Drugs are an important and common cause of hepatic injury. This is not surprising, as the liver is the predominant site of drug clearance, biotransformation and excretion. Abnormalities cover a wide spectrum from minor nonspecific derangements to fulminant hepatic necrosis. The two most common, however, are acute inflammation and cholestasis, which can closely mimic viral hepatitis and biliary obstruction, respectively. Various other acute and chronic disease patterns also occur (as noted below). Thus drug-induced liver disease is complex, has protean manifestations, and can simulate a wide variety of other hepatic disorders.

The pathogenesis varies with the offending agent, and in most cases is poorly understood. Sometimes the drug or one of its metabolites exerts a direct toxic effect on liver membranes. This type of injury is predictable and dose-related, but is relatively infrequent. Much more commonly, the injury occurs unpredictably in only a tiny fraction of individuals receiving the drug and is independent of dosage. In some such instances genetic predisposition or idiosyncratic metabolism of the drug may be responsible. Immune hypersensitivity is often invoked, but only a minority of cases have concomitant evidence of an allergic reaction such as a rash, arthralgias or eosinophilia. Many instances of putative hypersensitivity may actually be due to toxic intermediate drug metabolites in rarely susceptible individuals. In most situations the reasons for individual susceptibility are unknown, and the precise pathogenesis of the hepatic injury is equally obscure.

Diagnosis requires first and foremost a careful history of drug ingestion, including over-the-counter and illicit agents as well as prescribed medications. A temporal association is also important in cases of acute dysfunction: injury typically develops within days or a few weeks of starting the drug. Other reactions involve chronic insidious injury and therefore require prolonged drug exposure - e.g., methotrexate fibrosis and oral contraceptive-induced adenomas. Liver biopsy sometimes provides an important clue to certain drug injuries, but more commonly the histologic pattern is nonspecific and/or mimics other primary liver disorders. Thus in many cases the diagnosis of drug injury remains uncertain or unproven even after appropriate patient assessment.

The prognosis is variable. Acute damage usually resolves when the offending agent is withdrawn, but cases of severe acute necrosis can be fatal or result in postnecrotic scarring. In cases of chronic injury, further hepatocellular damage and inflammation will generally cease when the drug is stopped, but any concomitant fibrosis will be irreversible.

No physician can know the innumerable drugs capable of producing liver injury. Rather, it is best to maintain a constant awareness of the possibility, to understand the general types of damage, and to learn the most common agents responsible for each. Table 9 gives an arbitrary classification and examples of drug-induced hepatic injury. A few of the more important examples are briefly discussed below.

This takes at least two distinct forms, both characterized clinically and biochemically by features of acute liver cell destruction.

7.1.1 TOXIC NECROSIS

This involves direct membrane damage by the parent drug or a toxic metabolite. It is therefore dose-related and a predictable occurrence in anyone ingesting a sufficient quantity of the drug. Sometimes the histologic injury is characteristic - e.g., zonal necrosis and fat in carbon tetrachloride toxicity.

Acetaminophen is the most important example. This widely used analgesic is largely excreted as harmless conjugates, but a portion is transformed by hepatic microsomes to toxic intermediate metabolites. Normally these are safely eliminated by conjugation with hepatic glutathione, but a large enough dose of acetaminophen will deplete the available glutathione stores. Once this occurs, cell necrosis results from binding of the toxic intermediates to liver macromolecules. The threshold injurious dose of acetaminophen is usually about 10-15 g acutely; this is far beyond the normal dosage and is generally ingested only in suicide attempts. Alcoholics are susceptible at much lower dosage, however, as a result of heightened microsomal transformation coupled with nutritional depletion of glutathione. Acetaminophen should be suspected in an alcoholic with extremely high AST/ALT levels, as values rarely exceed 300 µmol/L in uncomplicated alcoholic hepatitis. Another clue to acetaminophen toxicity is a disproportionately elevated INR.

Acetaminophen hepatotoxicity typically becomes apparent only 36 to 48 hours after ingestion; by then it is too late to modify the process. Fortunately, injury is successfully aborted by early therapy with N-acetylcysteine, which repletes hepatic glutathione levels. This should be given within 10 to 16 hours of acetaminophen ingestion to be effective, though some benefit may be achieved even at 24 to 36 hours. To guide therapy, nomograms are available relating the probability of liver injury to blood acetaminophen levels and to the amount of time since ingestion.

7.1.2 ACUTE HEPATITIS

This pattern of injury closely mimics acute viral hepatitis clinically, biochemically and histologically. Unlike toxic necrosis, it occurs unpredictably, is not dose-related and affects only rare individuals exposed to the drug. Reasons for the idiosyncratic susceptibility are obscure. Numerous agents can produce this injury pattern; methyldopa, isoniazid and halothane are classic examples, the latter usually producing damage only after repeated exposure to the anesthetic. Acute isoniazid hepatitis occasionally develops only after several months of drug therapy. This is an exception to the general rule of a temporal relationship, and the association may therefore be overlooked.

 

7.2 Cholestasis

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This type of reaction also takes at least two distinct forms.

7.2.1 INFLAMMATORY TYPE

Chlorpromazine, other phenothiazines and many other drugs can produce an acute periportal necro-inflammatory reaction. This is characterized clinically and biochemically by a predominant cholestatic disorder with variable features of concomitant inflammation. Differentiation from extrahepatic biliary obstruction is usually required.

7.2.2 PURE TYPE

Certain steroid hormonal drugs, most notably oral contraceptives and methyltestosterone, can produce relatively pure impairment of bile flow with little or no associated hepatocellular injury (bland cholestasis). This appears to be due to an idiosyncratic exaggeration of the physiologic effect of sex hormones on bile canalicular transport, and may have a genetic component. The patient typically develops insidiously progressive pruritus, dark urine, and jaundice without associated systemic symptoms. Laboratory tests show high ALP with normal or minimally elevated AST/ALT levels. The liver biopsy is usually unremarkable aside from histologic cholestasis. Women who develop this reaction to oral contraceptives are predisposed to cholestasis of pregnancy, which appears to be similar or identical in pathogenesis (see Section 17).

Oral contraceptives are also associated with other, less common hepatobiliary effects. These are listed in Table 10.

Many hepatic drug reactions involve a variable mixture of hepatocellular and excretory impairments that do not neatly fit any of the above categories. Laboratory and histologic features are variable and nonspecific. Occasionally granulomatous inflammation occurs (e.g., with sulfonamides), often with acute systemic features. Differentiation from an infective granulomatous disorder may be challenging. A few drugs can produce an alcoholic hepatitis-like picture, including typical histologic features (e.g., amiodarone). Other unusual patterns of drug injury have also been described.

Though the large majority of drug-induced hepatic injury is acute or subacute, in a few reactions there is an insidious development of chronic disease. These vary in type.

7.4.1 CHRONIC HEPATITIS

A few agents that induce acute hepatitis are also capable of producing chronic inflammation if drug ingestion continues. Methyldopa and isoniazid are the prime examples. Clinically, biochemically and histologically the reaction may be indistinguishable from idiopathic or immune chronic hepatitis. The disorder typically resolves when the drug intake ceases.

7.4.2 CHRONIC CHOLESTASIS

In rare instances chlorpromazine cholestatic injury becomes prolonged and self-perpetuating even though the drug is discontinued. This can simulate primary biliary cirrhosis, though immunologic features of the latter are lacking.

7.4.3 FIBROSIS/CIRRHOSIS

Insidiously progressive hepatic fibrosis and eventual cirrhosis can occur from methotrexate, some chemotherapeutic agents, and chronic ingestion of arsenicals or vitamin A in megadoses. Scarring typically develops subclinically and with little or no biochemical evidence of hepatic dysfunction. Liver biopsy is therefore the only way to establish the diagnosis. Patients receiving long-term methotrexate therapy for psoriasis or rheumatoid arthritis should generally undergo biopsy after cumulative drug dosage reaches about 1.5 g, and at occasional intervals thereafter.

7.4.4 TUMORS

Prolonged intake of oral contraceptives is associated with an increased risk of developing benign hepatic adenomas. These are usually asymptomatic but occasionally produce an acute abdomen due to intraperitoneal rupture and hemorrhage. In rare instances, oral contraceptive-induced adenomas become malignant. Other unusual drug-related tumors are known to occur as well - e.g., angiosarcoma from chronic exposure to vinyl chloride.