Potential Celiac Children: 9-Year Follow-up on a Gluten-containing Diet

Renata Auricchio MD, PhD; Antonella Tosco MD; Emanuela Piccolo MD; Martina Galatola PhD; Valentina Izzo PhD; Mariantonia Maglio PhD; Francesco Paparo PhD; Riccardo Troncone MD, PhD; Luigi Greco MD, PhD


Am J Gastroenterol. 2014;109(6):913-921. 

In This Article

Abstract and Introduction


Objectives: Potential celiac disease (CD) is defined by the presence of serum anti-tissue-transglutaminase (anti-TG2) antibodies and normal duodenal mucosa. The major clinical problem is the management of asymptomatic patients and how to predict the development of villous atrophy. This prospective longitudinal cohort study describes the natural history of potential CD up to 9 years and explores risk factors associated with the development of mucosal damage.

Methods: Two hundred and ten potential CD children were eligible for the study; 175/210 asymptomatic children were left on a gluten-containing diet. Antibodies and clinical symptoms were checked every 6 months, and a small bowel biopsy was taken every 2 years to evaluate histological, immunohistochemical, and anti-TG2 deposits. Patients were genotyped for HLA and a set of non-HLA CD-associated genes.

Results: Forty-three percent of patients showed persistently elevated anti-TG2 level, 20% became negative during follow-up, and 37% showed a fluctuant anti-TG2 course with transiently negative values. At 3 years of follow-up, 86% of cases remained potential; 73 and 67% still had normal duodenal architecture at 6 and 9 years, respectively. Male sex, slight mucosal inflammation at time 0, and a peculiar genetic profile delineate a cohort of individuals who were prone to develop mucosal damage during time.

Conclusions: A sizeable proportion of asymptomatic potential celiac patients showed fluctuation or negativization of antibody production, and many of these, with persistently positive anti-TG2, did not develop mucosal damage after 9 years of follow-up. Celiac population is a multivariate aggregate of individuals with different genetic and phenotypic profiles. Caution is required before prescribing a gluten-free diet for life to asymptomatic individuals with potential CD.


Celiac disease (CD) is an immune-mediated systemic disorder elicited by gluten and related prolamines in genetically susceptible individuals, characterized by the presence of a variable combination of clinical manifestations, CD-specific antibodies, HLA-DQ2 or HLA-DQ8 haplotypes, and enteropathy.[1] In the past 10 years, the clinical picture of CD has radically changed. CD has a wide spectrum of clinical presentations, ranging from classical malabsorption to asymptomatic forms. There is also a spectrum of intestinal mucosal damage, from overt intestinal atrophy to light or absent histological alterations.

Potential CD is defined by the presence of anti-transglutaminase (TG2) and anti-endomysium (EMA) antibodies, with compatible HLA and without duodenal villous atrophy.[2] The patients may or may not have symptoms and signs of the disease and may or may not develop a gluten-dependent enteropathy later on. When mild histological lesions (Marsh grade 0 or 1) are observed, a very low diagnostic likelihood of CD is expected. Indeed, only 10% of subjects presenting inflammatory infiltration of the intestinal epithelium have CD.[3] There is a continuous search for criteria that could improve the diagnosis of initial mucosal damage in potential CD. A high γδ+ intraepithelial cell count remains a good predictor of CD among subjects with normal mucosa architecture.[4] Even the increase in IEL at the villous tip may be helpful for the diagnosis of CD.[5] More recently, the detection of anti-tissue-transglutaminase (anti-TG2) IgA deposits in the mucosa seems to be quite specific for CD and helpful to predict the evolution to more severe histological damage.[6] The detection of anti-TG2 intestinal antibodies by phage libraries is another predictor of CD diagnosis.[7] This test seems to be more sensitive for the detection of anti-TG2 antibody mucosal deposits,[8] but because of its complexity it cannot be proposed routinely.

The major clinical problem remains the management of asymptomatic patients with potential CD. There is no agreement about the treatment of these patients. It has been suggested that this condition is the first step of the disease and that, consequently, all potential CD patients will develop overt CD. Hence, the conclusion is a gluten-free diet for life for all such patients.[9] A study on serum antibody levels in subjects from Warren Air Force Base supports this hypothesis; it also suggests that undiagnosed CD is associated with a nearly fourfold increased mortality from all causes.[10]

To date, there have been few studies on potential CD children. One from Finland[11] showed that during a 2-year follow-up while consuming gluten 7 out of 8 children with normal small bowel mucosa and specific symptoms progressed to villous atrophy, and all 7 responded to a gluten-free diet. A preliminary study from our group showed that most of the 106 asymptomatic children with potential CD remained healthy on a gluten-containing diet. During 3 years of follow-up, CD-associated antibodies fluctuated (32.6%) or even disappeared (14.6%). After 3 years, only 33% of patients developed villous atrophy.[12] We still have no good way to identify which subsets of seropositive patients will go on to develop villous atrophy, and for those who remain clinically silent we are still unable to identify which patients will develop long-term mucosal damage. The European Society of Gastroenterology, Hepatology and Nutrition guidelines[1] suggest that a seropositive, asymptomatic at-risk person, who does not show clear evidence of small intestinal mucosal damage, should be followed up on a normal gluten-containing diet and re-evaluated at regular intervals.

Potential CD is a valuable biological model of the pathway leading to the small intestinal mucosal damage in genetically predisposed individuals. A better knowledge of the mechanism causing intestinal damage in CD would be of great help to identify the reasons why potential CD patients do not show substantial mucosal damage, although they are being genetically susceptible and produce gluten-induced anti-transglutaminase antibodies. We previously explored the genetic features of these patients and showed that potential CD patients have slightly different genetic features from celiacs. Genetic and expression markers help differentiate this condition.[13]

We have published preliminary short-term results from half of this study cohort.[12] We were aware of the necessity to have a larger sample size and a longer follow-up to support our clinical decisions. Here we explore a doubled cohort with a follow-up three times longer (up to 9 years). This study is a unique opportunity to evaluate the outcome and weigh genetic and personal risk factors over the course of a reasonable lifetime.