The liver is responsible for concentrating and metabolizing most drugs and toxins. Because of this function, toxic insults to the liver are common. In the US, drug-induced liver injury (DILI) is the most common cause of acute liver failure. Alcohol-related liver disease 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 (e.g., sulfonamides), substances are directly toxic to the liver. In others, liver damage occurs by immune-mediated hypersensitivity. Some common hepatotoxic substances include acetaminophen, antibiotics (most commonly amoxicillin-clavulanate), 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. Hepatotoxicity from use of herbal and dietary supplements accounts for about 20% of all cases of drug-induced liver injury, and may be the most common serious adverse effect of herbal supplements. Known hepatotoxic herbs include Ayurvedic herbs, kava, pennyroyal oil, Ma-huang ( Ephedra sinica), valerian, mistletoe, comfrey, chaparral, sassafras, borage, and germander.
The presentation and severity of liver disease vary widely. 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. Pruritus may occur if cholestasis develops. Jaundice is a common presentation in people with alcoholic hepatitis. Hepatic encephalopathy and coagulopathies may develop in severe instances.
Because of the liver’s regenerative ability, withdrawal of or abstinence from offending substances can sometimes result in significant reversal of liver damage, even in cases of advanced liver disease, so long as cirrhosis is not yet established.
Alcohol use. Sustained alcohol intake exceeding 30 g per day (one standard alcoholic drink has 14 g) is associated with progression to cirrhosis and non-cirrhotic liver damage in both men and women. Binge drinking, drinking alcohol outside of meal times, and drinking beer or hard alcohol versus wine have all been associated with increased rates of liver damage.
Sex. 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.
Malnutrition. Inadequate nutritional intake in chronic alcohol abusers may worsen the severity of liver disease.
Race. Many 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. Hispanic and African-American males tend to have higher rates of cirrhosis in comparison to Caucasian men, irrespective of the quantity of alcohol ingested.
Acetaminophen. The combination of alcohol and acetaminophen should be avoided, as acetaminophen toxicity is greatly increased with the concomitant ingestion of alcohol.
Drug dosages. Toxicity due to medications is typically dose-related.
Nutritional supplements. High doses of preformed vitamin A can be hepatotoxic, as can certain botanicals. See Nutritional Considerations below.
The diagnosis of drug- and toxin-induced liver injury is often difficult. A detailed history and physical examination are essential and should include an investigation for accidental, environmental, and intentional exposures.
Elevations of the aminotransferases aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are common and signify hepatocellular injury. A ratio of AST-to-ALT greater than 2 suggests alcoholic hepatitis.
Elevation of alkaline phosphatase or bilirubin out of proportion to the aminotransferases suggests cholestasis.
Low albumin concentration and extended prothrombin time (due to impaired synthesis of coagulation factors, primarily factor VII) reflect impaired hepatic synthetic function.
Bilirubin can be elevated due to either hepatocellular injury or cholestasis.
In suspected cases of alcohol abuse, a careful history and screening with a validated screening tool such as the CAGE questions or AUDIT may be used to establish the diagnosis.
Hematologic abnormalities may be present in patients with alcoholic liver disease, including macrocytosis, leukocytosis, thrombocytopenia, and folate deficiency.
Liver biopsy is useful in ruling out viral hepatitis and other specific causes of liver disease, but it is often not diagnostic for drug-induced toxicity. Biopsy can grade the severity of toxic liver disease and exclude coexisting liver diseases, but it may not be necessary when the clinical presentation is clear (e.g., the chronic use of a single drug associated with hepatotoxicity).
Right-upper-quadrant ultrasound, abdominal x-ray, CT scan, MRI, and/or endoscopic retrograde cholangiopancreatography (ERCP) may be indicated to rule out other liver and abdominal pathology, such as cholecystitis, pancreatitis, and malignancy.
Suspected drugs or toxins should be discontinued immediately. Recovery often occurs after withdrawal of the offending substance.
Abstinence from alcohol is essential. Patients should be appropriately counseled on alcohol cessation, including referral to Alcoholics Anonymous, psychotherapy, or similar programs.
Acetaminophen overdose is treated with activated charcoal and n-acetylcysteine.
Other than treatment for acute acetaminophen toxicity, specific therapies are generally not available. In cases of hypersensitivity reactions (e.g., penicillin, procainamide) or alcoholic hepatitis, corticosteroids may be useful.
Supportive treatments in cases of liver failure include nutritional changes (see Nutritional Considerations below), vitamin K for coagulopathy, and correction of micronutrient deficiencies (e.g., folate). Secondary complications (e.g., hepatic encephalopathy) should be addressed as necessary.
Liver transplantation may be required in patients with severe acute liver failure or chronic liver disease.
Although vitamin A deficiency has been reported in both patients with hepatitis C-related chronic liver disease and in approximately 50% of patients with alcoholic cirrhosis, vitamin A supplements are potentially hepatotoxic. D aily intakes of > 25,000 IU for at least 6 years or > 100,000 IU for at least 6 months are thought to produce hepatotoxic effects. Steatosis, perisinusoidal fibrosis, chronic hepatitis, and cirrhosis may result from chronic over administration. C arotenoids are safer, providing vitamin A activity without the risks of vitamin A taken either in the form of food or supplements.
Niacin also has hepatotoxic potential, and this appears to be caused by both plain niacin and most (if not all) sustained-release preparations.
Some herbal supplements, particularly those from China and India, have been found to induce hepatoxicity as a result of improper extraction methods and contamination with heavy metals, among other causes.
Hepatotoxic effects have been noted for weight loss aids, including usnic acid, 1,3-Dimethylamylamine (1,3-DMAA), conjugated linoleic acid (CLA), garcinia cambogia, Ma Huang (ephedra), and Herbalife products that contain mixtures of herbs.
Raw forms of certain botanical supplements, including comfrey, are sources of hepatotoxic pyrrolizidine alkaloids; topical forms used for the treatment of painful muscle and joint complaints are very low in or free of these alkaloids.
Kava is a botanical used for anxiolytic effects. It was withdrawn from the market in several countries after cases of severe liver injury had been established, despite the findings of clinical trials that were unable to demonstrate hepatotoxicity and systematic reviews and meta-analyses that found a positive benefit-to-risk ratio for kava in treating anxiety disorders. The use of acetone-based extracts are thought to be responsible for hepatotoxic effects of kava preparations, as opposed to water-based extraction methods.
Certain over-the-counter herbal products (e.g., pennyroyal) cause hepatotoxicity by inhibition of CYP450 and depletion of glutathione; liver damage by other herbs (e.g., chapparal) may be due to contaminants or improperly prepared extracts.
The above examples are by no means an exhaustive list. As the use of dietary supplements continues to grow, clinicians will be challenged with determining whether supplements are to blame for cases of liver injury, or if other causes (interaction with other supplements, medications, alcohol, past history of liver disease) are more likely.
Probiotic foods or supplements may be helpful for patients with alcohol-related hepatoxicity. In clinical trials with these patients, probiotics have been shown to r educe endotoxemia, improve liver function, and reduce the amount of microbe-derived lipopolysaccharide (LPS) that plays a key role in the pathophysiology of alcohol-related liver disease.
Liver damage most often results from excessive habitual alcohol intake. It can also be caused by several prescription medications, in addition to self-medication with over-the-counter (OTC) supplements. The family can support patients by providing an environment that discourages excessive alcohol consumption, making sure medications are taken only as directed, and checking with qualified health care personnel, such as a physician and a pharmacist, before allowing the use of OTC supplements.