2013-09-26 13:36:23 UTC

A Biopsy Should Not Be Required to Make the Diagnosis

Oct. 1, 2013


Alessio Fasano, MD

Director, Mucosal Immunology and Biology Research Center; Director, Center for Celiac Research,Massachusetts General Hospital for Children — Harvard Medical School


Celiac disease is an autoimmune disease triggered by dietary gluten, a protein contained in wheat, rye and barley, in genetically predisposed individuals.1 The autoimmune insult primarily involves the proximal intestinal mucosa and it is characterized by the typical jejunal damage associated with active celiac disease, showing villous atrophy, crypt hypertrophy and increased intraepithelial lymphocyte (IEL) count. For this reason, the histological analysis of small bowel biopsy specimens, formerly taken by capsule and now by standard upper endoscopy, has become the gold standard for celiac disease diagnosis. Until recently, the small intestinal biopsy was considered a necessary investigation (“no intestinal biopsy, no celiac disease”).2-3 However, during the last 25 years accurate tests have been developed, including the determination of serum IgA class anti-tissue transglutaminase (TTG) and endomysial (EMA) antibodies, IgG class anti-deamidated gliadin peptide (DGP) antibodies and HLA-DQ2 and –DQ8 predisposing genotypes. Thanks to the contribution of these new tools, diagnostic criteria were revisited in 19744 and five criteria were deemed necessary for the diagnosis:

  1. The presence of signs and symptoms compatible with celiac disease.
  2. Positive serology screening (high serum levels of anti-TTG and/or EMA).
  3. Presence of the predisposing genes HLA-DQ2 and/or –DQ8.
  4. Histological evidence of auto-insult of jejunal mucosa typical of celiac disease.
  5. Resolution of the symptoms and normalization of serology test following the implementation of a gluten-free diet.

In many cases all five clinical, serological and histological criteria are consistent and the diagnosis of celiac disease is straightforward. However, major limitations of conventional histology became clear, such as the frequent tangential artifact (a normal mucosa may appear atrophic when the specimen is not cut longitudinally), the poor specificity (particularly of minor lesions such as duodenal lymphocytosis, i.e. Marsh I lesions), and patchiness of the mucosal damage (some sections appearing normal and others showing variable degree of damage).5 What also became clear over time was the evidence that when celiac autoantibodies IgA-TTG and –EMA are found at high titers in a patient with typical symptoms, the probability of identifying a celiac enteropathy at the small intestinal biopsy is practically 100 percent.5 In these cases the intestinal biopsy does not add any relevant information for celiac disease diagnosis and treatment. Furthermore, the following “borderline” situations are increasingly detected in clinical practice in both children and adults:

  • Patients with so called “silent” celiac disease, namely asymptomatic patients diagnosed through routine screening (typically family members of celiac disease cases) that have no (or minimal) symptoms but have positive serology, presence of the predisposing genes and typical celiac disease enteropathy.
  • Patients with “potential” celiac disease show positivity of serum celiac autoantibodies despite a (nearly) normal histological picture at the intestinal biopsy. In many of these cases the deterioration of jejunal architecture takes place over time. Implementation of the gluten-free diet is indicated in potential celiac disease, both for treating symptoms and for preventing late-onset complications.6
  • Conversely, so-called seronegative celiac disease is characterized by clinical, genetic and histological data indicating the disease in a patient lacking serum TTG and EMA antibodies.7 Seronegative celiac disease is likely to be underestimated due to the tendency to perform the intestinal biopsy only in patients with positive celiac disease serum markers (so called “self-fulfilling prophecy”).8
  • The clinician is sometimes faced with the puzzling situation of “clear-cut” celiac disease in patients lacking the HLA-DQ2 or -DQ8 haplotypes. Large multicentre studies have indeed shown that 0.4 percent of celiac disease patients are both DQ2 and DQ8 negative.9
  • Finally, there are cases that, despite correct implementation of the gluten-free diet, remain symptomatic for a long period of time — sometimes one to two years.10

The above-mentioned wide variability of celiac disease-related findings suggests that it is difficult to conceptualize the diagnostic process into rigid algorithms that do not always cover all the facets of this chameleonic disease. Instead, we recently proposed shifting to a quantitative approach to celiac disease diagnosis that can be defined as the “four out of five” rule: the diagnosis of celiac disease is confirmed when at least four of these criteria are satisfied.11 This proposal apparently encompasses almost all of the typical and borderline situations that we have briefly listed above.

An important corollary of this rule is that the small intestinal biopsy may be avoided in selected cases, in which a typical clinical presentation, high titer IgA class anti-TTG and EMA antibodies, and the presence of HLA-DQ2 and/or –DQ8 predisposing genes are present. The diagnosis is confirmed by the resolution of the symptoms and normalization of the celiac disease serology markers upon implementation of the gluten-free diet. This new approach has been validated by the recent review of celiac disease diagnostic guidelines published by the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).12

Of course the small intestinal biopsy is still required in situations that are not clear cut, e.g. patients with minimal/absent complaints, or with modest/discordant elevation of celiac antibodies, or lacking the typical predisposing genotypes. In these situations, an accurate evaluation of small intestinal biopsy taken at different levels, including quantitative morphometry and detection of IgA deposits, should find wider application (fewer biopsies, better biopsies). In conclusion, the small intestinal biopsy should be “downgraded” from gold standard to one of the five celiac disease diagnostic criteria, with the understanding that it may not be necessary if the other four criteria necessary to finalize ascertainment of celiac disease are satisfied. These rules should periodically be revised to take into account the continuous evolution of both advances in pathophysiological knowledge of the disease and diagnostic tools development. Given the permanent nature of the celiac condition, diagnostic accuracy remains a must. This requirement depends more on the level of expertise provided by the diagnostic centers, in terms of clinical experience and diagnostic procedures, than on the rigid application of a protocol that always includes the small intestinal biopsy.

Dr. Fasano is an Alba Therapeutics stock holder.


1. Fasano A. Catassi C. Current approaches to the diagnosis and treatment of celiac disease: an evolving spectrum. Gastroenterology 2001; 120: 636-51.

2. Hill ID, Dirks MH, Liptak GS, et al. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2005; 40: 1-19.

3. Revised criteria for diagnosis of celiac disease. Report of Working Group of European Society of Pediatric Gastroenterology and Nutrition. Arch Dis Child 1990; 65: 909-11.

4. Walker-Smith JA, Guandalini S, Schmitz J, Shmerling Visakorpi JK. Revised criteria for diagnosis of coeliac disease. Arch Dis Child 1990;65:909-1 I.

5. Salmi TT, Collin P, Reunala T, et al. Diagnostic methods beyond conventional histology. Dig Liver Dis. 2010;42:28-32.

6. Hill PG, Holmes GK. Coeliac disease: a biopsy is not always necessary for diagnosis. Aliment Pharmacol Ther 2008; 27: 572-7.

7. Abrams JA, Diamond B, Rotterdam H, et al. Seronegative celiac disease: increased prevalence with lesser degrees of villous atrophy. Dig Dis Sci 2004; 49: 546-50.

8. Oberhuber G, Granditsch G, Vogelsang H. The histopathology of coeliac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol 1999; 11: 1185-94.

9. Karell K, Louka AS, Moodie SJ, et al. HLA type in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. Hum Immunol 2003; 64: 469-77.

10. Hollon JR, Cureton PA, Martin ML, Puppa EL, Fasano A. Trace gluten contamination may play a role in mucosal and clinical recovery in a subgroup of diet-adherent non-responsive celiac disease patients. BMC Gastroenterol. 2013 Feb 28;13:40.

11. Catassi C, Fasano A. Celiac disease diagnosis: simple rules are better than complicated algorithms. Am J Med. 2010;123:691-3.

12. Husby S, Koletzko S, Korponay-Szabó IR, Mearin ML, Phillips A, Shamir R, Troncone R, Giersiepen K, Branski D, Catassi C, Lelgeman M, Mäki M, Ribes-Koninckx C, Ventura A, Zimmer KP; ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012;54:136-60.

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