This cross-sectional study is the first to describe the profile of CVD risk factors in a cohort of children with CD in serologic remission on a GFD. Furthermore, this is the first report of insulin resistance in children with CD on a GFD.
Less than one third of our cohort did not have any CVD risk factors, while 14% had three or more risk factors. This finding suggests that CVD screening may be important in pediatric CD patients both at diagnosis and during follow-up. Studies have demonstrated that an earlier onset and greater number of CVD risk factors increase the chance of atheromatous plaque formation[10,11
Our study design, which did not include a healthy control group, did not intend to determine whether children with CD have a higher risk than the general population for the development of CVD. Further prospective studies are needed to evaluate if changes in lifestyle and environment are responsible for a higher cardiovascular risk in celiac patients compared with the normal population. Nevertheless, although this study is limited by the lack of data prior to initiation of a GFD, it may suggest that the clinical and dietary follow-up should target adiposity, lipid profile and other CVD risk factors in addition to the common practice of dietary monitoring of adherence to a GFD.
The introduction of a GFD in CD patients increases the intestinal absorption of both macro and micro-nutrients. This leads to improved weight and height in celiac children presenting with malabsorption (weight loss, failure to thrive, poor weight gain)[20
]. In our cohort, the majority of patients were of normal weight at the time of diagnosis and the percentage of overweight or obese patients was higher than those who were underweight. This drift in clinical presentation is concordant with previous reports[7
] and may be attributed to increased awareness and early diagnosis. Alternatively, it may be explained by the radical change in diet and lifestyle in developed countries in recent decades, in line with the increasing prevalence of overweight and obesity in the general population. The increased prevalence of overweight and obesity after the introduction of a GFD in this study, although not significant (P
= 0.10), may suggest the potential of a GFD to increase weight even in children presenting as normal or overweight at the time of CD diagnosis. The influence of a GFD on BMI remains unclear both in adults and children[9
]. In adults, the debate is mainly based on two discordant theories. Dickey et al[21
] demonstrated further weight gain in patients already overweight at the time of CD diagnosis after the introduction of a GFD, while Cheng et al[22
] showed a positive effect of a GFD by demonstrating weight gain in previously underweight patients and weight loss in those previously overweight. Furthermore a recent study[23
] recruiting a very large cohort of adult patients found that strict GFD adherence could increase the prevalence of overweight and obesity in CD patients. Contrasting studies have also recently appeared in the pediatric literature. Valletta et al[24
] reported an increase in the fraction of overweight children following the introduction of a GFD, while Brambilla et al[25
] demonstrated a beneficial effect of GFD on BMI in the majority of CD children. Reilly et al[26
] found a beneficial effect of GFD on the BMI of overweight celiac children. Our data, demonstrating that a GFD increases the prevalence of overweight and obesity in children with CD, is in agreement with studies reporting increased weight as a potential adverse effect of GFD.
The data concerning LDL cholesterol after at least one year of a GFD suggests an important role for cholesterol as a CVD risk factor in our cohort. In this study, LDL cholesterol was the third most prevalent CVD risk factor in celiac children on a GFD.
The increase in total and HDL cholesterol after GFD introduction in comparison to levels prior to initiation of a GFD (available from a subset of patients), is concordant with some studies which theorized that derangement of intestinal absorption, chylomicron production and lipoprotein metabolism may underlie the finding of lower levels of total and HDL cholesterol in untreated CD, which can revert to normal after treatment[27-30
]. In contrast, we found that the rate of borderline LDL cholesterol concentrations more than doubled (from 9.6% to 23.1%) following adherence to a GFD. This may be the result of a tendency in adult and adolescent patients to consume gluten-free products with high fat contents[31-33
] in order to compensate for the withdrawal of common gluten-containing carbohydrates from the diet.
Our data seem to suggest that although the increase in the rate of borderline LDL cholesterol could raise the cardiovascular risk, the concomitant increase in HDL may be cardioprotective, and thus future studies looking at surrogate markers of atherosclerosis are needed to determine whether a GFD is harmful in this regard.
Four children (3.5%) on a GFD had insulin resistance. As far as we are aware, the only studies reporting HOMA-IR in CD were performed in patients with concomitant insulin-dependent diabetes mellitus (IDDM) 1[34
]. It is not known whether insulin resistance was present on CD diagnosis. As such, this is the first description of the presence of insulin resistance in CD children.
Due to the lack of insulin levels before CD diagnosis, we were unable to assess whether such insulin resistance is directly related to the introduction of a GFD. Previous publications have reported that available gluten-free products (e.g
., gluten-free bread, pasta, pizza etc
.) have much higher glycemic indices than their gluten-containing equivalents, ingestion of which may lead to increased secretion of insulin[35-37
]. Our findings, along with the previously mentioned change in the pattern of CD presentation, may suggest that future assessment of fasting glucose and insulin in children diagnosed with CD before and during the introduction of GFD should be performed. This is especially true in light of the role of insulin resistance as a CVD risk factor, and a predisposing condition for the development of type 2 diabetes[19
]. The significantly higher fasting insulin levels and HOMA-IR in our Italian cohort may be explained by genetic and dietary differences between the two groups[37
]. Our findings suggest that despite the classical consideration of CD as a malabsorptive condition, metabolic derangements, generally not attributed to this condition, should be actively sought even in patients who are non-obese. Although our data may hint to insulin resistance as a new complication of CD, a word of caution is due, as this study was performed on a cohort of CD patients and data is lacking in the literature regarding the prevalence of glucose intolerance in the healthy, non-overweight/obese children and adolescents.
This study has a number of limitations such as the relatively small number of patients, the cross-sectional design which did not allow for pre-GFD levels of all measured parameters, and the lack of familial history for CVD risk factors which may have further impacted our findings. However, despite these limitations, we have described the presence of insulin resistance in pediatric CD for the first time, and specifically addressed other CVD risk factors in the pediatric CD population on a GFD in serological remission.
Prior to initiation of the study, the relationship between CD and CVD risk factors was not clear, and therefore screening of lipid and glucose profiles was not routinely performed in patients with suspected CD. Additionally, the similarity in most findings between patients from two different countries, suggest that these findings are neither geographically nor ethnically specific. Prospective studies are needed to delineate the role of the GFD in the development of CVD risk factors in celiac children.
In conclusion, this cross-sectional study demonstrates a relatively high proportion of children with CD adherent to a GFD with one or more CVD risk factors including insulin resistance. These findings suggest the importance of screening for CVD risk factors in celiac children both at diagnosis and during follow-up. Furthermore, dietary counseling over time, targeting obesity and CVD risk factors in addition to monitoring adherence to a GFD in children and adolescents diagnosed with CD, may be warranted.