Introduction
Although alcohol ingestion is required to develop alcoholic liver disease, not everyone who consumes the "threshold dose" of alcohol will develop the disease. Amazingly, nearly 50% of individuals who ingest large amounts of ethanol are spared serious injury. In addition to the amount and duration of alcohol use, several other factors have been linked to an increased risk for the development of liver disease. These include genetics, gender, viral liver disease, nutrition, and exposure to other hepatotoxins.
Genetics
Polymorphisms exist in the enzymes ADH, CYP2E1, and ALDH. Differences in ADH and ALDH certainly contribute to the negative association with ethanol dependence in some Asian populations. HLA phenotypes, a genetic predisposition toward alcoholism and female gender may also contribute to overall risk.
Viral Liver Disease
Concurrent viral hepatitis increases the incidence of liver injury in alcoholics. Studies have shown that alcoholics co-infected with hepatitis C virus (HCV), (but not necessarily hepatitis B virus), develop liver injury at a younger age and with a lower cumulative dose of alcohol than those not infected with HCV. These patients also have a much higher chance of developing cirrhosis and hepatocellular cancer compared to alcoholics without hepatitis C (Figure 9).
Nutrition
Initial hypotheses suggested that alcoholic liver disease was a result of alcohol intake in the face of poor nutrition. Today, however, it is understood that while malnutrition may worsen the severity of disease and obesity may increase the risk of developing disease, alcoholic liver disease does indeed occur in well-nourished individuals. Nutrition probably plays a role in hepatotoxicity. Current research suggests that patients with diets deficient in essential nutrients are more susceptible to the development of liver damage. Alcohol ingestion promotes the absorption of iron from the intestine, increasing hepatic iron stores. Iron acts as an electron donor, accelerating the generation of unstable free oxygen radicals. In addition to contributing to membrane injury, this may also exacerbate inflammatory response.
Hepatotoxin Exposure
In general, two insults are worse than one. Just as viral hepatitis increases the risk to develop alcohol related liver injury, other hepatotoxins may act synergistically or additively with alcohol. This is especially true with acetaminophen and vitamin A overdose.
Pathogenesis
Several factors have been proposed to explain the pathogenesis of alcoholic liver injury. These include: Variations in alcohol metabolism
Centrilobular hypoxia
Inflammatory cell infiltration and activation
Antigenic adduct formation
Variations in alcohol metabolism
Alcohol must be metabolized in order for liver injury to occur, and there are several pathways that contribute to its metabolism.
The major pathway occurs in the liver and begins by breaking ethanol into acetaldehyde via the enzyme alcohol dehydrogenase (ADH) (Figure 2). This in turn is broken down to acetate by the enzyme acetaldehyde dehydrogenase (ALDH). There is considerable genetic variability in both of these enzymes, which may account for differences in blood alcohol levels but does not predict susceptibility to liver disease. Asians typically have efficient ADH but deficient ALDH. This allows acetaldehyde to build up causing flushing, tachycardia, hypotension and, usually, an aversion to alcohol. When alcohol concentration overwhelms the ADH pathway, it is typically oxidized by the microsomal ethanol oxidizing system (MEOS) and catalase. Generally, these pathways are more likely to generate injurious byproducts. Cytochrome P-450 2E1 (CYP2E1), a critical enzyme in MEOS, is up-regulated with chronic alcohol ingestion. Polymorphisms of CYP2E1 also exist and may correlate with differences in susceptibility to hepatocellular (liver) damage. In addition, CYP2E1 is responsible for metabolizing other drugs such as acetaminophen. This may help explain an alcoholic's increased risk to Tylenol®-induced liver injury even at recommended doses. Centrilobular hypoxia
Liver injury is most prominent in the zonal region surrounding the central vein. This area is furthest from oxygenated blood and has the highest concentration of CYP2E1, suggesting that oxygen debt contributes to injury (Figure 12).  | | Figure 8. High concentration of CYP2E1 surrounding the central vein in the liver. |
Inflammatory cell infiltration and activation
Proinflammatory cytokines and inflammatory cells are often found in the blood and liver of patients with alcoholic hepatitis. Although several cytokines are present in patients with alcohol related liver injury, studies have concentrated on interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) as both correlate inversely with prognosis. These mediators may contribute to injury by promoting leukocyte adherence and activation. Kupffer cells (macrophages in the liver) may also be an important source of injury as they produce inflammatory and fibrogenic cytokines after being activated by alcohol. Chronic alcohol ingestion ultimately increases intestinal permeability, allowing endotoxins into the portal blood (Figure 4). This may exaggerate the release of cytokines and oxygen radicals from alcohol-primed Kupffer cells.  | | Figure 9. Initiation of inflammation in the liver. |
Antigenic adduct formation
Ethanol is metabolized to acetaldehyde and can also result in the formation of hydroxyethyl radicals. These radicals bind to hepatocellular proteins altering the proteins (forming adducts that are antigenic) and provoking an immune response. The contribution of autoimmunity in alcoholic liver injury is not clear. Antibodies to these adducts are found in serum from alcoholic patients. Animal studies have shown that guinea pigs immunized with acetaldehyde-protein adducts develop hepatic injury and fibrosis after ethanol ingestion. Other studies suggest that these adducts are not always located in areas that are accessible to the production of an immune response (e.g., retained within the hepatocyte). Make an appointment today - call (410) 955-4166.
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