Guidelines from both pediatric diabetes 19
and pediatric gastroenterology professional societies 7
recommend screening children with T1D for CD. On the other hand, a 2004 NIH consensus statement stated that “current data do not indicate clear outcome benefit for early detection and treatment of asymptomatic individuals in higher risk groups such as T1D” and that studies are needed to determine the natural history and benefit of screening and treatment 20
. The rationale for screening children with TID for CD includes reducing hypoglycemia events, maximizing growth, bone health, and nutrition, and reducing long-term malignancy risks and mortality 21,22
. In contrast, the argument against early GFD includes difficulty in handling the dietary, lifestyle, and medication management changes inherent in the care of children with both T1D and CD and lack of clear benefit in asymptomatic children 23
. In children with T1D, those with evidence of symptomatic CD benefit from GFD 4,24
; in asymptomatic cases the demonstrated benefit is limited to weight gain and BMD changes 25,8,5,26
. In any case, adherence to GFD by children with T1D is only about 50% 4,27,28,29,30
. The conflicting recommendations and diverse viewpoints highlight the need for better understanding of CD.
This 2-year prospective follow-up study has provided additional evidence that children with T1D who have few classical symptom of CD, but are screening-identified as TG+, present with a number of anthropometric and laboratory abnormalities, only some of which improve on GFD. We found that celiac autoimmunity was associated with lower weight and BMI and increased bone turnover, associated with increased fracture risk 31
independent of bone mineral density in adults. Increased bone resorption may precede changes on DEXA and may contribute to osteoporosis in adults with TID 32,33
. Low vitamin D, found in 53% of our subjects, may be an additional risk factor for fractures 34
. Of particular concern are children who continue with high TG levels, some despite reported GFD. Their bone mineral density, ferritin, and vitamin D 25OH levels were significantly lower, compared with the TG− group. School-children are less compliant to GFD than younger children and adults and less likely to recall dietary transgressions. This may explain persistence of TG+ despite reported GFD in some cases. The current study is the largest, carefully controlled, prospective study in children with T1D and celiac autoimmunity with 80% retention during the follow-up.
We did not see differences in HbA1c by TG status, consistent with many other studies 35,5,27,36
, except for one report demonstrating a lower HbA1c with a gluten-free diet 37
. There were also no differences in episodes of severe hypoglycemia.
This study has several important limitations. We did not randomize study participants to GFD or regular diet because families indicated they would not enroll or would not adhere to the diet they did not choose. Despite allowing self-selection to diet groups, adherence to the GFD was likely suboptimal since the TG levels did not normalize in most children reporting GFD. All families received identical initial dietary instruction; however, those diagnosed with CD by biopsy may have been more actively seeking additional resources, leading to possible improved adherence. Although there are no validated measures of gluten exposure, it has been suggested that antibodies to deamidated gliadin peptide decrease more promptly than TG in response to gluten elimination 38
. Additionally there has been significant cross-over in the self-selected diet over the 2-year follow-up. Although this could decrease our ability to detect a benefit of GFD, by itself, a 27% cross-over from regular to gluten-free diet provides important information concerning changing attitudes to GFD among families with TG+ children. This study has limited power and could miss small differences in outcomes, however, a type II error is an unlikely explanation for the lack of major difference between outcomes in the GFD and regular diet groups because the mean TG levels were similar, suggesting similar gluten exposure in both diet groups 30,39,40
. The duration of seropositivity prior to study enrollment was not possible to determine because many patients were positive for TG on first screening around the time of diagnosis of T1D. A few subjects reported starting GFD more than 6 months prior to enrollment. Finally, this 2 year follow-up cohort differs slightly from that used for baseline report 8
. Eight additional TG+ subjects were enrolled and followed for 2 years. Seven of the original 63 TG− subjects were excluded from analysis because they did not have any follow-up visits. Re-analyzing the group with 2 year follow-up for differences at baseline showed that there were no longer differences between groups at baseline for BMI z-scores (p=0.07) or IGF1 z-scores (p=0.07) but that the TG+ group required less insulin/kg/d compared with the TG− group (p=0.03).
In conclusion, this 2-year controlled prospective follow-up study of celiac autoimmunity in T1D children did not demonstrate significant adverse outcome in those children who delayed GFD. Differences in weight and bone turnover were found, but not in bone mineral density or glycemic control. Persistence of TG at high levels should be a reason for concern. The optimal timing of screening and treatment of celiac autoimmunity remains to be determined. Longer follow-up as well as cost-benefit and quality of life analyses will be helpful to further assess these issues.