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New therapeutic targets in alcoholic hepatitis

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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.

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Abbreviations

AASLD:

American Association for the Study of Liver Disease

ASH:

Alcoholic steatohepatitis

ABIC:

Age, Bilirubin, INR, Creatinine

ADH:

Alcohol dehydrogenase

AH:

Alcoholic hepatitis

ALD:

Alcoholic liver disease

AMPK:

AMP-activated protein kinase

CYP2E1:

Cytochrome P450 2E1

DF:

Maddrey discriminant function

EASL:

European Association for the Study of the Liver

ER:

Endoplasmic reticulum

GAHS:

Glasgow Alcoholic Hepatitis Score

HCC:

Hepatocellular carcinoma

HSC:

Hepatic stellate cell

IFN:

Interferon

IRAK-M:

Interleukin-1 receptor-associated kinase

IL:

Interleukin

MELD:

Model for end-stage liver disease

LPS:

Lipopolysaccharide

LT:

Liver transplant

NIAA:

National Institute of Alcohol Abuse and Alcoholism

NK:

Natural killer

PMN:

Polymorphonuclear leukocytes

PNPLA3:

Patatin-like phospholipase domain-containing protein 3

PPAR:

Peroxisome proliferator-activated receptor

ROS:

Reactive oxygen species

SAMe:

S-adenosylmethionine

SREBP-1c:

Sterol regulatory element-binding protein 1c

TLR:

Toll-like receptor

TLR4:

Toll-like receptor 4

TNF:

Tumor necrosis factor

UKELD:

UK End stage liver disease

WHO:

World Health Organization

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Authors and Affiliations

  1. Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, 7340.A Medical Biomolecular Research Building, Chapel Hill, NC, 27599, USA

    Diana Arsene, Omar Farooq & Ramon Bataller

  2. Department of Nutrition, University of North Carolina, Chapel Hill, USA

    Ramon Bataller

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  1. Diana Arsene
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  2. Omar Farooq
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  3. Ramon Bataller
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Correspondence to Ramon Bataller.

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This work was supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) (1U01AA021908-01) and P30 DK34987.

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Arsene, D., Farooq, O. & Bataller, R. New therapeutic targets in alcoholic hepatitis. Hepatol Int 10, 538–552 (2016). https://doi.org/10.1007/s12072-015-9701-6

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