Academic journal article Alcohol Research: Current Reviews

Alcoholic Liver Disease: Pathogenesis and Current Management

Academic journal article Alcohol Research: Current Reviews

Alcoholic Liver Disease: Pathogenesis and Current Management

Article excerpt

Excessive alcohol consumption is a global healthcare problem. The liver sustains the greatest degree of tissue injury by heavy drinking because it is the primary site of ethanol metabolism. Chronic and excessive alcohol consumption produces a wide spectrum of hepatic lesions, the most characteristic of which are steatosis, hepatitis, and fibrosis/cirrhosis. Steatosis is the earliest response to heavy drinking and is characterized by the deposition of fat in hepatocytes. Steatosis can progress to steatohepatitis, which is a more severe, inflammatory type of liver injury. This stage of liver disease can lead to the development of fibrosis, during which there is excessive deposition of extracellular matrix proteins. The fibrotic response begins with active pericellular fibrosis, which may progress to cirrhosis, characterized by excessive liver scarring, vascular alterations, and eventual liver failure. Among problem drinkers, about 35 percent develop advanced liver disease because a number of disease modifiers exacerbate, slow, or prevent alcoholic liver disease progression. There are still no FDA-approved pharmacological or nutritional therapies for treating patients with alcoholic liver disease. Cessation of drinking (i.e., abstinence) is an integral part of therapy. Liver transplantation remains the life-saving strategy for patients with end-stage alcoholic liver disease.

Key words: Alcohol consumption; heavy drinking; alcohol effects and consequences; abstinence; alcoholic liver disease; liver injury; hepatic lesions; steatosis; hepatitis; fibrosis; cirrhosis; treatment; pharmacological therapy; nutritional therapy; liver transplantation

Excessive alcohol consumption is a global healthcare problem with enormous social, economic, and clinical consequences, accounting for 3.3 million deaths in 2012 (World Health Organization 2014). Excessive drinking over decades damages nearly every organ in the body. However, the liver sustains the earliest and the greatest degree of tissue injury from excessive drinking because it is the primary site of ethanol metabolism (Lieber 2000). After a brief overview of alcohol metabolism in the liver, this article will summarize the mechanisms through which excessive alcohol consumption contributes to the development of various types of alcohol-induced liver damage. It also will review modifiers of alcoholic liver disease (ALD) and discuss currently used treatment approaches for patients with ALD.

Hepatic Alcohol Metabolism

Beverage alcohol (i.e., ethanol) is chiefly metabolized in the main parenchymal cells of the liver (i.e., hepatocytes) that make up about 70 percent of the liver mass (Jones 1996). These cells express the highest levels of the major ethanol-oxidizing enzymes, alcohol dehydrogenase (ADH), which is located in the cytosol, and cytochrome P450 2E1 (CYP2E1), which resides in the smooth endoplasmic reticulum (ER) (figure 1). Hepatocytes also express very high levels of catalase, an enzyme that inhabits peroxisomes. Catalase normally carries out the detoxification of hydrogen peroxide ([H.sub.2][O.sub.2]) to water and oxygen. However, when ethanol is present, catalase has an accessory role in ethanol metabolism by using [H.sub.2][O.sub.2] to oxidize ethanol to acetaldehyde. Ethanol oxidation by catalase is a relatively minor pathway in the liver, but has a larger ethanol-oxidizing function in the brain (Aragon et al. 1992).

ADH is the most catalytically efficient ethanol-metabolizing enzyme. It reaches its half-maximal velocity when circulating ethanol levels are about 5 to 10 milligrams per deciliter, well below levels that cause intoxication.1 ADH-catalyzed ethanol oxidation uses nicotinamide adenine dinucleotide ([NAD.sup.+]) as a cofactor, generating reduced [NAD.sup.+] (NADH) and acetaldehyde. The latter compound is highly reactive and toxic. It can covalendy bind to proteins (Donohue et al. 1983), lipids (Kenney 1982), and nucleic acids (Brooks and Zakhari 2014) to form acetaldehyde adducts, which, in turn, can disrupt the structure and function of these macromolecules (Mauch et al. …

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