Prospective Longitudinal Study

Use of Faecal Gluten Immunogenic Peptides to Monitor Children Diagnosed With Coeliac Disease During Transition to a Gluten-free Diet

Isabel Comino; Verónica Segura; Luis Ortigosa; Beatríz Espín; Gemma Castillejo; José Antonio Garrote; Carlos Sierra; Antonio Millán; Carmen Ribes-Koninckx; Enriqueta Román; Alfonso Rodriguez-Herrera; Jacobo Díaz; Jocelyn Anne Silvester; Ángel Cebolla; Carolina Sousa


Aliment Pharmacol Ther. 2019;49(12):1484-1492. 

In This Article


In this study of children with coeliac disease, the rate of GIP detection in stool dropped dramatically from 97% at diagnosis to 13% after 6 months of GFD. This high level of adherence after a GFD was not maintained on follow-up. Some children may relax the GFD as evidenced by an increasing rate of GIP detection with time. We found that 46% of non-adherent participants had two or more GIP positive stools on a GFD. This suggests a behavioural pattern involving repeated or chronic gluten exposure rather than infrequent episodic exposures. As expected, the stool GIP concentration in many non-adherent patients was low, close to the limit of quantification (0.16 μg GIP per gram faeces). Nevertheless, this level of exposure is likely significant as children who had detectable GIP in their stool at any time after diagnosis had a more prolonged elevation of their serum tTG antibody than those with all stools being negative while trying to follow a GFD. Furthermore, some patients had faecal GIP levels similar to those of healthy controls on a gluten containing diet.[19,20]

Investigation of factors underlying gluten exposure was beyond the scope of the current study; however, it must not be assumed that gluten ingestion was intentional. Although all families received GFD education from a dietician, it cannot be expected that they are implementing a GFD correctly. Similar to our previous studies,[20] children younger than two years old had the highest and most sustained adherence to GFD using objective measures. This group, beside having overall a more controlled diet, is highly dependent on their parent or guardian to be fed; therefore, strict control over the diet may be easier to achieve compared with older children (7–18 years old). Thus these differences may reflect the increasing autonomy of the patient regarding dietary decisions. Adolescence is a developmental phase characterised by rebellion and others have found that teenagers may be particularly susceptible to the burden of a GFD related to stigmatization and are more likely intentionally non-adherent in such settings.[25–27] Alternatively, older children and adolescents are also more likely to eat outside the home (eg, at school, at a friends' home) thus having food prepared by persons not always well-informed about the GFD requirements. The increased rate of GIP detection with age may simply reflect that these behaviours are inherently more "risky" with regards to gluten exposure. Among adults, symptomatic suspected gluten reactions are most commonly associated with eating at restaurants.[28] Alternatively, it may be that the habit of GFD adherence, when established in early childhood, is maintained through adolescence and adulthood. This would suggest that diagnosing patients with coeliac disease as early in life as possible should be a priority to avoid social problems and physical and psychological deterioration.[29]

The initial symptomatic response to a GFD tends to be relatively rapid, occurring within days to weeks, especially in patients presenting with classical symptoms. Conversely, gluten exposure on a GFD may not evoke symptoms.[28,30] We found the rate of GIP positive stools increased with time since diagnosis, which may reflect a tendency to relax GFD adherence over time as patients identify that they may tolerate some gluten without symptoms and adjust their diet accordingly. The estimated gluten intake of patients on a GFD (median 0.104 grams per day) was be more than 30-fold less than the typical amount used in gluten challenge (3–10 g/d).[30] Perhaps, ingestion of 0.1–0.5 g gluten does not generate symptoms in a significant proportion of non-adherent patients. A safe threshold for gluten consumption by persons with coeliac disease has not been established; however, it is accepted that gluten tolerance varies widely.[31,32] Consistent with this notion, those who were symptomatic at diagnosis were less likely than those who were asymptomatic to have detectable GIP in the stool. Other investigators have also identified a desire to avoid symptoms as a motivation for adhering strictly to a GFD.[33–35]

Our finding that most children were able to substantially reduce their gluten ingestion within 6 months has implications for the definition of "non-responsive coeliac disease". A categorization rather than a diagnosis, non-responsive coeliac disease has been defined as "persistent symptoms, signs, or laboratory abnormalities typical of coeliac disease despite 6–12 months of dietary gluten avoidance".[36] The duration of gluten avoidance required to be considered non-responsive has been controversial, with some groups requiring at least 12 months of gluten restriction before considering patients non-reponsive[37,38] and others suggesting that inadequate symptomatic response after 6 months on a GFD should prompt investigation for etiologies other than coeliac disease.[39] Our data suggest that 6 months may be a reasonable definition as most children substantially reduced their gluten intake within this timeframe. Regardless of the definition, gluten ingestion (either intentional or inadvertent) is consistently found to be the leading cause of non-responsive coeliac disease.[38,39] Testing for GIP in stool may be a useful tool in the evaluation of non-responsive coeliac disease. Identification of ongoing gluten exposure may guide treatment and obviate the need for expensive and invasive investigations.

Our findings also help to clarify the interpretation of coeliac serology tests after a diagnosis of coeliac disease is established. Although widely used to monitor patients on a GFD and highly specific for persistent villous atrophy on a GFD, the low sensitivity of serum tTG, EMA and DGP antibodies tests renders a negative test substantially less informative.[16,40] We found that those with detectable levels of GIP in stool had a more prolonged elevation and a more gradual fall in tTG antibody than those whose stools tested negative. However, in absolute and evolutive (dichotomous) terms, no concordance is observed between the tTG antibody and GIP levels.

Strengths of our study include the use of a robust and objective measure of gluten exposure in a population of children who all received formal GFD education and who were followed prospectively from diagnosis. Contemporaneous food record completion and stool and serum collection allowed for accurate correlation of serology with faecal GIP detection. Loss to follow-up is a limitation of our study that does complicate interpretation of increased gluten exposure.

In conclusion, serial analysis of faecal GIP allowed not only the first direct confirmation of gluten intake days before coeliac disease diagnosis, but also documentation of a substantial decrease in gluten consumption after diagnosis of coeliac disease and instruction in following a GFD. The introduction of GIP as an assessment tool of GFD adherence may help to ascertain dietary compliance and reduce the need for additional invasive investigations on follow-up.