New therapeutic targets in alcoholic hepatitis

Abstract

Alcoholic liver disease (ALD) is a leading cause of liver-related morbidity and mortality worldwide. ALD encompasses a spectrum of disorders including asymptomatic steatosis, steatohepatitis, fibrosis, cirrhosis and its related complications, and the acute-on-chronic state of alcoholic hepatitis. While multidisciplinary efforts continue to be aimed at curbing progression of this spectrum of disorders, there is an urgent need to focus our efforts on effective therapeutic interventions for alcoholic hepatitis (AH), the most severe form of ALD. AH is characterized by an abrupt development of jaundice and complications related to liver insufficiency and portal hypertension in patients with heavy alcohol intake. The mortality of patients with severe AH is very high (20-50 % at 3 months). The current therapeutic regimens are limited. The development of new therapies requires translational studies in human samples and suitable animal models that reproduce clinical and histological features of human AH. This review article summarizes the clinical syndrome, pre-clinical translational tools, and pathogenesis of AH at a molecular and cellular level, with the aim of identifying new targets of potential therapeutic intervention.

Figure 1

Natural progression along the spectrum of ALD, from steatosis, to the inflammatory state of steatohepatitis, to progressive fibrosis and cirrhosis, and finally, to decompensated cirrhosis and HCC. Exacerbations of AH occur at many of the later stages of disease. Predisposing risk factors to accelerated progression are listed.

Figure 2

Clinical evaluation for a patient with high suspicion of AH involves ruling out precipitating factors of decompensated liver disease and confounding illnesses. Role of transjugular liver biopsy is dependent on the care provider’s confidence in the diagnosis. Initial treatment requires ongoing surveillance for improvement.

Figure 3

Systematic approach to designing translational studies to evaluate important molecular markers and potential therapeutic targets in AH.

Figure 4

Potential molecular and cellular targets for therapy for AH identified in translational studies including human samples.