Pharmacological Treatment for Non-alcoholic Fatty Liver Disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the most frequently encountered chronic liver disease. NAFLD is associated with increased liver-related morbidity and mortality, but also contributes to cardiovascular disease, diabetes and non-liver-related malignancy. Non-alcoholic steatohepatitis (NASH) is considered the more severe subtype of NAFLD that drives most of these adverse outcomes. Lifestyle modification and associated weight loss can improve NASH but are not always sufficient and sustained results are difficult to obtain. There is hence an urgent need for pharmacological treatment. In this review we discuss some of the concepts and challenges in the development of pharmacological treatment. We also briefly summarise what can be achieved with some of the drugs that are currently available for other indications but have demonstrated benefit in the treatment of NASH. Finally we present an overview of some of the main drugs or types of drugs, mainly based on their mode of action, that are now being developed specifically to treat NASH and that might soon result in the availability of drugs licensed for NASH.

Keywords: Cardiovascular disease; Clinical trials; Diabetes; Endpoints; Hepatology; Non-alcoholic steatohepatitis; Pharmacological treatment.

Fig. 1

Current therapeutic targets in the complex pathophysiology of NASH. NASH is the result of a complex interplay of metabolic, inflammatory and fibrogenic processes. Within the liver, hepatocytes and several of its intracellular organelles, most notably mitochondria, play an important role, alongside the stellate cells and several resident and infiltrating immune cells of different populations. NASH furthermore results from and impacts on an important crosstalk between the liver, the adipose tissue, the gut (including the gut microbiome) and the muscle. The cardiovascular system is even so implicated (not depicted, see ref. [22]). Numerous mediators are involved. Drugs that have been tested in NASH or that are under development have differential targets inside and outside the liver to ultimately result in an improvement of the steatohepatitis and/or fibrosis. DNL de novo lipogenesis, FAS fatty acid synthase, FGF19 fibroblast growth factor 1, FGF21 fibroblast growth factor 21, GLP-1 glucagon-like peptide 1, IFN interferon gamma, IL1-β interleukin 1 beta, IL-6 interleukin 6, IL-17 interleukin 17, LD lipid droplets, LPS lipopolysaccharide, MCP-1 monocyte chemoattractant protein 1, NEFA non-esterified fatty acids, NKT cell natural killer T cell, OCA obeticholic acid, ROS reactive oxygen species, Th17 T helper 17 cell, TGFβ tumour growth factor beta, TNF tumour necrosis factor alpha, VLDL very low density lipoproteins. Reproduced with permission from the Annual Review of Physiology, Volume 78 © 2016 by Annual Reviews, http://www.annualreviews.org [10] (courtesy of J. Haas)