Cofactors that Potentiate the Development of Alcoholic Liver Disease
The amount of alcohol consumption required for progression to liver cirrhosis reported by Lelback and colleagues in 1975 was 80 g of ethanol daily (equivalent to 1 L of wine, a half pint of hard liquor, or 8 beers) consumed for 10–20 years. However, as noted, not all who ingest significant amounts of alcohol will develop cirrhosis. Several cofactors are known to accelerate progression of liver disease, and the risk for ALD increases with ingestion of more than 35 drinks per week. A "safe" amount is believed to be 21 drinks per week for men and 14 drinks per week for women, in the absence of the cofactors listed below.
Despite the legal alcohol drinking age of 21 years in the United States, a 2004 study revealed that 50% of high school students drank some amount of alcohol, and 20% of all alcohol consumption is suspected to be in individuals younger than age 21. Early alcohol use is associated with alcoholism later in life. At the opposite end of spectrum, an emergency department screening study revealed that 24.5% of subjects older than 65 years met criteria for alcohol abuse. However, the highest rate of alcohol abuse morbidity occurs among individuals aged 45–64 years, with a prevalence rate of 94.8 per 100,000.
The overall prevalence of alcohol abuse and related liver disease is higher among men than women. However, women are more prone than men to alcohol-related liver injury and fibrosis progression for the same amount of alcohol consumption. This may be due to different rates of alcohol metabolism, lower body mass index, effects of estrogens, or an increased intestinal permeability to endotoxin.
Susceptibility to ALD is believed to vary among different ethnic groups. In the United States, alcoholic cirrhosis–related deaths are highest in Hispanic males, followed by black non-Hispanics, white non-Hispanics, and black Hispanics. The prevalence among females is highest in black non-Hispanics, followed by white Hispanics, white non-Hispanics, and black Hispanics. Studies in the United Kingdom suggest that South Asian men are more susceptible to alcohol-related liver injury than European men. It is unclear whether these differences are due to genetic polymorphisms, types of alcohol consumed, or access to health care.
Hepatitis C (HCV) Infection
Between 14% and 36% of individuals with ALD also have chronic hepatitis C. The combination of HCV and ALD accelerates the progression and severity of liver disease, increases the risk for hepatocellular carcinoma, and decreases the likelihood of virologic response to interferon alfa therapy. The acceleration of liver disease has been postulated to be due to an increase in viral replication, a decrease in liver regenerative capability, and an increase in quasispecies complexity. Patients with HCV who consume excessive alcohol succumb at an earlier age. This affects the mortality in women more than men.
Hepatitis B (HBV) Infection
In a large population study performed in Taiwan, the data suggest that chronic HBV infection and alcohol consumption increase the risk for the development of hepatocellular carcinoma.
ALD and hepatitis C are the two most common causes of hepatocellular carcinoma. In a Veterans Administration study of patients between 1993 and 1998, the prevalence rate of hepatocellular carcinoma in patients with cirrhosis secondary to alcohol use was 9.1 per 100,000, whereas the rate was 7.0 per 100,000 in patients with HCV. The risk of hepatocellular carcinoma increases after consuming more than 60 g of alcohol per day for more than 10 years. Recent studies have also shown that there has been a dramatic increase in the incidence of hepatocellular carcinoma associated with hepatitis C infection, and the incidence may be comparable to that of ALD. The effect of alcohol and HCV in the development of hepatocellular carcinoma appears to be synergistic.
Patients with ALD appear to be at an increased risk for liver injury after ingestion of multiple or above recommended therapeutic doses of acetaminophen. This is believed to be due to rapid depletion of glutathione stores and competition with cytochrome P450 (CYP) 2E1. Although other medications may also compete with CYP450, there are limited data on increased hepatotoxicity in the setting of ALD.
The liver is able to tolerate high levels of intrahepatic iron without progression to fibrosis. However, when a cofactor, such as alcohol, is involved, liver damage is accelerated. Similar synergistic effects are also seen in nonalcoholic fatty liver disease, chronic HCV, and porphyria cutanea tarda. Both iron and alcohol generate reactive oxygen species that promote lipid peroxidation with consequent damage to cellular integrity. Alcohol has also been shown to suppress hepcidin activity in animal models. Excessive alcohol consumption (>60 g/day) in patients with hemochromatosis is associated with accelerated fibrogenesis, increased risk for hepatocellular cancer, and lower long-term survival. Because consumption of more than three drinks daily is associated with increased serum markers (ferritin) of iron overload from ALD, HFE genetic testing can differentiate ALD from hereditary hemochromatosis. Primary iron overload may be distinguished from secondary iron overload when the hepatic iron index is greater than 1.9 micromole per gram dry weight of liver per year of life.
There are limited data on dietary and lifestyle factors that may influence the natural history of ALD. Coffee may be protective in ALD and related cirrhosis. Studies on the effect of tobacco have been conflicting. Some studies have suggested that obesity (basal metabolic index >25 kg/m2) for more than 10 years accelerates progression of ALD. Pork products, on the other hand, have been shown to be associated with alcoholic hepatitis and cirrhosis but not steatosis. Other lifestyle factors that may be associated with ALD progression include single status, urban dwelling, unemployment, lower socioeconomic background, daily alcohol ingestion, and variable alcoholic beverage ingestion.
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The metabolic breakdown products of alcohol are essential in the progression of ALD. Ethanol is metabolized by alcohol dehydrogenase in the hepatic cytosol to acetaldehyde, which is subsequently metabolized in the mitochondria by acetaldehyde dehydrogenase. There are various acetaldehyde dehydrogenase isoforms. Seventy-five percent of Asians have a deficiency in acetaldehyde dehydrogenase 2, which results in accumulation of acetaldehyde, causing flushing. A similar mechanism is seen with the drug disulfiram (Antabuse), which inhibits acetaldehyde dehydrogenase, causing acetaldehyde accumulation and resultant flushing, tachycardia, nausea, vomiting, hypotension, and headache within 15–30 minutes of alcohol ingestion.
Ethanol may also be metabolized in minor hepatic pathways involving the microsomal enzyme oxidation system, via CYP2E1, and the enzyme catalase. The stomach can metabolize ethanol via gastric alcohol dehydrogenase. Women have less gastric alcohol dehydrogenase than men, offering a possible explanation for the observed increased female susceptibility to the effect of alcohol.
Although detailed mechanisms of ethanol-induced liver injury are incompletely understood, recent scientific advances have furthered our understanding of cellular and immunologic mechanisms through the use of in vitro and in vivo models.
Animal models of alcohol ingestion have demonstrated susceptibility of the hepatic pericentral area to hypoxemia due to competitive oxygen consumption by ethanol metabolism. Decreased intestinal permeability during alcohol ingestion results in an increase in serum endotoxin (lipopolysaccharide) levels, leading, in turn, to activation of Kupffer cells, which secrete cytokines such as tumor necrosis factor α (TNFα). It is believed that TNFα can induce cytotoxicity through caspase-dependent and caspase-independent pathways, leading to increased mitochondrial permeability and ultimately cell death. Both ethanol and decreased glutathione levels can sensitize the liver to TNFα-induced cytotoxicity.
In alcoholic hepatitis, elevated interleukin (IL)-18 levels result in neutrophil accumulation in the liver. Subsequently, neutrophil release of reactive oxygen species results in hepatocyte injury. Acute ethanol ingestion may also result in a suppressed T-cell response, decreased monocyte function, and increased levels of IL-1 and IL-6.
Ethanol metabolites, acetaldehyde and hydroxyethyl, may potentially play a major role in alcoholic liver injury. These metabolites bind to proteins to form adducts that result in altered intracellular protein function, and these adducts may also act as a neoantigen that can stimulate immune-mediated injury. Autoantibodies to various structures of the liver, such as liver membrane antigen, liver-specific protein, and CYP450, can be found in patients with ALD.
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