Celiac Disease. Table of Contents. Introduction...2 Epidemiology...2 Genetics and Pathogenesis...3 Clinical Approach...4 Summary...8 References...

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1 pediatric gastroenterology Board Review Manual Statement of Editorial Purpose The Hospital Physician Pediatric Gastroenterology Board Review Manual is a study guide for fellows and practicing physicians preparing for board examinations in pediatric gastroenterology. Each manual reviews a topic essential to the current practice of pediatric gastroenterology. PUBLISHING STAFF PRESIDENT, Group PUBLISHER Bruce M. White editorial director Debra Dreger SENIOR EDITOR Robert Litchkofski Associate EDITOR Tricia Faggioli EDITORial assistant Farrawh Charles executive vice president Barbara T. White executive director of operations Jean M. Gaul PRODUCTION Director Suzanne S. Banish PRODUCTION associate Kathryn K. Johnson ADVERTISING/PROJECT manager Patricia Payne Castle sales & marketing manager Deborah D. Chavis NOTE FROM THE PUBLISHER: This publication has been developed without involvement of or review by the American Board of Pediatrics. Endorsed by the Association for Hospital Medical Education Celiac Disease Editor: Elizabeth B. Rand, MD Associate Professor of Pediatrics, University of Pennsylvania School of Medicine; Medical Director, Liver Transplant Program; Director, Fellowship Training Program, Division of Gastroenterology, Hepatology & Nutrition, The Children s Hospital of Philadelphia, Philadelphia, PA Contributors: Muralidhar Jatla, MD Instructor, University of Pennsylvania School of Medicine; Fellow, Division of Gastroenterology, Hepatology & Nutrition, The Children s Hospital of Philadelphia, Philadelphia, PA Ritu Verma, MD Section Chief, Clinical Gastroenterology, The Children s Hospital of Philadelphia, Philadelphia, PA Table of Contents Introduction Epidemiology Genetics and Pathogenesis Clinical Approach Summary References Cover Illustration by Christine Armstrong Copyright 2007, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA ,. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications. The preparation and distribution of this publication are supported by sponsorship subject to written agreements that stipulate and ensure the editorial independence of Turner White Communications. Turner White Communications retains full control over the design and production of all published materials, including selection of appropriate topics and preparation of editorial content. The authors are solely responsible for substantive content. Statements expressed reflect the views of the authors and not necessarily the opinions or policies of Turner White Communications. Turner White Communications accepts no responsibility for statements made by authors and will not be liable for any errors of omission or inaccuracies. Information contained within this publication should not be used as a substitute for clinical judgment. Pediatric Gastroenterology Volume 1, Part 4

2 Pediatric Gastroenterology Board Review Manual Celiac Disease Muralidhar Jatla, MD, and Ritu Verma, MD INTRODUCTION Celiac disease is an immune-mediated enteropathy caused by inflammation induced by a permanent sensitivity to gluten, a protein found in wheat, barley, rye, and other grains, in genetically susceptible individuals. It presents in symptomatic patients with gastrointestinal and nongastrointestinal symptoms, in patients without specific celiac disease symptoms who are affected by type 1 diabetes, Down syndrome, Turner s syndrome, Williams syndrome, and selective IgA deficiency, and in first-degree relatives of individuals with celiac disease. 1 Although the classic patient with malnutrition and a distended abdomen is readily diagnosed, it is becoming increasingly evident that symptomatic celiac disease patients represent just the tip of the celiac iceberg (Figure). Affecting 1% of the general population in the United States, including children, untreated celiac disease poses long-term adverse health consequences, including osteoporosis, anemia, poor growth, increased risk for autoimmune conditions, and intestinal lymphoma. 2 This review describes the epidemiology, pathophysiology, associated conditions, and treatment of celiac disease, with an emphasis on aspects specific to the pediatric population. EPIDEMIOLOGY Hospital Physician Board Review Manual Once thought to be a rare childhood disorder, celiac disease is now recognized as a prevalent disease, with approximately 1 case per 100 persons. 3 The prevalence of celiac disease in children between ages 2.5 and 15 years of age is 3 to 13 per 1000 children (0.3% 1.25%). A substantial number of celiac disease cases go undiagnosed, and the number of missed cases may be 10 to 50 times greater than the number of diagnosed cases. 4 In silent celiac disease, patients have no or minimal symptoms but demonstrate mucosal damage on biopsy and have positive serologic testing (Figure). These patients represent the middle of the celiac iceberg and are identified by screening asymptomatic individuals from at-risk groups (eg, first-degree relatives of celiac disease patient, patients with Down syndrome or type 1 diabetes). 5 The base of the iceberg is comprised of patients with latent celiac disease. These asymptomatic patients may show positive serology and have the human leukocyte antigen (HLA)-DQ2 and/or HLA-DQ8 haplotype but have normal mucosa on biopsy. They also are typically identified by screening at-risk groups. Under certain circumstances (eg, stress, infection), these individuals will develop mucosal changes and/or symptoms at some point. 6 Higher prevalence groups A higher prevalence of celiac disease is seen in patients with certain genetic and autoimmune conditions and in relatives of those with celiac disease (Table 1). 7 The frequency of celiac disease in first-degree relatives of patients with diabetes or celiac disease is 5%, 8 and it is 5% in type 1 diabetes, 4% to 8% in autoimmune thyroiditis, 7% in IgA deficiency, 4% to 19% in Down syndrome, 9 8% in Williams syndrome, and 4% to 10% in Turner s syndrome. These groups have a celiac disease incidence rate roughly 5 times greater than that of the general population. Screening with serologic tests (tissue transglutaminase [ttg] antibody and endomysial antibody [EMA]) is recommended in these groups beginning at age 3 years; if the results are negative, serologic testing is recommended when symptoms occur. 10 Other conditions associated with a higher prevalence of celiac disease in adult studies include arthritis (1.5% 7.5%), autoimmune liver diseases (6% 8%), Sjögren s syndrome (2% 15%), idiopathic dilated cardiomyopathy (5%), and IgA nephropathy (4%). 11 Autoimmune disorders and celiac disease frequently coexist, and the 2 disorders are believed to have a common genetic and immunologic mechanism. The prevalence of autoimmune disorders in celiac disease is related to duration of gluten exposure. 12 A multicenter national study showed that if celiac disease is diagnosed before age 2 years, the risk for developing an autoimmune disorder by early adulthood is 5%. 12 The risk increases to 17% if celiac disease is diagnosed between ages 2 and 10 years and to 24% with diagnosis after age 10 years. The prevalence of autoimmune disorders in diabetic patients with celiac disease was significantly higher than Pediatric Gastroenterology Volume 1, Part 4

3 Table 1. Conditions Associated with Celiac Disease IgA deficiency Type I diabetes Down syndrome Autoimmune disorders Thyroid disease Turner s syndrome Williams syndrome Sjögren s syndrome IgA nephropathy Idiopathic dilated cardiomyopathy Mucosal damage Normal mucosa Silent CD Latent CD Symptomatic CD Adapted with permission from Hill ID, Dirks MH, Liptak GS, 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 2005;40:5. in patients with type 1 diabetes alone. 13 In addition, the prevalence of autoimmune disorders in these patients relatives was significantly higher than in those who had negative EMA test results. GENETICS AND PATHOGENESIS Genetic predisposition, environmental triggers, and dietary factors contribute to initiate the underlying mucosal damage that results in celiac disease. Inheritance of celiac disease is most likely multigenic, although a strong HLA association exists. HLAs are cell surface markers that facilitate immune responses. The vast majority of patients with celiac disease (90% 95%) have genetic markers encoded on chromosome 6 called HLA-DQ2, and most of the remainder have HLA-DQ8. Approximately 10% of patients have an affected firstdegree relative. Concordance in monozygotic twins is 70%, while concordance in HLA-identical siblings is only 30% to 40%, suggesting that other genes are involved. 14 HLA-DQ transcription may not be complete in some individuals, and this may help to explain the lateonset disease in these patients. A homozygous cis genotype confers 100% transcription, a heterozygous (cis and trans) genotype confers 50% expression, and a partial (cis or trans) genotype confers 25% expression. 15 The degree of damage induced by gluten is influenced by immunity, genetics, cytokines, and environmental factors. Gluten digestion is not complete in humans, and gliadin is one of the resultant peptides resistant to enzymatic processes. 16 Protein-binding receptors on antigen-presenting cells recognize a 33-amino-acid Serologic markers positive Genetic predisposition (DQ2 or DQ8) Figure. The celiac disease (CD) iceberg. (Adapted from National Institutes of Health Consensus Development Conference Statement on Celiac Disease, June 28 30, Gastroenterology 2005;128 [4 Suppl 1]:S70. Copyright 2005, with permission from the American Gastroenterological Association.) peptide in gliadin that contains critical epitopes high in glutamine and proline. This peptide is resistant to digestion in the lumen and penetrates the epithelial barrier. 17 Zonulin, a protein that can increase intestinal permeability by promoting tight-junction disruption, is upregulated, and this mechanism or alterations in permeability caused by infections may facilitate entry. 18 The enzyme ttg modifies this peptide as it deamidates glutamine residues to glutamic acid, resulting in highaffinity binding to HLA-DQ2 molecules on the surface of antigen-presenting cells. This results in activation of the mucosal cytokine system by upregulation of interleukin (IL)-2 receptor expression, increased interferon (IFN)-γ messenger RNA expression, activation of nuclear factor kappa B (NF-kB), and upregulation of IL-15. Presentation of modified gliadin peptides in the context of HLA-DQ2 leads to activation of CD4+ lamina propria T cells. Gliadin-specific T cells produce IFN-γ, which in turn enhances expression of DQ2/DQ8 molecules. 15 Epithelial cell infiltration comprised of increased intraepithelial lymphocytes (> 90% CD8+, < 10% CD4+) and increased mucosal gamma/delta T cells (normal, < 10%) is seen in celiac disease. The role of gamma/ delta cells in celiac disease is unknown. Mucosal surface alterations, including loss of epithelial cells and proliferation of crypt epithelial cells, are seen, although the mechanisms that lead to the typical celiac disease lesions are still unclear. 14 The humoral response includes enhanced antibody production, mainly anti-ttg, antigliadin, and other autoantigen (anti-actin) antibodies. The mechanism of antibody production is unknown. Hospital Physician Board Review Manual

4 When antibodies to ttg are formed, enterocyte destruction ensues, and signs and symptoms such as malabsorption and bloating result. The characteristic villous atrophy is seen on biopsy. 15 ttg is an enterocyte enzyme released during injury that stabilizes the crosslinking of proteins in granulation tissue. 19 Its role in celiac disease includes modification of gliadin epitopes. Formation of antibodies against ttg correlates with active celiac disease, 20 particularly with more severe mucosal damage. 21 Malabsorption of nutrients ensues, especially iron, folate, calcium, and vitamin D, and increased intestinal permeability may permit entry of other toxins that might induce autoimmune diseases. 22 There are several unanswered questions in the pathogenesis of celiac disease, including what mechanisms are responsible for the failure of gliadin tolerance, what the role of innate immunity is, which epitopes are immunodominant, whether gluten has a direct effect on the mucosa, and how the mucosal Th1 response is induced and maintained. CLINICAL APPROACH CASE PRESENTATION A 2-year-old white female is brought by her parents to a pediatric gastroenterologist with a 3-month history of loose stools 3 to 4 times per day, gassiness, and occasional epigastric abdominal pain. She tires easily and has become less playful. Her normal stool frequency was formed stool once a day. She eats a varied diet but avoids bread and pasta. She ingests grains via cereal, crackers, and pretzels. Her parents empirically switched her intake of whole milk to lactose-free milk without any significant improvement. Her past medical history reveals a term birth, uncomplicated infancy, and age-appropriate development. Immunizations are up-to-date, and she has 2 healthy siblings and parents. Family history is not significant for any gastrointestinal or allergic disorders. Physical examination reveals a pleasant, healthy appearing girl. Weight is at the 50th percentile, and height is at the 25th percentile. The remainder of the examination is unremarkable. The initial laboratory evaluation included stool cultures, which were negative, and some screening blood work. The results of a complete blood count and complete metabolic panel were normal. A celiac panel reveals significantly elevated levels of IgA ttg (> 100 U) and antigliadin antibody (> 100 U). What features of this case are consistent with celiac disease? CLINICAL FEATURES The classic form of celiac disease presents with diarrhea, weight loss, abdominal pain, and deficiencies of nutrients such as iron, folate, calcium, and vitamin D. When patients have the classic presentation, celiac disease is easy to diagnose, but in many patients the disease can be clinically silent or have predominantly extraintestinal manifestations. 23 Clinical presentation depends on age, sensitivity to gluten, gluten load, and other undetermined factors. Increased awareness and widespread serologic evaluation has resulted in a shift in patients who present with celiac disease from those few with classic symptoms of bloating and abdominal distension to a much larger population of asymptomatic individuals. 24 A multitude of signs and symptoms have been ascribed to celiac disease (Table 2). Weight loss and diarrhea are not present in the majority of patients. 25 The overall onset of symptoms is gradual, which can result in a significant lag between onset of symptoms and diagnosis. 25 Occasionally, a triggering event such as gastroenteritis, travel, stress, or a change in diet can be identified. Nonspecific constitutional symptoms (eg, fatigue, lethargy, headache, poor appetite, and depression) are often concomitantly reported. 26 Patients who present with symptoms of bloating, abdominal pain, and altered bowel habits are commonly diagnosed with irritable bowel syndrome. Patients satisfying the Rome II criteria for irritable bowel syndrome have a 5% risk for having undiagnosed celiac disease as the cause of their symptoms. 27 Children typically present between the ages of 6 and 24 months. The most common gastrointestinal symptoms are chronic or recurrent diarrhea, abdominal distension, anorexia, failure to thrive or weight loss, abdominal pain, vomiting, constipation, and irritability. 28 Celiac crisis, a life-threatening presentation of acute diarrhea, hypoalbuminemia, and multiple metabolic abnormalities including acidosis, hypokalemia, and hyponatremia, is extremely rare. Extraintestinal Manifestations There are myriad presentations of celiac disease in which the dominant manifestations are extraintestinal, including persistent hypertransaminasemia, osteopenia, affective disorders, features of hyposplenism, and autoimmune diseases. Extraintestinal manifestations tend to predominate in older children and adults. 8 These include dermatitis herpetiformis, dental enamel hypoplasia, osteopenia/osteoporosis, 29 short stature, delayed puberty, iron deficiency anemia refractory to oral iron therapy, 30 hepatitis, arthritis, and epilepsy with occipital calcifications. 31 Other manifestations include ataxia, 32 and peripheral neuropathy. 33 Pediatric Gastroenterology Volume 1, Part 4

5 Skin diseases. Patients with minimal or no gastrointestinal symptoms may present with cutaneous stigmata. Skin diseases that occur as extraintestinal manifestations of celiac disease are diverse and include dermatitis herpetiformis, urticaria, angioneurotic edema, cutaneous vasculitis, erythema nodosum, necrolytic migratory erythema, psoriasis, vitiligo, Behçet s disease, oral lichen planus, dermatomyositis, porphyria, alopecia areata, and pyoderma gangrenosum. 34 Most of these skin conditions improve when a gluten-free diet is maintained. 35 Dermatitis herpetiformis presents as an itchy, chronic, papulovesicular eruption that may result in scarring. 3 Typically seen as a symmetric eruption on extensor surfaces, dermatitis herpetiformis tends to occur more frequently in adult males (2:1) and more frequently in females in children (2:1). Characteristic histologic findings include microabscesses within the dermal papillae. 35 Antigliadin, antiendomysial, and anti-ttg antibodies have been found in patients with dermatitis herpetiformis. 36 It is estimated that 90% of patients with dermatitis herpetiformis have gluten-sensitive enteropathy. The rash of dermatitis herpetiformis is felt to be an external marker of intestinal sensitivity to gluten and is likely the result of molecular mimicry between the celiac disease autoantigen ttg and skin-derived epidermal transglutaminase. Gluten must be present in the diet for dermatitis herpetiformis to develop. Topical application of gluten does not induce dermatitis herpetiformis, whereas oral ingestion of gluten will induce dermatitis herpetiformis in susceptible patients. 37 Although patients with dermatitis herpetiformis may lack gastrointestinal symptoms, they do manifest characteristic histologic changes on small bowel biopsies. Dermatitis herpetiformis may need to be treated with dapsone in addition to a gluten-free diet. Patients with dermatitis herpetiformis are at increased risk for malignancy if they do not comply with a gluten-free diet, regardless of gastrointestinal symptoms. 38 Liver disease. Liver disease is also described in celiac disease and presents as mild liver dysfunction, chronic liver disease, or autoimmune liver disease. Central theories of a common pathogenesis include impaired gut mucosal integrity, malnutrition, and generation of autoantibodies. 39 Mild liver dysfunction characterized by elevated transaminase levels (aspartate aminotransferase and alanine aminotransferase) at the time of celiac disease diagnosis is reported in up to 42% of adults 40 and 54% of children. 41 γ-glutamyltransferase and bilirubin levels are usually normal. Liver enzymes normalize within 12 months of gluten elimination in most cases. Mild, nonspecific histologic changes are seen in cases where a liver Table 2. Signs and Symptoms Associated with Celiac Disease Children Fatigue Bloating Constipation Abdominal pain Chronic diarrhea Irritability Growth failure Osteopenia/osteoporosis Delayed puberty Hepatitis Dental anomalies Adults Abdominal pain Weight loss Chronic diarrhea Infertility Recurrent spontaneous abortion Dermatitis herpetiformis Peripheral neuropathy Depression Fatigue/malaise Hepatitis Aphthous stomatitis Alopecia Anemia Malignancy Seizures Ataxia Osteopenia/osteoporosis Arthritis Adapted from National Institutes of Health Consensus Development Conference Statement on Celiac Disease, June 28 30, Gastroenterology 2005;128(4 Suppl 1):S69. Copyright 2005, with permission from the American Gastroenterological Association. biopsy has been performed. Occasionally, mild hepatic steatosis is seen on histology, and this also responds to a gluten-free diet. Asymptomatic celiac disease has been found in 9% of adults being investigated for elevated transaminase levels. 42 Transaminase levels in adults and children returned to normal on a gluten-free diet. 43 Severe liver disease including chronic hepatitis, severe fibrosis, and cirrhosis responsive to a gluten-free diet has been reported in adults and children. 44 Four adults in whom liver transplantation was being considered were subsequently diagnosed with celiac disease, Hospital Physician Board Review Manual

6 and after initiation of a gluten-free diet hepatic function improved and transplantation was avoided. 45 An Italian study reported an increased risk of celiac disease in children with autoimmune hepatitis, with most having typical gastrointestinal symptoms. 12 These children achieved remission with immunosuppression and glutenfree diet, with relapse after gluten reintroduction. Neurologic disease. Young adults with celiac disease have been found to have a higher prevalence of both neurologic disorders and neurologic symptoms. 46 In a study of children and young adults with celiac disease, over half of the participants had neurologic disorders, including hypotonia, developmental delay, learning disorders, attention-deficit/hyperactivity disorder, headache, and cerebellar ataxia. 47 Epileptic disorders were only marginally more common in patients with celiac disease versus controls, but the prevalence of tic disorders was not found to be different between celiac disease and control patients. A gluten-free diet resulted in therapeutic benefit for patients with transient infantile hypotonia and migraine headache. 48 Bone disease. Celiac disease is associated with metabolic bone disease, particularly in adults. Studies estimate that 40% to 50% of adults with celiac disease have bone mineral density measurements at least 2.5 standard deviations below the mean, thereby meeting the criteria for osteoporosis. 49 Interestingly, no overall increased risk of fracture has been found in this group of patients. 50 Bone mineral density improves in patients with celiac disease after initiation of a gluten-free diet. 50 Consistent with findings from other centers, spine and whole body bone mineral composition abnormalities were not seen in pediatric celiac disease at diagnosis at our institution (unpublished data). 49 What other conditions should be considered as possible causes of the clinical findings in this child? DIFFERENTIAL DIAGNOSIS The differential diagnosis of celiac disease includes other forms of enteropathy such as malnutrition, viral gastroenteritis, giardiasis, tuberculosis, inflammatory bowel disease, food allergy, autoimmune enteropathy, disaccharidase deficiency, secretory diarrhea, lactose intolerance, small bowel bacterial overgrowth, anorexia nervosa, immunodeficiency, HIV infection, and immunodysregulation polyendocrinopathy enteropathy X-linked syndrome. What is the most appropriate next step in the workup and management of this patient? DIAGNOSTIC STUDIES It is crucial to confirm the diagnosis of celiac disease before initiating treatment, as the diagnosis mandates a strict gluten-free diet for life. Following the diet is not easy and there can be significant quality of life implications. More important, failure to treat has potential long-term adverse health consequences, including increased morbidity and mortality. The classic diagnosis of celiac disease requires (1) characteristic small intestinal histology in a symptomatic child and (2) complete symptom resolution on a gluten-free diet. The gold standard for celiac disease diagnosis in at-risk or asymptomatic patients remains characteristic histology on small intestine biopsy. Serologic tests may support the diagnosis, but they are most helpful when deciding which patients should undergo biopsy. Select cases may need additional diagnostic testing such as HLA haplotype testing. 15 Serologic Testing Serologic testing is primarily used to identify symptomatic or at-risk individuals who need to undergo biopsy. Because of their high sensitivity and specificity, serologic tests are excellent for screening asymptomatic at-risk individuals; they also can be used for monitoring dietary compliance. Serologic testing consists of measurement of antigliadin antibodies, EMA, and ttg antibodies. The first-generation (guinea pig protein) tests have lower sensitivity and specificity than the second-generation (human recombinant) tests. 51 Antigliadin antibody testing involves measuring antibodies (IgG and IgA) to the gluten protein in wheat, rye, and barley. Although antigliadin antibody testing is relatively inexpensive and easy to perform, it has poor sensitivity and specificity. EMA is an IgA-based antibody against reticulin connective tissue around smooth muscle fibers. EMA testing has very high sensitivity and specificity, but false-negative results occur in young children at an unknown rate, which may be related to limited duration of gluten exposure. In addition, EMA testing is operator-dependent, expensive, and time consuming. 52 Not surprisingly, EMA testing yields falsenegative results in IgA-deficiency states. Testing for the IgA-based antibody against ttg (celiac disease autoantigen) has high sensitivity and specificity (human ttg), is not operator-dependent (enzymelinked immunosorbent assay/radioimmunoassay), and is relatively inexpensive. 53 Like EMA testing, IgA ttg testing yields false-negative results in young children and in those with IgA deficiency. Studies have shown that ttg antibody testing may be slightly less specific Pediatric Gastroenterology Volume 1, Part 4

7 Table 3. Performance of Common Serologic Tests Serologic Tests Sensitivity, % Specificity, % IgG AGA IgA AGA IgA EMA IgA ttg AGA = antigliadin antibody; EMA = antiendomysial antibody; ttg = tissue transglutaminase. (Adapted with permission from Hill ID, Dirks MH, Liptak GS, 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 2005;40:1 19.) than EMA testing. 30 Reported sensitivity and specificity ranges found in hospital and research laboratory settings for the most common serology tests used in celiac disease are shown in Table 3 54 ; however, recent studies 55 have reported lower sensitivity and specificity rates in commercial laboratories and in clinical practice. 56 IgA levels are reported with most grouped celiac panel tests to decrease false-negative interpretation. Physicians should consider using IgG-based tests (EMA IgG and ttg IgG) in IgA-deficiency states. 57 Indications for serologic testing in children are listed in Table 4. HLA Haplotype Testing Up to 95% of patients with celiac disease are positive for HLA-DQ2, and most of the remaining patients are positive for HLA-DQ8. However, these alleles are also found in 40% of the general population. Although HLA-DQ2 and HLA-DQ8 are necessary in the disease process, they alone are not sufficient for celiac disease to develop. Thus, there is a low concordance between a positive HLA-DQ2 and celiac disease development. HLA testing has a high negative predictive value and can be useful in certain situations, such as when a diagnosis is unclear, when serologic testing or biopsy is performed in patients on a gluten-free diet, or in determining which family members to screen for celiac disease. 14 Endoscopy and Esophageal Biopsy Endoscopy-guided duodenal biopsy is the gold standard for diagnosis of celiac disease. Nodularity and scalloping can be seen in the duodenum during endoscopy, but these findings are not specific for celiac disease. Histologic features of celiac disease include increased intraepithelial lymphocytes (> 30 per 100 enterocytes), loss of nuclear polarity, change from columnar to cuboid cells, lamina propria cellular infiltration, crypt elongation and hyperplasia, increased crypt mitotic Table 4. Indications for Serologic Testing in Children Diarrhea and failure to thrive Recurrent abdominal pain Unexplained anorexia, constipation, or vomiting Delayed puberty Weight loss Growth failure Dermatitis herpetiformis Unexplained elevated transaminase levels Dental enamel hypoplasia of permanent teeth Osteoporosis Iron deficiency anemia resistant to oral iron therapy Asymptomatic children with conditions listed in Table 2 Adapted from Green PH, Rostami K, Marsh MN. Diagnosis of coeliac disease. Best Pract Res Clin Gastroenterol 2005;19:391. Copyright 2005, with permission from Elsevier. index, and progressive villous flattening or blunting. The Marsh criteria are the most commonly used grading scale of mucosal damage, ranging from 0 (normal) to IIIa-c (various degrees of villous atrophy). 58 CASE PRESENTATION CONTINUED The patient undergoes an upper endoscopy during which multiple biopsy specimens are obtained from the duodenum. On microscopy, intraepithelial lymphocytosis and mild villous blunting with crypt hyperplasia in the duodenum are seen, consistent with the diagnosis of celiac disease. What is the treatment for celiac disease? MANAGEMENT Primary management of a new diagnosis of celiac disease consists of education about the underlying gluten-induced enteropathy, need for strict adherence to a gluten-free diet, and monitoring for complications. Gluten-Free Diet Dietary therapy consisting of avoiding gluten is currently the only definitive treatment for celiac disease. Patients may ingest any foods not containing gluten, and all fruits and vegetables are safe foods. Adherence must be strict and life-long. Nutrition counseling regarding how to look for gluten in unusual sources such as lipstick, medications, and supplements is crucial for success and compliance. Numerous resources are available online, in bookstores, and through local support groups and national as well as global organizations (Table 5). Hospital Physician Board Review Manual

8 Table 5. Resources for Patients with Celiac Disease Celiac.com National Institutes of Health American Dietetic Association Gluten Intolerance Group (GIG) Celiac Disease Foundation (CDF) University of Maryland Center for Celiac Research Between 45% and 85% of children adhere to a gluten-free diet. 59 Factors that decrease compliance with a gluten-free diet include the inability to manage emotions, to resist temptation, and to exercise restraint. Feelings of deprivation and the fear generated from inaccurate information can be barriers as well. Time pressures around planning and preparing appropriate meals also must be considered. Assessing gluten content in foods, label reading, and eating out safely can present challenges. 28 In addition, social events, not wanting to look or be different, and a lack of support of family and friends (eg, statements like Just a little bit it won t hurt you ) can impair compliance. Compliance can be increased by optimizing patient knowledge about the gluten-free diet with the use of a dietitian. Understanding the risk factors and serious complications that can occur as well as empowering patients with the ability to break down big changes into smaller steps can help. Positive reinforcement and the ability to simplify or make behavior routine help greatly in increasing gluten-free diet adherence. Follow-up visits and testing measure the health effects of eating gluten and provide important feedback. Test results can be a powerful motivator, especially for those who do not have symptoms when they eat gluten. Patients and parents look to the physician to tell them when follow-up testing is needed. Proactive follow-up measures can increase adherence. 1 What is the follow-up care of celiac disease? Clinical Monitoring The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition guidelines for celiac disease recommend periodic visits for physical examination and assessment of symptoms, growth, and adherence to a gluten-free diet. The guidelines recommend ttg antibody testing at 6 months after gluten-free diet initiation and retesting approximately 12 months after that if the patient is asymptomatic. 54 ttg testing should be performed at any time the patient is symptomatic after gluten-free diet initiation Future Directions Future potential drug therapies include oral administration of bacterial endopeptidases that digest the toxic 33mer of gliadin, inhibitors of the zonulin pathway, 18 and peptides that block the binding groove of DQ2 and DQ8. Other potential therapies being investigated include cytokine therapy (IL-10, IFN-γ, and IL-15) and selective adhesion molecule inhibition. 59 These therapies may alleviate some of the difficulties in maintaining a life-long gluten-free diet. CASE RESOLUTION Following initiation of a gluten-free diet, the case patient has marked improvement of her symptoms, including less bloating, more consistent formed stool, and improved energy overall. She is scheduled for follow-up 6 months after initiation of the gluten-free diet to have serologic testing to determine compliance and assess the degree of intestinal damage. She also is referred to and continues to follow-up with a dietitian for gluten-free diet counseling. The physician recommends that all of the patient s first-degree relatives undergo screening with a celiac serology panel. Any family members found to have a positive celiac panel will need to undergo endoscopic small bowel biopsy. Finally, in older relatives, bone density should be assessed. SUMMARY Celiac disease is a common immune-mediated enteropathy caused by sensitivity to gluten. Although classic symptoms are easily identified, the majority of patients will present with nonspecific symptoms or no symptoms at all. Certain high-risk groups such as family members of patients with celiac disease, those who have autoimmune disease, and those with certain genetic conditions should be screened at least once, beginning at age 3 years. Undiagnosed asymptomatic individuals are at risk for complications of celiac disease and must be diagnosed at an early stage. Serologic tests have excellent sensitivity and specificity and are readily available. They are useful screening tools in determining which patients should undergo endoscopy. Because of the potential complications of celiac disease and because the gluten-free diet can be a significant undertaking for a child or their family, a diagnosis of celiac disease cannot be made by serology alone. Microscopic examination of small bowel biopsy specimens remains the gold standard method for diagnosis of celiac disease. Counseling by a dietitian and surveillance by a pediatric gastroenterologist can greatly improve adherence to Pediatric Gastroenterology Volume 1, Part 4

9 a gluten-free diet and decrease the complications of celiac disease. REFERENCES 1. National Institutes of Health Consensus Development Conference Statement on Celiac Disease, June 28 30, Gastroenterology 2005;128(4 Suppl 1):S Rampertab SD, Forde KA, Green PH. Small bowel neoplasia in coeliac disease. Gut 2003;52: Farrell RJ, Kelly CP. Celiac sprue. N Engl J Med 2002; 346: Catassi C, Ratsch IM, Fabiani E, et al. Coeliac disease in the year 2000: exploring the iceberg. Lancet 1994; 343: 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;92: Dewar DH, Ciclitira PJ. Clinical features and diagnosis of celiac disease. Gastroenterology 2005;128(4 Suppl 1): S D Amico MA, Holmes J, Stavropoulos SN, et al. Presentation of pediatric celiac disease in the United States: prominent effect of breastfeeding. Clin Pediatr (Phila) 2005;44: 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: Mackey J, Treem WR, Worley G, et al. Frequency of celiac disease in individuals with Down syndrome in the United States. Clin Pediatr (Phila) 2001;40: Hoffenberg EJ. Should all children be screened for celiac disease? Gastroenterology 2005;128(4 Suppl 1):S Green PH, Rostami K, Marsh MN. Diagnosis of coeliac disease. Best Pract Res Clin Gastroenterol 2005;19: Ventura A, Magazzu G, Greco L. Duration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease. SIGEP Study Group for Autoimmune Disorders in Celiac Disease. Gastroenterology 1999;117: Ventura A, Neri E, Ughi C, et al. Gluten-dependent diabetes-related and thyroid-related autoantibodies in patients with celiac disease. J Pediatr 2000;137: Kagnoff MF. Overview and pathogenesis of celiac disease. Gastroenterology 2005;128(4 Suppl 1):S Koning F, Schuppan D, Cerf-Bensussan N, Sollid LM. Pathomechanisms in celiac disease. Best Pract Res Clin Gastroenterol 2005;19: Maki M, Mustalahti K, Kokkonen J, et al. Prevalence of celiac disease among children in Finland. N Engl J Med 2003;348: Shan L, Molberg O, Parrot I, et al. Structural basis for gluten intolerance in celiac sprue. Science 2002;297: Fasano A, Not T, Wang W, et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet 2000;355: Alaedini A, Green PH. Narrative review: celiac disease: understanding a complex autoimmune disorder. Ann Intern Med 2005;142: Abrams JA, Diamond B, Rotterdam H, Green PH. Seronegative celiac disease: increased prevalence with lesser degrees of villous atrophy. Dig Dis Sci 2004;49: 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: Toscano V, Conti FG, Anastasi E, et al. Importance of gluten in the induction of endocrine autoantibodies and organ dysfunction in adolescent celiac patients. Am J Gastroenterol 2000;95: Bingley PJ, Williams AJ, Norcross AJ, et al. Undiagnosed coeliac disease at age seven: population based prospective birth cohort study. Avon Longitudinal Study of Parents and Children Study Team. BMJ 2004;328: Rewers M. Epidemiology of celiac disease: what are the prevalence, incidence, and progression of celiac disease? Gastroenterology 2005;128(4 Suppl 1):S Murray JA, Van Dyke C, Plevak MF, et al. Trends in the identification and clinical features of celiac disease in a North American community, Clin Gastroenterol Hepatol 2003;1: Westerberg DP, Gill JM, Dave B, et al. New strategies for diagnosis and management of celiac disease. J Am Osteopath Assoc 2006;106: 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: Fasano A. Clinical presentation of celiac disease in the pediatric population. Gastroenterology 2005;128 (4 Suppl 1):S Meyer D, Stavropolous S, Diamond B, et al. Osteoporosis in a north american adult population with celiac disease. Am J Gastroenterol 2001;96: Oxentenko AS, Grisolano SW, Murray JA, et al. The insensitivity of endoscopic markers in celiac disease. Am J Gastroenterol 2002;97: Gobbi G, Bouquet F, Greco L, et al. Coeliac disease, epilepsy, and cerebral calcifications. The Italian Working Group on Coeliac Disease and Epilepsy. Lancet 1992;340: Sander HW, Magda P, Chin RL, et al. Cerebellar ataxia and coeliac disease. Lancet 2003;362: Hospital Physician Board Review Manual

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