Alcoholic hepatitis: current challenges and future directions

Abstract

Alcoholic hepatitis is a distinct clinical syndrome among people with chronic and active alcohol abuse, with a potential for 30%-40% mortality at 1 month among those with severe disease. Corticosteroids or pentoxifylline are the current pharmacologic treatment options, but they provide only about 50% survival benefit. These agents are recommended for patients with modified discriminant function (mDF) ≥ 32 or Model for End-Stage Liver Disease score ≥ 18. The Lille score is used to determine response to steroids. Currently, a minimum of 6 months of abstinence from alcohol use is required for patients to receive a liver transplant, a requirement that cannot be met by patients with severe alcoholic hepatitis nonresponsive to steroids (Lille score ≥ 0.45). Data are emerging on the benefit of liver transplantation in select patients with first episode of severe alcoholic hepatitis. This review also focuses on recent treatment trials in alcoholic hepatitis including liver transplantation and its associated controversies, as well as possible future targets and pharmacologic treatment options for patients with alcoholic hepatitis that are being pursued through upcoming consortium studies.

Keywords: Alcoholic Hepatitis; Apoptosis; Liver Injury; MELD.

Figure 1

Suggested algorithm in diagnosis and management of alcoholic hepatitis. mDF: Modified discriminant function; LC P: Liver chemistry panel; CXR: Chest X-ray; DM: Diabetes mellitus; PTX: Pentoxifylline; ECBL: Early change in bilirubin level; LT: Liver transplantation

Figure 2

Pathogenesis of alcoholic hepatitis with identification of newer therapeutic targets. 1: Alcohol increases gut permeability and allows translocation of bacterial lipopolysaccharide which stimulates TLR-4 receptors in liver. Antibiotics, probiotics, and immunoglobulin to LPS may attenuate this response. 2: Kupffer cells stimulate inflammatory cascades including production of IL-1 which recruits white blood cells. Anikinra is an antagonist of IL-1 receptor. Macrophage inflammatory factor is another target. 3: TNF-α mediates cell death via caspase-8 (apoptosis) and caspase-1 (sterile necrosis). Caspase inhibitor Emricasan is a potential agent blocking final common pathway without affecting hepatic regeneration as seen with anti-TNF agents, corticosteroids, and other cytokine modulation. FXR agonists may also have hepatoprotective effects through multiple mechanisms. (Figure courtesy of Dr. Vikas Verma).