addition, the 2-year survival rate was superior with the combined regimen (26.5%) versus radiation alone (10.4%). O-6-methylguanine DNA methyltransferase (MGMT) is a DNA repair gene that reduces the efficacy of temozolomide and other DNA-damaging treatments for cancer. Methylation of the MGMT promoter in tumor tissue silences this gene and results in improved survival in glioblastoma. There is evidence that tumors harboring isocitrate dehydrogenase (IDH) 1and 2 mutations are correlated with a superior outcome compared with wild-type IDH. The discovery of molecular “drivers” may lead to identification of additional targets for therapy. New approaches using next-generation sequencing and DNAmethylation fingerprinting are being evaluated in trials of glioblastoma.

1089

The introduction of “targeted agents” that are designed to deactivate oncogenic pathways or angiogenesis is a major advance in cancer treatment. Bevacizumab, a monoclonal antibody to vascular endothelial growth factor, is associated with a high response rate and reduction in neurologic symptoms in recurrent glioblastoma, although the effect on overall survival is not significant. Because current treatment results are unsatisfactory, it is suggested that patients with glioblastoma be referred for clinical trial. Anaplastic gliomas, most commonly anaplastic astrocytoma and anaplastic oligodendroglioma, are treated by maximal surgical resection, followed by focal external beam radiation in association with chemotherapy. However, there is increasing reliance upon the molecular markers of MGMT and IDH1 status to predict survival and to dictate the utility of adding chemotherapy in poor prognosis patients. One type of anaplastic glioma exquisitely sensitive to chemotherapy is the anaplastic oligodendroglioma with co-deletions of 1p and 19q. The long-term progression-free survival and overall survival of low-grade glioma (grade 2) patients is better than those with glioblastoma or anaplastic glioma, but malignant transformation occurs in up to 50% of such patients and close monitoring with serial MRIs is required. Most patients with low-grade gliomas should be treated initially with maximal safe surgical resection. When grade 2 patients undergo resection, adjuvant therapy with radiation and chemotherapy is reserved for those who are older than 40 years of age or in whom the resection was subtotal. Characterizing low-grade gliomas by molecular markers such as IDH1 and chromosomal analysis for co-deletion of 1p and 19q mutations and (IDH) mutation predicts prognosis. Regardless of the treatment modality selected, serial monitoring for progression with regular MRIs is indicated. If there is disease progression or recurrence, repeat surgery, RT, and chemotherapy are all potential options depending on individual patient characteristics. The type of therapy selected for a meningioma depends on patient characteristics, tumor features, potential for harm if untreated, and consideration of side effects of the treatment. Maximal surgical resection is important to reduce the risk of relapse. When complete removal is not possible, radiation therapy should be considered postoperatively, especially for grade 2 tumors. Radiation therapy is recommended regardless of the extent of resection for malignant (grade 3) meningiomas. Chemotherapy for this disease has not been proven to be effective. Symptoms and imaging abnormalities associated with PCNSL often improve with the administration of corticosteroids because of the cytotoxic effects of steroids on lymphoma cells. However, administration of steroids before brain biopsy reduces the yield of tissue biopsy and can confound diagnosis. Therefore, delaying steroids prior to surgery is appropriate in suspected PCNSL because resection is often associated with neurologic deterioration and because there is no clear evidence that resection improves prognosis. A high-dose methotrexate-based regimen incorporating an alkylating agent and rituximab is the preferred induction therapy. Consolidation therapy may include other chemotherapies or low-dose whole brain radiation. High-dose radiation following chemotherapy should be avoided because of the risk of white matter damage. Up to a quarter of patients have ocular or CSF involvement at the presentation of CNS lymphomas, and staging by performing lumbar puncture and consultation with ophthalmology is appropriate prior to beginning therapy. Contemporary management of brain metastases is individualized and is often best accomplished by a multidisciplinary team including medical oncology, neuro-oncology, radiation oncology, and neurosurgery. Initial systemic evaluation for a suspected new brain metastasis should include contrast-enhanced CT scans of the chest, abdomen, and pelvis and additionally a mammogram if the patient is female. If

1090

SECTION XVI  Neurologic Disease

the lesions are multiple and the underlying diagnosis is not known, tissue from the safest and most readily accessible site should be obtained. Standard therapy for patients with a single brain metastasis is complete resection if the tumor is resectable and the patient has a good performance status and has limited extracranial disease. Some patients with limited systemic cancer show a survival benefit with resection of up to three metastatic tumors. Resection is typically followed by whole brain radiation or stereotactic surgery to the tumor margin. Radiosurgery to all lesions, avoiding resection, is also an option. The addition of whole brain radiation therapy (WBRT) after resection or radiosurgery provides better control of tumor in the brain but does not result in increased survival, and its use should be determined based on the individual clinical circumstances. Patients presenting with more than three brain metastases should be considered for WBRT. Novel approaches to preserving memory in patients undergoing WBRT include sparing the hippocampus during radiation and/or adding memantine. If the patient does not receive WBRT, close observation with periodic MRI scans is indicated to assess for recurrence at the original site or at other sites in the brain. A variety of systemic treatments show therapeutic efficacy in newly diagnosed and recurrent brain metastasis, depend upon the sensitivity of the brain metastasis to the agent. Examples include small molecule targeted agents for non–small cell lung cancer, immunotherapy for malignant melanoma, and chemotherapy with or without targeted agents for breast cancer. Leptomeningeal metastasis is treated based on the underlying pathology and the performance status of the patient. Options include radiation to symptomatic sites or bulky disease in the brain or spine on MRI, systemic chemotherapy, or intrathecal chemotherapy. The extent of resection is prognostic in medulloblastomas. Staging evaluations for the extent of disease include postoperative MRI of the brain and spine and lumbar CSF sampling. Prospective randomized trials and single-arm trials suggest that adjuvant chemotherapy administered during and after craniospinal radiation improves the progression-free survival and overall survival in both average and poor risk groups. The therapy for children younger than 3 years of age excludes craniospinal radiation therapy because of the long-term deleterious effects and includes surgery and chemotherapy alone. Distinct subgroups of medulloblastomas have been identified, and profiling of these subgroups reveals distinct genomic events, some of which represent actionable targets for therapy. Vasogenic edema associated with parenchymal and meningeal tumor causes neurologic symptoms and signs and can be life-threatening. Treatment with corticosteroids often reduces edema and improves neurologic function. Dexamethasone is the preferred steroid because of its long half-life and low mineralocorticoid activity. Patients with symptoms related to vasogenic edema often improve within 48 hours of dexamethasone administration. Doses used for treatment of tumor-related edema are typically 4 to 24 mg/day of dexamethasone given in divided doses (two to four times daily). Because steroids can be associated with a variety of adverse effects, the lowest dose and duration of administration should be sought. In patients with severe neurologic signs related to brain edema, an intravenous bolus of 10 mg dexamethasone should be considered. If the neurologic signs are life-threatening, including signs of brain herniation, mannitol and dexamethasone should be administered and urgent neurosurgical consultation obtained. Seizures should be aggressively managed with antiepileptic drugs. Liver nonenzyme-inducing antiepileptic drugs (e.g., phenytoin) are favored because of a better safety profile than liver enzyme-inducing drugs and because of the lack of interaction with other medications prescribed to treat the tumor, including steroids and chemotherapy. Prophylactic antiepileptic

drugs are generally not recommended for patients with a primary or metastatic brain tumor. One exception is melanoma brain metastases in which patients with multiple supratentorial brain metastases, especially those with hemorrhage, have a high risk of seizures.

PROGNOSIS The grade of glioma, performance status, and age are important predictors of prognosis. Glioblastoma has the worst prognosis, with a median survival of just over 1 year even with aggressive therapy. Favorable prognosis patients can live more than 2 years. Data from the nationwide Surveillance, Epidemiology, and End Results registry identified an overall median survival of 15 months and 42 months for patients with anaplastic astrocytomas and anaplastic oligodendrogliomas, respectively. This analysis did not include the status of 1p19q chromosomal loss, and the more favorable survival of patients with co-deletions was thus not demonstrated. Low-grade gliomas have a median survival of approximately 5 years, but there is individual variation depending on age, size of tumor, and extent of resection. The incorporation of molecular markers will allow for more specific prognostication in these tumors. Recurrence rates in meningioma depend upon grade and vary from greater than 25% in grade 1 to greater than 90% in grade 3. Risk factors for recurrence include incomplete resection, higher tumor grade, young age, specific subtypes, brain infiltration, and high proliferative rate. Median survival in PCNSL has improved with the introduction of high-dose methotrexate regimens in contrast to whole brain radiation that was used decades ago. Depending upon a variety of clinical factors, most importantly age and performance status, it ranges from 1 to 8 years. Elderly patients (>70 years) fare the worst. Performance status, age, status of the extracranial tumor, and number of brain metastases are some of the factors that predict prognosis in patients with brain metastasis. The prognosis of patients with brain metastases has become increasingly individualized. As newer targeted therapies become available, the particular genetic mutations driving the cancer are also becoming important for determination of prognosis. The median survival ranges from 3 to 6 months in patients with multiple metastases treated with whole brain radiation therapy. Patients with a single metastasis with limited extracranial disease who undergo surgical resection and whole brain radiation therapy have significantly improved survival (40 weeks) as compared with those who undergo whole brain radiation therapy alone (15 weeks). Importantly, the improved survival is accompanied by a longer period of functional independence. The 5-year progression-free survival in medulloblastomas is 70% to 85%. However, more than one third of patients experience recurrence, and there is no standard therapy at the time of recurrence. Median survival after recurrence is usually less than 1 year. The advent of molecular markers in the diagnostic evaluation of primary brain tumors, especially gliomas, has significantly altered the approach to predicting prognosis and treatment response. In addition, multi-institution trials have provided robust information regarding the optimal therapy for subgroups of glioma, subdivided by important clinical factors such as patient age, performance status, degree of surgical resection, and incorporation of molecular markers. It is anticipated that prospectively designed trials, stratified on these factors, will yield additional information to aid the clinician in treatment recommendations. Significant advances in the treatment of systemic cancer are providing additional therapies when those cancers spread to the central nervous system.

CHAPTER 121  Central Nervous System Tumors

SUGGESTED READINGS American Cancer Society: www.cancer.org. Accessed October 22, 2013. Backer-Grøndahl T, Moen BH, Torp SH: The histopathological spectrum of human meningiomas, Int J Clin Exp Pathol 5:231–242, 2012. Barnholtz-Sloan JS, Yu C, Sloan AE, et al: A nomogram for individualized estimation of survival among patients with brain metastasis, Neuro Oncol 14:910–918, 2012. Buckner, et al: Radiation plus procarbazine, CCNU, and vincristine in lowgrade-glioma, NEJM 374:1344–1355, 2016. CBTRUS: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004–2007, Central Brain Tumor Registry of the United States statistical Report, 2011. De Braganca KC, Packer RJ: Treatment options for medulloblastoma and CNS primitive neuroectodermal tumor (PNET), Curr Treat Options Neurol 15:593–606, 2013. Nuño M, Birch K, Mukherjee D, et al: Survival and prognostic factors in anaplastic gliomas, Neurosurgery 73:458–465, 2013. Olson JJ, Paleologos NA, Gaspar LE, et al: The role of emerging and investigational therapies for metastatic brain tumors: a systematic review

1091

and evidence-based clinical practice guideline of selected topics, J Neuro Oncol 96(1):115–142, 2010. Patil CG, Pricola K, Sarmiento JM, et al: Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases, Cochrane Database Syst Rev 9:CD006121, 2012. Rutkowski S, von Hoff K, Emser A, et al: Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis, J Clin Oncol 28:4961–4968, 2010. Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma, N Engl J Med 352(10):987– 996, 2005. Tawbi, et al: Combined nivolumab and ipilimumab in melanoma metastatic to the brain, NEJM 379:722–730, 2018. van den Bent MJ, Brandes AA, Taphoorn MJ, et al: Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951, J Clin Oncol 31:344–350, 2013. Wang Z, Bao Z, Yan W, et al: Isocitrate dehydrogenase 1 (IDH1) mutationspecific microRNA signature predicts favorable prognosis in glioblastoma patients with IDH1 wild type, J Exp Clin Cancer Res 32:59, 2013.

122 Demyelinating and Inflammatory Disorders Anne Haney Cross

INTRODUCTION In demyelinating CNS disorders, previously normal myelin is lost due to an acquired, typically inflammatory disease. The prototypic CNS demyelinating disorder is multiple sclerosis (MS). Other disorders of this type include neuromyelitis optica (NMO), acute disseminated encephalomyelitis (ADEM), acute transverse myelitis (TM), and optic neuritis (ON).

MULTIPLE SCLEROSIS Definition/Epidemiology Recent data indicate that MS affects between 600,000 and 900,000 people in the United States and over 2.3 million worldwide. Though presumed to be autoimmune, its exact etiology is still not fully understood. MS begins as a relapsing remitting disease in greater than 80% of patients and ultimately becomes progressive in greater than 50% of patients with untreated relapsing-­remitting MS (RRMS). Progressive MS patients accumulate neurologic disability unassociated with relapses (although relapses may be superimposed). MS is more common in females, with the current female to male ratio in North America and in Europe estimated at 2:1 to 4:1. An exception is primary progressive MS (see Clinical Presentation), where the female to male ratio is 1:1. MS is most common in persons of northern European ancestry. Recent genome-­wide association studies indicate that many genes affect the risk of MS, although most confer only a small risk of disease (odds ratios less than 1.5). Alleles within the HLA-­DR region (DRB1*15:01 > DRB1*13:03 > DRB1*03:01) are the most well established and confer the greatest risk with odds ratios between 1.5 and 4 for most populations of northern European ancestry. Environmental factors can confer risk for MS, including modifiable factors such as low vitamin D blood level, high body mass index during adolescence/young adulthood, and smoking cigarettes. Seropositivity to the Epstein-­Barr virus increases the risk of MS; a symptomatic case of infectious mononucleosis confers greater risk than seropositivity alone. Though relatively high at 1/1000 to 1/500, MS incidence appears to be relatively stable in North America, the United Kingdom, and Europe. Incidence of MS may be increasing in several regions where MS was not previously prevalent, such as Iran, Turkey, Sicily, and South Africa. These reports of increasing incidence may reflect a real increase, improved recognition, or both.

Pathology Classically, MS causes demyelinating CNS white matter lesions with relative sparing of axons. The most common pathology of active lesions in white matter is perivascular mononuclear cell infiltration

1092

(monocyte/macrophages, lymphocytes), with a variable presence of antibody and activated complement. Acutely active white matter lesions display blood-­brain barrier breakdown, manifest on MRI by gadolinium enhancement. Despite its categorization as a “white matter disease,” gray matter is also damaged in MS. Gray matter MS lesions have been under-­recognized because they are difficult to see by MRI and are often not appreciated pathologically without special stains. Such gray matter lesions may occur in the deep gray structures such as the thalamus and in the cerebral cortex. Cortical gray matter lesions can be subpial, extend into cortex from underlying white matter (leukocortical), or wholly within the cortex (intracortical). Cortical lesions are characterized by activated microglia and relatively fewer infiltrating lymphocytes and macrophages than white matter MS lesions. Ectopic lymphoid tissue containing components of secondary lymphoid tissues (B cells, follicular helper T cells, dendritic cells, CXCL13) has been observed in meninges of people with MS, especially those with progressive MS, and is associated with poor prognosis.

Clinical Presentation MS may manifest with a variety of symptoms and signs. Common presentations include: optic neuritis, diplopia (often caused by internuclear ophthalmoplegia due to a propensity of MS to affect the medial longitudinal fasciculus), other brain stem syndromes, partial transverse myelitis, sensory disturbances, and weakness. Less frequent presentations include seizures, cognitive problems, bladder control problems, and pain. Pain in MS is often of a burning, tingling, or electrical nature. Clinically isolated syndrome (CIS) refers to a single attack that is likely due to CNS demyelination. CIS may be acute or subacute in onset and may involve a single or more than one CNS region. CIS presentations may look identical to MS attacks, but a formal diagnosis of MS cannot be made without dissemination of lesions in space and time. New MS diagnostic criteria allow positive spinal fluid findings (CSF-­restricted oligoclonal bands) to substitute for dissemination in time. Ultimately, most CIS patients with typical demyelinating syndromes develop MS. In one study, over 85% of CIS patients with even one silent abnormality on brain or spinal cord magnetic resonance imaging (MRI) eventually developed clinically definite MS. Three main clinical subtypes of MS are defined based on clinical course: relapsing remitting, secondary progressive, and primary progressive. RRMS is characterized by clinical stability between individual attacks from which the person may or may not fully recover. Secondary progressive MS (SPMS) patients have gradual neurologic deterioration and may also have superimposed attacks (“active” SPMS). Secondary progressive MS develops following an initial relapsing-­remitting course in a substantial proportion of individuals with RRMS. This proportion may be declining with the advent of disease-­modifying therapies.

CHAPTER 122  Demyelinating and Inflammatory Disorders

1093

TABLE 122.1  The 2017 Revised McDonald Criteria Clinicala ≥2 attacks ≥2 attacks

Lesions With Objective Clinical Evidence

≥2 attacks

≥2 1 lesion, plus clear cut historical evidence of a prior attack in a different anatomic location 1

1 attack

≥2 lesions

1 attack

1 lesion (CIS)

Gradual neurologic progression suggestive of MS (PPMS)

Additional Data Needed for MS Diagnosis None None

DIS demonstrated by an additional clinical attack implicating a different anatomic location, or >1 new T2w lesion in at least one other region typical of MS (periventricular, cortical or juxtacortical, brain stem/cerebellar, spinal cord) DIT demonstrated by a 2nd clinical attack, or new T2w and/or gad+ lesion on follow-­up MRI, or simultaneous presence of gad+ and nonenhancing lesion on MRI at any time, or positive cerebrospinal fluid findings (oligoclonal bands restricted to CSF) DIS demonstrated by a 2nd clinical attack implicating a different CNS region, or ≥1 new T2w lesion in MS-­typical region of CNS; DIT demonstrated by a 2nd clinical attack plus either new T2w MRI lesion or CSF-­restricted oligoclonal bands

1 year or more of disease progression plus two of three of following criteria: evidence for DIS in the brain based on ≥1 T2w lesions characteristic of MS, evidence of DIS in the spinal cord based on ≥2 T2w cord lesions, positive CSF (elevated IgG index or oligoclonal bands not present in serum)

aThese

criteria were developed in Caucasian adults aged 18 to 50 years with CIS presentations typical of CNS inflammatory demyelinating disease. Care should be taken when applying these criteria to persons not fitting this description. Alternative diagnoses that might better explain the disorder must always be considered and reasonably excluded. DIS, Dissemination in space; DIT, dissemination in time. Modified from Thompson AJ, Banwell BL, Barkhof F, et al: Diagnosis of multiple sclerosis: 2017 revisions of the McDonald Criteria, Lancet Neurol 17:162–173, 2018.

About 10% of MS patients have primary progressive MS (PPMS), which from onset is characterized by gradual downhill progression without any clinical attacks. The International Advisory Committee on Clinical Trials of MS has proposed additional clinical descriptors that include disease activity (based on relapse rate and new imaging findings) and progression over the prior year.

Diagnosis The diagnosis of MS requires dissemination of CNS disease in time and in space, and no other disease should provide a better explanation. MRI, spinal fluid analyses, evoked potentials (EPs) and ocular coherence tomography (OCT) are tools that may aid in the diagnosis. The latest McDonald criteria (Table 122.1) allow CSF-­restricted oligoclonal bands to substitute for dissemination in time in the diagnosis of MS in the setting of a CIS typical of demyelination. The new diagnostic criteria allow more rapid diagnosis of MS and earlier treatment.

MRI The finding of classic imaging features on brain and spinal cord MRI greatly aids the certainty of diagnosis. MS lesions are characterized by increased intensity on T2-­weighted (T2w) and T2-­FLAIR (fluid attenuated inversion recovery) images (Fig. 122.1A). Lesions are usually ovoid and often localize to the periventricular or juxtacortical regions, the corpus callosum, the brain stem, and the cervical spinal cord. On sagittal images, lesions in the corpus callosum are usually flame-­shaped (Fig 122.1C). On T1w images, MS lesions may be isointense or hypointense. T1w hypointensity in a chronic inactive lesion denotes underlying tissue damage, including axonal loss (Fig.122.1D). Enhancement of lesions following administration of gadolinium containing contrast agents indicates blood-­brain barrier breakdown; such a lesion is considered to be active (Fig. 122.1B). Enhancing lesions are also often T1w hypointense, but this hypointensity resolves more than 50% of the time. A ring pattern (often an incomplete ring) of

enhancement is common. Most enhancing MS lesions display no mass effect. Occasional “tumefactive” MS lesions are difficult to distinguish from tumors and may require biopsy.

Spinal Fluid Analysis Evidence of increased intrathecal immunoglobulin synthesis is present in more than 90% of people with MS. Elevated concentrations of CSF IgG and IgM, CSF-­restricted oligoclonal bands of immunoglobulin (Fig. 122.2), and a high intrathecal IgG synthesis rate are seen. The IgG index, which is derived from the ratio of CSF to serum IgG and takes BBB integrity into account, is elevated in MS. A mild lymphocytic pleocytosis is frequently seen in CSF during MS relapses.

Evoked Potentials EPs detected by surface electrode recording were used in the past to detect subclinical demyelination in the brain stem (auditory EPs), spinal cord (somatosensory EPs), and optic nerves (visual EPs). The advent of high-­resolution MRI has led to far less use of EPs to aid MS diagnosis.

Optical Coherence Tomography OCT is a safe and rapid means to image the retina and detect evidence of prior optic neuritis. OCT uses infrared light to measure thickness of the retinal nerve fiber layer (RNFL), which contains axons that form the optic nerve. A thinned temporal region of the RNFL can be used as evidence of prior subclinical optic neuritis.

Differential Diagnosis The diagnosis of MS requires the exclusion of diseases that might better explain the clinical scenario. The differential diagnosis of MS is broad (Table 122.2). Some diseases that can mimic MS have relapses and others display progressive courses. “Red flags” that are atypical for MS, such as systemic (arthritis, rash, mouth or genital sores, or pulmonary) symptoms, bilateral hearing loss, peripheral neuropathy, or

1094

SECTION XVI  Neurologic Disease

A

B

C

D

Fig. 122.1  (A) Axial fluid-­attenuated inversion recovery (FLAIR) image of the brain from a person with MS revealing classical periventricular and deep white matter high-­signal intensity lesions. (B) Axial T1-­weighted image following gadolinium contrast administration in the same patient as A. Enhancing lesions after gadolinium contrast administration, indicating loss of integrity of the blood-­brain barrier that is seen with active MS lesions. One enhancing lesion in the right parietal region is ring enhancing. (C) Sagittal FLAIR image of the brain of a person with MS demonstrating classical flame-­shaped pericallosal lesions radiating outward from the ventricle. (D) Axial T1-­weighted image showing areas of T1 low signal intensity (“black holes”).

atypical age of onset (early childhood or after age 50) should lead the clinician to seek further support for the diagnosis of MS.

Prognosis of Multiple Sclerosis

CSF

Serum

Anodal

Cathodal

pH 8.0 Fig. 122.2 Isoelectric focusing gel of cerebrospinal fluid (CSF) and serum of a patient with multiple sclerosis. The CSF (upper lane) shows oligoclonal bands cathodal to the pH 8.0, which are not seen in the serum (lower lane).

MS is highly variable. It is occasionally “benign,” in which case the disease has little impact on quality of life. It can also be severe with considerable disability or early death. Most people with MS fall in between these extremes. It is currently not possible to predict the future course of MS in an individual patient with full accuracy. Poor prognostic indicators at onset of MS include primary progressive course, male gender, frequent attacks, prominent motor or cerebellar findings, and high initial MRI lesion burden. Expected lifespan of people with MS is reduced overall by 7 to 14 years. Suicide rate is 1.7 to 7.5 times that of the general population. The use of disease modifying therapies likely improves not only relapse rate but also long-­term disability and even mortality. In one nonrandomized study, early initiation of disease modifying therapies within a year of symptom onset was associated with better long-­ term outcomes.

CHAPTER 122  Demyelinating and Inflammatory Disorders

1095

TABLE 122.2  Differential Diagnosis of Demyelinating Diseases Disease Categorya

Examples of Disordersb

Immune-­mediated/autoimmune

Multiple sclerosis, neuromyelitis optica (NMO), anti-­MOG disorder, acute demyelinating encephalomyelitis (ADEM), idiopathic optic neuritis, CRION, idiopathic transverse myelitis, Behçet’s disease Progressive multifocal leukoencephalopathy (PML), HTLV-­I, HIV, CNS abscess, Lyme disease, Whipple disease, neurosyphilis Vitamin B12, vitamin E or copper deficiency, central pontine and extrapontine myelinolysis Spinocerebellar ataxias, spine disease (e.g., compressive cervical spondylopathy, central canal stenosis) Sarcoidosis, systemic lupus erythematosus, antiphospholipid antibody syndrome, Sjögren’s syndrome Adrenoleukodystrophy/adrenomyeloneuropathy, hereditary spastic paraparesis, CADASIL (a hereditary stroke disorder), Leber optic neuropathy, Perlizeus-­Merzbacher, Wilson’s disease CNS lymphoma, meningeal carcinomatosis, paraneoplastic CRMP-­5 IgG, anti-­amphiphysin-­1 Abs CNS vasculitis (e.g., giant cell arteritis, primary CNS vasculitis), spinal dural fistula, Susac syndrome TNF inhibitors, CNS irradiation, immune checkpoint inhibitors

Infectious Metabolic Neurodegenerative Rheumatologic Genetic disorders Neoplastic/paraneoplastic Vascular Iatrogenic aSeveral bThis

of the disorders listed could be placed in more than one category. list is not comprehensive.

For a deeper discussion of these topics, please see Chapter 383, “Multiple Sclerosis and Demyelinating Conditions of the Central Nervous System,” in Goldman-­Cecil Medicine, 26th Edition.

Treatment MS treatment can be divided into three categories: treatment of symptoms (e.g., spasticity, fatigue, or depression), treatment of acute relapses, and disease modifying therapies. The following discussion will be limited to the latter two categories. However, Table 122.3 lists some frequent MS symptoms and their therapies. Relapses that alter function or cause severe pain are usually treated with corticosteroids. Severe relapses are often managed with high-­dose corticosteroids, such as intravenous methylprednisolone at 500 to 1000 mg daily for 3 to 5 days, followed by a short oral taper. Lower dosed corticosteroid courses may be used for mild relapses. Blood pressure, serum electrolytes and glucose, and patient mood should be monitored during corticosteroid therapy. Based on the multicenter Optic Neuritis Treatment Trial (ONTT), this regimen will lead to more rapid recovery from the attack but is unlikely to alter the degree of eventual recovery. For severe relapses that do not respond to high-­dose IV corticosteroids, a small randomized study showed that plasma exchange can be effective. Rapid functional improvement in over 40% of patients occurred with early initiation of plasma exchange. Subjects in this trial likely included patients with NMO and ADEM, in addition to MS. MS is one of only a handful of chronic neurologic disorders with effective disease modifying therapies. The beta-­interferons (BIFNs) and glatiramer acetate (GA) are US Food and Drug Administration (FDA)-­approved for the treatment of patients with relapsing forms of MS to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability. The BIFNs and GA all reduced annualized relapse rate by about 30% in early pivotal studies. Most have been shown in randomized trials to delay progression to definite MS in those with CIS who are at high risk for developing MS. As of mid-2020, 19 different disease modifying therapies, plus several generics versions of these, with 10 different mechanisms of action are available for MS (Table 122.4). The approved agents have distinct risk profiles. As there are currently no biomarkers that direct the choice of disease modifying therapies for an individual patient, selection of the disease modifying therapy for an individual is based on disease course and severity, comorbidities, and patient preferences. Five BIFNs are approved for use in relapsing MS and CIS in the United States. They differ in dosage, mode of administration, side

TABLE 122.3  Selected MS Symptoms and

Their Management Symptom/Sign

Treatment(s)

Stiffness/cramps/spasms/­ spasticity Fatigue Depression

Baclofen, tizanidine

Amantadine, modafinil, armodafinil Selective serotonin reuptake inhibitors, cognitive behavioral therapy Pain/paresthesias/trigeminal Gabapentin, carbamazepine, oxcarbazeneuralgia pine, pregabalin, amitriptyline Gait impairment Fampridine SR Nystagmus, with visual impairment Gabapentin Dizziness/vertigo Meclizine, dimenhydrinate, benzodiazepines Urinary urgency/incontinence/neu- Mirabegron, oxybutynin, tolterodine, rogenic bladder other anticholinergics, BOTOX injection Impotence/erectile dysfunction Sildenafil, tadalafil, testosterone supplementation if low Tonic spasms Phenytoin, carbamazepine

effects, and incidence of neutralizing antibody induction. Three are identical to human BIFN-­1a. Polyethylene glycol has been covalently attached to one of the three for longer duration of effect. The other two are BIFN-­1b, which differs by one amino acid from BIFN-­1a. BIFNs are immunomodulators whose exact mechanism of action in MS is not fully established. BIFN therapy is associated with increased circulating soluble VCAM-­1, and increased IL-­10, an immunoregulatory cytokine. Hepatic transaminases and CBC should be monitored in those taking BIFNs. Common side effects include a “flu-­like” feeling for several hours after a dose, which can be lessened by nonsteroidal anti-­ inflammatory medications or acetaminophen. BIFNs are administered by injection and, as with any injectable drug, skin infection can occur. Although the risk of taking BIFNs during pregnancy and lactation are thought to be minimal, it is recommended that BIFNs be discontinued before conception. Glatiramer acetate is given as a subcutaneous injection at 20 mg per day or 40 mg three times per week. This drug is a random polymer of four amino acids that are abundant within myelin basic protein, a major protein in CNS myelin. It is considered immunomodulatory not immunosuppressive, although its mechanism of action is not

1096

SECTION XVI  Neurologic Disease

TABLE 122.4  Disease Modifying Medications for MS Drug (Brand Name), Dosing

Approved

MS Indication

Mechanism of Action

Interferon-­β-­1b (Betaseron, Extavia), 250 μg SQ qod Interferon-­β-­1a (Avonex) 30 μg IM weekly Interferon-­β-­1a (Rebif) 22 or 44 μg SQ 3×/wk Interferon-­β-­1a (Plegridy) 125 μg SQ every 14 days Glatiramer acetate (Copaxone) 20 mg SQ daily, or 40 mg SQ 3×/wk Mitoxantrone (Novantrone) 12 mg/m2 IV q 3 months Natalizumab (Tysabri) 300 mg IV q 4 weeks

1993, 2009

RRMS, CIS

1996 2002 2014

RRMS, CIS RRMS Relapsing forms of MS

Inhibits “pro-­inflammatory” cytokines, such as interferon (IFN)-­γ, tumor necrosis factor-­α, and lymphotoxin. Increases IL-­10. Adhesion molecule and class II MHC induction reduced.

1996, 2014

RRMS, CIS

2000

Worsening RRMS, relapsing SPMS, PRMS Relapsing forms of MS

Fingolimod (Gilenya) 0.5 mg po daily

2004/2006 (removed briefly from market) 2010

Relapsing MS, including children

Teriflunomide (Aubagio) 7 mg or 14 mg po daily 2012

Relapsing MS

Dimethyl fumarate (Tecfidera) 240 mg po BID; Diroximel fumarate (Vumerity) 231 mg po BID; Monomethyl fumarate (Bafiertam) 95 mg po BID Alemtuzumab (Lemtrada) IV infusion

2013 2020 2020 2014

Relapsing forms of MS, including active SPMS and CIS

Ocrelizumab (Ocrevus) IV infusion 600 mg every 24 weeks Oral cladribine (Mavenclad) 1.75 mg/kg po yearly ×2 Siponimod (Mayzent) usually 2 mg po daily; Ozanimod (Zeposia) 0.92 mg po daily

2017

Relapsing forms of MS, primary progressive MS Relapsing forms of MS, including active SPMS Relapsing forms of MS, including active SPMS and CIS

Ofatumumab (Kesimpta) 20 mg SQ monthly

2020

2019 2019 2020

Relapsing forms of MS

Relapsing forms of MS, including CIS and active SPMS

fully understood. Glatiramer acetate has no known drug interactions. Laboratory monitoring is not needed. Side effects include injection site reactions and a tachycardia reaction that occurs infrequently and seemingly randomly, but always soon after an injection. Lipoatrophy at injection sites may develop with prolonged use. Glatiramer acetate is considered the safest MS disease modifying therapy to use in women who may become pregnant. No increase in risks for malformations or fetal/neonatal toxicity or pregnancy loss has been noted in those who were exposed to branded glatiramer acetate, although exposure has been mostly limited to the first trimester. Mitoxantrone is an anthracenedione chemotherapeutic agent that is FDA approved for secondary progressive MS, progressive relapsing MS, or worsening relapsing-­remitting MS. It is administered by IV infusion every 3 months. Due to dose-­limiting cardiotoxicity and drug-­induced leukemia (the latter in approximately 1% of MS patients receiving it), mitoxantrone is rarely used any more. Natalizumab is a humanized monoclonal antibody targeting the α-­4-­integrins, part of the VLA-­4 adhesion-­related heterodimer. The dose is 300 mg infused intravenously every 4 weeks. A 2-­year phase 3 trial of natalizumab showed 68% reduction in annualized relapse rate, 42% reduction in sustained disability, and over 90% reduction in gadolinium-­enhancing lesions compared with placebo. Natalizumab was temporarily removed from the market in 2005 due to its association with progressive multifocal leukoencephalopathy

Alters T cell cytokine profile toward that of Th2 immunomodulatory cells Anthracenedione chemotherapeutic agent Monoclonal antibody targeting the alpha-­4-­ integrins, part of the VLA-­4 adhesion molecule Modulates sphingosine1-­phosphate receptors 1,3,4, and 5; lymphocytes unable to migrate out of lymphoid tissue. May have direct effects in CNS. Inhibits dihydroorotate dehydrogenase, thus inhibiting proliferation of activated lymphocytes Activates nuclear factor erythroid 2-­related factor 2 (Nrf2) pathway that enhances response to oxidative stress Monoclonal antibody that lyses cells expressing CD52 Lytic monoclonal antibody targeting B cells expressing CD20 Cytotoxic to T and B lymphocytes through impairment of DNA synthesis Modulates sphingosine 1-­phosphate receptors 1 and 5, lymphocytes are unable to migrate out of lymphoid tissue. May have direct effects in CNS. Human lytic monoclonal antibody targeting B cells expressing CD20

(PML), a severe and sometimes fatal viral disorder caused by the JC virus. Because of its association with PML, this drug is recommended mainly in cases of an inadequate response or intolerance of an alternative MS therapy. Patients should be tested for serum antibodies to the JC virus prior to initiating therapy with natalizumab and, if positive, treatment should proceed with caution. Enrollment in a risk-­ mitigation program is required, and the drug can only be infused at a certified infusion center. Infusion reactions are not uncommon, and neutralizing antibodies to natalizumab develop in some patients. It is not recommended that natalizumab be used during pregnancy or during breast-­feeding. Fingolimod, an oral disease modifying therapy, is indicated for those with relapsing forms of MS, including CIS, RRMS, and active SPMS MS patients 10 years of age and older. This daily 0.5-­mg capsule reduces annualized relapse rate in adults with RRMS by about 50% and disability progression by about 25% versus placebo. Fingolimod modulates sphingosine 1-­phosphate receptors 1, 3, 4, and 5 and is believed to work in relapsing MS primarily by the sequestration of lymphocytes in secondary lymphoid tissues. Fingolimod affects several organ systems. Adverse effects include macular edema, pulmonary dysfunction, bradycardia, and increased infection rate (including opportunistic infections such as herpetic and cryptococcal infections and PML). Patients who are varicella zoster virus antibody-­negative should be vaccinated prior to initiation. Fingolimod is contraindicated

CHAPTER 122  Demyelinating and Inflammatory Disorders in the setting of recent myocardial infarction, stroke, uncontrolled heart failure, unstable angina, stroke, transient ischemic attack, or if baseline QTc interval on ECG is 500 ms or greater. Fingolimod can interact with a number of other drugs; it should not be initiated in those taking class IA and class III antiarrhythmic drugs. Medical monitoring for potential bradycardia for at least 6 hours after the first dose is required. Fingolimod may cause fetal harm. Women of childbearing age should use contraception during fingolimod use and for 2 months after its discontinuation. Siponimod is a second-­generation sphingosine 1-­phosphate receptor modulator that was FDA-­approved in 2019 for adults with relapsing forms of MS, including active SPMS, RRMS, and CIS. Siponimod is more specific than fingolimod, primarily modulating sphingosine 1-­phosphate receptors 1 and 5. The maintenance dose is 2 mg per day by mouth but should be reduced to 1 mg/day for those with CYP2C9*1/*3 or *2/*3 genotype, and it is contraindicated for those who are CYP2C9*3/*3 homozygous. In a study of SPMS patients who were notably older (mean age 48 years) and more disabled (median EDSS 6.0) compared with most other MS clinical trials, siponimod reduced 3-­month confirmed disability progression by a statistically significant 21% (P = 0.013) versus placebo. First-­dose monitoring should be done in people with sinus bradycardia, first-­or second-­degree atrioventricular block, history of myocardial infarction or heart failure. Women of childbearing age who take siponimod should undergo effective contraception, as siponimod has potential for a serious risk to the fetus. Several other sphingosine 1-­phosphate receptor modulators are currently being studied in MS. Ozanimod is a second-generation sphingosine 1-phosphate receptor 1 and 5 modulator that was FDA-approved in 2020 for adults with relapsing forms of MS. In two trials enrolling over 800 subjects with active relapsing MS each, ozanimod was compared to BIFN 1a 30 g IM weekly, showing 48% and 38% relative reductions (each P < 0.0001) in annualized relapse rate versus active comparator. As with fingolimod and siponimod, patients should have baseline bloodwork to include CBC and liver function tests, an electrocardiogram to assess for preexisting conduction abnormalities, and baseline and follow-up ophthalmic assessments to assess for macular edema. If live attenuated vaccine immunizations are needed (such as for varicella zoster), these should be administered at least 1 month prior to starting ozanimod (or fingolimod or siponimod). Several other sphingosine 1-phosphate receptor modulators are currently being studied in MS with at least one of these expected to be approved in 2021. Teriflunomide is a once-­daily oral tablet of 7 mg/day or 14 mg/ day. Two phase 3 studies in patients with relapsing forms of MS found that the 14-­mg/day dose significantly reduced annualized relapse rate by over 30% and disability progression by around 30%. The 7-­mg dose had a lesser beneficial effect. Teriflunomide can cause hepatotoxicity, and liver blood work monitoring should continue monthly for 6 months after initiation. Based on animal data, teriflunomide may cause major birth defects and thus pregnancy must be avoided during treatment. If necessary, teriflunomide can be rapidly eliminated from the body using cholestyramine; otherwise, it persists for long periods. Teriflunomide may reactivate latent tuberculosis, is associated with peripheral neuropathy, and can increase blood pressure. Teriflunomide is closely related to the drug leflunomide, approved for rheumatoid arthritis in 1998. Dimethyl fumarate is an oral medication taken twice daily and is indicated for all relapsing forms of MS. In phase 3 trials, it reduced MS relapse rates by 44% to 53% and improved MRI outcomes. The white blood cell count may drop and should be monitored. In late 2014, the FDA issued a warning regarding the association of PML with this medication, and since then over 20 people have developed PML in

1097

the setting of dimethyl fumarate use. The risk of PML may be greater in those with persistent low lymphocyte counts and those over age 50. Adverse effects include flushing, gastrointestinal side effects, and rash. Dimethyl fumarate should be discontinued prior to conception. Several related fumarates with improved side effect profiles are under investigation for use in MS. Diroximel fumarate and monomethyl fumarate are two second generation oral fumarates each approved in 2020 by the FDA for relapsing forms of MS. These oral fumarates have similar efficacy and safety to dimethyl fumarate, but fewer gastrointestinal side effects. Alemtuzumab is a lytic monoclonal antibody targeting cells expressing CD52, which includes T and B lymphocytes, monocytes, and other mononuclear white blood cells. In the United States, it is indicated for people with relapsing forms of MS and, because of its health risks, is reserved for those with inadequate response to two or more disease-­ modifying drugs for MS. In the CARE-­MS I and II studies in RRMS patients, alemtuzumab infusions were compared to 44 μg BIFN-­1a given subcutaneously three times per week. Patients treated with alemtuzumab had a lower annualized relapse rate (by 49% and 53.8%) and disability progression (by 28% and 42%). Alemtuzumab leads to a profound drop in the white blood cell count, which may last for months or even years. In trials, secondary autoimmune diseases developed in a sizeable proportion of alemtuzumab-­treated subjects, with autoimmune thyroid disease being most common. Alemtuzumab may increase risk of malignancies, including thyroid cancer, melanoma, and lymphoproliferative disorders. Infusion reactions are common and can be life-­threatening. Alemtuzumab is available only through clinicians and infusion centers that have been certified to use it. Women of childbearing potential should use effective contraceptive measures when receiving a course of alemtuzumab and for 4 months following that course of treatment. Ocrelizumab is a fully humanized lytic monoclonal antibody targeting CD20, a cell surface antigen found on B lymphocytes. Ocrelizumab was FDA-­approved in 2017 for patients with relapsing or primary progressive forms of MS. Ocrelizumab is given as an intravenous infusion of 600 mg every 24 weeks. In the phase 3 studies, those in the ocrelizumab group had almost 50% reduction in annualized relapse rate and a 40% reduction in 12-­week confirmed disability progression compared to relapsing MS patients given subcutaneous BIFN-­1a at 44 micrograms three times per week. In the phase 3 ORATORIO study in primary progressive MS, those receiving ocrelizumab had 24% reduction in 3 month confirmed progression versus placebo. Side effects include infusion reactions, increased infection rate (including herpetic infections) and a possible increased risk of cancers, including breast cancer. Patients should screen negative for hepatitis B before commencing use of ocrelizumab. Risks associated with ocrelizumab in pregnant women are unclear, but transient B cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-­CD20 antibodies during pregnancy. Being of immunoglobulin G1 subtype, ocrelizumab is expected to cross the placental barrier. Women of childbearing potential should use contraception while receiving ocrelizumab and for 6 months after the last infusion. Ofatumumab is a human monoclonal antibody that targets and lyses cells expressing CD20. It is administered monthly, subcutaneously. In two clinical trials of over 900 relapsing MS patients each, ofatumumab was compared to teriflunomide 14 mg/day po. Annualized relapse rate reductions of 51% and 59% (both P < 0.001) were observed in the ofatumumab groups relative to teriflunomide groups. The combined studies showed ofatumumab to confer a 34.4% relative reduction in three-month confirmed disability progression (P = .002) versus teriflunomide. Potential risks and side effects are similar to those for

1098

SECTION XVI  Neurologic Disease

ocrelizumab and include infections, injection reactions, and reduced response to vaccinations. Oral cladribine was approved by the FDA in 2019 for the treatment of relapsing forms of MS in adults, including RRMS and active SPMS. This drug is recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternative disease modifying treatment of MS. Oral cladribine is a purine antimetabolite that destroys certain immune cells. It is given at a cumulative dosage of 3.5 mg/kg divided into two treatment courses at 1.75 mg/kg per treatment course given a year apart. Oral cladribine may increase the risk of malignancy, and it is contraindicated in those with concurrent malignancy. Patients should be screened for HIV, tuberculosis, and hepatitis B and C prior to use. Varicella zoster virus antibody-­negative persons should be vaccinated before initiation. Oral cladribine is contraindicated in pregnant or breast-­feeding women and in both women and men of reproductive potential who do not plan to use effective contraception because of risk of fetal harm.

States. It is even more female-­preponderant than MS, with female to male ratio estimated at 7:1. Children and adults both develop NMO. Unlike MS, NMO is not associated with HLA-­DRB1*15:01, and it affects those of Asian, African, Hispanic, and Polynesian ancestry disproportionately.

Clinical Presentation NMO presents clinically as an acute attack of optic neuritis and/or TM; it often takes a relapsing course. Gradually progressive NMO is exceedingly rare (helping to distinguish progressive MS from NMO). Other autoimmune diseases often occur together with NMOSD including Sjögren’s syndrome, systemic lupus erythematosus, Hashimoto disease, and myasthenia gravis.

Diagnosis/Differential In 2004, researchers first reported the presence of a serum IgG autoantibody targeting aquaporin 4 in NMO. NMO-­IgG/AQP4-­IgG is highly specific (>90%) and moderately sensitive (≈75%) for NMOSD. Fulfilling two out of three of the following criteria is reported to be 99% sensitive and 90% specific in the setting of optic neuritis and TM: (1) longitudinally extensive spinal cord lesion, which is greater than or equal to three segments in length (Fig. 122.3); (2) NMO-­IgG (anti-­ AQP4) positivity; and (3) brain MRI not typical or diagnostic for MS. For a deeper discussion of these topics, please see Chapter 383, “Multiple Sclerosis and Demyelinating Conditions of the Central Nervous System,” in Goldman-­Cecil Medicine, 26th Edition.

NEUROMYELITIS OPTICA SPECTRUM DISORDER (DEVIC DISEASE) Definition/Epidemiology Neuromyelitis optica spectrum disorders (NMOSD) comprise a spectrum of inflammatory CNS disorders causing both demyelination and necrosis that are clinically characterized by attacks of optic neuritis and longitudinally extensive TM that are not necessarily concurrent. Only rarely is NMOSD monophasic. In most cases serum autoantibodies to the aquaporin 4 (AQP4) water channels are found. AQP4 channels are strongly expressed by astrocytes. AQP4 is also expressed outside of the CNS in the kidney, stomach, and other tissues, but curiously no pathology has been recognized in the non-­CNS organs expressing AQP4. NMOSD is much less common than MS, with estimates by the Guthy-­Jackson Charitable Foundation of 15,000 patients in the United

A

Pathology Histopathologic changes in NMOSD are mostly in the spinal cord and optic nerves; the brain is less involved. Lesions affect both white and gray matter. In the brain, lesions are most common in the hypothalamus and around the fourth ventricle. NMO lesions center on blood vessels where IgG, IgM, and complement activation products are seen. The vessels are abnormally thickened and hyalinized. Active

B

Fig. 122.3  (A) Sagittal T2w image of the upper spinal cord in a 37-­year-­old female with NMO. She developed quadriparesis over several days and was AQP4-­IgG seropositive. Two years later she had right eye optic neuritis, which left her with visual acuity of only 20/200. The spinal cord lesion (arrows) had mild mass effect and was contiguous over six vertebral segments. (B) Sagittal T2w image of the upper spinal cord in a 24-­year-­old male with MS shows a lesion (arrow) in the posterior cord at C2. This patient had moderate vibration loss in the legs but was otherwise asymptomatic.

CHAPTER 122  Demyelinating and Inflammatory Disorders NMO lesions show infiltration by mononuclear cells (lymphocytes, monocytes), neutrophils, and eosinophils. Older lesions display demyelination, axon loss, and death of oligodendroglia and neurons. Accumulating data indicate that AQP4-­IgG itself is pathogenic, causing complement-­and antibody-­mediated damage.

Treatment Acute relapses are treated with high-­dose corticosteroids. If these are not quickly effective, plasma exchange is performed. Although NMO is rare, several multicenter randomized, controlled trials of disease modifying therapies have been completed recently with notably positive results. Eculizumab, a monoclonal antibody that inhibits the complement cascade, was compared to placebo in a randomized, double-­ blind, multicenter trial in adult NMOSD patients. The trial was stopped early when it showed that relapses occurred in only 3% in the eculizumab group versus 43% in the placebo group (hazard ratio, 0.06; 95% confidence interval, 0.02 to 0.20; P < 0.001). Upper respiratory tract infections and headaches were more common in the eculizumab group and a death from pulmonary empyema occurred in this group. Inebilizumab, a monoclonal antibody to CD19 that depletes B cells, was compared to placebo in adults with NMOSD in a randomized, double-­blind, multicenter study. Primary end point was time to onset of an NMOSD attack. This study too was stopped before complete enrollment because of a clear demonstration of efficacy. Twelve percent of 174 participants receiving inebilizumab had an attack versus 39% those receiving placebo (hazard ratio 0.272 [95% confidence interval 0.150 to 0.496]; P < 0.0001). Serious adverse effects were no higher in the active treatment group than in the placebo group. Satralizumab, a monoclonal antibody targeting the IL-­6 receptor and thereby inhibiting IL-­6 activity, has been reported to show positive results in NMOSD, particularly in those with positive ant-­AQP4 antibodies. Notably, beta-­interferons are not effective for NMOSD and may actually increase the rate of attacks.

Prognosis NMOSD typically displays worse outcomes than MS. Seropositive NMO patients tend to have more frequent and severe relapses than AQP4-­IgG negative patients. The death rate in a retrospective study covering 1950 to 1997 was over 30%. Less than 10% mortality was reported in a more recent retrospective study of Caucasian NMO patients. Death is often due to respiratory failure.

ANTI-­MYELIN OLIGODENDROCYTE GLYCOPROTEIN DISORDER A CNS demyelinating disease identified by its association with serum antibodies to the CNS myelin component, myelin oligodendrocyte glycoprotein (MOG), was recently described. Diagnosis is based on positive serum IgG1antibodies to MOG using cell-­based assays, as well as the absence of anti-­AQP4 antibodies, and absence of CSF-­restricted oligoclonal bands. Anti-­MOG disorder shares features with both MS and classical NMO. Anti-­MOG disorder occurs in children and adults and affects males and females in similar proportion. In adults, anti-­ MOG disorder is often characterized by optic neuritis and transverse myelitis (which may occur separately), but the disease is usually less severe than AQP4 antibody positive NMOSD and is often monophasic. An acute disseminated encephalomyelitis-­like presentation is common in children. The spectrum of anti-­MOG disorder is still being determined, as is the optimum treatment strategy.

1099

ACUTE DISSEMINATED ENCEPHALOMYELITIS ADEM is an acute, inflammatory, presumed immune-­mediated disorder of the CNS that is encountered primarily in children but may occur in adults. An antecedent viral infection or vaccination is common. ADEM presents with multifocal neurologic symptoms and signs. These can include encephalopathy, which may manifest as reduced level of consciousness (even coma) or as behavioral changes (e.g., confusion or irritability). Fever is common. Seizures, optic neuritis, and spinal cord involvement can all occur. Males and females are about equally affected. ADEM is usually monophasic, although relapsing ADEM has been described. On MRI, both white and gray matter CNS regions are affected. Gray matter involvement can include the basal ganglia, a region not typically affected in MS. The periventricular white matter region is often spared, unlike MS. When present, enhancement with gadolinium occurs in all lesions simultaneously. CSF often shows pleocytosis and an elevated protein but no infection. Findings typical of MS, such as oligoclonal bands, are unusual. No randomized prospective treatment trials for acute disseminated encephalomyelitis are reported. Intravenous methylprednisolone followed by a prednisone taper is typically administered with usually good response. Over 80% of cases recover. Because ADEM is only rarely recurrent, long-­term immunomodulatory/immunosuppressive therapy is not indicated. A rare hemorrhagic form of ADEM (Weston Hurst syndrome) is more severe and can lead to death or severe disability.

ACUTE TRANSVERSE MYELITIS TM is an inflammatory spinal cord syndrome presenting with abrupt or subacute onset of motor and/or sensory loss below a specific spinal level. Control of bladder and bowel is often affected, as is autonomic function below the level. Back pain and paresthesias may be prominent. Many cases of acute TM are idiopathic, but treatable causes must be ruled out. An urgent MRI with and without gadolinium should be obtained to look for compressive etiologies needing immediate treatment. After a compressive etiology has been ruled out, a lumbar puncture to assess CSF for cell count, glucose, and protein and cultures and PCRs for infectious causes should be done. The usual tests for MS should be performed, and CSF should be analyzed for evidence of neoplastic cells. Serum AQP4-­IgG, anti-­MOG using cell-­based assays, paraneoplastic panels, and chest CT should be considered. CSF may also be tested for NMO-­IgG, angiotensin converting enzyme, and paraneoplastic antibodies when no etiology is forthcoming. Acute TM can be the presenting episode for MS (in which case the TM is generally incomplete and asymmetrical) or NMO (where the TM affects ≥3 spinal cord segments). Acute TM can also be caused by spinal cord infarction due to occlusion of the anterior spinal artery. Infections by viruses can cause acute or subacute TM. The most common viruses associated with acute TM are varicella zoster, herpes virus type 2, and cytomegalovirus. The retroviruses HTLV-­I and HIV can each cause a myelopathy that is usually subacute. West Nile virus can cause a myelopathy that resembles poliomyelitis, with flaccid paralysis due to infection and death of anterior horn cells. Subacute TM may be caused by vitamin B12 or copper deficiency or infiltrating or compressive syndromes such as tumors or abscesses. Nitrous oxide anesthesia can precipitate an acute-­onset myelopathy in the case of borderline vitamin B12 deficiency. Rheumatologic disorders such as Sjögren’s disease, systemic lupus erythematosus, and Behçet’s disease can all cause TM. Paraneoplastic syndromes associated with anti-­CRMP-­5 and anti-­amphiphysin can cause a tract-­ specific myelopathy. The history and physical examination should be performed with these disorders in mind.

1100

SECTION XVI  Neurologic Disease

Treatment is determined by the most likely etiology. Idiopathic TM is treated much like TM in MS or NMO, with intravenous methylprednisolone at 500 mg to 1000 mg/day, usually followed by a short oral prednisone taper. When response to intravenous methylprednisolone is suboptimal, plasma exchange should be considered.

IDIOPATHIC ACUTE OPTIC NEURITIS Inflammatory demyelinating optic neuritis can occur as part of MS or NMO, or as an idiopathic entity. Classically, optic neuritis presents over hours with loss of vision together with pain exacerbated by eye movement. Vision loss may range from subclinical to frank blindness. Color vision and contrast sensitivity are disproportionately affected. On examination, a relative afferent pupillary defect is seen in unilateral optic neuritis. Acute demyelinating optic neuritis is often retrobulbar without papillitis. On MRI, the optic nerve can be swollen and enhance after gadolinium contrast. After recovery from the acute episode, the optic disk may appear pale, and the relative afferent pupillary defect may persist. Transient worsening of vision when the body temperature rises due to exercise or fever (Uhthoff phenomenon) may occur following recovery. The differential diagnosis includes other causes of acute monocular or binocular vision loss, such as Leber hereditary optic neuropathy, giant cell arteritis, and acute nonarteritic anterior ischemic optic neuropathy. The Optic Neuritis Treatment Trial studied patients with acute optic neuritis (either idiopathic or due to MS) who were randomized to one of three treatments, intravenous methylprednisolone versus oral prednisone taper versus oral placebo. Visual acuity initially recovered faster in the intravenous methylprednisolone group, but by 6 months later there was no difference among the three groups. Recovery of vision was good. Patients from this trial were examined 10 years later and acuity in the affected eyes was 20/20 or better in 74% and less than 20/200 in only 3%. However, recurrence of optic neuritis was common and had occurred in either eye in 35% of the patients. Recurrences were more frequent in those who had MS than in those with idiopathic optic neuritis (P < .001).

CHRONIC RELAPSING INFLAMMATORY OPTIC NEUROPATHY First described in 2003, chronic relapsing inflammatory optic neuropathy (CRION) is an inflammatory optic neuropathy characterized

by acute relapses, often with more severe visual loss than idiopathic optic neuritis or optic neuritis associated with MS. CRION can commence at any age and has been described worldwide. Prevalence rates and epidemiology are still unclear. As in other types of optic neuritis, eye pain at onset is frequent. Five diagnostic criteria for CRION have been suggested: (1) optic neuritis with at least one relapse, (2) visual loss, (3) AQP4-­IgG seronegativity, (4) contrast enhancement on MRI of acutely inflamed optic nerve, and (5) response to immunosuppressive treatment and relapse on withdrawal. Other diseases that might present similarly, such as sarcoidosis and giant cell arteritis, should be ruled out. Acute CRION is treated similarly to other causes of optic neuritis, with high-­dose methylprednisolone. Relapses are common upon corticosteroid discontinuation. Successful long-­term treatment with “steroid sparing” agents such as methotrexate, azathioprine, or mycophenolate mofetil has been reported. The underlying pathology is not yet known, but the disease appears inflammatory based on clinical presentation, imaging, and specific medication response. Eventual visual outcomes are often poor. One report indicated that visual acuity was less than 20/200 in one third of CRION patients.

SUGGESTED READINGS Correale J, Gaitán MI, Ysrraelit MC, Fiol MP: Progressive multiple sclerosis: from pathogenic mechanisms to treatment, Brain 140:527–546, 2017. Kim SH, Huh SY, Lee SJ: A 5-­year follow-­up of rituximab treatment in patients with neuromyelitis optica spectrum disorder, JAMA Neurol 70:1110–1117, 2013. Klaver R, De Vries HE, Schenk GJ, et al: Grey matter damage in multiple sclerosis: a pathology perspective, Prion 7:66–75, 2013. Langer-­Gould A, Brara SM, Beaber BE, et al: Incidence of multiple sclerosis in multiple racial and ethnic groups, Neurology 80:1734–1739, 2013. Lublin FD, Reingold SC, Cohen JA, et al: Defining the clinical course of multiple sclerosis: the 2013 revisions, Neurology 83:277–286, 2014. Petzold A, Plant GT: Chronic relapsing inflammatory optic neuropathy: a systematic review of 122 cases reported, J Neurol 261:17–26, 2014. Pittock SJ, Berthele A, Fujihara K, et al: Eculizumab in aquaporin-­4-­positive neuromyelitis optica spectrum disorder, N Engl J Med 381:614–625, 2019. Reindl M, Di Pauli F, Rostásy K, Berger T: The spectrum of MOG antibody-­ associated demyelinating disorders, Nat Rev Neurol 9:455–461, 2013. Thompson AJ, Banwell BL, Barkhof F, et al: Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria, Lancet Neurol 17:162–173, 2018. West TW, Hess C, Cree BA: Acute transverse myelitis: demyelinating, inflammatory, and infectious myelopathies, Semin Neurol 32:97–113, 2012.

123 Neuromuscular Diseases: Disorders of the Motor Neuron and Plexus and Peripheral Nerve Disease Carlayne E. Jackson, Ratna Bhavaraju-Sanka

INTRODUCTION Neuromuscular diseases are classified into four groups, according to which portion of the motor unit is involved (Table 123.1). Motor neuron and peripheral nerve diseases are considered in this chapter; myopathies are considered in Chapter 124, and neuromuscular junction diseases are considered in Chapter 125. The symptoms and signs of the neuromuscular diseases are at times indistinguishable. However, some useful general rules apply to assist with localization based on the distribution of weakness, presence or absence of sensory symptoms, reflex abnormalities, and specific associated clinical features (Table 123.2).

Electromyography and Nerve Conduction Studies Electromyography (EMG) and nerve conduction studies can also be useful diagnostic tools in localizing the lesion in a patient with a suspected neuromuscular disease. The measurement of electrical activity arising from muscle fibers is performed by inserting a needle electrode percutaneously into a muscle. Normal muscle is electrically silent at rest. Spontaneous activity during complete relaxation occurs in myotonic disorders, in inflammatory myopathies, and in denervated muscles. Spontaneous activity of a single muscle fiber is called a fibrillation, and such activity of part of or an entire motor unit is called a fasciculation. In myotonia, repeated muscle depolarization and contraction occur despite voluntary relaxation. Abnormalities in motor unit potentials occur during the course of denervation; with the development of reinnervation, the remaining motor units increase in amplitude and become longer in duration and polyphasic (E-Fig. 123.1). Conversely, in muscle diseases such as the muscular dystrophies and other diseases that destroy scattered fibers within a motor unit, the motor unit action potentials are of lower amplitude and shorter duration and are polyphasic. A reduced recruitment (interference) pattern from maximum voluntary effort occurs in denervation. Conversely, in patients with primary muscle disease, submaximal voluntary effort produces a full recruitment pattern despite marked weakness. Nerve conduction is studied by stimulating a peripheral nerve (e.g., the ulnar) with surface electrodes placed over the nerve or muscle. The resulting action potential is recorded by electrodes placed over the nerve more proximally in the case of large sensory nerve fibers and over the muscle distally in the case of motor nerve fibers in a mixed motor sensory nerve. For sensory nerves, the sensory nerve action potential (SNAP) is quantitated, and for motor nerves, the compound muscle action potential (CMAP) is quantitated. Abnormalities in sensory and motor nerve studies are suggestive of a peripheral neuropathy while abnormalities in motor nerve studies with normal sensory studies can indicate a myopathy, motor neuronopathy, pure motor neuropathy or radiculopathy.

DISEASES OF THE MOTOR NEURON (ANTERIOR HORN CELL) Amyotrophic Lateral Sclerosis Definition and Epidemiology The most common acquired motor neuron disease, amyotrophic lateral sclerosis (ALS), is a progressive, typically fatal disorder. The incidence is approximately 2 to 5 per 100,000 population, and there is a slight male predominance. The peak age of onset is in the sixth decade, although the disease can occur at any time throughout adulthood. The cumulative lifetime risk is about 1 in 400. Epidemiologic studies have incriminated risk factors for ALS including exposure to insecticides, smoking, participation in varsity athletics, and military service in the Gulf War. The cause of ALS is largely unknown, with 95% of cases considered “sporadic,” and 5% related to an autosomal dominant disease (familial ALS [FALS]). FALS is an adult-onset disease that is clinically and pathologically indistinguishable from sporadic ALS. FALS is caused by mutations in many genes, including the C9orf72, SOD1, TARDBP, FUS, ANG, ALS2, SETX, and VAPB genes. Mutations in the C9orf72 gene are responsible for 30% to 45% of FALS in the United States and Europe. Mutations in C9orf72 also cause sporadic ALS (E-Table 123.1).

Pathology ALS results from degeneration of the cortical motor neurons originating in layer five of the motor cortex and descending via the pyramidal tract (resulting in upper motor neuron signs and symptoms) and from degeneration of the anterior horn cells in the spinal cord and their brain stem homologues innervating bulbar muscles (resulting in lower motor neuron signs and symptoms) (Table 123.3).

Clinical Presentation Clinical symptoms relating to the upper motor neuron degeneration include loss of dexterity, slowed movements, muscle weakness, stiffness, and emotional lability. Signs on neurologic examination that confirm an upper motor neuron lesion include pseudobulbar affect, pathologic hyperreflexia, spasticity, and extensor plantar responses (Babinski sign). Lower motor neuron signs and symptoms caused by anterior horn cell degeneration include weakness, muscle atrophy, fasciculations, and cramps. Fasciculations in the absence of associated muscle atrophy or weakness are usually benign and may be aggravated by sleep deprivation, stress, and excessive caffeine ingestion. Muscle weakness in patients with ALS usually begins distally and asymmetrically and may manifest as a monoparesis, hemiparesis, paraparesis, or quadriparesis. It may also be limited initially to the bulbar region, resulting in difficulty with swallowing, speech, and movements of the

1101

1102

SECTION XVI  Neurologic Disease

face and tongue. For unclear reasons, ocular motility is spared until the very late stages of the illness. Bowel and bladder function and sensation remain spared throughout the course of the disease although patients may develop symptoms of bladder urgency. Up to 60% of patients with ALS may also have a component of frontotemporal dementia characterized by executive dysfunction, poor insight, personality changes (disinhibition, impulsivity, apathy), abnormal eating habits, poor hygiene, and language dysfunction.

Diagnosis/Differential The diagnosis of ALS remains one of “exclusion,” in which other potential causes must be ruled out through a variety of neuroimaging, laboratory, and electrodiagnostic investigations (E-Table 123.2). For example, compression of the cervical spinal cord or cervicomedullary junction from tumors or cervical spondylosis can produce weakness,

TABLE 123.1  Classification of

Neuromuscular Diseases Site of Involvement

Typical Examples

Anterior Horn Cell Without upper motor neuron involvement

Spinal muscular atrophy Progressive muscular atrophy Bulbospinal muscular atrophy Poliomyelitis West Nile virus Amyotrophic lateral sclerosis Primary lateral sclerosis

With upper motor neuron involvement Peripheral Nerve Mononeuropathy

atrophy, and fasciculations in the upper extremities and spasticity in the lower extremities, closely resembling ALS.

Treatment Specialized multidisciplinary clinic referral should be considered for patients with ALS to optimize health care delivery and prolong survival. The first US Food and Drug Administration (FDA)–approved therapy for ALS was riluzole 50 mg twice per day, which in clinical trials prolonged survival by 2 to 3 months. The mechanism of this effect is not known with certainty; however, riluzole may reduce excitotoxicity by diminishing presynaptic glutamate release. Edaravone was also recently FDA approved based on studies suggesting a slowing of the rate of functional decline by 33% (measured by the ALS Functional Rating Scale-Revised). Initiation of noninvasive ventilation (NIV) on a spontaneous timed mode has also been shown to prolong survival up to 20 months, to slow the rate of forced vital capacity (FVC) decline (level B) and to improve quality of life. NIV should be initiated when the FVC is less than 50%, the maximal inspiratory pressure is less than −60 cm, or when patients report symptoms that suggest nocturnal hypoventilation (daytime fatigue, frequent arousals, supine dyspnea, morning headaches). A cough-assist device can be used to assist with clearing upper airway secretions and has been shown to minimize the risk of pneumonia in clinical trials. A percutaneous gastrostomy (PEG) tube should be considered for prolonging survival and stabilizing body weight in patients with impaired oral food intake. Symptomatic therapy for spasticity, pseudobulbar affect, muscle cramping, and sialorrhea is also essential in maintaining patient dignity and quality of life (Table 123.4). Augmentative speech devices can assist patients with communication and computer access.

Carpal tunnel syndrome Ulnar palsy Meralgia paresthetica Mononeuritis multiplex (e.g., polyarteritis nodosa), leprosy, sarcoidosis, amyloidosis Diabetic neuropathy Charcot-Marie-Tooth disease Gullain-Barré syndrome

Multiple mononeuropathies

Polyneuropathies

Neuromuscular Junction Myasthenia gravis Lambert-Eaton syndrome Muscle Duchenne muscular dystrophy Dermatomyositis

TABLE 123.3  Symptoms and Signs

Associated With Amyotrophic Lateral Sclerosis Symptoms

Signs

Upper Motor Neuron Degeneration Loss of dexterity Pathologic hyperreflexia Slowed movements Babinski response Weakness Hoffman response Stiffness Jaw jerk Pseudobulbar affect Spasticity Lower Motor Neuron Degeneration Weakness Muscle atrophy Fasciculations Fibrillation potentials on electromyography Cramps Neurogenic atrophy on muscle biopsy

TABLE 123.2  Clinical Features of the Neuromuscular Diseases Clinical Feature

Anterior Horn Cell

Peripheral Nerve

Neuromuscular Junction

Muscle

Distribution of weakness Atrophy Sensory involvement

Asymmetrical limb or bulbar Marked and early None

Extraocular, bulbar, proximal limb None (or very late) None

Symmetrical, proximal limb Slight early; marked later None

Reflexes

Variable (depending on degree of upper motor neuron involvement) Fasciculations, cramps

Symmetrical, usually distal Mild, distal Dysesthesias, loss of sensation Decreased out of proportion to weakness

Normal in myasthenia gravis, depressed in Lambert-Eaton syndrome Fatigability

Decreased in proportion to weakness

Characteristic features

Combined sensory and motor abnormalities

Usually painless

CHAPTER 123  Neuromuscular Diseases

1102.e1

E-TABLE 123.1  Hereditary Motor Neuron Normal

Diseases

Locus Autosomal Dominant ALS 1 21q ALS 4 9q34 ALS 6 16p11 ALS 8 20q

A Myopathic

B

Reinnervated

C E-Fig. 123.1  Motor unit potentials. The shaded muscle fibers are functional members of the motor unit; the axon, which enters from the upper left, branches terminally to innervate the appropriate muscle fibers. The motor unit action potential produced by each motor unit is seen at the upper right; its duration is measured between the two small vertical lines. The normal-appearing but unshaded fibers belong to other motor units. (A) The normal situation, with five muscle fibers in the active unit. (B) In this myopathic unit, only two fibers remain active; the other three (shrunken and unshaded) have been destroyed by a muscle disease. (C) Four fibers that belonged to other motor units and had been denervated have now been reinnervated by terminal axon sprouting from the healthy motor unit. Both the motor unit and its action potential are now larger than normal. Note that only under these abnormal circumstances do fibers in the same unit lie next to one another. (From Griggs RC, Bradley WG: Approach to the patient with neuromuscular disease. In Isselbacher KJ, Braunwald E, Wilson JD, et al, editors: Harrison’s textbook of internal medicine, ed 13, New York, 1994, McGraw-Hill, p 2364.)

Gene

14q11 1p36 6q21 10p15 12q24 9p13 17p13 9p21

Superoxide dismutase Senataxin FUS Vesicle-associated protein B Angiogenin TDP-43 FIG4 OPTN Ataxin-2 VCP PFN1 C9orf72

Autosomal Recessive ALS 2 2q33 ALS 5 15q21 ALS 6 16p11 ALS 12 10p15 ALS 16 9p13 Spinal muscular 5q atrophy

Alsin Spatacsin FUS OPTN SIGMAR1 Survival motor neuron protein

ALS 9 ALS 10 ALS 11 ALS 12 ALS 13 ALS 14 ALS 18 ALS-FTD

X-Linked Spinobulbar muscular atrophy ALS 15

Xq 11-12

Androgen receptor

Xp11

UBQLN2

1102.e2

SECTION XVI  Neurologic Disease

E-TABLE 123.2  Differential Diagnosis

and Diagnostic Evaluation for Patients With Suspected Motor Neuron Disease Differential Diagnosis

Diagnostic Evaluation

Toxins—Lead, Mercury Metabolic Disorders Hypoglycemia Hyperparathyroidism Hyperthyroidism Paraneoplastic Disorder Immunologic Mechanism

24-hr urine collection for heavy metals

Vitamin/Mineral ­Deficiencies Bacterial/Viral Infection Structural Lesion Cervical spondylosis Chiari malformation or syrinx Spinal cord arteriovenous malformation Parasagittal or foramen magnum tumor

Serum chemistry Parathyroid hormone level, calcium Thyroid function studies MRI scan, anti-Hu antibody Complete blood count, sedimentation rate, anti-nuclear antibody, rheumatoid factor, serum protein electropheresis, anti-GM1 antibodies Copper, vitamin B12, folate levels HIV, HTLV-1, Lyme titers, CSF exam/ culture MRI of brain and cervical spine

CHAPTER 123  Neuromuscular Diseases

1103

TABLE 123.4  Symptom Management for

TABLE 123.5  Clinical Spectrum of Motor

Respiratory Insufficiency Noninvasive ventilation Cough-assist devices Dysarthria Augmentative speech device Dysphagia Percutaneous endoscopic gastrostomy (PEG) placement Suction machine Sialorrhea Amitriptyline 25-75 mg qhs Glycopyrrolate 1-2 mg q8h Botulinum toxin Spasticity Baclofen 10-20 mg QID Dantrium 25-100 mg QID Pseudobulbar Affect Serotonin reuptake inhibitors Amitriptyline 25-75 mg QHS Dextromethorphan/quinidine 20/10 mg BID Weakness Ankle-foot orthosis Wheelchair Elevated toilet seat

Upper and Lower Motor Neuron Involvement Sporadic amyotrophic lateral sclerosis Familial amyotrophic lateral sclerosis Upper Motor Neuron Involvement Primary lateral sclerosis Hereditary spastic paraparesis Lower Motor Neuron Involvement Motor neuronopathy related to malignancy or paraproteinemia Poliomyelitis West Nile virus Postpolio syndrome Hexosaminidase deficiency Progressive muscular atrophy Spinal muscular atrophy Type I: Infantile onset (Werdnig-Hoffmann disease) Type II: Late infantile onset Type III: Juvenile onset (Kugelberg-Welander disease)

Motor Neuron Diseases

Prognosis Mean survival from onset of symptoms is 2 to 5 years, with 10% of patients surviving beyond 10 years. The majority of deaths are related to respiratory muscle failure and aspiration pneumonia.

Other Acquired Motor Neuron Diseases Other motor neuron diseases involve only particular subsets of motor neurons (Table 123.5). Progressive muscular atrophy (PMA) is a pure lower motor neuron disease that accounts for 8% to 10% of patients with motor neuron disease. Weakness is typically distal and asymmetrical, and bulbar involvement is rare. Patients with PMA generally have a better prognosis than those with ALS, with a survival of 3 to 14 years. Primary lateral sclerosis (PLS) is a pure upper motor neuron syndrome in which patients demonstrate either a slowly progressive spastic paralysis or dysarthria. This is a rare disorder, accounting for 2% of all motor neuron cases. Survival is generally years to decades.

Spinal Muscular Atrophy Spinal muscular atrophy (SMA) is a hereditary form of motor neuron disease in which only the lower motor neuron is affected. It is an autosomal recessive disorder that may begin in utero, in infancy, in childhood, or in adult life and represents the first class of neurologic disorders in which a developmental defect in neuronal apoptosis most likely produces the disease. The most common forms of SMA are due to a defect in the survival motor neuron 1 (SMN1) gene localized to 5q11.2-q13.3. All affected individuals with SMA have mutations in both copies of the SMN1 gene causing little or no SMN (survival motor neuron) protein production from this gene. The SMN2 gene can help replace some of the missing SMN protein. Patients who have multiple copies of the SMN2 gene are usually associated with later onset and less severe disease. Nusinersen was recently approved for intrathecal use and has been shown to significantly slow functional decline and increase life expectancy. It is an antisense oligonucleotide targeted to increase the proportion of SMN2 mRNA transcripts, leading to

Neuron Diseasesa

aItalicized

disorders are hereditary.

translation of more full-length SMN protein. In May of 2019 the FDA also approved onasemnogene abeparvovec-xioi (Zolgensma), the first gene therapy to treat children less than 2 years of age with SMA. Bulbospinal muscular atrophy (BSMA) or Kennedy disease is an X-linked recessive disorder in which the mean age at onset is 30 years; the range is from 15 to 60 years. BSMA is a trinucleotide repeat disorder with a CAG expansion encoding for a polyglutamine tract in the first exon of the androgen receptor gene, on chromosome Xq11-12. The mechanism by which disruption of the androgen receptor gene alters the function of bulbar and spinal motor neurons is not known. An inverse correlation exists between the number of CAG repeats and the age of onset of the disease. Affected individuals exhibit chin fasciculations, midline furrowing and atrophy of the tongue, and proximal weakness. Dysphagia and dysarthria are common, and up to 90% of patients demonstrate gynecomastia and infertility. Two findings distinguishing this disorder from ALS are the absence of upper motor neuron signs and in some patients the presence of a subtle sensory neuropathy.

DISORDERS OF THE BRACHIAL AND LUMBOSACRAL PLEXUS The roots within the cervical, lumbar, and sacral regions organize into the cervical, lumbar, and sacral plexuses before giving rise to individual peripheral nerves. Diseases of these plexuses (plexopathies) tend to be focal in symptoms and signs, whereas many diseases of the peripheral nerves and muscles are generalized.

Brachial Plexopathy The brachial plexus is constituted by mixed nerve roots from C5 to T1 that fuse into upper, middle, and lower trunks above the level of the clavicle and redistribute into lateral, posterior, and medial cords below that landmark (E-Fig. 123.2). Symptoms include weakness, pain, and sensory loss in the shoulders or arms. Upper trunk lesions may be due to birth injury, trauma, and idiopathic brachial plexitis (see later). Lower trunk lesions may result from birth injury, malignant tumor invasion, thoracic outlet syndrome, or as a complication of sternotomy. If the entire plexus is involved, radiation injury, trauma, and late metastatic disease are the most common causes.

CHAPTER 123  Neuromuscular Diseases

C5 Middle scalene muscle

C6

Dorsal scapular artery and nerve Suprascapular nerve

Clavicle

Trunks: Superior Middle Inferior

C7 C8 T1

Axillary artery and vein Anterior scalene muscle (cut)

Manubrium

E-Fig. 123.2 The brachial plexus is comprised of mixed nerve roots from C5 to T1 that fuse into upper, middle, and lower trunks above the level of the clavicle and redistribute into lateral, posterior, and medial cords. (From Morton D, Peterson KD, Albertine KH: Gray’s dissection guide for human anatomy, ed 2, Philadelphia, 2006, Churchill Livingstone.)

1103.e1

1104

SECTION XVI  Neurologic Disease

Acute Autoimmune Brachial Neuritis Acute autoimmune brachial neuritis (or neuralgic amyotrophy or Parsonage-Turner syndrome) is characterized by the abrupt onset of severe pain, usually over the lateral shoulder, but at times extending into the neck or entire arm. The acute pain generally subsides after a few days to a week; by this time, weakness of the proximal arm becomes apparent. The serratus anterior, deltoid, and supraspinatus are the most commonly affected muscles, but other muscles of the shoulder girdle may also be affected. In rare cases, most of the patient’s arm and even the ipsilateral diaphragm are involved. Sensory loss is usually slight and generally involves the axillary nerve distribution. Weakness lasts weeks to months and will be accompanied by severe atrophy of the shoulder girdle. No therapy has been shown to alter or shorten the clinical course, although steroids and analgesics may reduce pain. Most patients recover within several months to 3 years. The disorder frequently follows an upper respiratory infection or an immunization, but in many instances no antecedent illness occurs. It is bilateral in one third of cases but is always asymmetrical; it may recur in 5% of patients. Recurrent brachial plexopathies that are painless may be related to an autosomal dominant disorder with mutation in the SEPTIN9 gene on chromosome 17q25 or hereditary neuropathy with liability to pressure palsies (HNPP), caused by a deletion or point mutation of PMP-22 protein (chromosome 17p).

Lumbosacral Plexopathy The lumbosacral plexus is formed from the ventral rami of spinal nerves T12 to S4. These divide within the plexus into ventral and dorsal branches that form the femoral, sciatic, and obturator nerves. The plexus is located within the substance of the psoas major muscle. Clinical features include proximal pain and weakness in anterior thigh muscles (femoral) or posterior thigh muscles and the buttocks. Bowel and bladder dysfunction may also occur. Diabetes, malignant invasion, radiation therapy, infection (herpes zoster), psoas abscess, trauma, and retroperitoneal hemorrhage are common causes. An autoimmune form is much less frequent than brachial neuritis.

DISORDERS OF THE PERIPHERAL NERVES Definition and Epidemiology Peripheral neuropathy refers to a large group of disorders that can produce focal (mononeuropathy or multiple mononeuropathies) or generalized nerve dysfunction (polyneuropathies) (Table 123.6). Peripheral neuropathies are prevalent neurologic conditions, affecting 2% to 8% of adults, with the incidence increasing with age. They range in severity from mild sensory abnormalities, found in up to 70% of patients with long-standing diabetes, to fulminant, life-threatening paralytic disorders such as Guillain-Barré syndrome (GBS) or acute inflammatory demyelinating polyradiculoneuropathy (AIDP). Mononeuropathies are disorders in which only a single peripheral nerve is affected. The most common cause is nerve entrapment such as median nerve compression resulting in carpal tunnel syndrome or peroneal nerve injury causing foot drop (Table 123.7). When more than one peripheral nerve is involved, the term mononeuropathy multiplex or multiple mononeuropathies is often used. Multiple mononeuropathies are most commonly seen in diabetes mellitus and vasculitis but also occur in leprosy, vasculitis, sarcoidosis, hereditary neuropathy with predisposition to pressure palsies, and amyloidosis. Polyneuropathies are a group of disorders affecting the motor, sensory, and autonomic nerves. These disorders may predominantly affect the nerve axon (axonal neuropathies), myelin sheath (demyelinating neuropathies), or the small- to medium-sized blood vessels supplying

TABLE 123.6  Classification and Causes of

Peripheral Neuropathy Type of Neuropathy Mononeuropathies Compressive Hereditary Inflammatory Multiple mononeuropathies Polyneuropathies Hereditary Endocrine Metabolic Infections Immune mediated Toxic Paraneoplastic

Examples Carpal tunnel syndrome, ulnar palsy Hereditary neuropathy with predisposition to pressure palsies Bell’s palsy Vasculitis (mononeuritis multiplex), diabetes, leprosy, sarcoidosis, amyloidosis Charcot-Marie-Tooth disease, familial amyloid polyneuropathy Diabetes, hypothyroidism Uremia, liver failure Leprosy, diphtheria, human immunodeficiency virus, Lyme disease Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy Lead-, arsenic-, alcohol-, drug-induced Lung cancer

the nerves (vasculitic neuropathies). The clinical features of the polyneuropathies reflect the pathology of the underlying process.

Pathology In the symmetrical axonal polyneuropathies, the underlying pathology is usually a slowly evolving type of axonal degeneration that involves the ends of long nerve fibers first and preferentially. With time, the degenerative process involves more proximal regions of long fibers, and shorter fibers are affected. This pattern of distal axonal degeneration or dying back of nerve fibers results from a wide variety of metabolic, toxic, and endocrinologic causes. In the demyelinating polyneuropathies, the underlying pathology involves the myelin sheath. Demyelination of a peripheral nerve at even a single site can block conduction, resulting in a functional deficit identical to that seen after axonal degeneration. In contrast to repair by regeneration, however, repair by remyelination can be rapid. Autoimmune attack on the myelin sheath occurs in the inflammatory demyelinating neuropathies (GBS/AIDP and chronic inflammatory demyelinating polyneuropathy [CIDP]) and some neuropathies associated with paraproteinemias (see later). Inherited disorders of myelin such as Charcot-Marie-Tooth (CMT) disease comprise the other major category of demyelinating neuropathies. Other causes include toxic, mechanical, and physical injuries to nerves. Although these examples have nearly pure demyelination, many neuropathies have both axonal degeneration and demyelination. This mixed pathologic abnormality reflects the mutual interdependency of the axons and the myelin-forming Schwann cells. Vasculitic neuropathies occur as a result of disease of the small or medium-sized blood vessels that leads to ischemia and infarction of isolated peripheral nerves. The term mononeuritis multiplex is also used to describe this clinical situation, in which there is multifocal involvement of individual nerves.

Clinical Presentation The clinical picture of an axonal polyneuropathy includes early loss of muscle stretch reflexes at the ankle and weakness that initially involves the intrinsic muscles of the feet, the extensors of the toes, and the dorsiflexors at the ankle. The motor signs are usually mild in

CHAPTER 123  Neuromuscular Diseases

1105

TABLE 123.7  Common Mononeuropathies Precipitating Factors Median Nerve Entrapment at the wrist (carpal tunnel syndrome)

Ulnar Nerve Entrapment at the elbow

Radial Nerve Entrapment at the spiral groove

Motor Signs and Symptoms

Sensory Signs and Symptoms

Treatment

Repetitive wrist flexion or sleep Weakness in thenar muscle

Numbness, tingling, and/or pain in thumb, index finger, middle finger, and medial half of ring finger. Tinel and Phalen signs

Neutral wrist splint, carpal tunnel injections or surgery

External compression in condylar groove, fracture of humerus

Sensory loss in the little finger and contiguous half of the ring finger

Elbow pads; ulnar nerve transposition or decompression of cubital tunnel

Weakness or atrophy of the interossei and thumb adductor

Prolonged sleeping on arm after Wrist drop with sparing of Sensory loss on dorsum of hand Spontaneous recovery; wrist drinking excessive amounts elbow extension; weakness splint of alcohol: “Saturday night of finger and thumb extensors palsy”

Femoral Nerve Abdominal hysterectomy, hematoma, prolonged lithotomy position, diabetes Lateral Femoral Cutaneous Nerve Meralgia paresthetica Obesity, pregnancy, diabetes, constrictive belts Peroneal Nerve Entrapment at the fibular head

Weakness and atrophy of quadriceps

Sensory loss in anterior thigh and medial calf

Physical therapy

None

Sensory loss, pain, or tingling over anterolateral thigh

Weight loss; spontaneous recovery

Habitual leg crossing, knee casts, prolonged squatting, profound weight loss

Weakness of ankle dorsiflexors Sensory loss in anterolateral or evertors and toe extensors leg and dorsum of foot

Ankle-foot orthosis; remove source of compression

Injection injury, fracture or dislocation of hip

Weakness of hamstrings, ankle Sensory loss in buttock, lateral plantar flexors or dorsiflexors calf, and foot

Ankle-foot orthosis; physical therapy

Sciatic Nerve

Tibial Nerve Entrapment in tarsal tunnel

External compression from tight None shoes, trauma, tenosynovitis

contrast to the sensory abnormalities, which may include numbness, tingling, and burning sensations (dysesthesias). The sensory symptoms usually begin symmetrically in the toes and feet and then ascend proximally to the legs in a “stocking” distribution. When the sensory abnormalities reach the level of the knees, the symptoms begin in the hands, in a “glove” distribution. Truncal and abdominal dysesthesias may develop once the sensory abnormalities ascend to the level of the elbows. The prominent clinical feature of an acquired demyelinating polyneuropathy is weakness that affects not only the distal muscles but also the proximal and facial muscles. Unlike in an axonal neuropathy, sensory loss is rarely the presenting symptom. Patients generally have diffuse hyporeflexia or areflexia. Vasculitic neuropathies typically present with acute or subacute asymmetrical, predominantly distal weakness and sensory loss associated with severe pain.

Sensory loss and tingling in sole of foot

Tarsal tunnel injection, eliminate source of compression, medial arch support

Diagnosis/Differential Neuropathic disorders can be broadly divided into those that are acquired and those that are hereditary (Table 123.8). Acquired disorders are the more common and have many causes: metabolic or endocrine disorders (diabetes mellitus, renal failure, porphyria); immune-mediated disorders (GBS, CIDP, multifocal motor neuropathy, anti-myelin-associated glycoprotein neuropathy); infectious causes (human immunodeficiency virus [HIV], Lyme disease, cytomegalovirus [CMV], syphilis, leprosy, diphtheria); medications (HIV drugs, chemotherapies); environmental toxins (heavy metals); or paraneoplastic processes. Diabetes mellitus and alcoholism are the most common causes of polyneuropathy in developed countries. As many as one third of acquired neuropathies are cryptogenic in which the etiology can never be identified. Causes of mononeuritis multiplex include systemic vasculitis (rheumatoid arthritis, systemic lupus erythematosus, Wegener granulomatosis, Churg-Strauss syndrome, polyarteritis nodosa) and primary peripheral system vasculitis (25% of cases).

1106

SECTION XVI  Neurologic Disease

TABLE 123.8  Hereditary Neuropathic Disorders Inheritance Pattern

Genetic Defect

Clinical Features

Hereditary sensorimotor neuropathies Familial amyloid polyneuropathy

AR, AD, or X-linked AD

Pes cavus, distal atrophy and weakness, hammer toes Pain, autonomic dysfunction, carpal tunnel syndrome, heart failure.

Fabry disease

X-linked

See E-Table 123.4 Transthyretin Gelsolin Apolipoprotein Al α-Galactosidase

Tangier disease Refsum disease

AR AR

Apolipoprotein A Phytanic acid oxidase

Cardiac ischemia, renal disease, stroke, cutaneous angiokeratomas, cornea verticillata Low HDL levels, orange tonsils Retinitis pigmentosa, cardiomyopathy, deafness, ichthyosis

AD, Autosomal dominant; AR, autosomal recessive; HDL, high-density lipoprotein.

TABLE 123.9  Differential Diagnosis of Neuropathic Disorders Based on Symptoms Motor Symptoms Only

Sensory Symptoms Only

Autonomic Symptoms

Porphyria Charcot-Marie-Tooth Chronic inflammatory demyelinating polyneuropathy Guillain-Barré syndrome Lead neuropathy Motor neuron disease

Cryptogenic sensory polyneuropathy Metabolic, drug-related, or toxic neuropathy Paraneoplastic sensory neuropathy

Amyloid neuropathy Diabetic neuropathy Fabry disease Guillain-Barré syndrome Hereditary sensory or autonomic neuropathy Porphyria

Because of the many causes, it is important to approach the patient with neuropathy systematically, beginning with the patient’s history and physical examination. It is essential to determine which nerves are involved (motor, sensory, or autonomic) and in what specific combination (Table 123.9). Small-fiber neuropathies often manifest with unpleasant or abnormal sensations such as a burning pain, electric shock–like sensations, cramping, tingling, pins and needles, or prickly feelings such as the limb “feeling asleep.” Large-fiber neuropathies can manifest as numbness, tingling, or as gait ataxia. Symptoms suggesting motor nerve involvement include muscle weakness that typically involves the distal foot muscles. Autonomic nerve involvement is suggested by symptoms of orthostatic hypotension, impotence, cardiac arrhythmia, or bladder dysfunction. The distribution of muscle weakness is important. In axonal neuropathies, the weakness predominantly involves the distal lower extremity muscles, and in demyelinating neuropathies the weakness can involve both proximal and distal muscles as well as facial muscles. Most neuropathies result in symmetrical weakness. If asymmetry is present, motor neuron disease, radiculopathy, plexopathy, compressive mononeuropathies, or mononeuritis multiplex should be considered. The intensity and distribution of painful dysesthesias can also be informative. Although many axonal neuropathies are associated with a burning sensation in the feet, pain as the chief complaint suggests specific causes of neuropathy (Table 123.10). A neuropathy that manifests with acute, asymmetrical weakness and severe pain suggests vasculitis. In patients with severe, asymmetrical proprioceptive deficits, with sparing of motor function, the site of the lesion is usually the sensory neuron/dorsal root ganglion. This specific syndrome has a relatively limited differential diagnosis, including paraneoplastic process with anti-Hu antibodies, Sjögren’s syndrome, cisplatinum toxicity, vitamin B6 toxicity, and HIV infection. Most neuropathies are relatively insidious in onset, particularly those associated with metabolic or endocrine disorders. Acute neuropathies may be caused by a vasculitic process, toxin exposure, porphyria, or GBS. GBS

TABLE 123.10  Neuropathies Associated

With Pain

Alcoholic neuropathy Amyloidosis Cryptogenic sensorimotor neuropathy Diabetic neuropathy Fabry disease Guillain-Barré syndrome Heavy metal toxicity (arsenic, thallium) Hereditary sensory or autonomic neuropathy HIV sensorimotor neuropathy Radiculopathy or plexopathy Vasculitis HIV, Human immunodeficiency virus.

is commonly preceded by a viral illness, immunization, or a surgical procedure. The neurologic history must thoroughly explore potential toxic exposures such as prior medications and alcohol use (E-Table 123.3). Because many neuropathies are hereditary, it is essential to obtain a detailed family history, specifically inquiring about a history of gait instability, use of adaptive equipment, or skeletal deformities of the feet. Hereditary neuropathies may be autosomal recessive, autosomal dominant, or X-linked. In some situations, it may be helpful to actually examine family members because the severity of disease may vary considerably from one generation to the next. The most common hereditary neuropathy is Charcot-Marie-Tooth disease (see later). A complete neurologic examination should always be performed in a patient complaining of numbness. If the patient shows evidence of upper motor neuron involvement in addition to the sensory loss, vitamin B12 or copper deficiency should be considered, even in the absence of apparent anemia. An elevated methylmalonic acid or homocystine level can also help confirm the diagnosis of B12 deficiency in patients

CHAPTER 123  Neuromuscular Diseases

1106.e1

E-TABLE 123.3  Etiology of Neuropathic Disorders: Toxic Agents AXONAL

DEMYELINATING

Sensory

Sensory & Motor

Motor

 

Chloramphenicol Doxorubicin Ethambutol Ethionamide Etoposide (VP-16) Flecainide Gemcitabine Glutethimide Hydralazine Interferon-α Isoniazid Lead Leflunomide Metronidazole Misonidazole Nitrous oxide Nucleosides ddC; ddI; d4T; 3TC Phenytoin Platinum analogs Pyridoxine Statins Thalidomide

Acrylamide Alcohol (Ethanol) Allyl chloride Arsenic Carbon disulfide Chlorophenoxy Ciguatoxin Cobalt Colchicine Cyanide Dapsone Dichloroacetate Dinitrophenol Disulfiram Ethylene oxide Heroin Lithium Methyl bromide Nitrofurantoin Organophosphates Taxol Tetrodotoxin Thallium Trichloroethylene Vacor (PNU) Vinca alkaloids

β-bungarotoxin Botulism Gangliosides Latrotoxin Black widow Lead Mercury Misoprostol Tetanus Tick paralysis

Buckthorn Chloroquine Diphtheria FK506 (Tacrolimus) Hexachlorophene Procainamide TNF-α antagonists

MIXED

Amiodarone Diethylene glycol Ethylene glycol I,I′-Ethylidinebis (tryptophan) Gold Hexacarbons n-Hexane Na+ Cyanate Suramin

CHAPTER 123  Neuromuscular Diseases

TABLE 123.11  Peripheral Neuropathy

Laboratory Studies Standard Tests B12 Complete blood count (CBC) Glucose tolerance test RPR Chem 20 Serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE) Thyroid function tests Nerve conduction studies or electromyogram (EMG)

Tests Indicated in Selected Cases Anti-Hu antibody ESR, ANA, RF, SS-A, SS-B Genetic studies for Charcot-Marie-Tooth Human immunodeficiency virus (HIV) Lyme antibody Phytanic acid Copper level 24-hr urine for heavy metals Quantitative sensory testing Lumbar puncture Nerve biopsy Skin biopsy Tilt table testing

with borderline levels. The presence of weakness and upper motor neuron signs without associated sensory loss suggests ALS. If the neuropathy is associated with mental status abnormalities, then pyridoxine intoxication or deficiencies of thiamine, niacin (“dementia, diarrhea, dermatitis”), and vitamin B12 should be considered in the differential diagnosis. Lyme disease (see Chapter 90) may result in both peripheral nervous system symptoms (facial nerve palsies, paresthesias, weakness) and central nervous system symptoms (dementia, headache). Acquired immunodeficiency syndrome (AIDS) can also affect both the central and the peripheral nervous systems. GBS and CIDP usually occur at the time of HIV seroconversion, whereas sensory neuropathy, mononeuritis multiplex, and CMV polyradiculopathy generally occur in the context of low CD4 counts in the later stages of the disease. Older antiretroviral drugs (e.g., stavudine) were associated with a significant rate of neuropathy. Once a preliminary differential diagnosis is developed based on the history and neurologic examination findings, laboratory studies can confirm the diagnosis. Laboratory tests to identify potentially treatable causes of neuropathy are included in Table 123.11. Additional studies can be ordered based on the suspected diagnosis. An impaired glucose tolerance test is found in more than half of patients with cryptogenic sensory peripheral neuropathy and is more sensitive than tests of fasting glucose or hemoglobin A1c (HbA1c). In a patient with acute, asymmetrical weakness and sensory loss, screening for an inflammatory process (ESR, ANA, RA, SS-A, SS-B) is appropriate. In addition, genetic testing is now available for most patients with CMT disease. If a monoclonal protein is identified on serum protein electrophoresis, a skeletal survey, urine immunofixation electrophoresis, and bone marrow biopsy should be ordered to rule out an underlying lymphoproliferative disorder. If the patient has a monoclonal protein associated with autonomic dysfunction, congestive heart failure, or renal insufficiency, a biopsy (rectal, abdominal fat, or sural nerve) should be considered for diagnosis of amyloidosis. Amyloidosis can be acquired or familial with mutations in the transthyretin (TTR) gene. CIDP can be associated with a monoclonal gammopathy, and in this situation patients should be treated with immunosuppressive therapy. Monoclonal gammopathies observed in patients with an axonal peripheral neuropathy are frequently benign (monoclonal gammopathy of unknown significance) and do not necessarily warrant therapy. A lumbar puncture is indicated only if an acquired demyelinating neuropathy such as GBS or CIDP is being considered. In these cases,

1107

one expects to find an “albuminocytologic dissociation” with an elevation in cerebrospinal fluid (CSF) protein and a relatively normal white blood cell (WBC) count. If the CSF WBC count is greater than 50, Lyme disease, HIV-associated disease, or a paraneoplastic process must be considered. Electrodiagnostic studies consisting of nerve conduction testing and EMG can be a helpful extension of the physical examination. These studies are useful in defining whether the neuropathic process is caused by a primarily axonal or demyelinating process. In general, axonal degeneration decreases the amplitude of the compound muscle action potential out of proportion to the degree of reduction in peripheral nerve conduction velocity, whereas demyelination produces prominent reduction in conduction velocities. Nerve conduction testing can help determine, in the case of a demyelinating neuropathy, whether the process has an acquired or hereditary cause. A uniform slowing of nerve conduction usually suggests a hereditary cause while focal demyelination causing conduction block suggests an acquired demyelinating neuropathy. Electrodiagnostic studies can identify subclinical neuropathy (in patients receiving potentially neurotoxic medications) and can quantitate the extent of axon loss. Finally, these studies can localize the lesion in the case of radiculopathies, dorsal root ganglionopathies, plexopathies, and multiple mononeuropathies. Sensory nerve biopsies should be obtained for diagnosis of a vasculitic neuropathy because treatment involves potentially toxic medications. Performing a muscle biopsy in addition to the nerve biopsy may improve the diagnostic yield and should be considered because the inflammation is random and focal and easily missed. Nerve biopsies are not indicated in “cryptogenic” neuropathies, diabetic neuropathy, or motor neuron disease. If nerve conduction studies are normal, skin biopsies allow quantification of the number of intraepidermal nerve fibers. A length-dependent decrease in the number of these fibers can help confirm a small-fiber neuropathy.

Treatment Despite a very thorough history, examination, and laboratory studies, the cause of as many as one third of neuropathies remains unknown. In this situation, the focus of management is pain control. Patients with neuropathy frequently report a burning, searing, and aching sensation in their feet and hands that interferes with sleep. Neuropathic pain is difficult to treat but may respond to various medications having different mechanisms of action (Table 123.12). It is important to “start low and taper slow” and to treat for a minimum of 4 weeks before concluding that an agent is ineffective. In patients with a vasculitic neuropathy, therapy with corticosteroids in addition to a cytotoxic agent can stabilize and, in some cases, improve the neuropathy.

Prognosis Peripheral neuropathies caused by axonal degeneration are generally progressive unless the underlying cause can be identified and treated. Recovery from axonal degeneration requires nerve regeneration, a process that often requires 2 to 3 years. Prognosis of demyelinating and vasculitic neuropathies is extremely variable, depending on the cause.

COMMON MONONEUROPATHIES Common mononeuropathies are explored in Table 123.7.

Carpal Tunnel Syndrome Carpal tunnel syndrome results from compression of the median nerve at the wrist as it passes beneath the flexor retinaculum. Precipitating factors include activities that require repetitive wrist movements:

1108

SECTION XVI  Neurologic Disease

TABLE 123.12  Symptomatic Treatment for

Neuropathic Pain

Tricyclic Antidepressants Amitriptyline 10-150 mg qhs Nortriptyline 10-150 mg qhs Imipramine 10-150 mg qhs Desipramine 10-150 mg qhs Venlafaxine 75-225 mg qd Anticonvulsants Gabapentin 300-1200 mg tid Carbamazepine 100-200 mg tid Topiramate 150-200 mg bid Duloxetine 60-120 mg qd Pregabalin 150-600 mg qd Sodium valproate 250-500 mg bid Alternative Treatments Tramadol 50-100 mg qid Lidoderm patches Capsaicin cream Transcutaneous nerve stimulation Acupuncture

mechanical work, gardening, house painting, and typing. Predisposing causes include pregnancy, diabetes, acromegaly, rheumatoid arthritis, chronic renal failure, thyroid disorders, and primary amyloidosis. Symptoms usually begin in the dominant hand but commonly involve both hands over time. Patients typically report numbness, tingling, and burning sensations in the palm and in the fingers supplied by the median nerve: the thumb, index finger, middle finger, and medial one half of the ring finger. Some patients report that all fingers become numb. Pain and paresthesias are most prominent at night and often interrupt sleep. The pain is prominent at the wrist but may radiate to the forearm and occasionally to the shoulder. Shaking the hand relieves both pain and paresthesias. Percussion of the median nerve at the wrist provokes paresthesias in a median nerve distribution in 60% of patients (Tinel sign), and flexion of the wrist for 30 to 60 seconds provokes pain or paresthesias in 75% of cases (Phalen sign). The diagnosis is based on clinical symptoms and signs. Electrodiagnostic studies may demonstrate prolongation of the sensory or motor latencies across the wrist in up to 85% of patients. In more severe cases, EMG may demonstrate evidence of denervation in the abductor pollicis brevis. Treatment initially includes avoidance of repetitive wrist activities and the use of a neutral wrist splint. If these conservative measures fail, injections of lidocaine and methylprednisolone can be given into the carpal tunnel or surgical treatment by section of the transverse carpal ligament can effectively decompress the nerve. Indicators that have been shown to predict failure with conservative management include age older than 50, disease duration longer than 10 months, constant paresthesias, and a positive Phalen sign in less than 10 seconds.

Ulnar Palsy The ulnar nerve may become entrapped at the elbow because of external compression in the condylar groove. Injury may also occur years after a malunited supracondylar fracture of the humerus with bony overgrowth. Contrary to the findings in carpal tunnel syndrome, muscle weakness and atrophy characteristically predominate over sensory symptoms and signs. Patients notice atrophy of the first dorsal

interosseous muscle and difficulty performing fine manipulations of the fingers. Numbness of the little finger, the contiguous one half of the ring finger, and the ulnar border of the hand may be present. Ulnar nerve compression can be confirmed with electrodiagnostic studies demonstrating slowed motor conduction velocity across the elbow. Treatment includes the use of elbow pads to avoid compression or surgical procedures including transposition of the ulnar nerve or decompression of the cubital tunnel.

Peroneal Neuropathy The peroneal nerve can become compressed as it wraps around the fibular head and passes into the fibular tunnel between the peroneus longus muscle and the fibula. Compression may occur as a result of habitual leg crossing, prolonged bed rest, knee casts, prolonged squatting, anesthesia, or profound weight loss. The nerve can also be compressed as a result of Baker cysts, fibular fractures, blunt trauma, tumors, or hematomas at the knee. Symptoms include “foot drop” with selective weakness of the ankle dorsiflexors and evertors as well as the toe extensors. Reflexes remain normal, and sensory loss generally involves the anterolateral leg and dorsum of the foot. Electrodiagnostic studies demonstrate slowing of the peroneal conduction velocity across the fibular head and may demonstrate denervation if axonal injury is present. Compressive injuries usually resolve spontaneously within weeks to months. Magnetic resonance imaging (MRI) and surgical exploration should be considered if symptoms are progressive.

SPECIFIC ACQUIRED POLYNEUROPATHIES Guillain-Barré Syndrome: Acute Inflammatory Demyelinating Polyneuropathy Since the advent of polio vaccination, GBS has become the most frequent cause of acute flaccid paralysis throughout the world. GBS is an immune-mediated disorder that follows an identifiable infectious disorder in approximately 60% of patients. The best-documented antecedents include infection with Campylobacter jejuni, infectious mononucleosis, CMV, herpesvirus, and mycoplasma. C. jejuni is often associated with more severe axonal cases. The initial symptoms of GBS often consist of tingling and pinsand-needles sensations in the feet and may be associated with dull low-back pain. By the time of presentation, which occurs hours to 1 to 2 days after the first symptoms, weakness has usually developed. The weakness is usually most prominent in the legs, but the arms or cranial musculature may be involved first. Muscle stretch reflexes are lost early, even in regions where strength is retained. Cutaneous sensory deficits (loss of pain and temperature) are relatively mild; however, large-fiber functions (vibration and proprioception) are more severely impaired. Other clinical features include pain (20%), paresthesias (50%), autonomic symptoms (20%), facial weakness (50%), ophthalmoparesis (9%), bulbar weakness, and respiratory failure (25%). Symptoms associated with GBS typically evolve over a 2- to 4-week period, with approximately 90% of patients showing no evidence of progression beyond 4 weeks. For this reason, patients who are seen within several weeks from onset continue to require hospitalization for close observation. Respiratory muscle strength should be monitored with bedside measurements of the FVC and negative inspiratory function (NIF). Intubation should be initiated when the FVC falls below 15 mL/kg or NIF is less than −20 cm of H2O. Treatment may include either intravenous gammaglobulin (0.4 g/kg/day × 5 days) or plasmapheresis—the exchange of the patient’s plasma for albumin (200 mL/kg over 7 to 10 days). Clinical studies have confirmed equal efficacy between these two therapies, with no additional benefit conferred with combination therapy. Corticosteroids are

CHAPTER 123  Neuromuscular Diseases not effective in GBS. Indications for therapy include inability to ambulate independently, impaired respiratory function, or rapidly progressive weakness. Clinical features predicting a poor prognosis or prolonged recovery time include rapidly progressive weakness, need for mechanical ventilation, and low-amplitude CMAPs. The mortality rate remains 5% to 10%, usually due to respiratory complications, cardiac arrhythmia, or pulmonary embolism. With appropriate supportive care and rehabilitation, 80% to 90% of patients recover with little or no disability.

Chronic Inflammatory Demyelinating Polyneuropathy CIDP has been considered the “chronic form” of GBS, because by definition the symptoms must progress for at least 8 weeks. The clinical features include proximal and distal weakness, areflexia, and distal sensory loss. Autonomic dysfunction, respiratory insufficiency, and cranial nerve involvement can occur but are much less common than in GBS. Treatment for CIDP includes the use of oral immunosuppressive agents such as prednisone, cyclosporine, mycophenolate mofetil, and azathioprine. Intravenous immune globulin and plasmapheresis are also indicated for severe or refractory cases.

Diabetic Neuropathy Diabetes mellitus is the most frequent cause of peripheral neuropathy worldwide. The diabetic neuropathies take many clinical forms, including symmetrical polyneuropathies and a wide variety of individual plexus or nerve disorders. Diabetes mellitus often causes a slowly progressive, distal, symmetrical sensorimotor polyneuropathy (DSPN). DSPN is uncommon at the time of diagnosis of diabetes, but its prevalence increases with duration of diabetes with a lifetime prevalence of 55% for type 1 and 45% for type 2. The precise pathogenesis is not defined, but, similar to the ocular and renal complications, diabetic neuropathy can be reduced in incidence and in severity by maintaining blood glucose levels close to normal. Initial symptoms may consist of numbness, tingling, burning, or prickling sensations affecting the feet and toes. Mild distal weakness and gait instability may subsequently develop. The sensory symptoms can then slowly progress to involve a “stocking-glove pattern.” The small-fiber dysfunction often produces spontaneous neuropathic pain in which unpleasant sensations can be evoked by normally innocuous stimuli, such as the bed sheets on the toes at night. Continuous burning or throbbing pain may occur, and prolonged walking is often distressing. In severe cases, patients may develop foot ulcers in insensitive areas that necessitate amputation. Autonomic dysfunction is also frequently associated with DSPN including impotence, nocturnal diarrhea, sweating abnormalities, orthostatic hypotension, and gastroparesis. Other less common neuropathies associated with diabetes include cranial neuropathies (the sixth, third, and rarely fourth nerves), mononeuropathies, mononeuropathy multiplex, radiculopathies, and plexopathies. Diabetic amyotrophy (also known as diabetic lumbosacral polyradiculoplexopathy) is a distinctive disorder characterized by severe thigh pain followed by proximal greater than distal lower extremity weakness that progresses over a period of months. The onset is invariably unilateral, but the condition may progress to involve both lower extremities. Physical therapy and effective pain management are essential; treatment with immune modulators is controversial.

1109

sensorimotor axonal neuropathy that chronically progresses over time unless the offending agent is eliminated. Clinical evaluation should focus on the temporal relationship between exposure and the onset of sensory or motor symptoms as well as symptoms of systemic toxicity.

Critical Illness Polyneuropathy Critical illness polyneuropathy (CIP) is a common cause of failure to wean from a ventilator in a patient with associated sepsis and multiorgan failure. Clinical features include generalized or distal flaccid paralysis, especially involving the lower extremities, depressed or absent reflexes, and distal sensory loss with relative sparing of cranial nerve function. The diagnosis can be confirmed with nerve conduction studies showing evidence of a severe, generalized axonal neuropathy. CSF protein should be normal and, in addition to conduction studies, distinguishes CIP from GBS.

SPECIFIC HEREDITARY POLYNEUROPATHIES Charcot-Marie-Tooth Disease CMT identifies a group of heritable disorders of peripheral nerves that share clinical features but differ in their pathologic mechanisms and the specific genetic abnormalities (E-Table 123.4). CMT is the most common heritable neuromuscular disorder, with an incidence of 17 to 40 cases per 100,000. CMT disease usually manifests during the first to second decades with symptoms related to insidious foot drop: frequent tripping and inability to jump well or run as fast as other children. Over time, distal upper extremity weakness develops, resulting in difficulty with buttoning, handling keys, and opening jars. Examination reveals distal weakness and wasting of the intrinsic muscles of the feet, the peroneal muscles, the anterior tibial muscles, and the calves (“inverted champagne bottle” legs). A variable degree of impaired large-fiber sensory function is reflected in reduced vibratory sensation at the toes. Muscle stretch reflexes are lost, first at the ankles. Typically, a foot deformity exists, with high arches (pes cavus) and hammer toes, reflecting long-standing muscle imbalance in the feet. Most patients with CMT disease have nearly normal occupational and daily activities, and they have a normal life span. Although no specific treatment has been developed, the foot drop can be treated by appropriate bracing of the ankle with ankle-foot orthoses. Genetic counseling and education of affected patients and their families are important, both for reassurance and to preclude unnecessary diagnostic evaluation of affected members in future generations. Demyelinating forms of CMT are classified as CMT1 and axonal forms as CMT2. CMT is usually transmitted as an autosomal dominant trait; however, X-linked dominant transmission is responsible for approximately 10% of cases. Rare autosomal recessive forms are designated CMT4, and these patients tend to have an earlier onset and more severe phenotype. CMT1A is the most common form and accounts for 90% of CMT1 and 50% of all CMT cases. CMT1A is associated with the 17p11.2-p12 duplication in the PMP22 gene expressed by Schwann cells. A deletion or a point mutation of the PMP22 gene produces a different phenotype, HNPP, which is characterized by recurrent episodes of focal entrapment with attacks of weakness and numbness in the peroneal, ulnar, radial, and median nerves (in descending order of frequency) or in a brachial plexus distribution.

Toxic-Induced Neuropathies

FAMILIAL AMYLOID NEUROPATHIES

Toxic neuropathies constitute a large number of disorders caused by alcohol, drugs, heavy metals, and environmental substances (see E-Table 123.3). The majority of toxic neuropathies manifest as a distal

Amyloid neuropathy is an autosomal dominant disorder caused by extracellular deposition of the fibrillary protein amyloid in peripheral nerve and sensory and autonomic ganglia, as well as around blood

CHAPTER 123  Neuromuscular Diseases

1109.e1

E-TABLE 123.4  Charcot-Marie-Tooth Disease Disorder

Locus/Protein

CMT1: Demyelinating CMT1A 17p11.2 Peripheral myelin protein 22 (PMP22) CMT1B 1q22 Myelin protein zero (P0) CMT1C 16p13.1-p12.3 LITAF CMT1D 10q21.1-q22.1 Early growth response protein 2 (EGR2) CMT1F 8p21 NF-68 CMTX Xq13.1 Connexin 32 HNPP Dejerine-Sottas (HSMN3)

17p11.2 Peripheral myelin protein 22 (PMP22) 8q23,17p11,10q21 Early growth response protein 2 (EGR2) Peripheral myelin protein 22 (PMP22)

CMT2: Dominant; Axonal CMT2A 1p36.2 Kinesin-like protein (KIF1B) CMT2A2 1p36 Mitofusin 2 (MFN2) CMT2B 3q21 RAB7 CMT2C CMT2D CMT2E

CMT2F CMT2G CMT2K CMT2L CMT2M CMT2N

12q23-24 TRPV4 7p15 Glycyl-tRNA (GARS) 8p21 Synthetase Neurofilament triplet L protein (NEFL Sequencing) 7q11-21 HSPB1 12q12 8q21 GDAP1 12q24 HSPB8 19p13 DNM2 16q22 AARS

CMT4: Recessive; Demyelinating CMT4A 8q13-q21.1 Ganglioside-induced differentiation protein-1 (GDAP1) CMT4B1 11q22 Myotubularin-related protein 2 (MTMR2) CMT4B2 11p15 Set binding factor 2 (SBF2) CMT4C

5q32 SH3TC2

Inheritance

Usual Onset

Specific Clinical Features

AD

1st decade

Distal weakness

AD

1st decade

AD

2nd decade

Distal weakness More severe Distal weakness

AD

2nd decade

AD

1 to 40 years

X-linked

2nd decade

AD

3rd decade

Distal weakness Ptosis Distal weakness Ataxia Distal weakness Hearing loss Encephalopathy Focal episodic weakness

AD

2 yrs

Severe weakness

AD

10 years

Distal weakness

AD

10 years

AD

2nd decade

AD

1st decade

Distal weakness Hearing loss Distal weakness Sensory loss Acromutilation Vocal cord and distal weakness

AD

16 to 30 years

Distal weakness arms > legs

AD

1 to 40 years

Distal weakness

AD

2nd decade

Difficulty walking

AD AD

15 to 25 years Infant

AD

15 to 33 years

Distal weakness Distal weakness Vocal cord Distal weakness

AD

0 to 50 years

AD

6 to 54 years

AR

Childhood

Distal weakness Vocal cord

AR

2 to 4 yrs

Distal and proximal weakness

AR

1st 2 decades

AR

5 to 15 yrs

Distal weakness Sensory loss Glaucoma Delayed walking

Distal weakness, legs > arms, ophthalmoparesis Distal leg weakness Asymmetric

(Continued)

1109.e2

SECTION XVI  Neurologic Disease

E-TABLE 123.4  Charcot-Marie-Tooth Disease—cont’d Disorder

Locus/Protein

Inheritance

Usual Onset

Specific Clinical Features

CMT4D

8q24.3 NDRG1 protein 10q21.1-q22.1 Early growth response protein 2 (EGR2)

AR

1 to 10 yrs

AR

Birth

19q13.1-q13.2 Periaxin (PRX) 12p11.21 FGD4 6q21 FIG4 P0, PMP-22, EGR2, Periaxin

AR

1 to 3 yrs

AR

10 to 24 mo

AR

Congenital to adult

AR

2 years

Gait disorder Hearing loss Infant hypotonia Arthrogryposis Respiratory failure Motor delay Sensory loss Walking delay Scoliosis Asymmetric proximal and distal weakness Severe weakness

CMT4E

CMT4F CMT4H CMT4J CMT3 (DejerineSottas)

1110

SECTION XVI  Neurologic Disease

vessels in nerves and other tissues. The age of onset varies from 18 to 83 years. In all forms of amyloidosis, the initial and major abnormalities affect the small sensory and autonomic fibers. Involvement of small fibers responsible for pain and temperature sensibilities leads to loss of the ability to perceive mechanical and thermal injuries and to an increased risk of tissue damage. As a result, painless injuries present a major hazard of this disorder; in advanced stages, they can lead to chronic infections or osteomyelitis of the feet or hands and the necessity for amputation. Amyloid deposition in the heart can lead to cardiomyopathy. Mutations in transthyretin, apolipoprotein A1, or gelsolin are responsible. Early recognition is essential, as liver transplantation has been shown to halt disease progression. Recently, the FDA approved two new medications, inotersen and patisiran, for treatment of transthyretin-associated familial amyloid polyneuropathy.

SUGGESTED READINGS Alport AR, Sander HW: Clinical approach to peripheral neuropathy: Anatomic localization and diagnostic testing, Continuum Lifelong Learning Neurol 18(1):13–38, 2012. Al-Zaidy, SA, Mendell JR: From clinical trials to clinical practice: Practical considerations for gene replacement therapy in SMA type 1. Pediatr Neurol 100:P3–11, 2019. Bril V, England J, Franklin GM, et al: Evidence-based guideline: treatment of painful diabetic neuropathy, Muscle Nerve 43:910–917, 2011.

Bromberg MB: An approach to the evaluation of peripheral neuropathies, Semin Neurol 25(2):153–159, 2005. Brown RH, Al-Chalabi: Amyotrophic lateral sclerosis, N Engl J Med 377:162– 172, 2017. Camdessanche JP, Jousserand G, et al: The pattern and diagnostic criteria of sensory neuronopathy: a case-control study, Brain 132(7):1723–1733, 2009. Chiriboga CA: Nusinersen for the treatment of spinal muscular atrophy, Expert Review of Neurotherapeutics 17(10):955–962, 2017. Ludolph AC, Brettschneider J, Weishaupt JH: Amyotrophic lateral sclerosis, Curr Opin Neurol 25(5):530–535, 2012. Mauermann ML, Burns TM: The evaluation of chronic axonal polyneuropathies, Semin Neurol 28(2):133–151, 2008. Miller RG, Jackson CE, Kasarkis EJ, et al: Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology, Neurology 73(15):1218–1226, 2009. Miller RG, Jackson CE, Kasarksi EJ, et al: Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology, Neurology 73(15):1227–1233, 2009. Oskarsson B, Gendron TF, Staff NP: Amyotrophic lateral sclerosis: an update for 2018, Mayo Clin Proc 93(11):1617–1628, 2018. Turner MR, Hardiman O, Benatar M: Controversies and priorities in amyotrophic lateral sclerosis, Lancet Neurol 12(3):310–322, 2013.

124 Muscle Diseases Johanna Hamel, Jeffrey M. Statland

INTRODUCTION Skeletal muscle fibers are the effector cells of the nervous system, turn thoughts into actions, and are the means by which we interact with our environment. Myopathies are primary diseases of the muscle and can be both inherited and acquired (Table 124.1). Myopathies can result in weakness and muscle wasting, myalgias, cramps, muscle breakdown, or contractures. Inherited disorders affect muscle proteins involved in transmission of signals from the neuromuscular junction, proteins involved in energy production or metabolism, or structural proteins that anchor and transmit force from the contractile apparatus to the extracellular matrix. They do this either by mutations directly to the muscle proteins or by mutations altering cell regulation of transcription or splicing. Acquired myopathies are caused by external factors and can be due to metabolic derangements, toxic exposures or drugs, infections, or autoimmune dysfunction often resulting in inflammation in the muscle. Acquired myopathies can improve with treatments geared towards eliminating or ameliorating the precipitating factors. With recent advances in our understanding of the genetic and molecular mechanisms in hereditary myopathies, coupled with advances in drug development targeting DNA and RNA, efforts to develop targeted therapies for hereditary muscle diseases accelerated and increased exponentially. The first treatment targeting the underlying genetic mechanism of a muscle disease (Duchenne muscular dystrophy) was approved by the US Food and Drug Administration (FDA) in 2016. Many more disease-specific treatments targeting genetic mechanisms of muscle diseases are currently in clinical trials with a subset expected to become available to patients in the future. This change in paradigm, from supportive to disease-­modifying therapies, targeting patients’ DNA or RNA that will alter the trajectory of progression, will change the landscape of how we care for patients with muscle diseases. One technology worth mentioning here due to imminent clinical trials and the possibility for transformational change in inherited myopathies is systemic gene replacement therapies. The three concepts that make up systemic gene therapy are: (1) the vector, which is a virus, serotypes of which can specifically target muscle or the heart; (2) the construct, which is the gene that will be packaged into the virus vector; the size can be limited by the capsid size, and so for large genes like dystrophin new engineered genes (i.e., microdystrophin) are used; and (3) the promotor, the on and off switch for the gene, which can also be tissue specific. The first such systemic gene replacement therapy was approved for spinal muscular atrophy, and several companies have phase 3 studies starting for muscular dystrophies. With these fundamental advances on the horizon, early recognition and diagnosis of these rare diseases will be important to achieve the greatest benefit from these treatments. Physicians administering the therapies not only need to be familiar with the disease and its complications but with molecular and genetic mechanisms that are being targeted. These advances provide abundant opportunities and challenges.

ORGANIZATION AND STRUCTURE OF NORMAL MUSCLE Each muscle is enclosed in a connective tissue sheath made up of collagen and extracellular matrix proteins called the epimysium, which merges at either end to form the tendons, which attach muscle to bone. The epimysium divides internally into the perimysium, which separates the muscle into individual bundles of muscle fibers called fascicles. The endomysium surrounds and provides support for the individual fibers. Each muscle fiber is a single multi-­nucleated syncytial cell and can be as long as 10 cm. On cross section, muscle fibers appear polygonal in shape and in adults range from 40 to 80 micrometers in diameter. Medium size arterioles and veins run in the perimysium, with capillaries between the individual muscle fibers. On hematoxylin and eosin stains, cytoplasm appears pink and the nuclei blue (Fig. 124.1A). Each individual muscle fiber has multiple nuclei, which are found beneath the sarcolemma membrane on the periphery of the cell. The plasma membrane around the muscle fiber is called the sarcolemma, and inside there are a large number of myofibrils made of thick (myosin) and thin (actin) filaments, which make up 70% to 80% of the volume of the cell, and when activated, create force. Electrochemical signals carry the signal from the nerve, through the neuromuscular junction, into the muscle fiber along the sarcolemma and t-­tubule system. Muscle ion channels line this network and carry electrochemical signals. Mitochondria and enzymes involved in glycolysis and fatty acid metabolism provide energy for muscle. A network of proteins, the dystrophin-­glycoprotein complex (DGC), anchors the myofibrils to the subsarcolemma cytoskeleton and connects to the extracellular matrix (Fig. 124.2). Many inherited myopathies are caused by mutations in these ion channels, metabolic enzymes, or structural anchoring proteins.

SYMPTOMS OF MUSCLE DISEASE The most common symptom of a patient with muscle disease is a loss of function caused by weakness (for an overview of symptoms see Table 124.2). Other common symptoms, like fatigue, exercise intolerance or myalgias (muscle pain), are less specific than muscle weakness. Muscle cramping is more commonly caused by disorders of the nerves, and not the muscle.

EXAMINATION The physical examination uses a standard modified Medical Research Council scale of motor strength to determine the pattern and degree of involvement of various muscles (Table 124.3). But just as important as isolated strength testing are functional

1111

1112

SECTION XVI  Neurologic Disease motor tasks, particularly in children. Muscles should be inspected for atrophy or hypertrophy and range of motion around the joints for evidence of tendon contractures. Ten broad patterns of muscle weakness occur in myopathies (Table 124.4). Most myopathies have the proximal, limb-­girdle pattern. There are other, highly distinctive, patterns. Weakness that is asymmetric and includes the face, proximal arms and shoulders, and distal lower extremities is characteristic of facioscapulohumeral muscular dystrophy. Weakness that starts in the distal finger flexors (patients cannot curl fingers when making a fist) and proximal lower extremities (the quadriceps) is virtually pathognomonic for sporadic inclusion body myositis. A patient in middle age who presents with ptosis and difficulty swallowing is highly characteristic for oculopharyngeal muscular dystrophy.

TABLE 124.1  Overview of Myopathies Hereditary Myopathies Muscular dystrophies Congenital myopathies Metabolic/mitochondrial myopathies Channelopathies Acquired Myopathies Inflammatory myopathies Myopathy with HMGCR antibodies Endocrine myopathies Systemic illness/infectious myopathies Toxic/drug-­induced myopathies

* A

D

B

C

E Fig. 124.1  Muscle biopsies hematoxylin and eosin staining. When assessing the health of muscle tissue, the pathologist evaluates the size, shape and internal architecture of muscle fibers, presence of inflammation and mitochondrial dysfunction, and amount of connective tissue. In a chronic myopathic muscle, the muscle fibers are typically more variable in size, rounded, and have central nuclei. Connective tissue can be increased. In an active myopathy, necrotic fibers undergoing phagocytosis and regenerating fibers can be seen. (A) Normal adult muscle, medium power. Notice polygonal muscle fibers arranged in fascicles with blue staining nuclei on the periphery. A small arteriole is visible (white arrow). (B) Chronic myopathy, Duchenne muscular dystrophy low power. Note the variability in fiber size with rounding of fibers, increase in connective tissue, and fatty deposition. (C) Acute myopathy, necrotizing myopathy with HMGCR antibodies. Necrotic fiber (white arrow) undergoing phagocytosis and regenerating fiber (*) with plump nuclei. Examples for disease characteristic findings on muscle pathology. (D) Centronuclear congenital myopathy. The NADH reaction shows numerous fibers with spoke-­like, radial projections with central nuclei. Also notable fiber size variability, identified as moderate type 1 fiber atrophy on other stains. (E) Dermatomyositis on low power. Notice the prominent pathognomonic perifascicular atrophy (white arrow) of fibers, and perivascular inflammatory infiltrates.

CHAPTER 124  Muscle Diseases

1113

Collagen VI → Ullrich/Bethlam myopathy

Extracellular

α2

Basal lamina β1

γ1 Laminin → Congenital muscular dystrophy

Congenital muscular ← Dystroglycan dystrophy

Integrin Dgα Iα Iβ

Plasma membrane Dgβ α Syntrophin

β2

β1

Sα Sβ Sδ Sγ

Sarcoglycan → LGMD 2C-F

C

Caveolin-3 → LGMD 1C

N Intracellular F-actin

Dystrophin → DMD/BMD LGMD 2A → Calpain Dysferlin → LGMD 2B

Fig. 124.2  The dystrophin-­glycoprotein complex. Muscle structural proteins connect the contractile apparatus to the internal cytoskeleton and the extracellular matrix. Mutations in proteins from the extracellular matrix to the anchoring proteins, which connect the extracellular matrix to the internal cytoskeleton, and mutations to proteins, which attach the internal cytoskeleton to the contractile apparatus, are all involved in the inherited muscular dystrophies and myopathies.

DIAGNOSTIC TESTING The work-­up of a patient with a suspected myopathy is a staged process, outlined in Table 124.2. A useful initial laboratory test is the serum creatine kinase (CK), which is elevated commonly in acquired and often in inherited myopathies. Despite the obvious localizing value of elevated muscle enzymes it is important to remember not all elevations in serum CK are due to myopathy and a normal CK does not exclude a myopathy (Table 124.5). Furthermore, CK levels can vary depending on physical activity, gender, and race. Electrodiagnostic testing can help distinguish between neurogenic and myopathic causes for weakness (see Table 124.2). Genetic testing is the initial test when a specific hereditary disease is suspected. Muscle biopsies can be important in patients whose family history and physical examination does not suggest a particular myopathic diagnosis and can help resolve variants of uncertain significance on genetic testing. Characteristic morphologic changes (see Fig. 124.1) are hallmarks of the congenital myopathies (e.g., centronuclear myopathy in Fig. 124.1D), inflammatory myopathies (dermatomyositis in Fig. 124.1E), and metabolic myopathies (glycogen storage disorders), but most myopathies result in nonspecific muscle changes, which confirms the localization (muscle), but not the cause.

into the dystrophinopathies, the myotonic dystrophies, facioscapulohumeral muscular dystrophy, Emery-­Dreifuss muscular dystrophy, and the limb-­girdle dystrophies (Tables 124.6, 124.7, and E-­Table 124.1). The limb-­girdle muscular dystrophies (LGMD) are a diverse group of diseases due to mutations in more than 20 genes. The LGMDs are inherited in either autosomal dominant or recessive fashion and present anywhere from childhood after achieving independent walking to later in life, with elevated CK and proximal muscle weakness (see E-­Table 124.1). Another group of patients who have dystrophic changes in the muscle from birth, often with accompanying changes in the brain on MRI, include congenital muscular dystrophies (see Table 124.7). The traditional distinction between dystrophies and other inherited myopathies is becoming blurred as our genetic understanding advances because mutations for different diseases are often allelic.

Dystrophinopathies

Definition and Epidemiology

INHERITED MYOPATHIES

Dystrophinopathies are X-­linked recessive disorders resulting from mutations of the large dystrophin gene located at Xp21. The incidence of Duchenne muscular dystrophy is 1 in 5300 male births; one third of the cases result from a new mutation. Becker muscular dystrophy is a milder form of dystrophinopathy and is less common than the Duchenne form, with an incidence of 5 per 100,000.

Muscular Dystrophies

Genetics and Pathology

The muscular dystrophies are inherited myopathies characterized by progressive weakness. Typically the muscular dystrophies are divided

The majority of patients have deletions or duplications in the dystrophin gene. In the remaining patients, mutations can be small insertions

1114

SECTION XVI  Neurologic Disease

TABLE 124.2  Evaluation for a Patient With Suspected Myopathy Feature History Age of onset Acute/subacute or chronic Progressive or episodic Triggers Myotonia Family History

Weakness on Exam Proximal Distal Facial Oculopharyngeal Respiratory Other Features Myotonia

Cardiac Multiorgan involvement Laboratory Creatine kinase (CK) Thyroid/Parathyroid Antibodies

Genetic Testing Electrodiagnostic Studies

Muscle Biopsy

Description Congenital, childhood, adult Hereditary myopathies are usually chronic with gradual onset, acquired myopathies can occur more acutely Dystrophies are usually progressive; congenital static; metabolic/channelopathies episodic Exercise, foods, temperature Delayed relaxation of muscle: e.g., difficulty letting go when shaking hands, opening doorknobs, myotonia can also affect tongue movements (speech) and chewing. Myotonia improves with repetition (warm-­up phenomenon) and gets worse in cold temperature. It can be helpful to draw out a pedigree to determine the pattern of inheritance, which can be dominant, recessive, or no family history. Questions about whether family members require assistive devices to walk or wheelchairs, and asking about extra-­muscular manifestation of muscular dystrophies can be useful, specifically as diseases may not have been recognized. Difficulty lifting objects, climbing stairs, getting up from chair, scapular winging, waddling gait, Gower sign Difficulty making a tight fist, fastening buttons, opening jars, wrist drop, foot drop Difficulty squeezing the eyes shut, transverse smile, inability to pucker or blow out cheeks, inability to whistle Ptosis, restricted extra-­ocular movements, coughing after drinking, and difficulty swallowing Shortness of breath with activity, with lying flat, use of accessory muscles Action Myotonia: Delayed hand opening after making a tight fist, or eye opening after tight closure Percussion Myotonia: With percussion of the extensor digitorum muscle in the forearm, the finger extensors relax with delay. Same can be observed with percussion of the thenar eminence Cardiac conduction defects, cardiomyopathy E.g., joint deformities, skin (rash), GI symptoms, eye (cataract), hearing loss, CNS involvement Dystrophies/inflammatory myopathy increased >10× normal; congenital 3–5× normal; metabolic >10× normal during attacks High TSH, low T4, low PTH, Ca2+ Patients with myositis: Myositis specific antibodies: Anti-­Jo-­1, antisynthetase antibodies, signal recognition particle (SRP) antibodies, Mi-­2 antibodies, anti hPMS-­1, anti-­MDA-­5 antibody, anti-­p140, anti-­p155/140. Inclusion Body myositis: Cytoplasmic 5′-­nucleotidase 1A (cN1A) Patients with proximal muscle weakness of unknown etiology or necrotizing myopathies: Antibodies to 3-­hydroxy-­3-­methylglutaryl coenzyme A reductase (HMGCR) Patients with family history and/or examination suggestive of a hereditary myopathy. A positive test can be confirmatory and avoid additional diagnostic testing. Nerve conduction studies are typically normal in muscle diseases. On electromyography, irritated muscle shows fibrillations and positive sharp waves; myopathic motor units are brief, low amplitude, and polyphasic; electrical myotonia is a repetitive muscle fiber potential discharge with waxing and waning frequency and amplitude with characteristic sound similar to an accelerating, decelerating motorcycle engine. Chronic: Changes in muscle fiber shape and composition of fiber types, central nuclei, increased amount of connective tissue Acute: Necrotic muscle fibers, regenerating fibers Other: Presence of inflammatory cells, number or morphology of mitochondria, or abnormal deposits of fat or glycogen

or deletions, point mutations, or splice site variants. Dystrophin is a large subsarcolemmal cytoskeletal protein that, along with the other components of the dystrophin-­glycoprotein complex, provides support to the muscle membrane during contraction. Mutations in dystrophin can result in a spectrum of dystrophin dysfunction, from a severely truncated protein that is rapidly degraded, as in Duchenne muscular dystrophy, to a semi-­functional protein still expressed such as in the milder form, Becker’s muscular dystrophy, or mild dysfunction such as in female carriers. Muscle biopsies are typically not required for diagnosis (example depicted in Fig. 124.1B).

to get up from the floor, boys use a Gower maneuver (use hands to push up). The average age of diagnosis is around 4 years of age. The proximal muscles are the most severely affected, and the course is relentlessly progressive. Patients begin to fall frequently by age 5 to 6, have difficulty climbing stairs by age 8 years, and are usually confined to a wheelchair in their early teens. Patients have a reduced life expectancy due to cardiac (dilated cardiomyopathy) and respiratory muscle weakness. The average IQ of boys with Duchenne muscular dystrophy is low, reflecting central nervous system involvement.

Clinical Presentation

Diagnosis is based on clinical history, physical examination, serum CK, and is confirmed by genetic testing. Other differential considerations are congenital myopathies, muscular dystrophies, and limb-­ girdle muscular dystrophies.

Duchenne muscular dystrophy manifests as early as age 2 to 3 years with delays in motor milestones and difficulty running. Patients can have marked pseudo-­hypertrophy of the calf muscles. And when asked

Diagnosis and Differential Diagnosis

CHAPTER 124  Muscle Diseases

Treatment Care for children with Duchenne muscular dystrophy involves a multidisciplinary team along with pulmonologists, orthopedists, and cardiologists, with monitoring of cardiac and respiratory function as well as scoliosis. Prednisone and deflazacort (a synthetic derivative of prednisolone) improve strength and motor function, pulmonary function, and prolong the ability to walk and survival in children with Duchenne muscular dystrophy. About 15% of patients with Duchenne muscular dystrophy carry a mutation on exon 51. Eteplirsen is a drug that binds to exon 51 and

TABLE 124.3  Modified Medical Research

Council Motor Strength Testing Scale Grade

Degree of Strength

5

Normal strength through entire range of motion and against resistance Equivocal, barely detectable weakness Able to move against gravity and resistance, but examiner can break Able to move against gravity and some resistance Able to resist gravity but only minimal resistance Able to overcome gravity and transient resistance, but then quickly gives out Able to overcome gravity but no resistance Able to resist gravity but not through full range of motion Able to move through range of motion with gravity eliminated Trace muscle contraction No contraction

5− 4+ 4 4− 3+ 3 3− 2 1 0

1115

induces “exon skipping,” resulting in production of a truncated, but potentially functional dystrophin protein. The drug was approved in the United States by the FDA in 2016 and current trials are carried out to demonstrate a clinical benefit. Subsequently, two therapies were approved for patients with pathogenic variants on exon 53 (about 8% of patients with Duchenne muscular dystrophy). These therapies, golodirsen and vitolarsen, target RNA and result in exon 53 skipping. Ataluren is approved in countries outside of the United States for children with nonsense mutation. The drug allows read-­through of premature stop mutations with the goal to produce a more functional dystrophin protein but with mixed results on functional outcome measures. Continued efforts and studies focus on strategies to make the cell produce some form of dystrophin, by targeting RNA or utilizing gene therapy targeting DNA. While these therapies will likely change the trajectory of DMD and care practices, new challenges will arise, such as costs, access (due to the genetic variability of DMD, therapies will target a subset of patients), duration of effect, and long-­term safety concerns. There are no guidelines for the treatment of Becker muscular dystrophy and clinical presentation is highly variable, but monitoring for cardiac and respiratory involvement is warranted. Some female carriers of dystrophin mutations may become symptomatic later in life and may have severe cardiomyopathy.

Prognosis Patients with Duchenne muscular dystrophy die of respiratory complications in their 20s unless they are provided with respiratory support. Emerging targeted therapies will likely change this trajectory. Congestive heart failure and arrhythmias can occur late in the disease.

TABLE 124.4  Characteristic Patterns of Muscle Weakness and Associated Myopathies Pattern

Weakness

Diseases

Proximal limb-­girdle

Symmetrical, pelvic and shoulder girdle muscles. Distal muscles to lesser extent. ±Neck flexor/ extensor Symmetrical, distal upper or lower extremity. Proximal muscles to lesser degree

Nonspecific: Duchenne muscular dystrophy; limb-­girdle muscular dystrophy; inflammatory myopathies; Myopathy with HMGCR antibodies; myotonic dystrophy type 2 Nonspecific: Miyoshi myopathy (calves); Welander myopathy (wrist and finger extensors); Nonaka and Markesbery/Udd myopathy (tibialis anterior); rule out neuropathy When face involved highly suggestive of facioscapulohumeral muscular dystrophy; with elbow contractures Emory-­Dreifuss dystrophy; scapuloperoneal dystrophies; certain limb-­girdle dystrophies; congenital myopathies

Distal

Proximal arm/distal leg

Distal arm/proximal leg

Ptosis ± ophthalmoparesis

Neck extensor weakness Bulbar weakness Episodic pain, weakness, and myoglobinuria Episodic weakness delayed or unrelated to exercise Stiffness and decreased ability to relax

Scapuloperoneal distribution: periscapular muscles (proximal arm) and anterior compartment distal leg (tibialis anterior). Scapular winging. Can be asymmetrical. Distal forearm muscles (distal finger flexors) and proximal leg (quadriceps). Other muscles variable. Often asymmetrical. Restriction of eye movements often without diplopia. Often with pharyngeal weakness and variable extremity weakness. Neck extensors, “dropped head syndrome.” Variable neck flexor. ±Extremity weakness. Tongue and pharyngeal weakness

Highly suggestive of sporadic inclusion body myositis; also consider myotonic dystrophy type 1 with distal leg, neck flexion, respiratory and facial weakness Ocular and pharyngeal weakness highly suggestive of oculopharyngeal muscular dystrophy; mitochondrial myopathies

May be triggered by exercise or metabolic stress

Inflammatory myopathies, in isolation consider isolated neck extensor myopathy; rule out amyotrophic lateral sclerosis and myasthenia gravis Certain myopathies (e.g., oculopharyngeal muscular dystrophy); significant overlap with neuromuscular junction and motor neuron disease Metabolic myopathies; may also occur in deconditioning

May be triggered by food, stress, rest after exercise

Characteristic of periodic paralyses

May be episodic, triggered by cold

Characteristic of myotonic disorders

Modified from Jackson CE, Barohn RJ: A pattern recognition approach to myopathy, Continuum (Minneap Minn) 19(6 Muscle Diseases): 1674-­1697, 2013.

1116

SECTION XVI  Neurologic Disease

TABLE 124.5  Causes for Elevated Serum CK

Myotonic Dystrophy

Myopathies Muscular dystrophies/Duchenne carrier state Congenital myopathies Metabolic myopathies Inflammatory myopathies

Myotonic dystrophies are the most common muscular dystrophies in adults of European ancestry with autosomal dominant inheritance. There are two types of myotonic dystrophy, type 1 (DM1) and type 2 (DM2). The frequency of DM1 in Europe is estimated at 1 in 8000. While DM1 and DM2 are equally frequent in Europe, DM2 seems less common in the United States.

Channelopathies Motor Neuron Disease (ALS, SMA) Neuropathies (GBS, CIDP) Viral Illness

Definition and Epidemiology

Genetics and Pathology DM1 is caused by a CTG repeat expansion on the DMPK gene whereas DM2 is caused by a CCTG repeat expansion on the CNBP gene. Both diseases share the same mechanism of RNA toxicity. Expanded CUG/ CCUG repeats accumulate in nuclear foci and sequester important proteins that typically regulate RNA splicing. Loss of function of these proteins results in missplicing of various RNAs of multiple genes, resulting in wide transcriptome changes and multisystemic disease. In DM1, some but not all of the variability in age of symptom onset is explained by repeat length, with earlier onset typically associated with greater disease severity and longer repeat length. The CTG repeat is unstable and increases in somatic tissue throughout a persons’ life (somatic instability) and tends to increase from generation to generation (anticipation). Genetic testing confirms the diagnosis and muscle biopsies are not required but characteristic findings

Medications Statins Fibric acid derivatives Chloroquine Colchicine Endocrine Abnormalities (Thyroid/Parathyroid) Surgery Trauma Strenuous Exercise Increased Muscle Mass Idiopathic—Ethnic Variability

TABLE 124.6  Prevalent Muscular Dystrophies Disease

Inheritance

Mutations

Age of Onset

Dystrophinopathies

X-­linked recessive Xp21; ≈75% deletion or Duchenne diagnosis duplication by age 4; Becker variable

Phenotypes Limb-­girdle pattern. Duchenne: severe progressive and life limiting. Becker: progressive but not as severe, more variable. Calf pseudo-­hypertrophy; isolated cardiomyopathy.

Treatment

For Duchenne: Prednisone (or deflazacort), Eteplirsen, golodirsen, and vitolarsen; surveillance for respiratory, cardiac, and orthopedic problems Myotonic dysAutosomal 19q13; CTG expansion Any age with marked Marked clinical variability but typically Mexiletine for symptomtrophy type 1 dominant >50 repeats variability; congen- muscle weakness and wasting affecting atic myotonia; yearly ital at birth face, neck flexion, respiratory and distal surveillance for ocular and muscles (finger flexion, ankle dorsiflexion); respiratory involvement myotonia; temporal wasting, frontal balding; and cardiac conduction multisystemic disease manifestations (e.g., deficits with cognitive deficits, hypersomnolence, cataracts); cardiac conduction deficits Myotonic dysAutosomal 3q13; CCTG expansion 30s and older Limb-­girdle pattern; myalgia; myotonia; multi- Mexiletine for symptomatic trophy type 2 dominant >75 repeats system involvement (e.g., cataracts, cardiac myotonia; surveillance conduction deficits); diabetes for ocular, cardiac, and respiratory involvement FacioscapuAutosomal 95%: 4q35 (FSHD1), Any age Scapuloperoneal pattern with facial Screening for extramuscular lohumeral dominant 5% digenic mutation involvement; can have marked asymmetry; manifestation muscular affecting methylation significant axial involvement dystrophy (FSHD2) Emery-­Dreifuss X-­linked reces≈70% Xq28 Emerin or Joint contractures Scapuloperoneal pattern; early joint contrac- Yearly surveillance for muscular sive; autosomal FHL1 mutation; 1q21 childhood; protures, particularly at elbows, marked cardiac cardiac and respiratory dystrophy dominant or lamin A/C, both domgressive weakness involvement involvement; orthopedic recessive inant and recessive 20s–30s evaluation for symptomatic mutations reported contractures Oculopharyngeal Autosomal 14q11 PABPN1 GCG 40s (range 20s–60s) Ptosis dysphagia; limb-­girdle pattern Swallow study; blephmuscular dominant and repeats >11 repeats weakness aroplasty for ptosis, dystrophy recessive cricopharyngeal myotomy for severe swallowing difficulty

CHAPTER 124  Muscle Diseases

1117

TABLE 124.7  Congenital Muscular Dystrophies Name/AKA

Gene

Inheritance

Phenotype

Merosin-­deficient

6q22; laminin alpha-­2

Autosomal recessive

Bethlem myopathy/ Ullrich muscular dystrophy Dystroglycanopathy

21q22; 2q37; COL6 (collagen 6 spectrum disorders) 9q34 (POMT1); 14q24 (POMT2); 9q31 (fukutin); 19q13 (FKRP); 22q12 (LARGE); 1q32 (POMGnT1); 7p21 (ISPD)

Autosomal dominant or recessive

Hypotonia; contractures; scoliosis or rigid MRI diffuse white matter changes; spine; respiratory involvement; external 20%–30% seizures ophthalmoplegia Hypotonia; contractures; distal joint laxity; keloid; respiratory involvement

Autosomal recessive

Spectrum of disorders but characteristic intellectual, eye, and brain involvement; motor early death, to acquiring ambulation

SEPN1-­related myopathy

1q36 (SEPN1)

Autosomal recessive

LMNA related

1q22 (lamin A/C)

Autosomal dominant and recessive

Cervicoaxial weakness, rigid spine syndrome, early nocturnal hypoventilation, medial thigh wasting Cervicoaxial weakness, dropped head, rigid spine syndrome, respiratory and cardiac involvement

include pyknotic clumps (result of severe fiber atrophy), ring fibers, and type 1 fiber predominance.

Clinical Presentation DM1 is one of the most variable monogenetic diseases and can present at any age. The wide spectrum of disease ranges from infants with hypotonia, respiratory weakness, and clubfeet at birth (congenital myotonic dystrophy) to late onset of disease at old age with minimal symptoms or signs. Typical features include facial weakness with temporalis muscle wasting, frontal balding, ptosis, and neck flexor weakness. Speech can be dysarthric with bulbar weakness resulting in dysphagia. Inspiratory (difficulty lying flat) and expiratory (weak cough) muscle weakness may be present. Extremity weakness usually begins distally and progresses slowly to affect the proximal limb-­girdle muscles. In conjunction with myotonia (see Table 124.2), this phenotype is nearly pathognomonic of DM1. DM2 is considered milder because age of onset occurs typically in the late 30s and there is no congenital or childhood form of the disease. The pattern of weakness predominantly affecting proximal muscles and less facial involvement is different than in DM1. Pain is commonly described by patients with DM2. Both disorders affect multiple organ systems, such as early cataracts ( R1 Variable

Normal to 5× Normal to 2900 Normal to 9× High in most Normal to 1700

R1 calpain3-­related

CAPN

2–40s

Normal to 80×

R2 dysferlin-­related

DYSF

Teens to 20s

High: 10× to 72×

R3 α-­sarcoglycan related R4 β-­sarcoglycan related R5 γ-­sarcoglycan related R6 δ-­sarcoglycan related R7 telethonin-­related R9 FKRP-­related

R3 SGCA R4 SGCB R5 SGCG R6 SGCD TCAP FKRP

3–15

R12 anoctamin 5-­related

ANO5

R22 collagen 6-­related

COL6A1, COL6A2, COL6A3

Phenotypic Characteristics (in Addition to Limb-­Girdle Pattern Weakness) Surveillance Legs > Arms Legs > Arms Proximal > distal Great variability Joint laxity, contractures IP joint medial 4 fingers, keloid formation Scapular winging; paraspinal involvement/scoliosis Allelic with distal myopathies

Dysphagia Respiratory weakness Cataracts

>10×

Respiratory weakness later in disease Mild to severe phenotype; contrac- Respiratory and cardiac tures/scoliosis; calf pseudo-­ involvement; orthopedics hypertrophy

9–15 1st–20s

3×-­30× High: 10× to 30×

Tibialis anterior affected in some Proximal > distal

Variable: 1–7th decade 2–4 years

Typically high: up to 150× 1.5×

Mild forms can have high CK with normal strength Proximal and distal, Contractures

Cardiac involvement Respiratory weakness, cardiomyopathy Cardiac involvement

Restrictive lung disease, conduction abnormalities Most common form

Respiratory weakness

D, Dominant; R, recessive. Other recessive mutations: LGMD R8 TRIM 32-­related, LGMD R10 titin-­related, LGMD R11 POMT1-­related, LGMD R13 Fukutin-­related, LGMD R14 POMT2-­related and others.

1118

SECTION XVI  Neurologic Disease

Clinical Presentation Although FSHD can affect people at all ages, most patients present in their late teens or early twenties with weakness in a characteristic pattern, often with dramatic side-­to-­side asymmetry: typically first in the face, shoulders, and arms, and later involving the trunk and distal lower extremities. Patients are unable to squeeze their eyes shut, have a transverse smile, scapular winging, loss of proximal muscle mass with often preserved forearm muscles, and a positive Beevor sign (movement of the umbilicus up or down when asked to tense the abdominal muscles). Extramuscular manifestations of FSHD are rare: retinal vascular changes, which can occasionally lead to symptomatic retinal vasculopathy termed Coat syndrome, high-­frequency hearing loss, and atrial arrhythmias.

Diagnosis and Differential Diagnosis Diagnosis is based on clinical examination and family history and is confirmed by genetic testing. The differential diagnosis includes other myopathies such as inclusion body myositis, limb-­girdle muscular dystrophies and acid maltase deficiency.

Treatment There are currently no pharmacologic disease-­modifying therapies available. However, several therapy approaches are being studied with the unifying goal to suppress DUX4. One drug is currently being tested in a multisite clinical trial. In the interim, treatment is supportive with ankle bracing and assistive devices. In selected patients surgical fixation of the scapular can improve function. Monitoring for retinal disease, hearing loss, and respiratory function is indicated.

Prognosis FSHD is not life limiting, but approximately 20% over the age of 50 will require a wheelchair.

CONGENITAL MYOPATHIES Congenital myopathies are defined by their appearance on biopsy (E-­Table 124.2; and see Fig. 142.1C) and have a large number of genetic mutations associated with them. They are usually present at birth with hypotonia and subsequent delayed motor development. If the child survives the perinatal period, most congenital myopathies are relatively nonprogressive and may not be diagnosed until the second or third decade. Clinical findings common in the congenital myopathies are reduced muscle bulk, slender body build, a long and narrow face, skeletal abnormalities (high-­arched palate, pectus excavatum, kyphoscoliosis, dislocated hips, and pes cavus), and absent or reduced muscle stretch reflexes.

METABOLIC MYOPATHIES Metabolic myopathies are muscle diseases due to mutations in enzymes responsible for energy production including glycogen, lipid, and mitochondrial metabolism (E-­Table 124.3). Classically, these disorders present in older children or adults with episodes of exercise intolerance, muscle cramping, myalgia, and recurrent rhabdomyolysis associated with myoglobinuria. Newborns and infants can present with severe multisystem disorders that are often fatal.

Glucose and Glycogen Metabolism Disorders Definition and Epidemiology

Glucose, and its storage from glycogen, is essential for the short-­term, predominantly anaerobic energy requirements of muscle (see E-­Table 124.3). Disorders of glucose and glycogen metabolism (called glycogenesis) have two distinct syndromes: (1) static symptoms of fixed weakness without exercise intolerance or myoglobinuria and (2) dynamic

symptoms of exercise intolerance, pain, cramps, and myoglobinuria. Acid maltase deficiency (Pompe disease) is an example of the first and is treatable with enzyme replacement therapy, which is life extending for the childhood variant. McArdle disease is an example of the second. The incidence varies between region and ethnic group. For example, acid maltase deficiency has an incidence as high as 1:14,000 in African Americans. The prevalence of McArdle disease is approximately 1:100,000.

Genetics and Pathology All are due to mutations in enzymes responsible for glucose or glycogen metabolism. Muscle biopsies usually show subsarcolemmal accumulation of glycogen.

Clinical Presentation Acid maltase disease typically has a severe infantile form with respiratory and cardiac involvement and a slowly progressive adult myopathy, which can present with respiratory muscle weakness as the initial symptom. McArdle disease presents with severe episodes of muscle cramping and contractures associated with exercise and a fixed myopathy later in life. Many patients note a “second wind” phenomenon, which means that after a brief period of rest patients can resume physical activity with improved tolerance.

Diagnosis and Differential Diagnosis Diagnosis is made by characteristic appearance on muscle biopsy with subsequent study of the enzyme activity or by searching for specific genetic mutations. The differential diagnosis includes other glycogen storage disorders, disorders of lipid metabolism, or mitochondrial disorders.

Treatment The only glycogen storage disorder with a therapy approved by the FDA is enzyme replacement for infantile or adult-­onset acid maltase deficiency. Therapies targeting the genetic mechanism of acid maltase deficiency are expected to enter clinical trials in the near future.

Prognosis The spectrum is wide from severe fatal infantile diseases to milder symptoms in adults.

DISORDERS OF FATTY ACID METABOLISM Disorders of lipid metabolism differ from glucose and glycogen disorders in that the metabolic derangement is in the enzymatic breakdown of fatty acids (see E-­Table 124.3). Many present in childhood with episodes of encephalopathy precipitated by fasting with hypoketotic hypoglycemia. Serum fatty acid profiles often show reduced carnitine and increased longer chain fractions, depending on whether the mutation is in very long chain, long chain, or medium chain fatty acid metabolism. Adults typically show exercise intolerance and myoglobinuria and may develop a mild limb-­girdle pattern myopathy. The most prevalent disorder of fatty acid metabolism is carnitine palmitoyltransferase II (CPT II) deficiency. This disease ranges from a lethal neonatal form to an adult form with muscle pain and recurrent myoglobinuria, often precipitated by exercise, febrile illness, or fasting. The diagnosis is usually made by detection of reduced CPT II activity in skeletal muscle with confirmatory genetic testing.

MITOCHONDRIAL MYOPATHIES Definition and Epidemiology Mitochondrial myopathies can present at any age, with varying degrees of severity or weakness, affect multiple organ systems, and have any

CHAPTER 124  Muscle Diseases

1118.e1

E-­TABLE 124.2 Congenital Myopathies Pathologic Finding

Associated Genes

Central core, multicore

19q13 RYR1 (ryanodine receptor); 1q36 SEPN1; 14q11 MYH7

Nemaline rod

Centronuclear

Fiber type disproportion (type 1) Reducing body Sarcotubular Myofibrillar

Phenotype

Surveillance

Limb-­girdle pattern weakness; scoliosis; Caution with anesthesia respiratory involvement; malignant hyperthermia susceptibility Sarcomeric thin filament genes: 1q42 Limb-­girdle pattern, hypotonia, absent Respiratory involvement; independent ACTA1; 1q21 TPM3; 9p13 TPM2; 2q23 tendon reflexes, facial weakness, ambulation by 18 months predictive NEB; 19q13 TNNT1; 14q13 CFN2; neck flexors of survival 3p22 KCHL40 Myotubular: Xq28 XMTM1; 19p13 Limb-­girdle pattern; hypotonia; respira- Respiratory involvement DNM2; 12q21 MYF6; 2q14 BIN1; tory involvement; cardiac rarely 19q13 RYR1; 2q31 TTN See nemaline rod; plus Xq13, 1p36 Limb-­girdle pattern, scoliosis, hypotoRespiratory involvement SEPN1 nia, respiratory involvement Xq26 FHL1 Limb-­girdle pattern, scoliosis, hypotoRespiratory involvement; cardiac late nia, respiratory involvement 9q31 TRIM32 Limb-­girdle pattern, scapular winging Desmin-­storage: 2q35 Desmin; 11q22 Limb-­girdle pattern, cardiomyopathy Cardiac involvement alpha beta crystalline; 5q31 myotilin; 10q23 ZASP; 2q32 filamin C; 10q25 BAG3

E-­TABLE 124.3 Selected Metabolic Myopathies Class

Enzyme/Gene

Phenotype

Glycogen Storage Type II Pompe disease

Name

Acid maltase/GAA, 17q21

Infantile: Hypotonia, cardiomegaly, hepatomegaly, fatal in 1st year without treatment. Adult: Limb-­girdle weakness, respiratory failure

Type III

Cori-­Forbes disease

Debrancher/AGL, 1p21

Type IV

Andersen disease

Branching/GBE1, 3p12

Type V

McArdle disease

Myophosphorylase/PYGM, 11q13, recessive

Type VII

Tarui disease

Phosphofructokinase/ PFKM, 12q13

Lipid Metabolism Carnitine palmitoyltransferase II deficiency Very long chain acylcoenzyme A dehydrogenase deficiency

CPT II, 1p32

ACADVL, 17p13

Testing

Muscle biopsy with non-­rimmed vacuoles and PAS positive material. Decreased enzyme activity in muscle, lymphocytes, or fibroblasts. Infantile: Hypotonia. Adult: Limb-­girdle pattern Muscle biopsy PAS positive glycogen with distal weakness, respiratory involvement deposits. Decreased enzyme activity in fibroblasts or lymphocytes. Infantile: Hypotonia. Adult: Limb-­girdle pattern, PAS-­positive, diastase-­resistant ± distal filamentous polysaccharides (polyglucosan bodies); decreased enzyme activity in skin fibroblasts, muscle or liver Infantile: Profound weakness. Adult: Exercise Electrically silent muscle contracintolerance, cramps, fatigue, limb-­girdle pattures; subsarcolemmal glycogen tern, second wind phenomenon, CK elevated deposits; decreased enzyme >90% activity from muscle Childhood: Cramps, fatigue, exercise intolerance Accumulation of free glycogen in muscle; hemolytic anemia; enzyme deficiency in muscle, erythrocytes Neonatal/infantile: Severe, fatal. Adult: Exercise Low total serum carnitine; increased or illness related, cramping, recurrent myogloacylcarnitine fraction; reduced binuria, usually no fixed weakness enzyme activity in skeletal muscle Childhood: Nonketotic hypoglycemia can have Reduced VLCAD activity in fibrosevere form with cardiomyopathy. Adult: blasts; increased lipid staining in Rare, exercise/fasting induced myalgias or muscle myoglobinuria Continued

1118.e2

SECTION XVI  Neurologic Disease

E-­TABLE 124.3 Selected Metabolic Myopathies—cont’d Class

Name

Phenotype

Testing

Long chain acylcoenzyme A ACADL, 2q34 dehydrogenase deficiency

Infancy: Failure to thrive, nonketotic hypoglycemia, cardiomegaly, encephalopathy. Adult: Myopathy with cramps and myoglobinuria

Medium chain acylcoenzyme A dehydrogenase deficiency

Infancy: Failure to thrive, nonketotic hypoglycemia, cardiomegaly, encephalopathy. Adult: Mild myopathy later in life

Reduced total and free carnitine levels; increased long chain acylcarnitine esters; reduced enzyme activity in fibroblasts Reduced total and free carnitine; decreased enzyme activity in lymphocytes, fibroblasts, and liver; excess lipid in muscle

Mitochondrial Myoclonic epilepsy associated with ragged red fibers (MERRF) Mitochondrial encephalopathy, lactic acidosis, and stroke-­like episodes (MELAS)

Enzyme/Gene

ACADM, 1p31

Mean onset 20s, epilepsy, myoclonus, ataxia, dementia, short stature, optic atrophy, Wolff Parkinson White syndrome Mitochondrial mutations, Onset variable, normal psychomotor devel≈80% m.3243 A>G opment, then episodes of encephalopathy, migraine, seizures, strokelike symptoms, anorexia and vomiting, short stature, deafness, myopathy with exercise intolerance Mitochondrial neurogastro- Genomic mutations, TYMP, Onset variable mostly motor neuropathy, hearing loss Kearns-­Sayre syndrome Single large mitochondrial Onset G

Nuclear: POLG 15q25; ANT1 4q35; Twinkle 10q23; POLG2 17q. Mitochondrial: deletions or depletion

GAA, Acid α-­glucosidase; GBE1, glycogen branching enzyme 1.

Muscle biopsy ragged red fibers; elevated lactic acid; mitochondrial sequencing Muscle biopsy ragged red fibers; elevated lactic acid; mitochondrial sequencing

Muscle biopsy ragged red fibers; elevated lactic acid; mitochondrial sequencing

Muscle biopsy ragged red fibers; elevated lactic acid; mitochondrial sequencing Muscle normal histology but COX negative; elevated lactate (CSF > blood); MRI high T2 in lentiform and caudate nuclei Onset variable typically >20 years; ptosis; Muscle biopsy ragged red fibers; ophthalmoparesis often without double vision; genetic testing or mitochondrial plus syndromes have myopathy and variable sequencing organ involvement

CHAPTER 124  Muscle Diseases pattern of inheritance (see E-­Table 124.3). Mutations affect enzymes necessary for normal mitochondrial function and can be mitochondrial or nuclear. The overall prevalence for mitochondrial disorders is thought to be approximately 1:8500; however, the prevalence of individual mitochondrial syndromes is much lower and ranges from just a handful of cases, to 1 to 6 per 100,000.

Genetics and Pathology Mutations can occur in both mitochondrial DNA (in which case inheritance is maternal) and nuclear DNA (autosomal dominant, recessive, or X-­linked). Mitochondrial disorders produce biochemical defects proximal to the respiratory chain (involving substrate transport and usage) or within the respiratory chain. On muscle biopsy, muscle fibers contain abnormal mitochondria. Pathologically, these fibers have a “ragged red” appearance on biopsy stains (trichrome) and fail to react for cytochrome C oxidase.

Clinical Presentation Despite the diversity, certain patterns are characteristic for mitochondrial disorders, including slowly progressive myopathy and myalgias, which worsen with exertion or illness, and ptosis and/or ophthalmoplegia. E-­Table 124.3 lists common clinical mitochondrial syndromes.

Diagnosis and Differential Diagnosis

1119

Clinical Presentation As the name implies, patients have myotonia (see Table 124.2). Chloride channel mutations have a characteristic warm-­up of myotonia with repetition. Sodium channel myotonias typically have more eye closure myotonia and can demonstrate a paradoxical worsening of myotonia with activity (paramyotonia). Symptoms usually start in the first decade, and patients can have a characteristic muscular build.

Diagnosis and Differential Diagnosis Diagnosis is based on family history, clinical examination, and electrodiagnostic testing. It is confirmed by genetic testing. The differential diagnosis includes myotonic dystrophy and secondary causes of myotonia (other myopathies and drugs associated with myotonia—e.g., statins, fibric acid derivatives, and colchicine).

Treatment Treatment for nondystrophic myotonias consists of non-­mutation– specific sodium-­channel blockade: mexiletine, a class IB antiarrhythmic, is the first-­line therapy, but ranolazine, phenytoin, procainamide, and flecainide can be considered. Certain sodium-­channel myotonias respond to the carbonic anhydrase inhibitor acetazolamide.

Periodic Paralyses

Definition and Epidemiology

The diagnosis is based on clinical history with recognition of multisystemic involvement, serum lactate levels, which can be elevated at rest, and characteristic findings on muscle biopsy. Diagnosis is confirmed by mitochondrial or nuclear genetic testing.

The periodic paralyses are disorders that present with episodic weakness often triggered by exercise or food. Overall prevalence for the primary periodic paralyses varies between conditions from 1:100,000 to 1:1,000,000.

Treatment

Genetics and Pathology

Treatment is largely supportive and includes identification of other multisystem involvement, including diabetes, cardiac and ophthalmologic involvement, and hearing loss. Many agents have been tried in mitochondrial diseases, including coenzyme Q10, creatine, and carnitine. Aerobic exercise may reduce fatigue and improve muscle function, although there are no large trials of efficacy for either supplements or exercise.

Periodic paralysis is caused by mutations in the calcium (CACN1AS), sodium (SCN4A), and potassium-­channel (KCNJ2) genes that result in depolarized but inexcitable sarcolemma and episodes of paralysis. Hyperkalemic periodic paralysis is due to sodium-­channel mutations that lead to persistent inward sodium current causing both myotonia and paralysis. Hypokalemic periodic paralysis can be caused by calcium-­, sodium-­, and potassium-­channel mutations and is due to an anomalous gating pore current that, in low potassium conditions, produces a depolarizing current larger than hyperpolarizing potassium currents. Andersen-­Tawil syndrome is due to loss of function in a potassium inward rectifier.

Prognosis The severity and prognosis depend partially on the load of abnormal mitochondrial DNA as well as the degree of multisystem involvement. Certain clinical syndromes with more predictable prognosis have been described (see E-­Table 124.3).

MUSCLE CHANNELOPATHIES The muscle channelopathies are a spectrum of disorders due to mutations in muscle ion channels commonly divided into the nondystrophic myotonias and periodic paralyses. Most are inherited in an autosomal dominant fashion, with episodic symptoms, often triggered by temperature or certain foods.

Nondystrophic Myotonias Definition and Epidemiology

Nondystrophic myotonias are due to dysfunction of sodium or chloride channels resulting in hyperexcitable muscle and myotonia. The overall worldwide prevalence for nondystrophic myotonias is 1:100,000.

Genetics Nondystrophic myotonias are caused by mutations in the muscle chloride (CLCN1) or sodium (SCN4A) channel genes causing alterations of depolarization and hyperpolarization of the muscle fiber membrane.

Clinical Presentation Common to all are attacks of weakness first presenting in childhood or early adulthood, often brought on by rest after exercise, or in the mornings, and associated with changes in extracellular potassium. Hyperkalemic periodic paralysis is associated with either high or normal extracellular potassium, triggered by potassium-­rich foods. In hypokalemic periodic paralysis attacks are associated with low extracellular potassium and are triggered by carbohydrates, stress, alcohol, or rest after exercise. Andersen-­Tawil syndrome is characterized by the clinical triad of attacks of flaccid paralysis, dysmorphic features (wide-­set eyes, narrow mandible, low-­set ears, bent fifth finger, and common origin for the second and third toes), and polymorphic ventricular tachyarrhythmias.

Diagnosis and Differential Diagnosis Diagnosis is based in family history and clinical history, supported by electrodiagnostic testing and confirmed by genetic testing.

Treatment In all of the periodic paralyses disorders mild exercise at onset of weakness can abort attacks of paralysis. Treatment for acute attacks

1120

SECTION XVI  Neurologic Disease

consists of carbohydrates (hyperkalemic periodic paralysis) or potassium supplementation (hypokalemic periodic paralysis). Prophylactic treatment for all the periodic paralyses consists of carbonic anhydrase inhibitors.

ACQUIRED MYOPATHIES Unlike the inherited myopathies, the acquired myopathies are typically secondary to another process: toxic, autoimmune, inflammatory, or infectious. Pathologic changes can be distinctive and are not due to mutations in muscle-­related proteins. Clinically, symptoms appear acutely or subacutely.

Inflammatory Myopathies The idiopathic inflammatory myopathies can be divided into dermatomyositis/polymyositis and sporadic inclusion body myositis (Table 124.8).

Dermatomyositis/Polymyositis Definition and epidemiology. Dermatomyositis/polymyositis (DM/PM) are acquired idiopathic diseases of muscle characterized by inflammation and variable symmetrical proximal muscle weakness, associated with elevated serum creatine kinase and irritable features on electromyography. The overall annual incidence is approximately 1 in 100,000. Pathology. Dermatomyositis shows a pathognomonic pattern on muscle biopsy of perifascicular atrophy and perivascular inflammatory infiltrates and positive pericapillary membrane attack complex staining (see Fig. 124.1D). In contrast, polymyositis shows endomysial inflammatory infiltrates with invasion of non-­necrotic fibers. Clinical presentation. Dermatomyositis can occur at any age with an acute to insidiously progressive onset of symmetrical proximal muscle weakness with characteristic skin changes, which include heliotrope rash, shawl sign (maculopapular violaceous rash in V-­shape around neck), Gottron nodules (erythematous papular rash on the extensor surfaces of the hands or fingers), and mechanic’s hands (dry, cracked skin on the dorsal or ventral hands). In contrast, polymyositis is largely a diagnosis of exclusion, occurring in adults without associated skin changes. Myalgias are more common in polymyositis. Both DM/PM can be associated with respiratory weakness, interstitial lung disease, difficulty swallowing, or cardiomyopathy. Both DM/ PM can be associated with underlying malignancy (dermatomyositis more frequently than polymyositis), so screening for malignancy is recommended especially in patients over age 40. Diagnosis and differential diagnosis. Diagnosis is based on clinical history and examination findings in conjunction with irritable

changes on electromyography (e.g., fibrillation potentials and positive sharp waves) and characteristic muscle biopsy. In about 30%, both DM/PM can be associated with myositis specific autoantibodies (see Table 124.2). Antibodies can help define a clinical syndrome and guide treatment. For example, patients with anti-­Jo-­1 antibodies can have interstitial lung disease and methotrexate may need to be avoided due to pulmonary toxicity. Patients may be at higher risk to develop malignancy with antibodies to transcription intermediary factor (TIF)-­ 1gamma (anti-­p155, anti-­p155/140) and to nuclear matrix protein (NXP)-­2 (anti-­MJ or anti-­p140). Muscle biopsy can help differentiate from other inflammatory myopathies associated with systemic disease (e.g., sarcoidosis). Treatment. For both DM/PM the first line of treatment is prednisone. Steroid-­ sparing immunosuppressive therapies (e.g., methotrexate, azathioprine) are often added for those patients requiring long-­term therapy in order to reduce the required dose of prednisone or to replace prednisone completely. In patients who do not respond to conventional therapy or have severe symptoms, intravenous immunoglobulin is used. Rituximab may also be effective. Prognosis. Most patients respond to immunosuppressive therapies.

Sporadic Inclusion Body Myositis Definition and epidemiology. Sporadic inclusion body myositis (s-­ IBM) is an idiopathic, slowly progressive muscle condition in older adults (occurring in more men than women), associated with inflammation and characteristic pathologic changes on muscle biopsy. It is the most common inflammatory muscle disease in patients over 50, affecting 3.5 per 100,000. Pathology. Muscle biopsies resemble polymyositis with endomysial inflammatory infiltrates and invasion of non-­ necrotic fibers. Distinctive for IBM are vacuoles rimmed by mitochondria, secondary mitochondrial changes, and electron microscopy, which shows 15-­to 18-­nm tubulofilamentous inclusions. Clinical presentation. S-­IBM causes slowly progressive, often asymmetric weakness. It occurs usually after 50 years of age in an initially distinctive pattern, including distal forearm muscles (distal finger flexors) and quadriceps wasting and weakness. This can progress to involve almost any muscle and can affect swallowing in up to 70% of patients. Diagnosis and differential diagnosis. Diagnosis is based on clinical history and examination and characteristic muscle pathology. In clinically challenging cases autoantibody levels directed against cytoplasmic 5′-­nucleotidase 1A (anti-­cN1A) can be helpful, with an estimated specificity around 90%. The main differential diagnosis is other idiopathic inflammatory myopathies or late-­ onset inherited

TABLE 124.8  Idiopathic Inflammatory Myopathies

Myopathy

Sex

Typical Age at Onset

Dermatomyositis Women > men Childhood and adult Polymyositis

Women > men Adult

Sporadic inclusion body myositis

Men > women Elderly (>50 yr)

Pattern of Weakness

Creatine Kinase

Proximal > distal, respiratory weakness, dysphagia Proximal > distal

Increased (up to 50× normal)

Proximal and distal; predilection for finger and wrist flexors, knee extensors

Increased (up to 50× normal) Increased (