Drug-Related Hepatic Injury

More than 1,100 drugs and herbal remedies have been reported to cause liver injury. Drug-induced liver injury can mimic almost all patterns of liver injury seen in humans. Among causes of acute liver failure, drug-induced liver injury accounts for more than 50% of them. 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. Antimicrobials, psychotropic drugs, lipid-lowering agents and nonsteroidal antiinflammatory drugs (NSAIDS), phenytoin, propylthiouracil antituberculosis drugs, sulfa compounds, and disulfirams are implicated most often. Table 53-1 is a partial list of drugs for which liver chemistry test monitoring is recommended. For the majority of drugs the risk of drug-induced liver injury is in the range of 1:104-105 in the United States. The risk is greater in women and the elderly, and the risk varies depending on the nutritional and other susceptibility characteristics of the patients and the drug class.

I. HEPATOCELLULAR NECROSIS.

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.

A. 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.

1. The severity

of the disease can range from minimal symptoms to fulminant hepatic failure. In fact, 20% to 50% of patients with fulminant hepatic failure have drugs, especially acetaminophen, as the cause of their liver failure.

2. Laboratory studies.

Serum glutamic-oxaloacetic transaminase (SGOT, or aspartate aminotransferase [AST]) and serum glutamic-pyruvic transaminase (SGPT, or alanine aminotransferase [ALT]) 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 (PT) 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.

a. Drugs such as carbon tetrachloride, acetaminophen, and halothane cause injury to the centrilobular or perivenular area.

TABLE 53-1 Drugs Recommended for Liver Chemistry Monitoring

Piroxicam, diclofenac, sulindac, aspirin, pyrazine, fluconazole, itraconazole, dapsone, isoniazid, rifampin, labetalol hydrochloride, amiodarone hydrochloride, atorvastin calcium, lovastatin, nicotinic acid, valproic acid, carbamazepine, phenytoin, tolcapone, tacrine hydrochloride, rosiglitazone maleate, pioglitazone hydrochloride, methotrexate, propylthiouracil

b. Drugs such as aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), 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.

c. Valproic acid, amiodarone, 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.

II. CHOLESTASIS.

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.

A. Diagnosis.

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.

1. Clinical presentation and laboratory studies.

Fever, pain, and tenderness in the upper abdomen (especially in the right upper quadrant), jaundice, and pruritus are 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.

2. Diagnostic studies.

Ultrasound should be performed in most patients to rule out possible bile duct obstruction. Endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC), or computed tomography (CT) may be necessary in difficult cases.

3. 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.

B. Treatment is supportive.

Prompt withdrawal of the drug is essential.

III. 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.

A. 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.

B. Drugs

such as quinidine, allopurinol, nitrofurantoin, diltiazem, and many others cause a granulomatous reaction with some hepatocytic necrosis.

C. For a detailed list

of drugs and their liver toxicity see the article by Lewis in the Selected Readings.

IV. AMIODARONE HEPATOTOXICITY.

Recently three cardioactive drugs—amiodarone, perhexiline maleate, and colalgia (4,4′-diethylaminoethoxyhexestrol)—have been found to cause liver injury resembling alcoholic hepatitis.

A. Pathogenesis. 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.

B. Diagnosis.

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