Nonalcoholic Fatty Liver Disease/Non-Alcoholic Steatohepatitis in Childhood: Endocrine-Metabolic “Mal-Programming”

Abstract

Context:Nonalcoholic Fatty Liver Disease (NAFLD) is the major chronic liver disease in the pediatric population. NAFLD includes a broad spectrum of abnormalities (inflammation, fibrosis and cirrhosis), ranging from accumulation of fat (also known as steatosis) towards non-alcoholic steatohepatitis (NASH). The development of NAFLD in children is significantly increased.Evidence Acquisition:A literature search of electronic databases was undertaken for the major studies published from 1998 to today. The databases searched were: PubMed, EMBASE, Orphanet, Midline and Cochrane Library. We used the key words: "non-alcoholic fatty liver disease, children, non-alcoholic steatohepatitis and fatty liver".Results:NAFLD/NASH is probably promoted by “multiple parallel hits”: environmental and genetic factors, systemic immunological disorders (oxidative stress, persistent-low grade of inflammation) as well as obesity and metabolic alterations (insulin resistance and metabolic syndrome). However its exact cause still underdiagnosed and unknown.Conclusions:Pediatric NAFLD/NASH is emerging problem. Longitudinal follow-up studies, unfortunately still insufficient, are needed to better understand the natural history and outcome of NAFLD in children. This review focuses on the current knowledge regarding the epidemiology, pathogenesis, environmental, genetic and metabolic factors of disease. The review also highlights the importance of studying the underlying mechanisms of pediatric NAFLD and the need for complete and personalized approach in the management of NAFLD/NASH.

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

“…A reduction of GSL biosynthesis in the adipose tissue of ob/ob mice restored insulin signaling in isolated ex vivo insulinstimulated adipocytes (168,172,176). The improved adipogenesis was a result of the reduced number of larger adipocytes and increased expression of PPAR␥, insulin-responsive glucose transporter (GLUT)-4, and adipsin (103,107,168,169,172,176). Adiponectin gene expression and protein were increased by AMP-DNM, leading to a decreased inflammation in adipose tissue.…”

“…Aspartyl-asparaginyl-␤-hydroxylase (AAH) mediates its effect by activating Notch. Insulin/IGF signaling, AAH, and Notch are inhibited in ALD (99,103,146). Chronic ethanol-fed rats had shown an increased Cer levels and steatohepatitis, with impairments in insulin receptor signaling, insulin receptor substrate, and Akt.…”

“…Based on the notion that increased Cer levels may be deleterious, inhibition of de novo Cer synthesis with myriocin affected lipid metabolism in the liver of rats with streptozotocin-induced Type 1 diabetes (91, 95, 150). Myriocin abrogated many of the adverse effects of ethanol, including hepatic Cer accumulation, steatohepatitis, and impairments of insulin signaling (99,103,146).…”

“…Carriers of GD might not have an increased risk in other diseases (100,136,140). Resistance to tuberculosis (88,92,101), superior intelligence (37,39,102), and increased fertility (103,162,166) are other possible advantages associated with GC.…”

Characterisation of betatrophin concentrations in childhood and adolescent obesity and insulin resistance

“…Furthermore, Peng et al (8) showed that the liver expressed the highest levels of betatrophin in humans, whereas expression was lower in adipose tissue and skeletal muscle. Additional studies demonstrated that hyperinsulinaemia could accelerate NAFLD in obesity, which subsequently might result in insulin resistance via mechanisms including inflammation and unsaturated fatty acids (24,32,33). Moreover, the prevalence of NAFLD in the insulin-resistant group was significantly higher than that in the non-insulin-resistant group.…”