Metabolic Syndrome in Patients With Celiac Disease
Metabolic Syndrome in Patients With Celiac Disease
The clinical presentation of CD has changed over time and symptoms like diarrhoea and weight loss have become less frequent, especially in adult patients. Several studies in adults and children affected by CD indicate that obesity/overweight at diagnosis is not unusual and that there is a trend towards the development of overweight/obesity in CD subjects who comply with a gluten-free diet. However, to date no study has focused on the prevalence of MS in patients with CD on free diet and after GFD. The present study was planned to generate new information on this underexplored issue.
Our study highlighted that patients with CD are at high risk of developing MS 1 year after starting GFD. In our sample, at this time point the prevalence of MS in patients with CD appeared to be about 30% (2% vs. 29.5%, P < 0.01). This data relate to the significantly higher proportion of patients with CD whose waist circumference exceeded the cut-off value at follow-up (mean values 85 cm ± 11 vs. 88 cm ± 12; P < 0.01; OR: 2.8), as this criterion is essential for the diagnosis of MS according to the IDF definition.
Our results suggest that the majority of newly diagnosed patients with CD who are normal or overweight at baseline are likely to become overweight or obese after the introduction of GFD, with the potential development of MS and/or HS. The increase in weight could be a consequence of the improvement in intestinal absorption (caused by the exclusion of gluten from the diet) in subjects who are in a compensative hyperphagic status. However, it remains to be established whether the GFD itself contributes to the development of overweight/obesity in patients with CD. Several studies have confirmed that long-term GFD may not be nutritionally balanced. Indeed, there is clinical evidence indicating high intake of simple sugars, proteins and saturated fat and intake of complex carbohydrates and fibre in such diets. In addition, increased total caloric intake, the macronutrient composition of the diet, may be involved in the pathogenesis of overweight and obesity in patients with CD. Many gluten-free foods are characterised by a glycemic index which is higher than that of equivalent gluten-containing foods, although this is refuted by some authors. The higher glycemic index of gluten-free foods could be partially explained by the fact that in 'normal' conditions gluten does not allow the amylase to easily access and hydrolyse starch granules in the lumen of the small intestine, thus reducing starch adsorption. Also, the unpalatability of some gluten-free foods may induce a preference towards hyperproteic and hyperlipidemic foods, which, in turn, may lead to increased energy intake and subsequent weight gain.
Among the other MS criteria showing significant changes, blood pressure was the most important: our results highlight that patients with CD on GFD show a 4-fold increase in their risk of developing systemic hypertension.
Glucose profile also appeared significantly different in patients with CD at diagnosis and after 1 year of GFD, with the latter time point being characterised by an approximately 4.5-fold increase in risk for the onset of hyperglycaemia. An elevated fasting plasma glucose concentration is an indicator of insulin resistance, which, in turn, is a potential causing factor of MS with central obesity. These two elements have a mutual relationship: tumour necrosis factor-a (TNF-a), whose increased expression has been demonstrated in human obesity, is thought to participate importantly in insulin resistance by inhibiting tyrosine kinase activity at the insulin receptor. Therefore, BMI increase after GFD might explain the higher prevalence of insulin resistance in patients with CD at follow-up. Another hypothesis about the pathogenesis of insulin resistance directly involves CD: a recent study reports that tTG drives inflammation in CD through the down-regulation of peroxisome proliferator-activated receptor γ (PPARG). As PPARG up-regulation is implicated in type 2 diabetes susceptibility, it is possible that by reducing inflammation the GFD might also influence this pathway. However, this theory needs to be corroborated by further research.
Our data about the lipid profile of patients with CD suggest that this shows no significant differences before and after the introduction of GFD. This finding, apparently in contrast with the other data, is confirmed by several studies which report increased serum levels of HDL cholesterol in patients with CD after starting a GFD in relation to an increment of body fat stores. However, the HDL increase is usually accompanied by an increase also in LDL, due to high fat consumption in patients with CD. The difference between levels of triglycerides at diagnosis and follow-up is at the limit of significance (P = 0.05).
Our results on the prevalence of MS, although not comparable with similar studies at this time, are indirectly confirmed by results from the analysis of BMI status. In our study: many patients with CD had a high or normal BMI at diagnosis (mean value 22.9 kg/m), and this value increased after the adoption of a GFD. This pattern is confirmed by other studies. Dickey et al. demonstrated further weight gain in patients already overweight at the time of CD diagnosis after the introduction of a GFD. A recent American study confirmed these findings, and reported that BMI increase was predominant in the GFD adherent group (evaluated using a GFD adherence score). In contrast with our findings, however, Cheng et al. showed a positive effect of GFD by demonstrating weight gain in previously underweight patients and weight loss in those previously overweight.
With regard to the prevalence of HS, in our study patients with MS had a higher risk of excessive fat accumulation in their liver than patients without MS (65% vs. 13%; P < 0.01). This finding confirms the experience of other authors who demonstrated that HS is strongly associated with MS.
The present work shows some limitations that we briefly discuss. First of all, ours was not designed as an interventional study so that the 'sample size' of the population was not calculated. However, we think that a number of about 100 patients affected by CD and prospectively followed-up for 1 year could offer interesting news and information about the potential risk of MS in subjects with CD on GFD; this could represent a stimulating starting-point for further studies including a larger population. In addition, obesity and MS seems to increase in general population similar to CD and the lack of control group of 'healthy' subjects in our study could represent a methodological shortcoming.
In view of our findings, we recommend that an in-depth nutritional assessment is carried out for all patients with CD at the time of diagnosis as well as at medium-term follow-up (3–6 months) in order to prevent excessive weight gain and the onset of MS. From this point of view, all Gastroenterological Units diagnosing CD should contemplate including in their staff of a nutritionist with experience in this particular clinical field.
In the last few years, GFD has been proposed as a treatment for conditions other than CD. In particular, it has been proposed as an affective dietary approach to noncoeliac gluten sensitivity, irritable bowel syndrome, inflammatory bowel diseases and several other conditions. The findings from our study have relevance for these different pathological settings and suggest that GFD should be prescribed with caution and only for the right indication.
In conclusion, patients with CD on a gluten-free diet are at risk of metabolic syndrome and hepatic steatosis and an in-depth nutritional assessment is required at diagnosis and during follow-up.
Discussion
The clinical presentation of CD has changed over time and symptoms like diarrhoea and weight loss have become less frequent, especially in adult patients. Several studies in adults and children affected by CD indicate that obesity/overweight at diagnosis is not unusual and that there is a trend towards the development of overweight/obesity in CD subjects who comply with a gluten-free diet. However, to date no study has focused on the prevalence of MS in patients with CD on free diet and after GFD. The present study was planned to generate new information on this underexplored issue.
Our study highlighted that patients with CD are at high risk of developing MS 1 year after starting GFD. In our sample, at this time point the prevalence of MS in patients with CD appeared to be about 30% (2% vs. 29.5%, P < 0.01). This data relate to the significantly higher proportion of patients with CD whose waist circumference exceeded the cut-off value at follow-up (mean values 85 cm ± 11 vs. 88 cm ± 12; P < 0.01; OR: 2.8), as this criterion is essential for the diagnosis of MS according to the IDF definition.
Our results suggest that the majority of newly diagnosed patients with CD who are normal or overweight at baseline are likely to become overweight or obese after the introduction of GFD, with the potential development of MS and/or HS. The increase in weight could be a consequence of the improvement in intestinal absorption (caused by the exclusion of gluten from the diet) in subjects who are in a compensative hyperphagic status. However, it remains to be established whether the GFD itself contributes to the development of overweight/obesity in patients with CD. Several studies have confirmed that long-term GFD may not be nutritionally balanced. Indeed, there is clinical evidence indicating high intake of simple sugars, proteins and saturated fat and intake of complex carbohydrates and fibre in such diets. In addition, increased total caloric intake, the macronutrient composition of the diet, may be involved in the pathogenesis of overweight and obesity in patients with CD. Many gluten-free foods are characterised by a glycemic index which is higher than that of equivalent gluten-containing foods, although this is refuted by some authors. The higher glycemic index of gluten-free foods could be partially explained by the fact that in 'normal' conditions gluten does not allow the amylase to easily access and hydrolyse starch granules in the lumen of the small intestine, thus reducing starch adsorption. Also, the unpalatability of some gluten-free foods may induce a preference towards hyperproteic and hyperlipidemic foods, which, in turn, may lead to increased energy intake and subsequent weight gain.
Among the other MS criteria showing significant changes, blood pressure was the most important: our results highlight that patients with CD on GFD show a 4-fold increase in their risk of developing systemic hypertension.
Glucose profile also appeared significantly different in patients with CD at diagnosis and after 1 year of GFD, with the latter time point being characterised by an approximately 4.5-fold increase in risk for the onset of hyperglycaemia. An elevated fasting plasma glucose concentration is an indicator of insulin resistance, which, in turn, is a potential causing factor of MS with central obesity. These two elements have a mutual relationship: tumour necrosis factor-a (TNF-a), whose increased expression has been demonstrated in human obesity, is thought to participate importantly in insulin resistance by inhibiting tyrosine kinase activity at the insulin receptor. Therefore, BMI increase after GFD might explain the higher prevalence of insulin resistance in patients with CD at follow-up. Another hypothesis about the pathogenesis of insulin resistance directly involves CD: a recent study reports that tTG drives inflammation in CD through the down-regulation of peroxisome proliferator-activated receptor γ (PPARG). As PPARG up-regulation is implicated in type 2 diabetes susceptibility, it is possible that by reducing inflammation the GFD might also influence this pathway. However, this theory needs to be corroborated by further research.
Our data about the lipid profile of patients with CD suggest that this shows no significant differences before and after the introduction of GFD. This finding, apparently in contrast with the other data, is confirmed by several studies which report increased serum levels of HDL cholesterol in patients with CD after starting a GFD in relation to an increment of body fat stores. However, the HDL increase is usually accompanied by an increase also in LDL, due to high fat consumption in patients with CD. The difference between levels of triglycerides at diagnosis and follow-up is at the limit of significance (P = 0.05).
Our results on the prevalence of MS, although not comparable with similar studies at this time, are indirectly confirmed by results from the analysis of BMI status. In our study: many patients with CD had a high or normal BMI at diagnosis (mean value 22.9 kg/m), and this value increased after the adoption of a GFD. This pattern is confirmed by other studies. Dickey et al. demonstrated further weight gain in patients already overweight at the time of CD diagnosis after the introduction of a GFD. A recent American study confirmed these findings, and reported that BMI increase was predominant in the GFD adherent group (evaluated using a GFD adherence score). In contrast with our findings, however, Cheng et al. showed a positive effect of GFD by demonstrating weight gain in previously underweight patients and weight loss in those previously overweight.
With regard to the prevalence of HS, in our study patients with MS had a higher risk of excessive fat accumulation in their liver than patients without MS (65% vs. 13%; P < 0.01). This finding confirms the experience of other authors who demonstrated that HS is strongly associated with MS.
The present work shows some limitations that we briefly discuss. First of all, ours was not designed as an interventional study so that the 'sample size' of the population was not calculated. However, we think that a number of about 100 patients affected by CD and prospectively followed-up for 1 year could offer interesting news and information about the potential risk of MS in subjects with CD on GFD; this could represent a stimulating starting-point for further studies including a larger population. In addition, obesity and MS seems to increase in general population similar to CD and the lack of control group of 'healthy' subjects in our study could represent a methodological shortcoming.
In view of our findings, we recommend that an in-depth nutritional assessment is carried out for all patients with CD at the time of diagnosis as well as at medium-term follow-up (3–6 months) in order to prevent excessive weight gain and the onset of MS. From this point of view, all Gastroenterological Units diagnosing CD should contemplate including in their staff of a nutritionist with experience in this particular clinical field.
In the last few years, GFD has been proposed as a treatment for conditions other than CD. In particular, it has been proposed as an affective dietary approach to noncoeliac gluten sensitivity, irritable bowel syndrome, inflammatory bowel diseases and several other conditions. The findings from our study have relevance for these different pathological settings and suggest that GFD should be prescribed with caution and only for the right indication.
In conclusion, patients with CD on a gluten-free diet are at risk of metabolic syndrome and hepatic steatosis and an in-depth nutritional assessment is required at diagnosis and during follow-up.
