Review article: the role of HSD17B13 on global epidemiology, natural history, pathogenesis and treatment of NAFLD

Summary Background Non‐alcoholic fatty liver disease (NAFLD) occurs in around a quarter of the global population and is one of the leading causes of chronic liver disease. The phenotypic manifestation and the severity of NAFLD are influenced by an interplay of environmental and genetic factors. Recently, several inactivating variants in the novel 17‐Beta hydroxysteroid dehydrogenase 13 (HSD17B13) gene have been found to be associated with a reduced risk of chronic liver diseases, including NAFLD. Aims To review the existing literature on the epidemiology of HSD17B13 and discuss its role in the natural history, disease pathogenesis and treatment of NAFLD. Methods We extensively searched relevant literature in PubMed, Google Scholar, clinicaltrials.gov and the reference list of articles included in the review. Results HSD17B13 is a liver‐specific, lipid droplet (LD)‐associated protein that has enzymatic pathways involving steroids, pro‐inflammatory lipid mediators and retinol. The estimated prevalence of the best characterised HSD17B13 variant (rs72613567) ranges from 5% in Africa to 34% in East Asia. Loss‐of‐function variants in HSD17B13 are protective against the progression of NAFLD from simple steatosis to non‐alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis and hepatocellular carcinoma. Emerging data from mechanistic and preclinical studies with RNA interference (RNAi) and small molecule agents indicate that inhibiting HSD17B13 activity may prevent NAFLD progression. Conclusions The loss‐of‐function polymorphisms of the newly identified HSD17B13 gene mitigate the progression of NAFLD. It is important to understand the exact mechanism by which these variants exert a protective effect and implement the gathered knowledge in the treatment of NAFLD.