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2. ANDREOLI and CARPENTERS C e c i l E s s e n t i a l s o f
MEDICINE 8th EDITION
3. This page intentionally left blank
4. ANDREOLI and CARPENTERS C e c i l E s s e n t i a l s o f
MEDICINE 8th EDITION Editor-in-Chief THOMAS E. ANDREOLI, MD, MACP,
FRCP (Edin.), FRCP (London), ScD (hon.), Docteur (hon.), MD (hon.)
Distinguished Professor Nolan Chair Emeritus Department of Internal
Medicine Department of Physiology and Biophysics University of
Arkansas College of Medicine Little Rock, Arkansas (Deceased)
Editors Ivor J. Benjamin, MD, FACC, FAHA Professor of Medicine
Adjunct Professor of Biochemistry Christi T. Smith Endowed Chair
for Cardiovascular Research Director, Center for Cardiovascular
Translational Biomedicine University of Utah School of Medicine
Salt Lake City, Utah Robert C. Griggs, MD, FACP, FAAN Professor of
Neurology, Medicine, Pediatrics, and Pathology and Laboratory
Medicine University of Rochester School of Medicine and Dentistry
Rochester, New York Edward J. Wing, MD, FACP, FIDSA Dean of
Medicine and Biological Sciences The Warren Alpert Medical School
of Brown University Providence, Rhode Island
5. 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA
19103-2899 ANDREOLI AND CARPENTERS CECIL ESSENTIALS OF MEDICINE
ISBN: 978-1-4160-6109-0 International Edition ISBN:
978-0-8089-2428-9 Copyright 2010 Elsevier Inc. All rights reserved.
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This book and the individual contributions contained in it are
protected under copyright by the Publisher (other than as may be
noted herein). Notices Knowledge and best practice in this eld are
constantly changing. As new research and experience broaden our
understanding, changes in research methods, professional practices,
or medical treatment may become necessary. Practitioners and
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in evaluating and using any information, methods, compounds, or
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contained in the material herein. Previous editions copyrighted
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Elsevier Inc. Library of Congress Cataloging-in-Publication Data
Andreoli and Carpenters Cecil essentials of medicine /
editor-in-chief, Thomas E. Andreoli; editors, Ivor J. Benjamin,
Robert C. Griggs, Edward J. Wing.8th ed. p. ; cm. Includes
bibliographical references and index. ISBN 978-1-4160-6109-0 1.
Internal medicineTextbooks. I. Andreoli, Thomas E., 1935-2009 II.
Cecil, Russell L. (Russell La Fayette), 1881-1965. III. Title:
Cecil essentials of medicine. IV. Title: Essentials of medicine.
[DNLM: 1. Internal Medicine. WB 115 A559 2010] RC46.C42 2010
616dc22 Cover: Hemoglobin subunit: Phantatomix / Photo Researchers,
Inc.; False-color (computer graphics) photograph of a resin cast of
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MRC-LMB / Photo Researchers, Inc.; Osteoarthritis of foot, X-ray:
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6. Dedication Thomas E. Andreoli When Dr. Thomas Andreoli died
of a cere- bral hemorrhage on April 14, 2009, he had nearly
completed the editorial oversight of this, the eighth edition of
the textbook he co-founded in 1986. In many ways this text- book
epitomizes his career as an educator, clinical scientist, and
international leader of the medical profession. As an outstanding,
life-long investigator in his chosen field of nephrology, Dr.
Andreoli served as president of both national and international
medical societies and was rec- ognized by honorary doctoral degrees
from both European and American universities. As a dedicated
bedside clinician and teacher, Dr. Andreoli served as an
outstanding chair of medicine, and endowed chairs in his name were
established at both the University of Alabama School of Medicine
and the University of Arkansas College of Medicine. His superlative
teaching was recognized by his receiving, inter alia, the Louis
Pasteur Award from the University Louis Pasteur, Mastership of the
American College of Physicians, and the Robert H. Williams
Distinguished Chair of Medicine Award from the Association of
Professors of Medicine. Perhaps Dr. Andreolis most distinguished
contribution was his lifelong Oslerian devotion to translating
medical science from bench to bedside. Despite his major national
and international commitments, he continued throughout his career
to hold morning resident teaching rounds five times weekly,
maintaining a broad knowledge of all aspects of internal medicine
and genuinely and gently transmitting that knowledge to two
generations of medical students. He was uniquely qualified for, and
committed to, imparting his wisdom and skill as a physician, which
provided the basis for his serving as a founding editor of
Essentials of Medicine, and editor-in-chief of its last three
editions. We feel immensely privileged to have been his co-editors
and friends, and we dedicate this text to Dr. Thomas Andreoli.
Charles C. J. Carpenter, MD, MACP Professor of Medicine Brown
Medical School Director, Brown University AIDS Center Providence,
Rhode Island Clementine M. Whitman No tribute to Dr. Andreolis
accomplishments would be complete without acknowledging the
contributions of Clementine Whitman, his personal assistant of 40
years, who moved with him from Alabama to Texas and to Arkansas.
Clementine was the hub of Dr. Andreolis professional and personal
life, meticulously handling every detail. Dr. Andreoli, a man as
demanding of others as of himself, was indeed blessed and fortunate
to have such a talented, dedicated, loyal, and hard-working person
by his side. Sudhir V. Shah, MD, FACP Professor of Medicine
Director, Division of Nephrology University of Arkansas College of
Medicine Little Rock, Arkansas Chief, Renal Section, Medicine
Service John L. McClellan Memorial Veterans Hospital Little Rock,
Arkansas
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8. Andreoli and Carpenters Cecil Essentials of Medicine
International Advisory Board NAME DISCIPLINE COUNTRY Professor J.
S. Bajaj Chief Consultant and Director Department of Diabetes,
Endocrine and Metabolic Medicine Batra Hospital and Medical
Research Centre New Delhi, India [email protected]
Endocrinology India Professor Massimo G. Colombo, MD Professor and
Chairman Department of Gastroenterology and Endocrinology IRCCS
Maggiore Hospital University of Milan Milan, Italy
[email protected] Hepatology/Gastroenterology Italy
Professor Bertrand Fontaine, MD Professor of Neurology Facult de
Mdecine Fdration des Maladies du Systme Nerveux Groupe Hospitalier
Piti-Salptrire Paris, France [email protected]
Neurology France Professor Arnoldo Guzmn-Sanchez Professor and
Chair Department of Obstetrics and Gynecology Hospital Civil de
Guadalajara Guadalajara, Jalisco, Mexico [email protected] Womens
Health Mexico Professor Kiyoshi Kurokawa, MD President, Science
Council of Japan Professor Emeritus, University of Tokyo Roppongi,
Minato-ku Tokyo, Japan [email protected] Nephrology
Japan Professor Umesh G. Lalloo, MD, FCCP Head, Department of
Pulmonology and HIV Nelson R. Mandela School of Medicine University
of Kwa-Zulu Natal Durban, South Africa [email protected] General
Internal Medicine/HIV South Africa Professor Pal Magyar Head,
Department of Pulmonary Medicine Semmelweis University Budapest,
Hungary [email protected] Pulmonary Medicine Hungary Professor
John Newsom-Davis, MD Emeritus Professor of Clinical Neurology
Radcliffe Infirmary Woodstock Road Oxford, United Kingdom
[email protected] Neurology United Kingdom
9. NAME DISCIPLINE COUNTRY Professor J. N. Pande Professor of
Medicine Department of Infectious Diseases Sita Ram Bhartia
Institute of Science and Research All India Institute of Medical
Sciences New Delhi, India [email protected] Infectious Diseases
India Dr. Mario Paredes-Espinoza Professor and Chair Department of
Internal Medicine Hospital Civil Fray Antonio Alcalde Guadalajara,
Jalisco, Mexico [email protected] Mens Health/General
Internal Medicine Mexico Professor Nestor Schor, MD, PhD Head
Professor of Medicine Nephrology Division UNIFESP-Escola Paulista
de Medicina So Paulo, Brazil [email protected] Nephrology
Brazil
10. ix Lead Authors and Contributors Section I Introduction to
Molecular Medicine Lead Author Ivor J. Benjamin, MD, FACC, FAHA
Professor of Medicine Adjunct Professor of Biochemistry Christi T.
Smith Endowed Chair in Cardiovascular Research Director, Center for
Cardiovascular Translational Biomedicine University of Utah School
of Medicine Salt Lake City, Utah [email protected] Section
II Evidence-Based Medicine Lead Authors Sara G. Tariq, MD Associate
Professor Department of Internal Medicine University of Arkansas
College of Medicine Little Rock, Arkansas [email protected] Susan
S. Beland, MD Associate Professor Department of Internal Medicine
University of Arkansas College of Medicine Little Rock, Arkansas
[email protected] Section III Cardiovascular Disease Lead
Author Ivor J. Benjamin, MD, FACC, FAHA Professor of Medicine
Adjunct Professor of Biochemistry Christi T. Smith Endowed Chair in
Cardiovascular Research Director, Center for Cardiovascular
Translational Biomedicine University of Utah School of Medicine
Salt Lake City, Utah [email protected] Contributors David
Bull, MD Professor of Surgery Director, Thoracic Surgery Residency
Program University of Utah School of Medicine Chief of
Cardiothoracic Surgery Salt Lake City VA Medical Center Salt Lake
City, Utah [email protected] Mohamed H. Hamdan, MD Professor
and Associate Division Chief Division of Cardiology University of
Utah School of Medicine Section Chief, Arrhythmia University of
Utah Healthcare Salt Lake City, Utah [email protected]
Dean Y. Li, MD, PhD Associate Professor Departments of Medicine and
Oncological Science Huntsman Cancer Institute University of Utah
School of Medicine Salt Lake City, Utah [email protected] Sheldon
E. Litwin, MD Amundsen Professor of Internal Medicine/Cardiology
Director of Cardiovascular Imaging University of Utah Hospital
University of Utah School of Medicine Salt Lake City, Utah
[email protected] Andrew D. Michaels, MD Associate
Professor of Internal Medicine Director, Cardiac Catheterization
Laboratory and Interventional Cardiology University of Utah School
of Medicine Salt Lake City, Utah [email protected] Jack
H. Morshedzadeh, MD Instructor Division of Cardiology University of
Utah School of Medicine Salt Lake City, Utah
[email protected] Josef Stehlik, MD Assistant
Professor of Internal Medicine Division of Cardiology University of
Utah School of Medicine Salt Lake City, Utah
[email protected] Kevin J. Whitehead, MD Associate
Professor of Cardiology University of Utah School of Medicine Salt
Lake City, Utah [email protected] Ronald G. Victor, MD
Associate Director Cedars-Sinai Heart Institute Director,
Cedars-Sinai Hypertension Center Los Angeles, California
[email protected]
11. x Lead Authors and Contributors Wanpen Vongpatanasin, MD
Associate Professor of Internal Medicine-Cardiology The University
of Texas Southwestern Medical School Dallas, Texas
[email protected] Section IV Pulmonary and
Critical Care Medicine Lead Author Sharon I. Rounds, MD Professor
of Medicine and of Pathology and Laboratory Medicine Brown Medical
School Chief of Pulmonary Critical Care Medicine Providence VA
Medical Center Providence, Rhode Island [email protected]
Contributors Jason M. Aliotta, MD Assistant Professor of Medicine
Division of Biology and Medicine Brown University Providence, Rhode
Island [email protected] Brian Casserly, MD Assistant
Professor of Medicine Brown University Providence, Rhode Island
[email protected] Matthew D. Jankowich, MD Instructor in
Medicine Division of Biology and Medicine Brown University
Providence, Rhode Island [email protected] F. Dennis
McCool, MD Chief, Pulmonary Critical Care Medicine Memorial
Hospital of Rhode Island Professor of Medicine Alpert Medical
School of Brown University Pawtucket, Rhode Island
[email protected] Section V Preoperative and Postoperative Care
Lead Author Kim A. Eagle, MD Albion Walter Hewlett Professor of
Internal Medicine Chief, Clinical Cardiovascular Medicine Director,
Cardiovascular Center University of Michigan Medical School Ann
Arbor, Michigan [email protected] Contributors Wei C. Lau, MD
Clinical Associate Professor Director, Adult Cardiovascular
Thoracic Anesthesiology Medical Director, Cardiovascular Center
Operating Rooms Department of Anesthesiology University of Michigan
Health System Ann Arbor, Michigan [email protected] Section VI
Renal Disease Lead Author Raymond C. Harris, MD Ann and Roscoe R.
Robinson Professor of Medicine Director, Division of Nephrology
Vanderbilt University School of Medicine Nashville, Tennessee
[email protected] Contributors Thomas E. Andreoli, MD,
MACP, FRCP (Edinburgh), FRCP (London), ScD (hon.), Docteur (hon.),
MD (hon.), Doctor (hon.) Distinguished Professor of Internal
Medicine and of Physiology and Biophysics Nolan Chairman Emeritus
of Internal Medicine University of Arkansas College of Medicine
Little Rock, Arkansas Amanda W. Basford, MD Kidney Associates, PLLC
6624 Fannin, Suite 1400 Houston, Texas [email protected]
Kerri L. Cavanaugh, MD Assistant Professor of Medicine Vanderbilt
University School of Medicine Nashville, Tennessee
[email protected] Jamie P. Dwyer, MD Assistant
Professor of Medicine, Nephrology and Hypertension Vanderbilt
University School of Medicine Nashville, Tennessee
[email protected] Thomas A. Golper, MD Professor of
Medicine/Nephrology Director, Medical Specialties Patient Care
Center Vanderbilt University School of Medicine Nashville,
Tennessee [email protected] Michelle W. Krause, MD, MPH
Assistant Professor of Medicine Division of Nephrology Department
of Internal Medicine University of Arkansas College of Medicine
Little Rock, Arkansas [email protected]
12. Lead Authors and Contributors xi T. Alp Ikizler, MD
Catherine McLaughlin Hakim Professor of Medicine Director, Clinical
Research in Nephrology Director, Master of Science in Clinical
Investigation Program Medical Director, Vanderbilt Outpatient
Dialysis Unit Division of Nephrology Vanderbilt University School
of Medicine Nashville, Tennessee [email protected] Julia
B. Lewis, MD Professor of Medicine Director, Fellowship Training
Division of Nephrology Vanderbilt University School of Medicine
Nashville, Tennessee [email protected] James M. Luther,
MD, MSCI Assistant Professor of Medicine Division of Nephrology
Vanderbilt University School of Medicine Nashville, Tennessee
[email protected] James L. Pirkle, MD Nephrology and
Hypertension Specialists, P.C. Dalton, Georgia [email protected]
Didier Portilla, MD Professor of Medicine Division of Nephrology
Department of Internal Medicine University of Arkansas College of
Medicine Little Rock, Arkansas [email protected] Robert L.
Safirstein, MD Professor, Executive Vice Chair Department of
Internal Medicine University of Arkansas College of Medicine Chief
of Medical Services Central Arkansas Veterans Hospital Little Rock,
Arkansas [email protected] Gerald Schulman, MD Professor
of Medicine Division of Nephrology Vanderbilt University School of
Medicine Nashville, Tennessee [email protected] Sudhir
V. Shah, MD Professor and Director Division of Nephrology
Department of Internal Medicine University of Arkansas College of
Medicine Little Rock, Arkansas [email protected] Roy Zent, MD
Associate Professor of Medicine, Cancer Biology, and Cell and
Developmental Biology Division of Nephrology Vanderbilt University
School of Medicine Nashville, Tennessee [email protected]
Section VII Gastrointestinal Disease Lead Author M. Michael Wolfe,
MD Professor of Medicine Research Professor of Physiology and
Biophysics Boston University School of Medicine Chief, Section of
Gastroenterology Boston Medical Center Boston, Massachusetts 02118
[email protected] Contributors Wanda P. Blanton, MD Instructor,
Department of Medicine Section of Gastroenterology Boston
University School of Medicine Boston, Massachusetts
[email protected] Charles M. Bliss Jr., MD, FACP Assistant
Professor of Medicine Section of Gastroenterology Boston University
School of Medicine Boston, Massachusetts [email protected]
Francis A. Farraye, MD, MSc Clinical Director, Section of
Gastroenterology Co-Director, Center for Digestive Disorders
Professor of Medicine Boston University School of Medicine Boston,
Massachusetts [email protected] Christopher S. Huang, MD
Instructor of Medicine Section of Gastroenterology Boston
University School of Medicine Boston, Massachusetts [email protected]
Brian C. Jacobson, MD, MPH Director of Endoscopic Ultrasonography
Associate Director of Endoscopy Services Boston Medical Center and
Assistant Professor of Medicine Boston University School of
Medicine Boston, Massachusetts [email protected]
13. xii Lead Authors and Contributors David R. Lichtenstein,
MD, FACG Director of Gastrointestinal Endoscopy Associate Professor
of Medicine Boston University School of Medicine Boston,
Massachusetts [email protected] Robert Lowe, MD Associate Professor of
Medicine Educational Director of the Section of Gastroenterology
Boston University School of Medicine Boston, Massachusetts
[email protected] Daniel S. Mishkin, MD, CM Director, The Endoscopy
Center of Brookline Instructor of Medicine Boston University School
of Medicine Boston, Massachusetts [email protected] T. Carlton
Moore, MD Assistant Professor in Medicine Section of
Gastroenterology Boston University School of Medicne Boston,
Massachusetts [email protected] Jaime A. Oviedo, MD, FACG
Greater Boston Gastroenterology Framingham, Massachusetts
[email protected] Marcos C. Pedrosa, MD, MPH Chief of Endoscopy
VA Boston HealthCare System Brigham and Womens Hospital Boston,
Massachusetts [email protected] Elihu M. Schimmel, MD
Director VA Advanced Specialty Training Program in Gastroenterology
and Hepatology Boston VA Hospital Boston, Massachusetts
[email protected] Paul C. Schroy, III, MD, MPH Director of
Clinical Research Section of Gastroenterology Associate Professor
of Medicine Boston University School of Medicine Associate
Professor of Epidemiology/Biostatistics Boston University School of
Public Health Boston, Massachusetts [email protected] Satish K. Singh,
MD Assistant Professor of Medicine Boston University School of
Medicine Staff Gastroenterologist VA Boston HealthCare System
Boston, MA 02118 [email protected] Chi-Chuan Tseng, MD, PhD Associate
Professor of Medicine Department of Medicine Boston University
School of Medicine Associate Chief Boston Veterans Administration
Health Care System Boston, Massachusetts [email protected] Section VIII
Diseases of the Liver and Biliary System Lead Author Michael B.
Fallon, MD Professor of Medicine Director, Division of
Gastroenterology, Hepatology and Nutrition The University of Texas
Medical School Houston, Texas [email protected]
Contributors Miguel R. Arguedas MD, MPH Assistant Professor
Division of Gastroenterology University of Alabama School of
Medicine MCLM 280 Birmingham, Alabama [email protected] Rudolf
Garcia-Gallont, MD Head, Department of Surgery Amedesgua Hospital
Guatemala City, Guatemala [email protected] Rajan Kochar,
MD Assistant Professor of Medicine Division of Gastroenterology,
Hepatology and Nutrition The University of Texas Medical School
Houston, Texas [email protected] Brendan M. McGuire, MD, MS
Associate Professor Medical Director, Liver
Transplantation/Medicine Liver Center, Department of Medicine
University of Alabama School of Medicine Birmingham, Alabama
[email protected] Klaus Mnkemller, MD Associate Professor Chief,
Endoscopy and Outpatient Clinic Division of Gastroenterology,
Hepatology and Infectious Diseases Otto-von-Guericke University
Magdeburg, Germany [email protected]
14. Lead Authors and Contributors xiii Helmut Neumann, MD
Faculty of Medicine Division of Gastroenterology, Hepatology and
Infectious Diseases Otto-von-Guericke University Magdeburg, Germany
[email protected] Aasim M. Sheikh, MD
Northwest Georgia Gastroenterology Associates Marietta, Georgia
[email protected] Shyam Varadarajulu, MD Assistant Professor,
Division of Gastroenterology Director, Interventional Endoscopy
University of Alabama at Birmingham Birmingham, Alabama
[email protected] Section IX Hematologic Disease Lead Author
Nancy Berliner, MD Professor of Medicine Harvard Medical School
Chief, Division of Hematology Brigham and Womens Hospital Boston,
Massachusetts [email protected] Contributors Jill Lacy, MD
Associate Professor of Medical Oncology Yale University School of
Medicine New Haven, Connecticut [email protected] Christine S.
Rinder, MD Associate Professor of Anesthesiology and Laboratory
Medicine Yale University School of Medicine Department of
Anesthesiology Yale-New Haven Hospital New Haven, Connecticut
[email protected] Henry M. Rinder, MD Professor of
Laboratory Medicine and Internal Medicine Director, Clinical
Hematology Laboratory Program Director, Clinical Pathology
Residency Training Yale University School of Medicine New Haven,
Connecticut [email protected] Michal G. Rose, MD Associate
Professor of Medicine Yale University School of Medicine Chief,
Cancer Center VA Connecticut HealthCare System New Haven,
Connecticut [email protected] Stuart E. Seropian, MD Associate
Professor of Medicine Yale Cancer Center Lymphoma, Leukemia and
Myeloma Program New Haven, Connecticut [email protected]
Christopher Tormey, MD Instructor, Laboratory Medicine Yale
University School of Medicine New Haven, Connecticut
[email protected] Richard Torres, MD Attending
Hematopathologist Yale University School of Medicine New Haven,
Connecticut [email protected] Eunice S. Wang, MD Research
Assistant Professor Leukemia Service, Departments of Medicine and
Immunology Staff Physician Leukemia Service Roswell Park Cancer
Institute Buffalo, New York [email protected] Section X
Oncologic Disease Lead Author Jennifer J. Griggs, MD, MPH Associate
Professor Department of Internal Medicine Division of
Hematology/Oncology Director, Breast Cancer Survivorship Program
University of Michigan Comprehensive Cancer Center University of
Michigan Medical School Ann Arbor, Michigan [email protected]
Contributors Barbara A. Burtness, MD Medical Oncologist Fox Chase
Cancer Center Philadelphia, Pennsylvania [email protected]
Alok A. Khorana, MD, FACP Assistant Professor of Medicine, James P.
Wilmot Cancer Center University of Rochester School of Medicine and
Dentistry Rochester, New York [email protected] Paula
M. Lantz, MD Professor and Chair Department of Health Management
and Policy Research Professor, Institute for Social Research
University of Michigan Health System Ann Arbor, Michigan
[email protected]
15. xiv Lead Authors and Contributors Robert F. Todd, III, MD,
PhD Margaret M. Alkek Distinguished Chair and Professor Department
of Medicine Baylor College of Medicine Houston, Texas
[email protected] Section XI Metabolic Disease Lead Author Robert J.
Smith, MD Director, Division of Endocrinology Director, Hallett
Center for Diabetes and Endocrinology Brown University Alpert
Medical School Providence, Rhode Island [email protected]
Contributors David G. Brooks, MD, PhD Medical Director, Global
Clinical Development Abraxis Bioscience, LLC Burlington,
Massachusetts [email protected] Geetha Gopalakrishnan, MD
Assistant Professor Division of Biology and Medicine Brown
University Alpert Medical School Providence, Rhode Island
[email protected] Osama Hamdy, MD Medical Director
Obesity Clinical Program Joslin Diabetes Center Assistant Professor
of Medicine Harvard Medical School Boston, Massachusetts
[email protected] Michelle P. Warren, MD Wyeth-Ayerst
Professor Founder and Medical Director Center for Menopause,
Hormonal Disorders and Womens Health Department of Obstetrics and
Gynecology Columbia University College of Physicians and Surgeons
New York, New York [email protected] Thomas R. Ziegler, MD
Professor of Medicine Atlanta Clinical and Translational Science
Institute Emory University School of Medicine Atlanta, Georgia
[email protected] Section XII Endocrine Disease Section Author
Glenn D. Braunstein, MD Professor of Medicine UCLA School of
Medicine Chair, Department of Medicine Cedars-Sinai Medical Center
Los Angeles, California [email protected] Contributors
Philip S. Barnett, MD, PhD Director Anna and Max Webb and Family
Diabetes Outpatient Treatment and Education Center Cedars Sinai
Medical Center Professor of Medicine David Geffen School of
Medicine University of California, Los Angeles Los Angeles,
California [email protected] Vivien S. Herman-Bonert, MD
Associate Professor of Medicine David Geffen School of Medicine
Division of Endocrinology University of California, Los Angeles
Attending Physician, Cedars Sinai Medical Center Los Angeles,
California [email protected] Theodore C. Friedman, MD, PhD
Associate Professor of Medicine UCLA School of Medicine
Endocrinology Division Cedars Sinai Medical Center Los Angeles,
California [email protected] Section XIII Womens Health Lead
Author Pamela A. Charney, MD Assistant Professor of Medicine Weill
Cornell Medical College New York, New York [email protected]
Contributors Patricia I. Carney, MD Department of Obstetrics and
Gynecology Christiana Care Health Services Newark, Delaware
[email protected]
16. Lead Authors and Contributors xv Deborah B. Ehrenthal, MD,
FACP Departments of Internal Medicine and Obstetrics and Gynecology
Christiana Care Health Services Newark, Delaware Clinical Assistant
Professor of Medicine Thomas Jefferson University Philadelphia,
Pennsylvania [email protected] Renee K. Kottenhahn, MD
Department of Pediatrics Christiana Care Health Services Newark,
Delaware [email protected] Section XIV Mens Health
Lead Author Joseph A. Smith, Jr., MD Professor and Chair Department
of Urologic Surgery Vanderbilt University School of Medicine
Nashville, Tennessee [email protected] Contributors
Douglas F. Milam, MD Associate Professor Department of Urologic
Surgery Vanderbilt University School of Medicine Nashville,
Tennessee [email protected] Johnathan S. Starkman, MD
Clinical Instructor Department of Urologic Surgery Vanderbilt
University School of Medicine Nashville, Tennessee
[email protected] Section XV Diseases of Bone and Bone
Mineral Metabolism Lead Author Andrew F. Stewart, MD Professor of
Medicine Chief, Division of Endocrinology and Metabolism University
of Pittsburgh School of Medicine Pittsburgh, Pennsylvania
[email protected] Contributors Susan L. Greenspan, MD Professor of
Medicine Director, Osteoporosis Prevention and Treatment Center
Associate Program Director, General Clinical Research Center
University of Pittsburgh School of Medicine Pittsburgh,
Pennsylvania [email protected] Steven P. Hodak, MD Clinical
Assistant Professor of Medicine Medical Director, Center for
Diabetes and Endocrinology University of Pittsburgh School of
Medicine Pittsburgh, Pennsylvania [email protected] Mara J. Horwitz,
MD Assistant Professor of Medicine Division of Endocrionology
University of Pittsburgh School of Medicine Pittsburgh,
Pennsylvania [email protected] Shane O. LeBeau, MD Clinical
Assistant Professor of Medicine Center for Diabetes and
Endocrinology University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania [email protected] G. David Roodman, MD, PhD
Professor of Medicine University of Pittsburgh Hillman Cancer
Center Pittsburgh, Pennsylvania [email protected] Section XVI
Musculoskeletal and Connective Tissue Disease Lead Author Larry W.
Moreland, MD Margaret Jane Miller Endowed Professor of Arthritis
Research Chief, Division of Rheumatology and Clinical Immunology
University of Pittsburgh School of Medicine Pittsburgh,
Pennsylvania [email protected] Contributors Surabhi Agarwal,
MD Medical Resident University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania [email protected] Dana P. Ascherman, MD
Assistant Professor of Medicine Divison of Rheumatology and
Clinical Immunology University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania [email protected] Robyn T. Domsic, MD
Assistant Professor of Medicine Division of Rheumatology and
Clinical Immunology University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania [email protected]
17. xvi Lead Authors and Contributors Jennifer Rae Elliott, MD
Division of Rheumatology and Clinical Immunology University of
Pittsburgh School of Medicine Pittsburgh, Pennsylvania
[email protected] Amy H. Kao, MD, MPH Assistant Professor of
Medicine Division of Rheumatology and Clinical Immunology
University of Pittsburgh School of Medicine Pittsburgh,
Pennsylvania [email protected] Fotios Koumpouras, MD Assistant
Professor of Medicine Medical Director, Lupus Center of Excellence
Division of Rheumatology and Clinical Immunology University of
Pittsburgh School of Medicine Pittsburgh, Pennsylvania
[email protected] C. Kent Kwoh, MD Professor of Medicine
Division of Rheumatology and Clinical Immunology University of
Pittsburgh School of Medicine Pittsburgh, Pennsylvania
[email protected] Douglas W. Lienesch, MD Assistant Professor of
Medicine Division of Rheumatology and Clinical Immunology
University of Pittsburgh School of Medicine Pittsburgh,
Pennsylvania [email protected] Kathleen McKinnon-Maksimowicz, DO
Assistant Professor of Medicine Division of Rheumatology and
Clinical Immunology University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania [email protected] Thomas A. Medsger,
Jr., MD Gerald P. Rodnan Professor of Medicine Division of
Rheumatology and Clinical Immunology Director, Scleroderma Research
Program University of Pittsburgh School of Medicine Pittsburgh,
Pennsylvania [email protected] Niveditha Mohan, MD Assistant
Professor of Medicine Division of Rheumatology and Clinical
Immunology University of Pittsburgh School of Medicine Pittsburgh,
Pennsylvania [email protected] Section XVII Infectious Disease Lead
Author Edward J. Wing, MD, FACP, FIDSA Dean of Medicine and
Biological Sciences The Warren Alpert Medical School of Brown
University Providence, Rhode Island [email protected] Contributors
Keith B. Armitage, MD Professor of Medicine Vice Chair for
Education Department of Medicine Co-Director, Medicine/Pediatrics
Residency Director, Internal Medicine Residency Training Program
Case Western Reserve University Cleveland, Ohio [email protected] Curt
G. Beckwith, MD Assistant Professor of Medicine Division of
Infectious Diseases Brown Medical School Providence, Rhode Island
[email protected] David A. Bobak, MD Associate Professor
Division of Infectious Diseases Case Western Reserve University
University Hospitals of Cleveland Cleveland, Ohio
[email protected] Jessica K. Fairley, MD Division of Infectious
Disease and HIV Medicine Case Western Reserve University Division
of Infectious Disease University Hospitals Cleveland, Ohio
[email protected] Scott A. Fulton, MD Assistant Professor
Division of Infectious Diseases Case Western Reserve University
University Hospitals of Cleveland Cleveland, Ohio
[email protected] Corrilynn O. Hileman, MD Internal Medicine
Infectious Disease Case Western Reserve University Cleveland, Ohio
[email protected]
18. Lead Authors and Contributors xvii Christoph Lange, MD, PhD
Medical Clinic Borstel Research Center Borstel, Germany
[email protected], [email protected] Michael M. Lederman, MD
Scott R. Inkley Professor of Medicine Case Western Reserve
University Co-Director, CWRU/University Hospitals of Cleveland
Center for AIDS Research Cleveland, Ohio [email protected]
Tracy L. Lemonovich, MD Instructor Division of Infectious Diseases
and HIV Medicine Case Western Reserve University Cleveland, Ohio
[email protected] Michelle V. Lisagaris, MD
Assistant Professor Department of Medicine University Hospitals of
Cleveland Cleveland, Ohio [email protected] Amy J. Ray, MD Clinical
Instructor and Division Chief University Hospitals Richmond Medical
Center Infectious Diseases Division University Hospitals, School of
Medicine Case Western Reserve University Cleveland, Ohio
[email protected] Benigno Rodriguez, MD Assistant Professor
Department of Medicine Case Western Reserve University Cleveland,
Ohio [email protected] Robert A. Salata, MD
Division Chief Division of Infectious Diseases and HIV Medicine
Case Western Reserve University Cleveland, Ohio [email protected]
Richard R. Watkins, MD, MS Division of Infectious Diseases Akron
General Medical Center Akron, Ohio Section XVIII Bioterrorism Lead
Author Robert W. Bradsher, Jr., MD Richard V. Ebert Professor of
Internal Medicine Vice-Chair for Education, Department of Internal
Medicine Director, Division of Infectious Diseases University of
Arkansas College of Medicine Little Rock, Arkansas
[email protected] Section XIX Neurologic Disease Lead Author
Robert C. Griggs, MD, FACP, FAAN Professor of Neurology, Medicine,
Pathology and Laboratory Medicine, and Pediatrics University of
Rochester School of Medicine and Dentistry Rochester, New York
[email protected] Contributors Michel J. Berg, MD
Associate Professor of Neurology and Medical Director, Strong
Epilepsy Center University of Rochester School of Medicine and
Dentistry Rochester, New York [email protected] Emma
Ciafaloni, MD Associate Professor Department of Neurology (SMD)
University of Rochester School of Medicine and Dentistry Rochester,
New York [email protected] Timothy J. Counihan, MD,
MRCPI Department of Neurology Galway University Hospital Galway,
Ireland [email protected] William P. Cheshire Jr., MD
Professor of Neurology Mayo Clinic Jacksonville, Florida
[email protected] Emily C. de los Reyes, MD Associate Professor of
Clinical Pediatrics and Neurology Nationwide Childrens Hospital The
Ohio State University Columbus, Ohio
[email protected]
19. xviii Lead Authors and Contributors Jennifer J. Griggs, MD,
MPH Associate Professor Department of Internal Medicine Division of
Hematology/Oncology Director, Breast Cancer Survivorship Program
University of Michigan Comprehensive Cancer Center University of
Michigan Medical School Ann Arbor, Michigan [email protected]
Carlayne E. Jackson, MD Professor of Neurology University of Texas
Medical School San Antonio, Texas [email protected] Kevin A.
Kerber, MD Assistant Professor Department of Neurology Director,
Dizziness Clinic University of Michigan Medical School Ann Arbor,
Michigan [email protected] Lynn C. Liu, MD Chief, Strong Sleep
Disorders Center Department of Neurology University of Rochester
School of Medicine and Dentistry Rochester, New York
[email protected] Geoffrey S.F. Ling, MD, PhD Defense
Advanced Research Projects Agency Defense Sciences Office
Arlington, Virginia [email protected] Jeffery M. Lyness, MD
Professor and Associate Chair for Education Department of
Psychiatry Director of Curriculum, Office of Curriculum and
Assessment University of Rochester School of Medicine and Dentistry
Rochester, New York [email protected] Deborah
Joanne Lynn, MD Associate Professor The Ohio State University
Department of Neurology Director, Department of Neurology Medical
Student Education Staff Neurologist The Ohio State University
Medical Center and The Arthur James Cancer Hospital and Research
Institute Co-director, Ohio State University Multiple Sclerosis
Center Columbus, Ohio [email protected] Frederick J. Marshall, MD
Associate Professor Department of Neurology (SMD) University of
Rochester Rochester, New York [email protected]
Allan McCarthy, MD, MRCPI Department of Neurology Galway University
Hospital Galway, Ireland [email protected] Sinad M. Murphy, BA,
MB, BCh, MRCPI Department of Neurology Galway University Hospital
Galway, Ireland [email protected] Avindra Nath, MD Professor of
Neurology Johns Hopkins University Baltimore, Maryland
[email protected] E. Steve Roach, MD Vice Chair for Clinical Affairs
Department of Pediatrics Director, Division of Pediatric Neurology
Professor of Child Neurology Nationwide Childrens Hospital The Ohio
State University Columbus, Ohio [email protected]
Lisa R. Rogers, DO Director, Medical Neuro-Oncology University
HospitalsCase Medical Center and Professor of Neurology Department
of Neurology Case Western University School of Medicine Cleveland,
Ohio [email protected] Roger P. Simon, MD Chair and Director
R.S. Dow Neurobiology Laboratories Legacy Research Hospital and
Adjunct Professor Neurology, Physiology and Pharmacology Oregon
Health and Science University Portland, Oregon
[email protected] Section XX The Aging Patient Lead Author
Harvey J. Cohen, MD Walter Kempner Professor and Chair of Medicine
Director, Center for the Study of Aging and Human Development Duke
University School of Medicine Durham, North Carolina
[email protected]
20. Lead Authors and Contributors xix Contributor Mitchell T.
Heflin, MD, MHS Assistant Professor of Medicine and Geriatrics
Center for the Study of Aging and Human Development Duke University
School of Medicine Durham, NC Durham, North Carolina
[email protected] Section XXI Palliative Care Lead Authors
Timothy E. Quill, MD Professor of Medicine, Psychiatry and Medical
Humanities Director, Palliative Care Program University of
Rochester School of Medicine Rochester, New York
[email protected] Robert G. Holloway, MD, MPH
Professor, Department of Neurology Professor, Department of
Community and Preventive Medicine (SMD) Rochester, New York
[email protected] Section XXII Alcohol and
Substance Abuse Lead Authors L. David Hillis, MD Dan Parman
Distinguished Professor Chair, Department of Internal Medicine
University of Texas Medical School San Antonio, Texas
[email protected] Richard A. Lange, MD Professor and Executive
Vice-Chair Department of Medicine University of Texas Medical
School San Antonio, Texas [email protected]
21. This page intentionally left blank
22. xxi Preface This is the eighth edition of Andreoli and
Carpenters Cecil Essentials of Medicine. Essentials VIII, like its
predecessors, is intended to be comprehensive but concise.
Essentials VIII therefore provides an exacting and thoroughly
updated trea- tise on internal medicine, without excessive length,
for stu- dents of medicine at all levels of their careers. We
welcome with enthusiasm a new editor, Edward J. Wing, MD, Frank L.
Day Professor of Biology, and Dean of Medicine and Biological
Sciences at Brown University Warren Alpert Medical School.
Essentials VIII has three cardinal components. First, at the
beginning of each sectionkidney,for examplewe provide a brief but
rigorous summary of the fundamental biology of the kidney and/or
the cardinal signs and symptoms of dis- eases of the kidney. The
same format has been used in all the sections of the book. Second,
the main body of each section contains a detailed, but again,
concise description of the diseases of the various organ systems,
together with their pathophysiology and their treatment. Finally,
Essentials relies heavily on the Internet. Essentials VIII is
published entirely on a Web site on the Internet. In the online
version of Essentials VIII, we provide a substantial amount of
supplemental material, indicated in the hard copy text by boldface
symbols (for example, Web Fig. 1) and denoted by an arrow icon
shown in the margin of this page. This icon is present throughout
the hard copy of the book as well as in the Internet version and
directs the reader to a series of illustrations, tables, or videos
in the Internet version of Essentials. This material is clearly
crucial to understanding modern medicine, but we hope that, in this
manner, the supplemental material will enrich Essentials VIII
without having enlarged the book significantly. As in prior
editions, we make abundant use of 4-color illustrations. And as in
prior editions, each section has been reviewed by one or another of
the editors, and finally by the editor-in-chief. We thank James T.
Merritt, Senior Acquisitions Editor, Medical Education, of
Elsevier, Inc., and especially Rebecca Gruliow, Managing Editor for
Global Medicine, Elsevier, Inc. Both Jim Merritt and Rebecca
Gruliow contributed heartily to the preparation of this eighth
edition of Essentials. Lastly, we thank our very able secretarial
staff, Ms. Clementine M. Whitman (Little Rock); Ms. Barbara S.
Bottone (Providence); Ms. Shirley E. Thomas (Rochester); Ms.
Jennifer F. Schroff (Salt Lake City); and Ms. Jean M. Drinan, and
Ms. Catarina A. Santos (Providence). The Editors
23. This page intentionally left blank
24. xxiii Contents SECTION I Introduction to Molecular Medicine
1 1 Molecular Basis of Human Disease 2 Ivor J. Benjamin SECTION II
Evidence-Based Medicine 15 2 Evidence-Based Medicine, Quality of
Life, and the Cost of Medicine 16 Sara G. Tariq and Susan S. Beland
SECTION III Cardiovascular Disease 21 3 Structure and Function of
the Normal Heart and Blood Vessels 22 Jack Morshedzadeh, Dean Y. Li
and Ivor J. Benjamin 4 Evaluation of the Patient with
Cardiovascular Disease 32 Sheldon E. Litwin and Ivor J. Benjamin 5
Diagnostic Tests and Procedures in the Patient with Cardiovascular
Disease 46 Sheldon E. Litwin 6 Heart Failure and Cardiomyopathy 66
Sheldon E. Litwin and Ivor J. Benjamin 7 Congenital Heart Disease
75 Kevin J. Whitehead 8 Acquired Valvular Heart Disease 84 Sheldon
E. Litwin 9 Coronary Heart Disease 95 Andrew D. Michaels 10 Cardiac
Arrhythmias 118 Mohamed H. Hamdan 11 Pericardial and Myocardial
Disease 145 Josef Stehlik and Ivor J. Benjamin 12 Other Cardiac
Topics 156 David A. Bull and Ivor J. Benjamin 13 Vascular Diseases
and Hypertension 165 Wanpen Vongpatanasin and Ronald G. Victor
SECTION IV Pulmonary and Critical Care Medicine 187 14 The Lung in
Health and Disease 188 Sharon Rounds and Matthew D. Jankowich 15
General Approach to Patients with Respiratory Disorders 192 Brian
Casserly and Sharon Rounds 16 Evaluating Lung Structure and
Function 198 F. Dennis McCool 17 Obstructive Lung Diseases 213
Matthew D. Jankowich 18 Interstitial Lung Diseases 225 Jason M.
Aliotta and Matthew D. Jankowich 19 Pulmonary Vascular Disease 241
Sharon Rounds 20 Disorders of Respiratory Control 245 Sharon Rounds
and Matthew D. Jankowich 21 Disorders of the Pleura, Mediastinum,
and Chest Wall 248 F. Dennis McCool 22 Infectious Diseases of the
Lung 254 Brian Casserly and Sharon Rounds 23 Essentials In Critical
Care Medicine 259 Brian Casserly and Sharon Rounds 24 Neoplastic
Disorders of the Lung 266 Matthew D. Jankowich and Jason M. Aliotta
SECTION V Preoperative and Postoperative Care 273 25 Preoperative
and Postoperative Care 274 Wel C. Lau and Kim A. Eagle SECTION VI
Renal Disease 26 Elements of Renal Structure and Function 286
Robert L. Safirstein 27 Approach to the Patient with Renal Disease
298 Michelle W. Krause, Thomas A. Golper, Raymond C. Harris and
Sudhir V. Shah 28 Fluid and Electrolyte Disorders 305 Thomas E.
Andreoli and Robert L. Safirstein 29 Glomerular Diseases 323 Jamie
P. Dwyer and Julia B. Lewis
25. xxiv Contents 30 Major Nonglomerular Disorders 333 James L.
Pirkle, Amanda W. Basford and Roy Zent 31 Vascular Disorders of the
Kidney 345 James M. Luther and Gerald Schulman 32 Acute Kidney
Injury 359 Didier Portilla and Sudhir V. Shah 33 Chronic Renal
Failure 369 Kerri Cavanaugh and T. Alp Ikizler SECTION VII
Gastrointestinal Disease 381 34 Common Clinical Manifestations of
Gastrointestinal Disease 382 A. Abdominal Pain 382 Charles M.
Bliss, Jr. and M. Michael Wolfe B. Gastrointestinal Hemorrhage 385
T. Carlton Moore, Chi-Chuan Tseng and M. Michael Wolfe C.
Malabsorption 389 Marcos C. Pedrosa and Elihu M. Schimmel D.
Diarrhea 396 Satish K. Singh 35 Endoscopic and Imaging Procedures
401 Brian C. Jacobson and Daniel S. Mishkin 36 Esophageal Disorders
408 Robert C. Lowe and M. Michael Wolfe 37 Diseases of the Stomach
and Duodenum 414 Wanda P. Blanton, Jaime A. Oviedo and M. Michael
Wolfe 38 Inflammatory Bowel Disease 430 Christopher S. Huang and
Francis A. Farraye 39 Neoplasms of the Gastrointestinal Tract 439
Paul C. Schroy III 40 Diseases of the Pancreas 445 David R.
Lichtenstein SECTION VIII Diseases of the Liver and Biliary System
455 41 Laboratory Tests in Liver Disease 456 Rajan Kochar and
Michael B. Fallon 42 Jaundice 460 Klaus Mnkemller, Helmut Neumann
and Michael B. Fallon 43 Acute and Chronic Hepatitis 466 Rajan
Kochar, Aasim M. Sheikh and Michael B. Fallon 44 Fulminant Hepatic
Failure 476 Brendan M. McGuire and Michael B. Fallon 45 Cirrhosis
of the Liver and its Complications 478 Rajan Kochar, Miguel R.
Arguedas and Michael B. Fallon 46 Disorders of the Gallbladder and
Biliary Tract 488 Shyam Varadarajulu, Rudolf Garcia-Gallont and
Michael B. Fallon SECTION IX Hematologic Disease 495 47
Hematopoiesis and Hematopoietic Failure 496 Eunice S. Wang and
Nancy Berliner 48 Clonal Disorders of the Hematopoietic Stem Cell
507 Eunice S. Wang and Nancy Berliner 49 Disorders of Red Blood
Cells 520 Michal G. Rose and Nancy Berliner 50 Clinical Disorders
of Neutrophils 533 Michal G. Rose and Nancy Berliner 51 Disorders
of Lymphocytes 539 Jill Lacy and Stuart Seropian 52 Normal
Hemostasis 555 Christine S. Rinder and Henry M. Rinder 53 Disorders
of Hemostasis: Bleeding 564 Christopher A. Tormey and Henry M.
Rinder 54 Disorders of Hemostasis: Thrombosis 580 Richard Torres
and Henry M. Rinder SECTION X Oncologic Disease 593 55 Cancer
Biology and Etiologic Factors 594 Alok A. Khorana and Barbara A.
Burtness 56 Cancer Epidemiology and Cancer Prevention 598 Paula M.
Lantz and Jennifer J. Griggs 57 Solid Tumors 603 Robert F. Todd lll
and Jennifer J. Griggs 58 Complications of Cancer and Cancer
Treatment 616 Alok A. Khorana and Jennifer J. Griggs
26. Contents xxv 59 Principles of Cancer Therapy 621 Alok A.
Khorana and Barbara A. Burtness SECTION XI Metabolic Disease 629 60
Obesity 630 Osama Hamdy and Robert J. Smith 61 Anorexia Nervosa and
Bulimia Nervosa 635 Michelle P. Warren 62 Malnutrition, Nutritional
Assessment, and Nutritional Support in Adult Patients 638 Thomas R.
Ziegler 63 Disorders of Lipid Metabolism 643 Geetha Gopalakrishnan
and Robert J. Smith 64 Disorders of Metals and Metalloproteins 651
David G. Brooks SECTION XII Endocrine Disease 659 65
Hypothalamic-Pituitary Axis 660 Vivien S. Herman-Bonert 66 Thyroid
Gland 670 Vivien S. Herman-Bonert and Theodore C. Friedman 67
Adrenal Gland 679 Theodore C. Friedman 68 Male Reproductive
Endocrinology 691 Glenn D. Braunstein 69 Diabetes Mellitus 697
Philip S. Barnett and Glenn D. Braunstein 70 Hypoglycemia 721
Philip S. Barnett SECTION XIII Womens Health 729 71 Womens Health
Topics 730 Deborah Ehrenthal, Patricia Carney, Renee Kottenhahn and
Pamela Charney A. Introduction 730 B. Preventive Health
Recommendations for Women 733 C. Health Issues Across the Life
Course 734 D. Special Topics 745 SECTION XIV Mens Health 751 72
Mens Health Topics 752 Jonathan S. Starkman, Douglas F. Milam and
Joseph A. Smith, Jr. A. Benign Prostatic Hyperplasia 752 B.
Prostatitis 757 C. Erectile Dysfunction 759 D. Carcinomas of Men
763 E. Benign Scrotal Diseases 768 SECTION XV Diseases of Bone and
Bone Mineral Metabolism 771 73 Normal Physiology of Bone and
Mineral Homeostasis 772 Andrew F. Stewart 74 Disorders of Serum
Minerals 783 Steven P. Hodak and Andrew F. Stewart 75 Metabolic
Bone Diseases 795 Shane O. LeBeau and Andrew F. Stewart 76
Osteoporosis 802 Susan L. Greenspan 77 Paget Disease of Bone 811
Mara J. Horwitz and G. David Roodman SECTION XVI Musculoskeletal
and Connective Tissue Disease 817 78 Approach to the Patient with
Rheumatic Disease 818 Niveditha Mohan 79 Rheumatoid Arthritis 823
Larry W. Moreland 80 Spondyloarthropathies 829 Douglas W. Lienesch
81 Systemic Lupus Erythematosus 834 Jennifer Rae Elliot 82
Antiphospholipid Antibody Syndrome 841 Surabhi Agarwal and Amy H.
Kao 83 Systemic Sclerosis (Scleroderma) 844 Robyn T. Domsic and
Thomas A. Medsger, Jr. 84 Idiopathic Inflammatory Myopathies 850
Larry W. Moreland 85 Sjgren Syndrome 855 Fotios Koumpouras
27. xxvi Contents 86 Systemic Vasculitis 858 Kathleen
Maksimowicz-Mckinnon 87 Crystal Arthropathies 864 Dana P. Ascherman
88 Osteoarthritis 870 C. Kent Kwoh 89 Nonarticular Soft Tissue
Disorders 873 Niveditha Mohan 90 Rheumatic Manifestations of
Systemic Disorders 878 Fotios Koumpouras SECTION XVII Infectious
Disease 883 91 Organisms that Infect Humans 884 Benigno Rodrguez
and Michael M. Lederman 92 Host Defenses Against Infection 890
Benigno Rodrguez and Michael M. Lederman 93 Laboratory Diagnosis of
Infectious Diseases 898 Benigno Rodrguez and Michael M. Lederman 94
Antimicrobial Therapy 904 Benigno Rodrguez and Michael M. Lederman
95 Fever and Febrile Syndromes 910 Tracy L. Lemonovich and Robert
A. Salata 96 Bacteremia and Sepsis Syndrome 925 Richard R. Watkins
and Robert A. Salata 97 Infections of the Nervous System 933 Scott
A. Fulton and Robert A. Salata 98 Infections of the Head and Neck
945 Christoph Lange and Michael M. Lederman 99 Infections of the
Lower Respiratory Tract 951 Christoph Lange and Michael M. Lederman
100 Infections of the Heart and Blood Vessels 961 Benigno Rodrguez
and Michael M. Lederman 101 Skin and Soft Tissue Infections 969
Christoph Lange and Michael M. Lederman 102 Intra-Abdominal Abscess
and Peritonitis 975 Christoph Lange and Michael M. Lederman 103
Infectious Diarrhea 979 Christoph Lange and Michael M. Lederman 104
Infections Involving Bones and Joints 985 Christoph Lange and
Michael M. Lederman 105 Infections of the Urinary Tract 989
Christoph Lange and Michael M. Lederman 106 Health CareAssociated
Infections 992 Amy J. Ray, Michelle V. Lisgaris and Robert A.
Salata 107 Sexually Transmitted Infections 998 Corrilynn O.
Hileman, Keith B. Armitage and Robert A. Salata 108 Human
Immunodeficiency Virus Infection and Acquired Immunodeficiency
Syndrome 1008 Curt G. Beckwith, Edward J. Wing, Benigno Rodrguez
and Michael M. Lederman 109 Infections in the Immunocompromised
Host 1028 Tracy Lemonovich, David A. Bobak and Robert A. Salata 110
Infectious Diseases of Travelers: Protozoal and Helminthic
Infections 1034 Jessica K. Fairley, Keith B. Armitage and Robert A.
Salata SECTION XVIII Bioterrorism 1043 111 Bioterrorism 1044 Robert
W. Bradsher, Jr. SECTION XIX Neurologic Disease 1051 112 Neurologic
Evaluation of the Patient 1052 Frederick J. Marshall 113 Disorders
of Consciousness 1058 Roger P. Simon 114 Disorders of Sleep 1064
Lynn Liu 115 Cortical Syndromes 1068 Sinad M. Murphy and Timothy J.
Counihan 116 Dementia and Memory Disturbances 1072 Frederick J.
Marshall 117 Major Disorders of Mood, Thoughts, and Behavior 1077
Jeffrey M. Lyness
28. Contents xxvii 118 Disorders of Thermal Regulation 1083
William P. Cheshire, Jr. 119 Headache, Neck Pain, and Other Painful
Disorders 1086 Timothy J. Counihan 120 Disorders of Vision and
Hearing 1096 Allan McCarthy and Timothy J. Counihan 121 Dizziness
and Vertigo 1104 Kevin A. Kerber 122 Disorders of the Motor System
1108 Frederick J. Marshall 123 Developmental and Neurocutaneous
Disorders 1119 Emily C. de los Reyes and E. Steve Roach 124
Cerebrovascular Disease 1123 Sinad M. Murphy and Timothy J.
Counihan 125 Traumatic Brain Injury and Spinal Cord Injury 1136
Geoffrey S. F. Ling 126 Epilepsy 1141 Michel J. Berg 127 Central
Nervous System Tumors 1154 Lisa R. Rogers and Jennifer J. Griggs
128 Infectious Diseases of the Nervous System 1159 Avindra Nath 129
Demyelinating and Inflammatory Disorders 1165 Deborah Joanne Lynn
130 Neuromuscular Diseases: Disorders of the Motor Neuron and
Plexus and Peripheral Nerve Disease 1171 Carlayne E. Jackson 131
Muscle Diseases 1182 Robert C. Griggs 132 Neuromuscular Junction
Disease 1191 Emma Ciafaloni SECTION XX The Aging Patient 1195 133
The Aging Patient 1196 Mitchell T. Heflin and Harvey Jay Cohen
SECTION XXI Palliative Care 1209 134 Palliative Care 1210 Robert G.
Holloway and Timothy E. Quill SECTION XXII Alcohol and Substance
Abuse 1219 135 Alcohol and Substance Abuse 1220 Richard A. Lange
and L. David Hillis Index 1235
29. This page intentionally left blank
30. Section I Introduction to Molecular Medicine 1 Molecular
Basis of Human Disease BENJAMIN
31. I 2 Chapter 1 Molecular Basis of Human Disease Ivor J.
Benjamin Medicine has evolved dramatically during the past century
from a healing art in which standards of practice were established
on the basis of personal experience, passed on from one
practitioner to the next, to a rigorous intellectual discipline
steeped in the scientific method. The scientific method, a process
that tests the validity of a hypothesis or prediction through
experimentation, has led to major advances in the fields of
physiology, microbiology, biochemistry, and pharmacology. These
advances served as the basis for the diagnostic and therapeutic
approaches to illness in common use by physicians through most of
the 20th century. Since the 1980s, the understanding of the
molecular basis of genetics has expanded dramatically, and advances
in this field have identified new and exciting dimensions for
defining the basis of conventional genetic diseases (e.g., sickle
cell disease) as well as the basis of complex genetic traits (e.g.,
hypertension). The molecular basis for the interaction between
genes and environment has also begun to be defined. Armed with a
variety of sensi- tive and specific molecular techniques,
contemporary physi- cians can now begin not only to understand the
molecular underpinning of complex pathobiologic processes but also
to identify individuals at risk for common diseases. Under-
standing modern medicine, therefore, requires an under- standing of
molecular genetics and the molecular basis of disease. This
introductory chapter offers an overview of this complex and rapidly
evolving topic and attempts to sum- marize the principles of
molecular medicine that will be highlighted in specific sections
throughout this text. Deoxyribonucleic Acid and the Genome All
organisms possess a scheme to transmit the essential information
containing the genetic make-up of the species through successive
generations. In human cells, 23 pairs of chromosomes are present,
each pair of which contains a unique sequence and therefore unique
genetic information. In the human genome, about 6 109 nucleotides,
or 3 109 pairs of nucleotides, associate in the double helix. All
the specificity of DNA is determined by the base sequence, and this
sequence is stored in complementary form in the dou- ble-helical
structure, which facilitates correction of sequence errors and
provides a mechanistic basis for replication of the information
during cell division. Each DNA strand serves as a template for
replication, which is accomplished by the action of DNA-dependent
polymerases that unwind the double-helical DNA and copy each single
strand with remarkable fidelity. All cell types except for
gametocytes contain this dupli- cate, diploid number of genetic
units, one half of which is referred to as a haploid number. The
genetic information contained in chromosomes is separated into
discrete func- tional elements known as genes. A gene is defined as
a unit of base sequence that usually, but with rare exceptions,
encodes a specific polypeptide sequence. New evidence sug- gests
that small, noncoding RNAs play critical roles in expression of
this essential information.An estimated 30,000 genes are present in
the human haploid genome, and these are interspersed among regions
of sequence that do not code for protein and whose function is as
yet unknown. For example, noncoding RNAs (e.g., transfer RNA
[tRNA], ribosomal RNA [rRNA], and other small RNAs) act as com-
ponents of enzyme complexes such as the ribosome and spliceosome.
The average chromosome contains 3000 to 5000 genes, and these range
in size from about 1 kilobase (kb) to 2 megabases (Mb). Ribonucleic
Acid Synthesis Transcription, or RNA synthesis, is the process for
transfer- ring information contained in nuclear DNA to an interme-
diate molecular species known as messenger RNA (mRNA).
32. Chapter 1Molecular Basis of Human Disease 3 Two biochemical
differences distinguish RNA from DNA: (1) the polymeric backbone is
made up of ribose rather than deoxyribose sugars linked by
phosphodiester bonds, and (2) the base composition is different in
that uracil is substi- tuted for thymine. RNA synthesis from a DNA
template is performed by three types of DNA-dependent RNA
polymerases, each a multi-subunit complex with distinct nuclear
location and substrate specificity. RNA polymerase I, located in
the nucleolus, directs the transcription of genes encoding the 18S,
5.8S, and 28S ribosomal RNAs, forming a molecular scaffold with
both catalytic and structural func- tions within the ribosome. RNA
polymerase II, located in the nucleoplasm instead of the nucleoli,
primarily tran- scribes precursor mRNA transcripts and small RNA
mole- cules. The carboxyl-terminus of RNA polymerase II is uniquely
modified with a 220-kD protein domain, the site of enzymatic
regulation by protein phosphorylation of criti- cal serine and
threonine residues. All tRNA precursors and other rRNA molecules
are synthesized by RNA polymerase III in the nucleoplasm. RNA
polymerases are synthesized from precursor trans cripts that must
first be cleaved into subunits before further processing and
assembling with ribosomal proteins into macromolecular complexes.
Ribosomal architectural and structural integrity are derived from
the secondary and terti- ary structures of rRNA, which assume a
series of folding patterns containing short duplex regions.
Precursors of tRNA in the nucleus undergo the removal of the 5
leader region, splicing of an internal intron sequences, and modi-
fication of terminal residues. Precursors of mRNA are produced in
the nucleus by the action of DNA-dependent RNA polymerase II, which
copies the antisense strand of the DNA double helix to synthesize a
single strand of mRNA that is identical to the sense strand of the
DNA double helix in a process called transcription (Fig. 1-1). The
initial, immature mRNA first undergoes modifica- tion at both the 5
and 3 ends. A special nucleotide structure called the cap is added
to the 5 end, which functions to increase binding to the ribosome
and enhance translational efficiency. The 3 end undergoes
modification by nuclease cleavage of about 20 nucleotides, followed
by the addition of a length of polynucleotide sequence containing a
uniform stretch of adenine bases, the so-called poly A tail that
stabilizes the mRNA. In addition to these changes that uniformly
occur in all mRNAs, other, more selective modifications can also
occur. Because each gene contains both exonic and intronic
sequences and the precursor mRNA is transcribed without regard for
exon-intron boundaries, this immature message must be edited in
such a way that splices all exons together in appropriate sequence.
The process of splicing, or remov- ing intronic sequences to
produce the mature mRNA, is an exquisitely choreographed event that
involves the intermedi- ate formation of a spliceosome, a large
complex consisting of small nuclear RNAs and specific proteins,
which contains a loop or lariat-like structure that includes the
intron tar- geted for removal. Only after splicing, a catalytic
process requiring adenosine triphosphate hydrolysis, has concluded
is the mature mRNA able to transit from the nucleus into the
cytoplasm, where the encoded information is translated into
protein. Alternative splicing is a process for efficiently
generating multiple gene products often dictated by tissue
specificity, developmental expression, and pathologic state. Gene
splic- ing allows the expression of multiple isoforms by expanding
the repertoire for molecular diversity. An estimated 30% of genetic
diseases in humans arise from defects in splicing. The resulting
mature mRNA then exits the nucleus to begin the process of
translation or conversion of the base code to polypeptide (Fig.
1-2). Alternative splicing pathways (i.e., alternative exonic
assembly pathways) for specific genes also serve at the level of
transcriptional regulation. The discovery of catalytic RNA, the
capacity for self-directed internal Figure 1-1 Transcription.
Genomic DNA is shown with enhancer and silencer sites located 5
upstream of the promoter region, to which RNA polymerase is bound.
The transcription start site is shown downstream of the promoter
region, and this site is followed by exonic sequences interrupted
by intronic sequences. The former sequences are transcribed ad
seriatim (i.e., one after another) by the RNA polymerase. Enhancer
Silencer RNA polymerase Promoter region Exon Intron Exon Intron
Transcription start site 5' 3' Figure 1-2 Translation. The open
reading frame of a mature messenger RNA is shown with its series of
codons. Transfer RNA molecules are shown with their corresponding
anticodons, charged with their specific amino acid. A short,
growing polypeptide chain is depicted. A, adenine; C, cytosine;
CYS, cysteine; G, guanine; MET, methionine; PRO, proline; THR,
threonine; U, uracil. MET PRO GGG UGC AUG UCG ACG THR CYS CCC UCG
Open reading frame Anticodon Codon AUU GUA
33. 4 Section IIntroduction to Molecular Medicine Figure 1-3
Secondary structure of transfer RNA (tRNA). The structure of each
tRNA serves as an adapter molecule that recognizes a specific codon
for the amino acid to be added to the polypeptide chain. About one
half the hydrogen-bonded bases of the single chain of
ribonucleotides are shown paired in double helices like a
cloverleaf. The 5 terminus is phosphorylated, and the 3 terminus
contains the hydroxyl group on an attached amino acid. The
anticodon loop is typically located in the middle of the tRNA
molecule. C, cytocide; DHU, dihydroxyuridine; G, guanine; UH2,
dihydrouridine; , pseudouridine; T, ribothymidine; U, uracil. (Data
from Berg JM, Tymoczko JL, Strayer JL: Berg, Tymoczko and Stryers
Biochemistry, 5th ed. New York, WH Freeman, 2006.) DHU loop Amino
acid attachment siteA 3' OH C C CU U Anticodon loop G G A UH2 G C T
Extra arm (variable) TC loop Phosphorylated 5' terminus 5' p tially
a polypeptide polymerase. At least one tRNA molecule exists for
each 20 amino acids, although degeneracy in the code expands the
number of available tRNA molecules, miti- gates the chances of
premature chain termination, and amel- iorates the potential
deleterious consequences of single-base mutations. The enzymatic
activity of the ribosome then links amino acids through the
synthesis of a peptide bond, releas- ing the tRNA in the process.
Consecutive linkage of amino acids in the growing polypeptide chain
represents the terminal event in the conversion of information
contained within the nuclear DNA sequence into mature protein (DNA
RNA protein). Proteins are directly responsible for the form and
function of an organism. Thus, abnormalities in protein structure
or function brought about by changes in primary amino acid sequence
are the immediate precedent cause of changes in phenotype, adverse
forms of which define a disease state. Inhibition of RNA synthesis
is a well-recognized mecha- nism of specific toxins and
antibiotics. Toxicity from the ingestion of the poisonous mushroom
(Amanita phalloides), for example, leads to the release of the
toxin -amanitin, a cyclic octapeptide that inhibits the RNA Pol II
and blocks elongation of RNA synthesis. The antibiotic actinomycin
D binds with high affinity to double-helical DNA and inter colates
between base pairs, precluding access of DNA- dependent RNA
polymerases and the selective inhibition of transcription. Several
major antibiotics function through inhibition of translation. For
example, the aminoglycoside antibiotics function through the
disruption of the mRNA- tRNA codon-anticodon interaction, whereas
erythromycin and chloramphenicol inhibit peptide bond formation.
Control of Gene Expression OVERVIEW The timing, duration,
localization, and magnitude of gene expression are all important
elements in the complex tapes- try of cell form and function
governed by the genome. Gene expression represents the flow of
information from the DNA template into mRNA transcripts and the
process of transla- tion into mature protein. Four levels of
organization involving transcription factors, RNAs, chromatin
structure, and epigenetic factors are increasingly recognized to
orchestrate gene expression in the mammalian genome.
Transcriptional regulators bind to spe- cific DNA motifs that
positively or negatively control the expression of neighboring
genes. The information contained in the genome must be transformed
into functional units of either RNA or protein products. How DNA is
packed and modified represents additional modes of gene regulation
by disrupting the access of transcription factors from DNA- binding
motifs. In the postgenomic era, the challenge is to understand the
architecture by which the genome is organ- ized, controlled, and
modulated. Transcription factors, chromatin architecture, and modi-
fications of nucleosomal organization make up the major mechanisms
of gene regulation in the genome. excision and repair, has advanced
the current view that RNA per se serves both as a template for
translation of the genetic code and, simultaneously, as an enzyme
(see Transcrip- tional Regulation later in this chapter). Protein
synthesis, or translation of the mRNA code, occurs on ribosomes,
which are macromolecular complexes of proteins and rRNA located in
the cytoplasm. Translation involves the conversion of the linear
code of a triplet of bases (i.e., the codon) into the corresponding
amino acid. A four- base code generates 64 possible triplet
combinations (4 4 4), and these correspond to 20 different amino
acids, many of which are encoded by more than one base triplet. To
decode mRNA, an adapter molecule (tRNA) recognizes the codon in
mRNA through complementary base pairing with a three-base anticodon
that it bears; in addition, each tRNA is charged with a unique
amino acid that corresponds to the anticodon (Fig. 1-3).
Translation on the mRNA template proceeds without punctuation of
the non-overlapping code with the aid of rRNA on an assembly
machine, termed ribosomesessen-
34. Chapter 1Molecular Basis of Human Disease 5 TRANSCRIPTIONAL
REGULATION The principal regulatory step in gene expression occurs
at the level of gene transcription. A specific DNA-dependent RNA
polymerase performs the transcription of information contained in
genomic DNA into mRNA transcripts. Trans cription begins at a
proximal (i.e., toward the 5 end of the gene) transcription start
site, containing nucleotide sequences that influence the rate and
extent of the process (see Fig. 1-1). This region is known as the
promoter region of the gene and often includes an element of
sequence rich in adenine and thymine (the TATA box) along with
other sequence motifs within about 100 bases of the start site.
These regions of DNA that regulate transcription are known as
cis-acting regulatory elements. Some of these regulatory regions of
promoter sequence bind proteins known as trans- acting factors, or
transcription factors, which are themselves encoded by other genes.
The cis-acting regulatory sequences to which transcription factors
bind are often referred to as response elements. Families of
transcription factors have been identified and are often described
by unique aspects of their predicted protein secondary structure,
including helix-turn- helix motifs, zinc-finger motifs, and
leucine-zipper motifs. Transcription factors make up an estimated
3% to 5% of the protein-coding products of the genome. In addition
to gene-promoter regions, enhancer sites are distinct from promoter
sites in that they can exist at distances quite remote from the
start site, either upstream or down- stream (i.e., beyond the 3 end
of the gene), and without clear orientation requirements.
Trans-acting factors bind to these enhancer sites and are believed
to alter the tertiary structure or conformation of the DNA in a
manner that facilitates the binding and assembly of the
transcription-initiation complex at the promoter region, perhaps in
some cases by forming a broad loop of DNA in the process.
Biochemical modification of select promoter or enhancer sequences,
such as methyla- tion of CpG-rich sequences
(cytosine-phosphate-guanine), can also modulate transcription;
methylation typically sup- presses transcription. The terms
silencer and suppressor ele- ments refer to cis-acting nucleotide
sequences that reduce or shut off gene transcription and do so
through association with trans-acting factors that recognize these
specific sequences. Regulation of transcription is a complex
process that occurs at several levels; importantly, the expression
of many genes is regulated to maintain high basal levels, which are
known as housekeeping or constitutively expressed genes. They
typically yield protein products that are essential for normal cell
function or survival and thus must be maintained at a specific
steady-state concentration under all circumstances. Many other
genes, in contrast, are not expressed or are only modestly
expressed under basal conditions; however, with the imposition of
some stress or exposure of the cell to an agonist that elicits a
cellular response distinct from that of the basal state, the
expression of these genes is induced or enhanced. For example, the
heat shock protein genes encod- ing stress proteins are rapidly
induced in response to diverse pathophysiologic stimuli (e.g.,
oxidative stress, heavy metals, inflammation) in most cells and
organisms. The increased heat shock protein expression is
complementary to the basal level of heat shock proteins whose
functions as molecular chaperones play key roles during protein
synthesis to prevent protein misfolding, increase protein
translocation, and accelerate protein degradation. These adaptive
responses often mediate changes in phenotype that are
homeostatically protective to the cell or organism. MICRORNAS AND
GENE REGULATION Less is currently known about the determinants of
transla- tional regulation than is known about transcriptional
regu- lation. The recent discovery and identification of small RNAs
(21 to 24mer), termed microRNAs (miRNAs), adds further complexity
to the regulation of gene expression within the eukaryotic genome.
First discovered in worms more than 10 years ago, miRNAs are
conserved noncoding strands of RNA that bind to the 3-untranslated
regions of target mRNAs, enabling gene silencing of protein
expression at the translational level. Gene-encoding miRNAs exhibit
tissue-specific expression and are interspersed in regions of the
genome unrelated to known genes. Transcription of miRNAs proceeds
in multiple steps from sites under the control of an mRNA promoter.
RNA polymerase II transcribes the precursor miRNA, termed primary
miRNA (primiRNA), containing 5 caps and 3 poly (A) tails. In the
nucleus, the larger primiRNAs of 70 nucleotides form an internal
hairpin loop, embedding the miRNA portion that undergoes
recognition and subse- quent excision by double-stranded
RNA-specific ribonucle- ase, termed Drosha. Gene expression is
silenced by the effect of miRNA on nascent RNA molecules targeted
for degradation. Because translation occurs at a fairly invariant
rate among all mRNA species, the stability or half-life of a
specific mRNA also serves as another point of regulation of gene
expression. The 3-untranslated region of mRNAs contains regions of
sequence that dictate the susceptibility of the message to nuclease
cleavage and degradation. Stability appears to be sequence specific
and, in some cases, dependent on trans- acting factors that bind to
the mRNA. The mature mRNA contains elements of untranslated
sequence at both the 5 and 3 ends that can regulate translation.
Beginning in the organisms early development, miRNAs may facilitate
much more intricate ways for the regulation of gene expression, as
have been shown for germline produc- tion, cell differentiation,
proliferation, and organogenesis. Because recent studies have
implicated the expression of miRNAs in brain development, cardiac
organogenesis, colonic adenocarcinoma, and viral replication, this
novel mechanism for gene silencing has potential therapeutic roles
for congenital heart defects, viral disease, neurodegen- eration,
and cancer. CHROMATIN REMODELING AND GENE REGULATION Both the size
and complexity of the human genome with 23 chromosomes, ranging in
size between 50 and 250Mb, pose formidable challenges for
transcription factors to exert the specificity of DNA-binding
properties in gene regulation. Control of gene expression also
takes place in diverse types of cells, often with exquisite
temporal and spatial specificity throughout the life span of the
organism. In eukaryotic cells, the genome is highly organized into
densely packed nucleic acid DNA- and RNA-protein structures, termed
chromatin.
35. 6 Section IIntroduction to Molecular Medicine The building
blocks of chromatin are called histones, a family of small basic
proteins that occupy one half of the mass of the chromosome.
Histones derive their basic properties from the high content of
basic amino acids, arginine, and lysine. Five major types of
histonesH1, H2A, H2B, H3, and H4have evolved to form complexes with
the DNA of the genome. Two pairs each of the four types of histones
form a protein core, the histone octomer, which is wrapped by 200
base pairs of DNA to form the nucleosome (Fig. 1-4). The core
proteins within the nucleosomes have protruding amino-terminal
ends, exposing critical lysine and arginine residues for covalent
modification. Further DNA condensa- tion is achieved as
higher-order structure is imparted on the chromosomes. The
nucleosomes are further compacted in layered stacks with a
left-handed superhelix resulting in negative supercoils that
provide the energy for DNA strand separation during replication.
Condensation of DNA in chromatin precludes the access of regulatory
molecules such as transcription factors. Reversal of chromatin
condensation, on the other hand, typically occurs in response to
environmental and other developmental signals in a tissue-dependent
manner. Pro- moter sites undergoing active transcription, as well
as relaxa- tion of chromatin structure, that become susceptible to
enzymatic cleavage by nonspecific DNAase I are called
hypersensitive sites. Transcription factors on promoter sites may
gain access by protein-protein interactions to enhancer elements
containing tissue-specific proteins at remote sites, several
thousand bases away, resulting in transcription activation or
repression. EPIGENETIC CONTROL OF GENE EXPRESSION Complex
regulatory networks revolve around transcription factors,
nucleosomes, chromatin structure, and epigenetic markings.
Epigenetics refers to heritable changes in gene expression without
changes in the DNA sequence. Such examples include DNA methylation,
gene silencing, chro- matin remodeling, and X-chromosome
inactivation. This form of inheritance involves the alterations in
gene function without changes in DNA sequence. Chemical marking of
DNA methylation is both cell specific and developmentally
regulated. Methylation of the 5 CpG dinucleotide by spe- cific
methyl transferases, which occurs in 70% of the mam- malian genome,
is another mechanism of gene regulation. Steric hindrance from the
bulky methyl group of 5 methyl- cytosine precludes occupancy by
transcription factors that stimulate or attenuate gene expression.
Most genes are found in CpG islands, reflecting sites of gene
activity across the genome. In an analogous manner, modifications
of histone by phosphorylation, methylation, ubiquination, and
acetyla- tion are transmitted and reestablished in an inheritable
manner. It is conceivable that other epigenetic mechanisms do not
involve genomic modifications of DNA. For example, modification of
the gene encoding the estrogen receptor has been implicated in gene
silencing at 5m C sites of multiple downstream targets in breast
cancer cells. Powerful new approaches are being developed to
examine feedback and feed-forward loops in transmission of
epigenetic markings. The concept that dynamic modifications (e.g.,
DNA methylation and acetylation) of histones or epigenesis con-
tribute, in part, to tumorigenic potential for progression has
already been translated into current therapies. Histone
acetyltransferases (HATs) and histone deacetyltransferases (HDACs)
play antagonistic roles in the addition and removal of acetylation
in the genome. Furthermore, genome-wide analysis of HATs and HDACs
is beginning to provide impor- tant insights into complex modes of
gene regulation. Several inhibitors of histone deacetylases, with a
range of biochemi- cal and biologic activities, are being developed
and tested as anticancer agents in clinical trial. Phase I clinical
trials have suggested these drugs are well tolerated. In general,
the inhi- bition of deacetylase remodels chromatin assembly and
reac- tivates transcription of the genome. Because the mechanisms
of actions of HDACs extend to apoptosis, cell cycle control, and
cellular differentiation, current clinical trials are seeking to
determine the efficacy of these novel reagents in the drug
compendium for human cancers. Genetic Sequence Variation,
Population Diversity, and Genetic Polymorphisms A stable, heritable
change in DNA is defined as a mutation. This strict contemporary
definition does not depend on the functional relevance of the
sequence alteration and impli- cates a change in primary DNA
sequence. Considered in historical context, mutations were first
defined on the basis of identifiable changes in the heritable
phenotype of an organism.As biochemical phenotyping became more
precise in the mid-20th century, investigators demonstrated that
many proteins exist in more than one form in a population, and
these forms were viewed as a consequence of variations Figure 1-4
Schematic representation of a nucleosome. Rectangular blocks
represent the DNA strand wrapped around the core that consists of
eight histone proteins. Each histone has a protruding tail that can
be modified to repress or activate transcription. (Adapted from
Berg JM, Tymoczko JL, Strayer JL: Berg, Tymoczko and Stryers
Biochemistry, 5th ed. New York, WH Freeman, 2006.)
36. Chapter 1Molecular Basis of Human Disease 7 in the gene
coding for that protein (i.e., allelic variation). With advances in
DNA-sequencing methods, the concept of mutation evolved from one
that could be appreciated only by identifying differences in
phenotype to one that could precisely be defined at the level of
changes in the structure of DNA. Although most mutations are stably
transmitted from parents to offspring, some are genetically lethal
and thus cannot be passed on. In addition, the discovery of regions
of the genome that contain sequences that repeat in tandem a highly
variable number of times (tandem repeats) suggests that some
mutations are less stable than others. These tandem repeats are
further described later in this section. The molecular nature of
mutations is varied (Table 1-1). A mutation can involve the
deletion, insertion, or substitu- tion of a single base, all of
which are referred to as point mutations. Substitutions can be
further classified as silent when the amino acid encoded by the
mutated triplet does not change, as missense when the amino acid
encoded by the mutated triplet changes, and as nonsense when the
mutation leads to premature termination of translation (stop
codon). On occasion, point mutations can alter the processing of
precursor mRNA by producing alternate splice sites or elim- inating
a splice site. When a single- or double-base deletion or insertion
occurs in an exon, a frameshift mutation results, usually leading
to premature termination of translation at a now in-frame stop
codon. The other end of the spectrum of mutations includes large
deletions of an entire gene or a set of contiguous genes; deletion,
duplication, and translocation of a segment of one chromosome to
another; or duplication or deletion of an entire chromosome. Such
chromosomal mutations play a large role in the development of many
cancers. Each individual possesses two alleles for any given gene
locus, one from each parent. Identical alleles define homozy-
gosity and nonidentical alleles define heterozygosity for any gene
locus. The heritability of these alleles follows typical mendelian
rules. With a clearer understanding of the molecular basis of
mutations and of allelic variation, their distribution in
populations can now be analyzed precisely by following specific DNA
sequences. Differences in DNA sequences studied within the context
of a population are referred to as genetic polymorphisms, and these
polymor- phisms underlie the diversity observed within a given
species and among species. Despite the high prevalence of benign
polymorphisms in a population, the occurrence of harmful mutations
is com- paratively rare because of selective pressures that
eliminate the most harmful mutations from the population
(lethality) and the variability within the genomic sequence to
polymor- phic change. Some portions of the genome are remarkably
stable and free of polymorphic variation, whereas other por- tions
are highly polymorphic, the persistence of variation within which
is a consequence of the functional benignity of the sequence
change. In other words, polymorphic differ- ences in DNA sequence
between individuals can be divided into those producing no effect
on phenotype, those causing benign differences in phenotype (i.e.,
normal genetic varia- tion), and those producing adverse
consequences in pheno- type (i.e., mutations). The last group can
be further subdivided into the polymorphic mutations that alone are
able to produce a functionally abnormal phenotype such as monogenic
disease (e.g., sickle cell anemia) and those that alone are unable
to do so but in conjunction with other mutations can produce a
functionally abnormal phenotype (complex disease traits [e.g.,
essential hypertension]). Polymorphisms are more common in
noncoding regions of the genome than they are in coding regions,
and one common type of these involves the tandem repetition of
short DNA sequences a variable number of times. If these tandem
repeats are long, they are termed variable number tandem repeats;
if these repeats are short, they are termed short tandem repeats
(STRs). During mitosis, the number of tandem repeats can change,
and the frequency of this kind of replication error is high enough
to make alternative lengths of the tandem repeats common in a
population. However, the rate of change in length of the tandem
repeats is low enough to make the size of the polymorphism useful
as a stable genotypic trait in families. In view of these fea-
tures, polymorphic tandem repeats are useful in determining the
familial heritability of specific genomic loci. Polymor- phic
tandem repeats are sufficiently prevalent along the entire genomic
sequence, enabling them to serve as genetic markers for specific
genes of interest through an analysis of their linkage to those
genes during crossover and recombi- nation events. Analyses of
multiple genetic polymorphisms in the human genome reveal that a
remarkable variation exists among individuals at the level of the
sequence of genomic DNA (genotyping). Single-nucleotide polymor-
phism (SNP), the most common variant, differs by a single base
between chromosomes on any given stretch of DNA sequence (Fig.
1-5). From genotyping of the worlds repre- sentative population, 10
million variants (one site per 300 bases) are estimated to make up
90% of the common SNP variants in the population, with the rare
variants making up the remaining 10%. With each generation of a
species, the frequency of polymorphic changes in a gene is 104 to
107 . Table 1-1 Molecular Basis of Mutations Type Examples Point
Mutations Deletion -Thalassemia, polycystic kidney disease
Substitution Silent Cystic fibrosis Missense Sickle cell anemia,
polycystic kidney disease, congenital long QT syndrome Nonsense
Cystic fibrosis, polycystic kidney disease Large Mutations (Gene or
Gene Cluster) Deletion Duchenne muscular dystrophy Insertion Factor
VIII deficiency (hemophilia A) Duplication Duchenne muscular
dystrophy Inversion Factor VIII deficiency Expanding triplet
Huntington disease Very Large Mutation (Chromosomal Segment or
Chromosome) Deletion Turner syndrome (45,X) Duplication Trisomy 21
Translocation XX male [46,X; t(X;Y)]* *Translocation onto an X
chromosome of a segment of a Y chromo- some that bears the locus
for testicular differentiation.
37. 8 Section IIntroduction to Molecular Medicine Thus, in view
of the number of genes in the human genome, between 0.5% and 1.0%
of the base sequence of the human genome is polymorphic. In this
context, the new variant can be traced historically to the
surrounding alleles on the chro- mosomal background present at the
time of the mutational event. A haplotype is a specific set or
combination of alleles on a chromosome or part of a chromosome (see
Fig. 1-5). When parental chromosomes undergo crossover, new mosaic
haplotypes, containing additional mutations, are created from such
recombinations. SNP alleles within hap- lotypes can be co-inherited
in association with other alleles in the population, termed linkage
disequilibrium (LD). The association between two SNPs will decline
with increasing dista