American Gastroenterological Association (AGA) Institute Technical Review on the Diagnosis and Management of Celiac Disease

  • Alaa Rostom
    Correspondence
    Address requests for reprints to: Chair, Clinical Practice and Economics Committee, AGA Institute National Office, c/o Membership Department, 4930 Del Ray Avenue, Bethesda, Maryland 20814. Fax: (301) 654-5920.
    Affiliations
    Division of Gastroenterology, Foothills Medical Centre, University of Calgary, Calgary, Alberta, Canada
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  • Joseph A. Murray
    Affiliations
    Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota
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  • Author Footnotes
    1 M.F.K. is supported by National Institutes of Health grants DK35108 and DK58960 and a grant from the William K. Warren Foundation, and J.A.M. is supported by National Institutes of Health grants DK 71003 and DK 57892.
    Martin F. Kagnoff
    Footnotes
    1 M.F.K. is supported by National Institutes of Health grants DK35108 and DK58960 and a grant from the William K. Warren Foundation, and J.A.M. is supported by National Institutes of Health grants DK 71003 and DK 57892.
    Affiliations
    Departments of Medicine and Pediatrics, The Wm. K. Warren Medical Research Center for Celiac Disease, University of California at San Diego, La Jolla, California
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  • Author Footnotes
    1 M.F.K. is supported by National Institutes of Health grants DK35108 and DK58960 and a grant from the William K. Warren Foundation, and J.A.M. is supported by National Institutes of Health grants DK 71003 and DK 57892.
Published:November 10, 2006DOI:https://doi.org/10.1053/j.gastro.2006.10.004
      This technical review addresses the state of evidence for celiac disease epidemiology, detection by serologic testing, diagnosis by biopsy, treatment, and outcome. It updates the previous American Gastroenterological Association (AGA) Institute technical review on celiac disease published in 2001.

      Abbreviations used in this paper:

      AGA (antigliadin antibodies), BMD (bone mineral density), BMI (body mass index), CI (confidence interval), DM1 (type 1 diabetes mellitus), EMA (endomysial antibodies), GFD (gluten-free diet), GP (guinea pig liver), HU (human umbilical cord), IDA (iron deficiency anemia), ME (monkey esophagus), NHL (non-Hodgkin’s lymphoma), PPV (positive predictive value), SDS (standard deviation score), SIR (standardized incidence ratio), SMR (standardized mortality rate), tTG (tissue transglutaminase), tTGA (tissue transglutaminase antibody)
      See CME Quiz on page 1972.
      Celiac disease is a unique disorder that is both a food intolerance and autoimmune disorder. Celiac disease can be defined as a permanent intolerance to the storage proteins from wheat rye and barley, herein after referred to as “gluten.” It is characterized by a chronic inflammatory state of the proximal small intestinal mucosa that heals when foods containing gluten are excluded from the diet and returns when these foods are reintroduced. Complex adaptive and innate immune reactions result in chronic inflammation of the mucosa and a panoply of structural and functional changes. There is atrophy of the small intestinal villi, deepening of the crypts, and infiltration of the lamina propria and intraepithelial compartments with chronic inflammatory cells. The functional changes include decreased digestion of food, decreased absorption of macronutrients and micronutrients, and increased net secretion of water and solute. Other consequences of chronic inflammation such as ulceration or stricturing may occur, although much less frequently. Extraintestinal manifestations affect many organ systems.

      Pathology

      Although celiac disease has consequences for many organs, the site of maximum impact is the proximal small intestine, which is where dietary gluten first encounters the mucosal immune system. Over the past 50 years, celiac disease has become defined by this small intestinal damage. Our understanding of the spectrum of injury and its consequences has increased substantially over the past several years. There are varying degrees of inflammation and architectural changes that occur at presentation and recur progressively when treated and healed celiac disease is rechallenged with gluten. A progression of mucosal injury was first described by Marsh et al and has evolved into a grading of histologic damage that reflects the varying degrees of villous atrophy and inflammatory change (Table 1 and Figure 1). Most symptomatic patients when diagnosed with celiac disease will have changes in villous morphology with some degree of atrophy. The finding of increased intraepithelial lymphocytes, without any other changes (Marsh grade 1), is not specific for celiac disease.
      • Mention J.
      • Ben Ahmed M.
      • Begue B.
      • Barbe U.
      • Verkarre V.
      • Asnafi V.
      • Colombel J.
      • Cugnenc P.
      • Ruemmele F.M.
      • McIntyre E.
      • Brousse N.
      • Cellier C.
      • Cerf-Bensussan N.
      Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease.
      • Kakar S.
      • Nehra V.
      • Murray J.A.
      • Dayharsh G.A.
      • Burgart L.J.
      Significance of intraepithelial lymphocytosis in small bowel biopsy samples with normal mucosal architecture.
      While it has been assumed that many of these subjects are asymptomatic, that is not necessarily true because some of these patients may have diarrhea that resolves with a gluten-free diet (GFD).
      • Kaukinen K.
      • Maki M.
      • Partanen J.
      • Sievanen H.
      • Collin P.
      Celiac disease without villous atrophy: revision of criteria called for.
      Further, because only ultramicroscopic changes have been described in some symptomatic subjects with a positive endomysial antibody (EMA), and those symptoms resolved with the exclusion of dietary gluten, minimal lesions may be associated with symptoms, although this is unusual.
      • Kaukinen K.
      • Collin P.
      • Holm K.
      • Karvonen A.L.
      • Pikkarainen P.
      • Maki M.
      Small-bowel mucosal inflammation in reticulin or gliadin antibody-positive patients without villous atrophy.
      • Picarelli A.
      • Maiuri L.
      • Mazzilli M.C.
      • Coletta S.
      • Ferrante P.
      • Di Giovambattista F.
      • Greco M.
      • Torsoli A.
      • Auricchio S.
      Gluten-sensitive disease with mild enteropathy.
      These minor degrees of damage are more commonly seen with dermatitis herpetiformis, which is an extremely itchy blistering rash that affects extensor surfaces and, like celiac disease itself, is dependent on the consumption of gluten.
      • Reunala T.
      Dermatitis herpetiformis: coeliac disease of the skin.
      Table 1Histologic Grading in Celiac Disease
      Marsh 0Normal mucosal and villous architecture
      Marsh IInfiltrative
       Normal mucosal and villous architecture
       Increased numbers of intraepithelial lymphocytes
      Marsh IIHyperplastic
       Similar to above, but with enlarged crypts and with increased crypt cell division
      Marsh IIIa. Partial villous atrophy
       Shortened blunt villi
       Mild lymphocyte infiltration
       Enlarged hyperplastic crypts
      b. Subtotal villous atrophy
       Clearly atrophic villi, but still recognizable
       Enlarged crypts whose immature epithelial cells are generated at an increased rate
       Influx of inflammatory cells
      c. Total villous atrophy
       Complete loss of villi
       Severe crypt hyperplastic, and infiltrative inflammatory lesion
      Marsh IVHypoplastic
       Total villous atrophy
       Normal crypt depth, but hypoplasia
       Normal intraepithelial lymphocyte count
       Many feel this does not exist and represents severe malnutrition
      Figure thumbnail gr1
      Figure 1Spectrum of malabsorption and symptoms in celiac disease. The magnitude of malabsorption and symptoms in patients with celiac disease (bottom) often correlates with the extent of small intestinal mucosal injury as depicted schematically from I to IIIc according to the Marsh histologic damage score (also see ).

      Pathogenesis

      Recent information has illuminated our understanding of the basic mechanisms that lead to the development of celiac disease. We briefly summarize these advances to provide a pathophysiologic context for the more detailed analysis of questions of immediate importance to clinical practice. Furthermore, such pathophysiologic insights into the disease suggest potential therapeutic alternatives that ultimately may be substitutes or adjuncts to the GFD. A full review of the processes that lead to the development of this unique disease is beyond this clinically focused document. It is clear that celiac disease occurs because of the interaction between derivatives of dietary grains, immune factors, and an individual’s genetic makeup.

       Gluten

      Celiac disease is activated by the dietary ingestion of gluten. Gluten, in the context of celiac disease, encompasses the storage proteins derived from the cultivated grasses: wheat, barley, and rye. These proteins are enriched in glutamines and prolines and undergo partial but incomplete digestion in the upper gastrointestinal tract, resulting in a wide variety of native peptide derivatives. The specific peptide sequences that can elicit immune responses are quite variable and occur throughout the storage proteins of all 3 grains. Of interest is a 33–amino acid peptide sequence from an α-gliadin that survives intestinal digestion intact, and this peptide contains several motifs that are especially immunogenic to the celiac intestine.
      • Shan L.
      • Molberg O.
      • Parrot I.
      • Hausch F.
      • Filiz F.
      • Gray G.M.
      • Sollid L.M.
      • Khosla C.
      Structural basis for gluten intolerance in celiac sprue.
      It is the persistence of highly immunogenic peptides, of which the 33 amino acid is one example, that seems to be crucial to the development of the immune response to gluten in the intestine of patients with celiac disease. These peptides pass through the epithelial barrier and reach antigen-presenting cells in the lamina propria.

       Mucosal Immune Response

      Immune responses to gluten in celiac disease activate an inflammatory reaction characterized by infiltration of the lamina propria and the epithelial compartments with chronic inflammatory cells and progressive architectural changes in the mucosa. Immunogenic peptides rich in glutamine and proline elicit a chronic immune response that is initiated and mediated by both the innate and adaptive arms of the mucosal immune system.

       Adaptive response

      The adaptive response is mediated by gluten-reactive CD4+ T cells in the lamina propria that recognize certain gluten-derived peptides when they are presented by the HLA class II molecules DQ2 or DQ8. These cells then produce proinflammatory cytokines. Although native peptides can elicit a response, if certain glutamine residues in the gluten peptides undergo deamidation, thereby forming a negatively charged glutamic acid residue, the resulting peptide can bind in the binding groove of the DQ2 or DQ8 molecules with a higher affinity. It has been shown that tissue transglutaminase (tTG) in the intestine can perform this targeted deamidation. T cells activated by gluten produce interferon gamma and other proinflammatory cytokines. During the resulting inflammatory cascade, the release of metalloproteinases and other tissue-damaging mediators results in villous injury and the associated crypt hyperplasia characteristic of fully developed celiac disease.

       Innate response

      Gluten-derived peptides can also activate an innate response. The innate response is typified by increased expression of interleukin-15 by enterocytes, which drives the activation of populations of intraepithelial lymphocytes that express the NK marker (NKG2D).
      • Mention J.
      • Ben Ahmed M.
      • Begue B.
      • Barbe U.
      • Verkarre V.
      • Asnafi V.
      • Colombel J.
      • Cugnenc P.
      • Ruemmele F.M.
      • McIntyre E.
      • Brousse N.
      • Cellier C.
      • Cerf-Bensussan N.
      Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease.
      These cells are then able to recognize and kill enterocytes that express stress molecules (MICA) on their surface.
      • Hue S.
      • Mention J.J.
      • Monteiro R.C.
      • Zhang S.
      • Cellier C.
      • Schmitz J.
      • Verkarre V.
      • Fodil N.
      • Bahram S.
      • Cerf-Bensussan N.
      • Caillat-Zucman S.
      A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease.
      • Meresse B.
      • Chen Z.
      • Ciszewski C.
      • Tretiakova M.
      • Bhagat G.
      • Krausz T.N.
      • Raulet D.H.
      • Lanier L.L.
      • Groh V.
      • Spies T.
      • Ebert E.C.
      • Green P.H.
      • Jabri B.
      Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease.
      Additionally, the innate response results in the activation of dendritic cells that influence the adaptive response. This is an area of intense research focus and may uncover targets suitable for therapeutic interventions.
      Less is known about some of the initiating steps that lead to celiac disease. How and when gluten sensitivity and development of autoimmunity first occur is unknown. The interplay between the innate responses and adaptive responses is likely crucial to the development of celiac disease and is the focus of much ongoing research. It has been hypothesized that, at least in some individuals, an insult such as an enteric infection or surgery or gluten itself may result in compromised epithelial barrier function and the initiation of intestinal inflammation. This would allow incompletely digested gluten peptides to be deamidated and to come into contact with an immune system able to respond because of the carriage and expression of the appropriate HLA class II molecules DQ2 or DQ8.

       tTG

      tTG is a ubiquitous enzyme found both within and outside of cells. It has many functions and physiologic roles. In celiac disease, it is involved in several processes. tTg is the target of an autoimmune humoral response that results in both secreted and circulating antibodies predominantly of the immunoglobulin (Ig) A isotype. It is the enzymatic deamidation by tTg of crucial glutamine residues in gluten peptides that make deamidated gluten peptides more antigenic than native gluten peptides. Finally, it has been suggested that tTG is important also in the destructive effect of CD8+ cytotoxic cells on the epithelium.
      • Maiuri L.
      • Ciacci C.
      • Ricciardelli I.
      • Vacca L.
      • Raia V.
      • Rispo A.
      • Griffin M.
      • Issekutz T.
      • Quaratino S.
      • Londei M.
      Unexpected role of surface transglutaminase type II in celiac disease.

      Aim of the Technical Review

      The aim of this technical review on celiac disease is to address specific areas of clinical importance relevant to practicing gastroenterologists and primary care practitioners who see and detect most cases of celiac disease. The major focus is on adults, although some data from studies on children are also included for completeness. The specific issues related to celiac disease in childhood have been recently addressed.
      • Hill I.D.
      • Dirks M.H.
      • Liptak G.S.
      • Colletti R.B.
      • Fasano A.
      • Guandalini S.
      • Hoffenberg E.J.
      • Horvath K.
      • Murray J.A.
      • Pivor M.
      • Seidman E.G.
      • North A.
      Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.

      Methods

      This technical review was conducted using standard systematic review methodology to address several key content areas regarding celiac disease: use of serologic testing in diagnosis, use of HLA-DQ2/DQ8 testing in diagnosis, prevalence of celiac disease in the general population and in groups of individuals presumed to be at increased risk for celiac disease, complications of celiac disease, benefits of a GFD, promoting adherence to a GFD, and maintaining adherence to a GFD. The specific methodology has been reported previously.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      The literature search is current and includes outcomes not covered in a prior report.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      Citations identified by the search strategy underwent multilevel screening by 2 independent reviewers using predetermined forms detailing the inclusion and exclusion criteria. Included articles were assessed for quality using a design-specific instrument. The obtained data were extracted and statistically pooled if clinically and statistically appropriate. If statistical pooling was not possible, a qualitative description of the studies is presented. The reference list for this review is extensive and has been shortened to meet length requirements. We reference sections of the Agency for Healthcare Research and Quality report,
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      and the updated list in its entirety is available online (http://www.ahrq.gov/downloads/pub/evidence/pdf/celiac/celiac.pdf and http://www.ahrq.gov/clinic/celiacinv.htm).

      Diagnosis of Celiac Disease

      The diagnostic approach to detecting celiac disease has undergone important changes in recent years. This reflects the development and application of serologic tests, particularly the EMA and tTG antibody tests, as an initial screen for this disease. Serologic tests are largely responsible for the recognition that celiac disease is not a rare disease. Moreover, with the recognition of a relatively high prevalence of celiac disease in the US population (∼1:100) has come increased recognition of its broad spectrum of clinical presentations.
      • McNeish A.S.
      • Harms H.K.
      • Rey J.
      • Shmerling D.H.
      • Visakorpi J.K.
      • Walker-Smith J.A.
      The diagnosis of coeliac disease A commentary on the current practices of members of the European Society for Paediatric Gastroenterology and Nutrition (ESPGAN).
      • Walker-Smith J.A.
      • Guandalini S.
      • Schmitz J.
      • Shmerling D.H.
      • Visakorpi J.K.
      Revised criteria for diagnosis of coeliac disease.
      • Marsh M.N.
      Gluten, major histocompatibility complex, and the small intestine: a molecular and immunobiologic approach to the spectrum of gluten sensitivity (’celiac sprue’).
      • Rostami K.
      • Kerckhaert J.
      • Tiemessen R.
      • von Blomberg B.M.
      • Meijer J.W.
      • Mulder C.J.
      Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice.
      Despite the fact that positive serologic test results can be supportive of the diagnosis, small intestinal mucosal biopsy remains the gold standard for establishing the diagnosis of celiac disease. A diagnosis of celiac disease requires demonstration of characteristic histologic changes in the small intestinal mucosa, which are generally scored based on a system initially put forth by Marsh
      • Marsh M.N.
      Gluten, major histocompatibility complex, and the small intestine: a molecular and immunobiologic approach to the spectrum of gluten sensitivity (’celiac sprue’).
      and subsequently modified.
      • Rostami K.
      • Kerckhaert J.
      • Tiemessen R.
      • von Blomberg B.M.
      • Meijer J.W.
      • Mulder C.J.
      Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice.
      The histologic changes in the small intestinal mucosa can range from total to partial villous atrophy.
      • Marsh M.N.
      Gluten, major histocompatibility complex, and the small intestine: a molecular and immunobiologic approach to the spectrum of gluten sensitivity (’celiac sprue’).
      • Rostami K.
      • Kerckhaert J.
      • Tiemessen R.
      • von Blomberg B.M.
      • Meijer J.W.
      • Mulder C.J.
      Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice.
      In some individuals, only more subtle changes of crypt lengthening with an increase in intraepithelial lymphocytes, or simply an increase in intraepithelial lymphocytes, are present. In routine practice, there is not a need for special stains such as staining for CD3 to detect the intraepithelial lymphocyte population. Mucosal changes can be patchy. Therefore, it is important to take multiple endoscopic biopsy specimens (ideally 4–6 biopsy specimens) from the proximal small intestine. Biopsy specimens should be of sufficient size, carefully oriented, and mounted villous side up to enable cross sectioning rather than tangential sectioning, because the latter can lead to misleading interpretations. Larger specimens can be obtained using a jumbo or a radial jaw biopsy forceps. Only a single biopsy specimen should be obtained with each pass of the biopsy forceps. It is important that the slides be reviewed by an experienced pathologist familiar with the spectrum of mucosal changes in celiac disease. Positive serologic test results may resolve and histologic findings may improve with the removal of gluten from the diet. Therefore, diagnostic tests should be performed before the initiation of gluten restriction. In addition, the extent of mucosal inflammation or architectural abnormality can be masked if individuals are taking corticosteroids or immunosuppressants. Although not all patients with celiac disease have positive serologic test results or significant symptoms, in those who do, it is anticipated that serologic test results will revert to normal over a period of 6 months to 1 year and symptoms will improve on a GFD. Notably, gluten challenge and a repeat biopsy are no longer required to establish the diagnosis of celiac disease in patients whose small intestinal biopsy specimen has the characteristic histologic appearance and in whom an objective response to a GFD is obtained. However, a gluten challenge with a subsequent biopsy does have a role in establishing the diagnosis in select clinical settings (eg, in those with a high suspicion for celiac disease, with a negative serologic test result, and started on a GFD without biopsy confirmation of disease).
      The diagnosis is not always clear-cut. This is the case in those with minimal histologic findings, negative serologic test results, and repeated positive serologic test results but no apparent abnormalities on histologic examination. Histologic findings can also be misleading if the disease is patchy and an insufficient number of biopsy specimens were taken or if the biopsy specimen was poorly oriented and tissue sections were cut tangentially. Inflammatory changes in the mucosa can also be due to other causes.
      • Leonard N.
      • Feighery C.F.
      • Hourihane D.O.’B.
      Peptic duodenitis—does it exist in the second part of the duodenum?.
      Multiple biopsy specimens are best obtained from the second part of the duodenum or beyond. There is no accepted norm as to whether the histologic changes are interpreted as the most severe changes seen, the least severe changes seen, or the average degree of injury, although many publications grade the pathologic change by the most severe injury seen on any biopsy specimen.
      There are other disease entities that can resemble celiac disease histologically. Most of these entities are either rare in the developed world, are suggested by the clinical history, or have distinguishing histologic findings on careful review of the biopsy samples. Furthermore, it is crucial that the dietary status of the patient at the time of biopsy be taken into account. Patients should undergo biopsy promptly after obtaining a positive serologic test result and should be instructed not to avoid gluten until after biopsy specimens are obtained. A gluten-reduced diet may reduce the severity of the lesion and hence impact pathologic interpretation. How long gluten must be reintroduced before biopsy specimens are taken can vary among individuals already on a GFD. A 4-week challenge with sufficient gluten to reproduce the symptoms is adequate in most. However, some patients may have very delayed responses, and it can take up to several years for relapse to occur.
      • Ansaldi N.
      • Tavassoli K.
      • Faussone D.
      • Forni M.
      • Oderda G.
      Clinico-histological behavior of celiac patients after gluten load following the definitive diagnosis.
      In some individuals, further evaluation with testing for the presence of specific HLA class II DQ alleles can help exclude the disease; if alleles that code for DQ2 or DQ8 are absent, the need for biopsy can be alleviated. As noted, a diagnosis of celiac disease and prescription of a GFD for life should not be made in the absence of compatible small intestinal histologic findings and irrespective of positive serologic test results.

       Serologic Tests

      Widely available serologic tests used for detecting celiac disease include antigliadin antibodies (AGA), EMA, and tTG antibodies (tTGA). The diagnostic performance of these tests in various studies and clinical situations is examined in the following sections.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      Many of the studies that were reviewed had important methodological limitations; therefore, strict inclusion and exclusion criteria were used. Threats to the validity of studies of diagnostic tests, and the justification for the exclusion criteria used herein, were reported previously.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      The information provided is summarized in Table 2.
      Table 2Sensitivity and Specificity of Serologic Tests
      AnalysisSensitivity95% CISpecificity95% CI
      IgA EMA-ME, adult0.9740.957–0.9850.9960.988–0.999
      IgA EMA-ME, child0.9610.945–0.9730.9740.963–0.982
      IgA EMA-HU, adult0.9020.863–0.9250.9960.984–0.999
      IgA EMA-HU, child0.9690.935–0.986∼0.99H
      Heterogeneity in analysis; best estimate provided.
      IgA tTGA-GP, adult∼0.90H
      Heterogeneity in analysis; best estimate provided.
      0.9530.925–0.981
      IgA tTGA-GP, child0.9310.888–0.9590.9630.931–0.980
      IgA tTGA-HR, adult0.9510.918–0.9810.9830.971–0.996
      IgA tTGA-HR, child0.9570.903–0.9810.9900.946–0.998
      a Heterogeneity in analysis; best estimate provided.

       EMA

      EMA is measured using an immunofluorescence technique with monkey esophagus or human umbilical cord as the tissue substrate. The resulting stained tissue is viewed under a fluorescence microscope to determine if the staining pattern is positive. As a result, this test is more time consuming and operator dependent than the others.
      IgA EMA performed using monkey esophagus as substrate. The diagnostic performance of the IgA EMA performed using monkey esophagus (ME) as substrate in adults has been evaluated in several studies.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      The pooled sensitivity was excellent at 97.4% (95% confidence interval [CI], 95.7–98.5), as was the pooled specificity at 99.6% (95% CI, 98.8–99.9). In children, IgA EMA-ME also demonstrated excellent performance, with a pooled sensitivity and specificity of 96.1% (95% CI, 94.5–97.3) and 97.4% (95% CI, 96.3–98.2), respectively.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      In mixed populations of children and adults, studies showed specificities of greater than 98%. However, those studies had some variation in sensitivities. One study reported a very low sensitivity of 75%, while in the remainder the sensitivity ranged from 86% to 98%.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      IgA EMA performed using human umbilical cord as substrate. The specificity of the IgA EMA using human umbilical cord (HU) as substrate in adults was reported as 100% in nearly all the studies that met the inclusion criteria.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      • Collin P.
      • Kaukinen K.
      • Vogelsang H.
      • Korponay-Szabo I.
      • Sommer R.
      • Schreier E.
      • Volta U.
      • Granito A.
      • Veronesi L.
      • Mascart F.
      • Ocmant A.
      • Ivarsson A.
      • Lagerqvist C.
      • Burgin-Wolff A.
      • Hadziselimovic F.
      • Furlano R.I.
      • Sidler M.A.
      • Mulder C.J.
      • Goerres M.S.
      • Mearin M.L.
      • Ninaber M.K.
      • Gudmand-Hoyer E.
      • Fabiani E.
      • Catassi C.
      • Tidlund H.
      • Alainentalo L.
      • Maki M.
      Antiendomysial and antihuman recombinant tissue transglutaminase antibodies in the diagnosis of coeliac disease: a biopsy-proven European multicentre study.
      However, there was greater variability in the sensitivity, which ranged from 87% to 100%. The pooled sensitivity and specificity of this test were 90.2% (95% CI, 86.3–92.5) and 99.6% (95% CI, 98.4–99.9), respectively. Studies that assessed IgA EMA-HU performance in children reported some variability in specificity.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      As a result, a pooled specificity was not calculated but is likely to be close to 100%. The pooled sensitivity in children was 96.9% (95% CI, 93.5–98.6). Two studies assessed IgA EMA-HU in a mixed-age population. The pooled sensitivity was 93% (95% CI, 88.1%–95.4%), while the specificity was 100% (95% CI, 97.5%–100%).

       tTGA

      tTGA is measured by quantitative enzyme-linked immunosorbent assay with guinea pig liver (GP) or human recombinant or red cell–derived tTG as the substrate.

       IgA tTGA-GP

      Studies of tTGA-GP in adults have marked variability in the reported sensitivity, which precludes statistical pooling. However, the overall sensitivity is likely to be close to 90%.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      The pooled specificity was 95.3% (95% CI, 92.5%–98.1%). In children, the pooled estimates of sensitivity and specificity were 93.1% (95% CI, 88.8%–95.9%) and 96.3% (95% CI, 93.1%–98.0%), respectively.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      Among studies that used mixed age groups, the pooled sensitivity and specificity were 93.7% (95% CI, 90.8%–96.7%) and 95.4% (95% CI, 92.7%–97.2%), respectively.

       IgA tTGA HU

      Most commercial tests for IgA tTGA now use human recombinant or red blood cell–derived tTG as substrate. In an adult population, the pooled estimates of the sensitivity and specificity of IgA tTGA-HU were 95.1% (95% CI, 91.8%–98.1%) and 98.3% (95% CI, 97.1%–99.6%), respectively. Among the studies in children, the pooled estimates of sensitivity and specificity were 95.7% (95% CI, 90.3%–98.1%) and 99.0% (95% CI, 94.6%–99.8%), respectively. In a mixed-age population, the pooled estimates of sensitivity and specificity were 90.2% (95% CI, 86.4%–93.0%) and 95.4% (95% CI, 91.5%–97.6%), respectively.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      • Collin P.
      • Kaukinen K.
      • Vogelsang H.
      • Korponay-Szabo I.
      • Sommer R.
      • Schreier E.
      • Volta U.
      • Granito A.
      • Veronesi L.
      • Mascart F.
      • Ocmant A.
      • Ivarsson A.
      • Lagerqvist C.
      • Burgin-Wolff A.
      • Hadziselimovic F.
      • Furlano R.I.
      • Sidler M.A.
      • Mulder C.J.
      • Goerres M.S.
      • Mearin M.L.
      • Ninaber M.K.
      • Gudmand-Hoyer E.
      • Fabiani E.
      • Catassi C.
      • Tidlund H.
      • Alainentalo L.
      • Maki M.
      Antiendomysial and antihuman recombinant tissue transglutaminase antibodies in the diagnosis of coeliac disease: a biopsy-proven European multicentre study.
      There does not appear to be a major difference between tests that use recombinant tTG and those that use tTG derived from red blood cells.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      Overall, these studies demonstrate a specificity of IgA tTGA that is greater than 95% and a sensitivity in the range of 90%–96%. False-positive results of the IgA tTG-HU (eg, in patients with liver disease, congestive heart failure, arthritis, and inflammatory bowel disease) are less common than with the earlier-generation IgA tTG-GP tests, although there still may be differences in the sensitivity and specificity of test kits used by different commercial laboratories.

       IgA AGA

      IgA AGA by enzyme-linked immunosorbent assay predates the previously described serologic tests. Methodology for the conduct of this test has changed and improved over time, and along with other issues, such as different study populations and different test cutoff levels, has made the identified articles quite heterogeneous. However, the bulk of the data suggest that the specificity of the IgA AGA approximates 90%. Far greater variation exists in estimates of the sensitivity of this test. However, our best estimate would place the sensitivity in the 85%–90% range. Nonetheless, even if considering the sensitivity and specificity of this test to be in the low 90% range, the use of IgA AGA would still not be attractive in usual clinical practice owing to a very low positive predictive value (PPV) and the existence of alternative serologic tests with better diagnostic performance.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.

       Serologic Tests in IgA-Deficient Patients

      Selective IgA deficiency, the commonest human immunodeficiency, is 10–15 times more common in patients with celiac disease than in the general population, with a prevalence of 1.7%–3% in patients with celiac disease.
      • Cataldo F.
      • Marino V.
      • Bottaro G.
      • Greco P.
      • Ventura A.
      Celiac disease and selective immunoglobulin A deficiency.
      • Cataldo F.
      • Marino V.
      • Ventura A.
      • Bottaro G.
      • Corazza G.R.
      Italian Society of Paediatric Gastroenterology and Hepatology (SIGEP) and “Club del Tenue” Working Groups on Coeliac Disease
      Prevalence and clinical features of selective immunoglobulin A deficiency in coeliac disease: an Italian multicentre study.
      • Heneghan M.A.
      • Stevens F.M.
      • Cryan E.M.
      • Warner R.H.
      • McCarthy C.F.
      Celiac sprue and immunodeficiency states: a 25-year review.
      • Kumar V.
      • Jarzabek-Chorzelska M.
      • Sulej J.
      • Karnewska K.
      • Farrell T.
      • Jablonska S.
      Celiac disease and immunoglobulin a deficiency: how effective are the serological methods of diagnosis?.
      • Collin P.
      • Maki M.
      • Keyrilainen O.
      • Hallstrom O.
      • Reunala T.
      • Pasternack A.
      Selective IgA deficiency and coeliac disease.
      The reverse association is also the case, with a higher prevalence of celiac disease in IgA-deficient subjects (up to 8%).
      • Meini A.
      • Pillan N.M.
      • Villanacci V.
      • Monafo V.
      • Ugazio A.G.
      • Plebani A.
      Prevalence and diagnosis of celiac disease in IgA-deficient children.
      The importance of this association lies first in recognizing its existence and second in recognizing that because the standard EMA, tTGA, and AGA tests are IgA based, patients with both celiac disease and IgA deficiency cannot be reliably detected by these tests.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      In individuals who are not IgA deficient, the measurement of IgG AGA offers fair sensitivity and specificity (most studies in the 80%–90% range). Although IgG EMA and IgG tTG have excellent specificity in those individuals (up to 100%), their sensitivity generally has been less than 70%.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      In contrast, in celiac disease, IgA deficiency appears to result in higher titers of IgG EMA, IgG tTGA, and IgG AGA,
      • Cataldo F.
      • Lio D.
      • Marino V.
      • Picarelli A.
      • Ventura A.
      • Corazza G.R.
      IgG(1) antiendomysium and IgG antitissue transglutaminase (anti-tTG) antibodies in coeliac patients with selective IgA deficiency Working Groups on Celiac Disease of SIGEP and Club del Tenue.
      and it appears that the sensitivity of IgG EMA and tTGA is close to 100% in IgA-deficient patients with celiac disease.
      • Kumar V.
      • Jarzabek-Chorzelska M.
      • Sulej J.
      • Karnewska K.
      • Farrell T.
      • Jablonska S.
      Celiac disease and immunoglobulin a deficiency: how effective are the serological methods of diagnosis?.
      • Cataldo F.
      • Lio D.
      • Marino V.
      • Picarelli A.
      • Ventura A.
      • Corazza G.R.
      IgG(1) antiendomysium and IgG antitissue transglutaminase (anti-tTG) antibodies in coeliac patients with selective IgA deficiency Working Groups on Celiac Disease of SIGEP and Club del Tenue.
      • Korponay-Szabo I.R.
      • Dahlbom I.
      • Laurila K.
      • Koskinen S.
      • Woolley N.
      • Partanen J.
      • Kovacs J.B.
      • Maki M.
      • Hansson T.
      Elevation of IgG antibodies against tissue transglutaminase as a diagnostic tool for coeliac disease in selective IgA deficiency.
      The prevalence of IgA deficiency in celiac disease is sufficiently low, such that we do not consider the routine measurement of serum IgA levels along with IgA EMA or tTGA to be warranted as a first step toward diagnosis unless IgA deficiency is strongly suspected. In patients with a negative IgA EMA or IgA tTG but in whom celiac disease is still suspected, measurement of serum IgA levels is reasonable as a next step. If celiac disease is strongly suspected despite negative serologic test results, one can test for the presence of the disease-associated HLA alleles and, if present, proceed to small intestinal mucosal biopsy. Alternatively, it is reasonable to proceed directly to upper intestinal endoscopy and small bowel biopsy if the signs and symptoms that suggested celiac disease would otherwise warrant those procedures.
      We recommend that, in the primary care setting, the IgA tTGA be used as the most efficient single serologic test for the detection of celiac disease. The inclusion of other tests in the panel, especially IgG AGA and IgA AGA, adds little to the sensitivity but a substantial economic cost to specificity if any positive result leads to further investigation.

       Use of HLA-DQ2/DQ8 to Exclude the Diagnosis of Celiac Disease

      Approximately 25%–40% of the general population in the United States carry the HLA class II heterodimer HLA-DQ2 or HLA-DQ8, which reflects the presence of the DQ alleles DQA1*05 and DQB1*02 (DQ2) or DQA1*03 and DQB1*0302 (DQ8). However, almost all patients with celiac disease carry the DQ2 or DQ8 molecule.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      DQA1*05 and DQB1*02 typically occur on the same chromosome (ie, in cis) in individuals with HLA-DR17, or one of these alleles is present on each chromosome (ie, in trans) in individuals who are HLA-DR11/DR7 or HLA-DR12/DR7. Individuals in each of these cases can form a DQ2 molecule associated with susceptibility to celiac disease. Approximately 95% of patients with celiac disease have HLA-DQ2, whereas the remaining ∼5% have HLA-DQ8 in association with DR4. In Europe, a small number of patients with celiac disease have been noted to have only DQA1*O5 or DQB1*02, the latter usually being associated with HLA-DR7 heterozygosity or homozygosity. Of note, individuals homozygous for DR17 and thus homozygous for the DQ2 molecule associated with celiac disease comprise approximately 2% of the population but make up approximately 25% of all patients with celiac disease. Nonetheless, once the disease develops, the clinical course of the disease generally appears to be similar whether or not the disease develops, the clinical course of the disease generally appears to be similar whether or not 100%, 50%, or 25% of an individual’s HLA-DQ molecules are DQ2.
      • Vader W.
      • Stepniak D.
      • Kooy Y.
      • Mearin L.
      • Thompson A.
      • van Rood J.J.
      • Spaenij L.
      • Koning F.
      The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses.
      The DQ alleles present in celiac disease are also found in 48%–65% of healthy relatives of patients with celiac disease and up to 73% of patients with type 1 diabetes mellitus (DM1), which is also associated with celiac disease.
      Virtually all patients with celiac disease have the celiac disease–associated alleles mentioned previously at the DQA1 and DQB1 loci. Thus, the presence of those alleles provides a sensitivity of close to 100% for celiac disease and a very high negative predictive value for the disease (ie, if individuals lack the relevant disease-associated alleles, celiac disease is virtually excluded). HLA testing for the relevant DQ alleles can be a very useful adjunct in an exclusionary sense when the diagnosis based on other test results is not clear.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      In contrast, given the marked prevalence of the celiac disease–associated HLA class II alleles in the general population,
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      the specificity of these alleles for the disease is poor. The specificity of HLA class II DQ and DR alleles is also low when the tested population is known to have a high prevalence of celiac disease, such as in those with DM1 or first-degree relatives of patients with celiac disease. Despite a higher prevalence of celiac disease in such patients, the poor specificity makes the PPV low.
      • Doolan A.
      • Donaghue K.
      • Fairchild J.
      • Wong M.
      • Williams A.J.
      Use of HLA typing in diagnosing celiac disease in patients with type 1 diabetes.
      Someone using HLA testing in the context of disease susceptibility in families, for example, must have the resources available to provide genetic counseling to subjects.

       Pitfalls of Relying on Serologic Test Results Without a Small Intestinal Mucosal Biopsy

      A small intestinal mucosal biopsy is the current gold standard for the diagnosis of celiac disease and must be used to confirm positive serologic test results before introduction of a lifelong dietary modification.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      The importance of a biopsy relates to concerns regarding the sensitivity of serologic tests in certain clinical circumstances and the potentially low PPV of serologic tests in usual clinical practice.
      Multiple studies have shown that the sensitivity of EMA, tTGA, or AGA is related to the grade of histologic damage in celiac disease.
      • Marsh M.N.
      Gluten, major histocompatibility complex, and the small intestine: a molecular and immunobiologic approach to the spectrum of gluten sensitivity (’celiac sprue’).
      • Rostami K.
      • Kerckhaert J.
      • Tiemessen R.
      • von Blomberg B.M.
      • Meijer J.W.
      • Mulder C.J.
      Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice.
      This has been observed both at the initial diagnosis and in the setting of monitoring for adherence to a GFD with serologic testing. The identified studies outlined earlier in this report were consistent in demonstrating a high sensitivity of the serologic tests in patients with total villous atrophy, with a subsequent decrease in sensitivity as less severe histologic grades of celiac disease were considered.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      The sensitivity of IgA EMA or tTG in patients with partial villous atrophy ranged from 89% to as low as 30%, while the sensitivity in patients with Marsh grade II lesions was less than 50%.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      The PPV of IgA EMA and tTGA is also of potential concern. These tests have reported specificities close to 100% in the identified studies, but unless the specificity is truly perfect in usual clinical practice (>99%), then the PPV can be low. For example, if the prevalence of celiac disease is 15% and the sensitivity and specificity are both 98%, the PPV will be 90% (90% of patients with a positive test result have celiac disease and 10% do not have celiac disease). Any decrease in the prevalence of celiac disease (note that the prevalence is 1% in the general population) or the specificity of the test will lead to further decreases in PPV, hence the absolute need for confirmatory biopsy. Stated in another way, the positive (49.0) and negative (0.02) likelihood ratios for these serologic tests are excellent. However, a clinician’s pretest probability for a patient having celiac disease has to be greater than 35% for the post-test probability to be greater than 95%. Given our new understanding of the spectrum of celiac disease and the celiac iceberg, situations wherein the pretest probability of celiac disease is 35% or higher are unusual. Therefore, it is prudent to confirm positive serologic test results before making a diagnosis of celiac disease and before instituting lifelong dietary changes.
      Nonetheless, we note that diagnosis by biopsy in itself is not a perfect gold standard in that the disease can be patchy and the histologic features are not unique to celiac disease. The diagnosis of celiac disease in patients with Marsh grade I or II lesions may need further supportive evidence, such as through serologic or HLA testing. Further, persistently positive celiac disease serologic test results in the presence of normal histologic findings may be an indicator of latent celiac disease.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.

      Epidemiology

      Celiac disease has been classified into 4 phenotypes,
      National Institutes of Health Consensus Development Conference Statement on Celiac Disease, June 28-30, 2004.
      as described in Table 3. “Classic” celiac disease is dominated by the symptoms and sequelae of gastrointestinal malabsorption. “Atypical” celiac disease is characterized by few or no gastrointestinal symptoms, with extraintestinal manifestations predominating.
      National Institutes of Health Consensus Development Conference Statement on Celiac Disease, June 28-30, 2004.
      Of note, atypical celiac disease is more prevalent than classic celiac disease, which could call into question the use of these terms. “Silent” celiac disease is used when asymptomatic individuals have villous atrophy on biopsy. They may also have positive serologic test results. “Latent” celiac disease is characterized by asymptomatic individuals with currently normal histologic findings on a gluten-sufficient diet who subsequently develop celiac disease or those with a prior diagnosis of celiac disease that responded to a GFD and retain normal mucosal histologic findings despite the long-term ingestion of gluten. These individuals are asymptomatic and may or may not have an increase in intraepithelial lymphocytes.
      Table 3Common Definitions of Celiac Disease
      ClassicClassic celiac disease is the most commonly described form. It describes patients with the classic features of intestinal malabsorption who have fully developed gluten-induced villous atrophy and other classic histologic features. These patients present because of gastrointestinal symptoms.
      AtypicalAtypical celiac disease appears to be the most common form. These patients generally have little to no gastrointestinal symptoms but come to medical attention because of other reasons such as iron deficiency, osteoporosis, short stature, or infertility. These patients generally have fully developed gluten-induced villous atrophy. Because these patients are “asymptomatic” from the gastrointestinal perspective, a large number go undiagnosed.
      SilentSilent celiac disease refers to asymptomatic patients who are discovered to have gluten-induced villous atrophy. They are discovered after serologic screening or perhaps during endoscopy and biopsy for another reason. These patients are clinically silent in that they do not manifest any clear gastrointestinal symptoms or associated atypical features of celiac disease such as iron deficiency or osteoporosis.
      LatentLatent celiac disease represents patients with a previous diagnosis of celiac disease that responded to a GFD and who retain a normal mucosal histology or manifest only an increase in intraepithelial lymphocytes. Latent celiac disease can also represent patients with currently normal intestinal mucosa on a gluten-containing diet who will subsequently develop celiac disease.
      RefractoryRefractory celiac disease represents patients with true celiac disease (ie, not a misdiagnosis) who do not or no longer respond to a GFD. Some of these patients develop complications such as ulcerative jejunoileitis or enteropathy-associated T-cell lymphoma.

      Prevalence of Celiac Disease

       Prevalence of Celiac Disease in the General Population

      Much of the data on the prevalence of celiac disease in the general population has come from western European countries, where celiac disease previously was believed to be more common than in other parts of the world, including the United States. However, it is now apparent that celiac disease is also common in the United States, Eastern Europe, and many other countries with the exception of Japan.
      • Catassi C.
      • Doloretta M.M.
      • Ratsch I.M.
      • De Virgiliis S.
      • Cucca F.
      The distribution of DQ genes in the Saharawi population provides only a partial explanation for the high celiac disease prevalence.
      • Poddar U.
      • Thapa B.R.
      • Nain C.K.
      • Prasad A.
      • Singh K.
      Celiac disease in India: are they true cases of celiac disease?.
      • Elsurer R.
      • Tatar G.
      • Simsek H.
      • Balaban Y.H.
      • Aydinli M.
      • Sokmensuer C.
      Celiac disease in the Turkish population.
      • Gursoy S.
      • Guven K.
      • Simsek T.
      • Yurci A.
      • Torun E.
      • Koc N.
      • Patiroglu T.E.
      • Ozbakir O.
      • Yucesoy M.
      The prevalence of unrecognized adult celiac disease in Central Anatolia.
      The prevalence of celiac disease varies greatly across and within different countries (Scandinavian countries,
      • Grodzinsky E.
      • Hed J.
      • Lieden G.
      • Sjogren F.
      • Strom M.
      Presence of IgA and IgG antigliadin antibodies in healthy adults as measured by micro-ELISA Effect of various cutoff levels on specificity and sensitivity when diagnosing coeliac disease.
      • Carlsson A.K.
      • Axelsson I.E.
      • Borulf S.K.
      • Bredberg A.C.
      • Ivarsson S.A.
      Serological screening for celiac disease in healthy 2.5-year-old children in Sweden.
      • Collin P.
      • Rasmussen M.
      • Kyronpalo S.
      • Laippala P.
      • Kaukinen K.
      The hunt for coeliac disease in primary care.
      • Grodzinsky E.
      Screening for coeliac disease in apparently healthy blood donors.
      • Grodzinsky E.
      • Franzen L.
      • Hed J.
      • Strom M.
      High prevalence of celiac disease in healthy adults revealed by antigliadin antibodies.
      • Hovdenak N.
      • Hovlid E.
      • Aksnes L.
      • Fluge G.
      • Erichsen M.M.
      • Eide J.
      High prevalence of asymptomatic coeliac disease in Norway: a study of blood donors.
      • Ivarsson A.
      • Persson L.A.
      • Juto P.
      • Peltonen M.
      • Suhr O.
      • Hernell O.
      High prevalence of undiagnosed coeliac disease in adults: a Swedish population-based study.
      • Lagerqvist C.
      • Ivarsson A.
      • Juto P.
      • Persson L.A.
      • Hernell O.
      Screening for adult coeliac disease - which serological marker(s) to use?.
      • Kolho K.L.
      • Farkkila M.A.
      • Savilahti E.
      Undiagnosed coeliac disease is common in Finnish adults.
      • Maki M.
      • Mustalahti K.
      • Kokkonen J.
      • Kulmala P.
      • Haapalahti M.
      • Karttunen T.
      • Ilonen J.
      • Laurila K.
      • Dahlbom I.
      • Hansson T.
      • Hopfl P.
      • Knip M.
      Prevalence of celiac disease among children in Finland.
      • Sjoberg K.
      • Alm R.
      • Ivarsson S.A.
      • Lindstrom C.
      • Eriksson S.
      Prevalence and clinical significance of gliadin antibodies in healthy children and adults.
      • Sjoberg K.
      • Eriksson S.
      Regional differences in coeliac disease prevalence in Scandinavia?.
      • Weile I.
      • Grodzinsky E.
      • Skogh T.
      • Jordal R.
      • Cavell B.
      • Krasilnikoff P.A.
      High prevalence rates of adult silent coeliac disease, as seen in Sweden, must be expected in Denmark.
      • Weile B.
      • Grodzinsky E.
      • Skogh T.
      • Jordal R.
      • Cavell B.
      • Krasilnikoff P.A.
      Screening Danish blood donors for antigliadin and antiendomysium antibodies.
      • Borch K.
      • Grodzinsky E.
      • Petersson F.
      • Jonsson K.-A.
      • Mardh S.
      • Valdimarsson T.
      Prevalence of coeliac disease and relations to Helicobacter pylori infection and duodenitis in a Swedish adult population sample: a histomorphological and serological survey.
      • Csizmadia C.G.D.S.
      • Mearin M.L.
      • Von Blomberg B.M.E.
      • Brand R.
      • Verloove-Vanhorick S.P.
      An iceberg of childhood coeliac disease in the Netherlands.
      Italy,
      • Tommasini A.
      • Not T.
      • Kiren V.
      • Baldas V.
      • Santon D.
      • Trevisiol C.
      • Berti I.
      • Neri E.
      • Gerarduzzi T.
      • Bruno I.
      • Lenhardt A.
      • Zamuner E.
      • Spano A.
      • Crovella S.
      • Martellossi S.
      • Torre G.
      • Sblattero D.
      • Marzari R.
      • Bradbury A.
      • Tamburlini G.
      • Ventura A.
      Mass screening for coeliac disease using antihuman transglutaminase antibody assay.
      • Catassi C.
      • Fabiani E.
      • Ratsch I.M.
      • Coppa G.V.
      • Giorgi P.L.
      • Pierdomenico R.
      • Alessandrini S.
      • Iwanejko G.
      • Domenici R.
      • Mei E.
      • Miano A.
      • Marani M.
      • Bottaro G.
      • Spina M.
      • Dotti M.
      • Montanelli A.
      • Barbato M.
      • Viola F.
      • Lazzari R.
      • Vallini M.
      • Guariso G.
      • Plebani M.
      • Cataldo F.
      • Traverso G.
      • Ventura A.
      The coeliac iceberg in Italy A multicentre antigliadin antibodies screening for coeliac disease in school-age subjects.
      • Catassi C.
      • Fanciulli G.
      • D’Appello A.R.
      • El Asmar R.
      • Rondina C.
      • Fabiani E.
      • Bearzi I.
      • Coppa G V.
      Antiendomysium versus antigliadin antibodies in screening the general population for coeliac disease.
      • Catassi C.
      • Ratsch I.M.
      • Fabiani E.
      • Ricci S.
      • Bordicchia F.
      • Pierdomenico R.
      • Giorgi P.L.
      High prevalence of undiagnosed coeliac disease in 5280 Italian students screened by antigliadin antibodies.
      • Catassi C.
      • Ratsch I.M.
      • Fabiani E.
      • Rossini M.
      • Bordicchia F.
      • Candela F.
      • Coppa G.V.
      • Giorgi P.L.
      Coeliac disease in the year 2000: exploring the iceberg.
      • Mazzetti D.P.
      • Giorgetti G.M.
      • Gregori M.
      • De Simone M.
      • Leonardi C.
      • Barletta P.A.
      • Ricciardi M.M.
      • Sandri G.
      Subclinical coeliac disease.
      • Pittschieler K.
      • Ladinser B.
      Coeliac disease: screened by a new strategy.
      • Trevisiol C.
      • Not T.
      • Berti I.
      • Buratti E.
      • Citta A.
      • Neri E.
      • Torre G.
      • Martelossi S.
      • Tommasini A.
      • Alu A.
      • Barillari G.
      • Facchini S.
      • Ventura A.
      Screening for coeliac disease in healthy blood donors at two immuno-transfusion centres in north-east Italy.
      • Volta U.
      • Bellentani S.
      • Bianchi F.B.
      • Brandi G.
      • De Franceschi L.
      • Miglioli L.
      • Granito A.
      • Balli F.
      • Tiribelli C.
      High prevalence of celiac disease in Italian general population.
      • Fabiani E.
      • Peruzzi E.
      • Mandolesi A.
      • Garbuglia G.
      • Fanciulli G.
      • D’Appello A.R.
      • Gasparin M.
      • Bravi E.
      • Bearzi I.
      • Galeazzi R.
      • Catassi C.
      Anti-human versus anti-guinea pig tissue transglutaminase antibodies as the first-level serological screening test for coeliac disease in the general population.
      • Castano L.
      • Blarduni E.
      • Ortiz L.
      • Nunez J.
      • Bilbao J.R.
      • Rica I.
      • Martul P.
      • Vitoria J.C.
      Prospective population screening for celiac disease: high prevalence in the first 3 years of life.
      the United Kingdom,
      • Johnston S.D.
      • Watson R.G.
      • McMillan S.A.
      • Sloan J.
      • Love A.H.
      Coeliac disease detected by screening is not silent—simply unrecognized.
      • McMillan S.A.
      • Watson R.P.
      • McCrum E.E.
      • Evans A.E.
      Factors associated with serum antibodies to reticulin, endomysium, and gliadin in an adult population.
      • Sanders D.S.
      • Patel D.
      • Stephenson T.J.
      • Ward A.M.
      • McCloskey E.V.
      • Hadjivassiliou M.
      • Lobo A.J.
      A primary care cross-sectional study of undiagnosed adult coeliac disease.
      • West J.
      • Logan R.F.A.
      • Hill P.G.
      • Lloyd A.
      • Lewis S.
      • Hubbard R.
      • Reader R.
      • Holmes G.K.T.
      • Khaw K.-T.
      Seroprevalence, correlates, and characteristics of undetected coeliac disease in England.
      • Dickey W.
      • McMillan S.A.
      • Bharucha C.
      • Porter K.G.
      Antigliadin antibodies in blood donors in Northern Ireland.
      and other countries [Spain,
      • Riestra S.
      • Fernandez E.
      • Rodrigo L.
      • Garcia S.
      • Ocio G.
      Prevalence of coeliac disease in the general population of northern Spain Strategies of serologic screening.
      Republic of San Marino,
      • Corazza G.R.
      • Andreani M.L.
      • Biagi F.
      • Corrao G.
      • Pretolani S.
      • Giulianelli G.
      • Ghironzi G.
      • Gasbarrini G.
      The smaller size of the ’coeliac iceberg’ in adults.
      The Netherlands,
      • Rostami K.
      • Mulder C.J.
      • Werre J.M.
      • van Beukelen F.R.
      • Kerchhaert J.
      • Crusius J.B.
      • Pena A.S.
      • Willekens F.L.
      • Meijer J.W.
      High prevalence of celiac disease in apparently healthy blood donors suggests a high prevalence of undiagnosed celiac disease in the Dutch population.
      • Schweizer J.J.
      • von B.
      • Bueno-de M.
      • Mearin M.L.
      Coeliac disease in The Netherlands.
      Switzerland,
      • Rutz R.
      • Ritzler E.
      • Fierz W.
      • Herzog D.
      Prevalence of asymptomatic celiac disease in adolescents of eastern Switzerland.
      and Germany
      • Jaeger C.
      • Hatziagelaki E.
      • Petzoldt R.
      • Bretzel R.G.
      Comparative analysis of organ-specific autoantibodies and celiac disease—associated antibodies in type 1 diabetic patients, their first-degree relatives, and healthy control subjects.
      ). This variability reflects true population differences in the risk of celiac disease as well as differences in study design and screening strategies, including the choice of serologic tests and whether biopsy confirmation was performed.
      The reported prevalence of celiac disease ranges from 1:658 (0.152%) to 1:37 (2.67%) by serologic testing and from 1:658 (0.152%) to 1:53 (1.87%) by biopsy. Among European studies, 4 reports found a prevalence of celiac disease of greater than 1:66 (1.5%) (United Kingdom,
      • Sanders D.S.
      • Patel D.
      • Stephenson T.J.
      • Ward A.M.
      • McCloskey E.V.
      • Hadjivassiliou M.
      • Lobo A.J.
      A primary care cross-sectional study of undiagnosed adult coeliac disease.
      Sweden,
      • Carlsson A.K.
      • Axelsson I.E.
      • Borulf S.K.
      • Bredberg A.C.
      • Ivarsson S.A.
      Serological screening for celiac disease in healthy 2.5-year-old children in Sweden.
      • Borch K.
      • Grodzinsky E.
      • Petersson F.
      • Jonsson K.-A.
      • Mardh S.
      • Valdimarsson T.
      Prevalence of coeliac disease and relations to Helicobacter pylori infection and duodenitis in a Swedish adult population sample: a histomorphological and serological survey.
      and Germany
      • Jaeger C.
      • Hatziagelaki E.
      • Petzoldt R.
      • Bretzel R.G.
      Comparative analysis of organ-specific autoantibodies and celiac disease—associated antibodies in type 1 diabetic patients, their first-degree relatives, and healthy control subjects.
      ). An additional 6 studies showed a prevalence of between 1:100 (1.0%) and 1:66 (1.5%) (United Kingdom,
      • West J.
      • Logan R.F.A.
      • Hill P.G.
      • Lloyd A.
      • Lewis S.
      • Hubbard R.
      • Reader R.
      • Holmes G.K.T.
      • Khaw K.-T.
      Seroprevalence, correlates, and characteristics of undetected coeliac disease in England.
      Sweden,
      • Sjoberg K.
      • Alm R.
      • Ivarsson S.A.
      • Lindstrom C.
      • Eriksson S.
      Prevalence and clinical significance of gliadin antibodies in healthy children and adults.
      Netherlands,
      • Csizmadia C.G.D.S.
      • Mearin M.L.
      • Von Blomberg B.M.E.
      • Brand R.
      • Verloove-Vanhorick S.P.
      An iceberg of childhood coeliac disease in the Netherlands.
      Ireland,
      • Dickey W.
      • McMillan S.A.
      • Bharucha C.
      • Porter K.G.
      Antigliadin antibodies in blood donors in Northern Ireland.
      and Finland
      • Kolho K.L.
      • Farkkila M.A.
      • Savilahti E.
      Undiagnosed coeliac disease is common in Finnish adults.
      • Maki M.
      • Mustalahti K.
      • Kokkonen J.
      • Kulmala P.
      • Haapalahti M.
      • Karttunen T.
      • Ilonen J.
      • Laurila K.
      • Dahlbom I.
      • Hansson T.
      • Hopfl P.
      • Knip M.
      Prevalence of celiac disease among children in Finland.
      ). Three of 8 studies conducted in children reported a prevalence of celiac disease of greater than 1:100 (1.0%) (Finland,
      • Maki M.
      • Mustalahti K.
      • Kokkonen J.
      • Kulmala P.
      • Haapalahti M.
      • Karttunen T.
      • Ilonen J.
      • Laurila K.
      • Dahlbom I.
      • Hansson T.
      • Hopfl P.
      • Knip M.
      Prevalence of celiac disease among children in Finland.
      Sweden,
      • Carlsson A.K.
      • Axelsson I.E.
      • Borulf S.K.
      • Bredberg A.C.
      • Ivarsson S.A.
      Serological screening for celiac disease in healthy 2.5-year-old children in Sweden.
      and The Netherlands
      • Csizmadia C.G.D.S.
      • Mearin M.L.
      • Von Blomberg B.M.E.
      • Brand R.
      • Verloove-Vanhorick S.P.
      An iceberg of childhood coeliac disease in the Netherlands.
      ). These studies would suggest a potentially higher prevalence of celiac disease in these countries. However, other reports from these same countries showed a prevalence of less than 1.0%, including 4 studies from Sweden.
      • Grodzinsky E.
      Screening for coeliac disease in apparently healthy blood donors.
      • Ivarsson A.
      • Persson L.A.
      • Juto P.
      • Peltonen M.
      • Suhr O.
      • Hernell O.
      High prevalence of undiagnosed coeliac disease in adults: a Swedish population-based study.
      • Sjoberg K.
      • Alm R.
      • Ivarsson S.A.
      • Lindstrom C.
      • Eriksson S.
      Prevalence and clinical significance of gliadin antibodies in healthy children and adults.
      • Sjoberg K.
      • Eriksson S.
      Regional differences in coeliac disease prevalence in Scandinavia?.
      Several studies on the prevalence of celiac disease in the general US population have been conducted. The largest of these found a prevalence of celiac disease in “not at risk” populations of 1:105 (0.95%) in adults, 1:322 (0.31%) in children, and 1:133 overall (0.75%).
      • Fasano A.
      • Berti I.
      • Gerarduzzi T.
      • Not T.
      • Colletti R.B.
      • Drago S.
      • Elitsur Y.
      • Green P.H.R.
      • Guandalini S.
      • Hill I.D.
      • Pietzak M.
      • Ventura A.
      • Thorpe M.
      • Kryszak D.
      • Fornaroli F.
      • Wasserman S.S.
      • Murray J.A.
      • Horvath K.
      Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study.
      In another study,
      • Not T.
      • Horvath K.
      • Hill I.D.
      • Partanen J.
      • Hammed A.
      • Magazzu G.
      • Fasano A.
      Celiac disease risk in the USA: high prevalence of antiendomysium antibodies in healthy blood donors.
      the prevalence of serologies suggestive of celiac disease was 1:250 (0.4%) by initial AGA testing followed by EMA confirmation (data from this study were also included in the first report
      • Fasano A.
      • Berti I.
      • Gerarduzzi T.
      • Not T.
      • Colletti R.B.
      • Drago S.
      • Elitsur Y.
      • Green P.H.R.
      • Guandalini S.
      • Hill I.D.
      • Pietzak M.
      • Ventura A.
      • Thorpe M.
      • Kryszak D.
      • Fornaroli F.
      • Wasserman S.S.
      • Murray J.A.
      • Horvath K.
      Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study.
      ). In neither report were serologic test results confirmed by biopsy.
      The prevalence of celiac disease in 9 Italian studies was similar to that reported in the United States, ranging from 1:500 (0.2%) to 1:93 (1.08%).
      • Tommasini A.
      • Not T.
      • Kiren V.
      • Baldas V.
      • Santon D.
      • Trevisiol C.
      • Berti I.
      • Neri E.
      • Gerarduzzi T.
      • Bruno I.
      • Lenhardt A.
      • Zamuner E.
      • Spano A.
      • Crovella S.
      • Martellossi S.
      • Torre G.
      • Sblattero D.
      • Marzari R.
      • Bradbury A.
      • Tamburlini G.
      • Ventura A.
      Mass screening for coeliac disease using antihuman transglutaminase antibody assay.
      • Catassi C.
      • Fanciulli G.
      • D’Appello A.R.
      • El Asmar R.
      • Rondina C.
      • Fabiani E.
      • Bearzi I.
      • Coppa G V.
      Antiendomysium versus antigliadin antibodies in screening the general population for coeliac disease.
      • Mazzetti D.P.
      • Giorgetti G.M.
      • Gregori M.
      • De Simone M.
      • Leonardi C.
      • Barletta P.A.
      • Ricciardi M.M.
      • Sandri G.
      Subclinical coeliac disease.
      • Pittschieler K.
      • Ladinser B.
      Coeliac disease: screened by a new strategy.
      • Trevisiol C.
      • Not T.
      • Berti I.
      • Buratti E.
      • Citta A.
      • Neri E.
      • Torre G.
      • Martelossi S.
      • Tommasini A.
      • Alu A.
      • Barillari G.
      • Facchini S.
      • Ventura A.
      Screening for coeliac disease in healthy blood donors at two immuno-transfusion centres in north-east Italy.
      • Volta U.
      • Bellentani S.
      • Bianchi F.B.
      • Brandi G.
      • De Franceschi L.
      • Miglioli L.
      • Granito A.
      • Balli F.
      • Tiribelli C.
      High prevalence of celiac disease in Italian general population.
      • Fabiani E.
      • Peruzzi E.
      • Mandolesi A.
      • Garbuglia G.
      • Fanciulli G.
      • D’Appello A.R.
      • Gasparin M.
      • Bravi E.
      • Bearzi I.
      • Galeazzi R.
      • Catassi C.
      Anti-human versus anti-guinea pig tissue transglutaminase antibodies as the first-level serological screening test for coeliac disease in the general population.
      • Castano L.
      • Blarduni E.
      • Ortiz L.
      • Nunez J.
      • Bilbao J.R.
      • Rica I.
      • Martul P.
      • Vitoria J.C.
      Prospective population screening for celiac disease: high prevalence in the first 3 years of life.
      • Riestra S.
      • Fernandez E.
      • Rodrigo L.
      • Garcia S.
      • Ocio G.
      Prevalence of coeliac disease in the general population of northern Spain Strategies of serologic screening.
      In 2 reports in children, the prevalence of celiac disease confirmed by biopsy was 1:106 (0.94%)
      • Tommasini A.
      • Not T.
      • Kiren V.
      • Baldas V.
      • Santon D.
      • Trevisiol C.
      • Berti I.
      • Neri E.
      • Gerarduzzi T.
      • Bruno I.
      • Lenhardt A.
      • Zamuner E.
      • Spano A.
      • Crovella S.
      • Martellossi S.
      • Torre G.
      • Sblattero D.
      • Marzari R.
      • Bradbury A.
      • Tamburlini G.
      • Ventura A.
      Mass screening for coeliac disease using antihuman transglutaminase antibody assay.
      and 1:119 (0.84%).
      • Castano L.
      • Blarduni E.
      • Ortiz L.
      • Nunez J.
      • Bilbao J.R.
      • Rica I.
      • Martul P.
      • Vitoria J.C.
      Prospective population screening for celiac disease: high prevalence in the first 3 years of life.
      These results are similar to that of another report in a population of mostly adult Italians of 1:126 (0.79%).
      • Fabiani E.
      • Peruzzi E.
      • Mandolesi A.
      • Garbuglia G.
      • Fanciulli G.
      • D’Appello A.R.
      • Gasparin M.
      • Bravi E.
      • Bearzi I.
      • Galeazzi R.
      • Catassi C.
      Anti-human versus anti-guinea pig tissue transglutaminase antibodies as the first-level serological screening test for coeliac disease in the general population.
      Overall, in interpreting these reports, we found that those studies with the smallest sample sizes tended to produce both the highest and lowest prevalence of celiac disease. Further, a number of studies did not mandate biopsy confirmation or a proportion of the patients did not undergo biopsy. In the last instance, the investigators tended to report the prevalence of celiac disease in a screened population based only on those patients with positive serologic test results who agreed to undergo biopsy, therefore potentially underestimating the true prevalence because some of those with positive serologic test results who declined to undergo a biopsy would also be expected to have celiac disease. With these limitations in mind, the prevalence of celiac disease in Western populations, including in the United States, appears to be approximately 1:100 (1%), with a reasonable range of 1:80 to 1:140 (1.25% to 0.71%).
      As described in the following text, there are a number of populations at high risk for celiac disease, and in some of those screening should be conducted routinely (eg, unexplained iron deficiency anemia [IDA]). In other high-risk categories (eg, first-degree relatives), only symptomatic individuals should undergo screening for celiac disease because current data do not support a clear outcome benefit for the early detection and treatment of asymptomatic individuals in those categories. Nonetheless, the physician may wish to engage in individual discussions with such patients regarding the benefits and consequences of testing for celiac disease.

       Prevalence of Celiac Disease in Relatives of Individuals With Known Celiac Disease

       First-degree relatives

      In 5 studies, the prevalence of celiac disease in first-degree relatives of patients with celiac disease was evaluated using small intestinal mucosal biopsy alone.
      • Robinson D.C.
      • Watson A.J.
      • Wyatt E.H.
      • Marks J.M.
      • Roberts D.F.
      Incidence of small-intestinal mucosal abnormalities and of clinical coeliac disease in the relatives of children with coeliac disease.
      • Rolles C.J.
      • Myint T.O.
      • Sin W.K.
      • Anderson M.
      Proceedings: family study of coeliac disease.
      • Stokes P.L.
      • Ferguson R.
      • Holmes G.K.
      • Cooke W.T.
      Familial aspects of coeliac disease.
      • Polvi A.
      • Eland C.
      • Koskimies S.
      • Maki M.
      • Partanen J.
      HLA DQ and DP in Finnish families with celiac disease.
      • Holm K.H.
      Correlation of HLA-DR alleles to jejunal mucosal morphology in healthy first-degree relatives of coeliac disease patients.
      In these studies, the percentage of at-risk family members tested varied from 34%
      • Stokes P.L.
      • Ferguson R.
      • Holmes G.K.
      • Cooke W.T.
      Familial aspects of coeliac disease.
      to 100%,
      • Rolles C.J.
      • Myint T.O.
      • Sin W.K.
      • Anderson M.
      Proceedings: family study of coeliac disease.
      and the specific biopsy criteria were either not reported
      • Rolles C.J.
      • Myint T.O.
      • Sin W.K.
      • Anderson M.
      Proceedings: family study of coeliac disease.
      or implied some degree of villous atrophy.
      • Robinson D.C.
      • Watson A.J.
      • Wyatt E.H.
      • Marks J.M.
      • Roberts D.F.
      Incidence of small-intestinal mucosal abnormalities and of clinical coeliac disease in the relatives of children with coeliac disease.
      • Polvi A.
      • Eland C.
      • Koskimies S.
      • Maki M.
      • Partanen J.
      HLA DQ and DP in Finnish families with celiac disease.
      • Holm K.H.
      Correlation of HLA-DR alleles to jejunal mucosal morphology in healthy first-degree relatives of coeliac disease patients.
      • Di Stefano M.
      • Jorizzo R.A.
      • Veneto G.
      • Cecchetti L.
      • Gasbarrini G.
      • Corazza G.R.
      Bone mass and metabolism in dermatitis herpetiformis.
      The prevalence of celiac disease among these first-degree relatives undergoing intestinal biopsy was reported to be 5.5%,
      • Rolles C.J.
      • Myint T.O.
      • Sin W.K.
      • Anderson M.
      Proceedings: family study of coeliac disease.
      10.3%,
      • Robinson D.C.
      • Watson A.J.
      • Wyatt E.H.
      • Marks J.M.
      • Roberts D.F.
      Incidence of small-intestinal mucosal abnormalities and of clinical coeliac disease in the relatives of children with coeliac disease.
      10.7%,
      • Holm K.H.
      Correlation of HLA-DR alleles to jejunal mucosal morphology in healthy first-degree relatives of coeliac disease patients.
      20%,
      • Polvi A.
      • Eland C.
      • Koskimies S.
      • Maki M.
      • Partanen J.
      HLA DQ and DP in Finnish families with celiac disease.
      and 22.5%.
      • Stokes P.L.
      • Ferguson R.
      • Holmes G.K.
      • Cooke W.T.
      Familial aspects of coeliac disease.
      The prevalence of celiac disease in first-degree relatives of patients with celiac disease was also evaluated in studies using initial serologic screening.
      • Fasano A.
      • Berti I.
      • Gerarduzzi T.
      • Not T.
      • Colletti R.B.
      • Drago S.
      • Elitsur Y.
      • Green P.H.R.
      • Guandalini S.
      • Hill I.D.
      • Pietzak M.
      • Ventura A.
      • Thorpe M.
      • Kryszak D.
      • Fornaroli F.
      • Wasserman S.S.
      • Murray J.A.
      • Horvath K.
      Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study.
      • Corazza G.
      • Valentini R.A.
      • Frisoni M.
      • Volta U.
      • Corrao G.
      • Bianchi F.B.
      • Gasbarrini G.
      Gliadin immune reactivity is associated with overt and latent enteropathy in relatives of celiac patients.
      • Pittschieler K.
      • Gentili L.
      • Niederhofer H.
      Onset of coeliac disease: a prospective longitudinal study.
      • Tursi A.
      • Brandimarte G.
      • Giorgetti G.M.
      • Inchingolo C.D.
      Effectiveness of the sorbitol HSUB2 breath test in detecting histological damage among relatives of coeliacs.
      • Rostami K.
      • Mulder C.J.
      • van Overbeek F.M.
      • Kerckhaert J.
      • Meijer J.W.
      • von Blomberg M.B.
      • Heymans H.S.
      Should relatives of coeliacs with mild clinical complaints undergo a small-bowel biopsy despite negative serology?.
      • Hogberg L.
      • Falth-Magnusson K.
      • Grodzinsky E.
      • Stenhammar L.
      Familial prevalence of coeliac disease: a twenty-year follow-up study.
      • Korponay-Szabo I.
      • Kovacs J.
      • Lorincz M.
      • Torok E.
      • Goracz G.
      Families with multiple cases of gluten-sensitive enteropathy.
      • Farre C.
      • Humbert P.
      • Vilar P.
      • Varea V.
      • Aldeguer X.
      • Carnicer J.
      • Carballo M.
      • Gassull M.A.
      Catalonian Coeliac Disease Study Group
      Serological markers and HLA-DQ2 haplotype among first-degree relatives of celiac patients.
      • Mustalahti K.
      • Sulkanen S.
      • Holopainen P.
      • Laurila K.
      • Collin P.
      • Partanen J.
      • Maki M.
      Coeliac disease among healthy members of multiple case coeliac disease families.
      • Book L.
      • Zone J.J.
      • Neuhausen S.L.
      Prevalence of celiac disease among relatives of sib pairs with celiac disease in U.S. families.
      • Kotze L.M.
      • Utiyama S.R.
      • Nisihara R.M.
      • Zeni M.P.
      • de Sena M.G.
      • Amarante H.M.
      Antiendomysium antibodies in Brazilian patients with celiac disease and their first-degree relatives.
      • Vitoria J.C.
      • Arrieta A.
      • Astigarraga I.
      • Garcia-Masdevall D.
      • Rodriguez-Soriano J.
      Use of serological markers as a screening test in family members of patients with celiac disease.
      Confirmatory intestinal biopsy was performed on at least 80% of the subjects who tested positive by serology in half of the studies and in 100% of subjects in the others.
      • Corazza G.
      • Valentini R.A.
      • Frisoni M.
      • Volta U.
      • Corrao G.
      • Bianchi F.B.
      • Gasbarrini G.
      Gliadin immune reactivity is associated with overt and latent enteropathy in relatives of celiac patients.
      • Pittschieler K.
      • Gentili L.
      • Niederhofer H.
      Onset of coeliac disease: a prospective longitudinal study.
      • Tursi A.
      • Brandimarte G.
      • Giorgetti G.M.
      • Inchingolo C.D.
      Effectiveness of the sorbitol HSUB2 breath test in detecting histological damage among relatives of coeliacs.
      • Rostami K.
      • Mulder C.J.
      • van Overbeek F.M.
      • Kerckhaert J.
      • Meijer J.W.
      • von Blomberg M.B.
      • Heymans H.S.
      Should relatives of coeliacs with mild clinical complaints undergo a small-bowel biopsy despite negative serology?.
      • Hogberg L.
      • Falth-Magnusson K.
      • Grodzinsky E.
      • Stenhammar L.
      Familial prevalence of coeliac disease: a twenty-year follow-up study.
      • Korponay-Szabo I.
      • Kovacs J.
      • Lorincz M.
      • Torok E.
      • Goracz G.
      Families with multiple cases of gluten-sensitive enteropathy.
      Serologic screening was performed with AGA alone in one study
      • Corazza G.
      • Valentini R.A.
      • Frisoni M.
      • Volta U.
      • Corrao G.
      • Bianchi F.B.
      • Gasbarrini G.
      Gliadin immune reactivity is associated with overt and latent enteropathy in relatives of celiac patients.
      or by EMA, either alone
      • Korponay-Szabo I.
      • Kovacs J.
      • Lorincz M.
      • Torok E.
      • Goracz G.
      Families with multiple cases of gluten-sensitive enteropathy.
      or in combination with AGA,
      • Pittschieler K.
      • Gentili L.
      • Niederhofer H.
      Onset of coeliac disease: a prospective longitudinal study.
      • Tursi A.
      • Brandimarte G.
      • Giorgetti G.M.
      • Inchingolo C.D.
      Effectiveness of the sorbitol HSUB2 breath test in detecting histological damage among relatives of coeliacs.
      • Rostami K.
      • Mulder C.J.
      • van Overbeek F.M.
      • Kerckhaert J.
      • Meijer J.W.
      • von Blomberg M.B.
      • Heymans H.S.
      Should relatives of coeliacs with mild clinical complaints undergo a small-bowel biopsy despite negative serology?.
      • Hogberg L.
      • Falth-Magnusson K.
      • Grodzinsky E.
      • Stenhammar L.
      Familial prevalence of coeliac disease: a twenty-year follow-up study.
      • Farre C.
      • Humbert P.
      • Vilar P.
      • Varea V.
      • Aldeguer X.
      • Carnicer J.
      • Carballo M.
      • Gassull M.A.
      Catalonian Coeliac Disease Study Group
      Serological markers and HLA-DQ2 haplotype among first-degree relatives of celiac patients.
      in the other 6 studies. The prevalence of celiac disease varied from 4%
      • Corazza G.
      • Valentini R.A.
      • Frisoni M.
      • Volta U.
      • Corrao G.
      • Bianchi F.B.
      • Gasbarrini G.
      Gliadin immune reactivity is associated with overt and latent enteropathy in relatives of celiac patients.
      to 12%,
      • Pittschieler K.
      • Gentili L.
      • Niederhofer H.
      Onset of coeliac disease: a prospective longitudinal study.
      with a pooled prevalence of 7.6% (95% CI, 6.59%–8.67%). However, when Marsh grade I lesions were also considered in the diagnosis of celiac disease, the prevalence of celiac disease among first-degree relatives was reported to be 44.1%.
      • Tursi A.
      • Brandimarte G.
      • Giorgetti G.M.
      • Inchingolo C.D.
      Effectiveness of the sorbitol HSUB2 breath test in detecting histological damage among relatives of coeliacs.
      This finding may partially explain the higher prevalence of 20%–22.5% reported previously for the biopsy-only studies.
      In 5 other studies of first-degree relatives,
      • Fasano A.
      • Berti I.
      • Gerarduzzi T.
      • Not T.
      • Colletti R.B.
      • Drago S.
      • Elitsur Y.
      • Green P.H.R.
      • Guandalini S.
      • Hill I.D.
      • Pietzak M.
      • Ventura A.
      • Thorpe M.
      • Kryszak D.
      • Fornaroli F.
      • Wasserman S.S.
      • Murray J.A.
      • Horvath K.
      Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study.
      • Mustalahti K.
      • Sulkanen S.
      • Holopainen P.
      • Laurila K.
      • Collin P.
      • Partanen J.
      • Maki M.
      Coeliac disease among healthy members of multiple case coeliac disease families.
      • Book L.
      • Zone J.J.
      • Neuhausen S.L.
      Prevalence of celiac disease among relatives of sib pairs with celiac disease in U.S. families.
      • Kotze L.M.
      • Utiyama S.R.
      • Nisihara R.M.
      • Zeni M.P.
      • de Sena M.G.
      • Amarante H.M.
      Antiendomysium antibodies in Brazilian patients with celiac disease and their first-degree relatives.
      • Vitoria J.C.
      • Arrieta A.
      • Astigarraga I.
      • Garcia-Masdevall D.
      • Rodriguez-Soriano J.
      Use of serological markers as a screening test in family members of patients with celiac disease.
      confirmatory biopsy specimens were available in 9%
      • Vitoria J.C.
      • Arrieta A.
      • Astigarraga I.
      • Garcia-Masdevall D.
      • Rodriguez-Soriano J.
      Use of serological markers as a screening test in family members of patients with celiac disease.
      to 58%
      • Mustalahti K.
      • Sulkanen S.
      • Holopainen P.
      • Laurila K.
      • Collin P.
      • Partanen J.
      • Maki M.
      Coeliac disease among healthy members of multiple case coeliac disease families.
      of the cases, but the reported prevalence of celiac disease was based on the serologic results. EMA was used for serologic screening in all of these studies, either alone
      • Fasano A.
      • Berti I.
      • Gerarduzzi T.
      • Not T.
      • Colletti R.B.
      • Drago S.
      • Elitsur Y.
      • Green P.H.R.
      • Guandalini S.
      • Hill I.D.
      • Pietzak M.
      • Ventura A.
      • Thorpe M.
      • Kryszak D.
      • Fornaroli F.
      • Wasserman S.S.
      • Murray J.A.
      • Horvath K.
      Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study.
      • Kotze L.M.
      • Utiyama S.R.
      • Nisihara R.M.
      • Zeni M.P.
      • de Sena M.G.
      • Amarante H.M.
      Antiendomysium antibodies in Brazilian patients with celiac disease and their first-degree relatives.
      or in combination with AGA
      • Mustalahti K.
      • Sulkanen S.
      • Holopainen P.
      • Laurila K.
      • Collin P.
      • Partanen J.
      • Maki M.
      Coeliac disease among healthy members of multiple case coeliac disease families.
      • Vitoria J.C.
      • Arrieta A.
      • Astigarraga I.
      • Garcia-Masdevall D.
      • Rodriguez-Soriano J.
      Use of serological markers as a screening test in family members of patients with celiac disease.
      or tTGA.
      • Book L.
      • Zone J.J.
      • Neuhausen S.L.
      Prevalence of celiac disease among relatives of sib pairs with celiac disease in U.S. families.
      The prevalence of celiac disease among these serology-tested first-degree relatives varied between 2.8%
      • Vitoria J.C.
      • Arrieta A.
      • Astigarraga I.
      • Garcia-Masdevall D.
      • Rodriguez-Soriano J.
      Use of serological markers as a screening test in family members of patients with celiac disease.
      and 4.5%.
      • Fasano A.
      • Berti I.
      • Gerarduzzi T.
      • Not T.
      • Colletti R.B.
      • Drago S.
      • Elitsur Y.
      • Green P.H.R.
      • Guandalini S.
      • Hill I.D.
      • Pietzak M.
      • Ventura A.
      • Thorpe M.
      • Kryszak D.
      • Fornaroli F.
      • Wasserman S.S.
      • Murray J.A.
      • Horvath K.
      Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study.
      The prevalence of celiac disease among first-degree relatives from families in which there were at least 2 index cases (sibling pairs) of known celiac disease or dermatitis herpetiformis was reported as 6.4%,
      • Gudjonsdottir A.H.
      • Nilsson S.
      • Ek J.
      • Kristiansson B.
      • Ascher H.
      The risk of celiac disease in 107 families with at least two affected siblings.
      9.4%,
      • Mustalahti K.
      • Sulkanen S.
      • Holopainen P.
      • Laurila K.
      • Collin P.
      • Partanen J.
      • Maki M.
      Coeliac disease among healthy members of multiple case coeliac disease families.
      and 17.2%.
      • Book L.
      • Zone J.J.
      • Neuhausen S.L.
      Prevalence of celiac disease among relatives of sib pairs with celiac disease in U.S. families.
      The utility of testing for celiac disease in symptomatic first-degree relatives is clear, whereas there is currently little evidence to support screening in asymptomatic first-degree relatives.

       Other relatives

      One study from the United States
      • Hill I.
      • Fasano A.
      • Schwartz R.
      • Counts D.
      • Glock M.
      • Horvath K.
      The prevalence of celiac disease in at-risk groups of children in the United States.
      reported a prevalence of presumed celiac disease in 4.7% of 192 first-degree and second-degree relatives, based strictly on the EMA test. The prevalence for first-degree and second-degree relatives was not reported separately. Two other studies
      • Fasano A.
      • Berti I.
      • Gerarduzzi T.
      • Not T.
      • Colletti R.B.
      • Drago S.
      • Elitsur Y.
      • Green P.H.R.
      • Guandalini S.
      • Hill I.D.
      • Pietzak M.
      • Ventura A.
      • Thorpe M.
      • Kryszak D.
      • Fornaroli F.
      • Wasserman S.S.
      • Murray J.A.
      • Horvath K.
      Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study.
      • Korponay-Szabo I.
      • Kovacs J.
      • Lorincz M.
      • Torok E.
      • Goracz G.
      Families with multiple cases of gluten-sensitive enteropathy.
      provided data on the presumed prevalence of celiac disease in second-degree relatives. The EMA-based prevalence of celiac disease in those groups was 2.6% and 5.5%, respectively. In the last study, presumed celiac disease by serologic testing in relatives of sibling pairs was 19.5% in second-degree relatives and 17.0% in first cousins.
      • Book L.
      • Zone J.J.
      • Neuhausen S.L.
      Prevalence of celiac disease among relatives of sib pairs with celiac disease in U.S. families.
      In this study, subjects were tested with EMA and tTGA, and the diagnosis was biopsy confirmed in 40% of the cases.
      In summary, relatives of patients with celiac disease are at a higher risk for celiac disease than those in the general population. Based on studies, with relatively complete biopsy confirmation, the prevalence is close to 10% but may be higher if lesser histologic grades are also considered to represent celiac disease. Among relatives, the highest prevalence of celiac disease occurs in families with more than one affected relative, while the prevalence when second-degree relatives are affected is lower (2.6%–5.5%) but still higher than that of the general population.

       Prevalence of Celiac Disease in Patients With IDA

      IDA is commonly reported to be associated with celiac disease,
      • Ackerman Z.
      • Eliakim R.
      • Stalnikowicz R.
      • Rachmilewitz D.
      Role of small bowel biopsy in the endoscopic evaluation of adults with iron deficiency anemia.
      • Annibale B.
      • Capurso G.
      • Chistolini A.
      • D’Ambra G.
      • DiGiulio E.
      • Monarca B.
      • DelleFave G.
      Gastrointestinal causes of refractory iron deficiency anemia in patients without gastrointestinal symptoms.
      • Corazza G.R.
      • Valentini R.A.
      • Andreani M.L.
      • D’Anchino M.
      • Leva M.T.
      • Ginaldi L.
      • De Feudis L.
      • Quaglino D.
      • Gasbarrini G.
      Subclinical coeliac disease is a frequent cause of iron-deficiency anaemia.
      • Dickey W.
      • Kenny B.D.
      • McMillan S.A.
      • Porter K.G.
      • McConnell J.B.
      Gastric as well as duodenal biopsies may be useful in the investigation of iron deficiency anaemia.
      • Howard M.R.
      • Turnbull A.J.
      • Morley P.
      • Hollier P.
      • Webb R.
      • Clarke A.
      A prospective study of the prevalence of undiagnosed coeliac disease in laboratory defined iron and folate deficiency.
      • Kepczyk T.
      • Kadakia S.C.
      Prospective evaluation of gastrointestinal tract in patients with iron-deficiency anemia.
      • McIntyre A.S.
      • Long R.G.
      Prospective survey of investigations in outpatients referred with iron deficiency anaemia.
      • Oxentenko A.S.
      • Grisolano S.W.
      • Murray J.A.
      • Burgart L.J.
      • Dierkhising R.A.
      • Alexander J.A.
      The insensitivity of endoscopic markers in celiac disease.
      • Ransford Rupert A.J.
      • Hayes M.
      • Palmer M.
      • Hall M.J.
      A controlled, prospective screening study of celiac disease presenting as iron deficiency anemia.
      • Unsworth D.J.
      • Lock R.J.
      • Harvey R.F.
      Improving the diagnosis of coeliac disease in anaemic women.
      • Annibale B.
      • Lahner E.
      • Chistolini A.
      • Gallucci C.
      • Di Giulio E.
      • Capurso G.
      • Luana O.
      • Monarca B.
      • Delle F.G.
      Endoscopic evaluation of the upper gastrointestinal tract is worthwhile in premenopausal women with iron-deficiency anaemia irrespective of menstrual flow.
      • Van Mook W.N.K.A.
      • Bourass-Bremer I.H.D.N.
      • Bos L.P.
      • Verhoeven H.M.J.M.
      • Engels L.G.J.B.
      The outcome of esophagogastroduodenoscopy (EGD) in asymptomatic outpatients with iron deficiency anemia after a negative colonoscopy.
      • Karnam U.S.
      • Felder L.R.
      • Raskin J.B.
      Prevalence of occult celiac disease in patients with iron-deficiency anemia: a prospective study.
      • Grisolano S.W.
      • Oxentenko A.S.
      • Murray J.A.
      • Burgart L.J.
      • Dierkhising R.A.
      • Alexander J.A.
      The usefulness of routine small bowel biopsies in evaluation of iron deficiency anemia.
      irrespective of whether patients have gastrointestinal symptoms.
      In asymptomatic patients with IDA evaluated by serologic testing, the prevalence of celiac disease ranged from 2.3% to 5.0%.
      • Corazza G.R.
      • Valentini R.A.
      • Andreani M.L.
      • D’Anchino M.
      • Leva M.T.
      • Ginaldi L.
      • De Feudis L.
      • Quaglino D.
      • Gasbarrini G.
      Subclinical coeliac disease is a frequent cause of iron-deficiency anaemia.
      • Howard M.R.
      • Turnbull A.J.
      • Morley P.
      • Hollier P.
      • Webb R.
      • Clarke A.
      A prospective study of the prevalence of undiagnosed coeliac disease in laboratory defined iron and folate deficiency.
      • Ransford Rupert A.J.
      • Hayes M.
      • Palmer M.
      • Hall M.J.
      A controlled, prospective screening study of celiac disease presenting as iron deficiency anemia.
      • Unsworth D.J.
      • Lock R.J.
      • Harvey R.F.
      Improving the diagnosis of coeliac disease in anaemic women.
      Similarly, in studies assessing the causes of IDA, typically by both upper and lower endoscopy, the prevalence of celiac disease by biopsy was found to be between 2.8% and 8.7%.
      • Annibale B.
      • Capurso G.
      • Chistolini A.
      • D’Ambra G.
      • DiGiulio E.
      • Monarca B.
      • DelleFave G.
      Gastrointestinal causes of refractory iron deficiency anemia in patients without gastrointestinal symptoms.
      • McIntyre A.S.
      • Long R.G.
      Prospective survey of investigations in outpatients referred with iron deficiency anaemia.
      • Van Mook W.N.K.A.
      • Bourass-Bremer I.H.D.N.
      • Bos L.P.
      • Verhoeven H.M.J.M.
      • Engels L.G.J.B.
      The outcome of esophagogastroduodenoscopy (EGD) in asymptomatic outpatients with iron deficiency anemia after a negative colonoscopy.
      • Karnam U.S.
      • Felder L.R.
      • Raskin J.B.
      Prevalence of occult celiac disease in patients with iron-deficiency anemia: a prospective study.
      • Grisolano S.W.
      • Oxentenko A.S.
      • Murray J.A.
      • Burgart L.J.
      • Dierkhising R.A.
      • Alexander J.A.
      The usefulness of routine small bowel biopsies in evaluation of iron deficiency anemia.
      In contrast, the prevalence of celiac disease in symptomatic patients with IDA ranged from 10.3% to 15% of the studied group, and in one small study of previously investigated patients with IDA, the prevalence of presumed celiac disease by AGA followed by EMA confirmation was 30%.
      • Dickey W.
      • Kenny B.D.
      • McMillan S.A.
      • Porter K.G.
      • McConnell J.B.
      Gastric as well as duodenal biopsies may be useful in the investigation of iron deficiency anaemia.
      In another small study, the prevalence of celiac disease in premenopausal women with IDA was assessed.
      • Annibale B.
      • Lahner E.
      • Chistolini A.
      • Gallucci C.
      • Di Giulio E.
      • Capurso G.
      • Luana O.
      • Monarca B.
      • Delle F.G.
      Endoscopic evaluation of the upper gastrointestinal tract is worthwhile in premenopausal women with iron-deficiency anaemia irrespective of menstrual flow.
      The overall prevalence of celiac disease in this population was 12.9% by tTGA and 8.5% after biopsy confirmation. Celiac disease was found in 1 of 22 women (4.5%) with heavy periods and 4 of 18 women (22%) with normal menstrual flow.
      Celiac disease should be considered in any adult with unexplained IDA, including menstruating women. Duodenal biopsies should be performed on patients with IDA presenting for upper intestinal endoscopy.

       Prevalence of Celiac Disease in Individuals With Low Bone Mineral Density

      Seven studies have assessed the prevalence of celiac disease in patients with low bone mineral density (BMD).
      • Gonzalez D.
      • Sugai E.
      • Gomez J.C.
      • Oliveri M.B.
      • Gomez A.C.
      • Vega E.
      • Bagur A.
      • Mazure R.
      • Maurino E.
      • Bai J.C.
      • Mautalen C.
      Is it necessary to screen for celiac disease in postmenopausal osteoporotic women?.
      • Lindh E.
      • Ljunghall S.
      • Larsson K.
      • Lavo B.
      Screening for antibodies against gliadin in patients with osteoporosis.
      • Mather K.J.
      • Meddings J.B.
      • Beck P.L.
      • Scott R.B.
      • Hanley D.A.
      Prevalence of IgA-antiendomysial antibody in asymptomatic low bone mineral density.
      • Ots M.
      • Uibo O.
      • Metskula K.
      • Uibo R.
      • Salupere V.
      IgA-antigliadin antibodies in patients with IgA nephropathy: the secondary phenomenon?.
      • Stenson W.F.
      • Newberry R.
      • Lorenz R.
      • Baldus C.
      • Civitelli R.
      Increased prevalence of celiac disease and need for routine screening among patients with osteoporosis.
      • Drummond F.J.
      • Annis P.
      • O’Sullivan K.
      • Wynne F.
      • Daly M.
      • Shanahan F.
      • Quane K.A.
      • Molloy M.G.
      Screening for asymptomatic celiac disease among patients referred for bone densitometry measurement.
      • Sanders D.S.
      • Patel D.
      • Khan F.B.
      • Westbrook R.H.
      • Webber C.V.
      • Milford-Ward A.
      • McCloskey E.V.
      Case-finding for adult celiac disease in patients with reduced bone mineral density.
      Six of these determined BMD using dual energy X-ray absorptiometry and appropriately defined osteoporosis by World Health Organization criteria.
      • Gonzalez D.
      • Sugai E.
      • Gomez J.C.
      • Oliveri M.B.
      • Gomez A.C.
      • Vega E.
      • Bagur A.
      • Mazure R.
      • Maurino E.
      • Bai J.C.
      • Mautalen C.
      Is it necessary to screen for celiac disease in postmenopausal osteoporotic women?.
      • Mather K.J.
      • Meddings J.B.
      • Beck P.L.
      • Scott R.B.
      • Hanley D.A.
      Prevalence of IgA-antiendomysial antibody in asymptomatic low bone mineral density.
      • Ots M.
      • Uibo O.
      • Metskula K.
      • Uibo R.
      • Salupere V.
      IgA-antigliadin antibodies in patients with IgA nephropathy: the secondary phenomenon?.
      • Stenson W.F.
      • Newberry R.
      • Lorenz R.
      • Baldus C.
      • Civitelli R.
      Increased prevalence of celiac disease and need for routine screening among patients with osteoporosis.
      • Drummond F.J.
      • Annis P.
      • O’Sullivan K.
      • Wynne F.
      • Daly M.
      • Shanahan F.
      • Quane K.A.
      • Molloy M.G.
      Screening for asymptomatic celiac disease among patients referred for bone densitometry measurement.
      • Sanders D.S.
      • Patel D.
      • Khan F.B.
      • Westbrook R.H.
      • Webber C.V.
      • Milford-Ward A.
      • McCloskey E.V.
      Case-finding for adult celiac disease in patients with reduced bone mineral density.
      One study used single-photon absorptiometry.
      • Lindh E.
      • Ljunghall S.
      • Larsson K.
      • Lavo B.
      Screening for antibodies against gliadin in patients with osteoporosis.
      Each of these studies used serologic screening with biopsy confirmation of screen-positive patients. Three studies relied on AGA testing as the initial screen
      • Gonzalez D.
      • Sugai E.
      • Gomez J.C.
      • Oliveri M.B.
      • Gomez A.C.
      • Vega E.
      • Bagur A.
      • Mazure R.
      • Maurino E.
      • Bai J.C.
      • Mautalen C.
      Is it necessary to screen for celiac disease in postmenopausal osteoporotic women?.
      • Lindh E.
      • Ljunghall S.
      • Larsson K.
      • Lavo B.
      Screening for antibodies against gliadin in patients with osteoporosis.
      • Ots M.
      • Uibo O.
      • Metskula K.
      • Uibo R.
      • Salupere V.
      IgA-antigliadin antibodies in patients with IgA nephropathy: the secondary phenomenon?.
      followed by biopsy
      • Lindh E.
      • Ljunghall S.
      • Larsson K.
      • Lavo B.
      Screening for antibodies against gliadin in patients with osteoporosis.
      or further confirmatory serologic testing with EMA
      • Gonzalez D.
      • Sugai E.
      • Gomez J.C.
      • Oliveri M.B.
      • Gomez A.C.
      • Vega E.
      • Bagur A.
      • Mazure R.
      • Maurino E.
      • Bai J.C.
      • Mautalen C.
      Is it necessary to screen for celiac disease in postmenopausal osteoporotic women?.
      or tTGA
      • Ots M.
      • Uibo O.
      • Metskula K.
      • Uibo R.
      • Salupere V.
      IgA-antigliadin antibodies in patients with IgA nephropathy: the secondary phenomenon?.
      or a combination of EMA and tTGA.
      • Stenson W.F.
      • Newberry R.
      • Lorenz R.
      • Baldus C.
      • Civitelli R.
      Increased prevalence of celiac disease and need for routine screening among patients with osteoporosis.
      • Drummond F.J.
      • Annis P.
      • O’Sullivan K.
      • Wynne F.
      • Daly M.
      • Shanahan F.
      • Quane K.A.
      • Molloy M.G.
      Screening for asymptomatic celiac disease among patients referred for bone densitometry measurement.
      • Sanders D.S.
      • Patel D.
      • Khan F.B.
      • Westbrook R.H.
      • Webber C.V.
      • Milford-Ward A.
      • McCloskey E.V.
      Case-finding for adult celiac disease in patients with reduced bone mineral density.
      The 3 most recent studies used well-conducted cohort designs with patients undergoing BMD measurements acting either as osteoporosis cases or controls.
      • Stenson W.F.
      • Newberry R.
      • Lorenz R.
      • Baldus C.
      • Civitelli R.
      Increased prevalence of celiac disease and need for routine screening among patients with osteoporosis.
      • Drummond F.J.
      • Annis P.
      • O’Sullivan K.
      • Wynne F.
      • Daly M.
      • Shanahan F.
      • Quane K.A.
      • Molloy M.G.
      Screening for asymptomatic celiac disease among patients referred for bone densitometry measurement.
      • Sanders D.S.
      • Patel D.
      • Khan F.B.
      • Westbrook R.H.
      • Webber C.V.
      • Milford-Ward A.
      • McCloskey E.V.
      Case-finding for adult celiac disease in patients with reduced bone mineral density.
      Overall, in these studies, the prevalence of celiac disease in patients with osteoporosis varied from 0.9% to 3.4%. Two of the 3 cohort studies reported the prevalence of celiac disease in osteopenic patients to be 3.0%
      • Drummond F.J.
      • Annis P.
      • O’Sullivan K.
      • Wynne F.
      • Daly M.
      • Shanahan F.
      • Quane K.A.
      • Molloy M.G.
      Screening for asymptomatic celiac disease among patients referred for bone densitometry measurement.
      and 1.2%,
      • Sanders D.S.
      • Patel D.
      • Khan F.B.
      • Westbrook R.H.
      • Webber C.V.
      • Milford-Ward A.
      • McCloskey E.V.
      Case-finding for adult celiac disease in patients with reduced bone mineral density.
      while the prevalence of celiac disease in osteoporotic patients was 1.0% (1.7% in severe osteoporosis),
      • Drummond F.J.
      • Annis P.
      • O’Sullivan K.
      • Wynne F.
      • Daly M.
      • Shanahan F.
      • Quane K.A.
      • Molloy M.G.
      Screening for asymptomatic celiac disease among patients referred for bone densitometry measurement.
      2.1%,
      • Sanders D.S.
      • Patel D.
      • Khan F.B.
      • Westbrook R.H.
      • Webber C.V.
      • Milford-Ward A.
      • McCloskey E.V.
      Case-finding for adult celiac disease in patients with reduced bone mineral density.
      and 3.4%.
      • Stenson W.F.
      • Newberry R.
      • Lorenz R.
      • Baldus C.
      • Civitelli R.
      Increased prevalence of celiac disease and need for routine screening among patients with osteoporosis.
      The true prevalence of celiac disease in patients with osteoporosis remains somewhat uncertain because of some methodological weaknesses of the identified studies and inclusion criteria for osteoporosis.
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      • Cranney A.
      • Rostom A.
      • Sy R.
      • Dube C.
      • Saloogee N.
      • Garritty C.
      • Moher D.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • Macneil J.
      Consequences of testing for celiac disease.
      Nonetheless, a reasonable estimate would place it between 1% and 3.4%. The prevalence could be higher (5%) if patients with positive serologic test results did not undergo confirmatory biopsy.
      • Gonzalez D.
      • Sugai E.
      • Gomez J.C.
      • Oliveri M.B.
      • Gomez A.C.
      • Vega E.
      • Bagur A.
      • Mazure R.
      • Maurino E.
      • Bai J.C.
      • Mautalen C.
      Is it necessary to screen for celiac disease in postmenopausal osteoporotic women?.
      • Stenson W.F.
      • Newberry R.
      • Lorenz R.
      • Baldus C.
      • Civitelli R.
      Increased prevalence of celiac disease and need for routine screening among patients with osteoporosis.
      Current evidence favors screening for celiac disease in individuals with premature-onset osteoporosis or a suggestion of metabolic bone disease.

       Prevalence of Celiac Disease in Patients With Autoimmune Disorders

      Celiac disease appears to be more prevalent in several autoimmune disorders than in the general population. Additionally, some evidence suggests that the longer the exposure to gluten, the higher the risk of autoimmune disorders in patients with celiac disease. Ventura et al
      • 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.
      found that autoimmune disorders were significantly more frequent in patients with celiac disease than controls (14% vs 2.8%), and the risk of autoimmune disorders appeared to increase with the duration of gluten exposure when age at diagnosis was used as a measure of years of exposure to gluten.
      Because approximately 95% of patients with celiac disease carry HLA-DQ2 and the remainder mostly DQ8, it is reasonable to assume that the association between celiac disease and these autoimmune disorders is on the basis of these shared HLA susceptibility genes. However, for the increased prevalence of celiac disease to be explained on this basis, DQ2/DQ8 should be expected to act as a susceptibility gene for these other disorders, or the prevalence of DQ2/DQ8 in these other disorders should be higher than that seen in the general population. While this may be the case for DM1,
      • Rostom A.
      • Dube C.
      • Cranney A.
      • Saloojee N.
      • Sy R.
      • Garritty C.
      • Sampson M.
      • Zhang L.
      • Yazdi F.
      • Mamaladze V.
      • Pan I.
      • McNeil J.
      • Moher D.
      • Mack D.
      • Patel D.
      Celiac disease.
      autoimmune thyroid disease,
      • Kaukinen K.
      • Collin P.
      • Mykkanen A.H.
      • Partanen J.
      • Maki M.
      • Salmi J.
      Celiac disease and autoimmune endocrinologic disorders.
      • Wallaschofski H.
      • Meyer A.
      • Tuschy U.
      • Lohmann T.
      HLA-DQA1*0301-associated susceptibility for autoimmune polyglandular syndrome type II and III.
      • Segni M.
      • Pani M.A.
      • Pasquino A.M.
      • Badenhoop K.
      Familial clustering of juvenile thyroid autoimmunity: higher risk is conferred by human leukocyte antigen DR3-DQ2 and thyroid peroxidase antibody status in fathers.
      and Addison’s disease,
      • Myhre A.G.
      • Undlien D.E.
      • Lovas K.
      • Uhlving S.
      • Nedrebo B.G.
      • Fougner K.J.
      • Trovik T.
      • Sorheim J.I.
      • Husebye E.S.
      Autoimmune adrenocortical failure in Norway autoantibodies and human leukocyte antigen class II associations related to clinical features.
      the situation is less clear for other celiac disease–associated conditions.

       Prevalence of Celiac Disease in Patients With DM1

      There is extensive literature on the higher prevalence of celiac disease in patients with DM1 than in the general population.
      • Doolan A.
      • Donaghue K.
      • Fairchild J.
      • Wong M.
      • Williams A.J.
      Use of HLA typing in diagnosing celiac disease in patients with type 1 diabetes.
      • Jaeger C.
      • Hatziagelaki E.
      • Petzoldt R.
      • Bretzel R.G.
      Comparative analysis of organ-specific autoantibodies and celiac disease—associated antibodies in type 1 diabetic patients, their first-degree relatives, and healthy control subjects.
      • Kaukinen K.
      • Collin P.
      • Mykkanen A.H.
      • Partanen J.
      • Maki M.
      • Salmi J.
      Celiac disease and autoimmune endocrinologic disorders.
      • Sjoberg K.
      • Eriksson K.F.
      • Bredberg A.
      • Wassmuth R.
      • Eriksson S.
      Screening for coeliac disease in adult insulin-dependent diabetes mellitus.
      • Li Voon Chong J.S.W.
      • Leong K.S.
      • Wallymahmed M.
      • Sturgess R.
      • MacFarlane I.A.
      Is coeliac disease more prevalent in young adults with coexisting type 1 diabetes mellitus and autoimmune thyroid disease compared with those with type 1 diabetes mellitus alone?.
      • Talal A.H.
      • Murray J.A.
      • Goeken J.A.
      • Sivitz W.I.
      Celiac disease in an adult population with insulin-dependent diabetes mellitus: use of endomysial antibody testing.
      • Rensch M.J.
      • Merenich J.A.
      • Lieberman M.
      • Long B.D.
      • Davis D.R.
      • McNally P.R.
      Gluten-sensitive enteropathy in patients with insulin-dependent diabetes mellitus.
      • Sategna-Guidetti C.
      • Grosso S.
      • Pulitano R.
      • Benaduce E.
      • Dani F.
      • Carta Q.
      Celiac disease and insulin-dependent diabetes mellitus Screening in an adult population.
      • Cronin C.C.
      • Feighery A.
      • Ferriss J.B.
      • Liddy C.
      • Shanahan F.
      • Feighery C.
      High prevalence of celiac disease among patients with insulin-dependent (type I) diabetes mellitus.
      • Sigurs N.
      • Johansson C.
      • Elfstrand P.O.
      • Viander M.
      • Lanner A.
      Prevalence of coeliac disease in diabetic children and adolescents in Sweden.
      • Roldan M.B.
      • Barrio R.
      • Roy G.
      • Parra C.
      • Alonso M.
      • Yturriaga R.
      • Camarero C.
      Diagnostic value of serological markers for celiac disease in diabetic children and adolescents.
      • Saukkonen T.
      • Savilahti E.
      • Reijonen H.
      • Ilonen J.
      • Tuomilehto-Wolf E.
      • Akerblom H.K.
      Coeliac disease: frequent occurrence after clinical onset of insulin-dependent diabetes mellitus Childhood Diabetes in Finland Study Group.
      • Barera G.
      • Bianchi C.
      • Calisti L.
      • Cerutti F.
      • Dammacco F.
      • Frezza E.
      • Illeni M.T.
      • Mistura L.
      • Pocecco M.
      • Prisco F.
      Screening of diabetic children for coeliac disease with antigliadin antibodies and HLA typing.
      • Calero P.
      • Ribes-Koninckx C.
      • Albiach V.
      • Carles C.
      • Ferrer J.
      IgA antigliadin antibodies as a screening method for nonovert celiac disease in children with insulin-dependent diabetes mellitus.
      • Lorini R.
      • Scotta M.S.
      • Cortona L.
      • Avanzini M.A.
      • Vitali L.
      • De Giacomo C.
      • Scaramuzza A.
      • Severi F.
      Celiac disease and type I (insulin-dependent) diabetes mellitus in childhood: follow-up study.
      • Arato A.
      • Korner A.
      • Veres G.
      • Dezsofi A.
      • Ujpal I.
      • Madacsy L.
      Frequency of coeliac disease in Hungarian children with type 1 diabetes mellitus.
      • Fraser-Reynolds K.A.
      • Butzner J.D.
      • Stephure D.K.
      • Trussell R.A.
      • Scott R.B.
      Use of immunoglobulin A-antiendomysial antibody to screen for celiac disease in North American children with type 1 diabetes.
      • Vitoria J.C.
      • Castano L.
      • Rica I.
      • Bilbao J.R.
      • Arrieta A.
      • Garcia-Masdevall M.D.
      Association of insulin-dependent diabetes mellitus and celiac disease: a study based on serologic markers.
      • Barera G.
      • Bonfanti R.
      • Viscardi M.
      • Bazzigaluppi E.
      • Calori G.
      • Meschi F.
      • Bianchi C.
      • Chiumello G.
      Occurrence of celiac disease after onset of type 1 diabetes: a 6-year prospective longitudinal study.
      • Aktay A.N.
      • Lee P.C.
      • Kumar V.
      • Parton E.
      • Wyatt D.T.
      • Werlin S.L.
      The prevalence and clinical characteristics of celiac disease in juvenile diabetes in Wisconsin.
      • Rossi T.M.
      • Albini C.H.
      • Kumar V.
      Incidence of celiac disease identified by the presence of serum endomysial antibodies in children with chronic diarrhea, short stature, or insulin-dependent diabetes mellitus.
      • Schober E.
      • Bittmann B.
      • Granditsch G.
      • Huber W.D.
      • Huppe A.
      • Jager A.
      • Oberhuber G.
      • Rami B.
      • Reichel G.
      Screening by anti-endomysium antibody for celiac disease in diabetic children and adolescents in Austria.
      • Acerini C.L.
      • Ahmed M.L.
      • Ross K.M.
      • Sullivan P.B.
      • Bird G.
      • Dunger D.B.
      Coeliac disease in children and adolescents with IDDM: clinical characteristics and response to gluten-free diet.
      • Gillett P.M.
      • Gillett H.R.
      • Israel D.M.
      • Metzger D.L.
      • Stewart L.
      • Chanoine J.P.
      • Freeman H.J.
      High prevalence of celiac disease in patients with type 1 diabetes detected by antibodies to endomysium and tissue transglutaminase.
      • Hansen D.
      • Bennedbaek F.N.
      • Hansen L.K.
      • Hoier-Madsen M.
      • Hegedu L.S.
      • Jacobsen B.B.
      • Husby S.
      High prevalence of coeliac disease in Danish children with type I diabetes mellitus.
      • Valerio G.
      • Maiuri L.
      • Troncone R.
      • Buono P.
      • Lombardi F.
      • Palmieri R.
      • Franzese A.
      Severe clinical onset of diabetes and increased prevalence of other autoimmune diseases in children with coeliac disease diagnosed before diabetes mellitus.
      • Agardh D.
      • Nilsson A.
      • Tuomi T.
      • Lindberg B.
      • Carlsson A.K.
      • Lernmark A.
      • Ivarsson S.-A.
      Prediction of silent celiac disease at diagnosis of childhood type 1 diabetes by tissue transglutaminase autoantibodies and HLA.
      • Lampasona V.
      • Bonfanti R.
      • Bazzigaluppi E.
      • Venerando A.
      • Chiumello G.
      • Bosi E.
      • Bonifacio E.
      Antibodies to tissue transglutaminase C in type I diabetes.
      • Spiekerkoetter U.
      • Seissler J.
      • Wendel U.
      General screening for celiac disease is advisable in children with type 1 diabetes.
      • Kordonouri O.
      • Dieterich W.
      • Schuppan D.
      • Webert G.
      • Muller C.
      • Sarioglu N.
      • Becker M.
      • Danne T.
      Autoantibodies to tissue transglutaminase are sensitive serological parameters for detecting silent coeliac disease in patients with Type 1 diabetes mellitus.
      • Page S.R.
      • Lloyd C.A.
      • Hill P.G.
      • Peacock I.
      • Holmes G.K.
      The prevalence of coeliac disease in adult diabetes mellitus.
      • De Vitis I.
      • Ghirlanda G.
      • Gasbarrini G.
      Prevalence of coeliac disease in type I diabetes: a multicentre study.
      • Not T.
      • Tommasini A.
      • Tonini G.
      • Buratti E.
      • Pocecco M.
      • Tortul C.
      • Valussi M.
      • Crichiutti G.
      • Berti I.
      • Trevisiol C.
      • Azzoni E.
      • Neri E.
      • Torre G.
      • Martelossi S.
      • Soban M.
      • Lenhardt A.
      • Cattin L.
      • Ventura A.
      Undiagnosed coeliac disease and risk of autoimmune disorders in subjects with Type I diabetes mellitus.
      • De Block C.E.
      • De Leeuw I.H.
      • Vertommen J.J.
      • Rooman R.P.
      • Du Caju M.V.
      • Van Campenhout C.M.
      • Weyler J.J.
      • Winnock F.
      • Van Autreve J.
      • Gorus F.K.
      Beta-cell, thyroid, gastric, adrenal and coeliac autoimmunity and HLA-DQ types in type 1 diabetes.
      • Bao F.
      • Yu L.
      • Babu S.
      • Wang T.
      • Hoffenberg E.J.
      • Rewers M.
      • Eisenbarth G.S.
      One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies.
      • Sakly W.
      • Bienvenu F.
      • Peretti N.
      • Lachaux A.
      • Morel S.
      • Bouvier R.
      • Nicolino M.
      • Bienvenu J.
      • Spiteri A.
      • Fabien N.
      IgA anti-transglutaminase antibodies as a tool for screening atypical forms of coeliac disease in a French at-risk paediatric population.
      • Armentia A.
      • Martin-Santos J.M.
      • Quintero A.
      • Fernandez A.
      • Barber D.
      • Alonso E.
      • Gil I.
      Bakers’ asthma: prevalence and evaluation of immunotherapy with a wheat flour extract.
      • Aygun C.
      • Uraz S.
      • Damci T.
      • Osar Z.
      • Yumuk V.
      • Akdenizli E.
      • Ilkova H.
      Celiac disease in an adult Turkish population with type 1 diabetes mellitus.
      • Sanchez-Albisua I.
      • Wolf J.
      • Neu A.
      • Geiger H.
      • Wascher I.
      • Stern M.
      Coeliac disease in children with type 1 diabetes mellitus: the effect of the gluten-free diet.
      • Shahbazkhani B.
      • Faezi T.
      • Akbari M.R.
      • Mohamadnejad M.
      • Sotoudeh M.
      • Rajab A.
      • Tahaghoghi S.
      • Malekzadeh R.
      Coeliac disease in Iranian type I diabetic patients.
      • Buysschaert M.
      • Tomasi J.P.
      • Hermans M.P.
      Prospective screening for biopsy proven coeliac disease, autoimmunity and malabsorption markers in Belgian subjects with Type 1 diabetes.
      • Peretti N.
      • Bienvenu F.
      • Bouvet C.
      • Fabien N.
      • Tixier F.
      • Thivolet C.
      • Levy E.
      • Chatelain P.G.
      • Lachaux A.
      • Nicolino M.
      The temporal relationship between the onset of type 1 diabetes and celiac disease: a study based on immunoglobulin an antitransglutaminase screening.
      Of note, both disorders can share the same HLA-DQ2/8 susceptibility alleles.
      The identified studies initially screened the study population with one or more serologic tests, followed by biopsy confirmation in the majority of studies. A few studies did not confirm positive serologic test results
      • Li Voon Chong J.S.W.
      • Leong K.S.
      • Wallymahmed M.
      • Sturgess R.
      • MacFarlane I.A.
      Is coeliac disease more prevalent in young adults with coexisting type 1 diabetes mellitus and autoimmune thyroid disease compared with those with type 1 diabetes mellitus alone?.
      • Lorini R.
      • Scotta M.S.
      • Cortona L.
      • Avanzini M.A.
      • Vitali L.
      • De Giacomo C.
      • Scaramuzza A.
      • Severi F.
      Celiac disease and type I (insulin-dependent) diabetes mellitus in childhood: follow-up study.
      • Lampasona V.
      • Bonfanti R.
      • Bazzigaluppi E.
      • Venerando A.
      • Chiumello G.
      • Bosi E.
      • Bonifacio E.
      Antibodies to tissue transglutaminase C in type I diabetes.
      ; in others, biopsy confirmation was performed in less than 75% of subjects.
      • Sjoberg K.
      • Eriksson K.F.
      • Bredberg A.
      • Wassmuth R.
      • Eriksson S.
      Screening for coeliac disease in adult insulin-dependent diabetes mellitus.
      • Talal A.H.
      • Murray J.A.
      • Goeken J.A.
      • Sivitz W.I.
      Celiac disease in an adult population with insulin-dependent diabetes mellitus: use of endomysial antibody testing.
      • Saukkonen T.
      • Savilahti E.
      • Reijonen H.
      • Ilonen J.
      • Tuomilehto-Wolf E.
      • Akerblom H.K.
      Coeliac disease: frequent occurrence after clinical onset of insulin-dependent diabetes mellitus Childhood Diabetes in Finland Study Group.
      • Rossi T.M.
      • Albini C.H.
      • Kumar V.
      Incidence of celiac disease identified by the presence of serum endomysial antibodies in children with chronic diarrhea, short stature, or insulin-dependent diabetes mellitus.
      • Spiekerkoetter U.
      • Seissler J.
      • Wendel U.
      General screening for celiac disease is advisable in children with type 1 diabetes.
      • Kordonouri O.
      • Dieterich W.
      • Schuppan D.
      • Webert G.
      • Muller C.
      • Sarioglu N.
      • Becker M.
      • Danne T.
      Autoantibodies to tissue transglutaminase are sensitive serological parameters for detecting silent coeliac disease in patients with Type 1 diabetes mellitus.
      • Page S.R.
      • Lloyd C.A.
      • Hill P.G.
      • Peacock I.
      • Holmes G.K.
      The prevalence of coeliac disease in adult diabetes mellitus.
      • De Vitis I.
      • Ghirlanda G.
      • Gasbarrini G.
      Prevalence of coeliac disease in type I diabetes: a multicentre study.
      • Bao F.
      • Yu L.
      • Babu S.
      • Wang T.
      • Hoffenberg E.J.
      • Rewers M.
      • Eisenbarth G.S.
      One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies.
      The studies that reported biopsy criteria used partial villous atrophy, or a greater degree of histologic abnormality, to define celiac disease.
      The minimum and maximum prevalence of celiac disease in DM1 by serologic testing in these reports was 1% and 12%, respectively, whereas the minimum and maximum prevalence of celiac disease by biopsy was 1% and 11%, respectively. Although not statistically significant, the prevalence range of celiac disease in adults was slightly lower than in children (1%–10% vs 3%–12%). Variability in the reported prevalence precluded statistical pooling of the results. However, the majority of studies clustered prevalence in the range of 2%–5% in adults and 3%–8% in children. Clinicians caring for patients with DM1 should be aware of the association with celiac disease and consider testing for celiac disease if symptoms occur (eg, unexplained hypoglycemia). If patients with DM1 present for upper endoscopy, small intestinal mucosal biopsies should be considered.

       Prevalence of Celiac Disease in Patients With Autoimmune Thyroid Disease

      The prevalence of celiac disease in patients with autoimmune thyroid disease has been assessed in multiple studies.
      • Akcay M.N.
      • Akcay G.
      The presence of the antigliadin antibodies in autoimmune thyroid diseases.
      • Ch’ng C.L.
      • Biswas M.
      • Benton A.
      • Jones M.K.
      • Kingham J.G.
      Prospective screening for coeliac disease in patients with Graves’ hyperthyroidism using anti-gliadin and tissue transglutaminase antibodies.
      • Berti I.
      • Trevisiol C.
      • Tommasini A.
      • Citta A.
      • Neri E.
      • Geatti O.
      • Giammarini A.
      • Ventura A.
      • Not T.
      Usefulness of screening program for celiac disease in autoimmune thyroiditis.
      • Larizza D.
      • Calcaterra V.
      • De Giacomo C.
      • De Silvestri A.
      • Asti M.
      • Badulli C.
      • Autelli M.
      • Coslovich E.
      • Martinetti M.
      Celiac disease in children with autoimmune thyroid disease.
      • Mainardi E.
      • Montanelli A.
      • Dotti M.
      • Nano R.
      • Moscato G.
      Thyroid-related autoantibodies and celiac disease: a role for a gluten-free diet?.
      • Ravaglia G.
      • Forti P.
      • Maioli F.
      • Volta U.
      • Arnone G.
      • Pantieri G.
      • Talerico T.
      • Muscari A.
      • Zoli M.
      Increased prevalence of coeliac disease in autoimmune thyroiditis is restricted to aged patients.
      • Valentino R.
      • Savastano S.
      • Maglio M.
      • Paparo F.
      • Ferrara F.
      • Dorato M.
      • Lombardi G.
      • Troncone R.
      Markers of potential coeliac disease in patients with Hashimoto’s thyroiditis.
      • Valentino R.
      • Savastano S.
      • Tommaselli A.P.
      • Dorato M.
      • Scarpitta M.T.
      • Gigante M.
      • Micillo M.
      • Paparo F.
      • Petrone E.
      • Lombardi G.
      • Troncone R.
      Prevalence of coeliac disease in patients with thyroid autoimmunity.
      • Volta U.
      • Ravaglia G.
      • Granito A.
      • Forti P.
      • Maioli F.
      • Petrolini N.
      • Zoli M.
      • Bianchi F.B.
      Coeliac disease in patients with autoimmune thyroiditis.
      • Meloni G.F.
      • Tomasi P.A.
      • Bertoncelli A.
      • Fanciulli G.
      • Delitala G.
      • Meloni T.
      Prevalence of silent celiac disease in patients with autoimmune thyroiditis from Northern Sardinia.
      • Sategna-Guidetti C.
      • Bruno M.
      • Mazza E.
      • Carlino A.
      • Predebon S.
      • Tagliabue M.
      • Brossa C.
      Autoimmune thyroid diseases and coeliac disease.
      • Cuoco L.
      • Certo M.
      • Jorizzo R.A.
      • De Vitis I.
      • Tursi A.
      • Papa A.
      • De Marinis L.
      • Fedeli P.
      • Fedeli G.
      • Gasbarrini G.
      Prevalence and early diagnosis of coeliac disease in autoimmune thyroid disorders.
      • Collin P.
      • Salmi J.
      • Hallstrom O.
      • Reunala T.
      • Pasternack A.
      Autoimmune thyroid disorders and coeliac disease.
      These studies are consistent in reporting that celiac disease occurs in 1.5%–6.7% of these patients, with a pooled estimate by biopsy of 3.0% (95% CI, 2.3–3.8). In one study, the investigators found that the prevalence of celiac disease was greater in those 65 years or older (3.6%) than those younger than 65 years (0.6%).
      • Ravaglia G.
      • Forti P.
      • Maioli F.
      • Volta U.
      • Arnone G.
      • Pantieri G.
      • Talerico T.
      • Muscari A.
      • Zoli M.
      Increased prevalence of coeliac disease in autoimmune thyroiditis is restricted to aged patients.
      None of the other identified studies performed this analysis. A recent large genetic linkage study failed to demonstrate a single major locus associated with autoimmune thyroid disease,
      • Taylor J.C.
      • Gough S.C.
      • Hunt P.J.
      • Brix T.H.
      • Chatterjee K.
      • Connell J.M.
      • Franklyn J.A.
      • Hegedus L.
      • Robinson B.G.
      • Wiersinga W.M.
      • Wass J.A.
      • Zabaneh D.
      • Mackay I.
      • Weetman A.P.
      A genome-wide screen in 1119 relative pairs with autoimmune thyroid disease.
      suggesting a genetically heterogeneous disease. Nonetheless, other reports have found an increased prevalence of DQ2/DQ8 in autoimmune thyroid disease.
      • Kaukinen K.
      • Collin P.
      • Mykkanen A.H.
      • Partanen J.
      • Maki M.
      • Salmi J.
      Celiac disease and autoimmune endocrinologic disorders.
      • Wallaschofski H.
      • Meyer A.
      • Tuschy U.
      • Lohmann T.
      HLA-DQA1*0301-associated susceptibility for autoimmune polyglandular syndrome type II and III.
      • Segni M.
      • Pani M.A.
      • Pasquino A.M.
      • Badenhoop K.
      Familial clustering of juvenile thyroid autoimmunity: higher risk is conferred by human leukocyte antigen DR3-DQ2 and thyroid peroxidase antibody status in fathers.
      The data do not present a compelling rationale for the screening of patients with thyroid disease for celiac disease.

       Prevalence of Celiac Disease in Patients With Liver Disease

      Celiac disease can be associated with mild asymptomatic elevations of transaminase levels found during routine blood testing. Celiac disease may also be found in patients with chronic liver disorders such as primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis, and cryptogenic liver disease. Elevated transaminase levels may be the only manifestation of celiac disease, and the introduction of a GFD may correct elevated transaminase levels in these patients.
      • 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.
      • Habior A.
      • Lewartowska A.
      • Orlowska J.
      • Zych W.
      • Sankowska M.
      • Bauer A.
      • Butruk E.
      Association of coeliac disease with primary biliary cirrhosis in Poland.
      • Farre C.
      • Esteve M.
      • Curcoy A.
      • Cabre E.
      • Arranz E.
      • Amat L.L.
      • Garcia-Tornel S.
      Hypertransaminasemia in pediatric celiac disease patients and its prevalence as a diagnostic clue.
      In the screening of patients with liver diseases, several studies indicate that tTGA, especially tTGA-GP, is less specific than EMA, particularly in those patients with more advanced liver disease.
      • Habior A.
      • Lewartowska A.
      • Orlowska J.
      • Zych W.
      • Sankowska M.
      • Bauer A.
      • Butruk E.
      Association of coeliac disease with primary biliary cirrhosis in Poland.
      • Vecchi M.
      • Folli C.
      • Donato M.F.
      • Formenti S.
      • Arosio E.
      • De Franchis R.
      High rate of positive anti-tissue transglutaminase antibodies in chronic liver disease Role of liver decompensation and of the antigen source.
      • Floreani A.
      • Betterle C.
      • Baragiotta A.
      • Martini S.
      • Venturi C.
      • Basso D.
      • Pittoni M.
      • Chiarelli S.
      • Sategna G.C.
      Prevalence of coeliac disease in primary biliary cirrhosis and of antimitochondrial antibodies in adult coeliac disease patients in Italy.
      • Gillett H.R.
      • Cauch-Dudek K.
      • Jenny E.
      • Heathcote E.J.
      • Freeman H.J.
      Prevalence of IgA antibodies to endomysium and tissue transglutaminase in primary biliary cirrhosis.
      • Kaukinen K.
      • Halme L.
      • Collin P.
      • Farkkila M.
      • Maki M.
      • Vehmanen P.
      • Partanen J.
      • Hockerstedt K.
      Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure.
      • Villalta D.
      • Crovatto M.
      • Stella S.
      • Tonutti E.
      • Tozzoli R.
      • Bizzaro N.
      False positive reactions for IgA and IgG anti-tissue transglutaminase antibodies in liver cirrhosis are common and method-dependent.
      • Bizzaro N.
      • Villalta D.
      • Tonutti E.
      • Doria A.
      • Tampoia M.
      • Bassetti D.
      • Tozzoli R.
      IgA and IgG tissue transglutaminase antibody prevalence and clinical significance in connective tissue diseases, inflammatory bowel disease, and primary biliary cirrhosis.
      • Bardella M.T.
      • Valenti L.
      • Pagliari C.
      • Peracchi M.
      • Fare M.
      • Fracanzani A.L.
      • Fargion S.
      Searching for coeliac disease in patients with non-alcoholic fatty liver disease.
      The prevalence of celiac disease in patients with elevated transaminase levels of unknown cause has been reported to be between 1.5% and 9.0%,
      • Carroccio A.
      • Giannitrapani L.
      • Soresi M.
      • Not T.
      • Iacono G.
      • Di Rosa C.
      • Panfili E.
      • Notarbartolo A.
      • Montalto G.
      Guinea pig transglutaminase immunolinked assay does not predict coeliac disease in patients with chronic liver disease.
      • Volta U.
      • Granito A.
      • De Franceschi L.
      • Petrolini N.
      • Bianchi F.B.
      Anti tissue transglutaminase antibodies as predictors of silent coeliac disease in patients with hypertransaminasaemia of unknown origin.
      • Buchan A.M.
      • Grant S.
      • Brown J.C.
      • Freeman H.J.
      A quantitative study of enteric endocrine cells in celiac sprue.
      between 2.9% and 6.4% in patients with autoimmune hepatitis,
      • Villalta D.
      • Girolami D.
      • Bidoli E.
      • Bizzaro N.
      • Tampoia M.
      • Liguori M.
      • Pradella M.
      • Tonutti E.
      • Tozzoli R.
      High prevalence of celiac disease in autoimmune hepatitis detected by anti-tissue tranglutaminase autoantibodies.
      • Volta U.
      • De Franceschi L.
      • Molinaro N.
      • Cassani F.
      • Muratori L.
      • Lenzi M.
      • Bianchi F.B.
      • Czaja A.J.
      Frequency and significance of anti-gliadin and anti-endomysial antibodies in autoimmune hepatitis.
      • Sjoberg K.
      • Lindgren S.
      • Eriksson S.
      Frequent occurrence of non-specific gliadin antibodies in chronic liver disease Endomysial but not gliadin antibodies predict coeliac disease in patients with chronic liver disease.
      and between 0%
      • Volta U.
      • De Franceschi L.
      • Molinaro N.
      • Cassani F.
      • Muratori L.
      • Lenzi M.
      • Bianchi F.B.
      • Czaja A.J.
      Frequency and significance of anti-gliadin and anti-endomysial antibodies in autoimmune hepatitis.
      and 6.0% in those with primary biliary cirrhosis.
      • Habior A.
      • Lewartowska A.
      • Orlowska J.
      • Zych W.
      • Sankowska M.
      • Bauer A.
      • Butruk E.
      Association of coeliac disease with primary biliary cirrhosis in Poland.
      • Floreani A.
      • Betterle C.
      • Baragiotta A.
      • Martini S.
      • Venturi C.
      • Basso D.
      • Pittoni M.
      • Chiarelli S.
      • Sategna G.C.
      Prevalence of coeliac disease in primary biliary cirrhosis and of antimitochondrial antibodies in adult coeliac disease patients in Italy.
      • Gillett H.R.
      • Cauch-Dudek K.
      • Jenny E.
      • Heathcote E.J.
      • Freeman H.J.
      Prevalence of IgA antibodies to endomysium and tissue transglutaminase in primary biliary cirrhosis.
      • Volta U.
      • De Franceschi L.
      • Molinaro N.
      • Cassani F.
      • Muratori L.
      • Lenzi M.
      • Bianchi F.B.
      • Czaja A.J.
      Frequency and significance of anti-gliadin and anti-endomysial antibodies in autoimmune hepatitis.
      • Kingham J.G.
      • Parker D.R.
      The association between primary biliary cirrhosis and coeliac disease: a study of relative prevalences.
      • Volta U.
      • Rodrigo L.
      • Granito A.
      • Petrolini N.
      • Muratori P.
      • Muratori L.
      • Linares A.
      • Veronesi L.
      • Fuentes D.
      • Zauli D.
      • Bianchi F.B.
      Celiac disease in autoimmune cholestatic liver disorders.
      The evidence is not as strong for primary sclerosing cholangitis, but it also appears that the prevalence of celiac disease is elevated in this disorder and is likely close to 1.5%.
      • Kaukinen K.
      • Halme L.
      • Collin P.
      • Farkkila M.
      • Maki M.
      • Vehmanen P.
      • Partanen J.
      • Hockerstedt K.
      Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure.
      • Volta U.
      • Rodrigo L.
      • Granito A.
      • Petrolini N.
      • Muratori P.
      • Muratori L.
      • Linares A.
      • Veronesi L.
      • Fuentes D.
      • Zauli D.
      • Bianchi F.B.
      Celiac disease in autoimmune cholestatic liver disorders.
      One study assessed the prevalence of celiac disease among liver transplant recipients and found that 8 of 185 patients (4.3%) had celiac disease.
      • Kaukinen K.
      • Halme L.
      • Collin P.
      • Farkkila M.
      • Maki M.
      • Vehmanen P.
      • Partanen J.
      • Hockerstedt K.
      Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure.
      Of these patients, 3 had primary biliary cirrhosis, one had autoimmune hepatitis, and one had primary sclerosing cholangitis. Celiac disease may also be associated with nonalcoholic fatty liver disease. In a study of 59 patients with nonalcoholic fatty liver disease, 2 (3.4%) were found to have celiac disease.
      • Bardella M.T.
      • Valenti L.
      • Pagliari C.
      • Peracchi M.
      • Fare M.
      • Fracanzani A.L.
      • Fargion S.
      Searching for coeliac disease in patients with non-alcoholic fatty liver disease.
      Finally, one study using AGA testing suggested that the prevalence of celiac disease may be elevated in patients with “cryptogenic” chronic liver disease.
      • Lindgren S.
      • Sjoberg K.
      • Eriksson S.
      Unsuspected coeliac disease in chronic ’cryptogenic’ liver disease.
      The reason for the association between celiac disease and these liver diseases is not understood and may differ among those diseases.
      • Gillett H.R.
      • Cauch-Dudek K.
      • Jenny E.
      • Heathcote E.J.
      • Freeman H.J.
      Prevalence of IgA antibodies to endomysium and tissue transglutaminase in primary biliary cirrhosis.
      For example, primary biliary cirrhosis has been associated with DQ2 in some reports
      • Morling N.
      • Dalhoff K.
      • Fugger L.
      • Georgsen J.
      • Jakobsen B.
      • Ranek L.
      • Odum N.
      • Svejgaard A.
      DNA polymorphism of HLA class II genes in primary biliary cirrhosis.
      but not in others,
      • Gillett H.R.
      • Cauch-Dudek K.
      • Jenny E.
      • Heathcote E.J.
      • Freeman H.J.
      Prevalence of IgA antibodies to endomysium and tissue transglutaminase in primary biliary cirrhosis.
      suggesting that primary biliary cirrhosis is genetically heterogeneous, and the association with celiac disease may not be on the basis of DQ2/DQ8 alone. Clinicians need to be aware of these associations of celiac disease and have a low threshold for testing for coexistent celiac disease in patients with those liver diseases.

       Prevalence of Celiac Disease in Patients With Other Disorders

      The prevalence of celiac disease in patients with Down syndrome has been evaluated in multiple studies showing evidence of a strong association. Studies that used AGA as the only screening test or those that used AGA with less than 90% biopsy confirmation were not considered for the pooled analysis. Overall, the prevalence of celiac disease in patients with Down syndrome ranged from 3% to 12%, with pooled estimates of 7.6% (95% CI, 6.63%–8.67%) by serologic testing and 5.5% (95% CI, 4.41%–6.16%) by biopsy.
      • Bonamico M.
      • Mariani P.
      • Danesi H.M.
      • Crisogianni M.
      • Failla P.
      • Gemme G.
      • Quartino A.R.
      • Giannotti A.
      • Castro M.
      • Balli F.
      • Lecora M.
      • Andria G.
      • Guariso G.
      • Gabrielli O.
      • Catassi C.
      • Lazzari R.
      • Balocco N.A.
      • De Virgiliis S.
      • Culasso F.
      • Romano C.
      Prevalence and clinical picture of celiac disease in italian Down syndrome patients: a multicenter study.
      • Bonamico M.
      • Rasore-Quartino A.
      • Mariani P.
      • Scartezzini P.
      • Cerruti P.
      • Tozzi M.C.
      • Cingolani M.
      • Gemme G.
      Down syndrome and coeliac disease: usefulness of antigliadin and antiendomysium antibodies.
      • Book L.
      • Hart A.
      • Black J.
      • Feolo M.
      • Zone J.J.
      • Neuhausen S.L.
      Prevalence and clinical characteristics of celiac disease in Down’s syndrome in a US study.
      • Carlsson A.
      • Axelsson I.
      • Borulf S.
      • Bredberg A.
      • Forslund M.
      • Lindberg B.
      • Sjoberg K.
      • Ivarsson S.A.
      Prevalence of IgA-antigliadin antibodies and IgA-antiendomysium antibodies related to celiac disease in children with Down syndrome.
      • Carnicer J.
      • Farre C.
      • Varea V.
      • Vilar P.
      • Moreno J.
      • Artigas J.
      Prevalence of coeliac disease in Down’s syndrome.
      • Cogulu O.
      • Ozkinay F.
      • Gunduz C.
      • Cankaya T.
      • Aydogdu S.
      • Ozgenc F.
      • Kutukculer N.
      • Ozkinay C.
      Celiac disease in children with Down syndrome: importance of follow-up and serologic screening.
      • Csizmadia C.G.
      • Mearin M.L.
      • Oren A.
      • Kromhout A.
      • Crusius J.B.
      • von Blomberg B.M.
      • Pena A.S.
      • Wiggers M.N.
      • Vandenbroucke J.P.
      Accuracy and cost-effectiveness of a new strategy to screen for celiac disease in children with Down syndrome.
      • Gale L.
      • Wimalaratna H.
      • Brotodiharjo A.
      • Duggan J.M.
      Down’s syndrome is strongly associated with coeliac disease.
      • George E.K.
      • Mearin M.L.
      • Bouquet J.
      • von Blomberg B.M.
      • Stapel S.O.
      • van Elburg R.M.
      • de Graaf E.A.
      High frequency of celiac disease in Down syndrome.
      • Hansson T.
      • Anneren G.
      • Sjoberg O.
      • Klareskog L.
      • Dannaeus A.
      Celiac disease in relation to immunologic serum markers, trace elements, and HLA-DR and DQ antigens in Swedish children with Down syndrome.
      • Luft L.M.
      • Barr S.G.
      • Martin L.O.
      • Chan E.K.
      • Fritzler M.J.
      Autoantibodies to tissue transglutaminase in Sjogren’s syndrome and related rheumatic diseases.
      • Jansson U.
      • Johansson C.
      Down syndrome and celiac disease.
      • Mackey J.
      • Treem W.R.
      • Worley G.
      • Boney A.
      • Hart P.
      • Kishnani P.S.
      Frequency of celiac disease in individuals with Down syndrome in the United States.
      • Pueschel S.M.
      • Romano C.
      • Failla P.
      • Barone C.
      • Pettinato R.
      • Castellano C.A.
      • Plumari D.L.
      A prevalence study of celiac disease in persons with Down syndrome residing in the United States of America.
      • Rumbo M.
      • Chirdo F.G.
      • Ben R.
      • Saldungaray I.
      • Villalobos R.
      Evaluation of coeliac disease serological markers in Down syndrome patients.
      • Zachor D.A.
      • Mroczek-Musulman E.
      • Brown P.
      Prevalence of celiac disease in Down syndrome in the United States.
      • Zubillaga P.
      • Vitoria J.C.
      • Arrieta A.
      • Echaniz P.
      • Garcia-Masdevall M.D.
      Down’s syndrome and celiac disease.
      These pooled data suggest that the risk of celiac disease in patients with Down syndrome is at least 5 times that of the average-risk population. This is further collaborated by a large UK cohort study of 1453 patients with Down syndrome and 460,000 controls that found the relative risk of celiac disease in patients with Down syndrome to be 4.7 (95% CI, 1.3–12.2) times that in controls.
      • Goldacre M.J.
      • Wotton C.J.
      • Seagroatt V.
      • Yeates D.
      Cancers and immune related diseases associated with Down’s syndrome: a record linkage study.
      Patients with Down syndrome with celiac disease have the HLA class II alleles coding for DQ2 and/or DQ8. However, the prevalence of DQ2/DQ8 in patients with Down syndrome is similar to that in the general population,
      • Book L.
      • Hart A.
      • Black J.
      • Feolo M.
      • Zone J.J.
      • Neuhausen S.L.
      Prevalence and clinical characteristics of celiac disease in Downs syndrome in a US study.
      indicating that some unknown factor(s) are associated with the increased risk of celiac disease in patients with Down syndrome. HLA typing can be useful to help exclude the possibility of the future development of celiac disease in these patients. In individuals with Down syndrome who are unable to describe symptoms, screening should be offered.
      The prevalence of celiac disease in patients with Turner’s syndrome also appears to be higher than in the general population, with a range of 2%–10% and a pooled estimate of 6.3% (95% CI, 4.57%–8.64%).
      • Bonamico M.
      • Bottaro G.
      • Pasquino A.M.
      • Caruso-Nicoletti M.
      • Mariani P.
      • Gemme G.
      • Paradiso E.
      • Ragusa M.C.
      • Spina M.
      Celiac disease and Turner syndrome.
      • Bonamico M.
      • Pasquino A.M.
      • Mariani P.
      • Danesi H.M.
      • Culasso F.
      • Mazzanti L.
      • Petri A.
      • Bona G.
      Prevalence and clinical picture of celiac disease in Turner syndrome.
      • Gilett P.M.
      • Gilett H.R.
      • Israel D.M.
      • Metzger D.L.
      • Stewart L.
      • Chanoine J.-P.
      • Freeman H.J.
      Increased prevalence of celiac disease in girls with Turner syndrome detected using antibodies to endomysium and tissue transglutaminase.
      • Ivarsson S.A.
      • Carlsson A.
      • Bredberg A.
      • Alm J.
      • Aronsson S.
      • Gustafsson J.
      • Hagenas L.
      • Hager A.
      • Kristrom B.
      • Marcus C.
      • Moell C.
      • Nilsson K.O.
      • Tuvemo T.
      • Westphal O.
      • Albertsson-Wikland K.
      • Aman J.
      Prevalence of coeliac disease in Turner syndrome.
      • Rujner J.
      • Wisniewski A.
      • Gregorek H.
      • Wozniewicz B.
      • Mlynarski W.
      • Witas H.W.
      Coeliac disease and HLA-DQ 2 (DQA1* 0501 and DQB1* 0201) in patients with Turner syndrome.
      As in Down syndrome, patients with celiac disease with Turner’s syndrome are DQ2 positive, but the prevalence of DQ2 in patients with Turner’s syndrome may not be higher than in the general population.
      • Rujner J.
      • Wisniewski A.
      • Gregorek H.
      • Wozniewicz B.
      • Mlynarski W.
      • Witas H.W.
      Coeliac disease and HLA-DQ 2 (DQA1* 0501 and DQB1* 0201) in patients with Turner syndrome.
      The prevalence of celiac disease may also be increased in patients with Williams syndrome, although limited data are available.
      • Giannotti A.
      • Tiberio G.
      • Castro M.
      • Virgilii F.
      • Colistro F.
      • Ferretti F.
      • Digilio M.C.
      • Gambarara M.
      • Dallapiccola B.
      Coeliac disease in Williams syndrome.
      • Santer R.
      • Pankau R.
      • Schaub J.
      • Burgin-Wolff A.
      Williams-Beuren syndrome and celiac disease.
      Symptomatic individuals with Turner’s syndrome or Williams syndrome should be tested for celiac disease, with a low threshold for testing in the latter group who are unable to describe symptoms.
      Celiac disease also appears to be associated with reproductive complications. A case-control study found that patients with celiac disease compared with controls had later menarche and fewer live births.
      • Sher K.S.
      • Mayberry J.F.
      Female fertility, obstetric and gynaecological history in coeliac disease A case control study.
      After the diagnosis of celiac disease, patients had similar numbers of births as controls, suggesting an initial lowered fertility related to celiac disease and an improvement after diagnosis that was presumably related to a GFD. The investigators also found higher rates of miscarriage in patients with celiac disease before diagnosis compared with controls. The prevalence of celiac disease in patients with unexplained infertility has been reported in several studies and also appears to be higher than that in the general population. In one series
      • Meloni G.F.
      • Dessole S.
      • Vargiu N.
      • Tomasi P.A.
      • Musumeci S.
      The prevalence of coeliac disease in infertility.
      and 4 case-control studies,
      • Kolho K.L.
      • Tiitinen A.
      • Tulppala M.
      • Unkila-Kallio L.
      • Savilahti E.
      Screening for coeliac disease in women with a history of recurrent miscarriage or infertility.
      • Collin P.
      • Vilska S.
      • Heinonen P.K.
      • Hallstrom O.
      • Pikkarainen P.
      Infertility and coeliac disease.
      • Tiboni G.M.
      • de Vita M.G.
      • Faricelli R.
      • Giampietro F.
      • Liberati M.
      Serological testing for celiac disease in women undergoing assisted reproduction techniques.
      • Shamaly H.
      • Mahameed A.
      • Sharony A.
      • Shamir R.
      Infertility and celiac disease: do we need more than one serological marker?.
      the prevalence of celiac disease was between 2.1% and 4.1% in women with unexplained infertility. The pooled relative risk of celiac disease in infertile women compared with controls was 3.7 (95% CI, 1.3–10.4).
      Celiac disease has also been associated with other conditions, including ulcerative colitis, Crohn’s disease, Addison’s disease, IgA nephropathy, idiopathic epilepsy, occipital calcifications, and ataxia.
      • Kaukinen K.
      • Collin P.
      • Mykkanen A.H.
      • Partanen J.
      • Maki M.
      • Salmi J.
      Celiac disease and autoimmune endocrinologic disorders.
      • Collin P.
      • Syrjanen J.
      • Partanen J.
      • Pasternack A.
      • Kaukinen K.
      • Mustonen J.
      Celiac disease and HLA DQ in patients with IgA nephropathy.
      • Gobbi G.
      • Bouquet F.
      • Greco L.
      • Lambertini A.
      • Tassinari C.A.
      • Ventura A.
      • Zaniboni M.G.
      Coeliac disease, epilepsy, and cerebral calcifications The Italian Working Group on Coeliac Disease and Epilepsy.
      • Fois A.
      • Vascotto M.
      • Di Bartolo R.M.
      • Di Marco V.
      Celiac disease and epilepsy in pediatric patients.
      • Arroyo H.A.
      • De Rosa S.
      • Ruggieri V.
      • de Davila M.T.G.
      • Fejerman N.
      • Aldao M.
      • Benavente R.
      • Caceres L.
      • Caraballo R.
      • Castagnino M.
      • Di Memo J.
      • Foster O.
      • Grippo J.
      • Guastavino E.
      • Kenny P.
      • Massaro M.
      • Mavromatopulos E.
      • Mora M.
      • Pasteris L.
      • Toca M.
      Epilepsy, occipital calcifications, and oligosymptomatic celiac disease in childhood.
      • Burk K.
      • Bosch S.
      • Muller C.A.
      • Melms A.
      • Zuhlke C.
      • Stern M.
      • Besenthal I.
      • Skalej M.
      • Ruck P.
      • Ferber S.
      • Klockgether T.
      • Dichgans J.
      Sporadic cerebellar ataxia associated with gluten sensitivity.
      Currently there is no evidence to support delaying the time of introduction of gluten into the diet of children in “at-risk” groups.

      Complications of Celiac Disease

       Mortality

      Mortality associated with celiac disease has been assessed in several cohort studies
      • Cottone M.
      • Termini A.
      • Oliva L.
      • Magliocco A.
      • Marrone C.
      • Orlando A.
      • Pinzone F.
      • Di Mitri R.
      • Rosselli M.
      • Rizzo A.
      • Pagliaro L.
      Mortality and causes of death in celiac disease in a Mediterranean area.
      • Corrao G.
      • Corazza G.R.
      • Bagnardi V.
      • Brusco G.
      • Ciacci C.
      • Cottone M.
      • Sategna G.C.
      • Usai P.
      • Cesari P.
      • Pelli M.A.
      • Loperfido S.
      • Volta U.
      • Calabro A.
      • Certo M.
      Mortality in patients with coeliac disease and their relatives: a cohort study.
      • Nielsen O.H.
      • Jacobsen O.
      • Pedersen E.R.
      • Rasmussen S.N.
      • Petri M.
      • Laulund S.
      • Jarnum S.
      Non-tropical sprue Malignant diseases and mortality rate.
      • Peters U.
      • Askling J.
      • Gridley G.
      • Ekbom A.
      • Linet M.
      Causes of death in patients with celiac disease in a population-based Swedish cohort.
      • Logan R.F.
      • Rifkind E.A.
      • Turner I.D.
      • Ferguson A.
      Mortality in celiac disease.
      • Holmes G.K.
      • Stokes P.L.
      • Sorahan T.M.
      • Prior P.
      • Waterhouse J.A.
      • Cooke W.T.
      Coeliac disease, gluten-free diet, and malignancy.
      and a survey. Among the cohort studies, included patients had biopsy-proven celiac disease, and the majority had symptomatic celiac disease. The death rate in patients with celiac disease was higher than that of a standardized population rate or of a control population in all but one study.
      • Johnston S.D.
      • Watson R.G.
      • McMillan S.A.
      • Sloan J.
      • Love A.H.
      Coeliac disease detected by screening is not silent—simply unrecognized.
      In the remaining studies, the standardized mortality rate (SMR; the ratio of the number of deaths observed in the studied patients with celiac disease to the number expected on the basis of age- and sex-specific rates in the region under study) was 1.9 to 3.4.