2013-09-26 13:34:56 UTC

A Biopsy Should Be Required to Make the Diagnosis

Oct. 1, 2013


Peter H.R. Green, MD

Celiac Disease Center, Columbia University


When a diagnosis of celiac disease is made, the therapy — a gluten-free diet — is prescribed for life! The diet is expensive. In the U.S. the cost of gluten-free items is three to five times greater than their regular counterparts.1 In addition the disease and therapy can be socially isolating and such aspects of life, such as eating out of the home or travelling, affect an individual’s quality of life, at least in adults. The diagnosis of celiac disease should therefore be well founded. Increasingly we see patients diagnosed with celiac disease based on minor elevations of tissue transglutaminase IgA antibody levels, genetic testing alone, stool or saliva tests, or even isolated tissue transglutaminase IgG or antigliadin antibody levels. The personal and financial burden of a false diagnosis of celiac disease can be great.

The biopsy has been the gold standard in the diagnosis of celiac disease. Historically, it was often a tour de force to perform a small intestinal biopsy. Suction biopsies were originally performed with a capsule placed fluoroscopically in the jejunum or at the ligament of Treitz.2 There were problems with priming the capsule, tolerance for the duration of the procedure and sometimes misfiring of the capsule with failure to obtain tissue. Subsequently, duodenal biopsies taken endoscopically were shown to be adequate and comparable to more distal biopsies. Currently, because of the issue of patchy areas of villous atrophy and variable degree of biopsy orientation, multiple biopsies are recommended. Adherence to these guidelines increases the chance of a celiac disease diagnosis.3 Duodenal bulb biopsies further increase the diagnostic yield.4

One usually diagnoses celiac disease when villous atrophy is present, therefore a biopsy is necessary. Villous atrophy is represented by Marsh IIIa, b or c lesions. Less severe lesions: Marsh I (lymphocytic duodenitis) or Marsh II lesions (crypt hyperplasia with normal villi) do not necessarily mean a patient has established celiac disease and provides reassurance that a patient need not start the gluten-free diet.

Another situation in which a biopsy is important is that of temporary celiac or gluten autoimmunity, that may occur in both children and adults. In this situation, positive antibodies (tissue transglutaminase and EMA) regress while still on a regular diet. Biopsies taken in these patients are normal and follow-up serological tests are negative. These patients do not require a gluten-free diet. They may receive a label of potential or latent celiac disease.5 They require close follow up.

Who is going to closely read and follow these guidelines; general pediatricians or pediatric gastroenterologists?6 The guidelines require that symptomatic children with a positive tissue transglutaminase IgA antibody more than 10 times the upper level of normal have endomysial antibody positivity confirmed on a subsequent blood sample as well as determination of HLA-DQ2 or –DQ8. Lack of availability of these two tests requires referral for endoscopy even in those with strongly positive tissue transglutaminase antibody levels. Surely, when the information conveyed in the guidelines trickle down to the general pediatrician, they will apply the no-biopsy-necessary policy to diagnose celiac disease to cases that do not fulfill the strict letter of the guidelines.

To which children do they apply? The no-biopsy policy applies to symptomatic children. Only 9 percent of about 250 children seen in our celiac disease center at Columbia University had a classical presentation of diarrhea and malabsorption.7 What about children with growth issues? These children comprised 25 percent of the cohort. Recurrent abdominal pain was the presentation in another 25 percent of the children. Surely they require endoscopy to exclude other pathology? Other coexistent endoscopic findings that would alter management include eosinophillic esophagitis, H. pylori infection and peptic ulcer disease.

The European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHN) guidelines for children were prompted by the reluctance of parents to subject their children to a sedated procedure. Should these pediatric guidelines apply to adults in whom an endoscopy carries neither much in the way of inconvenience nor risk? Biopsies are not only necessary to establish the diagnosis, but also for prognosis. Persistent villous atrophy, detected in follow-up biopsies, is associated with an increased risk for the development of lymphoma.8 In addition, persistent symptoms, despite a gluten-free diet, are common, requiring subsequent biopsies.9 This patient population is difficult to assess without the initial biopsy because some of these patients normalize their biopsies, while others show persistent villous atrophy. If a patient has a biopsy that is normal, we wouldn’t know if this is reassuring (i.e. consistent with healed celiac disease) or whether this patient did not have celiac disease to begin with.

The serum antibody tests for tissue transglutaminase IgA antibodies are powerful tests, but not perfect. The test has high sensitivity and specificity, approximately 90 percent and 98 percent respectively. In high risk, symptomatic patients (10 percent prevalence) the PPV is only 83 percent!10 Many biopsies are going to be negative, especially with lesser degrees of antibody positivity.

In addition, different laboratories use different commercial kits, all of which are not created equal. Some kits have lower sensitivities and specificities. One study demonstrated a greater false positivity in the setting of serum from patients with IBD with one specific kit.11 A clinician should familiarize themself with the specific tests used by their laboratory. We have encountered certain laboratories that systematically give false positive tissue transglutaminase IgA antibody results, at high titer. This can only be picked up when biopsy is routinely performed, but it would be missed (and patients needlessly put on a lifelong gluten-free diet) if the biopsy is not performed.

It is a great error to misdiagnose celiac disease resulting in an unnecessary lifelong gluten-free diet. The knowledge of celiac disease is not great among primary care physicians,12 and the opportunity for misinterpretation of the very strict new ESPGHAN guidelines is great.

Dr. Green has received research support from Alba Therapeutics Corporation and Alvine Pharmaceuticals Inc.


1. Lee AR, Ng DL, Zivin J, Green PH. Economic burden of a gluten-free diet. J Hum Nutr Diet 2007;20:423-30.

2. Smith RB, Sprinz H, Crosby WH, Sullivan BH, Jr. Peroral small bowel mucosal biopsy. Am J Med 1958;25:391-4.

3. Lebwohl B, Kapel RC, Neugut AI, Green PH, Genta RM. Adherence to biopsy guidelines increases celiac disease diagnosis. Gastrointest Endosc 2011;74:103-9.

4. Gonzalez S, Gupta A, Cheng J, Tennyson C, Lewis SK, Bhagat G, Green PH. Prospective study of the role of duodenal bulb biopsies in the diagnosis of celiac disease. Gastrointest Endosc 2010;72:758-65.

5. Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PH, Hadjivassiliou M, Kaukinen K, Kelly CP, Leonard JN, Lundin KE, Murray JA, Sanders DS, Walker MM, Zingone F, Ciacci C. The Oslo definitions for coeliac disease and related terms. Gut 2013;62:43-52.

6. Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R, Troncone R, Giersiepen K, Branski D, Catassi C, Lelgeman M, Maki M, Ribes-Koninckx C, Ventura A, Zimmer KP. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 2012;54:136-60.

7. Reilly NR, Fasano A, Green PH. Presentation of celiac disease. Gastrointest Endosc Clin N Am 2012;22:613-21.

8. Lebwohl B, Granath F, Ekbom A, Smedby KE, Murray JA, Neugut AI, Green PH, Ludvigsson JF. Mucosal Healing and Risk of Lymphoproliferative Malignancy in Celiac Disease. JAMA 2013;in press.

9. Leffler DA, Dennis M, Hyett B, Kelly E, Schuppan D, Kelly CP. Etiologies and predictors of diagnosis in nonresponsive celiac disease. Clin Gastroenterol Hepatol 2007;5:445-50.

10. Rostom A, Dube C, Cranney A, Saloojee N, Sy R, Garritty C, Sampson M, Zhang L, Yazdi F, Mamaladze V, Pan I, Macneil J, Mack D, Patel D, Moher D. The diagnostic accuracy of serologic tests for celiac disease: A systematic review. Gastroenterology 2005;128:S38-46.

11. Naiyer AJ, Hernandez L, Ciaccio EJ, Papadakis K, Manavalan JS, Bhagat G, Green PH. Comparison of Commercially Available Serologic Kits for the Detection of Celiac Disease. J Clin Gastroenterol 2008.

12. Catassi C, Kryszak D, Louis-Jacques O, Duerksen DR, Hill I, Crowe SE, Brown AR, Procaccini NJ, Wonderly BA, Hartley P, Moreci J, Bennett N, Horvath K, Burk M, Fasano A. Detection of Celiac disease in primary care: a multicenter case-finding study in North America. Am J Gastroenterol 2007;102:1454-60.

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