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Review
. 2015 Sep;39 Suppl 1(Suppl 1):S7-S11.
doi: 10.1016/j.clinre.2015.05.008. Epub 2015 Jul 17.

Combination therapy: New hope for alcoholic hepatitis?

Bin Gao  1 , Vijay H Shah  2
Affiliations
Review

Combination therapy: New hope for alcoholic hepatitis?

Bin Gao et al. Clin Res Hepatol Gastroenterol. 2015 Sep.

Abstract

Alcoholic hepatitis (AH) is a severe form of alcoholic liver disease with high mortality. The pathogenesis of AH is not fully understood, but it is generally believed that inflammation is a key factor leading to liver failure in AH. Steroids, which have broad immunosuppressive effects, have been used for the treatment of AH over the last forty years. Steroids elicit modest improvement in short-term survival rate in patients with severe AH, but also cause severe side effects. Several specific inflammatory targets (e.g., IL-1, LPS, and gut microbiota) are currently under investigation for the treatment of AH with the goal to obviate or reduce steroid administration. In addition to inflammation, impaired liver regeneration is another major cause of liver failure in AH, which deteriorates further after steroid treatment because inflammation plays a key role in promoting liver repair. Interleukin-22 (IL-22) is a promising drug for the treatment of AH because of its hepatoprotective and anti-fibrotic functions and relatively few known side effects. In addition, IL-22 treatment also ameliorates bacterial infection and kidney injury, two major complications associated with severe AH. IL-22 is currently under investigation in preclinical and clinical studies and may hold great promise for AH by providing more beneficial effects and fewer side effects than current therapies.

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Conflict of interest statement

Disclosure of interest

BG declares that he has no conflict of interest concerning this article. Generon Inc (Shanghai, China) will provide recombinant IL-22Fc for an upcoming NIAAA funded study to test safety of IL-22 in AH patients. VJ is PI of this study.

Figures

Figure 1
Figure 1
Pathogenesis of AH and potential combination therapy for AH. Pathogenesis: excessive alcohol consumption causes liver inflammation via three major mechanisms. First, alcohol damages hepatocytes, leading to the release of damage-associated molecular patterns that activate inflammatory cells. Second, chronic alcohol consumption results in gut bacterial overgrowth and dysbiosis, an increase in gut permeability, followed by elevation of bacterial products (e.g., LPS) in the liver and subsequent liver inflammation. Third, alcohol metabolites interact with proteins to form protein adducts, which can activate adaptive immunity and trigger liver inflammation. In addition, liver regeneration is impaired in severe AH, but the underlying mechanisms are still not known. Finally, severe AH is accompanied by many complications. Combination therapy: severe AH, which is associated with multiple problems, requires combination therapy. Several types of potential combination therapy are listed.
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