NIH Consensus Development Conference on 

Celiac Disease 

June 28−30, 2004 

William H. Natcher Conference Center 

National Institutes of Health 

Bethesda, Maryland 

Sponsored by: 

• National Institute of Diabetes and Digestive and Kidney Diseases 

• Office of Medical Applications of Research 

Cosponsored by: 

• U.S. Food and Drug Administration 

• U.S. Department of Agriculture 

• National Institute of Child Health and Human Development 

• National Cancer Institute 

• National Institute of Allergy and Infectious Diseases 

National Institutes of Health

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 
iii

Contents 

Introduction......................................................................................................................................1 

Agenda .............................................................................................................................................3 

Panel Members.................................................................................................................................9 

Speakers .........................................................................................................................................11 

Planning Committee.......................................................................................................................13 

Abstracts ........................................................................................................................................17 

I. How Is Celiac Disease Diagnosed? 

Overview and Pathogenesis of Celiac Disease 

Martin F. Kagnoff, M.D. .............................................................................................................19 

The Pathology of Celiac Disease 

Paul J. Ciclitira, M.D., Ph.D., FRCP..........................................................................................23 

What Are the Sensitivity and Specificity of Serological Tests for Celiac Disease? 

Do Sensitivity and Specificity Vary in Different Populations? 

Ivor D. Hill, M.D. .........................................................................................................................27 

Clinical Algorithm in Celiac Disease 

Ciaran P. Kelly, M.D. ..................................................................................................................33 

Genetic Testing: Who Should Do the Testing and What Is the Role of Genetic Testing 

in the Setting of Celiac Disease? 

George S. Eisenbarth, M.D. ........................................................................................................37 

Serological Testing for Celiac Disease 

Alaa Rostom, M.D., M.Sc., FRCPC ...........................................................................................41 

II. How Prevalent Is Celiac Disease? 

Epidemiology of Celiac Disease: What Are the Prevalence, Incidence, and Progression 

of Celiac Disease? 

Marian J. Rewers, M.D., Ph.D....................................................................................................45 

What Are the Prevalence and Incidence of Celiac Disease in High-Risk Populations: 

Patients With an Affected Family Member, Type 1 Diabetes, Iron-Deficiency Anemia, 

and Osteoporosis? 

Joseph A. Murray, M.D...............................................................................................................49 

Incidence and Prevalence of Celiac Disease 

Alaa Rostom, M.D., M.Sc., FRCPC ...........................................................................................57 
iv 

III. What Are the Manifestations and Long-Term Consequences of Celiac Disease? 

Clinical Presentation of Celiac Disease in the Pediatric Population 

Alessio Fasano, M.D.....................................................................................................................61 

The Many Faces of Celiac Disease: Clinical Presentation of Celiac Disease in the Adult 

Population 

Peter H.R. Green, M.D. ...............................................................................................................65 

Association of Celiac Disease and Gastrointestinal (GI) Lymphomas and Other GI Cancers 

Carlo Catassi, M.D., M.P.H. .......................................................................................................69 

Skin Manifestations of Celiac Disease 

John J. Zone, M.D........................................................................................................................73 

Neurological/Psychological Presentation of Celiac Disease: Ataxia, Depression, 

Neuropathy, Seizures, and Autism 

Khalafalla O. Bushara, M.D. ......................................................................................................77

IV. Who Should Be Tested for Celiac Disease? 

Should Children Be Screened for Celiac Disease? Is There Evidence To Support 

the Strategy of Screening All Children? 

Edward J. Hoffenberg, M.D........................................................................................................79 

Should Adults Be Screened for Celiac Disease? What Are the Benefits and Harms 

of Screening? 

Pekka Collin, M.D., Ph.D. ...........................................................................................................83 

Consequences of Testing for Celiac Disease 

Ann Cranney, M.D., M.Sc...........................................................................................................87 

V. What Is the Management of Celiac Disease? 

Dietary Guidelines for Celiac Disease and Implementation 

Cynthia Kupper, R.D., C.D.........................................................................................................91 

How To Provide Effective Education and Resources: Gluten-Free Diets 

Shelley Case, R.D. ........................................................................................................................97 

The Followup of Patients With Celiac Disease⎯Achieving Compliance With Treatment 

Michelle Maria Pietzak, M.D....................................................................................................103 
1

Introduction 

Background 

Celiac disease is a disorder primarily affecting the gastrointestinal tract that is 

characterized by chronic inflammation of the mucosa, which leads to atrophy of intestinal villi, 

malabsorption, and protean clinical manifestations that may begin either in childhood or adult 

life. Symptoms can include abdominal cramping, bloating, and distention, and untreated celiac 

disease may lead to vitamin and mineral deficiencies, osteoporosis, and other problems. The 

disease is also strongly associated with the skin disorder, dermatitis herpetiformis. Celiac 

disease’s major genetic risk factors (HLA-DQ2 and HLA-DQ8) and environmental triggers 

(specific peptides present in wheat, rye, and barley) have been identified, and most patients 

experience complete remission after exclusion of these grains from the diet. Thus, there has been 

considerable scientific progress in understanding this complex disease and in preventing or 

curing its manifestations by dietary interventions. 

At the present time, celiac disease is widely considered to be a rare disease in the United 

States. However, recent studies, primarily in Europe but also in the United States, suggest that its 

prevalence is much higher than previous estimates, raising the concern that the disease is widely 

under-recognized. Recent progress in identification of autoantigens in celiac disease have led to 

the development of new serological diagnostic tests, but the appropriate use of testing strategies 

has not been well defined. Some patients with celiac disease may be at risk for non-Hodgkin’s 

lymphoma, a rare cancer affecting the gastrointestinal tract. It is not yet clear, however, what the 

impact of this observation should be on diagnostic and treatment strategies. 

Conference Process 

To address these issues, the National Institute of Diabetes and Digestive and Kidney 

Diseases (NIDDK) and the Office of Medical Applications of Research (OMAR) of the National 

Institutes of Health (NIH) are sponsoring a consensus development conference to explore and 

assess the current scientific knowledge regarding celiac disease. The conference will be held 

June 28−30, 2004, at NIH in Bethesda, Maryland. Specifically, the conference will address the 

following key questions: 

• How is celiac disease diagnosed? 

• How prevalent is celiac disease? 

• What are the manifestations and long-term consequences of celiac disease? 

• Who should be tested for celiac disease? 
2 

• What is the management of celiac disease? 

• What are the recommendations for future research on celiac disease and related 

conditions? 

During the first 1 1/2 days of the conference, experts will present the latest celiac disease 

research findings to an independent panel. After weighing all of the scientific evidence, the panel 

will prepare a consensus statement answering the questions above. On the final day of the 

conference, the panel chairperson will read the draft statement to the conference audience, and 

invite comments and questions. A press conference that afternoon will allow the panel to respond 

to questions from the media. 

General Information 

Conference sessions will be held in the Natcher Conference Center, NIH, Bethesda, 

Maryland. 

The conference may be viewed live via Webcast at http://videocast.nih.gov/. Webcast 

sessions will also be available after the conference. 

The dining center in the Natcher Conference Center is located on the main level, one 

floor above the auditorium. It is open from 6:30 a.m. to 2:30 p.m., serving hot breakfast and 

lunch, sandwiches and salads, and snack items. An additional cafeteria is available from 

7:00 a.m. to 3:30 p.m., in Building 38A, level B1, across the street from the main entrance to the 

Natcher Conference Center. 

The telephone number for the message center at the Natcher Conference Center is 

301-594-7302. 

Conference Sponsors 

The primary sponsors of the conference are NIDDK and OMAR of the NIH, a 

component of the U.S. Department of Health and Human Services. The conference is 

cosponsored by the U.S. Food and Drug Administration, the U.S. Department of Agriculture, the 

National Institute of Child Health and Human Development, the National Cancer Institute, and 

the National Institute of Allergy and Infectious Diseases. 

The National Library of Medicine (NLM) and the Agency for Healthcare Research and 

Quality (AHRQ) provided additional support to conference development. 

Financial Disclosure 

Each speaker presenting at this conference has been asked to disclose any financial 

interests or other relationships pertaining to this subject area. Please refer to the material in your 

participant packet for details. 

Panel members signed a confirmation that they have no financial or other conflicts of 

interest pertaining to the topic under consideration. 
3

AGENDA 

Monday, June 28, 2004 

8:30 a.m. Opening Remarks 

 Allen M. Spiegel, M.D. 

 Director 

 National Institute of Diabetes and Digestive and Kidney Diseases 

 National Institutes of Health 

8:40 a.m. Charge to the Panel 

 Susan Rossi, Ph.D., M.P.H. 

 Deputy Director 

 Office of Medical Applications of Research, Office of the Director 

 National Institutes of Health 

8:50 a.m. Conference Overview and Panel Activities 

 Charles O. Elson, M.D. 

 Panel and Conference Chairperson 

 Professor of Medicine and Microbiology 

 Vice Chair for Research, Department of Medicine 

 University of Alabama at Birmingham 

I. How Is Celiac Disease Diagnosed? 

9:00 a.m. Overview and Pathogenesis of Celiac Disease 

 Martin F. Kagnoff, M.D. 

 Professor of Medicine and Pediatrics 

 Cancer Biology Program 

 University of California at San Diego 

9:20 a.m. The Pathology of Celiac Disease 

 Paul J. Ciclitira, M.D., Ph.D., FRCP 

 Professor 

 The Rayne Institute 

 St. Thomas’ Hospital 

 United Kingdom 

9:40 a.m. What Are the Sensitivity and Specificity of Serological Tests for Celiac Disease? 

 Do Sensitivity and Specificity Vary in Different Populations? 

 Ivor D. Hill, M.D. 

 Professor of Pediatrics 

 Wake Forest University School of Medicine 
4 

Monday, June 28, 2004 (continued) 

I. How Is Celiac Disease Diagnosed? (continued) 

10:00 a.m. Discussion 

Participants with questions or comments for the speakers should proceed to the 

microphones and wait to be recognized by the panel chair. Please state your 

name and affiliation. Questions and comments not heard before the close of the 

discussion period may be submitted at the registration desk. Please be aware that 

all statements made at the microphone or submitted later are in the public 

domain. 

10:30 a.m. Clinical Algorithm in Celiac Disease 

 Ciaran P. Kelly, M.D. 

 Director, Celiac Center 

 Herrman L. Blumgart Firm Chief 

 Director, Gastroenterology Fellowship Training 

 Associate Professor of Medicine 

 Beth Israel Deaconess Medical Center 

 Harvard Medical School 

10:50 a.m. Genetic Testing: Who Should Do the Testing and What Is the Role of Genetic 

 Testing in the Setting of Celiac Disease? 

George S. Eisenbarth, M.D. 

 Executive Director 

 Barbara Davis Center for Childhood Diabetes 

 University of Colorado Health Sciences Center 

11:10 a.m. Evidence-Based Practice Center Presentation: Serological Testing for 

 Celiac Disease 

Alaa Rostom, M.D., M.Sc., FRCPC 

 Assistant Professor 

 Division of Gastroenterology 

 University of Ottawa 

 The Ottawa Hospital – Civic Campus 

11:30 a.m. Discussion 

12:00 p.m. Lunch 
5

Monday, June 28, 2004 (continued) 

II. How Prevalent Is Celiac Disease? 

1:00 p.m. Epidemiology of Celiac Disease: What Are the Prevalence, Incidence, and 

 Progression of Celiac Disease? 

 Marian J. Rewers, M.D., Ph.D. 

 Professor 

 Clinical Director 

 Barbara Davis Center for Childhood Diabetes 

 University of Colorado Health Sciences Center 

1:20 p.m. What Are the Prevalence and Incidence of Celiac Disease in High-Risk 

 Populations: Patients With an Affected Family Member, Type 1 Diabetes, 

 Iron-Deficiency Anemia, and Osteoporosis? 

 Joseph A. Murray, M.D. 

 Professor of Medicine 

 Mayo Clinic 

1:40 p.m. Evidence-Based Practice Center Presentation: Incidence and Prevalence 

 of Celiac Disease 

 Alaa Rostom, M.D., M.Sc., FRCPC 

 Assistant Professor 

 Division of Gastroenterology 

 University of Ottawa 

 The Ottawa Hospital – Civic Campus 

2:00 p.m. Discussion 

III. What Are the Manifestations and Long-Term Consequences of Celiac Disease? 

2:30 p.m. Clinical Presentation of Celiac Disease in the Pediatric Population 

 Alessio Fasano, M.D. 

 Professor of Pediatrics, Medicine, and Physiology 

 Director, Mucosal Biology Research Center 

 Center for Celiac Research 

 University of Maryland School of Medicine 

2:50 p.m. The Many Faces of Celiac Disease: Clinical Presentation of Celiac 

 Disease in the Adult Population 

 Peter H.R. Green, M.D. 

 Professor of Clinical Medicine 

 Division of Digestive and Liver Disease 

 Columbia University 
6 

Monday, June 28, 2004 (continued) 

III. What Are the Manifestations and Long-Term Consequences of Celiac Disease? 

(continued) 

3:10 p.m. Association of Celiac Disease and Gastrointestinal (GI) Lymphomas and 

 Other GI Cancers 

 Carlo Catassi, M.D., M.P.H. 

 Co-Medical Director 

 Division of Pediatric Gastroenterology and Nutrition 

 Center for Celiac Research 

 University of Maryland School of Medicine 

3:30 p.m. Skin Manifestations of Celiac Disease 

 John J. Zone, M.D. 

 Chairman and Professor of Dermatology 

 University of Utah Health Sciences Center 

3:50 p.m. Neurological/Psychological Presentation of Celiac Disease: Ataxia, Depression, 

 Neuropathy, Seizures, and Autism 

 Khalafalla O. Bushara, M.D. 

 Assistant Professor 

 Department of Neurology 

University of Minnesota 

 Veterans Administration Medical Center 

4:10 p.m. Discussion 

5:00 p.m. Adjournment 

Tuesday, June 29, 2004 

IV. Who Should Be Tested for Celiac Disease? 

8:30 a.m. Should Children Be Screened for Celiac Disease? Is There Evidence To 

 Support the Strategy of Screening All Children? 

 Edward J. Hoffenberg, M.D. 

 Associate Professor of Pediatrics 

 Director, Center for Pediatric Inflammatory Bowel Disease 

 Children’s Hospital Denver 

 University of Colorado School of Medicine 

8:50 a.m. Should Adults Be Screened for Celiac Disease? What Are the Benefits and 

 Harms of Screening? 

 Pekka Collin, M.D., Ph.D. 

 Assistant Professor 

 Medical School 

 University of Tampere 

 Finland 
7

Tuesday, June 29, 2004 (continued) 

IV. Who Should Be Tested for Celiac Disease? (continued) 

9:10 a.m. Evidence-Based Practice Center Presentation: Consequences of Testing 

 for Celiac Disease 

 Ann Cranney, M.D., M.Sc. 

 Associate Professor 

 Clinical Epidemiology Program 

 Ottawa Health Research Institute 

 Civic Hospital Site 

9:30 a.m. Discussion 

V. What Is the Management of Celiac Disease? 

10:00 a.m. Dietary Guidelines for Celiac Disease and Implementation 

 Cynthia Kupper, R.D., C.D. 

 Executive Director 

 Gluten Intolerance Group of North America 

10:20 a.m. How To Provide Effective Education and Resources: Gluten-Free Diets 

 Shelley Case, R.D. 

 Case Nutrition Consulting

10:40 a.m. The Followup of Patients With Celiac Disease⎯Achieving Compliance 

 With Treatment 

 Michelle Maria Pietzak, M.D. 

 Director, Center for Celiac Research–West 

 Childrens Hospital Los Angeles 

 Assistant Professor of Pediatrics 

University of Southern California 

 Keck School of Medicine 

11:00 a.m. Discussion 

11:30 a.m. Adjournment 

Wednesday, June 30, 2004 

9:00 a.m. Presentation of the Consensus Statement 

9:30 a.m. Public Discussion 

The panel chair will call for questions and comments from the audience on the 

draft consensus statement, beginning with the introduction and continuing 

through each subsequent section in turn. Please confine your comments to the 

section under discussion. The chair will use discretion in proceeding to 

subsequent sessions so that comments on the entire statement may be heard 

during the time allotted. Comments cannot be accepted after 11:30 a.m. 
8 

Wednesday, June 30, 2004 (continued) 

11:00 a.m. Conference Adjourns 

Panel meets in executive session to review public comment. Conference 

participants are welcome to return to the main auditorium to attend the press 

conference at 2:00 p.m.; however, only members of the media are permitted to ask 

questions during the press conference. 

 

2:00 p.m. Press Conference 

The panel’s draft statement will be posted to consensus.nih.gov as soon as possible after the 

close of proceedings, and the final statement will be posted 3 to 4 weeks later. 
9

Panel Members 

 Panel Chair: Charles O. Elson, M.D. 

 Panel and Conference Chairperson 

 Professor of Medicine and Microbiology 

 Vice Chair for Research 

 Department of Medicine 

 University of Alabama at Birmingham 

 Birmingham, Alabama 

Martha Ballew, M.Ed., R.D., CNSD, LDN 

Pediatric Nutrition Support Dietitian 

Division of Pediatric Gastroenterology, 

 Hepatology, and Nutrition/ 

 Nutrition Services 

Vanderbilt University Medical Center 

Nashville, Tennessee 

John A. Barnard, M.D. 

Professor of Pediatrics 

Divisions of Molecular Medicine and 

 Gastroenterology 

The Ohio State University College of 

 Medicine and Public Health 

Vice President of Scientific Affairs and 

 Director of Center for Cell and Vascular 

 Biology 

Columbus Children’s Research Institute 

Columbus, Ohio 

Steven J. Bernstein, M.D., M.P.H. 

Associate Professor of Internal Medicine 

Associate Research Scientist of Health 

 Management and Policy 

University of Michigan 

Research Scientist 

Center for Practice Management and 

 Outcomes Research 

Ann Arbor VA Healthcare System 

Ann Arbor, Michigan 

Irene J. Check, Ph.D., D(ABMLI) 

Professor of Pathology 

The Feinberg School of Medicine 

Northwestern University 

Director, Clinical Pathology Division 

Department of Pathology 

Evanston Northwestern Healthcare 

Evanston, Illinois 

Mitchell B. Cohen, M.D. 

Professor of Pediatrics 

Division of Gastroenterology, Hepatology, 

 and Nutrition 

Cincinnati Children’s Hospital Medical 

 Center 

University of Cincinnati 

Cincinnati, Ohio 

Sara Fazio, M.D. 

Vice Chair, Core I Medicine Clerkship 

 Committee 

Harvard Medical School 

Division of General Internal Medicine 

Beth Israel Deaconess Medical Center 

Boston, Massachusetts 

John F. Johanson, M.D., M.Sc. 

Clinical Associate Professor 

Department of Medicine 

University of Illinois College of Medicine, 

 Rockford 

Rockford Gastroenterology Associates, Ltd. 

Rockford, Illinois

Noralane M. Lindor, M.D. 

Associate Consultant 

Department of Medical Genetics 

Mayo Clinic 

Rochester, Minnesota 

Elizabeth Montgomery, M.D. 

Associate Professor of Pathology 

 and Oncology 

Director 

Clinical Gastrointestinal Pathology 

Department of Pathology 

The Johns Hopkins Hospital 

Baltimore, Maryland 
10 

Lisa H. Richardson 

Consumer Representative 

Crohn’s and Colitis Foundation of 

 America, Inc. 

Chairperson of the Board Emeritus 

Houston, Texas 

Douglas Rogers, M.D. 

Section Head of Pediatric Endocrinology 

The Cleveland Clinic 

Cleveland, Ohio 

Sandeep Vijan, M.D., M.S. 

Assistant Professor of Internal Medicine 

University of Michigan 

Physician-Scientist 

Ann Arbor Veterans Affairs Health Services 

 Research and Development 

Ann Arbor, Michigan 
11 

Speakers 

Khalafalla O. Bushara, M.D. 

Assistant Professor 

Department of Neurology 

University of Minnesota 

Veterans Administration Medical Center 

Minneapolis, Minnesota 

Shelley Case, R.D. 

Consulting Dietitian 

Case Nutrition Consulting 

Regina, Saskatchewan, Canada 

Carlo Catassi, M.D., M.P.H. 

Co-Medical Director 

Division of Pediatric Gastroenterology and 

 Nutrition 

Center for Celiac Research 

University of Maryland School of Medicine 

Baltimore, Maryland 

Paul J. Ciclitira, M.D., Ph.D., FRCP 

Professor 

The Rayne Institute 

St. Thomas’ Hospital 

London, United Kingdom 

Pekka Collin, M.D., Ph.D. 

Assistant Professor 

Medical School 

University of Tampere 

Tampere, Finland 

Ann Cranney, M.D., M.Sc. 

Associate Professor 

Clinical Epidemiology Program 

Ottawa Health Research Institute 

Civic Hospital Site 

Ottawa, Ontario, Canada 

George S. Eisenbarth, M.D. 

Executive Director 

Barbara Davis Center for Childhood 

 Diabetes 

University of Colorado Health Sciences 

 Center 

Denver, Colorado 

Alessio Fasano, M.D. 

Professor of Pediatrics, Medicine, 

 and Physiology 

Director, Mucosal Biology Research Center 

Center for Celiac Research 

University of Maryland School of Medicine 

Baltimore, Maryland 

Peter H.R. Green, M.D. 

Professor of Clinical Medicine 

Division of Digestive and Liver Disease 

Columbia University 

New York, New York 

Ivor D. Hill, M.D. 

Professor of Pediatrics 

Wake Forest University School of Medicine 

Winston-Salem, North Carolina 

Edward J. Hoffenberg, M.D. 

Associate Professor of Pediatrics 

Director, Center for Pediatric Inflammatory 

 Bowel Diseases 

Children’s Hospital Denver 

University of Colorado School of Medicine 

Denver, Colorado 

Martin F. Kagnoff, M.D. 

Professor of Medicine and Pediatrics 

Cancer Biology Program 

University of California at San Diego 

La Jolla, California 
12 

Ciaran P. Kelly, M.D. 

Director, Celiac Center 

Herrman L. Blumgart Firm Chief 

Director, Gastroenterology Fellowship 

 Training 

Associate Professor of Medicine 

Beth Israel Deaconess Medical Center 

Harvard Medical School 

Boston, Massachusetts 

Cynthia Kupper, R.D., C.D. 

Executive Director 

Gluten Intolerance Group of North America 

Seattle, Washington 

Joseph A. Murray, M.D. 

Professor of Medicine 

Mayo Clinic 

Rochester, Minnesota 

Michelle Maria Pietzak, M.D. 

Director, Center for Celiac Research–West 

Childrens Hospital Los Angeles 

Assistant Professor of Pediatrics 

University of Southern California 

Keck School of Medicine 

Los Angeles, California 

Marian J. Rewers, M.D., Ph.D. 

Professor 

Clinical Director 

Barbara Davis Center for Childhood 

 Diabetes 

University of Colorado Health Sciences 

 Center 

Denver, Colorado 

Alaa Rostom, M.D., M.Sc., FRCPC

Assistant Professor 

Division of Gastroenterology 

The Ottawa Hospital, Civic Campus 

Ottawa, Ontario, Canada 

John J. Zone, M.D. 

Chairman and Professor of Dermatology 

University of Utah Health Sciences Center 

Salt Lake City, Utah 
13 

Planning Committee 

 Planning Chair: Stephen P. James, M.D.

 Director 

 Division of Digestive Diseases and Nutrition 

 National Institute of Diabetes and Digestive 

 and Kidney Diseases 

 National Institutes of Health 

 Bethesda, Maryland 

David Atkins, M.D., M.P.H. 

Chief Medical Officer 

Center for Practice and Technology 

 Assessment 

Agency for Healthcare Research 

 and Quality 

Rockville, Maryland 

Elsa A. Bray 

Senior Advisor for Consensus Development 

Office of Medical Applications of Research 

Office of the Director 

National Institutes of Health 

Bethesda, Maryland 

Charles O. Elson, M.D. 

Panel and Conference Chairperson 

Professor of Medicine and Microbiology 

Vice Chair for Research 

Department of Medicine 

University of Alabama at Birmingham 

Birmingham, Alabama 

James Everhart, M.D., M.P.H. 

Chief, Epidemiology and Clinical 

 Trials Branch 

Division of Digestive Diseases and Nutrition 

National Institute of Diabetes and Digestive 

 and Kidney Diseases 

National Institutes of Health 

Bethesda, Maryland 

Alessio Fasano, M.D. 

Professor of Pediatrics, Medicine, 

 and Physiology 

Director, Mucosal Biology Research Center 

Center for Celiac Research 

University of Maryland School of Medicine 

Baltimore, Maryland 

Hugo Gallo-Torres, M.D. 

Medical Team Leader, Gastrointestinal 

 Drugs 

Center for Biologics Evaluation and 

 Research 

U.S. Food and Drug Administration 

Rockville, Maryland 

Gilman D. Grave, M.D. 

Chief 

Endocrinology, Nutrition, and 

 Growth Branch 

National Institute of Child Health 

 and Human Development 

National Institutes of Health 

Bethesda, Maryland 

Frank A. Hamilton, M.D., M.P.H. 

Chief 

Digestive Diseases Program 

Division of Digestive Diseases and Nutrition 

National Institute of Diabetes and Digestive 

 and Kidney Diseases 

National Institutes of Health 

Bethesda, Maryland 
14 

Van S. Hubbard, M.D., Ph.D. 

Director 

Division of Nutrition Research Coordination 

National Institute of Diabetes and Digestive 

 and Kidney Diseases 

National Institutes of Health 

Bethesda, Maryland 

Martin F. Kagnoff, M.D. 

Professor of Medicine and Pediatrics 

Cancer Biology Program 

University of California at San Diego 

La Jolla, California 

Ciaran P. Kelly, M.D. 

Director, Celiac Center 

Herrman L. Blumgart Firm Chief 

Director, Gastroenterology Fellowship 

 Training 

Associate Professor of Medicine 

Beth Israel Deaconess Medical Center 

Harvard Medical School 

Boston, Massachusetts 

Barnett S. Kramer, M.D., M.P.H. 

Director 

Office of Medical Applications of Research 

Office of the Director 

National Institutes of Health 

Bethesda, Maryland 

Kelli K. Marciel, M.A. 

Communications Director 

Office of Medical Applications of Research 

Office of the Director 

National Institutes of Health 

Bethesda, Maryland 

Elaine Monarch 

Founder 

Executive Director 

Celiac Disease Foundation 

Studio City, California 

Joseph A. Murray, M.D. 

Professor of Medicine 

Mayo Clinic 

Rochester, Minnesota 

Lata S. Nerurkar, Ph.D. 

Senior Advisor for Consensus Development 

Office of Medical Applications of Research 

Office of the Director 

National Institutes of Health 

Bethesda, Maryland 

Karen Patrias, M.L.S. 

Senior Resource Specialist 

Public Services Division 

National Library of Medicine 

National Institutes of Health 

Bethesda, Maryland 

Jean Pennington, Ph.D., R.D. 

Research Nutritionist 

Division of Nutrition Research Coordination 

National Institute of Diabetes and Digestive 

 and Kidney Diseases 

National Institutes of Health 

Bethesda, Maryland 

Marian J. Rewers, M.D., Ph.D. 

Professor 

Clinical Director 

Barbara Davis Center for Childhood 

 Diabetes 

University of Colorado Health Sciences 

 Center 

Denver, Colorado 

Susan Rossi, Ph.D., M.P.H. 

Deputy Director 

Office of Medical Applications of Research 

Office of the Director 

National Institutes of Health 

Bethesda, Maryland 
15 

Annette Rothermel, Ph.D. 

Program Officer 

Clinical Immunology Branch 

Division of Allergy, Immunology, and 

 Transplantion 

National Institute of Allergy and 

 Infectious Diseases 

National Institutes of Health 

Bethesda, Maryland 

Jeffrey N. Siegel, M.D. 

Acting Branch Chief 

Immunology and Infectious 

 Diseases Branch 

Office of Therapeutics Research 

 and Review 

Center for Biologics Evaluation 

 and Research 

U.S. Food and Drug Administration 

Rockville, Maryland 

Joseph T. Spence, Ph.D. 

Director 

Beltsville Human Nutrition Research 

 Center 

Agriculture Research Service 

U.S. Department of Agriculture 

Beltsville, Maryland 

Carolyn Willard, M.L.S. 

Librarian 

National Library of Medicine 

National Institutes of Health 

Bethesda, Maryland 

Wyndham Wilson, M.D., Ph.D. 

Experiemental Transplantation and 

 Immunology Branch 

National Cancer Institute 

National Institutes of Health 

Bethesda, Maryland 
17 

Abstracts 

The following are abstracts of presentations to the NIH Consensus Development 

Conference on Celiac Disease. They are designed for the use of panelists and participants in the 

conference and as a reference document for anyone interested in the conference deliberations. 

We are grateful to the authors, who summarized their materials and made them available in a 

timely fashion. 

 Elsa A. Bray 

 Senior Advisor for Consensus Development 

 Office of Medical Applications of Research 

 Office of the Director 

 National Institutes of Health 

 Stephen P. James, M.D. 

 Director 

 Division of Digestive Diseases and Nutrition 

 National Institute of Diabetes and Digestive 

 and Kidney Diseases 

 National Institutes of Health 
19 

Overview and Pathogenesis of Celiac Disease 

Martin F. Kagnoff, M.D. 

Celiac disease (CD) is characterized by small intestinal mucosal inflammation and 

mucosal injury. Disease is seen in genetically susceptible individuals following enteric encounter 

with proteins in wheat, rye, and barley and often is accompanied by nutrient malabsorption. 

Mucosal damage, which is most marked in the proximal small intestine, is characterized by a 

spectrum of pathology that ranges from minimal to complete villous atrophy, an increased 

infiltrate of lymphocytes and plasma cell infiltrate in the lamina propria, increased numbers of 

intraepithelial lymphocytes, and varying degrees of crypt hyperplasia accompanied by increased 

crypt mitoses. 

CD was once considered a rare disorder in the U.S., occurring in as few as 1/10,000. 

However, with the advent and broader application of antibody tests as a screening tool over the 

past decade, it has been recognized to be far more common. Indeed, the prevalence of CD in the 

United States and in Europe appears to be in the range of 1:250 to 1:150, with increasing 

numbers of studies supporting the latter estimate.(1,2) Concurrently, the presenting clinical picture 

of CD has changed. The former classic “textbook description,” in which patients with CD 

presented with marked diarrhea, steatorrhea, and weight loss, is now overshadowed by the more 

frequent presentation with one or more complaints such as abdominal bloating, lethargy, a lack 

of energy, irritability or depression, menstrual abnormalities, growth disturbances in children, or 

neurological complaints compatible with peripheral neuropathy. In some patients, the only 

laboratory abnormalities may be evidence of iron deficiency or osteopenia. 

The pathogenesis of CD involves environmental, genetic, and immunologic factors.(3) For 

clarity of defining key factors in disease pathogenesis, the events contributing to the 

pathogenesis of CD can be viewed as luminal events and events that occur in the intestinal 

mucosa, including the eventual activation of immune cells and ensuing tissue damage. The key 

environmental factor known to be essential for the development of CD is enteric exposure to 

certain proline and glutamine rich proteins in the dietary grains wheat, rye, and barley. Often 

simply referred to as “gluten,” the actual proteins that can activate disease are the gliadins and, to 

a lesser extent, glutenins(4,5) in wheat, the hordeins in barley, and the secalins in rye. Peptides in 

these proline rich proteins are poorly digested into free amino acids or very small peptides (i.e., 

di, tri, and tetrapeptides) by pancreatic and intestinal brush border proteases in the human 

intestine.(6,7) Current models of disease envision that the larger remaining peptides ultimately lead 

to the activation of disease-associated mucosal T-cells. The latter is more efficient when those 

peptides are acted on by tissue transglutaminase to yield more negatively-charged peptides, 

which are more efficient in activating disease relevant T-cells and T-cell-mediated immune 

responses in genetically susceptible individuals. 

What are the relevant genes that contribute to susceptibility to CD? It is known that genes 

within the HLA class II DQ subregion on chromosome 6 are necessary, but not sufficient, to 

develop CD. Approximately 95 percent of patients with CD have a DQ2 heterodimer comprised 

of DQB1*02 and DQA1*05 and most of the remaining 5 percent have a DQ8 heterodimer 

comprised of DQB1*0302 and DQA1*03.(8,9) A small number of individuals lacking either of 

those heterodimers have either DQB1*02 or DQA1*05 alone.(10) Gene dosage also affects CD 
20 

susceptibility (e.g., DR17 homozygous individuals who carry DQB1*02 and DQA1*05 in cis on 

both chromosomes have a greater risk of disease).(11) CD is concordant in approximately 

70 percent of monozygotic twin pairs and approximately 30–40 percent of HLA identical 

siblings, and it has been estimated that HLA class II genes are responsible for about 40 percent 

of the genetic contribution to disease.(12) There is no clear definition of what other genes 

contribute to disease or how they do so, although linkage studies suggest disease-associated 

genes in a region of chromosome 5 and perhaps a region on chromosome 19 in some 

populations.(13)

What is the link between the DQ2 and DQ8 heterodimer, the disease activating peptides 

and T-cell-activated immune injury. CD4+ T-cell populations that recognize putative disease 

activating peptides are present in the intestinal mucosa of CD patients. Moreover, these peptides 

bind more efficiently in the peptide binding groove of the DQ2 or DQ8 heterodimer when 

specific glutamine residues are deamidated to negatively-charged glutamic acid by tissue 

transglutaminase.(14,15) Nonetheless, a broad array of peptides derived from gliadins, glutenins, 

hordeins, and secalins likely can activate disease(16,17) and their deamidation does not appear to be 

an absolute requirement, at least for initiating this disease.(17)

In summary, significant progress has been made at the protein, genetic and immunologic 

level in understanding the pathogenesis of CD. However, significant questions have not been 

answered and a great deal remains to be discovered regarding early luminal events that effect 

disease susceptibility and pathogenesis, the more complex and perhaps subtle genetic factors and 

mechanisms that enhance disease susceptibility, and the pathways involved in the mucosal entry 

and processing of disease activating peptides and the activation of T-cells and other cells that 

lead to the immune tissue injury. 

References 

1. Hoffenberg EJ, MacKenzie T, Barriga KJ, et al. A prospective study of the incidence of 

childhood celiac disease. J Pediatr. 2003;143:308–314. 

2. Maki M, Mustalahti K, Kokkonen J, et al. Prevalence of Celiac disease among children in 

Finland. N Engl J Med. 2003;348:2517–2524. 

3. Kagnoff MF. Celiac disease pathogenesis: the plot thickens. Gastroenterology. 

2002;123:939–943. 

4. Van de Wal Y, Kooy YM, Van Veelen P, et al. Glutenin is involved in the gluten-driven 

mucosal T cell response. Eur J Immunol. 1999;29:3133–3139. 

5. Molberg O, Solheim Flaete N, Jensen T, et al. Intestinal T-cell responses to highmolecular-weight glutenins in celiac disease. Gastroenterology. 2003;125:337–344. 

6. Hausch F, Shan L, Santiago NA, Gray GM, Khosla C. Intestinal digestive resistance of 

immunodominant gliadin peptides. Am J Physiol Gastrointest Liver Physiol.

2002;283:G996–G1003. 
21 

7. Shan L, Molberg O, Parrot I, et al. Structural basis for gluten intolerance in celiac sprue. 

Science. 2002;297:2275–2279. 

8. Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F, Thorsby E. Evidence for a primary 

association of celiac disease to a particular HLA-DQ alpha/beta heterodimer. J Exp Med.

1989;169:345–350. 

9. Mazzarella G, Maglio M, Paparo F, et al. An immunodominant DQ8 restricted gliadin 

peptide activates small intestinal immune response in in vitro cultured mucosa from 

HLA-DQ8 positive but not HLA-DQ8 negative coeliac patients. Gut. 2003;52:57–62. 

10. Karell K, Louka AS, Moodie SJ, et al. HLA types in celiac disease patients not carrying the 

DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on 

Celiac Disease. Hum Immunol. 2003;64:469–477. 

11. Vader W, Stepniak D, Kooy Y, et al. The HLA-DQ2 gene dose effect in celiac disease is 

directly related to the magnitude and breadth of gluten-specific T cell responses. Proc Natl 

Acad Sci U S A. 2003;100:12390–12395. 

12. Louka AS, Sollid LM. HLA in coeliac disease: unravelling the complex genetics of a 

complex disorder. Tissue Antigens. 2003;61:105–117. 

13. Van Belzen MJ, Meijer JW, Sandkuijl LA, et al. A major non-HLA locus in celiac disease 

maps to chromosome 19. Gastroenterology. 2003;125:1032–1041. 

14. Molberg O, McAdam SN, Korner R, et al. Tissue transglutaminase selectively modifies 

gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med.

1998;4:713–717. 

15. Kim CY, Quarsten H, Bergseng E, Khosla C, Sollid LM. Structural basis for 

HLA-DQ2-mediated presentation of gluten epitopes in celiac disease. Proc Natl Acad Sci 

U S A. 2004;101:4175–4179. 

16. Vader LW, de Ru A, Van der Wal Y, et al. Specificity of tissue transglutaminase explains 

cereal toxicity in celiac disease. J Exp Med. 2002;195:643–649. 

17. Vader W, Kooy Y, Van Veelen P, et al. The gluten response in children with celiac 

disease is directed toward multiple gliadin and glutenin peptides. Gastroenterology. 

2002;122:1729–1737. 
23 

The Pathology of Celiac Disease 

David H. Dewar, MRCP, and Paul J. Ciclitira, M.D., Ph.D., FRCP 

Celiac disease (CD) was first described in a lecture by Samual Gee in 1887. He noted the 

classical symptoms of diarrhoea, lassitude, and failure to thrive and commented from his 

observations that the cure might lie in the diet. The first accurate description of the celiac lesion 

was provided by Paulley in 1954, who examined full-thickness biopsies taken at laparotomy. He 

referred to broad villi and a chronic inflammatory cell infiltrate in the small intestinal mucosa. A 

detailed study of large numbers of intestinal biopsies was carried out by Marsh, who proposed a 

classification of different types of coeliac lesion.(1) He described distinct features characterizing 

pre-infiltrative, infiltrative, hyperplastic, destructive, and atrophic lesions (termed Marsh 

types 0–4). The majority of patients with CD have features distributed between Marsh types 1 

and 3 and, although this terminology is used by some pathologists, its use is not universal. 

The pathological lesion in CD is an inflamed and flattened small intestinal mucosa with 

impaired function. However, this inflammation results in highly variable clinical expression, 

particularly as the small intestine has a large amount of reserve functional capacity. The 

spectrum of severity extends from individuals with no symptoms to individuals presenting with 

critical malnutrition. The most common symptoms in adult patients are abdominal pain, lethargy, 

increased bowel frequency, and failure to maintain weight. These symptoms are often indolent 

and a significant latency may exist between their onset and diagnosis. Abnormal clinical signs 

are usually not seen. Severe cases do occur with generalized malabsorption resulting in 

steatorrhea, gross abdominal distension, and protein–energy malnutrition. More commonly and 

less dramatic, specific nutrient deficiencies arise which lead to anemia and low bone mineral 

density, which may also go unrecognized for a considerable time prior to eventual diagnosis of 

CD. 

The gold standard for diagnosis of CD remains the small bowel mucosal biopsy. 

Fortunately, the abnormalities are typically more pronounced in the proximal small intestine and 

are sufficiently diffuse to be identified in random samples taken endoscopically from the second 

part of the duodenum or beyond. There is a spectrum of abnormalities seen on biopsy with 

varying degrees of villus atrophy, crypt hyperplasia, and lymphocytic infiltration. These changes 

correspond to enterocyte damage, tissue inflammation, and increased epithelial proliferation in 

response to injury. Quantification of mucosal morphometry can be made by taking 

measurements of villus height, crypt–depth ratio, enterocyte height, and intra-epithelial 

lymphocyte cell counts. Although CD is the most common cause, these morphological changes 

can be induced by other causes of enteropathy. Therefore, central to the diagnosis of CD is the 

demonstration that these changes improve on a gluten-free diet, although in practice this is not 

always deemed necessary. 

The role of the pathologist is critical in the diagnosis of CD, as there are pitfalls in the 

assessment of biopsy specimens. It is vital to ensure correct orientation of the biopsy specimen as 

this can result in incorrect diagnosis. There are further difficulties if there are no architectural 

abnormalities and the changes are limited to an increase in number of intra-epithelial 

lymphocytes, which is generally accepted to be the earliest change detectable by light 

microscopy. There is debate over the accepted normal count with arbitrary values between 
24 

25 and 40 lymphocytes per 100 enterocytes being used. The significance of an isolated 

intra-epithelial lymphocytosis together with positive serology is not fully understood and 

recommended treatment will depend on the circumstances of clinical presentation. The term 

“latent” CD is sometimes applied to these individuals, although this also includes those with 

entirely normal biopsies and positive serology. 

In active CD, the lamina propria is expanded in volume, which is due, in part, to 

recruitment of T-lymphocytes, plasma cells, and dendritic macrophages expressing HLA 

molecules, ICAM-1, and CD25 (IL-2 receptor -chain)⎯an infiltrate indicative of a 

T-cell-mediated immune response. Although we know the toxic trigger (gluten) results in 

pathological changes in the small intestine, the intervening events remain unclear. 

There are several distinct populations of T-lymphocytes in CD. Within the lamina 

propria, a population of DQ2 restricted CD4+ T-cells can be isolated that become stimulated 

when cultured with gluten. These gluten sensitive T-cells express a memory phenotype and the 

predominant cytokine secreted is interferon-γ. Supernatant from isolated gluten specific 

lymphocytes induces damage to the normal intestine. The mucosa also contains an excess of 

fibroblasts with increased expression of matrix metalloproteinases that activate degradation of 

extracellular matrix proteins. 

A separate population of intra-epithelial lymphocytes is present, but their function 

remains unclear. The majority are CD8+ and express natural killer markers such as CD94, 

suggesting that they may be cytotoxic to enterocytes.(2) A smaller percentage of these 

lymphocytes are both CD4/CD8 negative and express the primitive γ/δ T-cell receptor. Unlike 

the CD8 intra-epithelial lymphocytes or lamina propria infiltrate, this population does not regress 

on gluten withdrawal. It has been proposed that these γ/δ lymphocytes form part of innate rather 

than acquired immunity. They do not appear to require HLA for antigen recognition and 

recognize stress proteins such as MICA and MICB expressed on epithelial cells, subsequently 

recruiting polymorphs and monocytes. 

The earliest changes in CD after gluten challenge can be seen at 1 hour, and this has led 

to the suggestion that the primary mechanism of injury is not related to a CD4+ T-cell response. 

Changes in intestinal morphology and membrane expression of HLA molecules and activation 

markers can be detected within 1 hour of gluten challenge, which precedes lymphocyte 

infiltration. CD4+ T-cell reactivity results in a delayed-type response, which would be expected 

to take days to effect significant cellular recruitment and an inflammatory response. Although 

much of the work has focused on these gluten sensitive T-cells, it is possible that they are a 

product of mucosal injury rather than the primary mechanism. It has recently been shown that 

IL-15 expression in the intestinal mucosa is significantly upregulated in active CD.(3) IL-15 is 

expressed by cells from the innate immune system such as enterocytes and monocytes within the 

lamina propria. This indicates a role for the innate immune system at an early stage in disease 

pathogenesis, which might suggest an alternative toxic mechanism for gluten. 
25 

In this regard, the transport pathway for gliadin may be relevant. In rat intestine, gliadin 

administration results in increased permeability of tight junctions, mediated by zonulin, which is 

likely to facilitate the delivery of gliadin to the lamina propria via the paracellular route. In 

human celiac mucosa, zonulin expression is increased. Further studies have examined the 

transcellular pathways in enterocytes using labeled monoclonal antibodies to a gliadin peptide.(4)

In patients with CD, staining was found to be granular, with gliadin located within apical 

vesicles and in larger vacuoles together with Class II MHC antigens. In controls, the staining was 

uniform with no such localization. It is known that antigens within endosomal compartments 

have a tendency to be processed and presented to CD4+ T-cells, which might explain the varied 

gluten epitopes that have been identified. Recent work has shown that several of the major 

epitopes remain largely undigested on delivery to the lamina propria.(5) 

References 

1. Marsh MN. Gluten, major histocompatability complex, and the small intestine. A molecular 

and immunobiological approach to the spectrum of gluten sensitivity. Gastroenterology.

1992;102:330–354. 

2. Jabri B, De Serre NP, Cellier C, et al. Selective expansion of intraepithelial lymphocytes 

expressing the HLA-E-specific natural killer receptor CD94. Gastroenterology.

2000;118:867–879. 

3. Maiuri L, Ciacci C, Ricciardelli I, et al. Association between innate response to gliadin and 

activation of pathogenetic T cells in coeliac disease. Lancet. 2003;362:30–37. 

4. Zimmer KP, Naim H, Weber P, Ellis HJ, Ciclitira PJ. Targeting of gliadin peptides, CD8, 

α/β-TCR, and γ/δ-TCR to Golgi complexes and vacuoles within celiac disease enterocytes. 

Federation of American Societies for Experimental Biology Journal. 1998;12:1349–1357. 

5. Matysiak-Budnik T, Candalh C, Dugave C, et al. Alterations of the intestinal transport and 

processing of gliadin peptides in celiac disease. Gastroenterology. 2003;125:696–707. 
27 

What Are the Sensitivity and Specificity of 

Serological Tests for Celiac Disease? 

Do Sensitivity and Specificity Vary in Different Populations? 

Ivor D. Hill, M.D. 

Clinical practice serological tests for celiac disease (CD) are useful for identifying 

individuals who require an intestinal biopsy to diagnose the condition, are supportive of the 

diagnosis in those with characteristic small intestinal histological changes, and may be used to 

monitor response to treatment. Tests most commonly offered by commercial laboratories include 

IgG- and IgA-based antigliadin antibodies (AGA-IgG and AGA-IgA), IgA endomysium 

antibody (EMA-IgA), IgA tissue transglutaminase antibody (TTG-IgA), and IgA antireticulin 

antibody (ARA-IgA). 

The sensitivity and specificity of these tests have been studied largely in research settings 

and their accuracy may not be as good in clinical practice. Reasons for this include (1) lack of 

test standardization between laboratories; (2) problems defining a “gold standard” for diagnosing 

CD; and (3) study populations in the research settings usually differ from those in clinical 

practice. The sensitivity and specificity for each test are illustrated in table 1. These values are 

based on studies comparing patients with biopsy-confirmed CD to those with normal small 

intestinal histology and/or disease controls. 

Table 1. Sensitivity and Specificity of Individual Serological Tests 

Test Age Group Sensitivity Specificity 

AGA-IgG Adults/Combined*(1,4,5,11) 

Children(2,3,7–10,12) 

57–100% 

88–100% 

69–87% 

47–94% 

AGA-IgA Adults/Combined (1,4,6,14,18) 

Children(2,3,7–10,12,13,15–17) 

54–100% 

52–100% 

79–100% 

71–100% 

EMA Adults(5,17,25,27,28) 

Children(2,8,9,15,17,19,24,25) 

Combined (1,4,20–23,26) 

87–95% 

88–100% 

91–98% 

95–100% 

90–100% 

99–100% 

TTG Children(19,25,33,34) 

Combined (20–32) 

90–100% 

84–100% 

94–100% 

91–100% 

ARA Children(7,8,36) 65–94% 93–100% 

*Combined—refers to studies involving both adults and children 

Both sensitivity and specificity for AGA tests are highly variable. In general, AGA-IgG 

in children has good sensitivity but poor specificity. Adult data is less reliable due to the 

relatively small number of studies in this age group. Sensitivity of AGA-IgA is lower than that 
28 

for the IgG-based test, while specificity is higher. Based on a small number of studies, sensitivity 

and specificity for AGA can be improved using a combination of the IgG and IgA tests. 

EMA-IgA is both highly sensitive and specific. Most studies demonstrate EMA 

sensitivities in excess of 94 percent in children and 90 percent in adults with specificities above 

97 percent in both age groups. Studies comparing the use of human umbilical cord with monkey 

esophagus as substrate for the EMA tests show no difference in their performance values. 

TTG-IgA is also highly sensitive and specific. Initial studies on TTG used guinea pig 

protein as antigen while most recent studies have used human recombinant protein. In two 

comparative studies, human-derived assays were shown to have improved sensitivity and 

specificity over guinea pig-derived tests.(26,35) One study found TTG-IgA by RIA to be more 

sensitive than by ELISA but with identical specificity.(19) In general, TTG-IgA and EMA-IgA 

tests have similar sensitivity and specificity. 

ARA-IgA is less frequently used in clinical practice and fewer studies are available to 

assess the sensitivity and specificity of this test. One study demonstrated a sensitivity of only 

64 percent(8) while others have found higher figures (table 1). 

Selective IgA deficiency is more common in individuals with CD and occurs in 

approximately 2 percent of those with the condition. IgA-based tests for AGA, EMA, and TTG 

are unable to identify individuals with IgA deficiency who require a biopsy to diagnose CD. 

AGA-IgG tests are most often used for this purpose but are poorly predictive for positive 

histological findings.(37,38) IgG-based tests for EMA and TTG may be more accurate for 

identifying symptomatic individuals with CD. Sensitivity and specificity of TTG-IgG in 

non-IgA-deficient individuals with CD range from 84–97 percent and 91–93 percent, 

respectively.(39–41) There was good concordance between TTG-IgG and EMA-IgG in one study.(39) 

Good comparative studies on the sensitivity and specificity of the serological tests in 

different ethnic populations are not available. A few studies have compared results between 

children and adults. One study suggested AGA tests were better for identifying children under 5 

years of age while EMA-IgA were better for those over 5 years of age.(1) Similarly, sensitivity 

and specificity for TTG-IgA was higher for adults (95 percent and 100 percent) than children 

(93 percent and 97 percent).(25) It is also possible that EMA-IgA is less reliable in children under 

2 years of age.(2) 

Summary 

TTG-IgA (human recombinant) and EMA-IgA are the most sensitive and specific 

serological tests available for identifying individuals who require an intestinal biopsy for CD 

diagnosis. Their accuracy in clinical practice may not be as good as that reported from the 

research setting. Therefore, a positive diagnosis of CD should not be made on the basis of a 

serological test alone without intestinal biopsy confirmation. Serological tests may be less 

reliable in very young children. AGA tests are no longer recommended as a screening test 

because of the variable sensitivity and specificity associated with this test. There is no advantage 

to using a panel of tests incorporating AGA, EMA, and TTG antibodies over a single test using 

EMA or TTG. 
29 

References 

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serologic markers for clinical diagnosis and population studies of coeliac disease. Scand J 

Gastroenterol. 1996;31:61–67. 

2. Burgin-Wolff A, Gaze H, Hadziselimovic F, et al. Antigliadin and antiendomysium antibody 

determination for coeliac disease. Arch Dis Child. 1991;66:941–947. 

3. Burgin-Wolff A, Berger R, Gaze H, Huber H, Lentze MJ, Nussle D. IgG, IgA and IgE 

gliadin antibody determinations as screening test for untreated coeliac disease in children, a 

multicentre study. Eur J Pediatr. 1989;148:496–502. 

4. Chirdo FG, Rumbo M, Carabajal P, et al. Determination of anti-omega-gliadin antibodies in 

serological tests for coeliac disease. Scand J Gastroenterol. 2000;35:508–516. 

5. Feighery C, Weir DG, Whelan A, et al. Diagnosis of gluten-sensitive enteropathy: is 

exclusive reliance on histology appropriate? Eur J Gastroenterol Hepatol. 1998;10:919–925. 

6. Berger R, Schmidt G. Evaluation of six antigliadin antibody assays. J Immunol Methods.

1996;191:77–86. 

7. Sacchetti L, Ferrajolo A, Salerno G, et al. Diagnostic value of various serum antibodies 

detected by diverse methods in childhood celiac disease. Clin Chem. 1996;42:1838–1842. 

8. Lerner A, Kumar V, Iancu TC. Immunological diagnosis of childhood coeliac disease: 

comparison between antigliadin, antireticulin and antiendomysial antibodies. Clin Exp 

Immunol. 1994;95:78–82. 

9. Carroccio A, Iacono G, Montalto G, et al. Immunologic and absorptive tests in celiac disease: 

can they replace intestinal biopsies? Scand J Gastroenterol. 1993;28:673–676. 

10. Not T, Ventura A, Peticarari S, Basile S. A new, rapid, non invasive screening test for celiac 

disease. J Pediatr. 1993;123:425–427. 

11. McMillan SA, Haughton DJ, Biggart JD, Edgar JD, Porter KG, McNeill TA. Predictive value 

for coeliac disease of antibodies to gliadin, endomysium, and jejunum in patients attending 

for jejunal biopsy. BMJ. 1991;303:1163–1165. 

12. Rautonen J, Rautonen N, Savilahti E. Antibodies to gliadin in children with coeliac disease. 

Acta Paediatr Scand. 199;80:1200–1206. 

13. Ribes-Koninckx C, Alfonso P, Ortigosa L, Escobar H, Suarez L, Arranz E, Mendez E. A 

beta-turn rich oats peptide as an antigen in an ELISA method for screening of coeliac disease 

in a paediatric population. Am J Gastroenterol. 2001 May;96(5):1536–1540. 

14. Corazza GR, Biagi F, Andreani ML, Gasbarrini G. Screening test for coeliac disease. Lancet.

1997;349:325–326. 
30 

15. de Lecea A, Ribes-Koninckx C, Polanco I, Calvete JF. Serological screening (antigliadin and 

antiendomysium antibodies) for non-overt coeliac disease in children of short stature. Acta 

Paediatr Suppl. 1996;412:54–55. 

16. Bode S, Weile B, Krasilnikoff PA, Gudmand-Hoyer E. The diagnostic value of the gliadin 

antibody test in celiac disease in children: A prospective study. J Pediatr Gastroenterol Nutr.

1993;17:260–264. 

17. Mascart-Lemone F, Lambrechts A. Serology of coeliac disease: Early diagnosis and 

therapeutic impact. Acta Gastroenterol Belg. 1995;58:388–396. 

18. Bardella MT, Molteni N, Cesana B, Baldassarri AR, Binanchi PA. IgA antigliadin 

antibodies, cellobiose/mannitol sugar test, and carotenemia in the diagnosis of and screening 

for celiac disease. Am J Gastroenterol. 1991;86:309–311. 

19. Bonamico M, Tiberti C, Picarelli A, et al. Radioimmunoassay to detect antitransglutaminase 

autoantibodies is the most sensitive and specific screening method for celiac disease. Am J 

Gastroenterol. 2001;96:1536–1540. 

20. Baldas V, Tommasini A, Trevisiol C, et al. Development of a novel rapid non-invasive 

screening test for coeliac disease. Gut. 2000;47:628–631. 

21. Stern M. Comparative evaluation of serologic tests for celiac disease: a European initiative 

toward standardization. J Pediatr Gastroenterol Nutr. 2000;31:513–519. 

22. Sulkanen S, Halttunen T, Laurila K, et al. M. Tissue transglutaminase autoantibody enzymelinked immunosorbent assay in detecting celiac disease. Gastroenetrology. 1998;115:1584–

1586. 

23. Yiannakou JY, Dell’Olio D, Saaka M, et al. Detection and characterisation of antiendomysial antibody in coeliac disease using human umbilical cord. Int Arch Allergy 

Immunol. 1997;112:140–144. 

24. Carroccio A, Cavataio F, Iacono G, et al. IgA antiendomysial antibodies on the umbilical 

cord in diagnosing celiac disease. Sensitivity, specificity, and comparative evaluation with 

the traditional kit. Scand J Gastroenterol. 1996;31:759–763. 

25. Salmaso C, Ocmant A, Pesce G, et al. Comparison of ELISA for tissue transglutaminase 

autoantibodies with antiendomysium antibodies in pediatric and adult patients with celiac 

disease. Allergy. 2001;56:544–547. 

26. Sblattero D, Berti I, Trevisiol C, et al. Human recombinant tissue transglutaminase ELISA: 

an innovative diagnostic assay for celiac disease. Am J Gastroenterol. 2000;95:1253–1257. 

27. Sategna-Guidetti C, Grosso SB, Bruno M, Grosso S. Is human umbilical cord the most 

suitable substrate for the detection of endomysium antibodies in the screening and follow-up 

of coeliac disease? Eur J Gastroenterol Hepatol. 1997;9:655–656. 
31 

28. McMillan SA, Haughton DJ, Biggart JD, Edgar JD, Porter KG, McNeill TA. Predictive value 

for coeliac disease of antibodies to gliadin, endomysium, and jejunum in patients attending 

for jejunal biopsy. BMJ. 1991;303:1163–1165. 

29. Dieterich W, Laag E, Schopper H, et al. Autoantibodies to tissue transglutaminase as 

predictors of celiac disease. Gastroenterology. 1998;115:1584–1586. 

30. Leon F, Camerero C, R-Pena R, et al. Anti-transglutaminase IgA ELISA: clinical potential 

and drawbacks in celiac disease diagnosis. Scand J Gastroenterol. 2001;36:849–853. 

31. Fabiani E, Catassi C. The serum IgA class anti-tissue transglutaminase antibodies in the 

diagnosis and follow up of coeliac disease. Results of an international multi-centre study. 

International Working Group on Eu-tTG. Eur J Gastroenterol Hepatol. 2001;13:659–665. 

32. Seissler J, Boms S, Wohlrab U, et al. Antibodies to human recombinant tissue 

transglutaminase measured by radioligand assay: evidence for high diagnostic sensitivity for 

celiac disease. Horm Metab Res. 1999;31:375–379. 

33. Troncone R, Maurano F, Rossi M, et al. IgA antibodies to tissue transglutaminase: An 

effective diagnostic test for celiac disease. J Pediatr. 1999;134:166–171. 

34. Vitoria JC, Arrieta A, Arranz C, et al. Antibodies to gliadin, endomysium, and tissue 

transglutaminase for the diagnosis of celiac disease. J Pediatr Gastroenterol Nutr.

1999;29:571–574. 

35. Wong RC, Wilson RJ, Steele RH, Radford-Smith G, Adelstein S. A comparison of 13 guinea 

pig and human anti-tissue transglutaminase antibody ELISA kits. J Clin Pathol.

2002;55:488–494. 

36. Kolho KL, Savilahti E. IgA antiendomysium antibodies on human umbilical cord: An 

excellent diagnostic tool for celiac disease in childhood. J Pediatr Gastroenterol Nutr.

1997;24:563–567. 

37. Mustalahti K, Sulkanen S, Holopainen P, et al. Coeliac disease among healthy members of 

multiple case coeliac disease families. Scand J Gastroenterol. 2002;37:161–165. 

38. Prince HE, Normal GL, Binder WL. Immunoglobulin A (IgA) deficiency and alternative 

disease-associated antibodies in sera submitted to a reference laboratory for endomysial IgA 

testing. Clin Diag Lab Immunol. 2000:7:192–196. 

39. Hansson T, Dahlbom I, Rogberg S, et al. Recombinant human tissue transglutaminase for 

diagnosis and follow up of childhood coeliac disease. Pediatr Res. 2002;51:700–705. 

40. Picarelli A, di Tola M, Sabbatella L, et al. Identification of a new coeliac disease subgroup: 

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41. Picarelli A, Sabbatella L, Di Tola M, et al. Celiac disease diagnosis in misdiagnosed 

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33 

Clinical Algorithm in Celiac Disease 

Ciaran P. Kelly, M.D. 

Celiac disease is characterized by inflammatory injury to the small intestinal mucosa that 

results from an aberrant immune response to specific ingested dietary peptides derived from 

cereals such as wheat, barley, or rye. Celiac disease is common in both the United States and 

Europe and affects 0.5 to 1 percent of the population. The variety of clinical presentations of 

celiac disease is broad and ranges from chronic and severe diarrhea with weight loss and 

malnutrition to symptomless disease with minimal or no clinically evident malabsorption. The 

fact that celiac disease is common and has protean manifestations means that the diagnosis is 

easily missed unless physicians and other health care providers include celiac disease in the 

differential diagnosis of common conditions such as iron deficiency anemia, mild chronic 

diarrhea, recurrent abdominal discomfort, failure to thrive as well as less common manifestations 

such as skin rashes, hair loss, neurological disorders, vitamin deficiency states, or infertility. In 

brief, the first and most critical step in making a diagnosis of this commonly overlooked disorder 

is to think of celiac disease as a diagnostic possibility. 

The primary diagnostic criterion is the identification of an enteropathy that is consistent 

with the inflammatory intestinal injury seen in celiac disease. This requires that a small bowel 

biopsy be obtained prior to effective treatment with a gluten-free diet. Changes of celiac 

enteropathy may be visually evident at endoscopy. These include: a reduction in the number or 

height of duodenal mucosal folds, mucosal nodularity, a mosaic pattern of mucosal fissures, and 

scalloping of the duodenal folds where the mucosal fissures cross the apex of a fold. These 

endoscopic findings, alone or in combination, are quite specific for celiac disease but are not 

sensitive. Thus, visualization of the duodenal mucosa at endoscopy cannot replace microscopic 

examination of duodenal biopsy tissue for diagnosis. Although intestinal histopathology remains 

the gold standard for diagnosis of celiac disease, the enteropathy may be mild and patchy and 

therefore missed on biopsy. Even when an inflammatory enteropathy is present, the histological 

features—while characteristic—are not pathognomonic since other disorders can result in a 

similar or identical histopathologic picture. In this regard, the diagnosis of celiac disease is aided 

or reinforced by the demonstration of serum IgA tissue transglutaminase autoantibody. 

The identification of human tissue transglutaminase (htTG) as a celiac autoantigen has 

revolutionized our understanding of celiac disease pathogenesis. Simultaneously, it has greatly 

enhanced our ability to identify individuals with untreated celiac disease by accurate and 

minimally invasive serologic testing. Measurement of serum IgA against htTG has now become 

the serologic test of choice for diagnosis or exclusion of untreated celiac disease. IgA htTG 

serology is far more specific than the older gliadin-based immunoassays, to the point that the 

antigliadin assays are now of minimal clinical utility. The identification of serum IgA 

endomycial antibodies (EMA) remains a sensitive and highly specific marker of untreated celiac 

disease. However, IgA EMA testing by indirect immunofluoresence is more cumbersome, 

expensive, and operator dependent than IgA htTG enzyme immunoassay. 
34 

Serum IgA htTG in concert with small intestinal histology are a powerful diagnostic duo, 

and when both are performed correctly and are positive, provide a near absolute diagnosis of 

untreated or incompletely treated celiac disease. As a result, other diagnostic criteria such as 

clinical response to a gluten-free diet, histological response to a gluten-free diet, and gluten 

challenge now play lesser roles in diagnosis. 

The remarkably high positive predictive value of IgA EMA or high-titer IgA htTG 

serology has led to debate as to whether endoscopy with biopsy is required for diagnosis—

especially in instances where the pretest probability of celiac disease was already high. Each 

patient must be the final and individual arbiter of this debate, however, most expert celiac 

clinicians advocate strongly for histological confirmation of a diagnosis of celiac disease for the 

following reasons: (1) celiac disease is defined by an enteropathy, not by the presence of a serum 

autoantibody; (2) positive serology in the absence of significant enteropathy does occur and does 

not predicate lifelong treatment with a gluten-free diet; (3) endoscopy with biopsy is readily 

available in the United States and is relatively simple and safe; (4) it is difficult to either confirm 

or refute the diagnosis after dietary treatment is initiated; and (5) the cost of a false-positive 

diagnosis is enormous in that a patient may needlessly and fruitlessly adhere to an inconvenient 

and expensive gluten-free diet for decades while the actual etiology of their initial symptoms and 

signs remains undiagnosed. 

A suggested clinical algorithm for diagnosis of celiac disease is shown in figure 1. The 

first and essential step is to consider the diagnosis. The next is to determine—on the basis of the 

patient’s clinical presentation, medical and family history, and available laboratory data—

whether a diagnosis of celiac disease is highly likely (e.g., greater than 10 percent pretest 

probability) or less likely. For those with a lower pretest probability, IgA htTG serology is the 

current test of choice. A positive IgA htTG serology indicates the need for small bowel biopsy to 

diagnose celiac disease prior to lifelong treatment with a gluten-free diet. For those who are 

negative by IgA htTG, a serum IgA level may be checked to exclude IgA deficiency; however, 

but this additional test has a relatively low diagnostic impact. Antigliadin serology is largely 

counterproductive especially in individuals older than 2 years because of the plethora of 

false-positive results in low-risk populations. For high-risk populations (e.g., greater than 

10 percent pretest probability), the likelihood of a false-negative IgA htTG serology may be 

unacceptably high; therefore, both serology and endoscopy with biopsy should be performed at 

the outset. Additional diagnostic steps are needed in instances where IgA htTG serology is 

positive but biopsy histology is reportedly normal, or where IgA htTG serology is negative but 

the small intestinal morphology and inflammatory infiltrate are consistent with a celiac lesion. 

There is no place for a trial of a gluten-free diet prior to diagnostic testing for celiac disease. 

Unfortunately, in some instances, patients present on treatment with a gluten-free diet in the 

absence of diagnostic pretreatment serology or histopathology. In such circumstances, gluten 

challenge followed by serology and biopsy is needed to establish a secure diagnosis. 

When celiac disease is diagnosed, there should be an evaluation for deficiencies in 

nutrients such as iron, folic acid, vitamin B12 and vitamin D. The patient should be educated on 

the cause of intestinal injury and malabsorption in celiac disease, encouraged to adhere to a 

lifelong gluten-free diet, and provided with access to expert nutritional counseling. The clinical 

and serologic response to treatment should be monitored and reversal of any identified 

nutritional deficiencies confirmed. With accurate diagnosis and appropriate treatment the 

substantial morbidity associated with unrecognized symptomatic celiac disease can be avoided 

completely. 
35 

Serum IgA htTG2

Determine

the pretest 

probability

Diagnosis

adequately

excluded

Serum IgA htTG

and

SI biopsy histology

• Exclude nutritional deficiency states

• Educate on celiac disease

• Encourage adherence to gluten free diet

• Ensure access to skilled nutritional counseling

• Evaluate response to treatment

Both

negative

Both

positive

Serology positive

Histology negative

Serology negative

Histology positive

Diagnose

Celiac disease

Consider

a diagnosis

of celiac disease

Histology

remains

negative

Identify another cause for enteropathy

or

HLA DQ2 and DQ8 both negative

Negative

Positive

Consider:

• Expert review of histopathology 

• Repeat serology using another assay method

• Ensure patient has adequate dietary gluten intake and

repeat biopsy with collection

of multiple tissue samples

Consider:

Expert review of histopathology

Other etiologies for celiac-like enteropathy3

Testing for celiac-associated MHC II

SI biopsy histology

Other causes 

excluded or unlikely

HLA DQ2 / DQ8 positive

>10%1 <10%1

1. The pretest probability level at which both IgA htTG serology and small bowel histology should be examined will 

vary in individual circumstances depending upon the severity of the presenting complaint, the age and general 

health of the patient, and the patient’s willingness to undergo endoscopy with biopsy versus risking a falsenegative diagnostic evaluation. 

2. Some clinicians also test for total IgA concentrations to identify IgA deficiency. 

3. These include: tropical sprue, postinfectious enteropathy, peptic duodenitis, Crohn’s disease, cow’s milk and 

other dietary protein intolerances, eosinophilic enteritis, small intestinal bacterial overgrowth, giardiasis, 

immunodeficiency states including common variable immunodeficiency, severe malnutrition, graft versus host 

disease, refractory sprue, and intestinal lymphoma. 

 Figure 1: Clinical algorithm for diagnosis of celiac disease 

 (based on references 1 and 2 below) 

References 

1. Farrell RJ, Kelly CP. Diagnosis of celiac disease. Am J Gastroenterol. 2001;96:3237–3246.

2. Farrell RJ, Kelly CP. Celiac sprue. N Eng J Med. 2002;346:180–188. 
37 

Genetic Testing: Who Should Do the Testing and What Is the 

Role of Genetic Testing in the Setting of Celiac Disease? 

George S. Eisenbarth, M.D. 

At present, there is public health screening for a series of disorders that can be identified 

shortly after birth. These disorders are all relatively infrequent, but include diseases such as 

hypothyroidism (1/4,000 newborns) and phenylketonuria (1/13,500 to 1/19,000), and for some 

U.S. States and France, even diseases such as cystic fibrosis are assessed with newborn 

screening. The major driving force for screening is the ability to identify a treatable disorder with 

significant incidence such that there is a public health risk. Essentially all of the disorders are 

identifiable as a neonatal disorder requiring immediate therapy (e.g., neonatal hypothyroidism) 

or are Mendelian disorders with high penetrance (e.g., cystic fibrosis). The threshold for 

determining the cost-effectiveness of screening for a given disease is very much influenced by 

the infrastructure put into place for newborn screening due to the almost universal screening for 

phenylketonuria and hypothyroidism. As we consider celiac disease, we are considering a very 

common disorder of children and adults, a disease that at present usually does not manifest 

(expression of transglutaminase autoantibodies) until after 2 years of age, and most important, a 

complex genetic disorder. For complex genetic disorders that do not manifest in neonates and in 

particular immune-mediated diseases, which is determined by HLA alleles, we lack a public 

health screening infrastructure. It is likely that if the paradigm of screening for celiac disease is 

developed, it will provide an infrastructure that would affect and lower the threshold for public 

health intervention for a series of disorders including type 1A diabetes and Addison’s disease. 

In many ways, celiac disease is an ideal HLA-associated disorder for public health 

screening consideration. The disease is common (approximately 1 percent of children in 

Colorado, 6 percent of children with type 1A diabetes, 16 percent of children who are DQ2 

homozygous with type 1A diabetes). Specific HLA class II alleles (DQ2 or DQ8) are present in 

approximately 95 percent of affected individuals. The disease is asymptomatic and thus not 

diagnosed in the majority of children. The transglutaminase autoantibody assay is inexpensive, 

sensitive, and specific, and small-bowel biopsy confirms diagnosis. There is an effective 

therapy (gluten-free diet). Major caveats include (1) whether the bulk of asymptomatic 

individuals with celiac disease would have morbidity/mortality, and whether early diagnosis 

and treatment are useful in preventing such morbidity/mortality; (2) only a subset of those 

identified with HLA-determined genetic risk will develop transglutaminase autoantibodies and 

biopsy-confirmed celiac disease (0.3 percent with no DR3/DQ2 allele develop persistent 

transglutaminase autoantibody by age 7 versus approximately 3 percent for those with 

DR3/DQ2); and (3) public health infrastructure is not in place for screening diseases that 

manifest by the expression of autoantibodies followed by diagnosed pathology in infancy, 

childhood, and adulthood. 
38 

There are populations at particularly high risk of developing celiac disease, including 

individuals with multiple different autoimmune disorders and with type 1A diabetes. Figure 1 

(from barbaradaviscenter.org Web book on immunology of diabetes) illustrates the risk of 

expression of transglutaminase autoantibodies (TGA) amongst patients and their relatives with 

type 1A diabetes subdivided by DR3 haplotypes containing DQ2. 

0%

5%

10%

15%

20%

25%

DR3+ DR3-

IDDM

Relatives

Population

BDC 

Figure 1. Prevalence of TGA by HLA-DR Amongst Patients With 

Type 1 Diabetes Mellitus, Relatives of Patients with Diabetes 

Mellitus, and the General Population 

Of newborns evaluated in the DAISY study, headed by Marian Rewers of the Barbara 

Davis Center, 39.5 percent have either DQ2 and/or DQ8. At present, this is the primary genetic 

locus that can be relied upon for determining risk at birth. Individuals not expressing DQ2 or 

DQ8 are at low risk. These same two alleles determine risk for type 1A diabetes and Addison’s 

disease but their negative predictive values (ability with celiac disease to “exclude” 60 percent of 

population) are lower. It is a difficult task to ascertain additional loci determining celiac disease 

given the development of complications such as intestinal T-cell lymphoma. At present only 

MHC alleles can be considered for genetic analysis. 

Given the ability to define a higher- and lower-risk group with relatively simple class II 

HLA typing, an important question is whether therapy would need to be instituted in early 

infancy. Prospective epidemiologic questions, in particular studies of diet headed by Jill Norris 

of the CEDAR study, are evaluating whether timing of introduction of, for instance, gliadin will 

influence the eventual development of celiac disease. If such a dietary influence is found and has 

a life-long benefit, it would be a major impetus for newborn screening. 
39 

0.0

0.5

1.0

1.5

2.0

2.5

tTG titer

0 1 2 3 

Marsh score

Spearman correlation 

r = 0.569 

p < 0.003

Hoffenberg, J. Peds 2000;137:356.

Figure 2. Transglutaminase Autoantibodies and Marsh Score 

(Disease Severity) 

Given genetic susceptibility, current TGA assays provide inexpensive, specific, and 

sensitive markers of the presence of celiac disease pathology with high levels of the autoantibody 

associated with intestinal biopsy-positive celiac disease. 

In summary, celiac disease is an important candidate for public health newborn genetic 

screening based upon HLA DQ alleles. Outside of the newborn period, and particularly for 

populations at increased risk (autoimmune disorders such as type 1A diabetes and their 

relatives), HLA analysis can contribute to defining a population not needing repeated testing 

over time to identify the development of TGAs. Such testing from a public health perspective is 

likely to be useful given the prevalence of celiac disease and the potential for altering relatively 

simple factors such as the timing of introduction of gliadin. 
41 

Serological Testing for Celiac Disease 

Alaa Rostom, M.D., M.Sc., FRCPC 

Context 

Mounting evidence suggests that celiac disease (CD) is much more common than 

previously suspected. Furthermore, with the availability of increasingly more sensitive and 

specific serological tests, it has become apparent that the majority of CD patients do not 

demonstrate the classically described features of symptomatic intestinal malabsorption, and an 

important proportion have milder histological grades that do not necessarily fit with commonly 

used histological criteria cut-offs for defining CD (i.e., requirement of some degree of villous 

atrophy). These findings have important implications for the assessment of the diagnostic 

performance of the available serological tests, since there is an inherent interdependence between 

the performance of these tests, and the clinical and histological criteria used to define CD. 

Objectives 

(1) To conduct a systematic review of the diagnostic performance of antigliadin antibody 

(AGA), endomyseal antibody (EMA), and transglutaminase antibody (tTG) and their subtypes 

for the screening and diagnosis of CD. (2) To assess the performance of these tests in unselected 

general populations; patients with suspected CD; and populations at high risk of CD. 

Data Sources

A comprehensive literature search was conducted by the National Library of Medicine in 

collaboration with the University of Ottawa Evidence-Based Practice Center (UO-EPC). The 

searches were run in MEDLINE (1966 to Oct 2003) and EMBASE (1974 to Dec 2003) 

databases. 

Study Selection and Data Extraction

This study was conducted using accepted systematic review methodology. Study 

selection was performed by two independent reviewers using three levels of screening with 

increasingly more strict criteria to ensure that all relevant articles were captured. Articles passing 

the third level screen fulfilled all the inclusion/exclusion criteria, allowed actual extraction of the 

sensitivity and specificity data, and did not have fatal methodological flaws. Articles were 

excluded if the control group did not have the gold standard test (biopsy) applied; no description 

of biopsy criteria given; celiac group known to be positive for test under evaluation; control 

group known to be negative for the test under evaluation; control groups included patients with 

Marsh I or II biopsy lesions; or AGA test performed without commercial ELISA kit or before 

1990. Study data was abstracted using a predetermined electronic form by one reviewer, and 
42 

verified by another. The quality of reporting of the included studies was assessed using the 

QUADAS tool. 

Data Synthesis

To minimize clinical and statistical heterogeneity, the included articles of a particular 

antibody test were divided into groups by age of the included population (adults, children, 

mixed); the study design (case control, or relevant clinical population/cohort); by antibody type 

(IgA or IgG); and by test methodology (e.g., monkey esophagus or human umbilical cord). 

Pooled estimates were only calculated if clinically and statistically appropriate. We calculated a 

weighted mean of the sensitivity and specificity from those of the included study. For each 

pooled estimate, a 95 percent confidence interval (CI) was calculated using both a fixed and 

random effects model, the results of which were compared as a further test for heterogeneity. 

The pooled estimates for the sensitivity and specificity were also compared to a summary ROC 

curve calculated for the same group of studies as a second check of the estimates. 

Results and Conclusions

Out of 3,982 citations identified by the search strategy, 907 met level 2 screening criteria. 

Of these, 204 diagnostic test studies of one or more of the serological markers of interest (AGA, 

EMA, tTG) were identified. Fifty-five studies fulfilled the level 3 inclusion criteria. 

The results of the systematic review demonstrate that in the studied populations 

IgA-EMA and IgA-tTG have sensitivities and specificities each in excess of 90 percent in both 

children and adults. The pooled specificity of EMA was 100 percent in adults using either 

EMA-ME or EMA-HU. In studies of children, the specificity of EMA using these two substrates 

was 97 percent and 95 percent, respectively, with overlapping 95 percent CIs, suggesting no 

statistical difference between these values. In adults, the pooled specificity of tTG-GP and tTGHR were 95 percent and 98 percent, respectively, with overlapping CIs. Similarly, in children, 

the specificities were 96 percent and 99 percent, again with overlapping CIs. Among the three 

studies in adults, and four studies in children that assessed both EMA and tTG, the specificities 

were nearly identical. Overall, these results suggest that EMA and tTG antibodies demonstrate 

extremely high specificities in both adults and children. 

We identified a tendency towards greater variability in sensitivity between studies and 

between antibodies, compared with specificity. IgA-EMA-ME demonstrated sensitivities of 

97 percent and 96 percent in adults and children, respectively. EMA-HU demonstrated a similar 

sensitivity of 97 percent in children, although the pooled estimate in adults was somewhat lower 

at 90 percent. Two studies assessed both EMA-ME and EMA-HU in adults, one demonstrated 

identical sensitivities of 95 percent, whereas the other showed a lower sensitivity of HU 

compared with ME (90 percent versus 100 percent). None of the included mixed-age studies 

assessed both of these antibodies. Heterogeneity existed in the analyses of sensitivity of tTG-GP 

in the adult, but it is likely close to 90 percent. In children, the pooled estimate was 93 percent. 

The sensitivity of tTG-HR was 98 percent in adults and 96 percent in children, although in both 

cases the CIs included a low of 90 percent. In studies of mixed-age populations, the sensitivity 

was 90 percent. 
43 

Estimates of the sensitivity of the IgG class antibodies of EMA and tTg suggest that these 

tests have poor sensitivities around 40 percent, although the specificities were high at around 

98 percent. These finding suggest that this class of antibody would be inappropriate as a single 

test for CD, but may be useful in IgA deficient patients, or in combination with an IgA class 

antibody. One study that assessed the use of IgA-tTG-HR with IgG-tTG-HR found a sensitivity 

of 99 percent and a specificity of 100 percent for the combination. 

The analyses of all the AGA subgroups demonstrated significant heterogeneity, and no 

statistical pooling was undertaken. The sensitivity of IgA-AGA in adults is likely not much 

higher than 80 percent, but seems somewhat higher in children. The specificity likely lies 

between 80 and 90 percent in adults and children, although the studies of serial testing of AGA 

followed by EMA or tTG in the prevalence section of this report suggest that the specificity is 

low as well. Even if one considers an optimistic range, the performance of IgA-AGA in both 

adults and children is inferior to that of the other antibodies discussed above. 

The analyses of IgG-AGA suffered from significant clinical and statistical heterogeneity 

making even general summary statements difficult. The typical sensitivity of this test likely lies 

below 80 percent in adults, and between 80 and 90 percent in children. The specificities are 

likely close to 80 percent in adults and between 80 and 90 percent in children with the same 

warning coming from the prevalence studies, suggesting that in the era of EMA and tTG, testing 

for CD with AGA has a limited role. 

The sensitivity of the studied serological tests appears to be lower than reported when 

milder histological grades are used to define CD. Several studies demonstrated sensitivities for 

EMA and tTG well below 90 percent when histological grades milder than Marsh 3 where 

considered. If true, than the nearly perfect negative predictive value of these tests would drop. 

Furthermore, the majority of studies assessed the performance of these antibodies in situations of 

high CD prevalence. Therefore, the positive predictive value of these tests is likely lower than 

reported when the tests are applied in general population screening. 

Abbreviations: ME—monkey esophagus; HU—human umbilical cord; GP—guinea pig 

liver; HR—human recombinant. 
45 

Epidemiology of Celiac Disease: What Are the Prevalence, 

Incidence, and Progression of Celiac Disease? 

Marian J. Rewers, M.D., Ph.D. 

Definition of Disease 

Celiac disease (CD) is a chronic, systemic, autoimmune disorder induced by gluten 

proteins present in wheat, barley, and rye. Genetically susceptible persons develop autoimmune 

injury to the gut, skin, liver, joints, uterus, and other organs. The classical definition of CD 

includes gastrointestinal manifestations confirmed by a small bowel biopsy (SBB) with findings 

of villous atrophy, crypt hyperplasia, and normalization of the villous architecture in response to 

gluten-free diet.(1,2) However, the clinical manifestation of CD has become more subtle and 

affects mostly older children or adults.(3) SBB is poorly accepted by a majority of patients with 

mild or no symptoms, and the pathological examination of biopsy material is suboptimal in most 

settings. SBB is also hardly a “gold standard”—occasionally false-negative due to patchy 

mucosal changes, often most severe in proximal jejunum, and typically not reached by 

endoscopic biopsy. This has led some to propose a new definition of CD, based on the presence 

of serum IgA autoantibodies to tissue transglutaminase (IgA TG) and HLA-DQB1*0201 or 

*0302 alleles.(4) These markers are increasingly used in screening for CD, but their true 

sensitivity and specificity is debatable due to problems with some IgA TG assays and 

verification bias—overestimation of sensitivity and underestimation of specificity due to lack of 

SBB studies in TG-negative screenees. 

Prevalence 

Prevalence of childhood CD has been reported to be as high as 1 in 77 among Swedish 

2 1⁄2-year-olds,(5) 1 in 99 (using SBB as criterion) or 1 in 67 (using presence of IgA TG and 

HLA-DQB1*0201 or *0302) in Finnish schoolchildren,(4) and 1 in 230 in Italian school-age 

children.(6) In the United States, the frequency of CD among adults varies from 1 in 1,750 (with 

CD defined as clinical cases including dermatitis herpetiformis)(3) to 1 in 105 (CD defined by 

presence of IgA TG in blood donors(7)). The estimates based on sero-epidemiological studies 

suggest that for each diagnosed case of CD, there may be 3–7 undiagnosed cases. 

Incidence 

Cumulative incidence of SBB-confirmed CD in children has been reported between 1 in 

285 in Sweden(8) and 1 in 588 in New Zealand.(9) In Colorado, the risk estimate for developing 

CD—defined as IgA TG positivity by the age of 5—was 1 in 104 (95 percent CI 1:49–221).(10)

Population-based estimates of the incidence of SBB-confirmed CD in adults vary from 

2–13/100,000.(3,9) The recent increase in the incidence rates is likely due to increasing use of 

serologic screening, leading to diagnosis in milder cases. Infant and early childhood nutrition 

varies among populations. Differences in the prevalence of susceptibility HLA alleles may 

explain interpopulation variation in the incidence of CD. The effects of nutritional practices on 
46 

the risk and severity of CD may also account for geographic and temporal variation in the 

incidence of CF and may be of great public health importance. 

Progression 

While there is growing evidence for a remitting-relapsing pattern of CD autoimmunity in 

some patients,(4,11) the disease process defined by current serological and histopathological 

techniques is remarkably persistent in the absence of gluten-free diet. A two- to threefold excess 

in all-cause mortality among CD patients, compared to the general population, has been reported 

in some studies(12,13) and attributed to GI tract malignancies.(14,15) 

In summary, CD is a protean systemic disease affecting up to 1 percent of the general 

population. Appropriate screening, diagnosis, and treatment guidelines are being redefined using 

improved diagnostic methods that include IgA TG testing and HLA-DQB1 typing, in addition to 

SBB. 

References 

1. Walker-Smith J, Guandalini S, Schmitz J, Shmerling D, Visakorpi J. Revised criteria for 

diagnosis of coeliac disease. Report of Working Group of European Society of Paediatric 

Gastroenterology and Nutrition. Arch Dis Child. 1990;65:909–911. 

2. Catassi C, Cellier C, Cerf-Bensussan N, et al. When is a coeliac a coeliac? Report of a 

working group of the United European Gastroenterology Week in Amsterdam. European 

Journal of Gastroenterology & Hepatology. 2001;13:1123–1128. 

3. Murray JA, Van Dyke C, Plevak MF, Dierkhising RA, Zinsmeister AR, Melton LJ, III. 

Trends in the identification and clinical features of celiac disease in a North American 

community, 1950–2001. Clin Gastroenterol Hepatol. 2003;1:19–27. 

4. Maki M, Mustalahti K, Kokkonen J, et al. Prevalence of celiac disease among children in 

Finland. N Engl J Med. 2003;348:2517–2524. 

5. Carlsson A, Axelsson I, Borulf S, et al. Prevalence of IgA-antigliadin antibodies and 

IgA-antiendomysium antibodies related to celiac disease in children with Down syndrome. 

Pediatrics. 1998;101:272–275. 

6. Catassi C, Ratsch IM, Fabiani E, et al. High prevalence of undiagnosed coeliac disease in 

5280 Italian students screened by antigliadin antibodies. Acta Paediatr. 1995;84:672–676. 

7. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk 

groups in the United States: A large multicenter study. Arch Intern Med. 2003;163:286–292. 

8. Cavell B, Stenhammar L, Ascher H, et al. Increasing incidence of childhood coeliac disease 

in Sweden. Results of a national study. Acta Paediatr. 1992;81:589–592. 
47 

9. Cook B, Oxner R, Chapman B, Whitehead M, Burt M. A thirty-year (1970–1999) study of 

coeliac disease in the Canterbury region of New Zealand. N Z Med J. 2004;117:U772. 

10. Hoffenberg EJ, Mackenzie T, Barriga KJ, et al. A prospective study of the incidence of 

childhood celiac disease. Journal of Pediatrics. 2003;143:308–314. 

11. Liu E, Bao F, Barriga K, et al. Fluctuating transglutaminase autoantibodies are related to 

histologic features of celiac disease. Clin Gastroenterol Hepatol. 2003;1:356–362. 

12. Ferguson A, Kingstone K. Coeliac disease and malignancies. Acta Paediatr Suppl.

1996;412:78–81. 

13. Corrao G, Corazza GR, Bagnardi V, et al. Mortality in patients with coeliac disease and their 

relatives: a cohort study. Lancet. 2001;358:356–361. 

14. Askling J, Linet M, Gridley G, Halstensen TS, Ekstrom K, Ekbom A. Cancer incidence in a 

population-based cohort of individuals hospitalized with celiac disease or dermatitis 

herpetiformis. Gastroenterology. 2002;123:1428–1435. 

15. Catassi C, Fabiani E, Corrao G, et al. Risk of non-Hodgkin lymphoma in celiac disease. 

JAMA. 2002;287:1413–1419. 
49 

What Are the Prevalence and Incidence of Celiac Disease 

in High-Risk Populations: Patients With an Affected 

Family Member, Type 1 Diabetes, Iron-Deficiency Anemia, 

and Osteoporosis? 

Joseph A. Murray, M.D. 

Outline 

The presence of autoimmune conditions like insulin-dependent diabetes mellitus (DM), a 

family history of celiac disease (CD), or dermatitis herpetiformis may increase the risk of 

coexisting CD. The prevalence of CD may be increased in certain patient groups including the 

following: osteoporosis or low bone mass, or iron-deficiency anemia. 

Family History of CD and Dermatitis Herpetiformis 

Many early case reports documented the occurrence of CD in siblings, identical twins, 

parent and child pairs, as well as more extended kindreds. At least 20 percent of index cases will 

have an affected family member if screening is done. The exact degree of increased risk for 

specific family members has not been reliably ascertained but estimates have been made based 

on screening studies undertaken at one point in time. Identical twins have a 75–100 percent 

concordance rate for the disease. Siblings are at the next highest risk at 7–20 percent 

concordance rate. It has been suggested that if siblings share the same HLA disease risk 

haplotype, their risk approaches 40 percent. It is less so for parents or children of the proband. 

Most of these studies were in homogenous populations where the background risk for CD was 

high. A recent multicenter study in the U.S. identified a rate of 4–5 percent of first-degree 

relatives had CD based on endomysial antibody testing, a rate significantly greater than the rate 

in the not-at-risk individuals. 

These studies have based their risk estimations on the numbers of relatives that were 

screened, not necessarily the number of first-degree relatives. Many of these studies are subject 

to the selection bias of family members coming forward or agreeing to screening. Additionally, 

there often is incomplete followup of family members to determine if the screening at one point 

in time is an adequate estimation of the risk over time. Not all studies were so positive. Two of 

100 first-degree family members underwent biopsy and only 2 had CD. Five others appeared to 

have transient changes. Occasional cases of progression to CD have been reported in a few cases 

initially negative for CD. In our ongoing community study, 10 percent of tested first-degree 

relatives are found to have undiagnosed CD. A further 2 percent had possible CD with subtle 

histopathological changes on intestinal biopsies. Almost as many family members were 

diagnosed clinically for CD via screening, usually because of a heightened awareness of the risk 

in a symptomatic relative. Serological testing detected most, but not all, screened-found patients 

with CD, however 4/41 patients were found to have CD based on biopsy alone. This was due to 

the protocol that included biopsying symptomatic family members who had the at-risk HLA type 

despite negative serology. While most screen-found patients had little or no symptoms, 

compliance with a gluten-free diet was good. 
50 

Type 1 Diabetes Mellitus 

An association between CD and type 1 DM has been recognized for more than 40 years. 

Several studies, both in children and adults, have shown that there is a 1.5–7 percent prevalence 

of CD in type 1 diabetics. There is some evidence that undiagnosed CD may not only coexist 

with diabetes but may precede it. It has been suggested that delayed diagnosis of CD is 

associated with an increased risk for subsequently developing diabetes. Patients in whom CD 

was identified and treated in early childhood had a lower rate of developing diabetes than 

children in whom CD was diagnosed later in childhood or as adults. Autoantibodies directed 

against islet cells are frequently present in untreated CD but disappear with the gluten-free diet. 

Studies of American children with type 1 DM revealed a prevalence of CD of 4–6 

percent and studies of adult American patients with type 1 DM reported a prevalence of CD of 

4–6.4 percent. These studies have largely been based in tertiary referral centers or specialized 

diabetic clinics and therefore may not be representative of the prevalence of CD in the type 1 

DM community. Studying the occurrence of CD in a pediatric group alone may underestimate 

the lifetime risk of the disease that requires extended followup. We have undertaken a 

community-based study of CD in residents of Olmsted County, MN, who have type 1 diabetes 

encompassing all ages. The prior incidence of CD in this cohort of approximately 502 

individuals was just 3 individuals. Unlike many prior studies that focused on just adults or 

children, we endeavored to study all ages. Two hundred and five type 1 diabetics have been 

tested, of whom a total of 12 have CD. We estimate that there should be 30 cases of CD within 

the type 1 diabetic cohort within the community. The prevalence of CD in the type 1 diabetics is 

substantially higher than expected in the general population. Fifty percent of subjects did not 

have gastrointestinal (GI) symptoms. It would seem that DM is a rich source for discovering CD. 

Indeed, many diabetic patients undergo endoscopy to investigate the frequent GI symptoms that 

afflict type 1 diabetics. It would require little extra effort or cost to obtain duodenal biopsies at 

least once to identify CD, and the biopsy result may explain the GI symptoms for which the 

procedure has been done. It is not clear what impact that discovery may have on diabetic control 

or complications, though GI symptoms seem to improve on a gluten-free diet. Certainly our data 

do not support the hypothesis that CD is a significant risk factor in the subsequent development 

of DM. 

Iron-Deficiency Anemia and CD 

Iron is absorbed by the proximal small intestine, the site of the greatest damage in CD. 

Active CD is also associated with heme-positive stools. It is not surprising, therefore, that 

iron-deficiency anemia is a common finding in newly diagnosed CD. It also usually resolves 

with the institution of a gluten-free diet. Several studies from Europe and North America have 

suggested that iron-deficiency anemia may be the sole manifestation of CD in the absence of 

diarrhea. The association of CD may be especially high in those unresponsive to oral iron 

therapy. An Italian study of 200 consecutive adult patients presenting with iron deficiency 

revealed a 5 percent prevalence of CD. The prevalence of CD in patients referred to GI 

endoscopy for investigation of iron deficiency varies from 3 to 12 percent. These studies may be 

subject to selection bias due to referral patterns. 

Iron deficiency may be present in as many as 50 percent of individuals at the time of 

diagnosis of CD but rarely is the reason for referral. If it occurs in young women it is often 
51 

ascribed to excess menstrual loss. The persistence of anemia after menopause is a frequent 

precipitant for investigation that leads to the detection of CD. Indeed patients have undergone 

hysterectomies to treat the iron deficiency that persisted until the correct diagnosis was made. If 

the majority of subjects with CD have iron malabsorption, then many of the undiagnosed 

subjects with CD should present and be detectable in this population of anemic individuals. We 

have identified a total of 529 prevalent cases of diagnosed iron-deficiency anemia residents in 

Olmsted County in 2001. One hundred sixty-one community residents with otherwise 

unexplained anemia have undergone testing for CD, of whom 6 have been found to have CD. 

Two additional patients had possible CD based on subtle pathologic changes. Anemia was rarely 

sought or diagnosed in children. However, iron-deficiency anemia is a very common illness in 

primary care and often does not spur investigation in the younger patient. In fact hemoglobin is 

not measured routinely in children. A potential confounder is the association between 

haemochromatosis (HFE) genes and CD. 282Y was more common in CD and was associated 

with higher Hgb and iron stores. Clinicians should consider CD as a possible though not 

common cause of unexplained anemia, and gastroenterologists should biopsy the duodenum 

when endoscoping patients with iron-deficiency anemia. 

Low Bone Mass and CD 

Individuals with bone mineral density more than 2.5 standard deviations below the sexspecific peak bone mass are presumed to have osteoporosis. Low bone mass is common in 

subjects with newly diagnosed CD. The mechanism for this effect may be due to malabsorption 

of vitamin D and calcium and decreased intake of calcium due to lactose intolerance. However, 

low bone mass may be due not only to osteoporosis but also to osteomalacia. While osteomalacia 

would therefore be expected to be the bone consequence of malabsorption, osteoporosis been 

described in CD on bone biopsy. A raised alkaline phosphatase and other stigmata of 

osteomalacia may not always be present. It is possible that low bone mass is the only 

manifestation of CD in a significant proportion of patients with this disorder and consequently, 

CD may be an underdiagnosed cause of low bone mass in the general population. There are two 

ways in which the epidemiology of CD and osteoporosis has been examined. 

The first is the screening of patients with osteoporosis for CD. A limited number of 

screening studies for CD among patients with low bone mass have been performed in Europe. 

CD was found in 3.4 percent of adults with low bone mass. One Scandinavian study screened a 

pediatric population with low bone density and demonstrated a 5 percent prevalence of CD. 

However, a carefully performed Canadian study in predominantly postmenopausal women with 

osteoporosis has not identified an increased prevalence of CD. Why the difference? The early 

studies were predominantly based in serology alone without biopsy confirmation. It is also not 

clear if referral bias may have been factor. 

Our studies in a population-based setting have not identified an increased rate of CD in 

over 290 patients with osteoporosis. Initial serological tests had a high rate of low-level 

positivity to tissue transglutaminase antibodies, however followup serological tests and biopsies 

only conformed CD in 2/25 initially seropositive persons. This yielded an overall positive rate of 

only 2/290, which is close to the expected general population by screening but greater than that 

of the diagnosed rate. 
52 

The second way the association has been examined is the screening of a large population 

for CD and relating it to measured bone density. The single best study is the Cambridge health 

study, which suggested a 3-fold increased risk of osteoporosis in seropositive individuals. 

However, the attributable risk to CD was low. 

It seems, therefore, that screening those postmenopausal osteoporosis patients defined by 

World Health Organization (WHO) criteria is unhelpful. By contrast, when patients with CD are 

screened for bone disorders, many have elevated parathyroid hormone (PTH) and low calcium; it 

would be in these patients whose Z-scores are low that CD should be considered. The real 

problem lies in how osteoporosis is defined. 

While low bone mass may remain unrecognized in many individuals with CD, bone pain 

is a common symptom in untreated adult patients with CD and may reflect more subtle 

osteomalacia (see preliminary results). It is not known what consequences of low bone mass may 

occur in CD. Low bone mass usually responds to the introduction of a gluten-free diet with a 

gradual restoration of bone over 2 years. However, it remains to be known if using the Z-score as 

a guide would be a better method to determine risk of CD in this population. The finding of low 

bone density in a young person may well be a risk factor for CD but bone densitometry is not a 

routine test at this age. There is no clear increase in fracture risk in patients diagnosed with CD. 

What effect undiagnosed CD has on lifelong fracture risk is not known. 

Conclusions 

Case finding of CD is feasible in some high-risk situations. Family members are often the 

most accessible and most likely of any of these groups to have the disease. Subjects with 

symptoms suggesting CD should not only have serologic testing done but also should be 

considered for intestinal biopsy, as some family members may have intestinal damage without 

serologic evidence of the disease. Type 1 diabetics and those with iron-deficiency anemia have a 

small but significant risk of CD. What impact screening these at-risk groups will have on the 

overall detection of CD is unknown but most likely represents only a small proportion of the 

prevalent cases overall. 

Screening for CD by any method or even case finding in asymptomatic people is not 

clearly justified without data on outcome. We do not know the outcome of undiagnosed CD as it 

is present in either the at-risk groups or the larger reservoir of undetected CD in the general 

population. As CD makes such a small impact on the overall risk of osteoporosis and fractures, it 

seems unjustified to undertake systematic searching for CD to reduce the burden of bone disease. 

The Cambridge study suggests, however, that our data based on diagnosed CD may 

underestimate the impact of CD on bone disease and anemia as most CD goes undiagnosed and 

untreated. Confirmation of these results with biopsy and studies on the long-term consequence of 

undetected or untreated CD is needed. To truly understand the potential consequences of CD, 

followup may need to be lifelong or at least extend into late adult life. Such studies may be 

possible by focusing these efforts on finding CD in an older cohort or in those populations whose 

health history has been followed up long-term and serum-stored. 
53 

References 

Family History of Celiac Disease 

Corazza G, Valentini R, Frisoni M, et al. Gliadine immune reactivity is associated with overt and 

latent enteropathy in relatives of coeliac patients. Gastroenterology. 1992;103:1517–1522. 

Houlston RS. Genetics of coeliac disease. QJM. 1996 Oct; 89(10):737–743. 

Korponay-Szabó I, Kovács J, Lörincz M, Török E, Gorácz G. Families with multiple cases of 

gluten-sensitive enteropathy. Z Gastroenterol. 1998;36:553–558. 

Mallas EG, Williamson N, Cooper BT, et al. IgA class reticulin antibodies in relatives of patients 

with coeliac disease. Gut. 1977;18:647–650. 

Niveloni S, Pedreira S, Sugai E, et al. The natural history of gluten sensitivity: report of two new 

celiac disease patients resulting from a long-term follow-up of nonatrophic, first-degree relatives. 

Am J Gastroenterol. 2000 Feb;95(2):463–468. 

Pittschieler K, Gentili L, Niederhofer H. Onset of coeliac disease: a prospective longitudinal 

study. Acta Paediatr. 2003 Oct;92(10):1149–1152. 

Stenhammar L, Brandt A, Wagermark J. A family study of coeliac disease. Acta Paediatr Scand. 

1982 Jul;71(4):625–628. 

Stokes PL, Ferguson R, Holmes GK, et al. Family aspects of coeliac disease. Q J Med.

1976;45:567–582. 

Vogelsang H. Screening for celiac disease in first-degree relatives of patients with celiac disease 

by lactulose/mannitol test. Am J Gastroenterol. 1995 Oct; 90(10):1838–1842. 

Diabetes Mellitus 

Bao F, Yu L, Babu S., et al. One third of HLA DQ2 homozygous patients with type 1 diabetes 

express celiac disease-associated transglutaminase autoantibodies. J Autoimmun. 

1999;13(1):143–148. 

Collin P, Salmi J, Hallstrom O, et al. High frequency of celiac disease in adult patients with 

type-I diabetes. Scand J Gastroenterol. 1988;24:81–84. 

Fraser-Reynolds KA, Butzner JD, Stephure DK, Trussell RA, Scott RB. Use of immunoglobulin 

A-antiendomysial antibody to screen for celiac disease in North American children with type 1 

diabetes. Diabetes Care. 1998;21(11):1985–1989. 

Harnden AR, Brown RS. Insulin dependent diabetes mellitus and coeliac disease. J R Soc Med.

1991;84:436. 
54 

Koletzko S, Burgin-Wolfe A, Koletzko B, et al. Prevalence of celiac disease in diabetic children 

and adolescents. Eur J Pediatr. 1988;148:113–117. 

Maki M, Hallstrom O, Huupponen T, et al. Increased prevalence of coeliac disease in diabetes. 

Arch Dis Child. 1984;59:739–742. 

Page SR, Lloyd CA, Hill PG, et al. The prevalence of coeliac disease in adult diabetes mellitus. 

Q J Med. 1994;87:611–617. 

Rensch MJ, Merenich JA, Lieberman M, et al. Gluten-sensitive enteropathy in patients with 

insulin-dependent diabetes mellitus. Ann Intern Med. 1996;124:564–567. 

Rossi MM, Albini CH, Kumar D. Incidence of CD identified by the presence of serum 

endomysial antibodies in children with chronic diarrhea, short stature, or insulin-dependent 

IDDM mellitus. Pediatrics. 1993;123:162–164. 

Sategna-Guidetti C, Grosso S, Pulitano R, et al. Celiac disease and insulin dependent diabetes 

mellitus: Screening in an adult population. Dig Dis Sci. 1994;39:1633–1637. 

Savilahti E, Simell O, Koskinie SS, et al. CD in insulin-dependent IDDM mellitus. J Pediatr.

1986;108:690–693. 

Sigurs N, Johansson C, Elfstrand P-O, et al. Prevalence of celiac disease in diabetic children and 

adolescents in Sweden. Acta Paediatr. 1993;82:748–751. 

Talal AH, Murray JA, Goeken JA, Sivitz WI. Celiac disease in an adult population with 

insulin-dependent diabetes mellitus: use of endomysial antibody testing. Am J Gastroenterol.

1997 Aug; 92(8):1280–1284. 

Usai P, Cherchi MV, Boi MF, et al. Studio della malattia celiaca in corso di diabete mellito 

insulino dipendente e di diabete insulinoindipendente. Recenti progressi in medicina.

1989;80:56–58. 

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Q J Med. 1978;185:89–91. 

Iron-Deficiency Anemia 

Ackerman Z, Eliakim R, Stalnikowicz R, Rachmilewitz D. Role of small bowel biopsy in 

the endoscopic evaluation of adults with iron deficiency anemia. Am J Gastroenterol.

1996;91(10):2099–2102. 

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patients. Scand J Gastroenterol. 1996;31(1):54–60. 

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gene mutations in protecting against iron deficiency in celiac disease. Gastroenterology.

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55 

Carroccio A, Iannitto E, Cavataio F, et al. Sideropenic anemia and celiac disease: one study, two 

points of view. Dig Dis Sci. 1998;43(3):673–678. 

Corazza GR, Valentini RA, Andreani ML, et al. Subclinical coeliac disease is a frequent cause of 

iron-deficiency anaemia. Scand J Gastroenterol. 1995;30(2):153–156. 

Garrido C, Gaya J, Liompart A, et al. A Prevalence of monosymptomatic celiac disease in 

patients with iron deficiency anemia. Gastroenterologia y Hepatologia. 1997;20(4):172–174. 

Osteoporosis 

Bernstein CN, Leslie WD, Leboff MS. AGA technical review on osteoporosis in gastrointestinal 

diseases. Gastroenterology. 2003 Mar;124(3):795–841. 

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disorders and clinical manifestations. Dig Dis Sci. 1999 May;44(5):966–972. 

Di Stefano M, Veneto G, Corazza GR. Screening for celiac disease in idiopathic osteoporosis. 

Am J Gastroenterol. 2001 Nov;96(11):3205–3206. 

Gonzalez D, Sugai E, Gomez JC, et al. Is it necessary to screen for celiac disease in 

postmenopausal osteoporotic women? Calcif Tissue Int. 2002 Aug;71(2):141–144. 

Mather KJ, Meddings JB, Beck PL, Scott RB, Hanley DA. Prevalence of IgAantiendomysial antibody in asymptomatic low bone mineral density. Am J Gastroenterol. 

2001 Jan;96(1):120–125. 

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coeliac syndrome in osteoporotic women. J Intern Med. 2001 Oct;250(4):361–366. 
57 

Incidence and Prevalence of Celiac Disease 

Alaa Rostom, M.D., M.Sc., FRCPC 

Context

Celiac disease (CD) appears to represent a spectrum of clinical features and 

presentations. Although “classical” CD (i.e., fully developed gluten-induced villous atrophy and 

classical features of intestinal malabsorption) is most commonly described, it appears that most 

patients have atypical CD (fully developed gluten-induced villous atrophy found in the setting of 

another presentation such as iron deficiency, osteoporosis, short stature, or infertility) or silent 

CD (fully developed gluten-induced villous atrophy discovered in an asymptomatic patient by 

serologic screening or perhaps an endoscopy for another reason). The true prevalence of CD is 

difficult to estimate because of this variable presentation, particularly when many patients may 

have little or no symptoms. With this limitation in mind, there appear to be important 

geographical and ethnic differences in the reported prevalence of CD. The prevalence appears 

highest in Celtic populations where estimates of 1:300 to 1:122 have been described. In North 

America, the prevalence has been estimated to be 1:3000, but a recent American study found it to 

be 1:105 among the general not-at-risk population suggesting that the disease is 

underrecognized. 

Objectives

(1) To conduct a systematic review of the prevalence and incidence of CD in North 

American and Western European populations. (2) To assess differences in prevalence among 

different geographical regions/countries and in at-risk populations such as relatives and patients 

with type I diabetes. 

Data Sources

A comprehensive literature search was conducted by the National Library of Medicine in 

collaboration with the University of Ottawa Evidence-Based Practice Center (UO-EPC). The 

searches were run in MEDLINE (1966 to Oct 2003) and EMBASE (1974 to Dec 2003) 

databases. 

Study Selection and Data Extraction

This study was conducted using accepted systematic review methodology. Study 

selection was performed by two independent reviewers using three levels of screening with 

increasingly more strict criteria to ensure that all relevant articles were captured. Articles passing 

the third level screen fulfilled all the inclusion/exclusion criteria, allowed actual extraction of the 

prevalence and/or incidence data, and did not have fatal methodological flaws. Articles were 

excluded if the studied population was non-North American or Western European; patients were 
58 

identified by surveys or through solicitation of celiac societies; or reported incidence without a 

population density denominator. Study data was abstracted using a predetermined electronic 

form by one reviewer, and verified by another. The quality of reporting of the included studies 

was assessed. 

Data Synthesis

The prevalence and incidence data were anticipated to be quite heterogeneous 

considering the different, countries, age groups, and risk characteristics of the studied patients. 

Attempts were made to group studies by age group, study population, and serological screening 

method. If the grouped studies did not show evidence of heterogeneity, pooled estimates of the 

prevalence were produced for that group of studies; otherwise a descriptive presentation of the 

data with a qualitative systematic review was conducted. For pooled estimates, statistical 

heterogeneity was assessed along with 95 percent confidence intervals. 

Results and Conclusions

The literature search yielded 2,116 references. Of these, 119 articles, were included in the 

review. Of these studies, 42 assessed the prevalence and/or incidence of CD in a general 

population. Twelve of the 42 reported on the incidence of CD, and 30 reported on the 

prevalence. Studies of the prevalence of CD in populations at risk were divided as follows: 18 

studies of the first-degree relatives of CD patients and 34 studies in patients with type 1 diabetes. 

Studies of the prevalence of CD in patients with associated clinical presentations were divided as 

follows: 12 studies in iron-deficiency anemia, 4 studies in metabolic bone disease, and 13 studies 

of patients with suspected CD. Several studies included data for multiple at risk groups. 

Incidence

The crude incidence of CD among western European and North American countries over 

the past 25 years has varied between 1 and 51 per 100,000, and the cumulative incidence by age 

5 between 0.118 and 9 per 1,000 live births. Important methodological differences existed among 

the studies, from using patient registers to identify patients to actively screening at-risk groups. 

The true incidence of CD is likely greater than reported. 

Prevalence

The included prevalence studies demonstrated important differences in execution, tests 

for prevalence assessment, patient sampling, rates of biopsy confirmation, and histological grade 

defining CD. The prevalence of CD in the general unselected populations of North America and 

Western Europe is quite high and likely falls within the range of 0.5–1.26 percent (1:200 to 

1:79). Smaller sample-size studies tended to give wider estimates ranging from 0.17 to 

2.67 percent. Among the studies from the United States, the range of prevalence was 

0.4–0.95 percent in adults, and 0.31 percent in children. In Italy, the range of prevalence was 

between 0.2 and 0.8 percent, whereas the Scandinavian countries, Ireland, and the United 

Kingdom, tended to show a higher prevalence of CD of approximately 1.0–1.5 percent . 
59 

The prevalence of CD in patients with type 1 diabetes is higher than the prevalence in the 

general not-at-risk population. The prevalence of CD by serology varied greatly with lows near 

1 percent and highs close to 12 percent. However, the majority of studies, and particularly those 

using EMA or tTG, demonstrated prevalence rates in the 4–6 percent range. Although the 

prevalence by biopsy also varied, and was usually lower than the prevalence by serology, the 

typical study with complete biopsy confirmation of serology-positive patients demonstrated a 

prevalence in the range of 3–6 percent. 

The prevalence of CD in relatives of patients with CD is also higher than that of the 

general population, both in first- and second-degree relatives. That prevalence varied between 

2.8 and 17.2 percent in first-degree relatives and between 2.6 and 19.5 percent in second-degree 

relatives. The prevalence remains elevated among first cousins, and was 17 percent in the single 

study of these subjects. 

The prevalence of CD among patients with iron-deficiency anemia is highest (between 

10 and 30 percent) in studies of patients with GI symptoms, or in patients who have no gross 

lesions seen at an initial investigation. CD appears to also be common in premenopausal women, 

both with (4.5 percent) and without (33 percent) heavy periods. Overall, in typical asymptomatic 

IDA patients assessed by serology or biopsy, the prevalence of CD was between 2.3 and 

6 percent. 

The studies of the prevalence of CD in patients with low BMD suggest that between 

0.9 and 3 percent of patients with osteoporosis have CD. However, the included studies 

demonstrated important methodological weaknesses, and contradictory results making it difficult 

to draw any firm conclusions about the true prevalence of CD in this population. 

Overall, CD appears common in the unselected general populations of North America 

and Western Europe with a prevalence in the range of 1:100 and a proportionally higher 

prevalence in various high risk populations such as relatives of CD patients. The true prevalence 

still requires further study based on some of the identified study limitations that include 

incomplete biopsy confirmation and reliance on serological tests whose performance has not 

been fully characterized in situations of low prevalence (<15–20 percent). 
61 

Clinical Presentation of Celiac Disease 

in the Pediatric Population 

Alessio Fasano, M.D. 

Introduction 

Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of 

gluten in genetically susceptible individuals. Gluten is a protein component in wheat and other 

cereals (rye and barley), and a staple food for most populations in the world. The major 

predisposing genes are located on the HLA system, namely the HLA-DQ2 and/or DQ8 

genotypes found in at least 95 percent of patients. 

CD can manifest with a previously unsuspected range of clinical presentations and can 

present at any age, including the elderly. However, typical cases often manifest in early 

childhood. 

Clinical Spectrum of CD in Children 

The clinical spectrum of CD in children is wide(1–7) (table 1). Typical forms of CD usually 

present in young children with impaired growth, chronic diarrhea, abdominal distention, muscle 

wasting and hypotonia, poor appetite, and unhappy behavior. Within weeks to months of starting 

to ingest gluten, weight gain velocity decreases and finally weight loss can be observed. Despite 

a wide variability between countries, classical CD still represents a common presentation in the 

pediatric age group. 

Table 1. Clinical Manifestations of Celiac Disease in Pediatrics 

Clinical Form Histological and Clinical Manifestations 

Typical Fully expressed enteropathy 

Intestinal symptoms, e.g., chronic diarrhea, weight loss, abdominal distention

Atypical Fully expressed enteropathy 

Extra-intestinal manifestations, e.g., iron deficiency, short stature, osteoporosis

Silent Fully expressed enteropathy 

Minimal complaints or symptom-free (occasionally discovered by serological 

screening)

Potential Minimal changes enteropathy or normal small intestinal mucosa 

Sometimes symptomatic

 

Atypical CD is characterized by unusual intestinal complaints (e.g., irritable bowel 

syndrome–like, nausea, vomiting) or by extra-intestinal manifestations (e.g., short stature, 
62 

pubertal delay, iron deficiency, dental enamel defects, and abnormalities in liver function test). 

Atypical presentation is usually encountered in association with the late onset of complaints, 

particularly in older children. Dermatitis herpetiformis, a blistering skin disease, is presently 

regarded as a variant of CD. 

CD is defined as silent whenever a typical gluten-sensitive enteropathy is found in a 

subject who is apparently healthy. Large numbers of silent cases of CD have been reported in atrisk groups (such as subjects with insulin-dependent diabetes and first-degree relatives) and in 

general population samples enrolled in screening programs. An indepth clinical examination 

shows that many of these “silent” cases are indeed affected with a low-grade intensity illness 

often associated with decreased psychophysical well-being. 

Finally, a potential form of CD is diagnosed in subjects showing positivity of EMA 

and/or anti-tTG antibodies, the typical HLA predisposing genotype (DQ2 or DQ8), but a normal 

or minimally abnormal mucosal architecture (increased IEL count) at the intestinal biopsy. These 

cases are at risk of developing a typical CD enteropathy later in life. 

Untreated CD is associated with a list of diseases and complications(1) (table 2). The 

possible association with Down syndrome is well known. Two recent studies provided further 

evidence of an increased prevalence of CD in Down syndrome in the United States, with a 

reported frequency of this disease association of 3.2–10.3 percent, respectively.(8,9) In Down 

syndrome children, CD is not detectable on the basis of clinical findings alone and is therefore 

underdetected. Even when there are symptoms, they may be considered clinically insignificant or 

possibly attributed to Down syndrome itself. Nevertheless, the reported resolution or 

improvement of gastrointestinal complaints on a GFD for all symptomatic patients suggest that 

identification and treatment can improve the quality of life for these children. 

Table 2. Associated Diseases 

Associated Diseases Associated Diseases Possibly Secondary to Untreated CD 

Down syndrome Autoimmune diseases (e.g., type 1 diabetes, thyroiditis, hepatitis, 

primary biliary chirrosis) 

Turner syndrome Epilepsy with or without occipital calcifications 

Williams syndrome Ataxia and other neurological disturbances 

IgA deficiency IgA nephropathy 

 

An increasing number of studies show that many CD-associated problems that were 

originally described mostly in adults can indeed be observed in children or adolescents.(7)

Osteoporosis is one of the well-known complications of untreated CD in adults. Several studies 

showed that bone mineral content, bone area, and bone mineral density could be significantly 

lower in CD adolescents than in controls. Further, it has been reported that a complete recovery 

of bone density can occur after 1 year of GFD, and maintenance of normal bone mineral density 

is achieved after long-term treatment. In the last decade, there has been an explosion of interest 

on the neurological manifestations associated with CD. The existence of a syndrome 

characterized by epilepsy, occipital calcifications, and CD is generally accepted. The strong 

association with autoimmune diseases, including type 1 diabetes(10,11) and thyroid disease(11) has 
63 

been widely reported. The question regarding the possible role of an early treatment of CD on 

the development of autoimmune complications is still open for debate. While some studies 

suggest that children with untreated CD have higher than expected prevalence of organ-specific 

autoantibodies (apparently “gluten-dependent”), which tend to disappear after starting the GFD, 

others deny this cause-effect relationship.(7)

Conclusions 

CD is a common disorder in children as well as in adults. The spectrum of clinical 

presentations is wide, and currently extra-intestinal manifestations (e.g., anemia or short stature) 

are more common than the classical malabsorption symptoms. A high degree of awareness 

among health care professionals and a “liberal” use of serological CD tests can help to identify 

many of the atypical cases. The primary care physician has a central role in this process of case 

finding. 

References 

1. Fasano A, Catassi C. Current approaches to diagnosis and treatment of celiac disease: an 

evolving spectrum. Gastroenterology. 2001;120:636–651. 

2. Catassi C, Fabiani E, Ratsch IM, et al. The coeliac iceberg in Italy. A multicentre antigliadin 

antibodies screening for coeliac disease in school-age subjects. Acta Paediatr Suppl.

1996;412:29–35. 

3. Hill I, Fasano A, Schwartz R, Counts D, Glock M, Horvath K. The prevalence of celiac 

disease in at-risk groups of children in United States. Ped Res. 2000;136:86–90. 

4. Hoffenberg EJ, MacKenzie T, Barriga KJ, et al. A prospective study of the incidence of 

childhood celiac disease. J Pediatr. 2003;143:308–314. 

5. Fasano A, Berti I, Gerarduzzi T, et al. A multicenter study on the sero-prevalence of celiac 

disease in the United States among both at-risk and not-at-risk groups. Arch Int Med.

2003;163:286–292. 

6. Maki M, Mustalahati K, Kokkonen J, et al. Prevalence of celiac disease among children in 

Finland. N Engl J Med. 2003;348:2517–2524. 

7. Catassi C, Fasano A. New developments in childhood celiac disease. Curr Gastroenterol 

Rep. 2002;4:238–243. 

8. Mackey J, Treem WR, Worley G, Boney A, Hart P, Kishnani PS. Frequency of celiac disease 

in individuals with Down syndrome in the United States. Clin Pediatr. 2001;40:249–252. 

9. Book L, Hart A, Black J, Feolo M, Zone JJ, Neuhausen SL. Prevalence and clinical 

characteristics of celiac disease in Down syndrome in a U.S. study. Am J Med Gen.

2001;98:70–74. 
64 

10. Rewers M, Liu E, Simmons J, Redondo MJ, Hoffenberg EJ. Celiac disease associated with 

type 1 diabetes mellitus. Endocrinol Metab Clin North Am. 2004;33:197–214. 

11. Buysschaert M. Coeliac disease in patients with type 1 diabetes mellitus and auto-immune 

thyroid disorders. Acta Gastroenterol Belg. 2003;66:237–240. 
65 

The Many Faces of Celiac Disease: Clinical Presentation 

of Celiac Disease in the Adult Population 

Peter H. R. Green, M.D. 

The presentation of adults with celiac disease can be broadly divided in two types: the 

classical diarrhea-predominate type and the silent type in which gastrointestinal symptoms are 

not prominent.(1) The latter group includes patients that may present with secondary 

manifestations of celiac disease (e.g., anemia or osteoporosis), associated autoimmune diseases 

(type 1 diabetes or peripheral neuropathy), or associated malignancies. The silent group includes 

those that are asymptomatic, and detected by screening relatives of patients with celiac disease. 

The lag between the clinical prevalence(2) and the serologic prevalence(3) of celiac disease 

(the iceberg phenomenon) in the United States demonstrates that most people with celiac disease 

are currently not diagnosed and probably have the silent form of celiac disease. This was 

confirmed in a population-based screening study from England in which those with undetected 

celiac disease (1.2 percent of those screened) had mild anemia, osteoporosis, and low serum 

cholesterol values and considered themselves well, and had a trend to participate in less 

cardiovascular events.(4)

Celiac disease is a proximal small intestinal inflammatory disease that may involve a 

variable length of the intestine. The proximal intestine is the site of absorption of iron, calcium, 

fat-soluble vitamins, and folic acid, as well as the products of the digestion of fats, 

carbohydrates, and proteins. When limited to the proximal intestine, vitamins and minerals 

usually absorbed may be selectively malabsorbed; however, diarrhea may not occur because the 

distal small intestine can compensate and absorb the products of the digestion of fats and 

carbohydrates. The length of intestine involved is more important than the degree of villous 

atrophy present in duodenal biopsies in determining whether diarrhea will occur. Other factors 

contributing to diarrhea include a reversible pancreatic insufficiency, secondary lactose 

intolerance, and bacterial overgrowth. 

In view of the lack of information about the clinical spectrum of celiac disease in the 

United States, we conducted a survey to obtain data. Information from more than 1,600 patients 

was obtained. This study confirmed a female predominance over males (3:1). The majority of 

patients were diagnosed in their fourth to sixth decades and 85 percent presented with diarrhea. 

The mean duration of symptoms prior to diagnosis was 11 years.(5) This delay in diagnosis is not 

unique to the United States and is considered to be physician-based rather than due to delay in 

patients seeking health care.(6) A contributing factor is that patients receive alternative diagnoses 

such as an irritable bowel syndrome.(7)

Two studies have shown a relative decrease in the percent of patients presenting with 

diarrhea, though it remains the most common mode of presentation accounting for about 

50 percent of patients.(2,8) The increasing availability of serologic testing may contribute to both 

the increased rate of diagnosis and to diagnosis of patients with nondiarrheal presentations. 

Despite an increased rate of diagnosis, patients still experience a long duration of symptoms 
66 

prior to diagnosis (4.4 ± 0.6 years for those diagnosed after 1993 compared to 9.0 ± 1.1 years for 

those diagnosed prior to 1993, p<.0001).(8)

The other major modes of presentation are screening of first-degree relatives of affected 

individuals, and the recognition of endoscopic signs of villous atrophy in patients undergoing 

endoscopy for symptoms not typically associated with celiac disease—for example, esophageal 

reflux symptoms(9) or dyspepsia.(10) These symptoms often improve after initiation of a gluten-free 

diet. Other major reasons for presentation are the evaluation of iron-deficiency anemia and 

reduced bone density. 

While weight loss may be a presentation of celiac disease, many patients are in fact 

overweight.(2) Females predominate although we found men had a shorter duration of symptoms, 

more severe osteoporosis, and lower serum cholesterol values compared to women, suggesting 

more severe malabsorption. 

Celiac disease may be diagnosed at the time patients present with an associated 

malignancy. These malignancies include esophageal adenocarcinoma, small intestinal 

adenocarcinoma, or non-Hodgkin’s lymphoma.(9,11) The risk factors for the development of 

adenocarcinoma of the small intestine have not been established; however, the cancer appears to 

arise in adenomatous lesions rather than via dysplasia.(12) Patients may present with neurological 

symptoms such as peripheral neuropathy or ataxia.(13) Apthous stomatitis, detection of dental 

enamel defects, and of abnormal liver chemistries are also modes of presentation. 

Laboratory abnormalities may be the presenting manifestations of the disease. These 

include the presence of abnormalities in the blood film such as Howell-Jolly bodies or 

thrombocytosis, a manifestation of hyposplenism, hyperamylasemia due to macroamylasemia,(14)

and an elevated sedimentation rate. 

Patients with celiac disease have a 10-fold prevalence of autoimmune diseases compared 

to the general population, suggesting that people with celiac disease have an increased burden of 

illness. Frequently the associated autoimmune disease is diagnosed first, with celiac disease 

diagnosed because of serologic screening of individuals with autoimmune disorders that have an 

increased incidence of celiac disease, such as type 1 diabetes, primary biliary cirrhosis, and 

peripheral neuropathy. 

At presentation, not all patients have positive celiac serologies. Those with sero-negative 

celiac disease have identical clinical presentations, associated disorders, and response to a 

gluten-free diet as those with positive serologies.(15) Negative serologic tests are seen more often 

in patients with lesser degrees of villous atrophy.(16)

The spectrum of presentations of celiac disease is great. The vast majority of patients 

have silent celiac disease, though the associated diseases may have severe manifestations. Many 

patients have associated autoimmune diseases. 
67 

References 

1. Green PH, Jabri B. Coeliac disease. Lancet. 2003;362:383–391. 

2. Murray JA, Van Dyke C, Plevak MF, Dierkhising RA, Zinsmeister AR, Melton LJ 3rd. 

Trends in the identification and clinical features of celiac disease in a North American 

community, 1950–2001. Clin Gastroenterol Hepatol. 2003;1:19–27. 

3. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk 

groups in the United States: a large multicenter study. Arch Intern Med. 2003;163:286–292. 

4. West J, Logan RF, Hill PG, et al. Seroprevalence, correlates, and characteristics of 

undetected coeliac disease in England. Gut. 2003;52:960–965. 

5. Green PHR, Stavropoulos SN, Panagi SG et al. Characteristics of adult celiac disease in the 

USA: results of a national survey. Am J Gastroenterol. 2001;96:126–131. 

6. Lankisch PG, Martinez Schramm A, Petersen F, Droge M, Lehnick D, Lembcke B. 

Diagnostic intervals for recognizing celiac disease. Z Gastroenterol. 1996;34:473–477. 

7. Sanders DS, Carter MJ, Hurlstone DP, et al. Association of adult coeliac disease with 

irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria referred 

to secondary care. Lancet. 2001;358:1504–1508. 

8. Lo W, Sano K, Lebwohl B, Diamond B, Green PH. Changing presentation of adult celiac 

disease. Dig Dis Sci. 2003;48:395–398. 

9. Green PH, Shane E, Rotterdam H, Forde KA, Grossbard L. Significance of unsuspected 

celiac disease detected at endoscopy. Gastrointest Endosc. 2000;51:60–65. 

10. Bardella MT, Minoli G, Ravizza D, et al. Increased prevalence of celiac disease in patients 

with dyspepsia. Arch Intern Med. 2000;160:1489–1491. 

11. Green PH, Fleischauer AT, Bhagat G, Goyal R, Jabri B, Neugut AI. Risk of malignancy in 

patients with celiac disease. Am J Med. 2003;115:191–195. 

12. Rampertab SD, Forde KA, Green PH. Small bowel neoplasia in coeliac disease. Gut.

2003;52:1211–1214. 

13. Alaedini A, Green PH, Sander HW, et al. Ganglioside reactive antibodies in the neuropathy 

associated with celiac disease. J Neuroimmunol. 2002;127:145–148. 

14. Rabsztyn A, Green PH, Berti I, Fasano A, Perman JA, Horvath K. Macroamylasemia in 

patients with celiac disease. Am J Gastroenterol. 2001;96:1096–1100. 

15. Dahele A, Kingstone K, Bode J, Anderson D, Ghosh S. Anti-endomysial antibody-negative 

celiac disease: does additional serological testing help? Dig Dis Sci. 2001;46:214–221. 
68 

16. Tursi A, Brandimarte G, Giorgetti GM. Prevalence of antitissue transglutaminase antibodies 

in different degrees of intestinal damage in celiac disease. J Clin Gastroenterol.

2003;36:219–221.
69 

Association of Celiac Disease and Gastrointestinal (GI) 

Lymphomas and Other GI Cancers 

Carlo Catassi, M.D., M.P.H.

The association between celiac disease (CD) and cancer is long established. The most 

frequent malignant complication of CD is a high-grade T-cell non-Hodgkin lymphoma (NHL) of 

the upper small intestine, usually defined as enteropathy-associated T-cell lymphoma (EATL). It 

has been suggested that patients with CD carry an increased risk of developing malignancies 

other than NHL, especially small-intestinal adenocarcinoma and oesophageal and pharyngeal 

squamous carcinomas.(1) 

Recent epidemiological studies have shown that CD is one of the most common life-long 

disorders in Western countries, affecting around 1 percent of the general population. Currently, 

most cases remain undiagnosed and are exposed to the risk of long-term complications.(2) For this 

reason, the CD–cancer connection has gained a renewed interest, as this treatable disorder could 

theoretically represent a major risk factor for NHL and other malignancies. 

CD-Associated GI Cancers 

EATL is an intestinal T-cell lymphoma that peaks in the sixth decade of life. With an 

annual incidence rate of 0.5–1 per million people in Western countries, this is a rare form of 

cancer covering around 35 percent of all small bowel lymphomas.(3) By definition, this NHL 

subtype arises in patients with either previously or concomitantly diagnosed CD. Occasionally, 

CD is recognized after the diagnosis of lymphoma has been made. The EATL immunophenotype 

is consistent with a derivation from a clonal proliferation of intraepithelial lymphocytes (IEL). In 

some cases EATL represents the end-stage evolution of refractory celiac sprue (RCS). RCS is 

defined as symptomatic villous atrophy not responding to gluten-free diet (GFD) in a subject 

initially showing diagnostic features of CD. In approximately 80 percent of RCS cases, an 

abnormal clonal IEL population can be shown, frequently diffused along the intestinal tract, 

characterized by a low ratio of CD8

+

/CD3

+

 and TCR gene rearrangeme gene rearrangement. This entity should be This entity should be 

classified as “cryptic EATL” as it is associated with a high risk of ulcerative jejunitis and 

lymphomatous transformation.(4)

EATL commonly develops in the jejunum but may also be found in the ileum and lymph 

nodes, and less frequently in the stomach and the colon. It is often multifocal with ulcerative 

lesions. Extranodal presentations are not uncommon in the liver/spleen, thyroid, skin, nasal 

sinus, etc. Most patients present with malaise, anorexia, weight loss, and diarrhea, often 

associated with abdominal pain. Physical signs include fever, lymphadenopathy, skin rash, 

hepatomegaly, and a palpable abdominal mass. Approximately 50 percent of patients require 

laparotomy for complications of haemorrhage, perforation, or obstruction. The suspicion of 

EATL prompts an extensive diagnostic workup that may include upper and lower intestinal 

endoscopy, CT scan with enteroclysis, or small bowel follow through; either push or wireless 

video-capsule enteroscopy. The final diagnosis is made on either endoscopic biopsies or full 

thickness laparoscopic small bowel biopsies. The immunoistochemical study shows a large- or 

medium-size T-cell proliferation mainly expressing a CD3

+

, CD8

-

,CD103

+ phenotype. In most 
70 

patients, EATL is disseminated at diagnosis and the outlook is poor, though it may improve with 

chemotherapy and surgery. The 1-year survival has been estimated to be 30 percent while the 

5-year survival is approximately 10 percent.(5)

Different studies have shown a significant association between adenocarcinoma of the 

small intestine and CD. In the largest series of this rare tumour, an associated CD was found in 

13 percent of cases, CD being diagnosed first in 63 percent of cases (mean lag time of 8.2 years). 

CD-associated adenocarcinoma was characterized by proximal (duodeno/jejunal) localization 

and presentation with either acute (obstruction, haemorrhage) or chronic signs (anemia, 

abdominal pain, weight loss). In the majority of patients, complete surgical resection was 

possible, and the overall survival at 30 months was 58 percent.(3)

In a population-based cohort study from Sweden, an increased risk of oropharingeal 

(standardized incidence ratio = SIR of 2.3) and esophageal (SIR = 4.2) carcinomas was found in 

patients with CD on long-term followup. This work also disclosed a minimal increase of the risk 

for colorectal cancer (SIR = 1.5) which was owing to an increased risk for ascending and 

transverse but not descending colon or rectal cancer.(6)

The Magnitude of the Cancer Risk 

Pioneer studies suggested that the CD-associated relative risk (RR) of developing NHL or 

other malignancies was very high, in the range of 40–100. This issue has recently been 

reconsidered in the light of significant advances on CD epidemiology and diagnosis. 

To quantify the risk for developing NHL of any primary site associated with CD, we 

performed a case control study on 653 Italian adults with NHL at the onset using the serum IgA 

class antiendomysial antibody as the screening test. CD was diagnosed in only 6 of 653 patients 

(0.92 percent) with lymphoma. Of the six cases, three were of B-cell and three were of T-cell 

origin. Four of six cases had lymphoma primarily located in the gut. The odds ratio (adjusted for 

age and sex) for NHL of any primary site associated with CD was 3.1 (95 percent CI 1.3–7.6), 

16.9 for gut lymphoma (95 percent CI 7.4–38.7), and 19.2 for T-cell lymphoma (95 percent CI 

7.9–46.6).(7)

The Swedish cohort study found a CD-associated overall SIR of 5.9 for malignant 

lymphoma (95 percent CI 4.3–7.9). The excess occurrence of malignant lymphoma was confined 

to adults, decreased with time of followup evaluation, and decreased over successive calendar 

periods. The analysis of the causes of death in the same cohort of CD patients showed that 

mortality from all malignant neoplasm combined was elevated 70 percent and was particularly 

high for cancer of the small intestine, NHL, and liver.(6)

In summary, these new studies seem to indicate that (1) CD is associated with a 

significantly increased risk for NHL, especially of the T-cell type and primarily localized in the 

gut (EATL), and other GI cancers; (2) the CD–lymphoma association is less common than 

previously thought, the RR being much lower than 10; and (3) the CD–cancer association is 

partially responsible for the increased mortality observed in patients with CD. 
71 

Does the Gluten-Free Diet Protect From Cancer Development? 

Data on the protective effect of treatment with the GFD are somewhat conflicting. On the 

one hand, it is evident that a large proportion of EATL and other GI cancers develop in subjects 

who have been already treated for CD, sometimes for decades.(3,8) It is, however, well known that 

complete avoidance of dietary gluten is difficult, and the possible link between the protracted 

ingestion of gluten traces and cancer development has never been investigated. By contrast, 

several studies provided indirect evidence for a protective role of the GFD. In 1989, Holmes 

reported that the RR of overall cancer was not significantly elevated among those on a strict 

GFD for at least 5 years.(9) This view has found further support in studies from Finland,(10)

Sweden,(6) and Italy.(11)

Strict adherence to the GFD seems to be the only possibility of preventing, at least 

partially, a subset of rare but very aggressive forms of cancer. 

References 

1. Holmes GKT, Catassi C. Coeliac disease. Oxford (UK): Health Press, 2000. 

2. Fasano A, Catassi C. Current approaches to diagnosis and treatment of celiac disease: an 

evolving spectrum. Gastroenterology. 2001;120:636–651. 

3. Howdle PD, Jalal PK, Holmes GKT, Houlston RS. Primary small-bowel malignancy in the 

UK and its association with coeliac disease. Q J Med. 2003;96:345–353. 

4. Cellier C, Delabesse E, Helmer C, et al. Refractory sprue, celiac disease, and 

enteropathy-associated T-cell lymphoma. Lancet. 2000;356:203–208. 

5. Egan LJ, Walsh SV, Stevens FM, et al. Coeliac-associated lymphoma. A single institution 

experience of 30 cases in the combination chemotherapy era. J Clin Gastroenterol.

1995;21:123–129. 

6. Askling J, Linet M, Grindley G, et al. Cancer incidence in a population-based cohort of 

individuals hospitalised with celiac disease or dermatitis herpetiformis. Gastroenterology.

2002;123:1428–1435. 

7. Catassi C, Fabiani E , Corrao G, et al. Risk of non-Hodgkin lymphoma in celiac disease. 

JAMA. 2002;287:1413–1419. 

8. Green PH, Fleischauer AT, Bhagat G et al. Risk of malignancy in patients with celiac 

disease. Am J Med. 2003;115:191–195. 

9. Holmes GKT, Prior P, Lane MR, et al. Malignancy in celiac disease. Effect of a gluten-free 

diet. Gut. 1989;30:333–338. 

10. Collin P, Reunala T, Pukkala E, et al. Coeliac disease—associated disorders and survival. 

Gut. 1994;35:1215–1218. 
72 

11. Corrao G, Corazza GR, Bagnardi V, et al. Mortality in patients with coeliac disease and their 

relatives: a cohort study. Lancet. 2001;358:356–361. 
73 

Skin Manifestations of Celiac Disease 

John J. Zone, M.D. 

Dermatitis herpetiformis (DH) is a cutaneous manifestation of celiac disease (CD). The 

spectrum of intestinal abnormalities in DH ranges from minimal lymphocyte infiltration of the 

small intestinal epithelium in some patients to complete villous atrophy in others. Only about 

20 percent of DH patients have intestinal symptoms of CD. Both the skin disease and the 

intestinal disease respond to gluten restriction and recur with institution of a gluten-containing 

diet. It seems likely that the presence of skin disease in DH patients is a marker of CD that is 

independent of the severity of the histological CD or the severity of intestinal symptoms. The 

complications and course of CD, as manifested in DH patients, may represent the true spectrum 

of CD that would otherwise largely go undiagnosed. Study of DH therefore gives insight into the 

nature of the spectrum of CD. For this reason, I will review the consensus questions relative to 

DH and will propose that understanding DH holds the potential to a better understanding of the 

entire spectrum of CD.(1)

How is DH Diagnosed? 

Three findings support the diagnosis of DH: (1) pruritic papulovesicles on extensor 

surfaces; (2) neutrophilic infiltration of the dermal papillae with vesicle formation at the 

dermal-epidermal junction; and (3) granular deposition of IgA in the dermal papillae of clinically 

normal-appearing skin adjacent to a lesion. The last finding is present in greater than 98 percent 

of DH patients and is the gold standard for diagnosis.(2) IgA tissue transglutaminase and IgA 

endomysial antibodies are found in 70–90 percent of patients, indicating that there is a 

population of CD patients who are negative for this serum antibody. IgA antibodies to epidermal 

transglutaminase have been proposed as the causative antibody in DH.(3)

How Prevalent is DH? 

DH is most common in those of northern European descent. It is exceedingly uncommon 

in African Americans and Asians. According to a study in Finland in 1978, the prevalence of DH 

is 10.4 per 100,000 and the incidence is 1.3 per 100,000. The mean age of onset was in the fourth 

decade, but ranged from age 2 to 90. Adolescent and prepubescent children are infrequently 

affected. This later age of onset is believed to indicate a need for chronic stimulation of the 

mucosal immune system for production of the immune response that causes DH. In contrast to 

CD in the absence of DH, males outnumbered females 2:1.(4) From 1979 to 1996, the familial 

incidence of DH was studied prospectively in Finland. DH was diagnosed in 1,018 patients. 

10.5 percent of patients with DH had one or more affected first-degree relatives.(5)

Studies in Utah confirm that DH and familial DH in the United States are of comparable 

prevalence to European studies. A study of a Utah population reflects the predominant northern 

European ancestry in that area of the United States. The prevalence of DH in 1987 was 11.2 per 

100,000. The incidence for the years 1978–1987 was 0.98 per 100,000 per year. The mean age of 

onset for males was 40.1 years. The mean age of onset for females was 36.2 years. The male to 
74 

female ratio was 1.44:1.(6) In another study of a Utah population, affected DH patients were 

studied and first-degree relatives were identified with DH or CD. The increased prevalence of 

CD and DH in first-degree relatives further confirmed the familial nature of CD in a U.S. 

population.(7)

What Are the Manifestations and Long-Term Consequences of DH? 

DH is associated with other disorders and complications that likely reflect the spectrum 

of CD. Autoimmune thyroid disease occurs in 20–30 percent of the cases.(8) Insulin-dependent 

diabetes and lymphoma occur in less than 5 percent of cases, while other autoimmune diseases 

such as alopecia areata, Addison’s disease, vitiligo, and psoriasis occur infrequently. However, 

diseases such as psoriasis and alopecia areata have been reported to remit when patients adhere 

to gluten restriction, indicating a causative role for gluten in the related autoimmune disorder in 

some cases. Whether the long-term risk of autoimmune disease is reversed by gluten restriction 

is unknown. 

DH patients are subject to complications of malabsorption such as anemia at a rate that is 

believed to be less than that of symptomatic CD without skin disease. This probably reflects the 

less severe nature of the malabsorption in DH patients, since the DH population includes those 

with histologic CD without intestinal symptoms. 

Who Should Be Tested for DH? 

Patients with otherwise unexplained skin disease that is characterized by intense pruritus 

should be tested for DH by biopsy for direct immunoflourescence. In addition, serologic testing 

for endomysial antibodies of first-degree relatives has yielded a CD prevalence of 12 percent in 

our patients. Serum IgA endomysial antibodies and IgA tissue transglutaminase antibodies 

represent an index of adherence to gluten restriction in individual patients. 

What Is the Management of DH? 

The treatment includes dapsone and a gluten-free diet. The pruritus of DH is relieved 

within 48 to 72 hours of instituting oral Dapsone (4’, 4’ diamino-diphenylsuphone) therapy, and 

the lesions recur within 24 to 48 hours of discontinuation of therapy. Dapsone will adequately 

suppress but not cure the disease. It has no effect on the associated gluten sensitive enteropathy 

or its complications. Gluten restriction results in clearing of the skin disease and the intestinal 

abnormality over months to years. Reinstitution of a gluten containing diet results in recurrence 

of disease in weeks to months.(9) The skin disease is known to spontaneously remit in the absence 

of gluten restriction on rare occasions.(10)

What Are the Recommendations for Future Research on DH? 

Study of a large cohort of DH patients is likely to expand our understanding of CD. Since 

DH patients are definitively identified on the basis of their skin disease and not their intestinal 

disease, DH patients usually have mild or asymptomatic CD. Detailed study of these patients will 
75 

allow a better understanding of the complications of mild CD. Because of the response of the 

skin disease to Dapsone, many patients opt to take only Dapsone and not adhere to gluten 

restriction. This allows for longitudinal study of a population of CD patients not adhering to 

gluten restriction. Study of the pathogenesis of DH will yield further understanding of the 

mucosal immune response to gluten and the process by which IgA produces inflammation. 

References 

1. Herron MD, Zone JJ. Dermatitis herpetiformis and linear IgA bullous dermatosis. Bolognia 

JL, Jorizzo JL, and Rapini RP, eds. Dermatology. London: Mosby; 2003;479–489. 

2. Zone JJ, Meyer LJ, Petersen MJ. Deposition of granular IgA relative to clinical lesions in 

dermatitis herpetiformis. Arch Dermatol. 1996;132:912–918. 

3. Sardy M, Karpati S, Merkl B, Paulsson M, Smyth N. Epidermal transglutaminase (TGase 3) 

is the autoantigen of dermatitis herpetiformis. J Exp Med. 2002;195(6):747–757. 

4. Reunala T, and Lokki J. Dermatitis herpetiformis in Finland. Acta Dermatovener.

(Stockholm). 1978;58:505–510. 

5. Reunala T. Incidence of familial dermatitis herpetiformis. Br J Dermatol. 1996;134(3):394–398. 

6. Smith JB, Tulloch JE, Meyer LJ, Zone JJ. The incidence and prevalence of dermatitis 

herpetiformis in Utah. Arch Dermatol. 1992;128:1608–1610. 

7. Meyer LJ, Zone JJ. Familial incidence of dermatitis herpetiformis. J Am Acad Dermatol.

1987;17:643–647. 

8. Cunningham MJ, Zone JJ. Thyroid abnormalities in dermatitis herpetiformis: prevalence of 

clinical thyroid disease and thyroid antibodies. Ann Intern Med. 1985;102:194–196. 

9. Leonard J, Haffenden G, Tucker W, et al. Gluten challenge in dermatitis herpetiformis. 

N Engl J Med. 1983;308:816–819. 

10. Bardella MT, Fredella C, Trovato C, et al. Long-term remission in patients with dermatitis 

herpetiformis on a normal diet. Br J Dermatol. 2003;149(5):968–971. 
77 

Neurological/Psychological Presentation of Celiac Disease: 

Ataxia, Depression, Neuropathy, Seizures, and Autism 

Khalafalla O. Bushara, M.D. 

Celiac disease (CD) has long been associated with a wide spectrum of neurological and 

psychiatric disorders including cerebellar ataxia, peripheral neuropathy, myositis, epilepsy, 

dementia, psychosis, and depression.(1–4) Earlier reports have mainly documented the involvement 

of the nervous system as a complication of prediagnosed CD. However, more recent studies 

emphasized that neurological syndromes may be the presenting extra-intestinal manifestation of 

gluten sensitivity with or without intestinal pathology.(5,6) These include migraine, 

encephalopathy, chorea, brain stem dysfunction, myelopathy, mononeuritis multiplex, Guillian 

Barre-like syndrome, and neuropathy with positive antiganglioside antibodies.(7–10) It has further 

been suggested that gluten sensitivity (as evidenced by high antigliadin antibodies) is a common 

cause of neurological syndromes (notably cerebellar ataxia) of otherwise unknown etiology.(11)

However, further studies showed high prevalence of gluten sensitivity in genetic 

neurodegenerative disorders such as hereditary spinocerebellar ataxia and Huntington’s 

disease.(12,13) It remains unclear whether gluten sensitivity contributes to the pathogenesis of these 

disorders or whether it represents an epiphenomenon. 

The mechanisms of nervous system pathology in association with gluten sensitivity is 

currently unclear. Nervous system involvement is unlikely to be due to malabsorption-related 

deficiencies.(14) Although few studies suggested immunological mechanisms, most studies 

showed no evidence for a direct immune-mediated insult to the nervous system.(1,11,15)

Studies of gluten-free diet in patients with gluten sensitivity and neurological syndromes 

showed variable results. In few patients, gluten-free diet was reported to result in improvement 

of neurological deficits while in the majority of patients reported, gluten-free diet had no 

significant effect.(1,11) Gluten-free diet trials have also been inconclusive in autism and 

schizophrenia; two diseases in which sensitivity to dietary gluten has been implicated. 

Further studies are clearly needed to assess the efficacy of gluten-free diet and to address 

the underlying mechanisms of nervous system pathology in gluten sensitivity. 

References 

1. Cooke W, Smith W. Neurological disorders associated with adult coeliac disease. Brain.

1966; 89(4):683–722. 

2. Collin P, Pirttila T, Nurmikko T, Somer H, Erila T, Keyrilainen O. Celiac disease, brain 

atrophy, and dementia. Neurology. 1991;41(3):372–375. 

3. Finelli PF, McEntee WJ, Ambler M, Kestenbaum D. Adult celiac disease presenting as 

cerebellar syndrome. Neurology. 1980;30(3):245–249. 
78 

4. Henriksson KG, Hallert C, Walan A. Letter: Gluten-sensitive polymyositis and enteropathy. 

Lancet. 1976;2(7980):317. 

5. Hermaszewski RA, Rigby S, Dalgleish AG. Coeliac disease presenting with cerebellar 

degeneration. Postgrad Med J. 1991;67(793):1023–1024. 

6. Luostarinen L, Pirttila T, Collin P. Coeliac disease presenting with neurological disorders. 

Eur Neurol. 1999;42(3):132–135. 

7. Wills AJ, Turner B, Lock RJ, Johnston SL, Unsworth DJ, Fry L. Dermatitis herpetiformis 

and neurological dysfunction. J Neurol Neurosurg Psychiatry. 2002;72(2):259–261. 

8. Hadjivassiliou M, Chattopadhyay AK, Davies-Jones GA, Gibson A, Grunewald RA, Lobo 

AJ. Neuromuscular disorder as a presenting feature of coeliac disease. J Neurol Neurosurg 

Psychiatry. 1997;63(6):770–775. 

9. Gabrielli M, Cremonini F, Fiore G, et al. Association between migraine and Celiac disease: 

results from a preliminary case-control and therapeutic study. Am J Gastroenterol.

2003;98(3):625–629. 

10. Shill HA, Alaedini A, Bushara K, Latov N, Hallett M. Anti-ganglioside antibodies in 

idiopathic and hereditary cerebellar degeneration. Neurology. 2003;60(10):1672–1673. 

11. Hadjivassiliou M, Grunewald RA, Chattopadhyay AK, et al. Clinical, radiological, 

neurophysiological, and neuropathological characteristics of gluten ataxia. Lancet.

1998;352(9140):1582–1585. 

12. Bushara KO, Nance M, Gomez CM. Antigliadin antibodies in Huntington’s disease. 

Neurology. 2004;62(1):132–133. 

13. Bushara KO, Goebel SU, Shill H, Goldfarb LG, Hallett M. Gluten sensitivity in sporadic and 

hereditary cerebellar ataxia. Ann Neurol. 2001;49(4):540–543. 

14. Ward ME, Murphy JT, Greenberg GR. Celiac disease and spinocerebellar degeneration with 

normal vitamin E status. Neurology. 1985;35(8):1199–1201. 

15. Dick DJ, Abraham D, Falkous G, Hishon S. Cerebellar ataxia in coeliac disease—no 

evidence of a humoral aetiology. Postgrad Med J. 1995;71(833):186. 
79 

Should Children Be Screened for Celiac Disease? 

Is There Evidence To Support the 

Strategy of Screening All Children? 

Edward J. Hoffenberg, M.D. 

The identification of accurate serologic markers for celiac disease (CD) provides a tool to 

study at-risk groups as well as whole populations. Although the ability to conduct widespread 

screening is evident, the wisdom of such an endeavor needs evaluation. 

How should the question of screening children be evaluated? Guides published 

30–40 years ago provide a framework still relevant today for CD screening.(1,2) Adapting from 

these sources, eight criteria relevant to screening children for CD merit consideration. 

Important Health Problem: Serious, Prevalent 

The prevalence of CD approaches 0.5–1 percent of the U.S. general population.(3,4) Most 

cases have no or mild symptoms and are identifiable only by screening. Whether all forms of CD 

have the same long-term consequences (i.e., osteoporosis, intestinal malignancy) has not been 

determined. Whether screening-identified CD represents a “serious” problem similar to that of 

clinically identified CD requires further study. 

Diagnostic Criteria Accepted and Widely Available 

The “ESPGN criteria” developed for the clinical diagnosis of CD requires characteristic 

histologic findings on small bowel biopsy plus a response to therapy with a strict gluten-free diet. 

This response may be improvement of symptoms or of intestinal injury.(5) Problems with this 

definition include patchiness of intestinal injury; expertise in histologic interpretation; 

assumption of compliance with a strict gluten-free diet; subjectivity in the assessment of 

symptomatic improvement (and specific to screening-identified CD, absence of symptoms); and 

poor acceptance of followup biopsy. 

Diagnostic criteria which incorporate autoantibody assays need updating. To address this 

need, algorithms for the evaluation of screening- and clinically-identified CD have recently been 

developed and will need validation and acceptance.(6)

Screening Tests Available, Acceptable, Reliable, and Valid 

The antitransglutaminase antibody screening test (TG) is widely available. In the clinical 

setting, TG has a sensitivity of 95–100 percent for biopsy confirmation of CD. But in screening 

at-risk populations, the predictive value lingers around 75 percent.(7) It is unknown whether 

biopsy negative cases represent false-positive TG results, false-negative biopsy results, mild 

disease (celiac autoimmunity without villous atrophy), or early “latent” CD. The significant 

variability among commercial tests is also an issue. Cutoffs, usually derived using well 
80 

characterized, clinically-identified adult cases, may require adjustment (i.e., higher cutoff values) 

for use in population screening. 

There is some evidence that TG expression can be transient or intermittent, although this 

phenomenon seems to be rare.(8,9) The significance of a single positive TG test should not be 

overestimated. An attractive model based on type 1 diabetes autoimmunity demonstrates that 

susceptible individuals may proceed through a period of TG expression and possibly even mild 

intestinal injury on the way to tolerance or frank disease. 

Disease Natural History, Transition to Declared Disease 

The natural history of screening-identified CD has not been determined, and tools do not 

exist for predicting or detecting the transition to declared disease. Initial prospective studies 

assessing the impact of TG seropositivity on growth and nutrition(10) and on outcome in type 1 

diabetes(11) are under way. Studies published to date are small, poorly controlled, underpowered, 

and provide no consensus. 

Agreement on Whom To Treat, and Benefit of Earlier Treatment 

The benefit of treating clinically identified CD includes normalization of intestinal 

absorptive function and bone mineralization as well as reduction in the risk for malignancy. It is 

assumed that this benefit also applies to screening-identified CD and provides the rationale for 

screening at-risk groups.(6) Given the lack of information, the benefit of “early” or “preventive” 

treatment of CD is controversial. 

Accepted Treatment 

The gluten-free diet is effective and available, but requires ongoing commitment. 

Adolescents with screening-identified CD seem less likely to comply with this diet than those 

with clinically-identified CD.(12) The benefit of reduced gluten intake and the likely compliance 

rates need to be factored into the decision to conduct screening. 

Cost/Benefit 

Cost/benefit analyses of early diagnosis and treatment of CD are lacking. 

Repeat Testing 

There is some data that seroconversion develops in childhood over time, at each 

increment in time.(3) The optimal age at which to begin testing and the frequency of repeat testing 

are unclear. It seems likely that testing school-age children will identify a large proportion of 

cases, but that retesting to detect late cases will be needed. 
81 

Conclusions 

In the clinical setting, serological screening of children for CD is highly accurate. 

Currently, there is no evidence to support screening all children for CD. Screening of at-risk 

children looks attractive but needs further study. Standardization of screening tests, assessment 

of appropriate cutoffs for screening, and algorithms for the evaluation of cases identified on 

screening are needed. 

Areas for Further Study 

(1) Clarify the natural history of CD and TG seropositivity (to assess the benefit of early 

or preventive treatment) in general, and on type 1 diabetes outcome specifically. (2) Standardize 

definitions and algorithms for evaluation of screening-identified CD. (3) Identify methods to 

predict progression to frank disease; possible factors include gene dosage, diet, modifier genes, 

environmental factors, TG quantitation, etc. (5) Analyze the cost/benefit/harm in screening, the 

optimal age to begin screening, and frequency of repeat screening. (6) Standardize methods for 

screening (tests, cutoffs) children. 

References 

1. Frankenburg WK. Selection of diseases and tests in pediatric screening. Pediatrics.

1974;54:612–616. 

2. Wilson JM, Jungner YG. Principles and practice of mass screening for disease. Bol Oficina 

Sanit Panam. 1968;65:281–393. 

3. Hoffenberg EJ, MacKenzie T, Barriga KJ, et al. A prospective study of the incidence of 

childhood celiac disease. J Pediatr. 2003;143:308–314. 

4. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk 

groups in the United States: A large multicenter study. Arch Intern Med. 2003;163:286–292. 

5. Revised criteria for diagnosis of coeliac disease. Report of Working Group of European 

Society of Paediatric Gastroenterology and Nutrition. Arch Dis Child. 1990;65:909–911. 

6. Hill ID, Dirks M, Liptak G, et al. Guideline for the diagnosis and treatment of celiac disease 

in children: recommendations of the North American Society for Pediatric Gastroenterology, 

Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2004;in press. 

7. Hoffenberg EJ, Bao F, Eisenbarth GS, et al. Transglutaminase antibodies in children with a 

genetic risk for celiac disease. J Pediatr. 2000;137:356–60. 

8. Maki M, Mustalahti K, Kokkonen J, et al. Prevalence of Celiac disease among children in 

Finland. N Engl J Med. 2003;348:2517–2524. 

9. Liu E, Bao F, Barriga K, et al. Fluctuating transglutaminase autoantibodies are related to 

histologic features of celiac disease. Clin Gastroenterol Hepatol. 2003;1:356–362. 
82 

10. Hoffenberg EJ, Emery LM, Barriga KG, et al. Clinical features of children with screeningidentified evidence of celiac disease. Pediatrics. 2004;113(5):1254–1259. 

11. Freemark M, Levitsky LL. Screening for celiac disease in children with type 1 diabetes: two 

views of the controversy. Diabetes Care. 2003;26:1932–1939. 

12. Fabiani E, Taccari LM, Ratsch IM, Di Giuseppe S, Coppa GV, Catassi C. Compliance with 

gluten-free diet in adolescents with screening-detected celiac disease: A 5-year follow-up 

study. J Pediatr. 2000;136:841–843. 
83 

Should Adults Be Screened for Celiac Disease? 

What Are the Benefits and Harms of Screening? 

Pekka Collin, M.D., Ph.D. 

Recent epidemiological studies have shown that the prevalence of celiac disease (CD) is 

as high as 1 percent in both the United States and in Europe.(1,2) The prevalence of detected 

disease is much lower, from 0.27 percent to 0.02 percent.(3,4) This means that for every patient 

with a diagnosis of CD, 3–10 patients with CD remain undetected. Symptoms of the disorder are 

diverse, and the disease is often asymptomatic.(1,2) Without active serologic screening, most cases 

of CD may remain undiagnosed. Recent serologic screening assays, especially the IgA-class 

tissue transglutaminase antibody test, are sufficiently inexpensive, sensitive, and specific to 

allow even mass screening for CD. The disease satisfies the criteria for mass screening and 

theoretically there are many standpoints favoring such an approach. CD is associated with many 

severe complications that can be prevented by gluten-free dietary treatment. The question 

remains whether we should apply screening to all adults or only to certain risk groups. 

The risk of small-intestinal lymphoma is increased in CD.(5) In retrospective and 

cross-sectional studies, dietary treatment has been shown to prevent the malignant 

development.(6) However, there is no evidence as yet to suggest that patients with mild or only 

subtle symptoms run an increased risk of lymphoma. There is, in fact, indirect evidence to the 

contrary; undetected CD has not proved a significant factor in the etiology of lymphoma.(7) Some 

cases may be detected by severe neurological disorders such as ataxia, without any symptoms 

indicative of CD.(8) However, such complications are rare and prevention of neurological 

sequelae does not justify mass screening. 

Screening has been advocated in order to prevent malabsorption. Again, the evidence is 

scarce. Subclinical osteoporosis occurs in undetected patients with CD, even in asymptomatic 

subjects.(9,10) The prevention of osteoporosis seems to be the strongest indicator for widespread 

screening today. It has also been hypothesized that early gluten-free dietary treatment might 

prevent the development of autoimmune conditions in CD.(11) The issue is controversial,(12) and 

does not therefore justify mass screening. 

Screening asymptomatic individuals for CD may be harmful. A lifelong gluten-free diet 

is not easy to maintain, and the subject’s quality of life may deteriorate. It is also debatable 

whether patients found by active screening adhere to a gluten-free diet similarly to symptomatic 

ones. In type 1 diabetes, it may be problematic to combine a diabetic and a celiac diet. Whether a 

gluten-free diet is of benefit or harm in celiac patients without symptoms and malabsorption is 

thus controversial. Screening is also costly; apart from serologic testing, even a small loss of 

specificity will result in numerous “useless” endoscopies. Compulsory testing would also entail 

ethical problems. 

CD is a common disorder with a specific treatment. Increased alertness should be 

observed in at-risk patients. Serologic screening should be applied in individuals with even 

subtle indicative symptoms such as subclinical isolated iron deficiency. In various autoimmune 

conditions the risk of CD is approximately 5 percent,(13) and in individuals with affected 

first-degree relatives, 15 percent. Infertility, neurological symptoms such as polyneuropathia, 
84 

ataxia, epilepsy with posterior cerebral calcification, and osteoporosis are conditions for which 

CD should be borne in mind. Elevated aminotransferases and possible liver failure can lead to a 

diagnosis of CD.(14,15) The recommendation for screening is depicted in the table below. 

Table 1. Screening for Celiac Disease in Adults 

Screening indicated, 

small-intestinal biopsy in 

selected cases 

Screening indicated, always 

when even subtle symptoms 

consistent with CD Screening not indicated 

Malabsorption, isolated iron 

deficiency 

Family history of CD Population in general 

(enrollment in clinical studies 

indicated) 

Infertility Autoimmune thyroid disease Acute short-term abdominal 

symptoms 

Osteoporosis Sjögren’s syndrome Atopic symptoms 

Ataxia and polyneuropathy Type 1 diabetes* Type 1 diabetes** 

Arthritis of unknown etiology Addison’s disease 

Chronic liver disease of unknown 

etiology 

Any gastrointestinal symptoms 

Suspicion of dermatitis 

herpetiformis (consider skin 

biopsy) 

 

Irritable bowel syndrome 

*With and **without any symptoms indicative of celiac disease. 

In conclusion, evidence today does not support mass screening. More research is needed 

to assess the cost-effective benefits of mass screening. The occurrence of osteoporosis and the 

effects of a gluten-free diet should be investigated in a large group of symptom-free patients. 

Dietary compliance and quality of life before and after a gluten-free diet should likewise be 

evaluated. 

References 

1. Mäki M, Mustalahti K, Kokkonen J, et al. Prevalence of celiac disease among children in 

Finland. N Engl J Med. 2003;348:2517–2524. 

2. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk 

groups in the United States: A large multicenter study. Arch Intern Med. 2003;163:286–292. 

3. Collin P, Reunala T, Rasmussen M, et al. High incidence and prevalence of adult coeliac 

disease. Augmented diagnostic approach. Scand J Gastroenterol. 1997;32:1129–1133. 

4. Talley NJ, Valdovinos M, Petterson TM, Carpenter HA, Melton L Jr. Epidemiology of celiac 

sprue: a community-based study. Am J Gastroenterol. 1994;89:843–846. 
85 

5. Green PH, Fleischauer AT, Bhagat G, Goyal R, Jabri B, Neugut AI. Risk of malignancy in 

patients with celiac disease. Am J Med. 2003;115:191–195. 

6. Holmes GKT, Prior P, Lane MR, Pope D, Allan RN. Malignancy in coeliac disease—effect 

of a gluten-free diet. Gut. 1989;30:333–338. 

7. Catassi C, Fabiani E, Corrao G, et al. Risk of non-Hodgkin lymphoma in celiac disease. 

JAMA. 2002;287:1413–1419. 

8. Hadjivassiliou M, Grunewald RA, Chattopadhyay AK, et al. Clinical, radiological, 

neuropscyhological, and neuropathological characteristics of gluten ataxia. Lancet.

1998;352:1582–1585. 

9. Cellier C, Flobert C, Cormier C, Roux C, Schmitz J. Severe osteopenia in symptom-free 

adults with a childhood diagnosis of coeliac disease. Lancet. 2000;355:806. 

10. Mustalahti K, Collin P, Sievänen H, Salmi J, Mäki M. Osteopenia in patients with clinically 

silent coeliac disease warrants screening. Lancet. 1999;354:744–745. 

11. Ventura A, Magazu G, Gerarduzzi T, Greco L. Coeliac disease and the risk of autoimmune 

disorders. Gut. 2002;51:897–898. 

12. Sategna Guidetti C, Solerio E, Scaglione N, Aimo G, Mengozzi G. Duration of gluten 

exposure in adult coeliac disease does not correlate with the risk of autoimmune disorders. 

Gut. 2001;49:502–505. 

13. Collin P, Kaukinen K, Välimäki M, Salmi J. Endocrinological disorders and celiac disease. 

Endocrine Reviews. 2002;23:464–483. 

14. Volta U, De Franceschi L, Lari F, Molinaro N, Zoli M, Bianchi FB. Coeliac disease hidden 

by cryptogenic hypertransaminasemia. Lancet. 1998;352:26–29. 

15. Kaukinen K, Halme L, Collin P, et al. Celiac disease in patients with severe liver diseases: 

gluten-free diet may reverse hepatic failure. Gastroenterology. 2002;122:881–888. 
87 

Consequences of Testing for Celiac Disease 

Ann Cranney, M.D., M.Sc. 

Context 

The prevalence of silent cases of celiac disease (CD) may be eight times that of 

classically symptomatic CD, and it is important to determine if the consequences of testing and 

the response to treatment differs by mode of diagnosis, and clinical presentation. 

Objective 

To conduct a systematic review of the expected consequences of testing for CD in the 

following populations: (a) patients with symptoms suggestive of CD, (b) asymptomatic at-risk 

populations, and (c) the general population. 

Data Sources 

A comprehensive literature search was conducted by the National Library of Medicine 

in collaboration with the University of Ottawa Evidence-Based Practice Center (UO-EPC). The 

searches were run in MEDLINE (1966–Oct 2003), EMBASE (1974–Dec 2003), CAB 

(1972–Dec 2003), PsycINFO (1840–2003), AGRICOLA (1970–2003), and Sociological 

Abstracts (1963–2003). 

Study Selection and Data Extraction 

This review was conducted using accepted systematic review methodology. Two 

independent reviewers selected the articles using three levels of screening. The strategy included 

articles that dealt with the consequences of testing for CD. We did not include articles that dealt 

with consequences addressed in celiac objectives one and two (e.g., cases diagnosed, 

false-positive results, invasive procedures [biopsies], and followup testing). Full data extraction 

was conducted on all articles that met the level 3 screening requirements by one reviewer and 

then verified by a second reviewer. The quality of the included studies was assessed. Outcomes 

included: (1) nutritional parameters (body composition and anthropometrics), anemia, and 

diabetic control; (2) compliance with a gluten-free diet (GFD); (3) costs; and (4) other clinical 

endpoints ( [a] osteoporosis and [b] mortality). 

Data Synthesis 

The studies identified dealt primarily with small populations of symptomatic individuals 

and not all studies reported clinical presentation in detail. The number of studies evaluating 

outcomes in asymptomatic, screen-detected patients was small, and it was difficult to determine 

if outcomes differed by population and clinical presentation. The majority of studies evaluating 
88 

consequences in asymptomatic at-risk populations pertained to studies of type 1 diabetics 

screened for CD. Few studies correlated the histological grade at biopsy with a change in 

outcomes. 

Results 

The search identified 1,199 potentially relevant citations. After 3 levels of screening, 

35 published studies fulfilled all the eligibility criteria. Sixteen relevant articles were identified 

from other celiac objectives in addition to a search on osteoporosis/CD, for a total of 51 studies. 

The search strategy did not identify any studies that would allow us to address the specific 

benefits and harms of testing with different strategies for CD. 

Body Composition/Anthropometrics 

In general, body composition and anthropometric parameters such as weight, body mass 

index (BMI), and fat mass improved after starting a GFD in symptomatic populations of CD. 

Individuals with CD on a strict GFD may have a lower BMI due to lower daily energy intakes. 

Anemia 

The studies evaluating the impact of a GFD on anemia demonstrated an improvement on 

a GFD with some studies linking recovery to improvement in villous atrophy. Iron-deficiency 

anemia improved 6–12 months after starting a GFD, but results indicated that iron deficiency 

(ferritin levels) may take longer to resolve. 

Diabetic control 

Diabetic control as measured by HbA1c levels did not improve after the institution of a 

GFD, although an improvement in body composition parameters was noted. 

Compliance 

Studies that assessed the outcome of compliance with a strict GFD in adolescent 

populations suggested that diagnosis in early childhood or symptomatic clinical presentation 

were associated with significant improvements in compliance with the GFD. 

Costs 

There were five studies that evaluated the costs of different screening strategies and only 

one contained the majority of the components that are recommended for the reporting of 

cost-effectiveness analyses.(1)
89 

Osteoporosis/Fractures 

There were 11 articles that evaluated bone mineral density (BMD) in individuals with CD 

and 6 controlled studies that assessed the outcome of fracture. Most studies documented an 

increased prevalence of osteopenia in newly diagnosed celiacs. One study found that femoral 

neck BMD was significantly lower in symptomatic celiacs.(2)

 In the majority of studies, a variable but significant increase in BMD was noted after 

1 year on a GFD. The issue of fracture prevalence in CD was controversial with some studies 

finding an increased rate of fractures and other studies not noting an increased risk. Difference in 

methodologies including sample size, study populations, and ascertainment of fractures could 

account for differences in fracture risk. The risk of fracture appeared to be highest prior to the 

diagnosis of CD. Moreno et al. found that the risk of fracture was not increased in subclinical 

and silent cases of CD in contrast to symptomatic cases.(2) Additional population based fracture 

studies in subpopulations of celiac individuals would help clarify risk of fracture. 

Mortality 

Seven studies evaluating mortality were included and the majority demonstrated an 

increase in the overall mortality rate for CD when compared with the general population 

(SMR = ≥ 2). Mortality rate was increased with longer delays in diagnosis and poor compliance 

with the GFD. Corraro et al. found that mortality was not increased when compared to the 

general population in those with mild symptoms or those who were asymptomatic at 

presentation.(3)

Conclusions 

Based on our literature review, the consequences of testing and identifying symptomatic 

CD patients can have a positive impact on patient relevant outcomes such as improved body 

composition, nutritional status, bone mineral density, and fractures. This improvement is in part 

due to the superior compliance that is seen in individuals with symptomatic CD. The data on 

consequences are less clear for asymptomatic at-risk populations and individuals identified 

through population screening programs. Although some studies suggest a lower risk of 

complications in asymptomatic individuals identified through screening, it is premature to 

conclude that the risks of complications are lower. At present, there is inadequate evidence from 

the published literature on the magnitude of the benefits and harms of screening the general 

population and the potential risks of undetected CD. Further research, including comprehensive 

economic evaluations, are recommended to adequately address the consequences of screening in 

both asymptomatic at-risk groups and the general population. 

References 

1. Canadian Coordinating Office of Health Technology Assessment (CCOHTA) Guidelines for 

Economic Evaluation of Pharmaceuticals: Canada, 2nd edition, 1997. 
90 

2. Moreno ML, Vazquez H, Mazure R, Smecuol E, Niveloni S, Pedreira S, et al. Stratification 

of bone fracture risk in patients with celiac disease. Clinical Gastroenterol Hepatol. 

2004;2:127–134. 

3. Corrarao G, Corrazza GR, Bagnardi V, Brusco G, Ciacci C, Cottone M, et al. Mortality in 

patients with celiac disease and their relatives: a cohort study. Lancet. 2001;358:356–61. 
91 

Dietary Guidelines for Celiac Disease and Implementation 

Cynthia Kupper, R.D., C.D. 

Medical nutrition therapy is the only accepted treatment for celiac disease (CD). It is a 

strict, gluten-free diet (GFD) for life. The GFD avoids the storage proteins from wheat, rye, 

barley, and hybrids of these grains, such as kamut and triticale. Historically, rice, corn, and 

potato were substitutes for gluten-containing grains. Today a number of nutrient-dense grains, 

seeds, legumes, and nut flours offer increased variety, improved palatability, and higher 

nutritional quality to the GFD. These grains and seeds include amaranth, buckwheat, flax, Indian 

rice grass, millet, tef, quinoa, and sorghum. 

The inclusion of oats and wheat starch in the GFD is controversial with no clear-cut 

guidelines for their use. Short- and long-term studies involving children and adults during the 

last decade suggest oats can be included safely in the GFD.(1–3) Størsrud found the use of oats 

increased the patient’s intake of iron, dietary fiber, thiamin, and Zn.(3). However, oats in the GFD 

are not widely recommended in the United States and Canada, due to concerns of unacceptably 

high levels of cross-contamination. A study by Lundin in Norway confirms that contamination of 

commercial oats can vary widely. Lundin found contamination levels between <1.5 ppm to 

>400 ppm in commercial oats. In the sample with the highest levels, it was difficult to determine 

the source of contamination, but Lundin suspects barley, not wheat, as the source. Testing of the 

“bottom of the bag” of the same product found contamination of <1.5 ppm. Further, Lundin 

demonstrated that even pure oats caused villous atrophy and dermatitis in at least one patient. 

This may be a rare situation but does cause concern.(4) Research supports that oats may be 

acceptable for the majority but not all patients with CD. At this time, there are no U.S. studies 

available to assess the potential contamination of commercial oats. Continued research is 

warranted. 

Wheat starch is used in some European countries as part of the GFD. A food product is 

considered GF by Codex Standards if it contains less than 0.05 grams (g) nitrogen per 100 g dry 

product matter. GF products containing wheat starch therefore may contain as much as 40–60 

mg gluten/100 g dry product. According to Codex Standards, wheat starch must contain not more 

than 0.3 percent protein in the dry matter. European GFDs containing wheat starch meet Codex 

Standards. Research on the use of strict GFDs containing wheat starch is limited; however, 

research by Peräaho et al. and Kaukinen et al. indicates no differences in villous architecture, 

density of intra-epithelial lymphocytes, serum antibodies, bone mineral density, or quality of life 

in patients choosing a strict wheat starch–containing GFD versus a natural GFD.(5,6) Complaints 

of adverse gastrointestinal (GI) symptoms were limited but did not alter the patient’s chosen diet. 

A study by Faulkner-Hogg et al. suggests the trace amounts of gluten allowed by the Codex 

Standards may be responsible for continued symptoms seen in some patients and that a 

“no-detectable” gluten GFD may be required in these patients.(7) Selby et al. found no differences 

between patients on a Codex GFD and those on a no-added-gluten GFD. He suggests factors 

other than trace amounts of gluten may cause continued villous atrophy in some patients.(8)

Wheat starch is not currently accepted in the United States or Canada. Based on definition of GF 

and tolerance studies, its addition seems to be worth consideration. 
92 

Worldwide, there is debate about the accepted definition for what constitutes 

“gluten-free.” Canadian standards state less than 20 ppm gluten, while other countries use 

200 ppm, and still others prefer a double standard for products rendered GF and those naturally 

GF. This debate fuels confusion about labeling products GF. The current Codex Standard for 

“Gluten-Free Foods” was adopted by the Codex Alimentarius Commission in 1976 and amended 

in 1983. In this document, gluten is defined as those proteins commonly found in wheat, triticale, 

rye, barley, or oats. The definition came under review in the1990s. As of the 25th Session of the 

Codex Alimentarius Commission, the definition of gluten-free continues to remain at Step 7 

while the committee awaits research on the scientific basis for the establishment of a tolerance 

level and a method of detection is clarified.(9,10) The Working Group on Prolamin Analysis and 

Toxicity is currently evaluating a sandwich R5-ELISA system as proposed by the Codex 

Alimentarius Commission. This new system has good reproducibility (8.7 percent) and 

repeatability (7.7 percent). In a study by Valdés et al.,(11) the R5-ELISA was able to identify 

gliadins, hordeins, and secalins sensitivities of 0.78, 0.39 and 0.39 ng/ml, respectively. The 

assay’s detection limit was 1.56 ppm gliadins, 3.2 ppm gluten.(12) Acceptance of R5-ELISA by the 

Codex Commission and results of ongoing research on tolerance levels will allow the 

Commission to advance towards a revised definition of gluten-free. The American Dietetic 

Association (ADA), in conjunction with the Dietitians of Canada, revised the GFD guidelines in 

2000. These guidelines are based on the best available information at the time. Currently the 

ADA is involved in a National Gluten-Free Diet Project to review these guidelines and provide 

evidence-based analysis.(13) 

Numerous studies document the impact of nutrient malabsorption caused from CD. 

Intestinal motor function caused by nutrient malabsorption may be partially responsible for the 

delayed gastric emptying seen in children in a study by Perri et al.(14) Bona et al. shows low 

dietary intake or malabsorption of B-vitamins, iron, and folic acid appear partially responsible 

for delayed puberty in children with CD.(15) Jameson(16) reports a correlation between zinc 

deficiencies and the severity of villous atrophy in adults. He also reports that the more 

pronounced the lesion, the lower the levels seen for iron, copper, folate, and vitamin B-12. 

Hallert et al. assessed the total plasma homocysteine levels in patients following a GFD. 

Compared to controls, persons following a GFD showed poorer vitamin status for folate, vitamin 

B-6, and vitamin B-12, even when taking nutrient supplements.(17) Studies report an incidence of 

4 percent anemia in the patients with newly diagnosed CD in the United States. While vitamin 

B-12 deficiency is not unusual in CD, pernicious anemia is considered uncommon.(18,19) Recovery 

from iron-deficiency anemia is possible with GFD alone.(20) Bone disease in CD of adults and 

children is well documented in the literature. Calcium, vitamin D, magnesium, and fiber are 

also limited in the GFD. In the United States, very few GF products are enriched, as are 

wheat-containing products, adding to the increased possibility of nutrient deficiencies. GF 

products, without enrichment, are lower in fiber, iron, folate, thiamin, riboflavin, and niacin.(12,21)

Some patients report additional food sensitivities. 

In an Italian study of body composition and dietary intakes of adults with CD following a 

strict GFD, weight and body mass index of patients with CD was significantly lower than that of 

controls, as was fat and lean body mass. Bone mineral content of women diagnosed as adults was 

significantly lower than controls. The diet of these patients was unbalanced and had a higher 

percentage of calories from fat and less from carbohydrates.(22) A study by Mariani et al. showed 

similar results of the nutritional analysis of children with CD. They found the children 

complying with a strict GFD had significantly greater nutrition imbalance in their diet than did 
93 

children cheating on their GFD. More troubling is that the incidence of children overweight or 

obese in the strict GFD group was more frequent (72 percent), compared to the children not 

following a strict GFD (51 percent), and only 47 percent in the healthy age-matched control 

group.(23)

Due to the nutritional inadequacies and potential health concerns caused by CD, a 

qualified dietitian must be an integral part of the health care team. When properly instructed by a 

dietitian with expert knowledge, the GFD can be nutritionally adequate, allow healing and return 

to good health, decrease risk of associated health conditions, as well as allow catch-up growth in 

children. Historically, training for dietitians in CD and GFD was limited. Because of the limited 

access of qualified dietitians, patient support organizations took on the role of making and 

revising diet recommendations, restrictions, and guidelines used in the United States, often 

without scientific, evidence-based qualifications for the changes. Over time, these modifications 

have caused a great deal of confusion for patients and may have added to increased 

noncompliance. Within the ADA today is a specialty group of dietitians involved in CD. It is 

important that patients receive medical nutrition therapy from dietitians knowledgeable about 

this disease. The diet is complicated and can be overwhelming if not presented using a proactive 

approach. A patient’s current nutritional status, instruction in the GFD, and correction of 

nutritional deficiencies and complications must be addressed by nutrition experts to help 

minimize additional complications of malnutrition and malabsorption, as well as noncompliance. 

Studies indicate that compliance to the GFD is compromised by a number of factors, including a 

lack of education. In a study by Ciacci, dietary compliance and the extent of intestinal damage on 

followup examination could be predicted by baseline education.(24) This study supports the need 

for frequent reinforcement and accurate explanation of dietary recommendations. Medical 

nutrition therapy is currently the only treatment for management of CD. Maintaining an optimal 

nutritional state with a GFD and avoidance of potential complications caused from inadequate 

care and treatment can be difficult. It is important that regular nutritional therapy be a part of 

management of CD; that access to care is readily available to all patients; that initial and routine 

followup nutrition therapy not is limited; and that insurance reimbursement is available. 

References 

1. Hoffenberg EJ, Haas J, Drescher A, et al. A Trail of Oats in Children with Newly diagnosed 

Celiac Disease. J Pediatr. 2000;137:361-366. 

2. Janatuinen EK, Kemppainen TA, Julkunen RJ, et al. No harm from five year ingestion of 

oats in coeliac disease. Gut. 2002 Mar;50(3):332-335. 

3. Størsrud S, Hulthén LR, Lenner RA. Beneficial effects of oats in the gluten-free diet of adults 

with special reference to nutrient status, symptoms and subjective experiences. Br J Nutr.

2003 Jul;90(1):101-107. 

4. Lundin KEA, Nilsen EM, Scott HG, et al. Oats Induced Villous Atrophy in Coeliac Disease. 

Gut. 2003;52:1649-1652. 

5. Kaukinen K, Collin P, Holm K, et al. Wheat Starch-Containing Gluten-Free Flour Products 

in the Treatment of Coeliac Disease and Dermatitis Herpetiformis. Scand J Gastroenterol.

1999;34(2)163-169. 
94 

6. Peräaho M, Kaukinen K, Paasikivi K, et al. Wheat-starch-based gluten-free products in the 

treatment of newly detected coeliac disease: prospective and randomized study. Aliment 

Pharmacol Ther. 2003 Feb 15; 17(4):587-594. 

7. Faulkner-Hogg KB, Selby WS, Loblay RH. Dietary Analysis in Symptomatic Patients with 

Coeliac Disease on a Gluten-Free Diet: the Role of Trace Amounts of Gluten and NonGluten Food Intolerances. Scan J Gastroenterol. 1999(8):784-789. 

8. Selby WS, Painter D, Collins A, Faulkner-Hogg KB, Loblay RH. Persistent mucosal 

abnormalities in coeliac disease are not related to the ingestion of trace amounts of gluten. 

Scand J Gastroenterol. 1999 Sep;34(9):909-914. 

9. Codex Standard For “Gluten-Free Foods.” Codex Stan 118-1981 (amended 1983). 

10. Draft Revised Standard for Gluten Free Foods. Report of the Joint FAO/WHO Food 

Standards Programme Codex Alimentarius Commission, Twenty-fifth Session. Rome, 

30 June-5 July 2003; para 9-10. 

11. Valdés I, García E, Llorente M, Méndez E. Innovative approach to low-level gluten 

determination in foods using a novel sandwich enzyme-linked immunosorbent assay 

protocol. Eur J Gastroenterol Hepatol. 2003 May;15(5):465-474. 

12. Thompson T. Folate, Iron and dietary fiber contents of the gluten-free diet. J Am Dietetic 

Assoc. 2000;100(11):1389–1396. 

13. Manual of Clinical Dietetics 6th Edition. American Dietetic Association, 2000. 

14. Perri F, Pastore M, Zicolella A, Annese V, Quitadamo M, Andriulli A. Gastric emptying of 

solids is delayed in celiac disease and normalizes after gluten withdrawal. Acta Paediatr.

2000;89:921–925. 

15. Bona G, Marinello D, Oderda G. Mechanisms of abnormal puberty in coeliac disease. Horm 

Res. 2002;57(suppl 2):63–65. 

16. Jameson S. Coeliac Disease, insulin-like growth factor, bone mineral density, and zinc. 

Scand J Gastroenterol. 2000;35:894–896. 

17. Hallert C, Grant C, Grehn S, et al. Evidence of Poor Vitamin Status in Coeliac Patients on a 

Gluten-Free Diet for 10 Years. Aliment Pharmacol Ther. 2002;16:1333–1339. 

18. Dahele A, Ghosh S. Vitamin B12 deficiency in untreated celiac disease. Am J Gastroenterol.

2001 Mar;96(3):745–750. 

19. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of Celiac Disease in At-Risk and Not-AtRisk Groups in the United States. Arch Intern Med. 2003;163:286–292. 

20. Annibale B, Severi C, Chistolini A, et al. Efficacy of gluten-free diet alone on recovery from 

iron-deficiency anemia in adult celiac patients. Am J Gastroenterol. 2001 Jan;96(1):132–137. 
95 

21. Thompson T. Thiamin, riboflavin, and niacin contents of the gluten-free diet: Is there cause 

for concern? J Am Dietetic Assoc. 1999;99(7):858–862. 

22. Bardella MT, Fredella C, Prampolini L, Molteni N, Giunta AM, Bianchi PA. Body 

composition and dietary intakes in adults celiac disease patients consuming a strict 

gluten-free diet. Am J Clin Nutr. 2000 Oct;72(4):937–939. 

23. Mariani P, Viti MG, Montuori M, et al. The gluten-free diet: a nutritional risk factor for 

adolescents with celiac disease? J Pediatr Gastroenterol Nutr. 1998 Nov;27(5):519–523. 

24. Ciacci C, Cirillo M, Cavallaro R, Mazzacca G. Long-Term Follow-Up of Celiac Adults on 

Gluten-Free Diet: Prevalence and Correlates of Intestinal Damage. Digestion. 2002;66:178–185. 
97 

How To Provide Effective Education and Resources: 

Gluten-Free Diets 

Shelley Case, R.D. 

A strict gluten-free diet (GFD) for life is the only treatment for celiac disease (CD). 

Successful management of CD requires (1) a team approach, including the person with CD, 

family, physicians, a registered dietitian, a celiac support group, and caregivers; (2) an 

individualized approach; (3) an understanding of quality-of-life issues; (4) use of evidencebased, current information and resources; and (5) regular followup to monitor compliance and 

nutritional status, as well as additional information and support.(3,16)

Once a diagnosis is made, the physician must clearly communicate, with a positive and 

optimistic attitude, an overview of CD and strongly emphasize the importance of a GFD for 

life.(16) It is essential that the physician initiate an immediate referral to a registered dietitian with 

expertise in CD for nutritional assessment, diet education, meal planning, and assistance with the 

social and emotional adaptation to the new gluten-free lifestyle.(2,7,15,16) A delay in referral, or no 

referral at all, increases the likelihood of the patient obtaining inaccurate information from the 

Internet, health food stores, alternative health practitioners, family, friends, and other sources, 

often resulting in confusion and frustration. The physician and dietitian should also encourage 

the patient to join a local and/or national celiac group for ongoing support, as patients who are 

active members are usually more knowledgeable and compliant with their diet.(16) The registered 

dietitian is the most qualified health care professional to provide medical nutrition therapy 

(MNT). Table 1 presents a summary of the nutritional assessment, education, and followup of 

newly diagnosed individuals with CD. 

Gluten-Free Diet and Quality of Life 

Dietary change requires modification of lifelong eating habits and adoption of new food 

habits. This can be a challenge for most patients with CD, as wheat and wheat-based products are 

major staples in the North American diet. Hectic lifestyles have resulted in more meals eaten 

away from home and reliance on prepackaged convenience foods. In addition, the cost of GF 

specialty foods is significantly higher than that of gluten-containing foods, and obtaining these 

specialty foods is difficult for some patients. 

Many studies have investigated the impact of CD and following a GFD on the quality of 

life in adults(4,6,8–10) and children(11,17) with varying results. In addition, several studies have looked 

at specific lifestyle issues and their effect on the patient’s ability to follow the GFD in 

adults(5,8,12,14) and children with CD.(18) A significant number of adults with CD report difficulties 

following the GFD, especially when eating out in restaurants, at social functions, and while 

traveling. Determining the GF status of foods, finding GF foods, and planning and cooking GF 

meals also interfere with their family life and career. Children often feel left out of activities at 

school or friends’ homes, are embarrassed to bring GF foods to parties, and are angry about 

having to follow a special diet. 
98 

Table 1. Nutrition Assessment and Education For Celiac Disease 

Complete Nutritional Assessment 

Anthropometrics Height, weight, body mass index, pediatric growth charts, skin, hair, nails 

Tests/Labs Celiac antibody and endoscopy results, bone density results, Hgb, Hct, Iron, Transferrin, 

Ferritin, TIBC, B12, Folate, Albumin, Chol, HDL, LDL, Sodium, Potassium, Calcium, other 

tests (e.g., hydrogen breath test) 

Symptoms Review Abdominal pain, bloating, gas, diarrhea, constipation, fatigue, bone/joint pain, depression, 

other 

Medical Associated symptoms or related illnesses (e.g., lactose intolerance, osteopenia, 

osteoporosis, anemia, diabetes, other food intolerances), medications, supplements, herbs, 

alternative therapies, family history 

Diet Hx./Food Record (1) Nutrient composition (look for adequate kcal, protein, B complex, vitamin D, calcium, 

iron, fiber, fluids) 

(2) Lifestyle Issues: Shopping and food preparation issues, cooking experience, willingness 

and time to cook, use of convenience foods, food preferences, eating away from home 

(e.g., restaurants, school, work), financial determinants, ethnic and religious belief 

considerations 

Social/Emotional 

Assessment 

Query response to diagnosis and diet, knowledge, readiness to learn, motivation, family 

support, literacy level 

Education 

1. Explanation of celiac disease, definition and role of gluten 

2. GFD instruction: 

a. Grains and flours allowed/to avoid 

b. Label reading, including safe and unsafe ingredients and hidden sources of gluten 

c. Variety of foods allowed, meal planning guidelines, nutritionally balanced eating 

d. Nutritional issues (e.g., iron, calcium, vitamin D, B vitamins, fiber, enrichment) 

e. Nutrition supplements as needed 

f. Shopping, cross-contamination issues, recipes, substitutions, how to use gluten-free grains 

g. Eating out, travel, how to deal with family and friends 

h. List of manufacturers of gluten-free foods and local stores that carry gluten-free foods 

3. Resources: Books, cookbooks, newsletters, magazines, Web sites, celiac support group contact information 

 (local and national) 

Followup 

1. Encourage patient to return for regular followup assessment, modifications to treatment plan, and further 

 information 

2. Schedule appointments based on patient’s need and/or interest 

3. Instruct patient to call with questions or concerns 

4. Communicate pertinent information to physician(s) 

Adapted from Anne Lee, R.D., Celiac Disease Center at Columbia University in the American Dietetic Association Clinical 

Connections, 2003.(15) 
99 

In order to effectively counsel individuals with CD, physicians and dietitians must 

understand the emotional and psychological impact of the disease and diet, as well as the 

complex quality-of-life issues patients and their families face on a daily basis, and offer practical 

advice and specific strategies to help them successfully follow the GFD.(5,14) 

Poorly Controlled/Nonresponsive Celiac Disease 

It is critical to conduct a systematic review of nonresponsive CD, as several factors may 

be responsible for poor control, such as intentional and/or unintentional gluten ingestion and 

co-existing gastrointestinal conditions (e.g., lactose intolerance, bacterial overgrowth, 

microscopic colitis, collagenous colitis, enteropathy-associated T-cell lymphoma and refractory 

sprue).(1,3,7,20) The most common cause of nonresponsive CD is gluten ingestion, either intentional 

or unintentional.(1,4,7,13) Therefore, it is essential that the patient have ongoing followup and 

education with a dietitian experienced in CD. Better dietary compliance can reduce the risk of 

further complications and associated health care costs. 

Sources and Quality of Information 

Patients seek information on CD and the GFD from a variety of sources including health 

professionals, celiac support groups, health food stores, alternative health practitioners, the 

Internet, libraries, dietetic associations, food companies, and the media. Unfortunately, patients 

frequently receive outdated, inaccurate, and/or conflicting information from some of these 

sources, resulting in patients unnecessarily restricting certain foods and thus limiting the variety 

and nutritional quality of their diet. Several studies have reported on the perceived quality of 

information that patients receive from different sources.(5,8,12,14,19) The majority of adults surveyed 

reported a high level of confidence in the information provided by celiac support groups; 

however, gastroenterologists, dietitians, and family physicians received significantly lower 

ratings. 

Access to Information 

As MNT is the only treatment for CD, it is essential that newly diagnosed patients be 

referred to a dietitian. Case (2004 unpublished) conducted an online and/or telephone survey of 

96 dietitians in the United States and Canada to ascertain referral procedures and practices. 

Although CD is considered to be a high priority by the majority of the dietitians, with patients 

being seen within 1–2 weeks of referral in both the United States and Canada, many patients are 

not always referred to a dietitian for MNT. Another major concern in the United States is the 

limited or lack of reimbursement for MNT by insurance companies. Most patients must pay for 

the service, which can range from $60–$295/hour with an average rate of $92/hour. Some 

patients are unwilling or unable to afford the counseling and are seeking alternative sources of 

information and education. 

Resources 

There are numerous resources available to patients and health professionals from a wide 

variety of sources such as celiac support groups (Celiac Disease Foundation, Gluten Intolerance 
100 

Group, Celiac Sprue Association, Canadian Celiac Association); self-help books (Danna Korn, 

Shelley Case, Tricia Thompson, Nancy Patin Falini, Bonnie Kruszka, LynnRae Ries); cookbooks 

(Bette Hagman, Carol Fenster, Connie Sarros, Karen Robertson, Donna Washburn, Rebecca 

Reilly, Roben Ryberg, Sheri Sanderson); and magazines (Gluten-Free Living, Living Without). 

Recommendations 

Additional training on CD and its dietary treatment at the undergraduate, 

internship/residency, and practicing levels for dietitians, physicians, nurses, and other allied 

health professionals is essential. Dietetic and medical associations need to establish specific 

MNT protocols for CD and offer CPE programs at national and regional conferences, as well as 

practical online and print resources. It is important that dietitian consultations providing MNT 

for CD be covered by insurance for initial and followup nutrition management. Enhanced and 

more comprehensive food labeling regulations are necessary so that patients can make informed 

decisions when purchasing foods. Greater cooperation and collaboration among celiac support 

groups is required to ensure that consistent, evidence-based information is being disseminated to 

patients, health professionals, the media, and others, as well as a strong, unified voice when 

lobbying Government for enhanced labeling regulations and MNT coverage for CD 

management. The food industry needs further education and training for staff about CD and the 

GFD. 

References 

1. Abdulkarim A, Burgart L, See J, Murray J. Etiology of nonresponsive celiac disease: results 

of a systematic approach. Am J Gastroenterol. 2002;97:2016–2021. 

2. American Gastroenterological Association medical position statement: celiac sprue. 

Gastroenterology. 2001;120:1522–1525. 

3. Ciacci C, Cirillo M, Cavallaro R, Mazzacca G. Long-term follow-up of celiac adults on 

gluten-free diet: prevalence and correlates of intestinal damage. Digestion. 2002;66:178–185. 

4. Ciacci C, D’Agate C, De Rosa A, et al. Self-rated quality of life in celiac disease. Dig Dis 

Sci. 2003;48:2216–2220. 

5. Cranney A, Zarkadas M, Graham, I, Switzer C. The Canadian celiac health survey—the 

Ottawa chapter pilot. BMC Gastroenterol. 2003;3:8. 

6. Fera T. Affective disorders and quality of life in adult coeliac disease patients on a 

gluten-free diet. Eur J Gastroenterol Hep. 2003;15:1287–1293. 

7. Green P, Jabri B. Coeliac disease. Lancet. 2003;362:383–391. 

8. Green P, Stavropoulos S, Panagi S, Goldstein S, et al. Characteristics of adult celiac disease 

in the USA: results of a national survey. Am J Gastroenterol. 2001;96:126–131. 
101 

9. Hallert C, Granno C, Hulten S, Midhagen G, Strom M, Svensson H, Valdimarsson T. Living 

with coeliac disease: controlled study of the burden of illness. Scand J Gastroenterol.

2002;37:39–42. 

10. Hallert C, Granno C, Grant C, et al. Quality of life of adult coeliac patients treated for 10 

years. Scand J Gastroenterol. 1998;33:933–939. 

11. Kolstern M, Koopman H, Schalekamp G, Mearin M. Health-related quality of life in children 

with celiac disease. J Pediatr. 2001;138:593–595. 

12. Lamontagne P, West G, Galibois I. Quebecers with celiac disease: analysis of dietary 

problems. Can J Diet Prac Res. 2001;62:175–181. 

13. Lardizabal A, Nieman L, Hefle S. Immunochemical analysis of various foods and food 

ingredients for detectable gluten content: implications for wheat-allergic and celiac sprue 

patients. J Allergy Clin Immunol. 2004;13:A297. 

14. Lee A, Newman J. Celiac diet: its impact on quality of life. J Am Diet Assoc.

2003;103:1533–1535. 

15. Lee A. Nutritional assessment and care of celiac disease. American Dietetic Association 

Clinical Connections. Winter 2003. 

16. Murray J. The widening spectrum of celiac disease. Am J Clin Nutr. 1999;69:354–365. 

17. Mustalahti K, Lohiniemi S, Collin P, Vuolteenaho N, Laippala P, Maki M. Gluten-free diet 

and quality of life in patients with screen-detected celiac disease. Eff Clin Pract. 

2002;5:105–113. 

18. Rashid M, Cranney A, Graham I, et al. Canadian celiac health survey: pediatric data. J 

Pediatr Gastroenterol Nutr. 2003;37:A127. 

19. Tidwell D, Bomba A. Attitude of people with celiac disease towards dietitians and medical 

nutrition therapy. J Am Diet Assoc. 2001;101:A29. 

20. Tursi A, Brandimarte G, Giorgetti G. High prevalence of small intestinal bacterial 

overgrowth in celiac patients with persistence of gastrointestinal symptoms after gluten 

withdrawal. Am J Gastroenterol. 2003;98:839–843. 
103 

The Followup of Patients With Celiac Disease— 

Achieving Compliance With Treatment 

Michelle Maria Pietzak, M.D. 

Once an individual has been diagnosed with celiac disease (CD) and received appropriate 

counseling about the gluten-free diet (GFD), how can the physician measure compliance? Prior 

to the advent of serology, the diagnosis of CD was based upon criteria published in 1970 by the 

European Society of Paediatric Gastroenterology, Hepatology and Nutrition.(1) This confirmed 

CD by histology showing intestinal healing after being on a GFD, with biopsy documented 

recurrence of damage after a gluten challenge. Revised criteria were published in 1990, which 

stated that the diagnosis was definitive in those over the age of 2 years who had initial 

characteristic histologic findings and clinical resolution of symptoms following the institution of 

a GFD. Repeat biopsy was not necessary.(2) Despite these recommendations in pediatric patients, 

recent studies have shown utility of repeat biopsies in adults. Intestinal damage has been 

significantly associated with poor dietary compliance, presence of serum anti-endomysial IgA 

antibodies (EMA), and low plasma albumin.(3) Despite a good clinical response to a GFD, 

abnormal endoscopic and histopathologic appearances persisted in 77 percent of adult CD 

patients in New York—even in those reporting compliance. Abnormalities included reduced and 

scalloped folds, mucosal nodularity and fissures, and partial or total villous atrophy.(4) The 

American Gastroenterological Association medical position statement recommended a repeat 

biopsy as early as 4 to 6 months after starting the GFD to assess improvement.(5)

The EMA titer was originally proposed to be indirectly related to mucosal recovery.(6)

However, there is not agreement in the literature that EMA is a reliable marker in monitoring 

compliance or histologic response to treatment. EMA+ in CD patients on a GFD has been 

reported to vary from 0 to 68 percent.(7) Of 53 initially EMA+ patients in Belfast, EMA was 

undetectable in 58 percent after 3 months, in 75 percent after 6 months, and in 87 percent after 

12 months on the GFD.(8) However, only 40 percent of all seronegatives had complete villous 

recovery by 12 months, and only 33 percent with subtotal or total villous atrophy remained 

EMA+. Several researchers believe that EMA negativity reflects the absence of gluten in the diet 

in those who were initially positive, but is not a predictor of mucosal damage, and that biopsy 

remains the best tool to measure villous injury.(9–11)

The reliability of tissue transglutaminase IgA antibodies (tTG) as a predictor of 

compliance in CD has also been examined. In Switzerland and Sweden, TTG levels correlated 

with the duration of the GFD, and tTG normalized for most patients after 1 year GF. 

Furthermore, elevated tTG and EMA could be detected 3–12 months after a gluten challenge.(12)

TTG values were strongly related to compliance in one Italian study,(13) and tTG better correlated 

with reported compliance than with intestinal biopsy morphology, suggesting that an accurate 

dietary interview with tTG testing be done before a repeat biopsy. 

The highest rates of compliance are reported for patients diagnosed with CD at a very 

young age. In Sweden, while 80 percent of adults who had been diagnosed with CD prior to 

4 years of age were compliant, only 36 percent were complaint of those who were older than 

4 years at diagnosis.(14) In France and Belgium less than half of the adults with CD strictly 
104 

adhered to the GFD after more than 1 year.(15) Reasons for transgressions included poor 

palatability of GF foods, absence of symptoms after “cheating,” high cost of the GFD, and the 

nonspecified presence of gluten or erroneous affirmation of gluten absence in foods and 

medications. Only 56–83 percent of teenagers with CD are considered to be on a strict GFD,(16–18)

while the reported adult compliance has varied between 17 percent and 45 percent.(19,20) Patients 

diagnosed with CD via serologic mass screening in Italy showed more EMA+ and lower 

compliance in comparison to age-matched patients diagnosed with “classic” symptoms during 

childhood.(21) Less than one-fourth of these patients followed a strict GFD, while 23 percent had 

returned to a normal diet after 5 years. 

Women with CD perceive a greater burden of illness, and express less satisfaction with 

the outcome of treatment. Women are also more concerned about needing more knowledge about 

CD, interference with socializing, and the possibility that their children could get CD. Both sexes 

express bitterness over not being diagnosed earlier, believing that this could have led to better 

outcomes.(22) For many persons with CD, the major complaints are general poor health, fatigue, 

and a feeling of decreased well-being.(23) These symptoms may improve once the patient starts a 

GFD.(24) Corrao et al. published that the overall mortality in adult CD patients was double that of 

the general population, and that a delay in diagnosis, poor adherence to treatment, and severity of 

symptoms at presentation unfavorably affected patients’ outlook.(25) The GFD has been shown to 

improve the quality of life even in patients with symptomless CD.(26) Patients at the time of CD 

diagnosis express fear, anger, anxiety, and sadness. Anger can worsen the patient–clinician 

relationship and has been inversely correlated with dietary compliance.(27)

In the United States, food labeling does not clearly state whether gluten is present in 

a product. The American Celiac Task Force made its debut in March 2003 

(http://capwiz.com/celiac/home/) to advocate for changing the food labeling law. In March 2004, 

the Senate passed the “Food Allergen Labeling and Consumer Protection Act.” Similar 

legislation was introduced into the House in December 2003. These bills require food 

manufacturers to clearly state if a product contains the top eight food allergens (including wheat) 

and calls for the Food and Drug Administration to issue rules defining and permitting the term 

“gluten-free” on food labeling. 

The management of CD primarily consists of monitoring for compliance and 

complications. The patient should follow up with the gastroenterologist who performed the 

biopsy once the results confirm CD, and be referred to a dietitian knowledgeable about the GFD 

(figure 1). Patients should be encouraged to join local chapters of national support organizations, 

which can aid in finding local resources such as supermarkets, food manufacturers, literature, 

and restaurants that are familiar with the GFD. Patients should be screened for nutritional 

deficiencies that can accompany this malabsorptive disorder and monitored for complications, 

including osteoporosis, neurologic complaints, other autoimmune diseases, refractory sprue, 

ulcerative enteritis, T-cell lymphoma, and other GI cancers. Numerous studies have documented 

low bone density in children and adults at the time of initial diagnosis of CD, which improves 

with the GFD.(28–31) Children should be examined for protein–calorie malnutrition, linear growth 

failure, and delayed puberty. First- and second-degree relatives should be offered screening for 

CD with serum antibodies. 
105 

Refer to support 

group 

Gluten-free diet 

counseling 

Education about 

resources 

Doing poorly: 

Elevated antibodies 

Clinical symptoms 

Nutritional deficiencies

Doing well:

Antibodies normal 

No clinical symptoms

Refer to dietitian 

Patient with newly diagnosed celiac 

disease 

Screen first- and second-degree relatives for CD

Screen for nutritional deficiencies: 

Bone density, PTH 

CBC, iron studies, folate, Vitamins A, E, D 

electrolytes, albumin, total protein 

liver enzymes, PT 

Vitamins A, E, 25OH D

Followup visit in 3–6 months to discuss 

compliance with diet, monitor for complications 

and signs of other autoimmune diseases 

First followup visit 1–2 weeks after 

endoscopy with gastroenterologist

Figure 1. An Approach to the Management of a Patient With Newly Diagnosed 

 Celiac Disease 

1 year after gluten-free diet 

Check serum antibodies annually 

Screen for nutritional deficiencies 

Examine for signs and symptoms of other 

autoimmune diseases

Followup with gastroenterologist or 

primary care practitioner 
106 

Patient education, close supervision by an interested physician, and regular dietary counseling by 

a dietitian are the most important factors in achieving dietary compliance.(32) Compliance is 

improved, even in adolescents, who are seen by a physician on regular basis.(33,34) Dietary 

compliance assessed by a trained interviewer is the best marker of CD control due to low cost, 

noninvasivity, and a strong correlation to intestinal damage. It will also reinforce the need for 

strict adherence to a GFD and educate the subjects in the avoidance of gluten-containing foods. 

Future research must be directed at finding alternatives to the GFD, which will in turn 

increase compliance with treatment. These future potential treatments may include the 

development of genetically detoxified grains, an oral or intranasal “celiac vaccine” to induce 

tolerance, inhibitors of the effects of zonulin on intestinal permeability,(35) or detoxification of 

immunogenic gliadin peptides via oral peptidase supplement therapy.(36)

References 

1. Meeuwisse GW. Diagnostic criteria in coeliac disease. Acta Paediatr Scand. 1970;59:461–

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2. European Society of Paediatric Gastroenterology and Nutrition. Revised criteria for diagnosis 

of coeliac disease. Report of Working Group of European Society of Paediatric 

Gastroenterology and Nutrition. Arch Dis Child. 1990;65:909–911. 

3. Ciacci C, Cirillo M, Cavallaro R, Mazzacca G. Long-term follow-up of celiac adults on 

gluten-free diet: prevalence and correlates of intestinal damage. Digestion. 2002;66:178–185. 

4. Lee SK, Lo W, Memeo L, Rotterdam H, Green PH. Duodenal histology in patients with 

celiac disease after treatment with a gluten-free diet. Gastrointest Endosc. 2003;57:187–191. 

5. American Gastroenterological Association medical position statement: celiac sprue. 

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7. Ferreira M, Lloyd Davies S, Butler M. Endomysial antibody: is it the best screening test for 

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patients. Br Med J. 1975;1:486–488. 

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gluten-free diet. Gut. 1991;32:881–885. 

19. Kluge F, Koch HK, Grosse-Wilde H, Lesch R, Gerok W. Follow-up of treated adult celiac 

disease: Clinical and morphological studies. Hepatogastroenterology. 1982;29:17–23. 

20. Bardella MT, Molteni N, Prampolini L, Giunta AM, Baldassarri AR, Morganti D. Need for 

follow-up in coeliac disease. Arch Dis Child. 1994;70:211–213. 

21. Fabiani E, Taccari LM, Rätsch I-M, Di Giuseppe S, Coppa GV, Catassi C. Compliance with 

gluten-free diet in adolescents with screening-detected celiac disease: a 5-year follow-up 

study. J Pediatr. 2000;136:841–843. 

22. Hallert C, Grännö C, Hultén S, et al. Living with coeliac disease: controlled study of the 

burden of illness. Scand J Gastroenterol. 2002;37:39–42. 

23. Hallert C, Derefeldt T. Psychic disturbances in adult coeliac disease. Clinical observations. 

Scand J Gastroenterol. 1982;17:17–19. 

24. Fabiani E, Catassi C, Villari A, Gismondi P, Pierdomenico R, Rätsch IM. Dietary 

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1996;412:65–67. 

25. Corrao G, Corazza GR, Bagnardi V, et al. for the Club del Tenue Study. Group mortality in 

patients with coeliac disease and their relatives: a cohort study. Lancet. 2001;358:356–361. 
108 

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