1Hunter Holmes McGuire Department of Veterans Affairs Medical Center, Gastrointestinal & Hepatology Service (111-N), 1201 Broad Rock Boulevard, Richmond, VA, 23249, USA, Michael.Fuchs2@va.gov.
Nonalcoholic steatohepatitis (NASH) is a severe form of fatty liver disease unrelated to chronic alcohol consumption. As nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions and is becoming the most common cause for chronic liver disease, NASH likely will replace chronic hepatitis C as leading indication for liver cirrhosis and liver transplantation in this decade. Despite this alarming trend, effective treatment is lacking and continues to rely on dietary interventions and physical exercise, known to be of limited effect. Hence, there is an urgent need for safe pharmacologic therapy that successfully reverses or prevents progression of liver injury and fibrosis in patients with NASH. Employing emerging concepts of disease development and progression that involve in parallel ongoing events originating from the liver, adipose tissue, and intestine will ultimately promote the development of effective agents for targeted therapies for NASH. Novel agents must be safe, optimally dosed, and finally pass clinical trials providing proof of concept and efficacy. In the case of NASH, trial design is not necessarily straightforward as surrogate end points to predict clinical benefits are not yet established. The level of unmet needs for NASH goes however even beyond therapeutic agents and also includes patient and physician awareness. This article focuses on identifying potential pathophysiology-guided targets for medical therapy of NASH.