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.

Diagnosis and Treatment

Diagnosis

The diagnosis of drug- and toxin-induced liver injury is often difficult. A detailed history and physical examination are essential, and should investigate the possibility of accidental, environmental, and intentional exposures.

Liver Function Tests

Elevations of aminotransferases such as 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 out of proportion to the aminotransferases indicates 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 alcoholism, a careful history and the CAGE criteria may be used to establish the diagnosis. A positive response to at least 2 questions is seen in the majority of patients with alcoholism and provides 93% sensitivity and 76% specificity.¹ Over 80% of nonalcoholics answer negatively to all 4 of the questions:

• Have you felt the need to Cut down drinking?
• Have you ever felt Annoyed by criticism of drinking?
• Have you had Guilty feelings about drinking?
• Do you ever take a morning Eye opener?

Hematologic abnormalities may be present in patients with alcoholic liver disease, including macrocytosis, leukocytosis, thrombocytopenia, and folate deficiency.

Liver biopsy is usually diagnostic and can grade the severity of liver disease and exclude coexisting liver diseases. However, biopsy may not be necessary when the clinical presentation is classic.

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, cholecystitis, and malignancy.

Treatment

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.

Weight reduction is a requirement for overweight patients.

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 (eg, 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 (eg, folate). Secondary complications (eg, hepatic encephalopathy) should be addressed as necessary.

Liver transplantation may be required in patients with severe acute liver failure or chronic liver disease.

Nutritional Considerations

High doses of preformed vitamin A and other supplements with potential or suspected hepatotoxicity should be avoided. Most cases of chronic hypervitaminosis A are the result of self-administration of preformed vitamin A (i.e. retinol, not provitamin A carotenoids).² Hepatotoxicity can occur with doses of more than 100,000 IU per day. However, rare cases have occurred with dosages of 25,000 IU per day, and alcohol potentiates the hepatotoxicity of vitamin A. Steatosis, perisinusoidal fibrosis, chronic hepatitis, and cirrhosis may result from chronic overadministration.³ Niacin also has hepatotoxic potential, although this may be limited to sustained-release preparations.⁴

Several botanical supplements are sources of hepatotoxic pyrrolizidine alkaloids (eg, comfrey). Kava, a botanical used for anxiolytic effects, was withdrawn from the market after suggestions of hepatotoxicity. Certain herbal products that are freely available to consumers (eg, pennyroyal, skullcap, and chaparral) and Chinese herbal formulas that are not commercially distributed are associated with hepatotoxic effects. The U.S. Food and Drug Administration has issued warnings regarding the hepatotoxicity of certain formulas touted for weight loss, such as LipoKinetix, although the active hepatotoxins in this product have not yet been identified.⁵ A surprising number of patients with acute hepatitis or acute liver failure have no identifiable cause of illness other than the use of herbal weight-loss products, particularly those containing hepatotoxins such as usnic acid, a lichen alkaloid. Ephedra alkaloids, which are also used for weight loss by millions of people, are associated with development of severe hepatic dysfunction and even fulminant hepatic failure.⁶

A botanical extract, called milk thistle, has shown promise, but has yet to be proven effective in clinical trials. Silymarin, the active principle of milk thistle, has antioxidant, radical-scavenging, anti-inflammatory, and liver-regenerative effects that have partly validated its history of use for toxic liver disorders.Treatment was associated with decreased levels of gamma-glutamyl transferase (GGT) activity and procollagen III peptide, and with normalization of serum bilirubin, AST, and ALT levels.⁷ However, there are several reasons to be cautious with silymarin. First, the majority of previously published studies are limited by a lack of high-quality evidence.^7,8 Second, isolated compounds from milk thistle, such as silymarin, may not have the same effect as the full mixture of flavanolignans found in the milk thistle plant.⁷

Orders

See Basic Diet Orders.

What to Tell the Family

Liver damage most often results from excessive habitual alcohol intake. However, 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 alcohol consumption, by making sure medications are taken only as directed, and by checking with qualified healthcare personnel, such as a physician and a pharmacist, before allowing the use of OTC supplements. If these conditions are met, recuperation of liver function may be expected.

References

1. Mayfield D, McLeod G, Hall P. The CAGE questionnaire. Validation of a new alcoholism screening instrument. Am J Psychiatry. 1974;131:1121-1123.

2. Scherl S, Goldberg NS, Volpe L, Juster F. Overdosage of vitamin A supplements in a child. Cutis. 1992;50:209-210.

3. Riley TR III, Bhatti AM. Preventive strategies in chronic liver disease: part I. Alcohol, vaccines, toxic medications and supplements, diet and exercise. Am Fam Physician. 2001;64:1555-1560.

4. Pieper JA. Overview of niacin formulations: differences in pharmacokinetics, efficacy, and safety. Am J Health Syst Pharm. 2003;60(suppl 2):S9-S14; quiz S25.

5. Willett KL, Roth RA, Walker L. Workshop overview: Hepatotoxicity assessment for botanical dietary supplements. Toxicol Sci. 2004;79:4-9.

6. Neff GW, Reddy KR, Durazo FA, Meyer D, Marrero R, Kaplowitz N. Severe hepatotoxicity associated with the use of weight loss diet supplements containing ma huang or usnic acid. J Hepatol. 2004;41:1062-1064.

7. Ball KR, Kowdley KV. A review of Silybum marianum (milk thistle) as a treatment for alcoholic liver disease. J Clin Gastroenterol. 2005;39:520-528.

8. Rambaldi A, Jacobs BP, Iaquinto G, Gluud C. Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Cochrane Database Syst Rev. 2005;(2):CD003620.