Alcoholic liver disease: pathogenesis, management, and novel targets for therapy

Abstract

Alcohol use is a leading cause of preventable morbidity and mortality worldwide, with much of its negative impact as the result of alcoholic liver disease (ALD). ALD is a broad term that encompasses a spectrum of phenotypes ranging from simple steatosis to steatohepatitis, progressive fibrosis, cirrhosis, and hepatocellular carcinoma. The mechanisms underlying the development of these different disease stages are incompletely understood. Standard treatment of ALD, which includes abstinence, nutritional support, and corticosteroids, has not changed in the last 40 years despite continued poor outcomes. Novel therapies are therefore urgently needed. The development of such therapies has been hindered by inadequate resources for research and unsuitable animal models. However, recent developments in translational research have allowed for identification of new potential targets for therapy. These targets include: (i) CXC chemokines, (ii) IL-22/STAT3, (iii) TNF receptor superfamily, (iv) osteopontin, (v) gut microbiota and lipopolysaccharide (LPS), (vi) endocannabinoids, and (vii) inflammasomes. We review the natural history, risk factors, pathogenesis, and current treatments for ALD. We further discuss the findings of recent translational studies and potential therapeutic targets.

Keywords: alcoholic liver diseases; fibrosis; inflammation; translational research.

© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Figures

Figure 1

Natural history of alcoholic liver disease and modifier factors. More than 80–90% of heavy drinkers develop fatty liver, but only up to 20–40% of this population develops more severe forms of alcoholic liver disease (ALD), including fibrosis, alcoholic hepatitis, cirrhosis, and hepatocarcinoma (HCC). Multiple other risk factors have been proposed to play a role in susceptibility to severe forms of ALD. HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIV, human immunodeficiency virus.

Figure 2

Pathogenic mechanisms of alcoholic liver disease proposed based in animal models evidence. Ethanol promotes the translocation of lipopolysaccharide from the gastrointestinal lumen to the portal vein, where it binds to the lipopolysaccharide-binding protein. In Kupffer cells, lipopolysaccharide binds to CD14, which combines with TLR4 activating multiple cytokine genes. The increase on inflammatory cytokine production in conjunction with a decrease in STATs expression reduces liver regeneration. Long-term alcohol consumption alters the intracellular balance of antioxidants with subsequent decrease in the release of mitochondrial cytochrome c and expression of Fas ligand, leading to hepatic apoptosis. Activated Kupffer cells and hepatocytes are suggested to be sources of free radicals (especially ROS), which are responsible for lipid peroxidation and further apoptotic damage. Activation of hepatic stellate cells also contributes to the production of cytokines, ROS and TGF-β exacerbating liver fibrosis. ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; CD14, CYP2E1, cytochrome P450 2E1; HSC, hepatic stellate cells; LPS, lipopolysaccharide; NADPH, nicotinamide adenine dinucleotide phosphate; NFκB, nuclear factor κB; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription; TGF-β, transforming growth factor β; TLR4, Toll-like receptor 4.

Figure 3

Potential therapeutic targets for alcoholic liver disease identified in translational studies. The expression and/or activation of different mediators of alcoholic liver disease in liver tissue from patients have been investigated. These findings have been correlated with disease severity and the patient’s outcome. These targets include: CXC chemokines, IL-22/STAT3, TNF receptor superfamily, osteopontin, gut microbiota and LPS, endocannabinoids and inflammasomes. CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; Gro-α growth-regulated α-protein; IL-8, interleukin 8; IL-22, interleukin 22; LPS, lipopolysaccharide; STAT3, signal transducer and activator of transcription 3; TNF, tumor necrosis factor; TLRs, toll-like receptors.