The liver plays a major role in the biotransformation of drugs and toxins, and it thereby becomes a major target for drug-induced injury. The recognition of this type of liver disease is a challenging but important task for both clinicians and pathologists. Over 600 different drugs have, at one time or another, been implicated as causing liver damage, and virtually any variety of hepatic disease can result. Moreover, establishing the correct cause has crucial therapeutic implications; most drug reactions regress if the offending agent is removed, but they often worsen or progress when the treatment is continued. The task is complicated by the introduction of new, potentially hepatotoxic drugs and the continuing appreciation of hepatotoxicity in agents currently available.

The scope of drug-induced hepatotoxicity is difficult to assess since its prevalence depends critically on the definition and methods of detection. Abnormalities in routine liver function tests are frequently found during therapy with numerous drugs, but the alterations often represent transient, minor findings are do not necessarily indicate clinically significant liver injury. On the other hand, surveys of drug reactions among hospitalized patients are apt to underestimate the true prevalence of adverse reactions and, at the same time, overrepresent severe or fatal cases.

Nonetheless, the evidence suggests that drug-induced hepatic injury is an uncommon -- but not rare -- circumstance, accounting for approximately 2% of cases of jaundice in hospitalized patients, 25% of cases of fulminant hepatic failure, and, from the pathologist's perspective, an estimated 5% to 10% of all liver biopsy specimens encountered.^{62,125,142,153}

The mechanisms of drug-induced hepatic injury are poorly understood and, indeed, have been extensively examined with only a few agents. Two pathogenetic groups, predictable and idiosyncratic, have been traditionally recognized.³⁴² Predictable injury is dose-related, can be reproduced in experimental animals, and results from the intrinsic toxicity of the drug or one of its metabolites. These metabolites are produced primarily by the cytochrome P-450 system, and include electrophiles and free radicals, two species capable of binding covalently to macromolecules or causing lipid peroxidation.

Idiosyncratic injury, on the other hand, is unpredictable; it develops in only a small fraction of patients receiving the drug, has no clear relationship to dosage, and is not replicated in animal models. A hypersensitivity pathogenesis has often been suggested because such manifestations as rash, fever, arthralgias, or eosinophilia are often concurrently present.^135,275

These distinctions have become blurred by progress in our understanding of drug biotransformation. In several instances of idiosyncratic injury, for example, the responsible mechanism appears to be the generation of toxic metabolites, just as in predictable injury. The differences in individual susceptibility derive from variations in the rates and activities of the metabolic pathways involved in forming and detoxifying the reactive intermediates. These variations are probably controlled by numerous genetic and environmental factors, and a particular constellation of factors may place certain individuals at particular risk of hepatic injury.²¹⁸

In other idiosyncratic cases, allergic reactions could be involved in the pathogenesis, although these have been less well established. Drug metabolites could presumably bind to membrane proteins or other components and create a neoantigens, perhaps by serving as haptens, and might thereby trigger an autoimmune response.^55,138,218

The basic axiom of drug-induced hepatic injury is that it can mimic any other form of liver disease. This is certainly true of the clinical manifestations, which encompass any of the usual findings of acute or chronic hepatic dysfunction. Drugs and toxins are therefore an etiologic consideration in any liver disease, and a complete drug history, including nonprescription medications, is imperative.

Acute drug-induced disease can be categorized clinically as hepatocellular, cholestatic, or mixed in nature (Table 12-1).³⁴² Although based primarily on the laboratory abnormalities, these categories broadly correlate with the histologic patterns described below. In most cases, the clinical features appear within weeks of starting therapy, although the latency period with some drugs can be delayed for up to a year. A further indication of a drug reaction is provided by the presence of systemic manifestations of hypersensitivity such as rash, fever, arthralgia, or eosinophils, but these are not specific features.

Chronic drug-induced disease, which is much less common than the acute varieties, encompasses a wide spectrum of clinical features indistinguishable from that of other advanced hepatic disorders. Some patients have nonspecific complaints and are identified only by abnormal liver enzymes, whereas others present with portal hypertension or hepatic failure. On occasion, serologic evidence of autoimmune disease such as antinuclear antibodies or antismooth muscle antibodies can be detected. A high level of suspicion is therefore necessary, with particular attention paid to any potentially culpable drugs.

The diagnosis of drug-induced hepatic injury depends on identifying a temporal relationships between drug administration and onset of liver dysfunction in the absence of other possible causes. The concurrent administration of several drugs can produce unexpected injury, and therefore the entire context of the liver disorder must examined.^9,79,267 The diagnosis is reasonably assured if discontinuation of the therapy is followed by improvement in the liver dysfunction. Typically this occurs within several weeks of cessation, but, in some cases, the recovery period is more protracted. The most conclusive evidence involves rechallenging the patient with the suspected drug and documenting an exacerbation of the liver disease; this can be a dangerous procedure, however, and is not generally recommended.^135,275

HISTOLOGIC PATTERNS

Drug-induced hepatic injury encompasses a wide morphologic spectrum, and virtually any histologic pattern of liver disease can be seen.^{73,112,115,290} In general, there are no specific features that allow a drug etiology to be established on histologic grounds. Liver biopsy can consequently be useful in raising the possibility of a drug reaction, in supporting a clinical suspicion, or in indicating the severity of the damage, but it generally cannot provide a definitive diagnosis.

The histologic features should be evaluated in concert with an adequate drug history, including the duration and dosage of therapy and the temporal relation between drug exposure and biopsy. Often the pathologist can help exclude drug-induced hepatic injury by identifying another cause for the clinical and laboratory abnormalities.

The major histologic patterns seen with drug-induced liver disease are summarized in Table 12-2. Although complete discussions of the differential considerations are presented elsewhere in the book, pertinent aspects are included here.

Acute hepatitis. This histologic pattern is characterized by hepatocyte injury and necrosis accompanied to varying degrees by lobular and portal inflammation. The severity and extent of the changes range across a broad spectrum. The mildest alterations consist of scattered acidophilic bodies and foci of hepatocyte necrosis with minor inflammatory infiltration, yielding a picture of nonspecific reactive hepatitis (Figure 12-1).

More substantial involvement yields a distinctive viral hepatitis-like appearance: diffuse lobular disarray with liver cell damage in the form of ballooning and acidophilic degeneration, spotty hepatocyte necrosis, and variable inflammatory infiltration, predominantly by mononuclear cells. The inflammatory component in some cases is sparse, whereas in others, mononuclear cells are prominently arranged along the sinusoids in a string-of-beads fashion (Figure 12-2). The latter picture resembles that seen with mononucleosis hepatitis and has been associated with such drugs as phenytoin, para-aminosalicylic acid, the sulfonamides, and dapsone.^75,192 Canalicular cholestasis is typically absent or minimal; cases with more substantial cholestasis merge into the category of cholestatic hepatitis, as discussed below.

The overall picture of drug-induced acute hepatitis is indistinguishable from other forms of acute hepatitis, and the distinction rests solely on clinical and laboratory data. There are, however, certain histologic findings that may prompt suspicion of a drug etiology, although they are neither specific or sensitive markers. These additional features include abundant eosinophils, granulomas, fatty change, bile duct damage, and an underdeveloped inflammatory response.¹⁹ Many drugs can produce acute hepatitis, and the more celebrated examples include isoniazid, methyldopa, halothane, sulfonamides, and phenytoin.^17,192,222

Chronic hepatitis. Most instances of drug-induced chronic hepatitis conform histologically to the pattern of chronic active hepatitis. This is exemplified by portal and periportal inflammation by mononuclear cells together with irregular destruction of adjacent periportal hepatocytes -- so-called piecemeal necrosis (Figure 12-3). Varying degrees of lobular necrosis, including focal or confluent necrosis, are noted in some cases. Periportal fibrosis can develop and, on occasion, can progress to fibrous septa and eventually lead to cirrhosis.

The most commonly incriminated drugs include the discontinued laxative oxyphenisatin, methyldopa, and nitrofurantoin, with occasional cases attributed to isoniazid, dantrolene, halothane, and aspirin.^171,294 Usually these agents have been administered over a prolonged period, and the acute injury is clinically either silent or unrecognized.²²²

Confluent Necrosis

This histologic pattern, which denotes a more severe grade of hepatocellular damage, is distinguished by the destruction and loss of continuous groups of hepatocytes (Figure 12-4). It can develop as a complication of diffuse acute hepatitis or occur as an isolated process with little associated inflammation. Depending on the cause and time course of the injury, the necrosis can derive from ballooning degeneration or, less often, ischemic-like coagulative alterations. Confluent necrosis may exhibit a particular zonal distribution, sometimes with bridging necrosis, but it can also extend to involve entire lobules and produce massive (or submassive) hepatic necrosis.²⁸³

With disappearance of the hepatocytes and eventual collapse of the reticulin framework, the necrotic zones accumulate pigment-laden Kupffer cells and other mononuclear cells. The inflammatory response in the adjoining parenchyma varies greatly in degree, and often the portal tracts are minimally involved; on occasion, eosinophils are a conspicuous component. In severe cases, proliferated bile ductular structures with attendant neutrophils are found in the periportal region. The surviving hepatocytes can show a variety of changes including fatty change, canalicular cholestasis, and regenerative hepatocyte alterations, but in some cases, they are barely affected and are sharply demarcated from the necrotic zone.

Centrilobular confluent necrosis is associated with numerous drugs, both predictable and idiosyncratic hepatotoxins, including acetaminophen, halothane and other halogenated anesthetic agents, isoniazid, methyldopa, ketoconazole, and hydralazine, as well as toxic exposures to Amanita mushrooms, carbon tetrachloride, and copper sulfate.^16,139,161

Periportal confluent necrosis is a less common variety, noted with ferrous sulfate and yellow phosphorus toxicity and occasional examples of acute hepatitis associated with cocaine and labetalol.^44,216

Multilobular confluent necrosis and resulting massive hepatic necrosis comprise the severe end of the spectrum, presumably progressing from lesser degrees of confluent necrosis. Numerous agents have been incriminated, including many substances capable of producing acute hepatitis or centrilobular necrosis; among the commonly cited drugs are acetaminophen, halothane, isoniazid, methyldopa, selacryn, and dihydralazine.^16,340

Pure cholestasis. In this histologic pattern, canalicular cholestasis is virtually the sole morphologic abnormality. Canalicular bile plugs are conspicuous in the centrilobular zone and may be accompanied by mild hepatocyte damage and, occasionally, cholestatic rosettes. Lobular and portal inflammation are absent or minimal, and no hepatocyte necrosis is noted (Figure 12-5).

The primary causes of drug-induced pure cholestasis are estrogenic and androgenic steroids, although sporadic reports implicate such agents as piroxicam and prochlorperazine.^37,111 In addition, early or minor examples of cholestatic hepatitis may be accompanied by little inflammatory reaction and thus become enlisted into the pure cholestasis category.¹⁴⁹

Cholestatic hepatitis. In this histologic pattern, canalicular cholestasis is combined with varying degrees of hepatocyte damage and inflammatory infiltration. Depending on the severity of these latter changes, a broad continuum of morphologic appearances can result. Typically the features tend toward the mild end of the spectrum; scattered acidophilic bodies and occasional hepatocyte ballooning with focal necroses are accompanied by moderate but patchy mononuclear inflammation of the portal tracts (Figure 12-6). Mononuclear inflammatory cells also infiltrate the lobules in both cholestatic, and to a lesser extent, noncholestatic areas. Eosinophils may be a striking accompaniment to the portal or lobular inflammatory infiltrates, particularly if a peripheral eosinophilia is present. In addition, bile ductular proliferation and portal edema are sometimes present and invite confusion with biliary obstruction.¹⁹

At the severe end of the spectrum, the degree of hepatocellular damage and inflammation overlaps with that found in acute hepatitis. This produces a mixed pattern that may either show a relative predominance of the cholestatic or hepatitic features, and, on that basis, is sometimes into mixed-hepatocanalicular or mixed-hepatocellular types.³⁴²

Cholestatic hepatitis is one of the more common forms of drug-related injury and has been associated with numerous agents from almost all pharmacologic categories. Notable examples include phenothiazines such as chlorpromazine, erythromycins, phenylbutazone, chlorpropamide, and various benzodiazepines.^149,342

Some instances of cholestatic hepatitis are complicated by alterations of the interlobular bile ducts. One such change is acute cholangitis, characterized by infiltration of ductal epithelium by neutrophils and accompanied by varying degrees of epithelial damage or destruction. Lymphocytes or eosinophils can join the infiltrating cells, and the affected portal tracts frequently demonstrate bile ductular proliferation with its attendant neutrophil response. Acute cholangitis is described with several agents including allopurinol, carbamazepine, chlorpromazine, hydralazine, and sulindac.^{151,156,198,298}

Other cases show bile ductal degeneration. The ductal epithelial cells become shrunken and darkly-stained with misshapen pyknotic nuclei and dense eosinophilic cytoplasm. Intraepithelial infiltration by inflammatory cells is either absent or minimal. This type of noninflammatory ductal degeneration is reported with toxic exposure to the herbicide paraquat, the epoxy resin hardener methylenedianiline (responsible for "Epping jaundice"), and adulterated rapeseed oil (the cause of Spanish toxic oil syndrome).^178,193,280

In cases of drug-induced sclerosing cholangitis, fibrosis and stricture of the large bile ducts, primarily the extrahepatic ducts, yields the biopsy pattern of cholestatic hepatitis. This has been described primarily with hepatic arterial administration of floxuridine (FUDR) for treatment of liver metastases. The diagnosis is based on the cholangiographic features.^61,107,224

Chronic cholestasis. The basic histologic features of this pattern include a combination of periportal hepatocyte swelling, mixed portal and periportal inflammation with foamy macrophages, lymphocytes, and neutrophils, and irregular ductular proliferation (Figure 12-7). The swollen hepatocytes typically contain stainable copper and may display Mallory bodies; varying degrees of canalicular cholestasis can also be noted. Portal and periportal fibrosis are regular accompaniments, but in severe cases, bridging fibrosis and even cirrhosis can develop.

Of special note in many cases, however, is the progressive destruction and disappearance of interlobular bile ducts.^52a This feature, a likely consequence of drug-induced acute cholangitis, is recognized by finding hepatic artery branches or portal tracts that are missing their companion bile ducts. In general, a 50% reduction in bile duct numbers is required to establish bile duct paucity by these criteria (Chapter 5). The overall appearances with chronic cholestasis and diminished bile ducts is reminiscent of primary biliary cirrhosis and similar conditions, although the prognosis is better with gradual clinical and biochemical improvement in most cases.

The incriminated drugs include chlorpromazine, tolbutamide, imipramine, piroxicam, thiabendazole, and ajmaline.^{94,109,152,172,323} Singular cases have also been associated with ampicillin and the concurrent administration of chlorpropamide and erythromycin ethylsuccinate.^41,79

Steatosis can be separated into two histologic groups depending on the size of the fat droplets. Macrovesicular fatty change is the commonplace variety in which a single large lipid globule fills the cytoplasm of the hepatocyte and displaces the nucleus to the periphery (Figure 12-8). Alcohol is, of course, the drug most responsible for this pattern, but certain therapeutic agents, including corticosteroids, methotrexate, and L-asparaginase, can also be responsible. Macrovesicular fatty change is also noted with total parenteral nutrition and with toxic exposure to carbon tetrachloride, chlorinated hydrocarbons, and phosphorus. In addition, it can be found as a secondary feature in cases of acute hepatitis or cholestatic hepatitis caused by such drugs as dapsone, phenothiazines, phenytoin, and the sulfonamides.³⁰⁴

In microvesicular fatty change, multiple small lipid droplets expand the hepatocyte but leave the nucleus centrally positioned (Figure 12-9). This can be accompanied by mild canalicular cholestasis and is infrequently complicated by parenchymal necrosis or inflammation. The causes include valproic acid, parenteral tetracyclines in large doses, and fatal salicylate intoxication.^223,284,343 Similar changes are seen in an alcohol-induced syndrome known as alcoholic fatty degeneration and in Jamaican vomiting sickness caused by the hypoglycin A toxin found in unripe akee fruit.³⁰⁰

A further consideration is steatohepatitis, a distinctive histologic pattern that generally develops within a background of fatty change. In addition to macrovesicular or microvesicular steatosis, steatohepatitis is characterized by a combination of hepatocyte swelling, Mallory bodies, inflammatory infiltration including neutrophils, and fibrosis or even cirrhosis (Figure 12-10). The features overlap greatly with those of alcoholic hepatitis, although the Mallory bodies may favor the periportal rather than the centrilobular region. The most strongly implicated drugs are three agents used to treat cardiac arrhythmias and angina -- amiodarone, perhexiline maleate, and 4,4'-diethylaminoethoxyhexestrol -- with sporadic cases associated with nifedipine, synthetic estrogens in high doses, and long-term glucorticosteroids.^{8,119,158,219,268,277} Steatohepatitis is an unusual complication of therapy with these agents, and long-term administration is usually required for its development.

Granulomas

Drug-induced granulomas typically consist of ordinary noncaseating granulomas that lack any unique distinguishing features (Figure 12-11). They range from poorly-formed collections of macrophages to well-defined sarcoidal aggregates and are regularly stationed in portal tracts, although they also occur in the lobules. An accompanying eosinophil infiltration is frequently, but not invariably, present and provides a useful diagnostic prompt; lymphocytes and plasma cells are also typically noted.^116,180 Fibrin-ring granulomas with a central fat vacuole and an encircling band of fibrin have been described in some allopurinol-associated cases.^291,318

Although sometimes the only histologic abnormality, drug-induced granulomas can be associated with several additional alterations, including nonspecific reactive changes, prominent microgranulomas, and fatty change. They can also represent a secondary feature of histologic reactions that are primarily cholestatic or hepatitic in nature. In some instances, the granulomas accompany acute cholangitis or portal vasculitis.^{74,192,198,298} They do not result in the development of fibrosis or progressive liver disease.

Numerous agents have been held responsible for hepatic granulomas; prominently examples include allopurinol, sulfonamide, phenylbutazone, hydralazine, carbamazepine, and diltiazem.^3,17,157,307

Fibrosis is an common component of several histologic patterns of drug-induced hepatic injury. Periportal fibrosis occurs, for example, with both chronic hepatitis and chronic cholestasis and may progress to bridging fibrosis and cirrhosis. Centrilobular fibrosis can complicate chronic venous outflow obstruction, as seen with veno-occlusive disease caused by drugs, and can also follow severe examples of confluent necrosis of any cause. Fibrosis with variable perivenular, pericellular, and periportal distributions can develop with steatohepatitis resulting from alcohol or other agents.

In other cases, however, fibrosis represents the major histologic finding. Often the pattern is one of pericellular or perisinusoidal fibrosis distinguished by collagen deposition along the space of Disse. Portal and periportal fibrosis of varying degree are also often present. In some cases, the fibrosis is accompanied by sinsuoidal dilatation or peliosis hepatitis. Among the implicated agents are methotrexate, vitamin A, azathioprine, and mercaptopurine, as well as toxic exposures to vinyl chloride, thorotrast, and organic arsenicals.^{20,182,209,339}

Cirrhosis is an infrequent outcome of drug-induced injury. Many of the documented examples have progressed from chronic varieties of hepatic injury such as chronic active hepatitis, chronic cholestasis, or steatohepatitis. Implicated drugs include methotrexate, methyldopa, isoniazid, amiodarone, and ticrynafen.^149,158,209

Various drugs are capable of producing vascular injury at any level of the hepatic vasculature from the afferent portal or arterial supply to the hepatic venous drainage.^313,339

Perhaps the best example of a drug-induced vascular disorder is veno-occlusive disease. Histologically this is characterized by fibrous occlusion of small hepatic vein branches and the development of acute, and later chronic, changes of venous outflow obstruction. This condition was first related to the consumption of herbal teas or folk remedies made from plant species that contain toxic pyrrolizidine alkaloids.²⁵² Other cases involve various immunosuppressive and antineoplastic agents, including thiopurine derivatives (azathioprine, mercaptopurine and 6-thioguanine), cyclophosphamide, mitomycin C, busulfan, carmustine, adriamycin, and intraarterial floxuridine.^{52,84,92,179,202} Two circumstances that are particularly implicated include azathioprine therapy in renal transplantation, and the intensive chemotherapy and irradiation conditioning regimes employed in bone marrow transplantation.^{137,173,176,177,241,252}

The Budd-Chiari syndrome denotes the occlusion, usually by thrombosis, of the large hepatic veins.¹⁸⁶ Drugs are not a prominent cause, although oral contraceptives and certain antineoplastic agents, including dacarbazine, doxorubicin, vincristine, and cyclophosphamide, have been implicated in some reports.^313,339

Sinusoidal dilatation has been noted with a variety of drugs. A curious periportal distribution of dilatation has been particularly associated with long-term oral contraceptive use.^334,339 Centrilobular sinusoidal dilatation, although described with many agents, is prominently noted with azathioprine and vitamin A, two agents that can also produce veno-occlusive disease, nodular regenerative hyperplasia, peliosis hepatis, and perisinusoidal fibrosis; these various lesions may share certain pathogenetic features.^{77,98,182,286}

Peliosis hepatis is characterized by blood-filled parenchymal cavities randomly scattered throughout the liver.³⁰¹ The major cause are androgenic steroids, particularly the 17-alkylated derivatives, but other cases have been attributed to corticosteroids, tamoxifen, hypervitaminosis A, azathioprine, 6-thioguanine, and exposure to arsenic, thorotrast, and vinyl chloride.^{54,56,150,167,205} Some examples have been related to oral contraceptives, although the association is controversial.³¹⁶

The portal veins are not commonly the targets of drug-related injury. Some cases of Budd-Chiari syndrome with portal vein thrombosis have been attributed to oral contraceptives.^111,314 In hepatoportal sclerosis, the small portal vein branches are sclerotic and narrowing, and accompanying portal, periportal, or pericellular fibrosis can be noted. Several agents have been implicated including chemotherapeutic drugs such as 6-thioguanine, hypervitaminosis A, and exposure to vinyl chloride and organic arsenicals.^12,274,306

Involvement of the hepatic arteries is uncommon, but several drug-induced lesions are described. Hepatic artery thrombosis has been associated with oral contraceptives and intraarterial perfusion with cancer chemotherapeutic agents.¹²² Oral contraceptives have also been related to arterial intimal hyperplasia, a lesion that may lead to multifocal hemorrhagic necrosis. The hepatic arteries can also display a necrotizing arteritis, similar to that found with polyarteritis nodosa; this is usually associated with a generalized vasculitis and is characterized by prominent eosinophils and, on occasion, with a granulomatous reaction. Among the incriminated drugs are phenytoin, allopurinol, penicillin, and the sulfonamides.^194,339

Several drugs have been implicated as causes of liver tumors. With some agents, the association is well established, but with most of the others, a causal relationship is more speculative.⁵

Hepatocellular adenomas are strongly associated with oral contraceptives (Figure 12-12). The risk increases with greater duration of use and is particularly strong after more than seven years of therapy.^110,111,253 Adenomas have also been reported in patients receiving long-term androgenic steroids, primarily the 17-alkylated derivatives.^{40,69,117,132}

Hepatocellular carcinoma is one of the neoplasms developing as a complication of thorotrast exposure. Androgenic and contraceptive steroids have also been implicated, although their etiologic roles remain controversial.^72,91,206

Other putative drug-induced neoplasms include cholangiocarcinoma, which has been associated with thorotrast and occasionally androgenic or contraceptive steroids, and angiosarcoma, occurring after exposure to thorotrast, vinyl chloride, or arsenical derivatives.^5,166

Phospholipidosis denotes the excessive accumulation of phospholipids in hepatocytes, Kupffer cells, and other hepatic cells, which imparts a swollen, foamy or granular appearance on histologic examination.²⁷³ The accumulation is best recognized, however, ultrastructurally by the presence of whorled lamellar inclusions within expanded lysosomes, producing an appearance resembling that seen in Niemann-Pick disease or Tay-Sachs disease.²³¹ It is seen with therapy by several drugs including amiodarone, perhexiline maleate, and 4,4'-diethylaminoethoxyhexestrol, and with total parenteral nutrition.^53,97,158 The consequences of phopholipidosis are not clear, but it forms the backdrop for the development of steatohepatitis in certain cases.

Certain drugs can also result in various hepatocellular accumulations. These include cytoplasmic inclusions as seen with cyanamide treatment, ground-glass cytoplasm as noted with phenobarbital therapy, and excessive lipofuscin as found with several drugs including phenothiazines and phenacetin.¹¹⁵

More than 600 drugs have been reported to produce hepatic injury, but the level of confidence in their hepatotoxicity varies considerable. Many of the agents have been the subject of only isolated reports, and liver biopsy specimens have either not been obtained or their histologic features are inadequately described. In other cases, confounding features hinder the evaluation; additional potential hepatotoxins have not been excluded, or the patients have concurrent hepatic disease unrelated to drug usage.

As a result, it is often difficult to assess the extent and nature of the liver damage produced by many agents. Nonetheless, authoritative compilations of drugs associated with hepatic injury have been offered and are summarized in the Appendix at the end of the chapter.^169,289,342 The table focuses primarily on agents available in the United States, although other drugs are listed when they are of historical or heuristic interest, and designates the major histologic patterns associated with each agent. Details about certain more notable drugs are provided below.

Acetaminophen. Although safe at usual therapeutic doses, acetaminophen can produce severe hepatic necrosis when excessive quantities are ingested. In most cases, a single overdose of more than 10 to 15 grams has been consumed, usually with suicidal intent. Lesser doses can, however, give rise to liver injury in particular setting such as chronic alcoholism or malnutrition.^236,267,340 The pathogenesis of the hepatic damage has been extensively studied, and the responsible mechanisms, although incompletely delineated, have been broadly established. A toxic quinoneimine intermediate is normally generated by the cytochrome P450-mediated biotransformation of the drug, but usually it is rapidly inactivated by conjugation with glutathione. When high doses of acetaminophen are encountered, however, hepatic glutathione stores are overwhelmed, and the reactive metabolite is then free to bind to hepatocellular proteins and cause cellular damage.²²

Clinical evidence of hepatic dysfunction does not develop until three to five days after the ingestion, following an initial phase of modest gastrointestinal complaints. Jaundice, hepatomegaly, and abdominal pain are present, and in severe cases, progress to fulminant hepatic failure. The serum aminotransferase and bilirubin levels are variably elevated, the prothrombin time is prolonged, and metabolic acidosis and hypoglycemia can be noted. The overall mortality rate is about 2%, but recovery is usually complete in nonfatal cases.^22,340

The histologic appearances provide a classic example of centrilobular confluent necrosis (Figure 12-13). Eosinophilic coagulative necrosis can be seen in the first four to six days after ingestion, but the affected hepatocytes quickly vanish, leaving zones of collapsed reticulin framework that are distributed uniformly across the liver. In severe cases, the necrosis can bridge centrilobular areas or extensively involve much of the lobule with focal sparing of the periportal parenchyma. Outside of the necrotic zone, inflammation is typically sparse, but mild fatty change or a mononuclear portal infiltrate is sometimes seen.^76,230

In a few reported cases, prolonged ingestion of acetaminophen has been associated with the development of chronic hepatitis.^22,128

Aspirin and Other Salicylates. Aspirin can cause hepatic injury when large therapeutic doses, typically exceeding two grams daily, are taken over several days or weeks. Younger patients with juvenile rheumatoid arthritis or systemic lupus erythematosus appear to be most susceptible. In general, the injury is mild, subclinical, and rapidly reversible if the drug is stopped, although more severe cases with encephalopathy are also reported.^236,340 A modest acute hepatitis is typically noted on liver biopsy, with occasional reports of a chronic active hepatitis-like pattern.²⁶⁶

Phenylbutazone. Hepatic injury caused by this agent generally appears during the first month of therapy, although the latent period may extend for up to one year. In about half the cases, manifestations of hypersensitivity such as fever, rash, or arthralgias are seen. The histologic features most often entail an acute hepatitis, mild to marked in degree and occasionally complicated by centrilobular necrosis. A cholestatic pattern is noted in other cases, and, on occasion, noncaseating granulomas can be present, particularly in cases with lesser degrees of acute hepatitis.¹⁷

Allopurinol. This drug can occasionally produce hepatotoxicity, particularly in individuals who are receiving diuretics or have impaired renal function. Liver damage, which usually arises within eight weeks of initiating treatment, is often associated with a systemic hypersensitivity syndrome that includes rash, fever, peripheral eosinophilia, and, in severe cases, vasculitis and renal failure. Histologically, centrilobular or extensive confluent necrosis is commonly found, with occasional examples of acute hepatitis. Other reports describe cholestatic hepatitis, and granulomas (including fibrin-ring granulomas) are identified in about half the cases, sometimes accompanied by acute cholangitis.^{3,100,298,318}

Dantrolene. This drug, a chemical relative of phenytoin, produces elevated serum aminotransferases in approximately 2% of treated patients, and a third of these develop overt liver disease. In most cases, hepatic injury arises only after six weeks of treatment. Several types of hepatocellular damage can be seen at liver biopsy, including acute hepatitis, confluent necrosis of varying degree, and chronic hepatitis or cirrhosis. Cholestatic hepatitis has been described in some instances.^312,332

Other Nonsteroidal Antiinflammatory Drugs. Several additional members of this pharmacologic family are potentially hepatotoxic; among those implicated are diclofenac, ibuprofen, indomethacin, naproxen, piroxicam, and sulindac.²³⁶ The incidence of liver injury with these agents generally appears to be low, although exact figures are not available. The reactions usually develop within the first few months of treatment, sometimes in association with manifestations of hypersensitivity, and are fatal in rare instances. The histologic findings are most often hepatitic in nature, ranging from an acute viral-like hepatitis to confluent or multilobular necrosis; chronic active hepatitis, cholestasis, and fatty change are also occasionally observed.^{82,226,265,329}

Hepatotoxicity is an infrequent complication of currently used anesthetic agents, but the most prominent offenders are the haloalkanes, with halothane being the most celebrated member.

Halothane. Halothane-induced hepatic injury can assume two different forms. A mild subclinical form, characterized by fever and elevated serum aminotransferases, occurs in approximately 25% of exposed patients, but is self-limited and of little consequence.²⁰⁷ The severe form, on the other hand, is associated with the development of overt, and frequently fatal, liver disease, but it is a rare complication with a prevalence estimated at one case in 10,000 to 35,000 anesthetic administrations. Patients manifest clinically with jaundice, tender hepatomegaly, myalgia, fever, and chills. These symptoms usually appear within two weeks post-operatively, but the latent period is significantly shorter in patients who have previously experienced halothane anesthesia. In serious cases, fulminant hepatic failure with encephalopathy, ascites, and coagulopathy, follows, and the mortality rate accordingly approaches 70%.²⁰⁷ The risk is increased by prior exposure to halothane, especially during the preceding three months, and obese, elderly women are particularly vulnerable.³⁴²

The pathogenesis of halothane-induced injury is much debated, and both direct toxicity and immunologically-mediated mechanisms have been advanced. The drug is metabolized by two distinct pathways, each of which is capable of producing reactive intermediates. These metabolites might then damage hepatocytes through free radical-related processes; alternatively, they could modify liver cell components, forming neoantigens that trigger an cytotoxic immunologic reaction.^55,138 Given the rarity of significant halothane toxicity, other factors must additionally contribute to individual susceptibility, whatever the exact mechanisms involved; possibilities include the degree of intraoperative hypoxia, variations in the activity of the metabolic pathways, and genetic differences in tissue susceptibility.⁶⁸

Characteristic histologic findings in severe cases entail confluent necrosis that varies from centrilobular to massive in extent and is often sharply demarcated from adjacent parenchyma (Figure 12-14). On occasion, the confluent necrosis exhibits a periportal distribution. In milder cases, an acute hepatitis resembling viral hepatitis is noted. Eosinophils are sometimes prominent, and fatty change, chronic hepatitis, or granulomas are described in sporadic instances.^16,145,269

Other Agents. Methoxyflurane and enflurane can cause hepatic injury that is clinically and pathologically analogous to that seen with halothane.^130,162

Phenytoin. Although phenytoin commonly induces minor liver enzyme abnormalities, clinically evident hepatic injury is much less frequent. Adults are more commonly affected than children, and the symptoms generally begin after two to four weeks of therapy. In addition to moderate to marked elevations of serum aminotransferases, the reaction is characterized by fever, rash, lymphadenopathy, eosinophilia, and lymphocytosis, sometimes with atypical lymphocytes; the clinical picture can resemble infectious mononucleosis. At liver biopsy, a histologic pattern of acute hepatitis is commonly present (Figure 12-15).¹⁹² This may be accompanied by prominent eosinophil infiltration, a mononucleosis-like sinusoidal pattern of lobular inflammation, microgranulomas, or epithelioid granulomas; portal tracts contain a prominent collection of lymphocytes, neutrophils, and eosinophils. In severe cases, confluent necrosis can be present and varies from centrilobular to multilobular in degree. Occasional reports describe chronic hepatitis, cholestatic hepatitis, or granulomatous vasculitis.^74,256,282

Valproic acid. Many patients treated with this agent develop transient and asymptomatic elevations of serum aminotransferase levels, but overt liver disease is uncommon with a prevalence of only about one of 10,000 to 49,000.^63,64 At greatest risk are infants and young children who are receiving other anticonvulsants. Clinically, the injury, which typically arises during the first six months of therapy, is characterized by nonspecific constitutional complaints followed by jaundice and, in severe cases, encephalopathy.²³³ The histologic hallmark is microvesicular fatty change combined with varying degrees of centrilobular confluent necrosis and cholestasis; in some cases, necrosis dominates the picture, and the distinctive steatosis is inapparent.^297,337,343

Penicillins. Natural pencillins are only rarely associated with hepatic injury, but occasional reports incriminate several of the semisynthetic derivatives including carbenicillin, cloxacillin, flucloxacillin, and oxacillin.^66,322,333 Although the histologic spectrum is not well defined, most of these cases primarily exhibit a cholestatic hepatitis. Amoxicillin is, by itself, not considered strongly hepatotoxic, but its combination with clavulanic acid can induce pure cholestasis or cholestatic hepatitis, sometimes with cholangitis or granulomas.^242,295,320

Erythromycin. Hepatic injury can complicate treatment with several erythromycin derivatives, including the ethylsuccinate, proprionate, and intravenous lactobionate compounds, but the best known culprit is the estolate ester. The clinical presentation typically entails jaundice, fever, and abdominal pain -- sometimes mimicking biliary obstruction -- together with peripheral eosinophilia. These features usually appear one to three weeks after exposure. At liver biopsy, cholestatic hepatitis with prominent portal eosinophilia is often observed, although other features including confluent necrosis or granulomas are noted in rare instances.^{59,81,248,338}

Tetracyclines. Large doses of tetracycline, particularly when given intravenously, can cause severe microvesicular fatty change with minimal necrosis or cholestasis. Pregnant women appear to be particularly susceptible, but other patient groups are not exempt. Clinical manifestations typically appear within ten days after treatment is begun and comprise nausea, vomiting, and abdominal pain followed, in severe cases, by hypotension, hemorrhagic complications, and coma.^223,342

Sulfonamides. Many members of this group are capable of producing hepatic injury, with recent interest focusing on the combined agent trimethoprim-sulfamethoxazole. The overall risk of hepatotoxicity is nonetheless low, estimated at about 0.5%. The clinical presentation is often distinguished by rash, fever, eosinophilia, or, in some cases, a serum sickness-like illness, usually appearing within the first six weeks of treatment. A wide range of histologic patterns have been described; the most common include acute hepatitis, confluent (sometimes massive) necrosis, pure cholestasis, and cholestatic hepatitis (Figure 12-16). The cholestatic reactions can exhibit a protracted period of recovery lasting as long as two years after discontinuation of therapy. Examples of chronic active hepatitis, fatty change, and granulomas have also been reported.^143,200,305

Nitrofurantoin. Hepatic injury, either acute or chronic in nature, is a rare complication of nitrofurantoin therapy; the frequency has been estimated at less than 0.04% of treated patients. Elderly women appear to be particularly susceptible, especially if they have been previously exposed to the drug. Acute injury is characterized by jaundice and hypersensitivity manifestations, usually developing within six weeks of treatment. The histologic picture varies from pure cholestasis or cholestatic hepatitis to acute hepatitis, centrilobular confluent necrosis or extensive hepatic necrosis.²⁹⁴ The abnormalities are generally reversible when treatment is withdrawn, but persistent administration can lead to chronic active hepatitis and cirrhosis. This development is typically associated with hypergammaglobulinemia and antinuclear or antismooth muscle antibodies, features that can lead to confusion with autoimmune chronic hepatitis.^271,294

Isoniazid. Transient and asymptomatic elevations of serum aminotransferase levels occur in up to 20% of individuals receiving isoniazid, but clinically overt hepatic injury is much less common, developing with frequency estimated at under 1%. The incidence of hepatotoxicity is age-related, being uncommon in those under 35 years and peaking in individuals aged 50 to 65 years of age, and is enhanced by concurrent administration of rifampin.^170,285 The pathogenesis of the damage involves the formation of a reactive acetyl intermediate during biotransformation of the drug; this metabolite can covalently bind to hepatic proteins, thus presumably causing cellular injury. Since the responsible metabolic steps are under genetic control, different individuals vary greatly in their susceptibility.¹⁷⁰

Both the clinical and the histologic features parallel the spectrum of changes seen in viral hepatitis. The acute presentation entails nonspecific gastrointestinal complaints and flu-like symptoms that may progress to jaundice and, in severe cases, hepatic failure. This usually develops within eight weeks of treatment, but it may be delayed for up to one year. Histologically, an acute viral-like hepatitis is commonly noted, sometimes complicated by the presence of cholestasis, bridging necrosis, or multilobular necrosis.¹⁹¹ In other cases, the clinical course is more prolonged, and chronic active hepatitis or cirrhosis are found.^24,170,184

Ketoconazole. This drug causes mild aminotransferase elevations in liver enzymes in about 10% of patients and gives rise to symptomatic hepatic injury with a frequency estimated at one in 2,000. Most reported cases have occurred in women over 40 years, typically after receiving the drug for less than six weeks, although latent periods of up to one year are described. The histologic features are often hepatitic in nature, ranging from acute hepatitis to confluent centrilobular or massive necrosis (Figure 12-17). Some cases, however, display a cholestatic reaction, either pure cholestasis or cholestatic hepatitis, and chronic active hepatitis has been uncommonly noted.^18,161,293

Methyldopa. As one of the classic causes of drug-induced hepatic injury, methyldopa is incriminated in a broad range of reactions. Asymptomatic increases in serum aminotransferase levels are noted in approximately 5% of treated individuals, but these usually disappear despite continued administration of the drug. Clinically evident liver disease, on the other hand, occurs in fewer than 1% and tends to be more common in women and patients over 35 years of age.^38,249

Acute hepatitis induced by methyldopa usually appears within the first 12 weeks of therapy. It is characterized by a clinical picture similar to that of acute viral hepatitis with nonspecific constitutional symptoms followed by jaundice, hepatomegaly, and moderate to marked elevations in serum aminotransferase values. Hypersensitivity manifestations are uncommon, but fulminant hepatic failure complicates the course in about 10% of cases. The histologic features consist of an acute hepatitis pattern with varying degrees of confluent bridging necrosis; extensive hepatic necrosis is seen in fatal cases.^7,38,249

In other cases chronic methyldopa-associated disease develops, typically as an insidious process after several months to years of treatment. Clinically the process can be indistinguishable from autoimmune chronic active hepatitis, including the presence of antinuclear and antismooth muscle antibodies, but it generally resolves upon withdrawal of the drug. At liver biopsy, marked portal and periportal inflammation with piecemeal necrosis are accompanied by varying degrees of bridging necrosis and fibrosis, in some cases resulting in established cirrhosis.^171,308

Amiodarone. This drug is strongly tissue-bound and can become concentrated, often in large quantities, in several sites including the liver. One frequent, and almost invariable, consequence of this accretion is the development of phospholipidosis. On light microscopy, this is characterized by a granular, foamy appearance, corresponding to the intralysosomal lamellar inclusions found by electron microscopy. The alteration results from the entrapment of amiodarone within lysosomes; the amphophilic molecule then binds to phospholipids, inhibiting their degradation and encouraging their excessive accumulation. Although phospholipidosis thus serves as a histologic marker of amiodarone administration, it is likely an incidental phenomenon with an uncertain relationship to hepatic injury.^97,158 Parenthetically, the high intrahepatic concentration of iodine-containing amiodarone can also produce an increase in hepatic density on computed tomography imaging.⁸⁸

Mild elevations of serum aminotransferase levels are noted in about 25% of treated individuals, although this is often transient and can resolve despite continued therapy. More striking hepatic disease occurs in an estimated 1% of patients after a latent period that varies between one month and several years.¹⁵⁹ The clinical presentation can include nonspecific constitutional complaints, hepatomegaly, or jaundice; in other examples, however, the disease has evolved insidiously and is recognized only by laboratory abnormalities. Cessation of therapy leads to regression of the hepatic injury, but, because of the long biologic half-life of the agent, several months may be required before improvement begins. If the drug is not withdrawn, the process can progress to cirrhosis, and death from hepatic failure can follow.

The histologic picture constitutes a classic example of drug-induced steatohepatitis (Figure 12-18). Hepatocyte swelling, Mallory bodies, fatty change, and neutrophil infiltration are combined with varying degrees of fibrosis or even cirrhosis.^{158,231,247,277} In sporadic cases, centrilobular confluent necrosis or cholestatic hepatitis have been reported.²⁸⁷

Other Drugs. Several additional agents used in cardiovascular disease are incriminated as causes of hepatic injury, although this is generally an infrequent complication of therapy. Often the injury is hepatitic in nature, as noted with the hydralazines and, in rare cases, beta-adrenergic blockers such as labetolol.^44,342 On the other hand, cholestatic injury is seen with others agents including captopril and verapamil.^15,36,95,238 Diuretics, despite their widespread use, are only rarely reported to produce hepatotoxicity. A notorious exception, however, is tricrynafen, which induced severe confluent necrosis and was consequentially withdrawn from clinical use in the U.S.³⁴⁵

Estrogenic steroids. Estrogens, primarily in the form of oral contraceptives, are responsible for several pathologic conditions, including cholestasis, vascular disorders, and neoplasms.¹¹¹

Although estrogen therapy commonly produces a mild and clinically insignificant disruption of bile secretion, the result in rare cases is overt cholestasis. This complication is seen with all estrogens, particularly the 17-ethinyl substituted derivatives, and develops in an estimated one in 10,000 U.S. women on oral contraceptives. An underlying genetic susceptibility to estrogens is probably responsible, as suggested by the familial predisposition and the association with another estrogen-related disorder, intrahepatic cholestasis of pregnancy.²⁴⁴

The clinical features entail pruritus, anorexia, and mild jaundice, typically appearing during the first two months of use, together with modest elevations of serum alkaline phosphatase and bilirubin levels. These findings generally resolve within three months of discontinuing therapy, although the recovery period may be prolonged in some instances.¹⁶⁴ The histologic features represent the prototype of pure cholestasis: Canalicular cholestasis accompanied by minimal or no portal inflammation or hepatocyte injury.³⁴⁴

Vascular lesions of several types have been attributed to estrogens. Periportal sinusoidal dilatation is identified in up to 50% of oral contraceptive users, but, except for mild hepatomegaly, it gives rise to few clinical manifestations.^313,334 Several cases of peliosis hepatis have been linked to estrogens, but a causal relationship is not clearly established.³¹⁶ The risk of Budd-Chiari syndrome is estimated to be increased 2.5-fold among individuals receiving contraceptive steroids, and thus hepatic vein thrombosis might represent another manifestation of the thrombogenic action of estrogens.^313,314 Lastly, estrogens have been associated with intimal hyperplasia and thrombosis of the hepatic arteries.¹²²

Convincing evidence links contraceptive steroids with hepatocellular adenomas. These tumors were rare before the widespread availability of oral contraceptives, and the relative risk of their development rises with duration of contraceptive use, ranging up to a 500-fold increase among long-term users.^110,253 Various case reports and epidemiologic investigations have related contraceptive steroids with a variety of additional neoplasms, including focal nodular hyperplasia, hepatocellular carcinoma, cholangiocarcinoma, angiosarcoma, and epithelioid hemangioendothelioma. However, the data are sparse and subject to interpretation, and these associations remain controversial.^{5,91,166,188,206}

Androgenic Steroids. Most of the hepatic toxicity of androgenic steroids is associated with the orally administered, 17-alkylated synthetic derivatives used an anabolic agents.¹¹⁷ On occasion, however, other types have also been implicated, particularly when used in high doses.

Androgens can cause a cholestatic reaction that is clinically and histologically similar to that seen with contraceptives steroids. This occurs in a small minority of treated patients, although, as with estrogens, most individuals develop mild, subclinical hepatic dysfunction. Cholestasis typically appears after two to five months of therapy and is clinically characterized by anorexia, jaundice, and, less commonly, pruritus.¹¹⁷ Histologically, the appearances are those of pure cholestasis. With cessation of therapy, the condition recovers completely over several months; although rare cases evolving to chronic cholestasis have been reported, this is not a well-established outcome.⁸⁶

The primary androgen-induced vascular disorder is peliosis hepatis. This complication, which is not clearly related to either the dosage or duration of treatment, typically develops insidiously, but it may manifest by hepatomegaly, life-threatening hepatic rupture, or liver failure. Although many reported cases have had fatal outcomes, the process can regress if therapy is stopped.^199,313,339

Both hepatocellular adenomas and carcinomas have been associated with androgen therapy. The adenomas are often multiple and may therefore be difficult to distinguish from cases of nodular regenerative hyperplasia. Typically they produce no symptoms, and rupture is an uncommon complication.^40,117 Many of the reported carcinomas, despite their histologic characteristics, have behaved in a benign fashion. They often demonstrate an indolent long-term course, rarely exhibit metastases or vascular invasion, and can regress with discontinuation of therapy, although exceptions with a more aggressive natural history have been described.^5,175 Sporadic examples of angiosarcoma or cholangiocarcinomas have also been attributed to androgenic steroids.¹¹⁷

Oral hypoglycemic drugs. Overall these agents are free of hepatotoxicity, although several of the sulfonylureas have been implicated. Chlorpropamide is the most prominent offender with a prevalence of hepatic injury estimated at about 1%. The reaction, which typically arises during the initial eight weeks of therapy, is usually cholestatic in nature and accompanied by hypersensitivity manifestations. The typical histologic pattern consists of cholestatic hepatitis or, less often, pure cholestasis.²⁶⁴ A similar clinicopathologic picture has occasionally been reported with acetohexamide, glyburide, tolazamide, and tolbutamide, but these drugs can also cause an acute hepatitis or, rarely, chronic hepatitis or cholestasis.^30,90,240

Antithyroid drugs. Hepatic injury is an uncommon complication of therapy with this groups of agents. Propylthiouracil can produce a range of hepatitic reactions including severe and fatal confluent necrosis; acute or chronic hepatitis have also been noted.^101,165 In contrast, the thioimidazoles, including carbimazole and methimazole, tend to provoke a cholestatic hepatitis, often mild in degree and occasionally accompanied by fatty change or granulomas.^26,208,210

The liver is surprisingly resistant to this group of otherwise potent drugs. Although therapy with many such agents is accompanied by liver enzyme abnormalities, a distinct, primary association with clinically significant hepatic injury is much less often established. The cause of this lack of vulnerability is not known, but the liver's low proliferative rate and facility for drug detoxification are probably key factors.^217,341

Methotrexate. This drug is a well-established cause of hepatic fibrosis and cirrhosis. These complications are best recognized following long-term use of the agent in inflammatory disorders such as psoriasis and rheumatoid arthritis, although cases have also followed administration for neoplastic diseases. The risk of liver damage depends largely on the dose, duration, and timing of therapy. In prospective studies, up to 25% of patients receiving a cumulative dose of 1.5 to 2 grams over five years have developed fibrosis or cirrhosis.^144,160 The risk appears to be lessened by weekly, as opposed to daily, administration of the drug, and exacerbated by concomitant obesity or alcohol abuse.^147,309

Methotrexate-induced hepatotoxicity is often clinically silent and, even in advanced disease, can exhibit an indolent clinical course. Evidence of portal hypertension or liver failure can nonetheless develop in some cirrhotic cases and may lead to death or the necessity for liver transplantation.⁸³ Laboratory studies are also inadequate indicators of the degree of the liver damage; normal values are sometimes noted in the face of severe histologic disease. As a result, current recommendations for patient monitoring include routine liver biopsy, both before treatment is started and then regularly during therapy, either at yearly intervals or after every 1.5 grams administered.^104,250

The histologic picture is composed of varying degrees of three main features: fatty change, nonspecific reactive alterations, and fibrosis (Figure 12-19).^{209,227,251,309} Macrovesicular steatosis is the rule, although on occasion, microvesicular fat droplets and hypertrophied, lipid-laden Ito cells can also be identified.¹⁰⁸ The various reactive changes include scattered hepatocyte necrosis with focal clusters of Kupffer cells, hyperchromatic and pleomorphic hepatocyte nuclei, and portal tract infiltration principally by mononuclear cells. In some cases, a dense portal inflammation can extend into the periportal zone in a piecemeal necrosis-like fashion.²⁰⁹ The fibrosis begins as irregular periportal spurs and progresses with portal-portal and portal-central bridging to eventuate in cirrhosis. In addition, pericellular fibrosis may be present and, by electron microscopy, can be identified even in histologically normal specimens.^6,21

For purposes of clinical decision-making, liver biopsy findings have been classified into four pathologic grades.²⁵⁰ Although this system suffers from several limitations, it has been widely used and therefore warrants attention. Grade I specimens are normal or show only mild fatty change or reactive changes; Grade II specimens show moderate to severe fatty change or reactive changes; Grade III specimens show fibrosis, either mild periportal involvement (Grade IIIA) or moderate to severe involvement (Grade IIIB); and Grade IV specimens are characterized by cirrhosis. The general recommendation is that methotrexate should be stopped in patients with grade IIIB or IV specimens and cautiously continued, with rebiopsy in six months, in patients with grade IIIA specimens.

Azathioprine. Hepatic injury produced by this agent can assume several different forms. An etiologic relationship is sometimes difficult to confirm, however, because, in the circumstances in which the drug is used, there are numerous other confounding causes of liver damage.

A cholestatic hepatitis has been described in several case reports. This process, generally attributed to an idiosyncratic reaction, appears after one to two months of therapy in most cases and rapidly regresses upon cessation. Histologically it is characterized by severe canalicular cholestasis and varying portal and lobular inflammation. Confluent centrilobular necrosis is an occasional accompaniment, although it can also occur as an isolated lesion.^{51,57,239,286}

Various vascular disorders constitute another group of azathioprine-related hepatic injury. Veno-occlusive disease has been recognized in several patients -- most of them renal transplant recipients -- after a treatment interval lasting anywhere from three months to nine years.^137,173,241 The clinical presentation involves jaundice and evidence of portal hypertension with hepatosplenomegaly, ascites, and esophageal varices. Although often fatal, the condition may partially regress with withdrawal of the drug, particularly in nonfulminant cases, and can recur with its readministration.

Other vascular lesions associated with azathioprine include peliosis hepatis and sinusoidal dilatation.^54,77,98 Although these can occur alone, they are also found in various combinations and can also be accompanied by nodular regenerative hyperplasia or pericellular fibrosis.^28,183 Because of the close affiliations among these various lesions, they have been proposed to represent a single pathogenetic complex, all manifestations of primary damage to the vascular endothelium. Which lesion develops would then depend on the level of damage; veno-occlusive disease might follow involvement of central vein endothelium, whereas sinusoidal dilatation and, later, peliosis hepatis could derive from involvement of the sinusoidal endothelium.^98,286

Other Drugs. Mercaptopurine and 6-thioguanine, two drugs chemically related to azathioprine, can cause confluent necrosis, often combined with cholestasis, and have also been associated with veno-occlusive disease.^217,341

Floxuridine administered via the hepatic artery for treatment of liver metastases can produce sclerosing cholangitis. The large bile ducts are primarily involved, and therefore this complication is best recognized by cholangiography, although it may be difficult to distinguish from primary sclerosing cholangitis. Liver biopsy specimens exhibit the usual changes of biliary obstruction -- in effect, a cholestatic hepatitis -- which can progress to biliary cirrhosis.^61,107,224

Numerous additional chemotherapeutic agents, used either singly or as part of a combined regimen, have been implicated as causes of hepatic injury in sporadic reports. The incriminated drugs encompass a broad pharmacologic range and include chlorambucil, cisplatin, cytosine arabinoside, dacarbazine, etoposide, mitramycin, mitomycin, and the nitrosoureas.^217,341 The histologic features are variable, but generally involve various forms of acute hepatitis, cholestatic hepatitis, and confluent necrosis. Veno-occlusive disease is additionally recognized as a complication treatment with cytosine arabinoside, dacarbazine, mitomycin, and nitrosureas.^313,339

Phenothiazines. Cholestatic hepatitis caused by chlorpromazine is one of the best known examples of drug-induced hepatic injury. Although mild abnormalities in liver enzymes develop in many treated patients, clinically evident disease occurs in less than 1%.³⁴² The presentation entails a nonspecific prodromal phase followed by jaundice and often pruritus, typically developing during the first month of therapy. Serum alkaline phosphatase levels are notably elevated, and mild to moderate increases in aminotransferase activity are noted.

The histologic features constitute a classic picture of cholestatic hepatitis (Figure 12-20). Canalicular cholestasis is conspicuous, particularly in the centrilobular region, and is accompanied by mild hepatocyte injury and lobular inflammation. The portal tracts acquire an inflammatory infiltrate, often containing eosinophils, and display proliferated bile ductules with accumulated neutrophils; the portal inflammation tends to be more prominent early in the course. In rare cases, confluent necrosis has been noted.¹¹³

Most patients recover completely within several months when therapy is stopped, but in a few instances, a chronic cholestatic syndrome develops. Although this is often nonprogressive, it may evolve to biliary cirrhosis.^113,323

Other phenothiazines, including fluphenazine, prochloperazine, and thioridazine, are also reported to be hepatotoxic, although this appears to be an uncommon complication. In most cases, they produce a cholestatic hepatitis picture similar to that seen with chlorpromazine.^113,279,342

Tricyclic Antidepressants. This group of drugs, including amitriptyline and imipramine, rarely produces overt hepatic injury, although minor abnormalities in liver enzymes are noted in up to 10% of patients. The principal histologic pattern is cholestatic hepatitis, but acute hepatitis and confluent necrosis, sometimes resulting in death, are described in several cases. On occasion, chronic cholestasis with progressive bile duct loss and fibrosis has followed discontinuation of treatment.^{35,50,109,148}

Other Drugs. One of the monoamine oxidase inhibitor family of antidepressants, iproniazid, has been withdrawn from clinical use because it produces confluent necrosis with a fatality rate of up to 20%.³⁴² With other such agents, hepatic injury is less common, although iproclozide and tranylcypromine have been associated with acute and cholestatic hepatitis.^221,289

The benzodiazepines are rarely hepatotoxic. In sporadic cases, diazepam and flurazepam has been associated with varying patterns of hepatitic and cholestatic injury.^245,302

Vitamin A. Hepatic injury is a well-recognized complication of chronic hypervitaminosis A. The ingestion of large doses, 100,000 IU or more per day, over weeks to months has typically held responsible, although increasing evidence indicates that moderate doses in the range of 20,000 IU to 40,000 IU daily can, over several years, also cause liver damage.^78,155,182 By contrast, the recommended daily intake is about 3,000 IU.

Some patients are asymptomatic and are identified only because of mild to moderate elevations of serum aminotransferase or alkaline phosphatase levels. In other cases, however, clinically evident liver disease develops with nonspecific systemic complaints, hepatomegaly, or evidence of portal hypertension, even in the absence of cirrhosis. Increased plasma levels of retinols or retinol-binding proteins are sometimes found, although normal values do not exclude the diagnosis. Treatment involves withdrawal of the vitamin A; this typically produces a slow biochemical recovery, but may not prevent histologic progression.^78,155

The histologic hallmark of vitamin A toxicity is hyperplasia and hypertrophy of the Ito cells (perisinusoidal lipocytes). These cells are recognized by their characteristic multivacuolated appearance and sinusoidal location, but they can easily be overlooked in routine sections. Their presence can be confirmed in frozen sections by the transient green fluorescence they exhibit under ultraviolet light; with unstained, deparaffinized sections, cytoplasmic fluorescence can sometimes be detected, but it is not an invariable finding.⁹⁶ Moreover, Ito cell hyperplasia is not specific for vitamin A toxicity, but can be seen in a variety of conditions including therapy with methotrexate or corticosteroids and the administration of intravenous fat emulusions.

The Ito cell alterations are accompanied by focal collections of lobular inflammatory cells and varying degrees of pericellular fibrosis (Figure 12-21).^20,182 This fibrosis may be irregularly distributed across the lobule, but it can extend to the centrilobular area, producing perivenular fibrosis and central vein obliteration resembling veno-occlusive disease. Sinsuoidal dilatation is occasionally noted, and peliotic changes can be seen.³³⁶ Advanced disease is characterized by the formation of fibrous septa, which may also harbor hypertrophied Ito cells, and in rare instances, progression to cirrhosis has been reported.^123,260

Total parenteral nutrition. One of the chief complications of this technique of nutritional maintenance is the development of hepatobiliary dysfunction.^10,11,235 This problem is more common in infants and children, particularly premature newborns, but adults are not exempt. The prevalence, however, is not well defined. Abnormalities in liver enzymes have been reported in anywhere between 10% and 100% of treated pediatric or adult patients, but histologic confirmation is available in only a minority of cases. The issue is further confused because patients who receive total parenteral nutrition are, simply because of their clinical condition, subject to a wide range of additional injurious agents.³³⁵ The pathogenesis of the hepatic injury is therefore uncertain, although many possibilities are suggested, and is likely multifactorial in nature.

A range of morphologic alterations can be encountered, and the predominant histologic patterns differ somewhat between pediatric and adult cases.

Cholestasis is the leading abnormality in infants and children, and its incidence correlates inversely with gestational age and birth weight.³²⁸ Although pure cholestasis can be seen early in the course, the more typical picture is one of cholestatic hepatitis. Accompanied by varying degrees of canalicular cholestasis, the portal tracts exhibit bile ductular proliferation, sometimes embellished by ductular cholestasis, and an inflammatory infiltrate composed principally of lymphocytes with scattered neutrophils and eosinophils (Figure 12-22). Fatty change may be present, and clusters of ceroid-laden Kupffer cells or foci of extramedullary hematopoiesis are often conspicuous. Multinucleated giant hepatocytes are an inconstant finding. Variable portal and periportal fibrosis develops; progression to portal-portal bridging fibrosis and cirrhosis is described in several cases, usually after more than three months of treatment.^47,49

In adults, fatty change is the predominant histologic pattern early in the course, typically appearing during the first two weeks of therapy. The steatosis varies from mild to severe in degree and often displays a predominantly periportal distribution.¹⁰ With longer-term therapy, several patterns can develop. A cholestatic hepatitis similar to that seen in infants has sometimes been noted, but seldom leads to chronic progressive liver disease. In certain cases, this picture might result from additional, biliary-related complications of total parenteral nutrition, specifically, cholelithiasis or biliary sludge formation.¹⁸¹

Other adult patients develop steatohepatitis with fatty change, hepatocyte swelling, lobular inflammation, and pericellular fibrosis.^27,48 These patients have generally required hyperalimentation because of an extensive loss of functioning small bowel; hence the pathogenetic contribution of total parenteral nutrition cannot be clearly separated from that of a shortened intestine, which, in the form of jejuno-ileal bypass, can also cause steatohepatitis. Another feature of long-term parenteral nutrition is phospholipidosis, similar to that seen, for example, with amiodarone therapy. The consequences of this change are not known.⁵³