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Alcoholic liver disease: A current molecular and clinical perspective.

ABSTRACT: Heavy alcohol use is the cause of alcoholic liver disease (ALD). The ALD spectrum ranges from alcoholic steatosis to steatohepatitis, fibrosis, and cirrhosis. In Western countries, approximately 50% of cirrhosis-related deaths are due to alcohol use. While alcoholic cirrhosis is no longer considered a completely irreversible condition, no effective anti-fibrotic therapies are currently available. Another significant clinical aspect of ALD is alcoholic hepatitis (AH). AH is an acute inflammatory condition that is often comorbid with cirrhosis, and severe AH has a high mortality rate. Therapeutic options for ALD are limited. The established treatment for AH is corticosteroids, which improve short-term survival but do not affect long-term survival. Liver transplantation is a curative treatment option for alcoholic cirrhosis and AH, but patients must abstain from alcohol use for 6 months to qualify. Additional effective therapies are needed. The molecular mechanisms underlying ALD are complex and have not been fully elucidated. Various molecules, signaling pathways, and crosstalk between multiple hepatic and extrahepatic cells contribute to ALD progression. This review highlights established and emerging concepts in ALD clinicopathology, their underlying molecular mechanisms, and current and future ALD treatment options.

SUBMITTER: Ohashi K

PROVIDER: S-EPMC6581514 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Alcoholic liver disease: A current molecular and clinical perspective.

Ohashi Koichiro K Pimienta Michael M Seki Ekihiro E

Liver research 20181212 4

Heavy alcohol use is the cause of alcoholic liver disease (ALD). The ALD spectrum ranges from alcoholic steatosis to steatohepatitis, fibrosis, and cirrhosis. In Western countries, approximately 50% of cirrhosis-related deaths are due to alcohol use. While alcoholic cirrhosis is no longer considered a completely irreversible condition, no effective anti-fibrotic therapies are currently available. Another significant clinical aspect of ALD is alcoholic hepatitis (AH). AH is an acute inflammatory ...[more]

PMID: 31214376

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Project description:Alcoholic liver disease is the result of cascade events, which clinically first lead to alcoholic fatty liver, and then mostly via alcoholic steatohepatitis or alcoholic hepatitis potentially to cirrhosis and hepatocellular carcinoma. Pathogenetic events are linked to the metabolism of ethanol and acetaldehyde as its first oxidation product generated via hepatic alcohol dehydrogenase (ADH) and the microsomal ethanol-oxidizing system (MEOS), which depends on cytochrome P450 2E1 (CYP 2E1), and is inducible by chronic alcohol use. MEOS induction accelerates the metabolism of ethanol to acetaldehyde that facilitates organ injury including the liver, and it produces via CYP 2E1 many reactive oxygen species (ROS) such as ethoxy radical, hydroxyethyl radical, acetyl radical, singlet radical, superoxide radical, hydrogen peroxide, hydroxyl radical, alkoxyl radical, and peroxyl radical. These attack hepatocytes, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells, and their signaling mediators such as interleukins, interferons, and growth factors, help to initiate liver injury including fibrosis and cirrhosis in susceptible individuals with specific risk factors. Through CYP 2E1-dependent ROS, more evidence is emerging that alcohol generates lipid peroxides and modifies the intestinal microbiome, thereby stimulating actions of endotoxins produced by intestinal bacteria; lipid peroxides and endotoxins are potential causes that are involved in alcoholic liver injury. Alcohol modifies SIRT1 (Sirtuin-1; derived from Silent mating type Information Regulation) and SIRT2, and most importantly, the innate and adapted immune systems, which may explain the individual differences of injury susceptibility. Metabolic pathways are also influenced by circadian rhythms, specific conditions known from living organisms including plants. Open for discussion is a 5-hit working hypothesis, attempting to define key elements involved in injury progression. In essence, although abundant biochemical mechanisms are proposed for the initiation and perpetuation of liver injury, patients with an alcohol problem benefit from permanent alcohol abstinence alone.

Dataset Information

Alcoholic liver disease: A current molecular and clinical perspective.

Publications

Alcoholic liver disease: A current molecular and clinical perspective.

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