Tietz’s applied laboratory medicine 2e 2007

Professor, Department of Laboratory Medicine and Pathology,University of Minnesota School of Medicine; Medical Director of Clinical Chemistryand Toxicology Laboratories, Hennepin County

Tietz’s Applied

Laboratory Medicine Second Edition

Tietz’s Applied

Laboratory Medicine Second Edition

Copyright # 2007 by John Wiley & Sons, Inc All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data is available.

ISBN-13 978-0-471-71457-6

ISBN-10 0-471-71457-6

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

Part One Cardiac Disease

Case 1 A 45-Year-Old Man

with Substantial

Fred S Apple

Case 2 A 48-Year-Old Cocaine User

Fred S Apple and Ramona Evans

Part Two Pulmonary Diseases

Case 3 Shortness of Breath with

and Dennis Dietzen

Part Three Renal Disease

Case 5 Man with Hypertension

C Darrell Jennings

Case 6 Oliguria with Metabolic Acidosis

after Renal Transplantation 41

Case 8 Young Man with Edema and

Decreased Urine Output 55

H William Schnaper

Case 9 A New Doctor for a Man with

Diabetes and Hypertension 65Michael E Hull

Case 10 A Pain in the Back 75

Kevin J Martin andEsther A Gonza´lez

Case 11 Refractory Hyponatremia

with Lung Cancer 79Manish J Gandhi

Part Four Liver Diseases

Case 12 Adolescent Female with

Tremor, Depression,

Steven I Shedlofsky

v

Case 13 Adult Male with New-Onset

Steven I Shedlofsky

Case 14 An Unexpected Finding .: 105

Nathan C Walk

Case 15 I Did It Just Once—A

37-Year-Old Man with

Alvaro Koch and Luis R Pen˜a

Case 16 Obese Woman with Persistently

Abnormal Liver Enzymes 121

Iliana Bouneva

Part Five Thyroid Diseases

Case 17 The Irritable Wife 131

Part Six Adrenocortical Diseases

Case 20 Child with Rapid Growth and

Precocious Sexual Maturation 149

Case 23 The Hypertensive Accountant 175

Michael Stowasser andRichard D Gordon

Case 24 Don’t “Take Two Aspirin and

Call Me in the Morning” 183Jacqueline E Payton

Case 25 Unpleasant Spells 189

Les G K Q Burke andRavinder J Singh

Part Seven Diabetes

Case 26 Recent Weight Loss and

Case 29 Bad to the Bone 219

Chelsea A Sheppard andCorinne R Fantz

Case 30 A Middle-Aged Woman with

Colle’s Fracture 225Catherine A Hammett-Stabler

vi Contents

Case 31 A 10-Year-Old Boy with

Pain-Induced Seizures 233

Lorin M Henrich, Alan D Rogol,

and David E Bruns

Part Nine Miscellaneous Endocrine

Part Ten Genetically Inherited Disorders

Case 34 Feed a Cold 257

Dennis Dietzen

Case 35 Acute Neonatal Ammonia

Dennis Dietzen

Case 36 Not Just a Picky Eater 269

Douglas F Stickle and

Richard E Lutz

Case 37 The “Fussy” Neonate 275

Patricia M Jones and

Dinesh Rakheja

Case 38 The “Sleepy” Neonate 281

Dinesh Rakheja and

Patricia M Jones

Case 39 A Happy but Developmentally

Delayed 5-Year-Old Boy 287

Alison E Presley and

David E Bruns

Case 40 The Asymptomatic

Elise Krejci

Part Eleven Infectious Diseases

Case 41 Tired, Hot, and Lumpy 301

Case 48 Increasing Abdominal Girth 343

Nicholas P Taylor andRandall K Gibb

Case 49 To Screen or Not to Screen? 349

Da-elene van der Merwe andEleftherios P Diamandis

Contents vii

Case 50 A Male with Confusing

Kingshuk Das

Case 51 Size Greater than Dates 363

Randall K Gibb and

Nicholas P Taylor

Part Thirteen Hematologic Malignancies

Case 52 A Man with Anemia and

Sylva Bem, Robert E Hutchison,

and Naif Z Abraham, Jr

Case 53 A Teenager with Pneumonia,

Leukopenia, and Ecchymoses 379

Anna Hallsdordottir

Case 54 A Middle-Aged Man with

Chronic Foot Ulcer 387

Brian Watson

Case 55 A Man with Progressive Effort

Intolerance and Splenomegaly 393

Mrinal M Patnaik and

Case 61 Young Girl with a Bloody

Danielle Stueber

Case 62 A Young Man with

Chest Pain Following

Ganesh C Kudva

Case 63 A Young Woman with

Postpartum Cerebral VenousThrombosis and AbnormalCoagulation Tests 459Hans-Joachim Reimers

Case 64 A Baby with Petechiae

Case 66 A Woman with Abdominal

Pain and Thrombocytopenia 485

Ji Lu

Case 67 Sudden Jaundice and

Painful Fingers 491Arnel Urbiztondo

Case 68 The Good in “Bad”

Kimberley G Crone

Case 69 The Jaundiced Mother 503

Nathan Walkviii Contents

Part Fifteen Porphyrias

Case 70 Young Woman with

Recurrent Abdominal Pain 513

Steven I Shedlofsky

Case 71 A 9-Year-Old Boy

with Skin Lesions and

David Bruns and

Audrey K Bennett

Part Sixteen Pharmacogenomics

Case 72 Personalized Medicine for a

Renal Transplant Patient 533

Case 75 A 46-Year-Old Female

with a Painful, Swollen

Syamal Bhattacharya,

Bradley D Freeman, and

Barbara A Zehnbauer

Part Seventeen Toxicology

Case 76 A Case of Mixed Club

Susan B Gock, Run-Zhang Shi,

Jeffery M Jentzen, and

Case 78 Metabolic Acidosis of Unknown

Origin Among Burn Patients 567Deborah Chute and

David Bruns

Part Eighteen Lipid Disorders

Case 79 The Family Reunion Party 575

Veronica Luzzi

Case 80 A 5-Year-Old Boy with

Yellow-Orange Tonsils:

Hypoalphalipoproteinemia 581Raffick A R Bowen and

Alan T Remaley

Case 81 Worsening Diarrhea in a

5-Year-Old Girl 585Masako Udewa and

Alan T Remaley

Case 82 A 4-Year-Old Girl with Yellow

Xanthomas and Arthritis 589Robert D Shamburek and

Alan T Remaley

Part Nineteen Autoimmune Diseases

Case 83 Woman with Morning Stiffness

and Tender, Swollen Joints 595Liron Caplan and

Sterling G West

Case 84 Woman with a Rash and

Lower Extremity Pain 601Liron Caplan and

Sterling G West

Contents ix

Case 85 Woman with Diarrhea

Nikola Baumann

Part Twenty Analytical Errors

Case 86 Where’s My Baby? 617

Jennifer A Egan and

David G Grenache

Case 87 Elevated Concentrations, but

Not Elevated Enough 623

Part Twenty-One Miscellaneous

Case 90 A Man with Fever and

Acute Polyarthritis 643William Eugene Davis

Case 91 Middle-Aged Alcoholic with

Jaundice and Ascites 649Luis R Pen˜a and Alvaro Koch

Case 92 Where Did the Red Cells Go? 658

Arnel Urbiztondo

x Contents

It has been said that 80% of all medical decisions encompass clinical laboratory data in thedecision process! While we know of no evidence to support this statement it is probablynot far off the mark Laboratory medicine plays an integrated role in the diagnosis, prog-nosis, treatment, and long-term management of disease Proper selection and interpret-ation of laboratory tests is critical for quality patient care In the last few decades, therehas been an information explosion in the field of laboratory medicine, making it difficultfor health care professionals to remain fluent in all aspects of laboratory testing AppliedLaboratory Medicine, Second Edition provides a comprehensive overview of modern lab-oratory medicine in a “real-life” case-based format Each Case presents a patient withhistory and accompanying laboratory data This is followed by discussions of how thelaboratory data is used in relation to symptoms and the differential diagnosis Most discus-sions also provide a definition of the disease, its pathophysiology, and treatment We hopethis book will be an excellent problem-based learning tool

The first edition of Applied Laboratory Medicine focused primarily on traditionalclinical chemistry tests In the Second Edition, the case studies have been expanded toinclude hematology, coagulation, infectious disease, autoimmune disease, and moleculardiagnostics In addition, cases illustrate many new laboratory tests, new treatments,current risk factor guidelines based upon laboratory tests, and new testing algorithms.Furthermore, some examples of common laboratory problems and interferences arepresented Understanding of such interferences is paramount for proper interpretation oflaboratory tests that do not fit the clinical presentation

We hope Applied Laboratory Medicine, Second Edition will be an excellent resourcefor medical students during their pathology course, residents, fellows, nurses, physician’sassistants, medical technologists, educators, physicians, laboratorians, and many otherallied health workers

Mitchell G ScottAnn M GronowskiCharles S Eby

xi

Naif Z Abraham, Jr., M.D., Ph.D Staff Pathologist, Veterans Affairs MedicalCenter; Assistant Professor, State University of New York, Upstate Medical University,Syracuse, NY

Case 52, A Man with Anemia and Lymphocytosis; Case 59, A Woman with Fatigue and PallorKenneth B Ain, M.D Assistant Professor of Medicine, Division of Endocrinology andMetabolism, Department of Medicine, University of Kentucky Medical Center; VeteransAdministration Medical Center, Lexington, KY

Case 18, The Fatigued Attorney; Case 19, The Reluctant Chef

Fred S Apple, Ph.D Professor, Department of Laboratory Medicine and Pathology,University of Minnesota School of Medicine; Medical Director of Clinical Chemistryand Toxicology Laboratories, Hennepin County Medical Center, Minneapolis, MNCase 1, A 45-Year-Old Man with Substantial Chest Pain; Case 2, A 48-year-old CocaineUser With Chest Pain

Robyn Atkinson, Ph.D Director of Bacteriology, New York State Department ofHealth, Wadsworth Center, Albany, NY

Case 42, A Rash on the Soles of the Feet

Karen Austin, M.D Resident, Department of Medicine, Washington University School

of Medicine, St Louis, MO

Case 56, A Man with Splenic Vein Thrombosis and Polycythemia

Nikola Baumann, Ph.D Director of Clinical Laboratories, Assistant Professor ofPathology, University of Illinois Medical Center, Chicago, IL

Case 85, A Woman with Diarrhea and Anemia

Sylva Bem, M.D Staff Pathologist, Veterans Affairs Medical Center, AssistantProfessor, State University of New York, Upstate Medical University, Syracuse, NYCase 52, A Man with Anemia and Lymphocytosis

Anders H Berg Department of Pathology, Harvard Medical School, Boston, MACase 26, Recent Weight Loss and Polyuria in a 52-Year-Old Man; Case 27, AnUnconscious Diabetic Male; Case 28, A Diabetic Woman’s “Episode”

Syamal Bhattacharya Medical Student, University of Tennessee, Memphis, TNCase 75, A 46-Year-Old Female with a Painful, Swollen Right Calf

Iliana Bouneva, M.D University of Kentucky, Department of Gastroenterology,Lexington, KY

Case 16, Obese Woman with Persistently Abnormal Liver Enzymes

Raffick A R Bowen, Ph.D Department of Laboratory Medicine, National Institutes ofHealth, Bethesda, MD

Case 80, A 5 Year-old Boy with Yellow-orange Tonsils: Hypoalphalipoproteinemia

xiii

Nancy Bratanow, M.D Midwest Comprehensive Pain Care Center, Milwaukee, WICase 73, Personalized Medicine for Pain Management

David E Bruns, M.D Professor, Department of Pathology, University of VirginiaMedical Center, Charlottesville, VA

Case 31, 10-Year-Old Boy with Pain-Induced Seizures; Case 39, A Happy, But mentally Delayed, 5-Year-Old Boy; Case 71, 9-Year-old with Hyperpigmentation andStomach Aches; Case 78, Metabolic Acidosis of Unknown Origin Among Burn PatientsLes G.K.Q Burke, M.D Department of Laboratory Medicine and Pathology, MayoClinic, Rochester, MN

Develop-Case 25, Unpleasant Spells

Nausherwan K Burki, M.D Professor, Department of Medicine, University ofKentucky College of Medicine; Chief, Division of Pulmonary and Critical Care Medicine,University of Kentucky Medical Center; Staff, Veterans Administration Medical Center;Staff, Humana Hospital, Lexington, KY

Case 3, Shortness of Breath with Productive Cough

Liron Caplan, M.D University of Colorado at Denver and Health Science Center,Denver, CO

Case 83, Woman with Morning Stiffness and Tender, Swollen Joints; Case 84, Womanwith a Rash and Lower Extremity Pain

Deborah Chute, M.D Resident, Department of Pathology, University of VirginiaMedical Center, Charlottesville, VA

Case 78, Metabolic Acidosis of Unknown Origin Among Burn Patients

Kimberly Crone, M.D Resident, Department of Pathology and Immunology, Division

of Laboratory Medicine, Washington University School of Medicine, St Louis, MOCase 68, The Good in “Bad” Fish Tacos

Kingshuk Das, M.D Resident, Department of Pathology and Immunology, Division ofLaboratory Medicine, Washington University School of Medicine, St Louis, MOCase 50, A Male with Confusing hCG Results

William Davis, M.D Program Director of Internal Medicine Residency, Ochsner cal Foundation and Clinical Associate Professor of Medicine, Tulane University, NewOrleans, LA

Clini-Case 90, A Man with Fever and Acute Polyarthritis

Eleftherios Diamandis, M.D., Ph.D Head, Section of Clinical Biochemistry, ment of Pathology and Laboratory Medicine, Mount Sinai Hospital, Professor andHead, Division of Clinical Biochemistry, Department of Laboratory Medicine and Patho-biology, University of Toronto, Ontario, Canada

Depart-Case 49, To Screen or Not to Screen

Dennis Dietzen, Ph.D Assistant Professor of Pediatrics and Pathology, WashingtonUniversity School of Medicine, St Louis, Missouri, Assistant Director, Clinical Chemistryand Metabolic Genetics Laboratories, St Louis Children’s Hospital, St Louis, MOCase 4, Genotype-Phenotype Correlations in Cystic Fibrosis; Case 34, Feed a Cold;Case 35, Acute Neonatal Ammonia Intoxication

xiv Contributors

Charles Eby, M.D Associate Professor of Pathology and Immunology, Division ofLaboratory Medicine, Washington University School of Medicine, St Louis, MOCase 65, Evaluation of a Reference Range Outlier

Jennifer A Egan, M.D Resident, Department of Pathology and Laboratory Medicine,University of North Carolina School of Medicine, Chapel Hill, NC

Case 86, Where’s My Baby?

Ramona Evans, M.D Resident in Pathology, University of Minnesota, Department ofLaboratory Medicine and Pathology, Minneapolis, MN

Case 2, A 48-Year-Old Cocaine User With Chest Pain

Corinne Fantz, Ph.D Assistant Professor, Core Labs, Emory University, CrawfordLong Hospital, Department of Pathology and Laboratory Medicine, Atlanta, GACase 29, Bad to the Bone

Bradley D Freeman, M.D Associate Professor of Surgery, Washington UniversitySchool of Medicine, St Louis, MO

Case 75, A 46-Year-Old Female with a Painful, Swollen Right Calf

Manish J Gandhi, M.D Resident in Department of Pathology and Immunology,Division of Laboratory Medicine, Washington University School of Medicine,

St Louis, MO

Case 11, Refractory Hyponatremia with Lung Cancer

Randall K Gibb, M.D Assistant Professor of Obstetrics and Gynecology, WashingtonUniversity School of Medicine, St Louis, MO

Case 48, Increasing Abdominal Girth; Case 51, Size Greater than Dates

Susan B Gock Technical Director, Milwaukee County Medical Examiners Office,Medical College of Wisconsin, Milwaukee, WI

Case 76, Case of Mixed Club Drugs Abuse; Case 77, A 43-Year-Old Male with ChronicPain

Ariel Goldschmidt, M.D Resident in Laboratory Medicine, Department of Pathologyand Immunology, Washington University School of Medicine, St Louis, MO

Case 45, Not Just Heartburn

Esther A Gonza´lez, M.D Associate Professor of Internal Medicine, Division ofNephrology, St Louis University, St Louis, MO

Case 10, A Pain in the Back

Richard Gordon, MBBS, FRACP, Ph.D., M.D Professor and Co-Director, EndocrineHypertension Research Centre, University of Queensland School of Medicine, PrincessAlexandra Hospital, Brisbane, Australia

Case 23, The Hypertensive Accountant

David Grenache, Ph.D Assistant Professor, Department of Pathology and LaboratoryMedicine, University of North Carolina School of Medicine, Chapel Hill, Chapel Hill, NCCase 86, Where’s My Baby?

Ann M Gronowski, Ph.D Associate Professor of Pathology and Immunology, ision of Laboratory Medicine, Washington University School of Medicine, AssociateMedical Co-Director of Clinical Chemistry, Barnes-Jewish Hospital, St Louis, MOCase 87, Elevated Concentrations, but Not Elevated Enough

Div-Contributors xv

Anna Halldo´rsdo´ttir, M.D Resident in Department of Pathology and Immunology, ision of Laboratory Medicine, Washington University School of Medicine, St Louis, MOCase 53, A Teenager with Pneumonia, Leukopenia, and Ecchymoses

Div-Catherine Hammett-Stabler, Ph.D Associate Professor of Pathology and LaboratoryMedicine, University of North Carolina, Chapel Hill, NC

Case 30, A Middle-Aged Woman with Colle’s Fracture

Lorin M Henrich, Ph.D Postdoctoral Fellow in Clinical Chemistry, Department ofPathology, University of Virginia Medical Center, Charlottesville, VA

Case 31, 10-Year-Old Boy with Pain-Induced Seizures

Michael Hull, M.D Resident in Department of Pathology and Immunology, Division ofLaboratory Medicine, Washington University School of Medicine, St Louis, MOCase 9, A New Doctor for a Man With Diabetes and Hypertension

Robert T Hutchison, M.D Professor of Pathology, State University of New York,Upstate Medical University, Syracuse, NY

Case 52, A Man with Anemia and Lymphocytosis; Case 59, A Woman with Fatigue andPallor

Paul Jannetto, Ph.D Assistant Professor of Pathology, Medical College of Wisconsin,Milwaukee, WI

Case 72, Personalized Medicine for A Renal Transplant Patient; Case 73, PersonalizedMedicine for Pain Management

C Darrell Jennings, M.D Associate Professor, Department of Pathology and tory Medicine; Director of Immunopathology, University of Kentucky College of Medi-cine; Associate Director of Clinical Laboratories, University of Kentucky MedicalCenter, Lexington, KY

Labora-Case 5, Man with Hypertension and Fever; Labora-Case 6, Oliguria with Metabolic Acidosis AfterRenal Transplantation; Case 7, A Woman with Uremia, Pulmonary Infiltration, andHemoptysis

Jeffrey M Jentzen, M.D Professor of Pathology, Medical College of Wisconsin,Milwaukee, WI

Case 76, Case of Mixed Club Drugs Abuse; Case 77, A 43-Year-Old Male with ChronicPain

Patricia M Jones, Ph.D Children’s Medical Center, Dallas, TX

Case 37, The “Fussy” Neonate; Case 38, The “Sleepy” Neonate

J Stacey Klutts, M.D., Ph.D Resident in Department of Pathology and Immunology,Division of Laboratory Medicine, Washington University School of Medicine, St.Louis, MO

Case 41, Tired, Hot, and Lumpy

Alvaro Koch, M.D Assistant Professor of Medicine, Medical Director, Liver plantation Program, Division of Digestive Diseases and Nutrition, University of Kentucky,Lexington, KY

Trans-Case 15, “I Just Did It Once”—A 37 Year-Old Man with Hepatitis C; Trans-Case 91,Middle-aged Alcoholic with Jaundice and Ascites

xvi Contributors

John A Koepke, Ph.D Professor Emeritus, Duke University Medical Center,Durham, NC

Case 57, A Child with Pneumonia; Case 58, A Man with a Tender Toe and AnemiaElise Krejci, M.D Resident in Laboratory Medicine, Department of Pathology andImmunology, Washington University School of Medicine, St Louis, MO

Case 40, The Asymptomatic Iron Man

Ganesh C Kudva, M.D Division of Hematology and Oncology, St Louis UniversitySchool of Medicine, St Louis, MO

Case 62, A Young Man with Chest Pain Following a Knee Injury

Nathan Ledeboer, Ph.D Postdoctoral Fellow, Medical and Public Health biology, Department of Pathology and Immunology, Division of Laboratory Medicine,Washington University School of Medicine, St Louis, MO

Micro-Case 46, The Dangers of Yard Work

Robert Liao, Ph.D Assistant Professor, Department of Pathology and Molecular cine and Director of Clinical Microbiology, Queens University Hospital, Kingston,Ontario, Canada

Medi-Case 43, When Life Gives You Lemons

Latisha Love-Gregory, Ph.D Postdoctoral Fellow in Clinical Chemistry, Department

of Pathology and Immunology, Division of Laboratory Medicine, Washington UniversitySchool of Medicine, St Louis, MO

Case 4, Genotype-Phenotype Correlations in Cystic Fibrosis (CF)

Lu Ji, M.D Resident in the Department of Pathology and Immunology, WashingtonUniversity School of Medicine, St Louis, MO

Case 66, A Woman with Abdominal Pain and Thrombocytopenia

Lori Luchtman-Jones, M.D Assistant Professor of Pediatrics, Division of Hematologyand Oncology, Washington University School of Medicine, St Louis, MO

Case 64, A Baby with Petechiae and Bruises

Veronica Luzzi, Ph.D Research Associate Professor of Medicine, Department ofInternal Medicine, Division of Lipid Research, Washington University School of Medi-cine, St Louis, MO

Case 79, The Family Reunion Party

Richard E Lutz, M.D Department of Pathology and Microbiology, University ofNebraska Medical Center, Omaha, NE

Case 36, Not Just a Picky Eater

Kevin J Martin, M.B., B.Ch Professor of Internal Medicine, Director, Division ofNephrology, St Louis University Health Science Center, St Louis, MO

Case 10, A Pain in the Back

Mrinal M Patnaik, M.D Postdoctoral Fellow, Department of Hematology, MayoClinic, Rochester, MN

Case 55, A Man with Progressive Effort Intolerance and Splenomegaly

Jacqueline Payton, M.D., Ph.D Resident in Department of Pathology and Immunology,Division of Laboratory Medicine, Washington University School of Medicine, St Louis, MOCase 24, Don’t “Take Two Aspirin and Call Me in the Morning”

Contributors xvii

Luis R Pen˜a, M.D., F.A.C.G Assistant Professor of Medicine, Director, ology Fellowship Program, Division of Digestive Diseases and Nutrition, University ofKentucky Medical Center, Lexington, KY

Gastroenter-Case 15, “I Just Did It Once ”— A 37 Year-Old Man with Hepatitis C

Alison E Presley, M.D Transfusion Medicine Fellow, University of Virginia HealthSystems, Department of Pathology, Charlottesville, VA

Case 39, A Happy, But Developmentally Delayed, 5-Year-Old Boy

Dinesh Rakheja Department of Pathology, University of Texas Southwestern MedicalCenter, Dallas, TX

Case 37, The “Fussy” Neonate; Case 38, The “Sleepy” Neonate

Majed Refaai, M.D Resident in Department of Pathology and Immunology,Division of Laboratory Medicine, Washington University School of Medicine,

St Louis, MO

Case 60, Pulseless Leg Nine Days After a Myocardial Infarction

Hans-Jochim Reimers, M.D., Ph.D St Louis University, Department of Hematologyand Oncology, St Louis, MO 63110

Case 64, Acquired Venous Thromboembolism

Alan T Remaley, Ph.D., M.D National Institutes of Health, Department of LaboratoryMedicine, Bethesda, MD

Case 80, A 5-Year-old Boy with Enlarged Yellow-orange Tonsils: mia; Case 81, Worsening Diarrhea in a 5-Year-old Girl; Case 82, A 4-Year-Old Girl withYellow Xanthomas and Arthritis

Hypoalphalipoproteine-Paula Revell, Ph.D Postdoctoral Fellow, Medical and Public Health Microbiology,Department of Pathology and Immunology, Division of Laboratory Medicine,Washington University School of Medicine, St Louis, MO

Case 44, The Wheezing Woodsman

Joan Riley, Ph.D Postdoctoral Fellow in Clinical Chemistry, Department of Pathologyand Immunology, Division of Laboratory Medicine, Washington University School ofMedicine, St Louis, MO

Case 47, An Important Finding on Routine Screening

Alan D Rogol, M.D Department of Pathology, University of Virginia Medical Center,Charlottesville, VA

Case 31, A 10-Year-Old Boy with Pain-Induced Seizures

David B Sacks, M.B., ChB Associate Professor of Pathology, Harvard MedicalSchool, Boston, MA

Case 26, Recent Weight Loss and Polyuria in a 52-Year-Old Man; Case 27, An scious Diabetic Male; Case 28, A Diabetic Woman’s “Episode”

Uncon-H William Schnaper, M.D Associate Professor, Department of Pediatrics, GeorgeWashington University; Department of Nephrology, Children’s National MedicalCenter, Washington, DC

Case 8, Young Man with Edema and Decreased Urine

Mitchell G Scott, Ph.D Professor of Pathology and Immunology, Division ofLaboratory Medicine, Washington University School of Medicine, Medical Co-Director

of Clinical Chemistry, Barnes-Jewish Hospital, St Louis, MO

Case 88, I Want to Go Home!; Case 89, Is that really the Calcium Value?

xviii Contributors

Robert D Shamburek, M.D National Institutes of Health, Department of LaboratoryMedicine, Bethesda, MD

Case 82, A 4-Year-Old Girl with Yellow Xanthomas and Arthritis

Steven I Shedlovsky, M.D Associate Professor, Department of Medicine andGraduate Center for Toxicology, University of Kentucky College of Medicine, StaffGastroenterologist, Veterans Administration Hospital and University of KentuckyMedical Center, Lexington, KY

Case 12, Adolescent Female with Tremor, Depression, and Hepatitis (Wilson’s Disease);Case 13, Adult Male with New Onset Ascites; Case 70, Young Woman with RecurrentAbdominal Pain

Chelsea Sheppard, M.D Clinical Fellow, Core Labs, Emory University, CrawfordLong Hospital, Department of Pathology and Laboratory Medicine, Atlanta, GACase 29, Bad to the Bone

Run-Zhang Shi, Ph.D Department of Pathology, Medical College of Wisconsin,Milwaukee, WI

Case 76, Use of “Club Drugs” by a 24-Year-old Female

Ravinder Singh, Ph.D Department of Laboratory Medicine and Pathology, MayoClinic, Rochester, MN

Case 25, Unpleasant Spells

Jennifer Snyder Department of Pathology and Laboratory Medicine, University ofNorth Carolina School of Medicine, Chapel Hill, NC

Case 33, Hot Flashes and Abdominal Pain

Phyllis Speiser, M.D Associate Professor, Pediatric Endocrinology, SchneiderChildren’s Hospital, New Hyde Park, NY

Case 20, Child with Rapid Growth and Precocious Sexual Maturation

Douglas F Stickle, Ph.D Technical Director of Clinical Chemistry, Assistant fessor, Department of Pathology and Microbiology, University of Nebraska MedicalCenter, Omaha, NE

Pro-Case 36, Not Just a Picky Eater

Michael Stowasser, MBBS, FRACP, Ph.D Associate Professor and Co-Director,Endocrine Hypertension Research Centre, University of Queensland School of Medicine,Princess Alexandra Hospital, Brisbane, Australia

Case 23, The Hypertensive Accountant

Danielle Stueber, M.D Research Technologist, Department of Medicine, WashingtonUniversity School of Medicine, St Louis, MO

Case 61, Young Girl with a Bloody Knee Effusion

Nicholas Taylor, M.D Clinical Fellow, Department of Obstetrics & Gynecology,Washington University School of Medicine, St Louis, MO

Case 48, Increasing Abdominal Girth; Case 51, Size Greater than Dates

Ayalew Tefferi, M.D Department of Hematology, Mayo Clinic, Rochester, MNCase 55, A Man with Progressive Effort Intolerance and Splenomegaly

Masako Ueda, M.D Department of Laboratory Medicine, National Institutes of Health,Bethesda, MD

Case 81, Worsening Diarrhea in a 5-Year-Old Girl

Contributors xix

Arnel Urbiztondo, M.D Transfusion Medicine Fellow, Department of Pathology andImmunology, Division of Laboratory Medicine, Washington University School of Medi-cine, St Louis, MO

Case 67, Sudden Jaundice and Painful Fingers; Case 92, Where Did the Red Cells Go?Da-olone van der Merwe, M.D Department of Pathology and Laboratory Medicine,Mount Sinai Hospital, Toronto, Ontario, Canada

Case 49, To Screen or Not to Screen

Nathan Walk, M.D Resident in Department of Pathology and Immunology, Division

of Laboratory Medicine, Washington University School of Medicine, St Louis, MOCase 14, An Unexpected Finding .; Case 69, The Jaundiced Mother

Brian Watson, M.D., Ph.D Resident in Department of Pathology and Immunology,Division of Laboratory Medicine, Washington University School of Medicine, St.Louis, MO

Case 54, A Middle-Aged Man with Chronic Foot Ulcer

Sterling G West, M.D Professor of Rheumatology/Allergy and Clinical Immunology,University of Colorado at Denver and Health Science Center, Denver, CO

Case 83, Woman with Morning Stiffness and Tender, Swollen Joints; Case 84, Womanwith a Rash and Lower Extremity Pain

William E Winter, M.D Professor, Department of Pathology, University of Florida,Gainesville, FL

Case 17, The Irritable Wife; Case 21, Weight Gain, Infertility, and Hypertension; Case 22,The Tired Teenager

Steven Wong, Ph.D Professor, Department of Pathology, Medical College ofWisconsin, Milwaukee, WI

Case 76, Case of Mixed Club Drugs Abuse; Case 77, A 43-Year-Old Male with ChronicPain

Alison Woodworth, Ph.D Postdoctoral Fellow in Clinical Chemistry, Department ofPathology and Immunology, Division of Laboratory Medicine, Washington UniversitySchool of Medicine, St Louis, MO

Case 74, A Man with Colitis and Pancytopenia

Barbara Zehnbauer, Ph.D Clinical Professor in the Departments of Pathology andImmunology, and Pediatrics, Director, Molecular Core Laboratory, Site-man CancerCenter, Washington University School of Medicine, St Louis, MO

Case 4, Genotype-Phenotype Correlations in Cystic Fibrosis (CF); Case 75, A46-Year-Old Female with a Painful, Swollen Right Calf

Oren Zinder, Ph.D Professor, Department of Clinical Biochemistry, Rambam MedicalCenter, Haifa, Israel

Case 32, Laboratoy Tests Ignored

xx Contributors

Part One

Cardiac Disease

Cases of cardiac risk with myocardial infarction and with cocaine abuse are presented and discussed in Cases 1 and 2 [both edited by MGS (editors’ names are listed on title page in book Frontmatter)], respectively.

Tietz’s Applied L aboratory Medicine, Second Edition Edited by Mitchell G Scott, Ann M Gronowski, and Charles S Eby

Copyright # 2007 John Wiley & Sons, Inc.

1

Case 1

A 45-Year-Old Man with

Substantial Chest Pain

Fred S Apple

History of Current Presentation

The subject is a 45-year-old African-American male who presents with a chief complaint of

“substantial chest pain” that radiated through his right arm and back The pain awoke himfrom his sleep at approximately 3 : 30 am and was described as constant and as “8 out of 10.”

He also complained of nausea and shortness of breath Over the past 2 – 3 months he statedthat he had experienced similar symptoms that radiated through both arms One month prior

to admission, he visited his primary care internist, during which time his electrocardiogram(EKG) and x-rays were normal A stress test was scheduled but the appointment was missed

On the morning of presentation, the patient took 1 aspirin (325 mg) within 30 minutes ofawakening The subject presents to the emergency department 1 hour [0430 h (4: 30 am)]after onset of acute chest pain

He had a past medical history of hypertension and takes both antihypertensive cation and aspirin daily He is a smoker (20 years), and occasional drinker, and his fatherhad a fatal myocardial infarction (MI) at the age of 72 At physical examination, tempera-ture, pulse, and respiration were normal, blood pressure 200/40, O2saturation (pulse oxi-metry) 92% on room air and 99% after receiving 100% oxygen He was alert, awake, andoriented in moderate discomfort His lungs were clear to auscultation bilaterally with norales or wheezes Heart rate and rhythm were regular without murmurs Chest x-rayshowed borderline cardiomegaly, without infiltrates

medi-At presentation, routine chemistries, CBC, and cardiac biomarkers were withinnormal limits The EKG at presentation shows poor R-wave progression anteriorly,with an ST depression in lead III Consultation with the attending cardiologist following

a similar EKG repeated at 1 hour after presentation ruled out MI The patient was managedmedically with nitroglycerin sublingually (3 doses), which improved his discomfort tothe point where he was pain-free His blood pressure improved (decreased) followingmedication He was also given multiple doses of morphine sulfate for his right arm pain.Given the history and current presentation, the patient was admitted to the cardiacshort-stay unit, and monitored He was given nitrogycerine and low-molecular-weight

Tietz’s Applied L aboratory Medicine, Second Edition Edited by Mitchell G Scott, Ann M Gronowski, and Charles S Eby

Copyright # 2007 John Wiley & Sons, Inc.

3

heparin (LMWH, enoxaparin) Repeat cardiac biomarkers were ordered for 4 and 8 hoursafter presentation Four hours following presentation, the EKG showed inverted T waves,now with new Q waves in the anterior leads Repeat measurements of biomarkers at 0845 h(8 : 45 am) showed elevated values for total CK, CKMB, and condiac troponin T(cTnT).Day

In the hospital, the patient tolerated progressive ambulation without difficulty He wasdischarged on day 4, on multiple medications, and scheduled for cardiac rehabilitation,medication assessment, and outpatient follow-up Presently use of biomarkers such ascardiac troponin, BNP (B-type natriurtic peptide), or hsCRP are not routinely used forfollow-up in post-MI patients for risk assessment, unless clinically indicated

Definition of the Disease

Acute myocardial infarction (AMI) is defined as an imbalance between myocardial oxygensupply and demand resulting in injury and eventual death of myocytes It is now thought thatthe migration of stem cells has the potential to replace at least some damaged myocytes.When the blood supply to the heart is interrupted, “gross necrosis” of the myocardiumresults Necrosis is most often associated with a thrombotic occlusion superimposed on cor-onary atherosclerosis The process of plaque rupture and thrombosis is one of the ways inwhich coronary atherosclerosis progresses and that we currently recognize only the moresevere of these events Total loss of coronary blood flow in a major coronary arteryresults in a clinical syndrome known as ST-segment elevation AMI (STEMI) Partial loss

of coronary perfusion can also lead to necrosis as well, is generally less severe, and isknown as non-ST-elevation myocardial infarction (NSTEMI) Other events of still lesserseverity may be missed entirely and can range from stable to unstable angina

Presenting Symptoms

The clinical history remains of substantial value in establishing a diagnosis A prodromalhistory of angina can be found in 40 – 50% of patients with AMI; approximately one-thirdhave symptoms 1 – 4 weeks before hospitalization In the remaining two-thirds, symptoms

4 Case 1 A 45-Year-Old Man with Substantial Chest Pain

predate admission by a week or less, and one-third of these patients will have had symptomsfor 24 hours or less.

The pain of AMI is variable in intensity; in most patients it is severe but rarely erable The pain may be prolonged, up to 30 minutes The discomfort is described as con-stricting, crushing, oppressing, or compressing; often the patient complains of somethingsitting on or squeezing the chest Although usually described as a squeezing, choking,viselike, or heavy pain, it may also be characterized as a stabbing, knifelike, boring, orburning discomfort The pain is usually retrosternal in location, spreading frequently toboth sides of the chest, often favoring the left side and radiating down the left arm Insome instances, the pain of AMI may begin in the epigastrium and simulate a variety ofabdominal disorders, which often causes MI to be misdiagnosed as indigestion In otherpatients, the discomfort radiates to the shoulders, upper extremities, neck, and jaw.Older individuals, diabetics, and women often present without the typical pain Forexample, less than 50% of those over age 80 who present with AMI will have chest dis-comfort Sometimes, these patients will present with shortness of breath, fatigue, or evenconfusion The pain of AMI may have disappeared by the time physicians first encounterthe patient (or the patient reaches the hospital), or it may persist for a few hours

intol-Diagnostic Criteria

Previously, the diagnosis of AMI established by the World Health Organization in 1986required at least two of the following criteria: a history of chest pain, evolutionarychanges on the ECG, and/or serial elevations of cardiac markers However, it wasrare for a diagnosis of AMI to be made in the absence of biochemical evidence A 2000European Society of Cardiology/American College of Cardiology (ESC/ACC) consensusconference has codified the role of biomarkers, specifically cardiac troponin I or T, by advo-cating that the diagnosis be based on biomarkers of cardiac damage in the appropriate clini-cal situation.1 – 5The criteria for diagnosis of an acute and established AMI are described inTable 1.1 The guidelines recognize the reality that neither the clinical presentation nor theECG has adequate sensitivity and specificity for myocardial necrosis This guideline doesnot suggest that all elevations of these biomarkers should elicit a diagnosis of AMI;Table 1.1 Diagnosis of Myocardial Infarction

Acute MI: Either one of the following criteria satisfies the diagnosis for an acute, evolving, orrecent MI:

1 Typical rise and gradual fall (cardiac troponin) or more rapid rise and fall (CK-MB) ofbiochemical markers of myocardial necrosis with at least one of the following:

a Ischemic symptoms

b Development of pathological Q waves on ECG

c ECG changes indicative of ischemia (ST-segment elevation or depression)

d Coronary artery intervention (e.g., coronary angioplasty)

2 Pathological findings of an acute MI

Established MI: Any one of the following criteria satisfies the diagnosis for established MI:

1 Development of new pathologic Q waves on serial ECGs The patient may or may not rememberprevious symptoms Biochemical markers of myocardial necrosis may have normalized,depending on the length of time that has passed since the infarct developed

2 Pathological findings of a healed or healing MI

Diagnostic Criteria 5

only those associated with the appropriate clinical and/or ECG findings.6,7 Whenelevations that are not caused by an acute ischemia event, the clinician is obligated

to search for another etiology for the elevation The criteria suggested for use with thesebiomarkers by the Biochemistry Panel of the ESC/ACC Committee is listed in Table 1.2.The use of these new criteria has led to the NSTEMI diagnosis The initial ECG used

to have a sensitivity of about 50% for AMI As the diagnosis of NSTEMI is made withgreater and greater sensitivity, the frequency of STEMI among all AMI has decreased.Serial ECG tracings are helpful for STEMI but not for what now makes up almost 70%

of AMIs, those with NSTEMI The classic ECG changes of an STEMI are ST-segmentelevation, which often evolves to the development of Q waves without intervention.Most NSTEMIs present with either ST segment depression, with or without T-wavechanges; T-wave changes alone; or occasionally in the absence of any ECG findings.Those with ST-segment change have a substantially worse prognosis There are manyother clinical aspects that might suggest AMI as the etiology of a given biomarkerelevation For example, the finding of significant coronary obstructive lesions, especially

in a pattern suggestive of recent plaque rupture, is highly suggestive At times, a positivestress test with or without imaging may be necessary to help make the diagnosis However,

if the clinical situation is not suggestive, other sources for cardiac injury should be sought.The term acute coronary syndrome (ACS) is increasingly used in the literature andencompasses all patients who present with unstable ischemic heart disease If they haveSTE, they are called STEMI If they do not have STE but have biochemical criteria forcardiac injury, they are called NSTEMI, few of whom develop ECG Q waves Thosewho have unstable ischemia and do not manifest cardiac necrosis markers are designatedpatients with unstable angina (UA) Most of these syndromes occur in response to an acuteevent in the coronary artery when circulation to a region of the heart is obstructed If theobstruction is high-grade and persists, then necrosis usually ensues Since necrosis isknown to take some time to develop, it is apparent that opening the blocked coronaryartery in a timely fashion can often prevent death of myocardial tissue

Cardiac troponins (I or T) are preferred markers for diagnosis of myocardial injury

Increases in cardiac marker proteins reflect irreversible injury

Improved quality control of troponin assays is essential

Myocardial infarction is present when there is cardiac damage, as detected by marker proteins (anincrease above the 99th percentile of the normal range) in a clinical setting consistent with myo-cardial ischemia

For patients with an ischemic mechanism of injury, prognosis is related to the extent of troponinincreases

If an ischemic mechanism is unlikely, other etiologies for cardiac injury should be pursued.Samples must be obtained at least 6 – 9 hours after the symptoms begin

After PCI and CABG, the significance of marker elevations and patient care should be individualized

6 Case 1 A 45-Year-Old Man with Substantial Chest Pain

Myocardial ischemia and subsequent infarction usually begin in the endocardium andspread toward the epicardium The extent of myocardial injury reflects (1) extent of theocclusion, (2) duration of the imbalance between coronary supply and substrate avail-ability, and (3) the metabolic needs of the tissue Irreversible cardiac injury consistentlyoccurs in animals when complete occlusion is present for at least 15 – 20 minutes Most

of the damage occurs within the first 2 – 3 hours Restoration of flow within the first

60 – 90 minutes evokes maximal salvage of tissue, but the benefits of reperfusion up to

4 – 6 hours are sufficient to be associated with increased survival The percentage oftissue at risk that undergoes necrosis (infarct size) is highly variable and difficult topredict

In most cases, the left ventricle is affected by AMI However, with right coronaryand/or circumflex occlusions, the right ventricle can also be involved Coronarythrombi will undergo spontaneous lysis, even if untreated, in about 50% of cases within

10 days However, for patients with STEMI, opening the vessel earlier with dissolving agents (thrombolysis) and/or percutaneous intervention (PCI) can often savemyocardium and lives Consequently, percutaneous intervention with stenting is the pre-ferred therapy for STEMI However, many hospitals cannot or do not offer urgent PCI 24hours a day, 365 days per year Thus clot-dissolving medications still play a major role inthe treatment of these patients It is now apparent that urgent invasive revascularizationalso benefits those with NSTEMI We now know that many treatments, such as neweranticoagulant, antiplatelet, and antiinflammatory agents in conjunction with coronaryrevascularization, save lives in this group

clot-Precipitating Factors

In many patients with AMI, no precipitating factor can be identified Studies have notedthe following patient activities at the onset of AMI: modest, heavy, or usual physical exer-tion, surgical procedure, rest, and sleep If and when these activities trigger an infarction,the window of risk is often brief, usually only an hour or two The severe exertion thatpreceded an infarction was often performed at times when the patient was fatigued oremotionally stressed

There are causes of infarction other than acute atherothrombotic coronary occlusion.Prolonged vasospasm can induce infarction, and spontaneous dissections are becomingmore commonly appreciated, especially in pregnant females Other conditions can alsocause the death of cardiomyocytes and lead to a biochemical signal of myocyte damage,but should not be confused with myocardial infarction These include (1) trauma thatmay precipitate myocardial contusion; (2) toxic reactions to chemotherapy agents, such

as Adriamycin, or myocardial depressant substances released with sepsis; (3) heat-inducedinjury after cardioversion; (4) increases in wall stress with impairment of subendocardialperfusion caused by severe hypo- or hypertension; and/or (5) injury caused by catechol-amine release in patients with acute neurological catastrophes Pulmonary embolism isanother common cause of biomarker increase

Anatomy of an MI

On gross pathological examination, AMI can be divided into subendocardial mural) infarctions and transmural infarctions The pathological changes correlate poorlywith clinical, ECG, and biochemical markers of necrosis In experimental infarction,

(nontrans-Anatomy of an MI 7

the earliest ultrastructural changes in cardiac muscle following occlusion of a coronaryartery noted within 20 minutes by electron microscopy, consist of a reduction in thesize and number of glycogen granules, intracellular edema, and swelling and distortion

of the transverse tubular system, the sarcoplasmic reticulum, and the mitochondria.These early changes are partially reversible Changes after 60 minutes of occlusioninclude myocardial cell swelling and mitochondrial abnormalities After 20 minutes to

2 hours of ischemia, changes in some cells become irreversible, with a progression

of these alterations, including enlarged mitochondria with few cristae and clumping,and thinning and disorientation of myofibrils Cells irreversibly damaged by ischemiaare usually swollen, with an enlarged sarcoplasmic reticulum Defects in the plasmamembrane may appear

In some infarcts a pattern of wavy myocardial fibers may be seen by light microscopy 1 –

3 hours after onset, especially at the periphery After 8 hours, edema of the interstitiumbecomes evident, as do increased fatty deposits in the muscle fibers By 24 hours there isclumping of the cytoplasm and loss of cross-striations, with appearance of irregular cross-bands in the involved myocardial fibers During the first 3 days, the interstitial tissuebecomes edematous On about day 4 after infarction, removal of necrotic fibers by macro-phages begins, again commencing at the periphery By day 8, the necrotic muscle fibershave become dissolved; by about 10 days the number of polymorphonuclear leukocytes isreduced, and granulation tissue first appears at the periphery Removal of necrotic musclecells continues until weeks 4 – 6 following infarction By the sixth week, the infarcted areahas usually been converted into a firm connective tissue scar with interspersed intactmuscle fibers Gross alterations of the myocardium are difficult to identify until at least

6 – 12 hours following the onset of necrosis By 18– 36 hours after onset of the infarct, themyocardium is tan or reddish purple (because of trapped erythrocytes) These changespersist for approximately 48 hours; the infarct then turns gray and fine yellow lines Eight

to 10 days following infarction, the thickness of the cardiac wall in the area of the infarct

is reduced as necrotic muscle is removed by mononuclear cells Over the next 2 –3months, the infarcted area gradually acquires a gelatinous, gray appearance, eventually con-verting into a shrunken, thin, firm scar that whitens and firms progressively with time

Prognosis

The prognosis of patients with ischemia but without necrosis is far better, and there are nodifferences thus far described that distinguish medical from invasive therapies A majordeterminant of mortality and morbidity is the amount of myocardial damage WithSTEMI, most of it is acute whereas with NSTEMI, it may evolve because of repetitiveevents over many months Thus interrupting the process improves survival

STE and NSTE infarctions have distinctly different short-term prognoses STEMI isassociated with a higher early and in-hospital mortality It is said that mortality associated

by STEMI can occur up to 6 months postevent, but the vast majority (at least two-thirds)occurs during the first 30 or 40 days It is this process that coronary recanalization seems tobenefit NSTEMI is associated with a lower acute mortality and complication rates but alonger period of vulnerability to reinfarction and death As a result, 1 – 2-year survivalrates are similar to those for transmural infarction This is why intervention has been soeffective in this group

In today’s environment of preventive and evidence-based medicine, the use of cTnI orcTnT measured once at presentation and again at 12 – 24 hours in patients with ischemia

8 Case 1 A 45-Year-Old Man with Substantial Chest Pain

will allow clinicians to use markers as both exclusionary and prognostic indicators.8 – 12The results will assist in determining who is more at risk for AMI and death, andthereby determine who may benefit from early medical or surgical intervention An evalu-ation of the majority of risk stratification studies shows that approximately 30% of all UAand NSTEMI patients present with an increased cardiac troponin level Of these, approxi-mately 30% (or 9 – 10% overall) have an adverse short-term (30 – 40 days) and long-term(1 – 2 years) prognosis Identifying patients at greater risk for cardiac events allows them to

be treated more aggressively, with proven beneficial outcomes Clinical performance ofcardiac troponin assays have been shown to be strongly dependent on the analytical sen-sitivity and precision of measured concentrations around the 99th percentile referencelimit.13 – 16Several studies have now documented that assays with lower limits of detectionare able to identify more ACS patients with poor prognosis who may be candidates forearly invasive procedures There are now data that such patients benefit from the use oflow-molecular-weight heparin, IIB/IIIA platelet antagonists, and an early invasive strat-egy General population screening of hospitalized patients with cTnI or cTnT is notrecommended

References

1 A LPERT , J S, T HYGESEN , K., A NTMAN , E ET AL :

Myo-cardial infarction redefined—a consensus document of

The Joint European Society of Cardiology/American

College of Cardiology Committee for the redefinition

of myocardial infarction J Am Coll Cardiol.

36:959 – 69, 2000.

2 A PPLE , F S., W U , A H B., AND J AFFE , A S.: European

Society of Cardiology and American College of

Cardiology guidelines for redefinition of myocardial

infarction: How to use existing assays clinically and

for clinical trials Am Heart J 144:981 – 6, 2002.

3 B RAUNWALD , E., A NTMAN , E M., B EASLEY , J W.

ET AL : American College of Cardiology /American

Heart Association Task Force on practice guidelines

(Committee on the Management of Patients with

Unstable Angina) ACC /AHA guideline update for

the management of patients with unstable angina and

non-ST-segment elevation myocardial infarction—

2002: summary article: A report of the American

College of Cardiology /American Heart Association

Task Force on Practice Guidelines (Committee on the

Management of Patients with Unstable Angina)

Circu-lation 106:1893– 2000, 2002.

4 L UEPKER , R V., A PPLE , F S., C HRISTENSON , R H.

ET AL : Case definitions for acute coronary heart

disease in epidemiology and clinical research studies.

Circulation 108:2543 – 9, 2003.

5 N EWBY , L K., A LPERT , J S., O HMAN , E M ET AL :

Changing the diagnosis of acute myocardial

infarction: implications for practice and clinical

investi-gations Am Heart J 144:957 – 80, 2002.

6 A PPLE , F S.: Tissue specificity of cardiac troponin I,

cardiac troponin T, and creatine kinase MB Clin.

Chim Acta 284:151 – 9, 1999.

7 J AFFE , A S., R AVKILDE , J., R OBERTS , R ET AL : It’s time for a change to a troponin standard Circulation 102:1216 – 20, 2000.

8 B ERTRAND , M E., S IMONS , M L., F OX , K A A ET AL : Management of acute coronary syndromes: Acute cor- onary syndromes without persistent ST-segment elevation Eur Heart J 21:1406 – 32, 2000.

9 H AMM , C W., H EESCHEN , C., G OLDMANN , B ET AL : Benefit of ABCIXIMAB in patients with refractory unstable angina in relation to serum troponin T levels.

N Engl J Med 340:1623 – 9, 1999.

10 H EIDENREICH , P A., A LLOGGIAMENTO , T., M ELSOP , K.

ET AL : The prognostic value of troponin in patients with non-ST elevation acute coronary syndromes: A meta analysis J Am Coll Cardiol 38:478 – 85, 2001.

11 M ORROW , D A., C ANNON , C P., R IFAI , N ET AL : Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction JAMA 286:2405 – 12, 2001.

12 V ENGE , P., L AGERQUIST , B., D IDERHOLM , E ET AL : On behalf of the FRISC II study group Clinical perform- ance of three cardiac troponin assays in patients with unstable coronary artery disease (a FRISC II substudy).

Am J Cardiol 89:1035 – 41, 2002.

13 A PPLE , F S., Q UIST , H E., D OYLE , P J ET AL : Plasma 99th percentile reference limits for cardiac troponin and creatine kinase MB mass for use with European Society

of Cardiology /American College of Cardiology consensus recommendations Clin Chem 49:1331–6, 2003.

14 A PPLE , F S., P ARVIN , C A., B UECHLER , K F.,

C HRISTENSON , R H., W U , A H B., AND J AFFE , A S.: Validation of the 99th percentile cutoff independent of assay imprecision (%CV) for cardiac troponin

References 9

monitoring for ruling out myocardial infarction Clin.

Chem 51:2198 – 200, 2005.

15 L IN , J C., A PPLE , F S., M URAKAMI , M M ET AL :

Rates of positive cardiac troponin I and creatine

kinase MB among patients hospitalized for suspected

acute coronary syndromes Clin Chem 50:333 – 8, 2004.

16 P ANTEGHINI , M., G ERHARDT , W., A PPLE , F S ET AL : Quality specifications for cardiac troponin assays Clin Chem Lab Med 39:174 – 8, 2001.

10 Case 1 A 45-Year-Old Man with Substantial Chest Pain

Case 2

A 48-Year-Old Cocaine User

with Chest Pain

Fred S Apple and Ramona Evans

Case Presentation

A 48-year-old male presented to the emergency department with constant, “squeezing,”left sided and substernal chest pain following a night of partying with friends that includedingestion of alcohol and crack cocaine He stated that the pain started acutely around

0230 h (2:30 am) while he was sleeping and was temporarily relieved following the tion of two nitroglycerin tablets at home He was not short of breath or diaphoretic Thepain did not radiate, was nonpleuritic, and was not associated with exertion but wassimilar in character to the chest pain he experienced when admitted last month for a myo-cardial infarction Improvement, but not resolution, of the pain was noted by the patientfollowing administration of an aspirin, nitroglycerin, and metoprolol

inges-His past medical history is significant for a non-ST-segment elevation myocardialinfarction suffered last month following the ingestion of crack cocaine Cardiac catheter-ization at that time revealed essentially normal coronary arteries that required no interven-tion An echocardiogram completed 2 months prior to this presentation revealed a normalejection fraction, mild left ventricular hypertrophy, and no wall motion abnormalities.His medical history is also noteworthy for a diagnosis of small cell lung carcinomathat was treated with radiation and chemotherapy 7 years ago He had metastasis involvinghis brain with multiple strokes and transient ischemic attacks secondary to whole-brainradiation in 1998 He has only mild residual deficits secondary to these multiplestrokes Additionally, he has hypertension and a history of substance abuse

His current medications include lisinopril, metoprolol, and atorvastatin

On physical examination, his blood pressure was 170 – 200 systolic and 90 – 104 tolic with a heart rate in the 60s and a respiration rate 20 His oxygen saturation was 98%;temperature, 97.38F; and he appeared to be in mild distress Diminished breath soundswere found on auscultation of the bilateral upper lobes of his lungs, while the remainder

dias-of his lung and cardiovascular examination was unremarkable No neck vein distention orlower extremity edema was seen and his abdomen was benign Neurologic examinationwas normal

An EKG demonstrated a normal sinus rhythm An echocardiogram completed the lowing morning demonstrated a normal left ventricular ejection fraction, no wall motionabnormalities, mild left ventricular hypertrophy, left atrial enlargement, a small pericar-dial effusion, and insufficiency of the aortic, mitral, and tricuspid valves.

fol-Laboratory tests included a cTnI, total creatine kinase (CK) and CKMB and the culated percent relative index (CKMB/total CK  100) Additional tests included a basicchemistry profile and a complete blood count Laboratory data were as follows:

cal-Time, hReference Interval

Definition of the Disease

Data from 1999 estimates that 25 million Americans have tried cocaine at least once andthat 1.5 million people were active users during the data collection period.1Cocaine isnoted to be the most frequent drug used in patients who present to the emergency depart-ment and is listed by medical examiners as the most common cause of drug-relateddeaths.2 – 5 The risk of myocardial infarction increases to 24 times that of baseline inthe first hour following cocaine use, and the risk of nonfatal myocardial infarction is 7times greater in cocaine users versus nonusers

Acute myocardial infarction is defined as an imbalance between oxygen supply anddemand that results in injury and necrosis of the myocytes.6The European Society ofCardiology and the American College of Cardiology outline the diagnosis of acute, evol-ving or recent myocardial infarction to include either (1) a characteristic rise and fall of thebiochemical markers cardiac troponin I or T and CKMB within 24 hours of the onset ofischemic symptoms, pathological Q waves on ECG, ECG changes consistent with ische-mia (i.e., ST-segment elevation) and coronary artery intervention (angioplasty); or (2)pathological findings of an AMI

Differential Diagnosis

The most important diagnostic decision to make in the setting of chest pain followingcocaine use is to determine whether the patient has actually sustained acute myocardialdamage that requires prompt medical and surgical management It is estimated thatonly 6% of persons who present to the emergency department with chest pain after theingestion of cocaine will actually have an acute myocardial infarction This small percen-tage of persons likely to have myocardial ischemia together with the fact that distinguish-ing chest wall and skeletal pain from acute myocardial ischemia is challenging becausethree of the main criteria for a diagnosis of AMI are similar in both settings

12 Case 2 A 48-Year-Old Cocaine User with Chest Pain

Frequently the patient’s presentation is atypical for myocardial infarction, the diogram demonstrates nonspecific abnormalities, and the serum markers CK and CKMB,which lack specificity for cardiac muscle, are elevated Also, although it is widely recognizedthat myocardial infarction can occur after use of cocaine, the specific risk and risk factors thatportend acute myocardial damage following use of cocaine are not well characterized.Approximately one-half of patients with myocardial infarction will not have the classicrisk factors associated with AMI such as older age and previous CAD history.

electrocar-An electrocardiogram following cocaine use without myocardial infarction candemonstrate PR, QRS, and QT interval prolongation, elevation of ST segments, and patho-logic Q waves In contrast, 90% of patients with myocardial infarction following cocaineuse have changes seen on the electrocardiogram that include ST-segment elevation,T-wave inversions, and Q waves The use of echocardiography is often helpful in thissetting to demonstrate new wall motion abnormalities

The biochemical markers cardaiac troponin I (cTnI) or T (cTnT), total creatine kinase(CK), and CKMB are crucial in diagnosing AMI in these patients.6 – 10Total CK and CKMBlevels rise to twice the reference range within 6 hours of myocardial necrosis and peak atapproximately 24 hours, but these markers lack the specificity necessary to distinguishcardiac muscle necrosis from the skeletal muscle necrosis that is often seen in personswho have recently used cocaine Serum CK and CKMB elevations seen are often thought

to be secondary to skeletal muscle damage because of trauma or rhabdomyolysis, and thechest pain experienced by these patients may be a result of a transient coronary vasospasmwithout necrosis of the myocytes A calculation of the percent relative index of the CKMB

to total CK will usually be above 3% if actual myocardial necrosis has occurred and,3% ifthe elevation of these biochemical markers is due instead to skeletal muscle damage

It is now widely recognized that cTnI or cTnT are the most specific markers formyocardial injury The cardiac troponins are the serum markers of choice to differentiatemyocardial infarction from skeletal muscle damage Cardiac troponin I or T are contractileproteins of the myofibril, and thus the presence of these proteins in serum is consistent andspecific for damage to myocardial tissue Cardiac troponins are elevated within 4 – 6 hours

of injury, peak at 12 – 36 hours, and remain elevated for 4 – 10 days A characteristic rise orfall of cTnI or cTnT in the correct clinical setting should be seen in order to diagnose acutemyocardial ischemia The rise – fall pattern distinguishes AMI from other disorders thatmay lead to an elevation in cardiac troponins but are not related to myocardial infarction.Serial cardiac troponin levels taken over at least a 8 – 12-hour period is a conservative andreasonable diagnostic approach to evaluate a suspected infarction in high risk or suspi-cious patients

In summary, the symptomatic presentation, electrocardiogram, and biochemicalmarkers can be strikingly similar in patients with cocaine-related chest wall pain or acutemyocardial infarction The diagnosis of AMI depends on the use of cardiac troponins I or

T and echocardiography to distinguish the two entities in this challenging patient population

Pathogenesis 13

atherosclerosis, increased platelet aggregation, and thrombus formation within the ary arteries after cocaine ingestion The incidence of myocardial infarction followingcocaine use is not related to and cannot be predicted by the route, frequency, or dose ofcocaine ingested An elevated heart rate and increased systolic and diastolic blood press-ures are known effects of cocaine ingestion secondary to blockage of the reuptake of nor-epinephrine into the preganglionic neurons with resultant elevation in the concentration ofnorepinephrine at the postganglionic neuron receptors The coronary vasoconstriction ismediated by stimulation of the a-adrenergic receptors on the coronary vessels Vasocon-triction of the arteries is further exacerbated by the cocaine-stimulated production ofendothelin by endothelial cells and inhibition of the production of nitric oxide Endothelin

coron-is a potent vasoconstrictor, while nitric oxide coron-is a potent vasodilator, and the alteration oftheir production disallows a compensatory response to the a-adrenergic vasoconstriction.Vasoconstriction of the coronary arteries may disrupt susceptible atherosclerotic plaques

in addition to causing the release of von Willebrand factor from the endothelium

In one controlled cocaine administration trial, a significant elevation (40% at its peak)

of von Willebrand factor was demonstrated which lasted for 30 – 240 minutes This samestudy showed a transient erythrocytosis that was hypothesized to allow for maintenance oftissue oxygenation during vasoconstriction The elevation of von Willebrand factor withthe concomitant erythrocytosis were postulated as potential factors that lead to the elev-ated risk of platelet aggregation and thrombus formation

Although cocaine is a known toxin to myocardial tissue, this toxicity is thought toonly play a minor role in the damage to the tissue, and the main pathological disorder

is due mainly to an imbalance of demand and delivery of oxygen to the myocytes

indi-Coronary vasospasm is best treated with nitrates, and either calcium channel blockers

or a-blockers instead of the more commonly used b-blockers in non-cocaine-inducedmyocardial infarction Unopposed a-receptor stimulation may intensify coronary vasos-pasm if b-blockers are administered and hence should be either avoided altogether orgiven with great caution However, the administration of labetalol, which is both ana- and b-receptor blocker, may be used as it can reverse the systemic hypertensionwithout exacerbating the a-adrenergic induced vasoconstriction

References

1 W EBER , J., S HOFER , F., L ARKIN , G., K ALARIA , A S.,

AND H OLLANDER , J E.: Validation of a brief

observation period for patients with

cocaine-associated chest pain N Engl J Med 348:510 – 17,

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2 S IEGEL , A., S HOLAR , M., M ENDELSON , J ET AL : Cocaine-induced erythrocytosis and increase in von Willebrand factor: Evidence for drug-related blood doping and prothrombotic effects Arch Intern Med 159:1925 – 9, 1999.

14 Case 2 A 48-Year-Old Cocaine User with Chest Pain

3 H OLLANDER , J E., L EVITT , M A., Y OUNG , G P.,

B RIGLIA , E., W ETLI , C V., AND G AWAD , Y.: Clinical

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4 K LONER , R AND R EZKALLA , S.: Cocaine and the heart.

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5 L ANGE , R AND H ILLIS , L Cardiovascular

compli-cations and cocaine use N Engl J Med 345:351 – 8,

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6 A PPLE , F S AND J AFFE , A S.: Cardiac function In:

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References 15

He gave a history of having developed a noticeable cough during the past 10– 15 years.This cough had been present daily and had been productive of small amounts of sputum(approximately one tablespoon per day) Sputum production had occurred mainly in themorning It was usually white but at times had been yellowish green The patient also gave

a history of shortness of breath on exertion that he first noticed about 5 – 7 years ago Thisshortness of breath had steadily progressed until, in the month before admission, he wasunable to walk one block or to go up one flight of stairs without pausing to catch his breath.His current illness started about 3 days prior to admission when he developedincreased frequency and intensity of coughing spells and increased production ofsputum that became greenish yellow He was febrile; his shortness of breath had increased;and he had developed some swelling of his feet and ankles that was particularly noticeable

On physical examination, the patient was alert, cooperative, and short of breath at rest;

he had some central cyanosis but showed no pallor, jaundice, or lymphadenopathy Theoral temperature was 100.48F (388C)

The pulse rate was 110 per minute and regular The blood pressure in the left arm withthe patient in the supine position was 120/76 mm Hg Jugular venous pressure was