Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in children. Genetic variability, which is a main player in NAFLD, is especially characterized by polymorphisms in genes involved in the development and progression of the disease to nonalcoholic steatohepatitis (NASH). Recently, the rs738409 C>G adiponutrin/patatin-like phospholipase domain-containing 3 ( PNPLA3 ) polymorphism, which encodes the I148M protein variant in the catalytic domain, has been associated with severe steatosis, NASH, and liver fibrosis in adults. In this study, we investigated the association between the rs738409 PNPLA3 gene polymorphism and NAFLD in 149 consecutive children and adolescents (age = 6-13 years) with biopsy-proven NAFLD. We analyzed the rs738409 polymorphism by a 5′-nuclease TaqMan assay and assessed its association with NASH: 41% of the subjects with NAFLD showed heterozygosity and 15% showed homozygosity for the at-risk G allele. The rs738409 genotype did not influence the body mass, adiposity, lipid levels, or insulin resistance and was not associated with alanine aminotransferase levels. Interestingly, the rs738409 G allele was strongly associated with the severity of steatosis ( P < 0.0001), the presence of NASH ( P < 0.0001), hepatocellular ballooning ( P < 0.0001), lobular inflammation ( P < 0.0001), and the presence of fibrosis ( P = 0.01) independently of confounders. Individuals carrying two minor G alleles almost always had severe steatosis and NASH, heterozygotes were at intermediate risk, and patients negative for G alleles had milder and often uncomplicated steatosis. Conclusion: The PNPLA3 rs738409 polymorphism is associated with steatosis severity, hepatocellular ballooning, lobular inflammation, and perivenular fibrosis in pediatric NAFLD. (Hepatology 2010)

Objective: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease characterised by accumulation of large-droplet fat in hepatocytes with possible progression to inflammation and fibrosis. Breastfeeding has benefits for child health, both during infancy and later in life, reducing the risk of manifestations of the metabolic syndrome. Here we investigated the association between early type of feeding (breastfed versus formula-fed and duration of breastfeeding) and later NAFLD development. Study design: We investigated 191 young Caucasian children (3–18 years old) with NAFLD consecutively enrolled between January 2003 and September 2007 in our centre. 48% of these children (n = 91) had been breastfed for a median (interquartile range) time of 8 (7) months. Results: After correction for age, waist circumference, gestational age and neonatal weight, the odds of non-alcoholic steatohepatitis (NASH) (OR 0.04, 95% CI 0.01 to 0.10) and fibrosis (OR 0.32, 95% CI 0.16 to 0.65) were lower in breastfed versus not breastfed infants. Moreover, the odds of NASH (OR 0.70, exact 95% CI 0.001 to 0.87) and fibrosis (OR 0.86, exact 95% CI 0.75 to 0.98) decreased for every month of breastfeeding. Conclusions: This observational study suggests that earlier feeding habits might affect the clinical expression of NASH from 3 to 18 years later, with an apparent drug-like preventive effect of breastfeeding.

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of disease ranging from simple steatosis to inflammatory steatohepatitis (NASH) with different degrees of fibrosis that can ultimately progress to cirrhosis. Accumulating evidence suggests the involvement of the endocannabinoid-system in liver disease and related complications. In particular, hepatoprotective properties for Cannabinoid Receptor type 2 (CB2) have been shown both through experimental murine models of liver injury and association study between a CB2 functional variant, Q63R, and liver enzymes in Italian obese children with steatosis. Here, in order to clarify the role of CB2 in severity of childhood NAFLD, we have investigated the association of the CB2 Q63R variant, with histological parameters of liver disease severity in 118 Italian children with histologically-proven NAFLD. CB2 Q63R genotype was assigned performing a TaqMan assay and a general linear model analysis was used to evaluate the association between the polymorphism and the histological parameters of liver damage. We have found that whereas CB2 Q63R variant is not associated with steatosis or fibrosis, it is associated with the severity of the inflammation (p = 0.002) and the presence of NASH (p = 0.02). Our findings suggest a critical role for CB2 Q63R variant in modulating hepatic inflammation state in obese children and in the consequent increased predisposition of these patients to liver damage.

During the last decade, paediatricians have observed a dramatic increase of non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) in children. Furthermore, several lines of evidence have reported that a large part of children with NAFLD presents one or more traits of MS making plausible that, in the coming years, these subjects may present a rapid course of disease towards more severe cirrhosis and cardiovascular disease. Genetic susceptibility and the pressure of intrauterine environment and lifestyle are all crucial to activate molecular machinery that leads to development of NAFLD and MS in childhood. In this scenario, central obesity and consequent adipose tissue inflammation are critical to promote both MS-associated metabolic dysfunctions and NAFLD-related hepatic damage. An excessive dietary intake may in fact cause a specific lipid partitioning and induce metabolic stressors, which in turn promote insulin resistance and the release of several circulating factors. These molecules, on the one hand, trigger steatosis and the inflammatory response that characterize liver damage in NAFLD, and on the other hand contribute to the onset of other features of MS. This review provides an overview of current genetic, pathogenetic and clinical evidence of the vicious circle created by NAFLD and MS in children.