Diagnosis of Celiac Disease in Adults Based on Serology Test Results, Without Small-Bowel Biopsy

Published:January 09, 2013DOI:

      Background & Aims

      Celiac disease is underdiagnosed, with nonspecific symptoms and high morbidity. New diagnostic factors are needed. We aimed to estimate the frequency at which adult patients with positive results from serology tests are referred for small-bowel biopsies and to identify factors that improve the diagnosis of celiac disease.


      We performed a retrospective analysis of data from 2477 subjects who received serology tests for celiac disease between 2005 and 2007. We analyzed results for total levels of IgA, IgA against human tissue transglutaminase (hTTG), IgA and IgG against gliadin, as well as dilution titers of IgA against endomysial antibodies (EMA). Biopsy samples were analyzed by pathologists experienced in detecting mucosal changes associated with celiac disease and graded according to the Marsh system.


      Of the 2477 patients, 610 (25%) had abnormal results from serology tests, and 39% of these patients (240 of 610) underwent small-bowel biopsy analyses. Of these patients, 50 (21%) had biopsy findings consistent with celiac disease (Marsh 3 lesions) and were placed on gluten-free diets. Titers of IgA hTTG greater than 118 U identified patients with celiac disease with a 2% false-positive rate. Titers of 21 to 118 U, in combination with an EMA dilution titer of 1:160 or greater, had a positive predictive value of 83% for celiac disease. IgA hTTG levels less than 20 U, in combination with an EMA dilution titer less than 1:10, had a negative predictive value of 92% for celiac disease.


      Serum levels of IgA hTTG greater than 118 U, or 21 to 118 U in combination with an EMA dilution titer of 1:160 or greater, can be used to identify adult symptomatic patients with celiac disease, in the absence of a small-bowel biopsy.


      Abbreviations used in this paper:

      AUC (area under the receiver operating characteristic curve), CD (celiac disease), ELISA (enzyme-linked immunosorbent assay), EMA (endomysial antibody), GFD (gluten-free diet), hTTG (human tissue transglutaminase), NPV (negative predictive value), PPV (positive predictive value), ROC (receiver operating characteristic), SB (small bowel), SBB (small-bowel biopsy), VA (villous atrophy)
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      1. NIH Consensus Development Conference on Celiac Disease. NIH consensus and state-of-the-science statements. 2004;21:1–23.

        • Fasano A.
        • Berti I.
        • Gerarduzzi T.
        • et al.
        Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study.
        Arch Intern Med. 2003; 163: 286-292
        • Dubé C.
        • Rostom A.
        • Sy R.
        • et al.
        The prevalence of celiac disease in average-risk and at-risk western European populations: a systematic review.
        Gastroenterology. 2005; 128: S57-S67
        • Green P.H.R.
        • Stavropoulos S.N.
        • Panagi S.G.
        • et al.
        Characteristics of adult celiac disease in the USA: results of a national survey.
        Am J Gastroenterol. 2001; 96: 126-131
        • Norström F.
        • Lindholm L.
        • Sandström O.
        • et al.
        Delay to celiac disease diagnosis and its implications for health-related quality of life.
        BMC Gastroenterol. 2011; 11: 118
        • Murray J.A.
        Celiac disease in patients with an affected member, type 1 diabetes, iron-deficiency, or osteoporosis?.
        Gastroenterology. 2005; 128: S52-S56
        • Gasbarrini G.
        • Miele L.
        • Malandrino N.
        • et al.
        Celiac disease in the 21st century: issues of under- and over-diagnosis.
        Int J Immunopathol Pharmacol. 2009; 22: 1-7
        • Godfrey J.D.
        • Brantner T.L.
        • Brinjikji W.
        • et al.
        Morbidity and mortality among older individuals with undiagnosed celiac disease.
        Gastroenterology. 2010; 139: 763-769
        • Hin H.
        • Bird G.
        • Fisher P.
        • et al.
        Coeliac disease in primary care: case finding study.
        BMJ. 1999; 318: 164-167
        • Rubio-Tapia A.
        • Kyle R.A.
        • Kaplan E.L.
        • et al.
        Increased prevalence and mortality in undiagnosed celiac disease.
        Gastroenterology. 2009; 137: 88-93
        • Collin P.
        • Kaukinen K.
        • Vogelsang H.
        • et al.
        Antiendomysial and antihuman recombinant tissue transglutaminase antibodies in the diagnosis of coeliac disease: a biopsy-proven European multicentre study.
        Eur J Gastroenterol Hepatol. 2005; 17: 85-91
        • Dickey W.
        • Joint BAPEN and British Society of Gastroenterology
        Symposium on “Coeliac disease: basics and controversies.” Coeliac disease in the twenty-first century.
        Proc Nutr Soc. 2009; 68: 234-241
        • Parakkal D.
        • Du H.
        • Semer R.
        • et al.
        Do gastroenterologists adhere to diagnostic and treatment guidelines for celiac disease?.
        J Clin Gastroenterol. 2012; 46: e12-e20
        • Catassi C.
        • Fasano A.
        Celiac disease diagnosis: simple rules are better than complicated algorithms.
        Am J Med. 2010; 123: 691-693
        • Kurien M.
        • Evans K.E.
        • Hopper A.D.
        • et al.
        Duodenal bulb biopsies for diagnosing adult celiac disease: is there an optimal biopsy site?.
        Gastrointest Endosc. 2012; 75: 1190-1196
        • Rashid M.
        • MacDonald A.
        Importance of duodenal bulb biopsies in children for diagnosis of celiac disease in clinical practice.
        BMC Gastroenterol. 2009; 9: 78
        • Salmi T.T.
        • Collin P.
        • Reunala T.
        • et al.
        Diagnostic methods beyond conventional histology in coeliac disease diagnosis.
        Dig Liver Dis. 2010; 42: 28-32
        • Katz K.D.
        • Rashtak S.
        • Lahr B.D.
        • et al.
        Screening for celiac disease in a North American population: sequential serology and gastrointestinal symptoms.
        Am J Gastroenterol. 2011; 106: 1333-1339
        • Fasano A.
        Should we screen for coeliac disease? Yes.
        BMJ Clin Res Ed. 2009; 339: b3592
        • Green P.H.
        • Neugut A.I.
        • Naiyer A.J.
        • et al.
        Economic benefits of increased diagnosis of celiac disease in a national managed care population in the United States.
        J Insur Med. 2008; 40: 218-228
        • Mariné M.
        • Fernández-Bañares F.
        • Alsina M.
        • et al.
        Impact of mass screening for gluten-sensitive enteropathy in working population.
        World J Gastroenterol. 2009; 15: 1331-1338
        • AGA Institute
        AGA Institute medical position statement on the diagnosis and management of celiac disease.
        Gastroenterology. 2006; 131: 1977-1980
        • Rostom A.
        • Murray J.A.
        • Kagnoff M.F.
        American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease.
        Gastroenterology. 2006; 131: 1981-2002
        • Marsh M.N.
        Gluten, major histocompatibility complex, and the small intestine.
        Gastroenterology. 1992; 102: 330-354
        • Leffler D.A.
        • Schuppan D.
        Update on serologic testing in celiac disease.
        Am J Gastroenterol. 2010; 105: 2520-2524
        • Ravelli A.
        • Villanacci V.
        • Monfredini C.
        • et al.
        How patchy is patchy villous atrophy?.
        Am J Gastroenterol. 2010; 105: 2103-2110
        • Kakar S.
        • Nehra V.
        • Murray J.A.
        • et al.
        Significance of intraepithelial lymphocytosis in small bowel biopsy samples with normal mucosal architecture.
        Am J Gastroenterol. 2003; 98: 2027-2033
        • Hopper A.D.
        • Cross S.S.
        • Sanders D.S.
        Patchy villous atrophy in adult patients with suspected gluten-sensitive enteropathy: is a multiple duodenal biopsy strategy appropriate?.
        Endoscopy. 2008; 40: 219-224
        • Hill P.G.
        • Holmes G.K.
        Coeliac disease: a biopsy is not always necessary for diagnosis.
        Aliment Pharmacol Ther. 2008; 27: 572-577
        • Mubarak A.
        • Wolters V.M.
        • Gerritsen S.A.
        • et al.
        A biopsy is not always necessary to diagnose celiac disease.
        J Pediatr Gastroenterol Nutr. 2011; 52: 554-557
        • DeLong E.R.
        • DeLong D.M.
        • Clarke-Pearson D.L.
        Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach.
        Biometrics. 1988; 44: 837-845
        • Ravelli A.
        • Villanacci V.
        Tricks of the trade: how to avoid histological pitfalls in celiac disease.
        Pathol Res Pract. 2012; 208: 197-202
        • Hill I.D.
        What are the sensitivity and specificity of serologic tests for celiac disease?.
        Gastroenterology. 2005; 128: S25-S32
        • Naiyer A.J.
        • Hernandez L.
        • Ciaccio E.J.
        • et al.
        Comparison of commercially available serologic kits for the detection of celiac disease.
        J Clin Gastroenterol. 2009; 43: 225-232
        • Husby S.
        • Koletzko S.
        • Korponay-Szabó I.R.
        • et al.
        European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease.
        J Pediatr Gastroenterol Nutr. 2012; 54: 136-160
        • Hopper A.D.
        • Hadjivassiliou M.
        • Hurlstone D.P.
        • et al.
        What is the role of serologic testing in celiac disease?.
        Clin Gastroenterol Hepatol. 2008; 6: 314-320
        • Taavela J.
        • Kurppa K.
        • Collin P.
        • et al.
        Degree of damage to the small bowel and serum antibody titers correlate with clinical presentation of patients with celiac disease.
        Clin Gastroenterol Hepatol. 2013; 11: 166-171
        • Abrams J.A.
        • Diamond B.
        • Rotterdam H.
        • et al.
        Seronegative celiac disease: increased prevalence with lesser degrees of villous atrophy.
        Dig Dis Sci. 2004; 49: 546-550
        • Vermeersch P.
        • Geboes K.
        • Mariën G.
        • et al.
        Defining thresholds of antibody levels improves diagnosis of celiac disease.
        Clin Gastroenterol Hepatol. 2012 Oct 25; (Epub ahead of print)
        • Bizzaro N.
        The predictive significance of autoantibodies in organ-specific autoimmune diseases.
        Clin Rev Allergy Immunol. 2008; 34: 326-331
        • Nahin R.L.
        • Barnes P.M.
        • Stussman B.J.
        • et al.
        Costs of complementary and alternative medicine (CAM) and frequency of visits to CAM practitioners: United States, 2007.
        Natl Health Stat Rep. 2009; 18: 1-14

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