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Nier A¹, Brandt A¹, Conzelmann IB², Özel Y², Bergheim I¹

¹Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, AT-1090 Vienna, Austria; ²Department of Nutritional Medicine, (180), University of Hohenheim, Stuttgart, Germany

Nutrients 2018;10:1329

Abstract: The role of nutrition and diet in the development of non-alcoholic fatty liver disease (NAFLD) is still not fully understood. In the present study, we determined if dietary pattern and markers of intestinal permeability differ between overweight children with and without NAFLD. In addition, in a feasibility study, we assessed the effect of a moderate dietary intervention only focusing on nutrients identified to differ between groups on markers of intestinal barrier function and health status. Anthropometric data, dietary intake, metabolic parameters, and markers of inflammation, as well as of intestinal permeability, were assessed in overweight children (n = 89, aged 5–9) and normalweight healthy controls (n = 36, aged 5–9). Sixteen children suffered from early signs of NAFLD, for example, steatosis grade 1 as determined by ultrasound. Twelve children showing early signs of NAFLD were enrolled in the intervention study (n = 6 intervention, n = 6 control). Body mass index (BMI), BMI standard deviation score (BMI-SDS), and waist circumference were significantly higher in NAFLD children than in overweight children without NAFLD. Levels of bacterial endotoxin, lipopolysaccharide-binding protein (LBP), and proinflammatory markers like interleukin 6 (IL-6) and tumor necrosis factor α (TNFα) were also significantly higher in overweight children with NAFLD compared to those without. Total energy and carbohydrate intake were higher in NAFLD children than in those without. The higher carbohydrate intake mainly resulted from a higher total fructose and glucose intake derived from a significantly higher consumption of sugar-sweetened beverages. When counseling children with NAFLD regarding fructose intake (4 times, 30–60 min within 1 year; one one-on-one counseling and 3 group counselings), neither alanine aminotransferase (ALT) nor aspartate aminotransferase (AST) activity in serum changed; however, diastolic blood pressure (p < 0.05) and bacterial endotoxin levels (p = 0.06) decreased markedly in the intervention group after one year. Similar changes were not found in uncounseled children. Our results suggest that a sugar-rich diet might contribute to the development of early stages of NAFLD in overweight children, and that moderate dietary counseling might improve the metabolic status of overweight children with NAFLD.

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Comments

As a result of the increasing prevalence of pediatric obesity, non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common cause of chronic hepatopathies in children. NAFLD is a progressive disease that encompasses a spectrum of liver diseases, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Data related to survival in children are scarce, but data firmly associate NAFLD with higher risks of hepatic and non-hepatic morbidities and mortalities compared with the general population. More recently, the association between NAFLD and cardiovascular disease among children has increasingly been recognized. Considering the risk of progression of liver damage to cirrhosis and end-stage liver disease, in the last decades, scientific research in this field has been directed to the identification of pathogenetic mechanisms and possible therapeutic strategies for NAFLD. Overweight and insulin resistance are among the key risk factors for the development of NAFLD; however, the question as to why some overweight individuals develop NAFLD and others do not is yet to be fully answered.Although it is clear that glucose has important effects on obesity and other adverse health responses, it appears that fructose, when consumed at high levels, has additional adverse effects on increased liver fat, visceral fat, muscle fat, and triglycerides [24, 25].Indeed, in the present study, overweight children with early signs of NAFLD had a significantly higher mean daily total energy intake when compared to overweight children without NAFLD (∼250 kcal/day), which mainly seemed to result from a higher daily total fructose (free fructose and fructose derived from sucrose) and total glucose (free glucose and glucose derived from sucrose) intake originating from a markedly higher soft-drink and juice intake.Results of the present study suggest that, in overweight children, very early stages of NAFLD are associated with higher body weight, greater waist circumference, and elevated proinflammatory cytokine levels, while markers of insulin resistance are not different. Therefore, the results of the present study preclude that an impaired glucose tolerance or insulin resistance contributes to the onset of NAFLD. Indeed, in adults and mouse models, it was shown that both fasting insulin and glucose levels can still be within the normal range in peripheral blood, while, in liver tissue, the expressions of insulin receptor and insulin receptor substrate were markedly lower [26]. Therefore, it could be that, such as in the present study, overweight children with NAFLD may have suffered from impairments of insulin signaling and glucose metabolism in liver tissue, while fasting glucose and insulin concentrations in peripheral blood were still within the normal range.In this study, both bacterial endotoxin and lipopolysaccharide-binding protein (LBP) levels were significantly higher in overweight children with NAFLD than in those without, suggesting that alterations of intestinal barrier function and, subsequently, an increased translocation of bacterial endotoxin are critical in the development of NAFLD. This study also suggests that targeting sugar or fructose intake even with moderate measures may be beneficial for overall health status of overweight children with NAFLD.However, the study is limited by the small sample size of the intervention group. Furthermore, no power calculation was performed to determine the number of subjects needed to be included for statistically significant outcomes. Thus, the characteristics of the feasibility study are rather explorative, and the effect of a moderate dietary intervention on metabolic and inflammatory markers needs to be assured in a larger randomized population.Also, no valid data were available regarding nutritional intake and dietary pattern at the end of the intervention. Therefore, it is not clear if the beneficial effects on bacterial endotoxin levels found at the end of the study resulted from a change in fructose intake or dietary pattern or other factors. Furthermore, physical and sedentary activities were only acquired by questionnaires rather than activity monitors that are subject to report bias.Finally, lifestyle modification and diet remain the mainstay of treatments of pediatric obesity and NAFLD, but with disappointing results because of the difficulty in obtaining sustained long-term results. The findings of this study call for design of larger randomized trials with a longer duration and follow-up that may give a better overview if targeting fructose intake may be beneficial for overall health status of overweight children with NAFLD.

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