Alcoholic hepatitis: Translational approaches to develop targeted therapies

Abstract

Alcoholic liver disease is a leading cause of liver-related mortality worldwide. In contrast to recent advances in therapeutic strategies for patients with viral hepatitis, there is a significant lack of novel therapeutic options for patients with alcoholic liver disease. In particular, there is an urgent need to focus our efforts on effective therapeutic interventions for alcoholic hepatitis (AH), the most severe form of alcoholic liver disease. 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 AH is very high (20%-50% at 3 months). Available therapies are not effective in many patients, and targeted approaches are imminently needed. The development of such therapies requires translational studies in human samples and suitable animal models that reproduce the clinical and histological features of AH. In recent years, new animal models that simulate some of the features of human AH have been developed, and translational studies using human samples have identified potential pathogenic factors and histological parameters that predict survival.

Conclusion: This review summarizes the unmet needs for translational studies on the pathogenesis of AH, preclinical translational tools, and emerging drug targets to benefit the AH patient. (Hepatology 2016;64:1343-1355).

Figure 1. Histology, pathogenesis, and experimental models for various stages of ALD, including steatosis, subclinical ASH ± fibrosis, and AH

Histology and pathogenesis of steatosis, subclinical ASH with or without fibrosis, and AH are briefly summarized with more details in the text. Several animal models currently used in the field could represent the different stages of ALD. Chronic ab lib feeding of the Lieber-DeCarli (L/D) ethanol diet is a model to study the early stage of ALD such as steatosis. Several models have been used to investigate subclinical ASH with the strongest liver damage in western diet ab lib + iG alcohol +weekly binge, followed by western diet ab lib + iG alcohol, iG alcohol with HFD, L/D+ multiple binges, and L/D+ single binge.^, The western diet ab lib + iG +weekly binge model recapitulates some of histologic and clinical features of human AH and the L/D+ multiple binge model also partially reproduces these features but to a lesser degree. Models using second hits such as LPS or CCl₄ exhibit coagulative necrosis, failing to recapitulate clinical AH features.

Figure 2. Pathogenesis and molecular mechanisms that trigger liver failure, SIRS, and multi-organ failure in AH

Excessive drinking in alcoholics with underlying ALD induces hepatocellular damage, induces systemic inflammation, and impairs liver regeneration, resulting in liver failure and other complications in AH.

Figure 3. Clinical and Translational Methods in AH

Description of the step-wise process to test plausible drug targets is briefly described here. The method involves omics analysis to animal models, preclinical drug development culminating in testing drugs systematically in phase I-IV clinical trials in AH patients.