Pharmacological management of nonalcoholic fatty liver disease: Limitations, challenges and new therapeutic opportunities

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of metabolic disorders ranging from a simple accumulation of excess triglycerides in the liver (hepatic steatosis) to hepatic steatosis with inflammation, fibrosis, and cirrhosis (steatohepatitis or non-alcoholic steatohepatitis (NASH)). Studies in humans and animal models suggested that alterations in hepatic lipid metabolism, increased generation of reactive oxygen species and consequently oxidative stress, changes in mitochondrial function, DNA damage, microbial infections and release of various cytokines may contribute to the pathogenesis of NAFLD and its progression to NASH. Recent data also suggest an important role of the lipoprotein transport system in hepatic lipid deposition. Currently, no drugs are approved for the treatment of NAFLD and NASH and existing pharmacotherapy aims at the management of intercurrent diseases such as obesity, hyperlipidemia, insulin resistance, and type 2 diabetes mellitus. All guidelines acknowledge that any medicines prescribed for NAFLD treatment should be considered as an off-label treatment and that their efficacy and safety should be carefully monitored. Although current pharmacotherapy may seem limited and of questionable efficacy, there is optimism that innovative safe and effective options for the management of the disease will be made available shortly since specialized drugs such as obeticholic acid, elafibranor and cenicriviroc, are presently tested in clinical trials. Given that patients with NAFLD without steatohepatitis or fibrosis have excellent prognosis if they adopt appropriate therapeutic lifestyle changes, it is generally accepted that pharmacological treatments should be limited to those with established NASH and fibrosis while subjects with early manifestations of NAFLD should resort to therapeutic lifestyle and nutritional changes.