Screening Detected Celiac Disease in Children

Sammanfattning: Background: The prevalence of celiac disease (CD) is estimated to be around 1%, but most CD cases are undiagnosed. Sweden experienced an epidemic of clinically detected celiac disease in children younger than 2 years of age, partly due to changes in infant feeding practices, were the amount of gluten and age at introduction was changed. However, it was not clear if the increase in clinically detected children was due to more CD cases being detected due to symptoms and thus previously undiagnosed, or if it was a true change in CD prevalence. In the revised 2012 ESPGHAN criteria for CD diagnosis, a small intestinal biopsy is no longer mandatory in symptomatic patients when the tTG-IgA levels exceeding ten times the upper limit of normal (> 10xULN) in combination with positivity for EMA and HLA- DQ2 and/or DQ8. Biopsy is still recommended in asymptomatic screening detected cases, were symptoms suggestive of CD is the main difference of the approach to the diagnostic process. Recent studies have shown that screening also detects symptomatic cases, whereas many are unaware of symptoms until after starting on the GFD. Furthermore, there are many pitfalls in the diagnostic process, were the choice of biopsy method and the histopathological evaluation have a significant impact on the diagnostic outcome. To use a capsule device to obtain mucosal specimens was previously considered to be gold standard, but the lesions may be patchy and missed if only one mucosal specimen is obtained. In a clinical setting there can be an advantage of using endoscopy due to the ability to take multiple biopsies. The treatment with a gluten-free diet is a life-long challenge and entails social sacrifices, which may effect the adherence. To be a teenager at the time of diagnosis can be a negative factor, alongside with being screening detected. Objectives: To study the total prevalence of clinical and screening detected celiac disease in children born during the Swedish epidemic, and to investigate the effect and accuracy in each step of the diagnostic process to obtain CD diagnosis. Furthermore, to investigate the correlation between the level of the serological markers (tTG-IgA) and the degree of gluten induced enteropathy and applying the revised 2012 ESPGHAN guidelines on screened CD cases. Additionally, to evaluate the adherence to the GFD in adolescents with screening detected CD. Method: We performed a two-phased screening study, ETICS (Exploring the Iceberg of Celiacs In Sweden). A total of 13 279 twelve year old children were investigated, belonging to two different birth cohorts. The first birth cohort was born during the epidemic period in 1993 and the second cohort was born in the post-epidemic period in 1997. The prevalence of clinically detected CD was gathered from the National Swedish Childhood Celiac Disease Register and the total prevalence was estimated together with the ETICS screening study. Screening for CD was conducted by using a serological marker, anti-tissue transglutaminase antibodies (tTG-IgA). The CD diagnosis was confirmed by a small intestinal biopsy using either a suction capsule or endoscopy according to local routine in the study sites. The clinical diagnostic procedure was reviewed by performing endoscopic re-biopsies in children who hade normal or inconclusive primary biopsy. All of the mucosal specimens were re-evaluated by an expert pathologist and when disagreement with the local pathologist, a second expert pathologist re-evaluated the specimens to reach a diagnostic consensus. The correlation between the degree of enteropathy and the level of the serological markers (tTG-IgA) was investigated by comparing the level of tTG-IgA at the time of biopsy to the degree of gluten induced enteropathy. The revised ESPGHAN guidelines for symptomatic CD was hypothetically applied to the screening cases to evaluate if the biopsy could have been omitted. The adherence to the GFD was measured both by the change of tTG-IgA levels after 12 months and by self-reported questionnaires were the response alternatives were; always, often, sometimes and never. Results: The total prevalence of CD in children born 1993 was 2.9%, with two thirds of the cases being unrecognized. Endoscopic biopsies were inconclusive in 0.6% compared to 7.4% of the capsule biopsies and patchy enteropathy was found in 9% of the children who had conclusive fractions from both proximal and distal duodenum. By controlling the diagnostic process several CD cases were found, re-biopsy resulted in 8 new cases and re-evaluation of all mucosal specimens by an expert pathologist, resulted in additional 6 CD cases. In our screened population all cases with tTG-IgA levels exceeding ten times of normal values (> 10xULN) at a cut-off of 5 U/mL got CD diagnosis and all except for one child got CD diagnosis at a cut-off of 3 U/mL, were the majority had Marsh 3 lesions. The adherence was high in the screened population where 83% had tTG-IgA levels <5 U/mL after 12 months on GFD. Most of the children reported to always (75%) or often (14%) be adherent. There where children who reported to always be adherent but the serological markers were not yet normalized after 12 months. All of these children had halved their initial values, whereof the majority (85%) of these children initially had high serological markers >50 U/mL. Conclusions: The prevalence of 3% was unexpectedly high, whereof two thirds were previously unrecognized. This finding underlines the fact that many CD cases remain undiagnosed, but also that the exposure to an unfavourable infant feeding in this birth cohort may have affected the high total prevalence. The accuracy in the diagnostic procedure is dependant on various factors, where biopsy method and the pathological evaluation are crucial in finding the CD cases. The preferable method for biopsies to be recommended is by using endoscopy and to sharpen the diagnostics to perform re-biopsies and/or re-evaluating in normal or inconclusive biopsies. The revised ESPGHAN guidelines for symptomatic cases seems to be applicable even on screening detected cases, due to the correlation between high levels of tTG-IgA and degree of enteropathy in this group. Screening detected children have a high adherence to the treatment with GFD, which can be measured by using self-reported questionnaires in combination with the change of the serological markers.