Alcoholic and Toxic Liver Disease: Overview and Risk Factors

The liver is responsible for concentrating and metabolizing most drugs and toxins. Because of this function, hepatotoxicity is common. Drug– or alcohol–related hepatotoxicity is the most common cause of fulminant liver failure. Alcohol–related liver disease alone accounts for more than 12,000 deaths yearly in the United States, and alcohol abuse is the most common cause of cirrhosis.

Alcohol is the most frequently abused drug worldwide. Its major metabolite, acetaldehyde, is directly toxic to the liver. Abuse results in a broad spectrum of liver disease, including asymptomatic fatty liver, alcoholic hepatitis, cirrhosis, and end–stage liver failure. Many alcoholics become symptomatic only when severe, life–threatening liver disease is already present.

Virtually any drug can cause some degree of hepatotoxicity, although certain drugs are more toxic than others. In some cases (eg, sulfonamides), substances are directly toxic to the liver. In others, liver damage occurs by immune–mediated hypersensitivity. Some common hepatotoxic substances include acetaminophen, tetracycline, aspirin, phenytoin, methyldopa, isoniazid, methotrexate (when combined with alcohol), HMG–CoA reductase inhibitors (“statins”), and valproic acid. In high doses, vitamin A, arsenic, iron, and copper can be hepatotoxic. Further, hepatotoxicity may be the most common adverse effect of herbal supplements. Known hepatotoxic herbs include kava, pennyroyal oil, Ma–huang (Ephedra sinica), valerian, mistletoe, comfrey, chaparral, sassafras, borage, and germander.

The presentation and severity of liver disease vary significantly. Some patients remain asymptomatic despite significant liver damage, while others present with a severe, acute illness. Nausea, vomiting, malaise, and diaphoresis are common symptoms. A syndrome similar to viral hepatitis may occur, including fever, headache, jaundice, and right–upper–quadrant pain.

Because of the liver’s regenerative ability, withdrawal of or abstinence from offending substances can result in significant reversal of liver damage, even in cases of advanced liver disease.

Risk Factors

Sustained alcohol intake exceeding 80 grams per day is strongly associated with progression to hepatic fibrosis, cirrhosis, and liver failure. However, about half of chronic alcohol abusers do not develop severe liver disease, a fact that suggests the importance of other risk factors. Additional contributors to risk include:

• Gender. Females have an increased risk of liver disease for a given amount and duration of alcohol use, and liver disease in women tends to progress more rapidly than in men.
• Genetics. There appear to be genetic predispositions to alcohol abuse and alcoholic liver disease. However, specific genes have yet to be definitely identified.
• Viral hepatitis. Concurrent infection with hepatitis B virus or hepatitis C virus is strongly associated with risk of accelerated liver disease in alcoholic patients.
• Obesity.
• Malnutrition. Inadequate nutritional intake in chronic alcohol abusers may worsen the severity of liver disease.
• Asian race. Asians have a relative deficiency of the mitochondrial aldehyde dehydrogenase–2 (ALDH2) enzyme, which results in flushing upon alcohol intake and may create an aversion to alcohol use in these populations.
• Acetaminophen. The combination of alcohol and acetaminophen should be avoided, as acetaminophen toxicity is highly increased with the concomitant ingestion of alcohol.