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Clinical Diagnosis
AND Management
BY Laboratory Methods
''N
RICHARD A. MCPHERSON
MATTHEW R. PINCUS
ASSOCIATE EDITORS
ii
24th EDITION
HENRY’S
Clinical Diagnosis
AND Management
BY Laboratory Methods
Richard A. McPherson, MD, MSc
Professor Emeritus
Department of Pathology
Virginia Commonwealth University School of Medicine
Richmond, Virginia
All rights reserved. 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).
Previous editions copyrighted 2017, 2011, 2007, 2001, 1996, 1991, 1984, 1979, 1974, 1969, 1962, 1953, 1948,1943,
1939, 1935, 1931, 1927, 1923, 1918, 1914, 1912, 1908.
Notices
Knowledge and best practice in this field 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 researchers must always rely on their own experience and knowledge
in evaluating and using any information, methods, compounds, or experiments described herein. In using
such information or methods they should be mindful of their own safety and the safety of others, includ-
ing parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical
products identified, readers are advised to check the most current information provided (i) on procedures
featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose
or formula, the method and duration of administration, and contraindications. It is the responsibility of
practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to
determine dosages and the best treatment for each individual patient, and to take all appropriate safety
precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors,
assume any liability 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.
The Publisher
Printed in Canada
9 8 7 6 5 4 3 2 1
CONTRIBUTORS
v
Paul Brandt-Rauf, MD, PhD, DScD, DrPH Laura Lee Cooling, MD, MS
CONTRIBUTORS
Dean, School of Biomedical Engineering Professor
Drexel University Department of Pathology
Philadelphia, Pennsylvania University of Michigan
Ann Arbor, Michigan
Robert Bray, PhD
Professor Lynsey Daniels, MD
Department of Pathology General Surgery Fellow
Emory University School of Medicine Department of Surgery
Atlanta, Georgia Drexel University College of Medicine
Philadelphia, Pennsylvania
Cindy L. Bredefeld, DO, FACE
Attending Physician Robertson D. Davenport, MD
Division of Endocrinology, Diabetes, and Metabolism Professor
Assistant Professor of Clinical Medicine Department of Pathology
Department of Medicine University of Michigan
NYU Long Island School of Medicine Ann Arbor, Michigan
Mineola, New York
Robert P. DeCresce, MD, MBA, MPH
Gary Briefel, MD Director of Clinical Laboratories
Clinical Associate Professor Department of Pathology
Department of Medicine Rush University Medical Center
SUNY Downstate Medical Center Chicago, Illinois
Brooklyn, New York
Julio C. Delgado, MD, MS
M. Jana Broadhurst, MD, PhD, DTM&H Professor
Director, Nebraska Biocontainment Unit Clinical Laboratory Department of Pathology
Director, Emerging Pathogens Laboratory University of Utah
Assistant Professor, Pathology & Microbiology Salt Lake City, Utah
University of Nebraska Medical Center
Omaha, Nebraska Robert A. DeSimone, MD
Assistant Professor
Robert P. Carty, PhD Department of Pathology and Laboratory Medicine
Associate Professor Weill Medical College of Cornell University
Department of Biochemistry New York-Presbyterian Hospital
SUNY Downstate Medical Center New York, New York
Brooklyn, New York
Margaret A. DiGuardo, MD
Angela Ceribelli, MD, PhD Medical Director
Unit of Rheumatology Immunohematology Laboratory
Department of Internal Medicine Division of Transfusion Medicine
Humanitas Clinical and Research Center – IRCCS Mayo Clinic
Rozzano, Milan, Italy Rochester, Minnesota
vi
Marvin J. Fritzler, PhD, MD Julie Woolworth Hirschhorn, PhD, HCLD
CONTRIBUTORS
Professor Assistant Professor
Department of Medicine Department of Pathology and Laboratory Medicine
Cumming School of Medicine Medical University of South Carolina
University of Calgary Charleston, South Carolina
Calgary, Alberta, Canada
Catherine A. Hogan, MDCM, MSc
Howard M. Gebel, PhD Instructor
Professor Department of Pathology
Department of Pathology Stanford University
Emory University Hospital Stanford, California
Atlanta, Georgia
Joseph Holup, PhD, (D)ABMLI
Eve Goldstein, MD Assistant Clinical Professor
General Surgery Fellow Department of Pathology
Department of Surgery NYU Grossman School of Medicine
Drexel University College of Medicine New York, New York
Philadelphia, Pennsylvania
Henry A. Homburger, MD
Susan S. Graham, MS Professor Emeritus
Associate Professor and Chair Mayo College of Medicine
Department of Clinical Laboratory Science Department of Laboratory Medicine and Pathology
SUNY Upstate Medical University Mayo Clinic
Syracuse, New York Rochester, Minnesota
vii
Jeffrey S. Jhang, MD, MBA Attila Kumánovics, MD
CONTRIBUTORS
Professor and Vice Chair Senior Associate Consultant
Department of Pathology, Molecular and Cell-Based Medicine Department of Laboratory Medicine and Pathology
Icahn School of Medicine at Mount Sinai Mayo Clinic
Medical Director, Center for Clinical Laboratories Rochester, Minnesota
Mount Sinai Health System
New York, New York Anthony Kurec, MS, MASCP, MLT(ASCP)H, DLM
Clinical Associate Professor, Emeritus
Donald S. Karcher, MD Clin Lab Science
Professor and Immediate Past Chair SUNY Upstate Medical University
Department of Pathology Syracuse, New York
George Washington University Medical Center
Washington, DC Charles LaDoulis, MD
Chairman Emeritus
Yasushi Kasahara, PhD, DMSc Department of Pathology
Visiting Professor Maimonides Medical Center
Department of Clinical Pathology Brooklyn, New York
Showa University School of Medicine
Tokyo, Japan Raymond G. Lau, MD
Clinical Assistant Professor
Samuel W. Kaskovich Director of Medical Weight Management
MD/MSc Candidate Division of Endocrinology, Diabetes, and Metabolism
Medicine & Biomedical Informatics Division of Bariatric Surgery
University of Chicago Department of Medicine
Chicago, Illinois NYU Long Island School of Medicine
Mineola, New York
Craig M. Kessler, MD, MACP
Professor of Medicine and Pathology Eszter Lázár-Molnár, PhD
Director, Division of Coagulation Assistant Professor
Georgetown University Medical Center Department of Pathology
Washington, DC University of Utah
Salt Lake City, Utah
Marian Khalili, MD
General Surgery Fellow Grace Ming Lee, MD
Department of Surgery Assistant Professor
Drexel University College of Medicine Division of Hematology
Philadelphia, Pennsylvania Department of Medicine
Duke University
Jason Kidd, MD Durham, North Carolina
Associate Professor
Department of Internal Medicine, Division of Nephrology Peng Lee, MD, PhD
Virginia Commonwealth University Medical Center Professor of Pathology and Urology
Richmond, Virginia New York University Langone Medical Center and School of Medicine
Chief, Pathology and Laboratory Medicine Service
Michael J. Klein, MD VA NY Harbor Healthcare System
Pathologist-in-Chief and Director Emeritus New York, New York
Department of Pathology and Laboratory Medicine
Hospital for Special Surgery Jing Li, PhD
Professor of Pathology and Laboratory Medicine Professor
Department of Pathology and Laboratory Medicine Department of Oncology
Weill Cornell School of Medicine Karmanos Cancer Institute
New York, New York Wayne State University School of Medicine
Detroit, Michigan
Katrin M. Klemm, MD
Medical Director Mark S. Lifshitz, MD
Aperian Laboratory Solutions Clinical Professor
Medical Director Department of Pathology, Molecular, and Cell-Based Medicine
EAMC Hospital Laboratory Icahn School of Medicine at Mount Sinai
Department of Pathology New York, New York
East Alabama Medical Center
Opelika, Alabama Bo Lin, MD, PhD
Resident Physician
Stefanie Krick, MD, PhD Department of Pathology
Assistant Professor SUNY Downstate Medical Center
Department of Medicine Brooklyn, New York
The University of Alabama at Birmingham
Birmingham, Alabama Ronald P. Mageau, MD
KWB Pathology Associates
Scott Krummey, MD, PhD Tallahassee, Florida
Assistant Professor
Johns Hopkins School of Medicine Mariana Markell, MD
Baltimore, Maryland Professor
Department of Medicine
SUNY Downstate Health Sciences University
Brooklyn, New York
viii
H. Davis Massey, DDS, MD, PhD Dejan Nikolic, MD, PhD
CONTRIBUTORS
Chief Director of Microbiology and Immunology
Department of Pathology and Laboratory Medicine Site Pathology Residency Program Director
McGuire VA Medical Center Department of Pathology and Laboratory Services
Associate Professor Cooper University Health Care
Department of Pathology Assistant Professor of Pathology
Virginia Commonwealth University Cooper Medical School of Rowan University
Richmond, Virginia Camden, New Jersey
ix
Bobbi S. Pritt, MD, MSc, (D)TMH Shabnam Seydhafkan, MD
CONTRIBUTORS
Professor Resident Physician
Department of Laboratory Medicine and Pathology Department of Pathology
Mayo Clinic SUNY Downstate Medical Center
Rochester, Minnesota Brooklyn, New York
x
Hannah Wang, MD Christina M. Wojewoda, MD
CONTRIBUTORS
Resident Director, Clinical Microbiology Laboratory
Department of Pathology Department of Pathology and Laboratory Medicine
Stanford University University of Vermont Medical Center
Stanford, California Associate Professor
Department of Pathology and Laboratory Medicine
Victor W. Weedn, MD, JD University of Vermont
Chief Medical Examiner Burlington, Vermont
Office of the Chief Medical Examiner
Maryland Department of Health Brent L. Wood, MD, PhD
Baltimore, Maryland Professor
Department of Pathology and Laboratory Medicine
Eric T. Weimer, PhD, D(ABHI, ABMLI) Childrens Hospital Los Angeles
Assistant Professor University of Southern California
Department of Pathology and Laboratory Medicine Los Angeles, California
University of North Carolina
Chapel Hill, North Carolina Gail L. Woods, MD
Former Professor
Ruth S. Weinstock, MD, PhD University of Arkansas for Medical Sciences
SUNY Distinguished Service Professor Chief of Pediatric Pathology
Department of Medicine Department of Pathology
SUNY Upstate Medical University Arkansas Children’s Hospital
Syracuse, New York Little Rock, Arkansas
Nathan P. Wiederhold, PharmD, FCCP, FIDSA, FECMM Yaxia Zhang, MD, PhD
Professor Chief of Clinical Pathology
Department of Pathology and Laboratory Medicine Head of Pathology Research
University of Texas Health Science Center Associate Director of Fellowship Program
San Antonio, Texas Department of Pathology and Laboratory Medicine
Hospital for Special Surgery
William E. Winter, MD Associate Professor of Pathology and Laboratory Medicine
Professor Department of Pathology and Laboratory Medicine
Departments of Pathology, Immunology, and Laboratory Medicine, Weill-Cornell School of Medicine
Pediatrics, and Molecular Genetics and Microbiology New York, New York
University of Florida College of Medicine
Gainesville, Florida
Jeffrey L. Winters, MD
Medical Director
Therapeutic Apheresis Treatment Unit
Division of Transfusion Medicine
Mayo Clinic
Rochester, Minnesota
xi
PREFACE
Clinical laboratory measurements form the scientific basis upon which from specimen collection, transport, and handling and other variables are
medical diagnosis and management of patients is established. These results discussed in Chapter 3. The principles of analysis and instrumentation are
constitute the largest section of the medical record of patients, and labora- presented in Chapter 4. Since the field of mass spectroscopy has begun to
tory examinations will only continue to grow in number as new procedures play an important role in a wide variety of areas of laboratory medicine,
are offered and well-established ones are ordered more frequently in the including clinical chemistry and microbiology, we have now introduced a
future. The modern concept of an electronic health record encompasses new chapter, Chapter 5, in this new edition that is devoted to the principles
information from a patient’s birth through that individual’s entire life, and and practice of mass spectrometry. Chapter 6 covers laboratory automa-
laboratory testing is a significant component of that record from prena- tion. The growing arena of near-patient laboratory services beyond cen-
tal and newborn screening through childhood, adulthood, and geriatric tral hospital laboratories in the format of point-of-care testing is presented
years. Traditional areas of testing are well established in clinical chem- in Chapter 7 along with presentation on this application in the military.
istry, hematology, coagulation, microbiology, immunology, and transfu- Postanalysis processes of result reporting and medical decision making, are
sion medicine. Genetic testing for disease detection, hereditary disease risk presented in Chapter 8 while a systematic approach that allows the clini-
assessment and definitive diagnosis and prognosis is becoming a reality, cian and laboratorian to interpret and assess laboratory results is presented
beginning with individual disease testing that is expected to be followed in Chapter 9. This chapter provides the basis for formulation of differen-
by whole genome screening for a multitude of conditions. The rapid pace tial diagnosis from laboratory values, choice of possible reflex testing and
in the introduction of new testing procedures demands that laboratory the ordering of further testing to confirm diagnoses. A key component to
practitioners be experts in several divergent aspects of this profession. The all phases of laboratory processes, interpretation of results, and decision
environment of clinical laboratories is extremely well-suited for translation making is statistical analysis, which is presented in Chapter 10. Explicit
of research procedures into diagnostic assays because of their traditional applications of statistics are in quality control and proficiency testing for
involvement in basic analysis, quality control, professional competencies, oversight of the entire analytic process (Chapter 11). Maintaining order
and cost-effective strategies of operation. All of these applications are for the complexities of laboratory test result ordering and reporting and
made stronger for occurring under regulations of federal and state gov- the management of clinical information are possible only through sophis-
ernments, as well as the standards of accreditation of professional pathol- ticated information systems that are essential to all clinical laboratories
ogy organizations. Clinical laboratories excel in these tasks, and they are (Chapter 12). Management decisions in the clinical laboratory involve
now responding to pressures for even greater accomplishments in areas the choice of analytic instrumentation, automation to process and deliver
of informatics, advanced analytic methods, interpretation of complex data, specimens to analytic stations, and computer systems to coordinate all of
and communication of medical information in a meaningful way to physi- the preanalytic, analytic, and postanalytic processes to meet the mission of
cian colleagues and even directly to patients in some health care models. the institution. These choices determine the productivity that a laboratory
The most successful practitioners of laboratory medicine will incorporate can achieve (especially its ability to respond to increased volumes of test-
all of these approaches into their daily lives and will be leaders in their ing and complexity of measurements and examinations as the standards
institutions for developing initiatives to promote outstanding health care in of practice advance). Paramount is the manner in which the laboratory
a fiscally responsible endeavor. This textbook strives to provide the back- can muster its resources in equipment, personnel, reagent supplies, and
ground knowledge by which trainees can be introduced to these practices ingenuity of its leadership to respond to the needs of health care providers
and to serve as a resource for pathologists and other laboratory personnel and patients in terms of access, timeliness, cost, and quality of test results.
to update their knowledge to solve problems that they encounter daily. New challenges continue to emerge for the laboratory to provide excellent
This twenty-fourth edition marks more than 100 years since A Manual quality services at a fiscally responsible expense; the changing models of
of Clinical Diagnosis, authored by James Campbell Todd, was introduced in reimbursement for medical and laboratory services demand that patholo-
1908. In its current format as Henry’s Clinical Diagnosis and Management by gists and laboratory leaders develop and maintain a strong understanding
Laboratory Methods, this textbook remains the authoritative source of infor- of the principles of financial management and be well aware of mecha-
mation for residents, students, and other trainees in the disciplines of clini- nisms that laboratories can utilize for responding to these new approaches
cal pathology and laboratory medicine, and for physicians and laboratory to reimbursement (Chapter 13). Chapter 14 on ethics in laboratory medi-
practitioners. The current edition continues the tradition of partnership cine provides a framework for appropriate delivery of clinical laboratory
between laboratory examinations and the formulation and confirmation of testing and human subjects research in accordance with accepted principles
clinical diagnoses followed by monitoring of body functions, therapeutic of behavior.
drug levels, other results of medical treatments, and risk assessment for dis- Part 2, Clinical Chemistry, is organized to present laboratory examina-
ease. Beginning with the twenty-first edition, color illustrations have been tions according to organ systems and their disorders. Some of the most
used throughout the book to accurately and realistically depict clinical lab- commonly ordered laboratory tests are directed at the evaluation of renal
oratory test findings and their analysis. The overriding mission of this book function, water, electrolytes, metabolic intermediates and nitrogenous
is to incorporate new discoveries and their clinical diagnostic applications wastes, and acid-base balance, all of which are critically important for
alongside the wealth of information that forms the core knowledge base of monitoring acutely ill patients and in the management of patients with
clinical pathology and laboratory medicine. It is also our objective to call kidney and pulmonary disorders (Chapter 15). The important field of bone
the reader’s attention to important unsolved problems in diagnostic medi- metabolism and bone diseases, stemming from the enormous public inter-
cine and to stimulate the reader to formulate ways to solve these problems. est in osteoporosis of our aging population, is covered in Chapter 16. The
Our contributing authors, who are experts in their specialties, present to significance of carbohydrate measurements, with particular emphasis on
the reader the essential basic and new information that is central to clinical diabetes mellitus, the overall hormonal regulation of glucose metabolism,
laboratory practice. and disorders of other sugars, is reviewed in Chapter 17. Chapter 18 covers
Part 1, The Clinical Laboratory, covers the organization, purposes, and the extremely important topic of lipids and disorders in their metabolism
practices of analysis, interpretation of results, and management of the clini- and highlights the critical patterns in lipoprotein profiles that indicate dis-
cal laboratory from quality control through informatics and finances. The position to atherosclerosis and cardiac malfunction, especially myocardial
general structure of this section includes general management principles, infarction. In Chapter 19, the serodiagnostic markers for cardiac injury
with emphasis on preanalytic, analytic, and postanalytic components of evaluation and the related disorders of stroke are elaborated. The clinical
laboratory analysis as well as oversight functions. Administrative concepts significance of specific proteins and their analysis, with emphasis on elec-
for the laboratory are considered in Chapter 1, with optimization of work- trophoresis of blood and body fluids, is covered in Chapter 20. The field
flow presented in Chapter 2. Preanalytic factors such as variations arising of clinical enzymology, with applications to assessment of organ injury,
xii
is covered in Chapter 21. The principles of enzymology (e.g., transition disorders includes many standard examinations for protein and cellular
PREFACE
state theory) have been used directly in the design of new effective drugs functions plus new genetic tests for specific abnormalities (Chapter 52).
against specific diseases such as hypertension and AIDS. A new section has The assessment of autoimmune diseases is presented for the systemic rheu-
been introduced into this chapter concerning the mechanism of infection matic diseases (Chapter 53), with new chapters covering the vasculitides
of cells by the Coronavirus-19, (Covid-19), the cause of the current world (Chapter 54) and organ- specific autoimmune diseases (Chapter 55).
pandemic, because, incredibly, this virus binds uniquely to the angioten- Allergic diseases, with their ever-increasing laboratory evaluations, are
sin converting enzyme, ACE2, which acts as its receptor on cell surfaces. presented in Chapter 56.
Laboratory assessment of liver function is presented in Chapter 22 (which Part 7, Medical Microbiology, covers an enormous spectrum of infec-
includes new treatments for hepatitis C) and that of gastrointestinal and tious diseases and related topics that include medical bacteriology (Chapter
pancreatic disorders in Chapter 23. Toxicological analysis and therapeu- 57); susceptibility testing of antimicrobial agents (Chapter 58); mycobacte-
tic drug monitoring are covered in Chapter 24, with applications of both ria with immense concern for the emergence of resistant strains (Chapter
immunoassays and mass spectroscopy emerging in endocrinology (Chap- 59); mycotic diseases with a wide array of photographs of cultures and pho-
ter 25) and pregnancy and perinatal testing as well (Chapter 26). Nutri- tomicrographs (Chapter 60); spirochete infections (Chapter 61); chlamyd-
tional analysis, with examination of vitamins and trace metals, is presented ial and mycoplasmal infections (Chapter 62); rickettsiae (Chapter 63); viral
in Chapter 27. Chapter 28 elaborates the chemical principles of analysis, infections with new material on human coronavirus-19 (Chapter 64); and
which is crucial to the understanding of virtually all laboratory measure- medical parasitology which has a worldwide significance that is growing as
ments and the common interferences encountered with blood and biologi- large numbers of people move between countries and continents(Chapter
cal fluids. 65). In line with the importance of achieving maximum diagnostic ben-
Part 3, Urine and Other Body Fluids, reviews the utility and methods efit from the laboratory, specimen collection and handling for diagnosis of
for examining fluids other than blood. Chapter 29 presents the basic exam- infectious disease are detailed in Chapter 66. Although classic techniques
ination of urine, with extensive discussions of both chemical testing and have consisted of culturing microbiological organisms with identification
microscopic examination of urine sediment. A special area for consider- and antimicrobial susceptibility testing through functional bioassays, mod-
ation is body fluid analysis, which has received national attention recently ern methods of nucleic acid amplification and detection are now becoming
in terms of standardizing the approach to testing of typical fluids and other widespread for each type of microbiological organism; these applications
alternative specimens (Chapter 30). A large range of specimen types is con- are described in each chapter about the various organisms. In addition,
sidered in this discussion, with extensive coverage of both microscopic and the use of mass spectroscopy, that has revolutionized the microbiology
chemical examinations. laboratory in the identification of pathogens, is likewise discussed in each
Part 4, Hematology and Transfusion Medicine, introduces techniques appropriate chapter.
for the basic examination of blood and bone marrow (Chapter 31) and Part 8, Molecular Pathology, covers some of the most rapidly chang-
provides a wealth of background on the physiological processes involved ing and exciting areas of clinical laboratory testing. Chapter 67 provides
in hematopoiesis (Chapter 32). Erythrocytic disorders and leukocytic dis- an introduction to the role of molecular diagnostics, with an updated
orders and their diagnosis are covered in Chapters 33 and 34, respectively. discussion of the principles and techniques of the field in Chapter 68.
Modern techniques for use of flow cytometry for diagnosis of hematopoi- Similar updates are provided for the vital molecular diagnostic tech-
etic neoplasias are presented in Chapter 35 to round out the approaches niques of polymerase chain reaction and other amplification meth-
to diagnosis in this rapidly changing field. Immunohematology, which is ods (Chapter 69) and newer approaches to nucleic acid hybridization
so important for the understanding of erythrocyte, leukocyte, and plate- (Chapter 70). The application of cytogenetics, with modern methods of
let antibodies and their impact on transfusion, is covered in Chapter 36. karyotyping, including fluorescent in situ hybridization and examina-
Blood component manufacture and utilization are covered in Chapter 37 tion for chromosomal abnormalities, is covered in Chapter 71. Chapter
along with transfusion reactions. Chapters 38 and 39 deal with the rap- 72 comprehensively presents the application of molecular diagnos-
idly expanding areas of apheresis, with its applications to therapy of mul- tics to genetic diseases, for which screening is becoming more widely
tiple blood disorders as well as the collection, processing, and dispensing practiced. In view of the revolutionary development of genome-wide
of hematopoietic progenitor cells (adult stem cells) from bone marrow, association studies (GWAS), major discoveries of genomic alterations
peripheral blood, and cord blood for treatment of both malignant and non- in neuropsychiatric diseases such as Alzheimer’s disease, schizophrenia,
malignant diseases. and post-traumatic stress disorder (PTSD) have been found. Therefore,
Part 5, Hemostasis and Thrombosis, covers the vast increase in our a new presentation (Chapter 73) on the molecular biology of neuro-
knowledge of the pathways involved in clotting and in fibrinolysis and psychiatric diseases provides understanding for diagnosis and therapy
the panoply of new testing and therapeutic modalities that have evolved of these disorders. Identity testing as used in modern parentage testing
as a result. This section continues to reflect the impact of our growing and forensic analysis is presented in Chapter 74. Chapter 75 on phar-
knowledge of coagulation and fibrinolysis (Chapter 40) plus that of plate- macogenomics provides an understanding of how molecular analysis
let function disorders, with emphasis on von Willebrand disease (Chapter of selected genes crucial for response to therapeutic drugs or for the
41). Advances in the diagnosis and monitoring of thrombotic disorders are metabolism of drugs can be used to optimize individualized treatment
covered extensively in Chapter 42, with particular interest in the prediction plans, also known as personalized or precision medicine.
of thromboembolic risk. Along with our better understanding of thrombo- Part 9, Clinical Pathology of Cancer, is a further outgrowth of this sec-
sis have come new drugs for treatment of patients with vascular occlusive tion that was introduced in the twenty-first edition. Because of the explo-
disorders, particularly ischemic events in the heart or brain. Principles of sion of new diagnostic information as a result of the successful sequencing
antithrombotic therapy and the laboratory’s role in its monitoring are cov- of the human genome, genetic profiles of different forms of cancers are
ered in Chapter 43. Also discussed in this section is the major advance in now available. Specific forms of cancer are beginning to be diagnosed
pharmacogenomics (fully discussed later in Chapter 75) as it impacts anti- using microchips containing gene arrays in which patterns of gene expres-
coagulant therapies for individual patients. sion and mutation are evaluated. In addition, new methods of proteomics
Part 6, Immunology and Immunopathology, presents a framework (i.e., determination of the patterns of expression of multiple proteins in
both for classifying disorders of the immune system and for the role of lab- patients’ body fluids and tissues) allow for cancer detection, monitoring,
oratory testing in diagnosing those diseases (Chapter 44). Measurements and treatment. Thus there has been a vast increase in information about
based on immunoassays have long been the essential components of under- the principles and applications of laboratory methods for diagnosis and
standing a multitude of disorders; an excellent and comprehensive account monitoring of malignancies in just the past few years. Chapter 76 deals
of the principles of immunoassay and immunochemistry is included in with the important protein markers for cancer in blood and tissues that are
Chapter 45. Evaluation of the cellular immune system for diagnosing and commonly used for the diagnosis and management of malignant diseases.
monitoring immune defects is described in Chapter 46, which is newly Chapter 77 extends this discussion through exciting new applications of
updated. Humoral immunity and the examination of immunoglobulins in oncoproteins and growth factors and their receptors in the assessment of
disease are covered in Chapter 47, with particular emphasis on the evalu- malignancies and modification of therapies. A broad spectrum of molecular
ation of monoclonal disorders in the blood. Material on complement and and cytogenetic markers is now commonly used for the initial evaluation
its role in inflammation is presented in Chapter 48. Chapter 49 presents of hematopoietic neoplasms (Chapter 78) that could well become a model
cytokines and adhesion molecules that are vital to inflammation and have for assessment of most, if not all, malignancies. Because the methods in
become targets for therapeutic interventions. Also brought up to date are molecular pathology used in diagnosing cancer in body fluids are the same
Chapter 50 on the major histocompatibility complex (MHC), with its sig- as in solid-tissue diagnosis, breaking down the barriers between anatomic
nificant applications to organ transplantation, and Chapter 51, which looks and clinical pathology, we include Chapter 79 on the evaluation of solid
at MHC and disease associations. The evaluation of immunodeficiency tumors by these methods.
xiii
The prospects for early detection, prognosis, and implementation of for screening a wide array of proteins in blood, body fluids, and tissues for
PREFACE
treatment regimens for cancer based on specific alterations in the genome disease detection and evidence of progression. The configuration of these
have never been more apparent. These chapters on cancer diagnostics assays will consolidate multiple analyses onto miniature platforms such as
emphasize genome-based approaches and other new methods such as pro- chip technologies.
teomics, which has the potential to identify patterns of protein alterations We also note that new methods of microanalysis have now been
that can be used both for discovery of new targets for examination and for implemented so as to enable rapid point-of-care testing on critically ill
direct detection of clinical abnormalities. Many of these technologies have patients on small volumes of whole blood. These include the “stat” ana-
been developed in the past few years, and many more versions of them lytes (sodium, potassium, chloride, bicarbonate, calcium, BUN, creatinine
are sure to appear as the competitive advantage of rapid and inexpensive and glucose and, now, several critical enzymes) in addition to blood gas
genomic analysis emerges. We think it is vital for pathologists to under- determinations, all performed on hand-held analyzers and also on blood
stand the bases of molecular diagnostics, the power of this type of analysis gas analyzers. In a recent breakthrough in testing, a new mass spectrometer
for clinical decision making, and the paths such testing is likely to take in has been devised that is the size of a brief case allowing for point-of-care
the future. To this end, the final chapter (Chapter 80) presents the diag- testing by mass spectroscopy.
nostic and prognostic impact of high-throughput genomic and proteomic Although these new technologies will likely be expensive to imple-
technologies and the role they can play in the present and future practice ment initially, the hope is that they will reduce costs in other parts of the
of pathology. health care system through initiating prevention or treatment earlier than
The fundamental task for trainees in laboratory medicine is to achieve would be possible without such complex and intimate information about a
a sound understanding of analytic principles and the power and limita- patient’s disease state or propensity to develop a disease.
tions of laboratory examinations so that they can interpret whether abnor- Within this context, it is clear that the role of the clinical laboratory
mal results are due to a patient’s physical condition or to other potential in the future will involve more than simply providing numeric results for
interferences such as altered physiological state, drug interactions, or physicians to glance at during rounds or after clinic duty. The complexity
abnormalities introduced by specimen mishandling. Based on mastery of and enormity of the test results that will be routinely available will require
these technical aspects of test performance and interpretation, patholo- entirely new approaches to data presentation and interpretation to provide
gists should be able to recommend strategies to provide the appropri- useful information for clinical diagnosis and management. The challenge
ate level of care for multiple purposes: to screen for disease, to confirm to laboratories and clinicians alike is to develop “meaningful uses” in which
a diagnosis, to establish a prognosis, to monitor the effects of treatment, electronic health records can store and present all of this information about
and (more recently) to assess the future risk of disease. National practice a patient—from cradle through an entire life—into which several segments
recommendations from the American Medical Association and the U.S. are integrated: genetic background, environmental factors, previous diag-
Department of Health and Human Services have led to the formulation nostic and monitoring tests, and contemporaneous monitoring tests. All of
of standardized panels of multiple individual tests that are targeted to sev- these aspects of a patient’s history have the potential to be meaningful in
eral organ systems, such as the basic metabolic panel and comprehensive the most rigorous sense to provide personalized medical treatments.
metabolic panel (Appendix 7, available online with the other appendices). This textbook provides grounding in the practice of modern laboratory
These panels consist of individual tests that are highly automated and medicine, and it points the way to new disciplines that will contribute to
can be conveniently and inexpensively delivered through most hospital the evolution of strategies for creating, analyzing, and presenting medical
laboratories. Such convenience was not always the case when the assays information in the future. We hope that the discussions in this textbook
for basic constituents such as potassium, sodium, chloride, bicarbonate, will stimulate our colleagues at all levels to conceive of and/or embrace
calcium, bilirubin, and all the various metabolites, proteins, and enzyme new diagnostic laboratory technologies (in addition to those that are now
activities were performed manually, as documented in previous editions standard) and to retain the most valuable from each of these into practices
of this textbook. Beyond those relatively simple tests, immunoassays have of the future. The legacy of this book over the past century has been to
also undergone a similar transformation. A few decades ago, the rapid assay provide a clear and useful account of laboratory tests that generate the solid
for thyroid-stimulating hormone (TSH) required 2 days, whereas today a scientific information upon which medical decisions are based. Building on
third-generation TSH measurement can be completed in 20 minutes or that foundation, we enthusiastically anticipate new diagnostic capabilities,
less. Conversion from highly complex and operator-interactive testing to and we hope that this textbook will be a stimulus to their development.
immediately available and inexpensive assays will almost certainly occur It is a privilege and an honor to serve as editors for this twenty-fourth
with procedures that are now at the cutting edge of technology and require edition.
elaborate instrumentation and special expertise to perform. These include Richard A. McPherson, MD, MSc
tandem mass spectrometry for small molecules such as hormones, vita- Matthew R. Pincus, MD, PhD
mins, and drugs; whole genome sequencing for assessing the risk of devel- April 2021
oping hereditary disorders and diagnosing malignancies; and proteomics
xiv
ACKNOWLEDGMENTS
We gratefully acknowledge the outstanding contributions made by our positions for the American Society of Microbiology both nationally and
expert colleagues and collaborators who served as associate editors: Katalin regionally.
Banki, MD; Martin H. Bluth, MD, PhD; Jay L. Bock, MD, PhD; Wil- Omar Fagoaga, PhD. Dr. Fagoaga was director of the Histocompat-
bur B. Bowne, MD; Robert E. Hutchison, MD; Donald S. Karcher, MD; ibility Laboratory of the Detroit Medical Center and Wayne State Uni-
Mark S. Lifshitz, MD; H. Davis Massey, DDS, MD, PhD; A. Koneti Rao, versity having immigrated to the United States from El Salvador where he
MBBS; and Gail L. Woods, MD. They all have made extensive contribu- had been the target of terrorists as a youth. Despite that experience, he was
tions to the quality of this book, both through development of textual mat- known for his warm personality and for being a fast learner of laboratory
ter and through the exercise of practiced review of the chapters under their methodologies. He was at the forefront of DNA typing in histocompatibil-
guidance. We deeply appreciate their efforts in this edition. We gratefully ity testing. Among his greatest accomplishments was the mapping of HLA
acknowledge the participation in previous editions of Elizabeth R. Unger, alleles and antibodies in African American populations.
MD, PhD. Nancy S. Jenny, PhD. Dr. Jenny was Associate Professor in the
It is with sadness that we note the passing of four authors who made sig- Department of Pathology and Laboratory Medicine at the University of
nificant contributions to the previous edition of this text. We wish to honor Vermont. Her research in the biochemical mechanisms of diseases of aging
their memories and recognize their professional achievements. including atherosclerosis, dementia, and general frailty led to numerous
Martin J. Salwen, MD. Dr. Salwen was a Distinguished Service Pro- prestigious publications.
fessor at the State University of New York (SUNY) Downstate Medical All of our students, residents, and colleagues have for decades contrib-
Center and former Director of Pathology at both SUNY Downstate Uni- uted enormously to the development of our knowledge of human disease
versity Hospital and the Kings County Hospital. After graduating from and the use of laboratories for diagnosis and patient management. We are
SUNY Downstate, he performed his residency in Pathology and Labora- grateful for all of their questions and the stimulus they have provided to
tory Medicine at Yale University Medical Center after which he served our professional growth. We are especially grateful for the mentorship
with distinction in East Asia as a Captain in the medical corps in the United and encouragement provided in our careers by Alfred Zettner, MD; Cecil
States Air Force. After his military service, he became the Director of Hougie, MD; Abraham Braude, MD; Charles Davis, MD; James A. Rose,
Laboratories at Monmouth Medical Center, New Jersey. He then became MD; Robert P. Carty, PhD; Donald West King, MD; George Teebor,
Director of Pathology at both the Downstate University Hospital and MD; Phillip Prose, MD; Fred Davey, MD; and Gerald Gordon, MD. We
the Kings County Hospital, and Professor of Pathology at SUNY Down- will always remember them and the standards for excellence they set.
state Medical Center, where he revolutionized the practice of laboratory The development of this edition, with its myriad details, would not have
medicine and trained several generations of pathology residents. Under been possible without the outstanding professional efforts of our editors at
his leadership the laboratories were equipped with advanced instrumenta- Elsevier: Kathryn DeFrancesco, Michael Houston, and John Casey, each of
tion using state-of-the art technology, and embarked on the use of efficient whom added tremendously to this enterprise. We are sincerely grateful to
laboratory information systems. He revolutionized the clinical pathology them and to all the staff of Elsevier. They have made this endeavor a happy
services at both medical centers whereby attending physicians and house one. We also send very special thanks to Anne Erickson, a supreme medical
officers made joint rounds on patients with unusual laboratory findings, illustrator, who has drawn many of the illustrations in the most recent four
greatly increasing the efficacy of both the clinical and anatomic pathol- editions with a fine eye to beauty in presentation and ease of comprehension.
ogy services. His elective course in the interpretation of laboratory data We are grateful to all of the authors for accepting the challenge to par-
for senior medical students was immensely popular and benefitted them ticipate in the education of future and present laboratorians and physicians
in understanding clinical medicine. In collaboration with Drs. William in all fields of medicine by distilling the essential information from each of
Sunderman Sr. and Jr., Dr. Salwen helped found and promote the clinical their fields of expertise and creating a readable and authoritative text for
pathology journal, Annals of Clinical and Laboratory Science and served on its our audience. Special thanks to the authors who have created wholly new
editorial board for many years. Dr. Salwen made enormous contributions chapters on mass spectroscopy, ethics in laboratory medicine, and molecu-
to the clinical pathology literature in many areas including documentation lar biology of psycho-neurologic disease for this edition.
of multisystem failure in gram-negative sepsis, and the graphic presenta- We also remember with perpetual gratitude the inspiration provided to
tion of laboratory data that facilitated clinical interpretation and under- us by John Bernard Henry, MD. He provided leadership for seven editions
standing. He received many awards during his tenure at SUNY Downstate of this book. Moreover, he encouraged us, guided us, and demanded excel-
Medical Center, including the prestigious Ailanthus Award, the Jean Red- lence from us in our profession.
mond Oliver Teaching Award, and the Dr. Frank L. Babbott Memorial Upon the completion of this twenty-fourth edition, we humbly thank
Award for distinguished service to the medical profession and community. all the individuals who have played roles in making it possible. It is not pos-
Dr. Salwen’s passing is a tremendous loss to SUNY Downstate Medical sible to name all of the individuals who have contributed to this textbook.
Center, to the field of clinical pathology, and especially to this book to To those mentioned here and to those not explicitly named, we thank you
which he contributed over its many editions. for your prodigious efforts and support. We also gratefully acknowledge
Geraldine S. Hall, PhD. Dr. Hall was a Clinical Microbiologist at the loving support of our wives, Stephanie Sammartino McPherson and
the Cleveland Clinic and served as the Section Head of Microbiology. She Naomi Pincus, in developing this edition and in all our endeavors.
was dedicated to education and excelled in the practice of microbiology Richard A. McPherson, MD, MSc
which she conveyed to numerous trainees. She served in many leadership Matthew R. Pincus, MD, PhD
xv
CHAPTER
2
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Päästyään mäen harjalle, näki hän hevosen syövän pienessä
heinäisessä laaksossa allaan. Eläin oli kirjava, epäsäännölliset
valkoiset läikät näkyivät oikeassa kyljessä, sä'ässä ja polvien
alapuolella. Nähdessään sen, veti Brannon suunsa tiukalle.
Yksi häiritsevä epätietoisuus oli taas hävinnyt. Jos Billy olisi vain
lähtenyt tallista tuoreen heinän hakuun, niin se ei olisi tullut
tännepäin, koska idässä päin oli heinää yltäkylläisesti ja vielä
lähempänä karjataloa ja siellä oli sitäpaitsi vettäkin.
Billy oli ollut suljettuna talliin useamman päivän, jotta sitä olisi voitu
hoitaa paremmin vatsahäiriön vuoksi. Carson, hevospuoskari, oli
hoitanut sitä erikoisen huolellisesti, sukien sitä joka päivä. Brannon
oli myös usein pistäytynyt katsomassa, miten sen parantuminen
edistyi.
Callahanin murha oli nyt Brannonille yhtä selvä, kuin jos se olisi
painettu paperille. Kannettuaan Callahanin ruumiin asuntoonsa, oli
Brannon tutkinut hänen asettaan ja huomannut, että yksi panos oli
ammuttu tyhjäksi. Koska hän oli tullut siihen johtopäätökseen, että
Josephine oli ampunut Callahanin, oli hän hämmästynyt tuota tyhjää
panosta ja hän päätteli lopuksi, että Callahan oli aikaisemmin
ampunut jotakin ja sitten huolimattomasti laiminlyönyt täyttää aseen
uudelleen.
Nyt oli selvää, että Les Artwell oli saanut tuon puuttuvan panoksen
ruumiiseensa, vaikka sen oli täytynyt tapahtua sangen kaukana
karjatalolta, sillä muutoin se varmasti olisi kuulunut. Senvuoksi oli
Artwellin myös täytynyt seurata Callahanin jälkiä ja ampua Starin
omistaja hänen kääntäessään selkänsä kuistille astuessaan.
Se tosiasia, että Artwell oli piiloutunut talliin, oli syynä siihen, ettei
Brannon, juostuaan kuistille heti laukauksen jälkeen, ollut kuullut
mitään kiireellistä kavion kapsetta, joka olisi ilmoittanut salakytän
pakenevan.
Ainoa hämärä seikka oli enää se, että Brannon oli löytänyt
satuloidun hevosen, jolla oli Lattimerin polttomerkki. Vaikka eihän
sekään asia ollut erikoisen hämmästyttävä, kun otti huomioon
satulan huonon kunnon, poikkinaiset ohjat ja nimikirjaimet
partasudissa, jonka Brannon oli löytänyt matkalaukussa. Artwell oli
tietenkin ratsastanut sillä hevosella, mutta oliko hän varastanut sen
Lattimerilta vai oliko Lattimer myynyt tai lainannut sen, siinä oli
kysymys. Se seikka, että Josephine oli vienyt Artwellin Lattimerin
karjatalolle, näytti todistavan, että heidän välillään vallitsi ystävyys ja
kaikenlainen ystävyys kunniallisenkin karjamiehen ja tunnetun
hevosvarkaan välillä oli epäilyttävä asia, joka vaati ankaraa
tutkimusta.
"Mikä hätänä?"
"Eilen aamuna. Tallin ovi oli selkosen selällään. Missä tapasit sen,
Brannon?"
Yhdeksästoista luku.
Vaikka Betty oli koettanut parastaan ollakseen entiseen tapaansa
ystävällinen Josephineä kohtaan, oli Josephine kuitenkin huomannut
jäykkyyttä hänen käytöksessään sen jälkeen kun Betty oli tullut
Brannonin asunnosta.
Mutta hän muisti, että kun hän oli kertonut Bettylle olleensa
Brannonin kanssa vain kahden karjatalolla sinä iltana, oli Betty
katsonut häneen terävästi ja että Betty vielä myöhemmin oli mennyt
Brannonin asuntoon. Josephine oli pitänyt häntä silmällä ja hän
muisti nyt, että Bettyn kylmyys häntä kohtaan oli alkanut sen jälkeen
kuin hän oli palannut Brannonin asunnosta.
Hän uskoi, että Brannon oli tehnyt juuri sen ja sen vuoksi mahtoi
hänen yrityksensä antaa Starin omistajan murhalle oikeutetun
leiman, näyttää Bettyn silmissä naurettavalta.
Betty oli puhunut Mrs Whitmanin pojasta ja koska Mrs Whitman oli
pieni, hoikka ja hento, oli Josephine otaksunut, että poika olisi
samanlainen.
"Minähän kerroin sinulle, että hän teki sen, Ben", vastasi Mrs
Whitman
Josephinen puolesta.
"En saa sitä päähäni, näen mä" sanoi hän, katsoen Josephineen,
"mutta jos kerran sanotte sen, niin sen luonnollisesti täytyy olla
totta." Hän kääntyi ovelle. "Minä vien hevosenne kauemmaksi",
lopetti hän, mennessään ulos.
"En", sanoi Josephine lyhyesti. "Se on, minä — minä luulen, että
kunnioitan häntä, luonnollisesti. Mutta hän on ylpeä ja käskevä."
Hän tunsi itsekin, että se epäonnistui. Ja hän tiesi, että hän oli
oikeutettu vaatimaan oikeudenmukaista kohtelua, vaikka Josephine
olikin hänen vieraansa. Koettaen sitten tukahduttaa suuttumustaan,
hymyili hän iloisesti Mrs Whitmanille ja lausui valittelunsa hänen
sairautensa johdosta.
"Olisit sanonut minulle, minne olit menossa, Jo", sanoi hän. "Silloin
en olisi ollut huolissani. Ehkäpä olisin tullut kanssasi. Sinähän olit
täällä koko yön?"
Kun Betty syöksyi ovesta ulos, otti Josephine pari askelta hänen
perässään, mutta pysähtyi ja jäi seisomaan jäykkänä, kalpeana ja
uhmailevana kuunnellen nopeasti poistuvaa kavion kapsetta.
Nyt se oli sanottu eikä kukaan ollut "viekotellut" sitä häneltä "ulos."
Hän oli kokonaan antautunut intohimoisen suuttumuksen valtaan,
joka koko aamun oli kasvanut hänessä sen kautta, että hän oli
alituisesti ajatellut Bettyn puolelta osakseen tullutta luuloteltua
huonoa kohtelua. Mutta hän oli varma siitä, että hän ei olisi sanonut
mitään, ellei hän olisi ollut puolihulluna siitä hermojännityksestä,