Alcohol Liver Disease

In addition to the disruption of fatty acid synthesis and oxidation, ethanol alters lipid droplet (LD, the storage form of TG) metabolism in hepatocytes and very low-density lipoprotein secretion from the liver. This effect, together with the inhibition of mitochondrial fatty acid β-oxidation, contributes to the pathogenesis of fatty liver (hepatosteatosis), the initial stage of ALD.

Another major pathway of ethanol metabolism that involves CYP2E1, results in the increased production of ROS, highly reactive molecules that interact with and alter lipoprotein lipids, mitochondrial membranes, DNA, and proteins, causing the state known as oxidative stress. Unlike ADH and ALDH, found essentially only in the liver, CYP2E1 is present in other organs, including brain, heart and lungs, thus, consequences of ethanol metabolism via this pathway affect numerous tissues. Ethanol-induced formation of ROS can also be attributable to overproduction of NADH, damage to mitochondria, and activation of Kupffer cells. Additionally, ROS stimulate the release of TNF-α from Kupffer cells, which play an important role in the development of inflammatory reactions and are implicated in tissue damage and formation of fibrosis in the liver. The metabolites formed after alcohol breakdown in the liver can also lead to the formation of ROS. Furthermore, alcohol facilitates production of ROS by reducing the levels of antioxidants, agents that can eliminate ROS (e.g., mitochondrial and cytosolic glutathione, vitamin E).

Acetaldehyde formed as a result of ethanol oxidation and ROS interact with amino acids and other molecules, potentially resulting in the formation of stable and unstable adducts (e.g., malondialdehyde adduct). Formation of protein adducts in hep...

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...d of chronic liver disease. Typically, AH is described as an acute-on chronic type of liver damage, in which acute events overwhelm the ability of the liver to respond to alcohol-induced damage. The true prevalence is unknown, but histological studies of patients with ALD suggest that AH may be present in as many as 10%-35% of hospitalized alcoholic patients. Even individuals with only a relatively mild presentation of AH, however, are at high risk of progressive liver injury, with cirrhosis developing in up to 50% of cases. Although abstinence from alcohol does not guarantee complete recovery, the likelihood that AH will progress to permanent damage is increased among those who continue to abuse alcohol.

Elucidating molecular mechanisms and processes associated with the development of alcoholic liver disease in humans is critical for its treatment and prevention.