Pediatric non alcoholic fatty liver disease: old and new concepts on development, progression, metabolic insight and potential treatment targets

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. NAFLD has emerged to be extremely prevalent, and predicted by obesity and male gender. It is defined by hepatic fat infiltration >5% hepatocytes, in the absence of other causes of liver pathology. It includes a spectrum of disease ranging from intrahepatic fat accumulation (steatosis) to various degrees of necrotic inflammation and fibrosis (non-alcoholic steatohepatatis [NASH]). NAFLD is associated, in children as in adults, with severe metabolic impairments, determining an increased risk of developing the metabolic syndrome. It can evolve to cirrhosis and hepatocellular carcinoma, with the consequent need for liver transplantation. Both genetic and environmental factors seem to be involved in the development and progression of the disease, but its physiopathology is not yet entirely clear. In view of this mounting epidemic phenomenon involving the youth, the study of NAFLD should be a priority for all health care systems. This review provides an overview of current and new clinical-histological concepts of pediatric NAFLD, going through possible implications into patho-physiolocical and therapeutic perspectives.

Figure 1

The “two hits” hypothesis. Transformation from NAFLD to NASH can be explained by the so called “two hit” hypothesis. The “first hit consists of the intrahepatic accumulation of fatty acids, which is closely associated with insulin resistance, and which increases the susceptibility of hepatocytes to secondary injuries or insults (oxidative stress, mitochondrial dysfunction, overproduction and the release of pro-inflammatory cytokines, and the endotoxin-mediated activation of the innate immune response).

Figure 2

Proposed treatment schedule in pediatric NAFLD. Multi-targeted therapy could be the way forward for treating children with NAFLD. Such therapy consists of combinations of the therapeutic approaches directed against various potential targets added to intervention on lifestyle and diet. Psychological therapies could improve adherence to therapies.