Biography
Biography: Dimitar Tonev
Abstract
Nonalcoholic fatty liver disease (NAFLD) is becoming the leading cause of liver disease worldwide, and the prevalence is still increasing, potentially becoming a leading cause of liver transplantation in the developed world. NAFLD is defined in the presence of increased hepatic fat content not explained by at risk alcohol intake, and is epidemiologically associated with obesity, insulin resistance and metabolic disorders. It covers a broad histological spectrum ranging from simple uncomplicated steatosis, to nonalcoholic steatohepatitis (NASH), which is characterized by hepatocellular damage and inflammation and may progress to advanced liver disease and hepatocellular carcinoma. The pathogenesis of NASH is multifactorial and badly understood and stratified, but an important role is likely played by inflammation triggered by predisposing genetic factors, oxidative stress, and bacterial products derived from the gut. Recent data seem to suggest that hepatic lipid accumulation itself may also be involved in NASH by inducing lipotoxicity and driving secondary inflammation, leading to activation of fibrogenesis. Although lifestyle modification, weight loss and increased physical activity are effective in improving liver histology in patients with NASH, these goals are only achieved in a minority of patients. Unfortunately, pharmacological treatments for this condition are not yet registered and we have seen multiple, largely a negative results from the initial wave of predominantly academic research cohorts. Pharmaceutical companies’ efforts in this field have been reinvigorated after the publication of the successful NIDDK study FLINT. Multiple drug classes under development either tackle hepatic fat accumulation or act downstream by modulating inflammation and fibrogenesis. Among drugs that influence hepatic lipid metabolism, particularly promising results have been reported for agonists of Farnesoid X receptor (FXR), ASK inhibitors and PPAR agonists, which are the agents currently in phase three trials in patients with NASH and was associated with a higher rate of amelioration of hepatic steatosis or fibrosis as compared to placebo. This presentation will address complicated topic of current patient’s pathways, non-invasive biomarkers and recruitment hurdles associated with big scale clinical trials with multiple liver biopsies. As a parallel analysis this presentation will cover intriguing similarities with historical developments in HCV field and some potentially helpful recruitment enrichment strategies that’s has been utilized in the preceding wave of clinical trials in viral hepatitis domain.