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 defi ned
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 infl ammation and may progress
to advanced liver disease and hepatocellular carcinoma. Th e pathogenesis of
NASH is multifactorial and badly understood and stratifi ed, but an important
role is likely played by infl ammation 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 infl ammation, leading to activation
of fi brogenesis. Although lifestyle modifi cation, weight loss and increased physical
activity are eff ective 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’ eff orts in this fi eld have been reinvigorated
aft er the publication of the successful NIDDK study FLINT. Multiple drug classes
under development either tackle hepatic fat accumulation or act downstream by
modulating infl ammation and fi brogenesis. Among drugs that infl uence 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 fi brosis as compared
to placebo. Th is 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 fi eld and some potentially helpful recruitment enrichment strategies that’s
has been utilized in the preceding wave of clinical trials in viral hepatitis domain.