A review of the pathogenic and therapeutic role of nutrition in pediatric nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a multifaceted disorder that ranges from simple fatty liver to nonalcoholic steatohepatitis (NASH) with or without fibrosis, which may evolve toward cirrhosis and hepatocellular carcinoma. It is currently considered a "global" and "epidemic" disease, whose prevalence is progressively increasing even in pediatric age. The incidence of NAFLD is very high in overweight/obese children, and a greater risk of disease progression is associated with severe obesity, highlighting the role of nutrition. To date, for NAFLD, there are few guidelines for diagnostic and follow-up methods, and scarce validated protocols for treatment. The initial indications consist of gradual weight loss and regular exercise, but in children, the difficulty of adhering to long-term behavioral changes makes this approach limited. The purpose of this narrative review is to examine the mechanism underlying the pathogenic mechanisms that lead to NAFLD in children, with a major focus on the role of nutrition. Because this is particularly relevant in light of the absence of pharmacological treatments suitable for children, we also overview clinical studies on the potential effects of nutritional supplementations, including vitamins, docosahexaenoic acid, and probiotics.in children. To this aim, updated search was conducted on PubMed and clinicaltrials.gov databases. Future research should consider additional clinical studies in pediatric NAFLD patients to validate the benefits of dietary supplements and to define the appropriate dosage and duration for intervention. Furthermore, experimental studies with -omics approaches could be helpful to deepen the related mechanisms and to search for a possible optimal supplement combination against NAFLD in children.

Efficacy of docosahexaenoic acid-choline-vitamin E in paediatric NASH: a randomized controlled clinical trial.

Nonalcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty liver disease, is one of the most common hepatic diseases in children. We conducted a randomized controlled clinical trial on children with biopsy-proven NASH based on a combinatorial nutritional approach compared with placebo. Participants were assigned to lifestyle modification plus placebo or lifestyle modification plus a mix containing docosahexaenoic acid, choline, and vitamin E (DHA-CHO-VE). Forty children and adolescents participated in the entire trial. The primary outcome was the improvement of liver hyperechogenicity. Secondary outcomes included alterations of alanine aminotransferase (ALT) and other metabolic parameters. Furthermore, changes of serum bile acids (BA) and plasma fibroblast growth factor 19 (FGF19) levels were evaluated as inverse biomarkers of disease severity. At the end of the study, we observed a significant decrease in severe steatosis in the treatment group (50% to 5%, p = 0.001). Furthermore, although the anthropometric and biochemical measurements in the placebo and DHA-CHO-VE groups were comparable at baseline, at the end of the study ALT and fasting glucose levels improved only in the treatment group. Finally, we found that BA levels were not influenced whereas FGF19 levels were significantly increased by DHA-CHO-VE. The results suggest that a combination of DHA, VE, and CHO could improve steatosis and reduce ALT and glucose levels in children with NASH. However, further studies are needed to assess the impact of a DHA and VE combination on repair of liver damage in paediatric NASH.

Docosahexaenoic Acid and Its Role in G-Protein-Coupled Receptor 120 Activation in Children Affected by Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the most important causes of chronic liver disease in children and adults. Recently, therapeutic supplementation with docosahexaenoic acid (DHA) showed an anti-inflammatory and insulin-sensitizing effect in children with NAFLD. The anti-inflammatory effects of DHA depend on its ability to alter phospholipid composition of the cell membrane, to disrupt lipid rafts and to hamper the transcriptional activity of nuclear factor-x03BA;B that controls the expression of proinflammatory cytokines. These effects of DHA are due to the interaction with the G-protein-coupled receptor 120 (GRP120), a lipid-sensing receptor highly expressed in activated macrophages. In fact, DHA may activate GPR120 expression in macrophages causing anti-inflammatory effects, and insulin-sensitizing and antidiabetic effects in vivo. Recently, it has been shown that GPR120 is also expressed by the Kupffer cells of the liver. A diet low in n-3 polyunsaturated fatty acids, as well as the presence of genetic factors, may induce a reduction in the GRP120 signal and the activation of Kupffer cells and inflammation during NAFLD. Therefore, it is conceivable that DHA/GRP120 may play a key role in slowing the progression of liver damage in patients with NAFLD.

Current pharmacotherapy for treating pediatric nonalcoholic fatty liver disease.

INTRODUCTION: In the past decade, nonalcoholic fatty liver disease (NAFLD) had rapidly become one of the most common liver diseases. If efficient therapeutic strategies will not reduce the prevalence of NAFLD in children soon, serious deleterious effects on the quality of life of these patients in adulthood are expected. Lifestyle modification is the current first-line therapy for pediatric NAFLD, even though it is difficult to obtain and to maintain. Therefore, lifestyle changes are usually ineffective and long-lasting improvement of the NAFLD-associated liver damage is rarely observed. As guidelines for the management of NAFLD in children are still lacking, the identification of effective treatments represents a challenge for pediatric hepatologists in the near future. AREAS COVERED: Here, we review the existing therapeutic approaches for treating NAFLD in children and overview all ongoing clinical trials for new promising drugs in pediatric setting. EXPERT OPINION: Considering the multifactorial pathogenesis and the wide spectrum of histological and clinical features of NAFLD, we believe that a drug mix, containing agents that are effective against the principal pathogenetic factors, associated with lifestyle modification, could represent the winning choice of treatment for pediatric NAFLD.

Pediatric non-alcoholic fatty liver disease: recent advances.

Central obesity represents the major factor responsible for NAFLD, but several immunological and endocrinological mechanisms are involved in fatty infiltration in the liver, inflammation and fibrosis. Gut microbiota and genetic factors were recently indicated as major players in liver injury. Loss of weight and physical activity represent till now the cornerstone of treatment, but they are very difficult to obtain and to maintain. Several pharamocotherapeutic approaches including insulin sensitizers, omega-3 fatty acids and vitamin E have been extensively studied in randomized trials, but final conclusions still could not be formulated. Therefore, new treatments based on pathogenetic mechanisms leading to NAFLD are under evaluation to establish the effective pharmacological therapy of this disorder.

Autoimmune hepatitis in children: an overview of the disease focusing on current therapies.

Autoimmune hepatitis (AIH) is an immune-mediated necroinflammatory disease of the liver characterized by elevation of IgG, presence of characteristic autoantibodies, and histological features of interface hepatitis. Two types of juvenile AIH have been recognized according to seropositivity for smooth muscle and/or antinuclear antibody (AIH type 1) or liver kidney microsomal antibody (AIH type 2). The exact pathogenesis of AIH is still unclear, but it is known that unidentified environmental factors, and occasionally drugs, might trigger disease in genetically susceptible individuals. The clinical spectrum of this disease is very wide, ranging from asymptomatic individuals with abnormal liver function to those with fulminant liver failure. The diagnosis is based on a combination of biochemical and histological parameters and on exclusion of other liver diseases. It is a relatively rare but devastating disease, which progresses rapidly unless immunosuppressive treatment is started promptly. Standard therapy consists of a combination of corticosteroids and azathioprine, which is efficacious in 80% of patients. Alternative therapies are increasingly being explored in patients who do not respond to standard treatment and/or have intolerable side-effects. The purpose of this paper is to review our current knowledge about AIH in children, evaluating mainly the therapeutic options for its treatment, considering also the newer immunosuppressant agents used in difficult-to-treat cases.