Alcoholic Liver Disease: Current Mechanistic Aspects with Focus on Their Clinical Relevance

Abstract

The spectrum of alcoholic liver disease (ALD) is broad and includes alcoholic fatty liver, alcoholic steatohepatitis, alcoholic hepatitis, alcoholic fibrosis, alcoholic cirrhosis, and alcoholic hepatocellular carcinoma, best explained as a five-hit sequelae of injurious steps. ALD is not primarily the result of malnutrition as assumed for many decades but due to the ingested alcohol and its metabolic consequences although malnutrition may marginally contribute to disease aggravation. Ethanol is metabolized in the liver to the heavily reactive acetaldehyde via the alcohol dehydrogenase (ADH) and the cytochrome P450 isoform 2E1 of the microsomal ethanol-oxidizing system (MEOS). The resulting disturbances modify not only the liver parenchymal cells but also non-parenchymal cells such as Kupffer cells (KCs), hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs). These are activated by acetaldehyde, reactive oxygen species (ROS), and endotoxins, which are produced from bacteria in the gut and reach the liver due to gut leakage. A variety of intrahepatic signaling pathways and innate or acquired immune reactions are under discussion contributing to the pathogenesis of ALD via the five injurious hits responsible for disease aggravation. As some of the mechanistic steps are based on studies with in vitro cell systems or animal models, respective proposals for humans may be considered as tentative. However, sufficient evidence is provided for clinical risk factors that include the amount of alcohol used daily for more than a decade, gender differences with higher susceptibility of women, genetic predisposition, and preexisting liver disease. In essence, efforts within the last years were devoted to shed more light in the pathogenesis of ALD, much has been achieved but issues remain to what extent results obtained from experimental studies can be transferred to humans.

Alcoholic-Hepatitis, Links to Brain and Microbiome: Mechanisms, Clinical and Experimental Research

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Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support

“…Alcoholic liver disease (ALD) is well characterized and represents a worldwide health problem [104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120][121]. Main issues relate to early recognition of the disease and clear differentiation from other frequent acute and chronic liver diseases.…”

TSG-6 Inhibits Oxidative Stress and Induces M2 Polarization of Hepatic Macrophages in Mice With Alcoholic Hepatitis via Suppression of STAT3 Activation

“…Alcoholic liver disease (ALD) is a leading cause of mortality with increasing prevalence worldwide (Liangpunsakul et al, 2016). The spectrum of ALD is broad, ranging from alcoholic fatty liver, alcoholic steatohepatitis, alcoholic hepatitis (AH), fibrosis, cirrhosis, and hepatocellular carcinoma (Teschke, 2019). They may coexist in a given patient, and are often classified into three histological stages: alcoholic fatty liver or simple steatosis, AH, and alcoholic cirrhosis (MacSween and Burt, 1986).…”