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Abstract
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.
Highlights
Alcohol is chemically ethyl alcohol, or in condensed form described as ethanol, whereby these terms are often used interchangeably in the clinical context
Acetaldehyde generated via alcohol dehydrogenase (ADH) and microsomal ethanol-oxidizing system (MEOS) is further metabolized in the liver cell by mitochondrial acetaldehyde dehydrogenase (ALDH) to acetate (Table 1, Figure 5) [25], which is released into the bloodstream and oxidized to CO2 in various extrahepatic tissues
Ethanol is metabolized through these two super-active ADH variants at a 30–40-fold increased rate to Acetaldehyde plays a critical role in East Asian individuals, who are genetically deficient in hepatic ALDH2, which upon alcohol drinking causes increased blood acetaldehyde levels and the so‐
Summary
Alcohol is chemically ethyl alcohol, or in condensed form described as ethanol, whereby these terms are often used interchangeably in the clinical context. Among various liver diseases such as drug-induced liver injury (DILI), herb-induced liver injury (HILI), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or those caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, especially ALD continues to attract much interest from scientists and clinicians worldwide [4,5,6,7,8,9,10,11,12,13,14,15] Their stimulating and partially controversial discussions focused on the pathogenetic aspects [4,5], clinical features [6], and therapeutic approaches [7,8,9] including liver transplantation [10,11,12,13]. It is well recognized that there exist myriads of alcoholic studies with several hundreds of molecular mechanisms, and many mediators are provided by expert biochemists rather than a satisfactory unifying mechanistic approach that is considered valid for a sound discussion of a yet partially controversial clinical topic
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