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The mechanisms by which drugs damage the liver are variable, complex, and often poorly understood. Some drugs are directly toxic: with these, injury is generally characteristic for the drug, begins within hours of exposure, and is dose-related. Other drugs produce damage only rarely and only in susceptible people; the injury generally first occurs within a few weeks but occasionally may be delayed for several months after drug exposure. This injury is not dose-related. These reactions are rarely allergic; they are more accurately described as idiosyncratic. The distinction between direct toxicity and idiosyncrasy may not always be clear; eg, some drugs whose injury appears idiosyncratic probably damage cell membranes directly with toxic intermediate metabolites.

Although there is no perfect system for classifying liver damage caused by drugs, damage can be categorized as acute reactions (which consist of hepatocellular necrosis), cholestasis (with or without inflammation), and miscellaneous reactions (see Table 1: Drugs and the Liver: Common Hepatotoxic Drug Reactions). Some drugs can cause chronic damage, which rarely leads to tumor growth.

Table 1
Common Hepatotoxic Drug Reactions Drug Reaction Acetaminophen Some Trade Names GENAPAP TYLENOL VALORIN Click for Drug Monograph Acute, direct hepatocellular toxicity; chronic toxicity Allopurinol Some Trade Names ZYLOPRIM Click for Drug Monograph Miscellaneous acute reactions Amanita mushrooms Acute, direct hepatocellular toxicity Aminosalicylic acid Miscellaneous acute reactions Amiodarone Some Trade Names CORDARONE Click for Drug Monograph Chronic toxicity Antibiotics, various Miscellaneous acute reactions Antineoplastics, various Miscellaneous acute reactions Arsenic compounds Chronic toxicity Aspirin Some Trade Names BUFFERIN ECOTRIN GENACOTE Click for Drug Monograph Miscellaneous acute reactions C‑17 alkylated steroids Acute cholestasis, steroid type Chlorpropamide Some Trade Names DIABINESE Click for Drug Monograph Acute cholestasis, phenothiazine type Diclofenac Some Trade Names CATAFLAM VOLTAREN Click for Drug Monograph Acute, idiosyncratic hepatocellular toxicity Erythromycin Some Trade Names ERY-TAB ERYTHROCIN Click for Drug Monograph estolate Acute cholestasis, phenothiazine type Halothane-related anesthetics Acute, idiosyncratic hepatocellular toxicity Hepatic intra-arterial antineoplastics Chronic toxicity HMG‑CoA reductase inhibitors (statins) Miscellaneous acute reactions Hydrocarbons Acute, direct hepatocellular toxicity Indomethacin Some Trade Names INDOCIN Click for Drug Monograph Acute, idiosyncratic hepatocellular toxicity Iron Acute, direct hepatocellular toxicity Isoniazid Some Trade Names INH NYDRAZID Click for Drug Monograph Acute, idiosyncratic hepatocellular toxicity; chronic toxicity Methotrexate Some Trade Names RHEUMATREX Click for Drug Monograph Chronic toxicity Methyldopa Some Trade Names ALDOMET Click for Drug Monograph Acute, idiosyncratic hepatocellular toxicity; chronic toxicity Methyltestosterone Some Trade Names ORETON Click for Drug Monograph Acute cholestasis, steroid type Monoamine oxidase inhibitors Acute, idiosyncratic hepatocellular toxicity Niacin Some Trade Names NIACOR NIASPAN SLO-NIACIN Click for Drug Monograph Chronic toxicity Nitrofurantoin Some Trade Names FURADANTIN MACROBID MACRODANTIN Click for Drug Monograph Chronic toxicity Oral contraceptives Acute cholestasis, steroid type Phenothiazines (eg, chlorpromazine Some Trade Names THORAZINE Click for Drug Monograph ) Acute cholestasis, phenothiazine type; chronic toxicity Phenylbutazone Some Trade Names No US trade name Acute cholestasis, phenothiazine type Phenytoin Some Trade Names DILANTIN Click for Drug Monograph Acute, idiosyncratic hepatocellular toxicity Phosphorus Acute, direct hepatocellular toxicity Propylthiouracil Some Trade Names No US trade name Click for Drug Monograph Acute, idiosyncratic hepatocellular toxicity Quinidine Some Trade Names CARDIOQUIN QUINAGLUTE Click for Drug Monograph Miscellaneous acute reactions Sulfonamides Miscellaneous acute reactions Tetracycline Some Trade Names ACHROMYCIN V TETRACYN TETREX Click for Drug Monograph , high-dose IV Acute, direct hepatocellular toxicity Tricyclic antidepressants Acute cholestasis, phenothiazine type Valproate Some Trade Names DEPAKENE Click for Drug Monograph Miscellaneous acute reactions Vitamin A Chronic toxicity

Diagnosis and Treatment

Drug-induced hepatotoxicity is suspected when patients have unusual patterns of liver disease (eg, mixed or atypical patterns of cholestasis and hepatitis); in hepatitis or cholestasis for which common causes have been excluded; during administration of a drug with known hepatotoxicity (see Table 1: Drugs and the Liver: Common Hepatotoxic Drug Reactions), even in the absence of symptoms or signs; or if a liver biopsy reveals histologic features suggesting a drug etiology. Jaundice due to drug-induced hemolysis may at first suggest hepatotoxicity, but in such cases, bilirubin is unconjugated and other liver function test results are normal.

No diagnostic tests can confirm that a drug caused hepatotoxicity. Diagnosis requires exclusion of other possible causes (eg, imaging tests to exclude obstruction if cholestasis is present; viral serology if hepatitis is present) and a temporal relationship between the drug and hepatotoxicity. A pattern of repeated, reversible hepatotoxicity after repeated doses is the most conclusive evidence, but because of the risk of serious liver damage, rechallenging a patient with a suspected hepatotoxic drug generally is not done. Biopsy is sometimes necessary, generally to exclude other treatable conditions. If the diagnosis is still unclear after testing, a trial of drug withdrawal may be indicated for diagnosis as well as treatment.

For a few drugs that cause direct hepatotoxicity (eg, acetaminophen Some Trade Names
GENAPAP
TYLENOL
VALORIN
Click for Drug Monograph
), blood levels can be used to assess the probability of liver damage. However, drug levels may fall if tests are delayed. Many nonprescription herbal products cause liver toxicity; patients with unexplained liver injury should be asked whether they are taking such products.

Treatment for drug-induced hepatotoxicity generally consists of withdrawing the drug and providing supportive therapy.

Hepatocellular Necrosis

Hepatocellular necrosis is conceptually divided into direct toxicity and idiosyncrasy, although this distinction may be artificial. The hallmark is elevated aminotransferase levels, often to a striking degree. Patients with mild or moderate hepatocellular necrosis may develop manifestations of hepatitis (eg, jaundice, malaise). Patients with severe necrosis may develop manifestations of fulminant hepatitis (eg, hepatic insufficiency, portal-systemic encephalopathy).

Direct toxicity: Most direct hepatotoxins produce dose-related hepatic necrosis and often affect other organs (eg, kidneys).

Direct hepatotoxic damage from prescribed drugs can generally be prevented or minimized by following recommendations regarding maximum drug dosing and patient monitoring. Poisoning with direct hepatotoxins (eg, acetaminophen Some Trade Names
GENAPAP
TYLENOL
VALORIN
Click for Drug Monograph
, iron, Amanita mushrooms) often produces gastroenteritis within hours. However, manifestations of liver damage may develop after only 1 to 4 days. Cocaine use occasionally causes acute hepatocellular necrosis, perhaps by inducing hepatocellular ischemia.

Idiosyncrasy: Drugs can produce acute hepatocellular necrosis that is indistinguishable, even histologically, from viral hepatitis. The mechanisms are uncertain and probably vary with individual drugs. Isoniazid Some Trade Names
INH
NYDRAZID
Click for Drug Monograph
and halothane have been most thoroughly studied.

The mechanism of the rare halothane-related hepatitis is unclear but may include formation of reactive intermediates, cellular hypoxia, lipid peroxidation, and autoimmune-mediated damage. Risk factors include obesity (possibly because halothane metabolites are stored in adipose tissue) and repeated exposures to the anesthetic at relatively short intervals. Hepatitis typically develops within a few days to 2 wk after exposure, is heralded by fever, and is often severe. Occasionally, eosinophilia or a skin rash develops. Mortality is 20 to 40% if severe jaundice is present, but survivors usually recover completely. Methoxyflurane and enflurane, which are related anesthetics, can produce the same syndrome.

Cholestasis

Many drugs can produce a primarily cholestatic reaction. Usually the pathogenesis is poorly understood, but at least two forms of cholestatic injury—phenothiazine- and steroid-type—are clinically and histologically distinct. Diagnostic testing often includes noninvasive imaging to exclude biliary obstruction. Further testing (eg, magnetic resonance cholangiopancreatography, ERCP, liver biopsy) is necessary only if cholestasis persists after the drug is stopped.

Phenothiazine-type cholestasis is a periportal inflammatory reaction. Immunologic mechanisms are suggested by some evidence, such as occasional eosinophilia or other signs of hypersensitivity reactions, but direct toxicity to hepatic canaliculi is also possible. This type of cholestasis occurs in about 1% of patients given chlorpromazine Some Trade Names
THORAZINE
Click for Drug Monograph
and less often in those given other phenothiazines. Cholestasis is often acute and is accompanied by fever and high levels of aminotransferases and alkaline phosphatase. Differentiation from extrahepatic obstruction may be difficult, even by liver biopsy. If the drug is stopped, complete resolution is typical, although progression to chronic cholestasis with fibrosis occurs rarely. Cholestasis produced by tricyclic antidepressants, chlorpropamide Some Trade Names
DIABINESE
Click for Drug Monograph
, phenylbutazone Some Trade Names
No US trade name

, erythromycin Some Trade Names
ERY-TAB
ERYTHROCIN
Click for Drug Monograph
estolate, and many other drugs is clinically similar; however, progression to chronic liver damage from these drugs has not been clearly established.

Steroid-type cholestasis appears to be an exaggeration of the physiologic effect of sex hormones on bile formation rather than an immunologic sensitivity or membrane cytotoxicity. Impaired canalicular water flow, microfilament dysfunction, altered membrane fluidity, and genetic factors may be responsible. Little or no hepatocellular inflammation exists. Although the incidence varies worldwide, it occurs in 1 to 2% of women taking oral contraceptives. Gradual onset of cholestasis without systemic symptoms is characteristic. Alkaline phosphatase is elevated, but aminotransferase levels are usually not very high, and liver biopsy shows only centrizonal bile stasis with little portal or hepatocellular damage. Complete resolution follows drug withdrawal in most cases but may be prolonged.

Cholestasis of pregnancy (see Pregnancy Complicated by Disease: Cholestasis (pruritus) of pregnancy) is closely related to steroid-related cholestasis. Women with cholestasis of pregnancy may develop cholestasis with subsequent oral contraceptive use and vice versa.

Miscellaneous Acute Reactions

Some drugs cause mixed forms of hepatic dysfunction, granulomatous reactions (eg, quinidine Some Trade Names
CARDIOQUIN
QUINAGLUTE
Click for Drug Monograph
, allopurinol Some Trade Names
ZYLOPRIM
Click for Drug Monograph
, sulfonamides), or variants of liver injury that are difficult to classify. HMG-CoA reductase inhibitors (statins) produce subclinical aminotransferase elevations in 1 to 2% of patients, although clinically important liver injury is infrequent. Many antineoplastic drugs also cause liver damage; the mechanisms vary.

Chronic Liver Disease

Certain drugs can cause chronic liver disease. Isoniazid Some Trade Names
INH
NYDRAZID
Click for Drug Monograph
, methyldopa Some Trade Names
ALDOMET
Click for Drug Monograph
, and nitrofurantoin Some Trade Names
FURADANTIN
MACROBID
MACRODANTIN
Click for Drug Monograph
can produce chronic hepatitis. Resolution usually occurs if fibrosis is not present. The illness may begin acutely or insidiously. Progression to cirrhosis may occur. Chronic hepatitis-like histology with scarring occurs rarely in patients using acetaminophen Some Trade Names
GENAPAP
TYLENOL
VALORIN
Click for Drug Monograph
long-term in doses as low as 3 g/day, although higher doses are usually required. Alcoholics appear to be more susceptible, and the disorder is suspected in alcoholics found incidentally to have unusually high aminotransferase levels, especially AST (values rarely exceed 300 IU in alcoholic hepatitis alone). Amiodarone Some Trade Names
CORDARONE
Click for Drug Monograph
occasionally produces chronic liver injury with Mallory bodies and histologic features otherwise similar to alcoholic liver disease; membrane phospholipidosis is a factor in pathogenesis.

A sclerosing cholangitis–like syndrome can develop from hepatic intra-arterial chemotherapy, especially with floxuridine Some Trade Names
FUDR
Click for Drug Monograph
. Patients receiving methotrexate Some Trade Names
RHEUMATREX
Click for Drug Monograph
long-term (usually for psoriasis or RA) can develop insidiously progressive hepatic fibrosis, particularly in the case of alcoholics or if the drug is given daily; liver function tests are often unremarkable, and liver biopsy is needed. Although fibrosis caused by methotrexate Some Trade Names
RHEUMATREX
Click for Drug Monograph
is rarely clinically important, most authorities recommend biopsy when the cumulative drug dose reaches 1.5 to 2 g and occasionally thereafter. Noncirrhotic hepatic fibrosis that can produce portal hypertension can result from use of arsenical compounds or excessive amounts of vitamin A (eg, > 15,000 U/day for months) or niacin Some Trade Names
NIACOR
NIASPAN
SLO-NIACIN
Click for Drug Monograph
(see Vitamin Deficiency, Dependency, and Toxicity: Niacin Toxicity). In many tropical and subtropical countries, chronic liver disease and hepatocellular carcinoma are believed to result from ingesting foods containing fungal aflatoxins.

Besides causing cholestasis, oral contraceptives may also occasionally cause benign hepatic adenomas and, very rarely, hepatocellular carcinoma. Adenomas are usually subclinical but may present with sudden intraperitoneal rupture and hemorrhage, requiring emergency laparotomy. Most adenomas do not cause symptoms and are found incidentally during imaging tests. Because oral contraceptives increase clotting generally, they increase the risk of hepatic vein thrombosis (Budd-Chiari syndrome). Use of these drugs also increases the risk of gallstones because they enhance bile lithogenicity.

Last full review/revision November 2005

Content last modified November 2005