Abstract
Non-alcoholic steatohepatitis (NASH) develops from non-alcoholic fatty liver disease (NAFLD). Currently, around 25% of the population is estimated to have NAFLD, and 25% of NAFLD patients are estimated to have NASH. NASH is typically characterized by liver steatosis inflammation, and fibrosis driven by metabolic disruptions such as obesity, diabetes, and dyslipidemia. NASH patients with significant fibrosis have increased risk of developing cirrhosis and liver failure. Currently, NASH is the second leading cause for liver transplant in the United States. More importantly, the risk of developing hepatocellular carcinoma from NASH has also been highlighted in recent studies. Patients may have NAFLD for years before progressing into NASH. Although the pathogenesis of NASH is not completely understood, the current “multiple-hits” hypothesis suggests that in addition to fat accumulation, elevated oxidative and ER stress may also drive liver inflammation and fibrosis. The development of clinically relevant animal models and pharmacological treatments for NASH have been hampered by the limited understanding of the disease mechanism and a lack of sensitive, non-invasive diagnostic tools. Currently, most pre-clinical animal models are divided into three main groups which includes: genetic models, diet-induced, and toxin + diet-induced animal models. Although dietary models mimic the natural course of NASH in humans, the models often only induce mild liver injury. Many genetic and toxin + diet-induced models rapidly induce the development of metabolic disruption and serious liver injury, but not without their own shortcomings. This review provides an overview of the “multiple-hits” hypothesis and an evaluation of the currently existing animal models of NASH. This review also provides an update on the available interventions for managing NASH as well as pharmacological agents that are currently undergoing clinical trials for the treatment of NASH.
Highlights
First discovered in 1980, non-alcoholic steatohepatitis (NASH) is a type of fatty liver disease characterized by excessive liver fat accumulation, hepatic inflammation and fibrosis (Ludwig et al, 1980; Kleiner et al, 2005; Diehl and Day, 2017)
Epidemiological studies show that roughly 82% of NASH patients are obese, 83% exhibit hyperlipidemia and 48% are diagnosed with type 2 diabetes (Younossi et al, 2016b)
Longitudinal follow-up studies suggest that adolescent diagnosed with non-alcoholic fatty liver disease (NAFLD)/NASH have increased risk of cirrhosis and mortality compared to age-matched average population (Feldstein et al, 2009; Goyal and Schwimmer, 2016; Doycheva et al, 2017)
Summary
First discovered in 1980, non-alcoholic steatohepatitis (NASH) is a type of fatty liver disease characterized by excessive liver fat accumulation, hepatic inflammation and fibrosis (Ludwig et al, 1980; Kleiner et al, 2005; Diehl and Day, 2017). In parallel with the development and progression of obesity and type 2 diabetes a recent study highlighted that the annual health care cost associated with NAFLD in the United States was approximately US$103 billion, and €35 billion in four European countries combined (Germany, Italy, United Kingdom., and France) (Younossi et al, 2016a). These costs are estimated to rise to US$908 and €302 billion in the United States and in these European countries, respectively within 10 years (Younossi et al, 2016a). Early detection, diagnosis and treatment of fatty liver disease are of paramount importance in controlling the impact of this disease
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