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Nonbiopsy Diagnosis of Celiac Disease: Are We Nearly There Yet?

Hill, Ivor D.*; Horvath, Karoly

Journal of Pediatric Gastroenterology & Nutrition: March 2012 - Volume 54 - Issue 3 - p 310–311
doi: 10.1097/MPG.0b013e31823fb056
Invited Commentaries

*Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, NC

Arnold Palmer Hospital for Children, Orlando, FL.

Address correspondence and reprint requests to Ivor D. Hill, MD, Department of Pediatrics, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157 (e-mail:

Received 27 October, 2011

Accepted 31 October, 2011

I.D.H. received consulting fees from AstraZeneca and receives royalties from UpToDate. K.H. reports no conflicts of interest.

See “Utility of the New ESPGHAN Criteria for the Diagnosis of Celiac Disease in At-risk Groups” by Kurppa et al on page 387.

Recently, the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition released its updated guidelines on the diagnosis of celiac disease (CD) (1). These guidelines are timely, detailed, and thoughtful, and the recommendations reflect changes in our understanding of CD that have occurred since the guidelines of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition were published in 2005 (2). Although many of the recommendations are similar to those published previously, 2 new recommendations deserve mention.

The first is a broader definition of CD that incorporates a “variable combination of gluten-dependent clinical manifestations, CD-specific antibodies, HLA-DQ2 and DQ8 haplotypes, and enteropathy.” This definition diminishes the relative diagnostic importance of the biopsy so as to include symptomatic individuals who may have positive serological tests that precede histological changes by up to 2 years (3–5). The definition will need to be tested over time, particularly in light of the emerging concept of non-CD gluten sensitivity (6). Distinguishing between CD and non-CD gluten sensitivity may have prognostic and therapeutic implications that have yet to be identified, and the distinction could be dependent on the presence or absence of an enteropathy. The second is the suggestion to omit a biopsy in symptomatic patients with tissue transglutaminase (tTG) antibody levels >10 times above the upper limit of normal provided they are also both endomysial antibody (EMA) positive and human leukocyte antigen (HLA)-DQ2 and/or -DQ8 heterodimer positive. To some these recommendations represent a radical change in thinking and will no doubt generate discussion.

Although guidelines are helpful to the practicing clinician, the data upon which they are based are often generated in a research setting and may be subject to some bias. Therefore, the recommendations require testing in a real-world setting so that adjustments can be made if necessary. The article by Kurppa et al (7) in this issue of the Journal attempts to do just that. Their study involved >3000 family members and relatives of patients with CD. Subjects were screened for tTG and EMA antibodies and were grouped according to the level of red blood cell (RBC)-tTG2 antibodies into negative (<20 U), weakly positive (20–29 U), moderately positive (30–99 U), and strongly positive (>100 U). Seropositive subjects were tested for HLA-DQ alleles and offered intestinal biopsy. The strongly positive tTG correlated well with positive EMA and DQ2/8, and in 94% of those who underwent a biopsy, the diagnosis of CD was confirmed. These results support the suggestion that in certain circumstances, a biopsy is not necessary to diagnose CD. In contrast, the association between moderately or weakly positive tTG and positivity for EMA, celiac-type HLA, and biopsy evidence for CD was poor. It is noteworthy that the subjects in the present study were asymptomatic relatives of patients with CD, and a tTG level >5 times the upper limit of normal was designated strongly positive. This differs from the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines, which suggests omitting biopsies only in symptomatic individuals and uses a tTG >10 times the upper limit of normal (1).

Does this study mean we are now ready to abandon biopsies in individuals who have “strongly” positive tTG levels together with EMA and CD-type HLA positivity? A diagnosis of CD should not be made lightly, given that it entails strict lifelong adherence to a burdensome dietary change. Although the ultimate goal is to confidently diagnose CD without the need for a biopsy, there are still some hurdles to overcome. Kurppa et al discuss some discrepancies with other studies that may be dependent on variables in age and pretest probability in the population under study. Additionally, in the United States, there is presently no standardization of CD tests, and wide interlaboratory variation in test results on the same serum samples of patients with known CD has been documented (8).

The intestinal biopsy is an invasive procedure, the lesions can be patchy, proper orientation of the specimens is not standardized, and interpretation is subjective. Despite these limitations, intestinal biopsies will continue to play an important role in the diagnosis of CD in the majority of cases for the foreseeable future. Hopefully, there will be further improvements in the reliability of noninvasive tests, and additional studies will confirm the findings of Kurppa et al in other populations. Nonbiopsy diagnosis of CD can be likened to the young child who asks his parents shortly after starting a long journey “are we nearly there yet?” In both cases, the answer is “there is still a long way to go but we are headed in the right direction.”

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