More than 600 drugs have been reported to cause liver injury. Drug-related hepatic injury can mimic almost all patterns of liver injury seen in humans. The injury can be hepatocellular necrosis, cholestatic disease, deposition of microvesicular fat in hepatocytes, or mixed patterns. In most cases, the damage is caused by toxic metabolites of the drug or immune response to the drug or its metabolites. It may result in chronic hepatitis and cirrhosis. Table DRUGS RECOMMENDED FOR LIVER CHEMISTRY MONITORING is a partial list of drugs for which liver chemistry test monitoring is recommended.
Drug-induced hepatocellular necrosis is clinically indistinguishable from cell injury from other causes such as viruses or ischemia. Thus it is important to obtain a drug history and note the presence of any hypersensitivity reactions such as rash or eosinophilia.
The diagnosis is usually established by a history of drug ingestion and the elimination of other possible causes such as viruses or ischemia by appropriate serology and clinical data.
The severity of the disease can range from minimal symptoms to fulminant hepatic failure. In fact, 10% to 20% of patients with fulminant hepatic failure have drugs as the cause of their liver failure.
Serum glutamic-oxaloacetic transaminase, or aspartate aminotransferase and serum glutamic-pyruvic transaminase or alanine aminotransferase levels are elevated (2-30 times normal). These enzymes leak into the circulation from the cytoplasm of damaged or dying hepatocytes. The alkaline phosphatase and albumin levels are usually affected to a lesser extent. Serum bilirubin levels and the increase in prothrombin time correlate with the severity of the liver damage.
A percutaneous liver biopsy performed early in the course of the disease can be helpful in identifying the type and extent of injury.
Drugs such as carbon tetrachloride, acetaminophen, and halothane cause injury to the centrilobular or perivenular area.
Drugs such as aspirin, nonsteroidal antiinflammatory drugs, thiazide diuretics, nicotinic acid, clofibrate, gemfibrozil, oxacillin, sulfonamides, rifampin, ketoconazole, fluorocytosine, zidovudine, isoniazid, tacrine, trazodone, calcium channel blockers, beta blockers and methyldopa cause diffuse parenchymal injury similar to viral hepatitis.
Valproic acid and intravenous tetracycline can cause extensive microvesicular fat infiltration of the hepatocytes and liver failure, as seen in Reye’s syndrome or fatty liver of pregnancy.
Treatment consists of prompt discontinuation of the offending drug and supportive measures. In most cases, patients recover over weeks to months. However, fatality in fulminant cases is still significant.
Drug-induced cholestasis is due to impairment of bile secretion by the hepatocytes. It may be caused by a change in the chemical and physical properties of the hepatocyte membranes as with estrogen and 17C-alkyl-steroids. In addition, drugs, directly or by their toxic metabolites, may induce cholestasis by their effects on cytoskeletal elements, inhibition of membrane Na-K-ATPase, or immunologic damage to the hepatocytes or to the small bile ducts. Drugs most commonly involved in cholestatic liver injury are phenothiazines, tricyclic antidepressants, erythromycin, carbamazepine, cyproheptadine, tolbutamide, captopril, phenytoin, trimethoprim-sulfamethoxazole, sulfasalazine and lipid-lowering drugs.
Patients with drug-induced cholestatic liver disease may present with clinical and laboratory findings very similar to those in intra- or extrahepatic bile duct obstruction, septic cholangitis, or acute cholecystitis.
|TABLE. DRUGS RECOMMENDED FOR LIVER CHEMISTRY MONITORING|
Clinical presentation and laboratory studies. Fever, pain, and tenderness in the upper abdomen, especially in the right upper quadrant, jaundice, and pruritus is commonly present. The serum alkaline phosphatase level is usually significantly elevated (2-10 times normal), with a mild increase in serum transaminases. Conjugated hyperbilirubinemia may be severe (2-30 mg/dl). There may be an accompanying rash or other signs of hypersensitivity.
Ultrasound should be performed in most patients to rule out possible bile duct obstruction. Endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography, or computed tomography may be necessary in difficult cases.
Liver biopsy should be considered if the diagnosis cannot be made with the preceding clinical data. Histology usually shows cholestasis with or without inflammation. Microscopic cholangitis, infiltration of the portal tracts with inflammatory cells, and limited hepatocellular necrosis may be present.
Treatment is supportive
Prompt withdrawal of the drug is essential.
Mixed-pattern liver injury
In most cases, drug-induced liver injury causes a combination of cholestasis and hepatocyte necrosis. Patients usually have moderate elevation of the serum transaminases, bilirubin, and alkaline phosphatase levels. Most of these reactions are the result of hypersensitivity to the drug and affect only a few susceptible individuals.
Phenytoin (Dilantin) toxicity resembles viral mononucleosis. Patients present with fever, lymphadenopathy, and a tender liver. The liver biopsy shows portal lymphocytic infiltration and spotty necrosis of parenchymal cells.
Drugs such as quinidine, allopurinol, nitrofurantoin, diltiazem, and many others cause a granulomatous reaction with some hepatocytic necrosis.
For a detailed list of drugs and their liver toxicity is see the article by Lewis in Recommended Reading Section.
Recently three cardioactive drugs, amiodarone, perhexiline maleate, and coralgil (4,4’-diethylaminoethoxyhexestrol), have been found to cause liver injury resembling alcoholic hepatitis.
Amiodarone has been reported to cause corneal and skin deposits, hypo- and hyperthyroidism, pulmonary infiltrates and interstitial fibrosis, peripheral neuropathy, and hepatomegaly with transaminase elevation in 20% to 40% of the patients receiving the drug. Liver histology in these patients resembles that of alcoholic hepatitis. There may be bile duct proliferation, fibrosis, and cirrhosis. Electron microscopy shows the presence of trapped phospholipids in secondary lysosomes.
Amiodarone has been found to accumulate in acidic lysosomes and to competitively inhibit lysosomal phospholipases and phospholipid degradation leading to accumulation of phospholipids in lysosomes of liver cells. The relation of this phospholipidosis to the formation of a state resembling alcoholic liver injury and cirrhosis is not known.
Amiodarone has a long half-life and a large volume of distribution. The blood levels remain elevated, and the drug is present in the liver for months after the drug is stopped. The hepatotoxicity is usually clinically insidious. It usually develops after a year of therapy but can occur after 1 month.
Liver disease is diagnosed by the findings of hepatomegaly, a moderate rise in serum transaminases, and occasionally elevated bilirubin.
Liver biopsy with histologic and electron microscopic examination may be necessary.
Treatment and clinical course
Therapy is supportive after discontinuation of the drug. Even though hepatomegaly usually reverses in time, the liver disease may progress, leading to cirrhosis and its complications.
Aspirin and other salicylates have been noted to cause liver injury in patients with rheumatic and collagen vascular diseases such as juvenile and adult rheumatoid arthritis, rheumatic fever, and systemic lupus erythematosus. Normal subjects and patients with nonrheumatic diseases such as orthopedic problems may also be affected.
The blood level of the drug (> 5 mg/dl) and the duration of intake (> 6 days to weeks) seem to play an important role in the production of liver damage. The injury appears to be a cumulative phenomenon, appearing after many days of intake of large therapeutic doses. A single, toxic overdose of aspirin produces little or no hepatic injury.
Patients with rheumatic and collagen vascular disorders may be more susceptible to liver injury with aspirin than others. This may be due to the presence of hypoalbuminemia allowing higher serum levels of unbound aspirin, underlying liver damage, and possibly altered metabolism of the salicylates. The mechanism of hepatic injury seems to be intrinsic toxicity of the salicylate moiety rather than host idiosyncrasy to the drug.
Salicylate choline and sodium salicylate also can induce hepatic injury. The liver disease is usually mild, acute, and reversible. Lowering the dose of Aspirin without totally discontinuing its use may be sufficient to reverse the injury. There is strong evidence to suggest that aspirin in the setting of a viral infection may provoke the development of Reye’s syndrome in children.
Clinical manifestations of hepatic injury are not prominent. Most patients remain asymptomatic. Some patients complain of anorexia, nausea, and mild abdominal distress. Almost all patients are anicteric.
The liver disease is usually mild. However, encephalopathy, severe coagulopathy, and fatal liver failure have been reported. There is no established evidence that aspirin causes chronic liver injury.
Serum transaminases are usually moderately elevated (2-10 times normal). In 10% of the individuals, serum glutamic-oxaloacetic transaminase levels are greater than 100 IU/ ml. The serum glutamic-oxaloacetic transaminase (aspartate aminotransferase) levels are usually higher than the serum glutamic-pyruvic transaminase (alanine aminotransferase) levels. The alkaline phosphatase levels are usually normal or only modestly elevated. Serum bilirubin levels have been elevated only in about 3% of the reported cases.
Treatment is supportive. In most instances, it is not necessary to discontinue the drug for reversal of liver injury. Decreasing the dosage to attain blood levels less than 15 mg/dl seems to be sufficient.
Drug-induced chronic hepatitis
Drugs that have been documented to cause chronic hepatitis include oxyphenisatin, alpha methyldopa, nitrofurantoin, dantrolene, isoniazid, propylthiouracil, sulfonamides, and halothane. The incidence of chronic hepatitis with any one drug is low, and the total number of cases is small. However, a drug history should be obtained from each patient suspected to have chronic hepatitis. In most cases, if drug-induced chronic hepatitis has not developed into cirrhosis, it improves or resolves with discontinuation of the drug.
The incidence of hepatitis with methyldopa is very low; however, if the hepatitis is not noted in early stages, the disease may progress to chronic active hepatitis. Hepatitis occurs within weeks after starting the drug, suggesting a role for hypersensitivity. If the lesion is recognized early on, the injury and inflammation regress with discontinuation of the drug.
This laxative, although taken off the market in the United States, is still in popular use, especially among women in Europe and South America. Oxyphenisatin has been shown to cause acute and chronic hepatitis resembling «lupoid hepatitis.» The disease may progress to cirrhosis if the drug is continued after the onset of liver injury. In most instances, however, after the withdrawal of the drug, the disease is halted and even reversed.
Isoniazid produces asymptomatic elevation of serum transaminases with mild liver injury in up to 20% of the patients within the first 2 to 3 months of therapy. However, approximately 1% of the individuals develop severe hepatic injury, even fulminant hepatic failure, associated with a high mortality. Chronic hepatitis generally does not develop if the drug is stopped within the first few weeks of recognition of the hepatitis. However, severe chronic active hepatitis accompanied by cirrhosis develops with persistent administration of Isoniazid.
Isoniazid-induced liver injury is thought to result from hepatotoxic reactive intermediates of Isoniazid metabolism. Isoniazid is first acetylated and then converted to acetylphenylhydrazine, which is a potent hepatotoxin. There are some data to suggest that rapid acetylators (e.g., most East Asians) are more susceptible to Isoniazid-induced liver injury.
The clinical features of hepatitis induced by Isoniazid are nonspecific and resemble those of viral hepatitis. Fatigue, malaise, anorexia, nausea, vomiting, and abdominal discomfort are commonly noted. Jaundice is the presenting complaint in 10% of the patients. Signs and symptoms of hypersensitivity, rash, lymphadenopathy, arthralgia, and arthritis are rare.
Older patients, especially older women, have a higher susceptibility to Isoniazid-induced hepatitis. Hepatitis is rare in patients younger than 20 years of age. The risk increases to 0.5% in patients 20 to 35, 1.5% for patients 35 to 50, and 3% for those over 50 years old. Alcohol and drugs that induce the hepatic P-450 enzyme system such as rifampin seem to increase susceptibility to Isoniazid injury. Continuation of Isoniazid after the onset of prodromal symptoms increases the severity of the hepatitis. Thus it is crucial to stop Isoniazid therapy in symptomatic patients immediately during the first 1 to 2 weeks.
There is no specific therapy for Isoniazid hepatitis other than prompt withdrawal of the drug. Patients should be given supportive care. There is no role for corticosteroid therapy.