Drug-induced Liver Disease

Hepatic Diseases

0025--7125/89 $0.00

+

.20

Drug-induced Liver Disease lames H. Lewis, MD, * and Hyman]. Zimmerman, MDt

Hepatic injury represents a relatively small proportion of all adverse effects from medicinal agents. 26, 106 However, drugs are responsible for 2 to 5 per cent of hospital admissions for jaundice in the United States37. 60 and account for approximately 10 per cent of hospitalized cases of "acute hepatitis" abroad.6.21 The relative importance of drug-induced liver disease (DILD) assumes an even greater significance among certain groups of patients. For example, in the geriatric population, a 20 per cent incidence of drug-induced jaundice has been described. 23 In a recent report from France, drugs were responsible for 43 per cent of admissions of "acute hepatitis" in patients over 50 years of age. 6 Among the causes of fulminant hepatic failure, certain drugs (for example, halothane, acetaminophen, phenytoin, and alpha-methyldopa) account for 20 to 50 per cent of cases. 10.106 Many agents cause only subclinical injury as reflected by abnormal liverassociated enzymes. The estimated prevalence of such subclinical DILD as well as overt hepatitis or jaundice varies from agent to agent as listed in Tables 1 and 2. In general, DILD is less common in children compared to adults. 106 Notable exceptions include valproic acid (VPA)108 and salicylate-induced injury.107 The vast majority of cases of DILD occur as unexpected reactions to a therapeutic dose of a drug and much less commonly as a predictable consequence of the intrinsic toxicity of certain agents taken in sufficiently large doses to produce liver damage. Factors affecting susceptibility to DILD are diverse and will be discussed below.

SPECTR UM OF DILD Drugs produce a wide array of hepatic lesions and may mimic many clinical syndromes. The liver may be the only organ involved or it may be accompanied by injury to other organs and by a variety of extrahepatic manifestations (Table 3). DILD may develop within days of exposure to a known (intrinsic) hepatotoxin; after 1 to several weeks of taking a drug producing a hypersensitivity reaction (drug allergy); or after weeks to months of taking a drug that causes injury as a result of metabolic idiosyncracy (see mechanisms). *Associate Professor of Medicine, Division of Gastroenterology, Georgetown University School of Medicine and Hospital, Washington, DC tProfessor of Medicine, George Washington University School of Medicine; Distinguished Physician, Veterans Administration Medical Center; and Distinguished Scientist, Division of Hepatic Pathology, Armed Forces Institute of Pathology, Washington, DC

Medical Clinics of North America-Vo!' 73, No. 4, July 1989

775

776

JA'"IES H. LEWIS AND HY'>IAN J. ZIM'>IERMAN

Table 1. Estimated Prevalence of Subclinical Hepatic Enzyme Elevations with Various Drugs* Chlorpromazine, TAO, phenytoin, amiodarone, perhexiline, papaverine, cisplatin, nicotinic acid, valproate, heparin, nafcillin, 6-MP INH, ketoconazole, androgens, erythromycin estolate, etretinate Penicillamine, chenodeoxycholate, fiucytosine, disulfiram Salicylates, gold salts, sulfonamides, dantrolene, sulfonylureas, quinidine, thiabendazole, ticarcillin, tricyclic antidepressants, ethionamide

20-50% 10-20% 5-10% <5%

*Percentages listed are generally the highest reported in the literature. TAO = triacetyloleandomycin; INH = isoniazid.

Acute DILD Acute hepatic injury may be cytotoxic (overt damage to hepatocytes), cholestatic (arrested bile flow), or mixed (simultaneous features of cytotoxic and cholestatic injury). As is evident in Table 4, a limited relationship exists between the category of a drug and the type of injury it produces. Clinical jaundice is an inconstant feature of acute liver injury and depends on the degree of parenchymal damage and the integrity of the bile excretory system. Overt jaundice due to drug-induced cytotoxic injury is generally associated with a mortality rate of 10 per cent or more. 106 In contrast, acute cholestatic injury is rarely fatal. Morphologically, cytotoxic injury includes hepatocellular necrosis (zonal, diffuse, or massive), degeneration, or steatosis (both macro- and microvesicular). The syndrome of drug-induced hepatic necrosis resembles acute viral hepatitis with levels of aminotransferases (AST and ALT) elevated eight- to SOD-fold and alkaline phosphatase (AP) levels usually less than threefold. Acute steatosis leads to clinical, morphologic, and biochemical features that resemble acute fatty liver of pregnancy or Reye's syndrome. Acute drug-induced cholestatic lesions are now recognized to be in greater variety than before. ,og Many cholestatic agents produce injury that resemble extrahepatic obstructive jaundice clinically and biochemically. Jaundice and pruritus are the main clinical manifestations, with aminotransferase levels only modestly elevated while AP levels are raised more than threefold. Several other categories of cholestatic injury are given in Table S. The prognosis for complete recovery for patients who survive acute DILD, including fulminant hepatic injury, is good. Chronic liver damage is a rare sequel to acute cytotoxic or cholestatic injury after the drug is withdrawn. Recovery from jaundice due to some cytotoxic agents (for example, ketoconazole,9 halothane 63) may be prolonged, and a syndrome of chronic intrahepatic cholestasis mimickiillg primary Table 2. Estimated Frequency of Overt Hepatitis or Jaundice from Medicinal Agents >2% 1-2% 1% 0.5-1% 0.1-0.5% <0.01% <0.001% <0.0001%

PAS, TAO, dapsone, chenodeoxycholate Lovastatin, cyclosporine, dantrolene INH, PAS, amiodarone Phenytoin, sulfonamides, chlorpromazine Gold salts, salicylates, methyldopa, chlorpropamide, E. estolate Ketoconazole, contraceptive steroids Hydralazine, halothane Penicillin, enfiurane, cimetidine, ranitidine

PAS = para-aminosalicylate; TAO = triacetyloleandomycin; INH

isoniazide.

777

DRUG-INDUCED LIVER DISEASE

Table 3. Clinical Syndromes Caused by Acute Hepatotoxins Fever, rash, eosinophilia Acute viral hepatitis Obstructive jaundice Pseudomononucleosis Serum sickness syndrome Autoimmune hemolysis Muscular syndrome* Antinuclear antibodies Associated marrow injury Associated pulmonary injury Associated renal injury Fatty liver of pregnancy Bland jaundice

CPZ, PBZ, halogenated anesthetics INH, halothane CPZ, erythromycin estolate DPH PAS, DPH, sulfonamides Methyldopa, oxyphenisatin Clofibrate Procainamide Anticonvulsants, gold salts, propylthiouracil, PBZ, chloramphenicol Amiodarone, nitrofurantoin Methoxyflurane, gold salts, penicillamine, paraquat Tetracycline C-17 steroids, rifampicin

* Myalgia, stiffness, weakness, elevated creatine phosphokinase. PAS = para-aminosalicylate; CPZ = chlorpromazine; PBZ = phenylbutazone; INH isoniazid; DPH = diphenylhydantoin.

biliary cirrhosis (PBe) has been reported to evolve from acute cholestasis induced by chlorpromazine (CPZ), amitriptyline, and other agents. 109

Chronic DILD Injury from drugs also includes chronic necroinflammatory disease, chronic steatosis, pseudoalcoholic liver disease, chronic cholestasis, granulomatous disease, vascular injury, cirrhosis, noncirrhotic portal hypertension, and several types of hepatic tumors. Chronic necroinflammatory disease resembles "autoimmune" chronic active hepatitis in many respects, including a female predominance, the presence of autoimmune markers (antinuclear and smooth muscle antibodies), hyperglobulinemia, and morphologic features.105 Frequently incriminated drugs are listed in Table 6. Chronic steatosis, in contrast to the acute form, tends to have few clinical manifestations; hepatomegaly may be the only feature. 106 Exceptions appear to be chronic steatogenic injury produced by VPA and amiodarone (AD) that may result in chronic liver failure with encephalopathy and a fatal outcome. 51. lOB Drug-induced chronic cholestasis (DICe) leading to a syndrome resembling PBC has become a recognized, albeit rare, sequel of acute hepatocanalicular cholestasis due to phenothiazines (CPZ, prochlorperazine, haloperidol), organic arsenicals, cyproheptadine, tolbutamide, thiabendazole, ajamaline, and amitriptyline, among others. 109 The drug-induced syndrome usually presents with acute jaundice that remains prominent throughout the illness. In contrast, jaundice is generally a late feature of PBC. In addition, DICC may be accompanied by ductal injury or a reduction in the number of bile ducts resembling the histologic injury of PBC. Most important, the prognosis of the DICC syndrome is better than that of PBC in that recovery is the rule in many cases. A second form of DICC results from injury to the ductal system provoked by the infusion of oncotherapeutic agents such as fluorodeoxyuridine into the hepatic artery for the treatment of liver metastases. The resulting biliary sclerosis is clinically, radiographically, and histologically identical with sclerosing cholangitis. 14 Phospholipidosis (PL) is a lesion that has attracted recent attention as a consequence of its association with several antiarrhythmic drugs used in coronary artery disease, most notably Coralgil in Japan (4,4' -diethylaminoethoxyhexestrol [DEAl),87 perhexiline maleate (PH M) in Europe,46. 71 and AD in the United States

778

JA.\1ES H. LEWIS AND HYMAN J. ZIMMERMAN

Table 4. Types of Acute Hepatic Injury Caused by Drugs in Various Therapeutic Categories CYTOTOXIC

Anesthetics

CHOLESTATIC

~IXED*

Enflurane Fluroxcne

Halothane Isoflurane? Methoxyflurane Neuropsychotropics

Anticonvulsants

Analgesic,

antiinfiammatory, antimuscle spasm,

antigout agents

Cocaine

Hydrazides ~iethylphenidate Tricyclics (most)

CPZ Haloperidol

Trimipramine

PhenytOin Progabide Valproatet Acetaminophen

Chlorzoxazone Clomatadne

Dantrolene Diclofenac Fenclozic acid Ibuprofen Indomethacin Salicylates Pirprofen Tolmetin

Chlordiazepoxide Diazepam

Trazodone

Tricyclics (some) Carbamazepine Phenobarbital

Benoxaprofen Diflunisal

Allopurinol Gold compounds

Propoxyphenc

Phenylbutazone

Penicillamine

Naproxen

Piroxicam

Sulindac

Zoxazolamine

Hormonal derivatives

and drugs used in endocrine disease

Acetohexamide Carbutamide Cyclofeuil Glipizide Metahexamide Propylthiouracil

Tamoxifen

Diethylstilbesterol

Antimicrobials

Amphotercin B Antimonials

Clindamycin Hycanthone Hydroxystil-bamidine Idoxyu;ide Ketoconazole

Mebendazole Mepacrine

Metronidazole Novobiocin

Oxacillin PAS Penicillin (very rare) Rifampicin Sulfonamides Sulfones Tetracyclinet

Thiosemicarbazone

Zidovudine?

Carhimazole Chlorpropamide Tolazemide Tolbutamide Methimazole Methylthiouracil Anabolic and

Thiouracil

Carbenicillin Erythromycin estolate E. proprionate E. ethysuccinate

Cephalosporins (very rare) Chloramphenicol Nitrofurantoin Penicillins Triacetyloleandomycin Sulfamethoxazoletrimethoprim Sulfadoxine-pyrimethamine

Contraceptive steroids

Organic arsenicals

Thiobendazole Xenelamine

779

DRUG-INDUCED LIVER DISEASE

Table 4. Types of Acute Hepatic Injury Caused by Drugs in Various Therapeutic Categories (Continued) CYTOTOXIC

Drugs uscd to treat cardiovascular disease

Amiodarone+ Apridinc Diltiazem Alpha-methyldopa Mexiletine Hydralazine Dihvdralazine N ic~tinic acid Nifedipine

CHOLESTATIC

Ajrnaline Captopril Chlorthalidone

~lIXED*

Amrinone Disopyramide

Coumadin

Phenindione Prajmaline Thiazides Verapamil

Papaverine

Perhexiline:j:

Procainamide

Quinidine Ticrvnafen

Toc~inamide

Antineoplastic and

immunosuppressive§

Asparaginaset Cis-platinum Cyclophosphamide Dacarbazine DES

Arninoglutethamide Busulfan 5-Floxuridine

Azathioprine

Propoxyphene Rapeseed oil-aniline Methylene dianiline

Cimetidine Ranitidine Etretinate

Doxorubicin Fluorouracil

Methotrexate# N-methvl-formamide

'Jithra~ycin

6-MP

Nitrosoureas

Tamoxifen

Thioguanine Vincristine

Miscellaneous

Disulfiram Iodide ion Oxyphenisatin Salizopyridine

Tannic acid

Vitamin A

Para-aminobenzoic acid

*Mixed forms of injury are categorized according to the predominant injury as cytotoxic or cholestatic. tMicrovesicular steatosis. Valproate injury also includes necrosis in some cases. :j:Also leads to phospholipidosis and changes resembling alcoholic liver disease. §Some of their agents alone or as combinations lead to veno-occlusive disease. # Macrovesicular steatosis.

and abroad. 44 A number of other agents also lead to PL as an intrinsic property of their cationic amphiphilic structure. 53 Morphologically, PL is characterized by whorled lamellated lysosomes packed with phospholipid as seen on electron microscopy. Hepatocytes and Kupffer cells containing the engorged liposomes are seen on light microscopy and resemble those seen in Tay-Sachs, Neimann-Pick, and other inborn PLs. PL is thought to be the result of binding of phospholipids within the lysosome by the amphiphilic drug molecule. Intralysosomal retention of phospholipid appears to be abetted by inhibition of phospholipases. 31 • 77 Clinical manifestations of hepatic PL are minimal with hepatomegaly predominating. Indeed, other organ involvement (for example, lung, thyroid, nerves, skin, and eye) may overshadow the liver disease. 5.5

00

-:t

o

Indirect Cytotoxic

Intrinsic Toxicity Direct

CATEGORY

Interference with specific metabolic pathways leading to structural injury

Direct physicochemical destruction or distortion of cells

MECHANISMS

1-2X

1-2X

1-2X

5-20X

1-3X

1-2X

Alk Phos

8-500X

8-500X

ASTIALT

Steatosis (macrovesicular)

Steatosis (microvesicular)

Necrosis

Necrosis andlor steatosis

Histology

BIOCHEMICAL ABNORMALITY*

Fatty liver of pregnancy, Reye's syndrome Few manifestations

Severe viral hepatitis-like illness

Hepatic, renal failure

CLINICAL ASPECTS

Table 5. Classification of Acute Hepatotoxic Agents

High

10-50%

High

MORTALITY

MTX, ethanol

Valproate, ethionine, tetracycline

INH, DPH, halothane, ACM, 6MP, ticrynafen, ketoconazole, methyldopa, dantrolene

CCl" CHCI 3 , phosphorus

EXA~IPLES

~ ......

-l

Variable

Production of hepatotoxic metabolites

*Fold increased above normal. tMortality due to other factors.

Metabolic abnormality

Host Idiosyncracy Hypersensitivity Drug allergy

Mixed Injury

Septal ducts

Variable Variable

Variable

Variable

Variable

Variable

Necrosis or cholestasis Necrosis or cholestasis Variable

Variable

Jaundice Primary biliary cirrhosis Sclerosing cholangitis May resemble viral hepatitis or obstructive jaundice

3-lOX

1-5X

Ductal Inspissated bile Destruction of portal area ducts Fibrosis of septal ducts Variable cholestatic and hepatocellular injury

Resembles extrahepatic obstruction

Portal infiltrates

3-lOX

1-8X

Hepatocanalicular

Ductules Interlobular ducts

Bland jaundice

Bile casts

Canalicular

1-3X

Interference with hepatic excretory pathways

1-5X

Cholestatic

Variable

Increased

Hight High

19%

Nil

Phenytoin, PAS, CPZ, sulfonamides, E. estolate INH, halothane, ACM, hydralazine, valproate, ticrynafen, ketoconazole, methyldopa

PBZ, PAS, sulfonamides

5-FUDR

Benoxaprofen Paraquat, Margosa oil

Anabolic, contraceptive steroids CPZ, E. estolate

782

JA\IES H. LEWIS AND HYMAN J. ZIMMERMAN

Several instances of cirrhosis with other changes resembling alcoholic liver disease (pseudoalcoholic liver disease [PsALDJ), namely steatosis, necrosis, and Mallory bodies, in association with PL, have resulted from the chronic administration of DEA, PHM, and AD. The cause of this chronic cytotoxic injury is presumed to be secondary to production of a toxic metabolite(s) (metabolic idiosyncracy), possibly under the influence of genetic mechanisms. 44 Seventy-five per cent of patients who develop injury from PHM, for example, have been shown to be slow metabolizers of debrisoquine, in contrast to the 90 per cent of general population who exhibit phenotypically extensive (rapid) metabolism (oxidation) of debrisoquine. 65 Fibrosis and cirrhosis due to drugs may result from chronic active hepatitis (for example, alpha-methyldopa,8o nitrofurantoin, 91 oxyphenisatin,78 propylthiouracil, 59 ticrynafen" 2 ), pseudoalcoholic changes (for example, AD and PHM),44, 71 chronic cholestatic (PBC-like) injury (for example, CPZ, amitriptyline), 109 and chronic injury from methotrexate (MTX),43 and etretinate. 17 Clinical manifestations of drug-induced cirrhosis are those of portal hypertension (in advanced cases) in addition to those of the causativc lesion. Certain drugs lead to portal hypertension without cirrhosis. Causes of noncirrhotic portal hypertension or hepatoportal sclerosis include chronic exposure to inorganic arsenicals, vinyl chloride, and copper sulfate and vitamin A intoxication. 97 Vascular injury to the liver from drugs may affect the small or large hepatic veins, the sinusoids, the hepatic artery and its branches, and the portal venous system lOI (Table 7). Several drug-induced vascular lcsions continue to command attention, including Budd-Chiari syndrome (BCS), veno-occlusive disease (VOD), and peliosis hepatitis. BCS is caused by occlusion of the large hepatic veins resulting in the acute or subacute onset of hepatomegaly, ascites, abdominal pain, and mild jaundice. Drugs account for approximately 10 per cent of cases, oral contraceptive steroids (OCS) being incriminated almost exclusively. 45,95 In many instances, a latent myeloproliferative disorder seems to underlie the etiologic association with OCS.94 Portal decompressive surgery or liver transplantation is often required for cases manifesting severe hepatic necrosis and failure. The prognosis of OCS-related cases treated conservatively, however, may be somewhat better than that of other causes. 45 VOD is the term coined by Bras et al in 1954 to describe the BCS-like illness resulting from the ingestion of "bush teas" containing hepatotoxic pyrrolizidine alkaloids and resulting in a nonthrombotic concentric occlusion of the lumen of the small intrahepatic veins. I,' In Jamaica, "bush tea disease" commonly progresses to cirrhosis, accounting for 30 per cent of cirrhosis of all causes. 15 The most commonly implicated drug causing VOD in the United States is azathioprine, occurring in approximately 20 per cent of patients subjected to bone marrow'6 and renal transplantation. 76 In these patients, VOD is associated with a mortality rate that

Table 6. Chronic Parenchymal Drug-induced Hepatic Injury* Chronic hepatitis Autoimmllne-Iike Chronic active viral hepatitis-like Steatosis Phospholipidosis Pselldoalcoholic disease Cirrhosis

Oxyphenisatin, methyldopa, papaverine, c1ometacine, nitrofurantoin, dantrolene, ticrynafen, ?PTU, slllfonamides Acetaminophen, aspirin, INH, ETOH? MTX, ethanol, GLC, anticancer drugs, VPA DEA, PM, AD, many amphiphilic agents DEA, PM, AD, DES Drugs that lead to chronic hepatitis, steatosis, phospholipidosis, pselldoalcoholic liver disease

*PTU = propylthiouracil; PM = perhexiline maleate; GLC = glucocorticoids; AD amiodarone; MTX = methotrexate; DES = diethylstilbestrol; VPA = valproate; DEA = 4,4' -diethylaminoethoxyl hexesterol.

DRUG-INDUCED LIVER DISEASE

783

Table 7. Drug-induced Chronic Hepatic Vascular Lesions DRUGS

Hepatic vein thrombosis Veno-occlusive disease Sinusoidal lesions Peliosis Sinusoidal dilatation Perisinusoidal fibrosis Hepatoportal sclerosis Hepatic artery: arteritis Intimal hyperplasia

Contraceptive steroids; anticancer drugs* Pyrrolizidine alkaloids, anticancer drugs, t azathioprine, alcohol, aflatoxin, dietary estrogens:j: Anabolic steroids, contraceptive steroids, vinyl chloride, arsenic, medroxy progesterone, azathioprine, thorotrast, hydroxyurea Contraceptive steroids, anabolic steroids? chenodiol? Vitamin A, arsenic, copper sulfate, thorotrast, anticancer drugs, azathioprine, urethane, methotrexate, mercaptopurine Arsenic, vinyl chloride, Vitamin A, anticancer drugs, contraceptive steroids, azathioprine Methamphetamine HCI?, phenytoin, sulfonamides, allopurinol Contraceptive steroids

*Combination chemotherapy (doxorubicin, dacarbazine, vincristine, cyclophosphamide). tCombination chemotherapy (carmustine, urethane, mitomycin, cytarabine, thioguanine). :j:In captive cheetahs"

approaches 50 per cent. Other drugs causing a VOD-like lesion are listed in Table 7. In captive cheetahs, dietary estrogens have been cited as the suspected cause of species-threatening infertility and fatal VO D. 86 Peliosis, derived from the Greek meaning extravasation of blood, is generally regarded as a coincidental (usually postmortem) curiosity.'o, Rarely, however, it may result in acute rupture leading to hemoperitoneum with hemorrhagic shock and death. 4 While originally described in patients with chronic wasting diseases such as tuberculosis and generalized carcinomatosis, peliosis is increasingly being recognized as a consequence of anabolic and, less convincingly, of contraceptive steroids. 101 The number of drugs causing hepatic granulomas continues to grow. 54, 106 While many lead to granulomas as part of a hypersensitivity reaction accompanied by overt cytotoxic or cholestatic injury (for example, allopurinol, methyldopa, penicillin, quinidine, sulfonamides), others are associated with no clinical evidence of liver injury. Gold salts may be associated with lipogranulomata with a characteristic black pigment. Allopurinol-associated granulomata have a characteristic fibrin ring. 54, 106 A relatively small number of medicinal agents have been incriminated or are suspected to cause hepatic neoplasms.101 The etiologic responsibility of OCS for hepatocellular adenoma appears unquestionable and, for rare instances of hepatocellular carcinoma, also seems clear, although the incidence of carcinoma in OC users is still low. The role of anabolic steroids in the pathogenesis of carcinoma is even more convincing. 32 Both groups of steroids also appear to have a relationship to nodular regeneration and hyperplasia. Angiosarcoma has been linked most conclusively to exposure to thorium dioxide (thorotrast), vinyl chloride, arsenic, and convincingly to copper sulfate. 73 The suspicion that estrogens, OCS, or anabolic steroids may cause angiosarcoma must await confirmation. Similarly, no causal relationship between OCS and hemangiomas or hemangioendothelioma has been established. 33

MECHANISMS OF DILD Intrinsic Hepatotoxins Relatively few intrinsically hepatotoxic drugs are available for use (see Table 5), most having been excluded from further investigation or withdrawn from

784

JA\IES H. LEWIS A:-ID HnlAN J. ZIM\1ERMAN

marketing oncc their hepatotoxic potential was recognized. In some cases, however, hepatotoxic drugs were used for years before they were withdrawn. For example, tannic acid was used in burn victims into the 1940s, and in roentgenographic contrast media into the 1960s; carbon tetrachloride was employed as an anthelminthic agent as late as 1954; and chloroform was used as an anesthetic into the 1960s.106 \Videly used agents that were withdrawn more recently include oxyphenisatin,78 ticrynafen, Il2 and benoxaprofen. 2 . 42 Acetaminophen (ACM) and inorganic iron in an acute overdose are intrinsic hepatotoxins. 106 Toxic steatosis occurs with several drugs including tetracycline (given intravenously in high doses), MTX, VPA, L-asparaginase, and alcohol. Examples of cholestatic intrinsic hepatotoxins include the C-17 alkylated contraceptive and anabolic steroids,lo£ methylene dianiline,106 and paraquat. 109

Idiosyncratic DILD Idiosyncratic hepatotoxins are subdivided into those associated with hypersensitivity (drug allergy) and those thought to produce injury through the production of hepatotoxic metabolites (metabolic idiosyncracy) (see Table 5). IOri Injury attributed to hypersensitivity generally develops after a period of sensitization from 1 to 5 weeks, and is often associated with clinical hallmarks of hypersensitivity (fever, rash, eosinophilia), as well as histologic evidence of drug allergy (eosinophilic or granulomatous inflammation). Lymphocytosis, "atypical" lymphocytes, and lymphadenopathy are frequent, and the syndrome resembles serum sickness or infectious mononucleosis. Reproduction of the patient's clinical symptoms or enzyme abnormalities after a challenge dose is characteristic, and permits the inference that the drug (or a metabolite) has acted as a hapten. The development of hepatic injury after weeks or months of exposure to a drug, unaccompanied by the traditional hallmarks of hypersensitivity, may be the result of a different immunological mechanism or the result of aberrant metabolism leading to hepatotoxic metabolites. A reaction occurring late and unaccompanied by rash, fever, or eosinophilia and yet responding promptly to a challenge dose of the drug, probably results from an immunological mechanism different from the serum sickness type. A delay of days to weeks in recurrence of hepatic injury on readministration of the drug is consistent with metabolic injury. Examples of drugs in each of the categories of idiosyncracy are listed in Table 4. The classification of drugs into thosc that cause damage as intrinsic and idiosyncratic hepatotoxins is in many instances an oversimplific~tion. The potential for producing injury is arranged along a spectrum heavily dependent on the interplay between intrinsic toxicity and host susceptibility. For a number of drugs, hypersensitivity appears to lead to overt hepatic injury only when the particular drug has some intrinsic hepatotoxic potential. Indeed, many drugs that frequently lead to generalized hypersensitivity reactions, such as penicillin and procainamide, are apparently almost devoid of any intrinsic hepatotoxic potential and lead to hepatic injury very rarelyl06; yet others that can be shown to have some intrinsic toxic potential produce hepatic injury in conjunction with hypersensitivity. This appears to be the case with CPZ, J06 erythromycin estolate,109 and phenylbutazone. 8 Several recent studies throw important light on the relevance of drug metabolism in idiosyncratic injury, both metabolic and immunologic. Of particular importance is the role of genetic and other factors in modifying susceptibility, including polymorphic differences, in drug metabolism,34 the related topic of cytochrome P450 isoenzymes and their respective genes, r2 and the effects of alcohol on drug toxicity.lO' For example, efforts to correlate DILD with the rate of oxidative metabolism of the antihypertensive, debrisoquine, have revealed that phenotypically slow (poor) metabolizers are also defective oxidizers of PHM and subject to PHMinduced hepatic injury.63 In contrast, injury from other drugs, such as metoproloP9

DRUG-INDUCED LIVEH DISEASE

785

and amitriptyline,38 does not appear to be dependent on a slow debrisoquine metabolizer phenotype.

Drug Metabolism A number of individual agents provide important lessons in any understanding of drug metabolism and related hepatic injury. Several of these drugs are discussed below. Valproate. Injury from VPA occurs rarely but is potentially fatal. 108 Among the factors that appcar to affect susceptibility is age, with infants and young children at appreciably higher risk. Similarities to the lesion produced by 4-pentenoic acid in animals and to Jamaican vomiting sickness and Reye's syndrome in humans invite the hypothesis that a metabolite of the omega oxidation pathway is responsible for hepatic injury. JOB Indeed, the metabolite has reproduced the lesion in rats 36. 48 and appears to be cytochrome P450-dependent, leading to or accompanied by decreased activity of beta-oxidation. Whether enhanced susceptibility in the individual patient depends on increased activity of an isozyme of cytochrome P450 (for example, induced by phenobarbital or phenytoin taken concomitantly), or a defect in mitochondrial enzvme function, or both, is not clear. Phenytoin. Another lesion that has thrown light on metabolic factors in idiosyncrasy is phenytoin injury. Elegant studies by Spielberg et algO have shown that patients (as well as some of their relatives) who develop hepatic injury are unable to detoxify an active intermediate of phenytoin metabolism, the arene oxide. Failure to detoxify this epoxide results from defective activity of epoxide hydrolase. Spielberg and associates suggest that the undetoxified active metabolite might behave as a hapten, generating the immunological reactions leading to the hypersensitivity syndrome, and/or to hepatic injury as a toxic metabolite. Halothane. Features of combined immunologic and toxic metabolic injury and genetic factors are seen with the hepatotoxicity of halothane. The involvement of immunological factors is strongly suggested by the importance of prior exposure and the accompanying clinical hallmarks of hypersensitivity. 20. 66 That hepatotoxic metabolites may play a role, however, is also strongly suggested by the striking similarity of the halothane lesion, in many instances, to other known toxic haloalkanes (for example, carbon tetrachloride),7. 106 and by the enhanced ability to reproduce the lesion in several animal species when the cytochrome P450 is induced with phenobarbital or a polychlorinated biphenyl, III or alcohol. 103 The available data demonstrate that halothane may be metabolized along two pathways. In the presence of ample oxygen, oxidative biotransformation yields a metabolite that appears to bind to the hepatocyte membrane and alters its antigenic character. Neuberger et al at Kings College Hospital66 have proposed that hepatic necrosis by halothane is the result of the production of this neoantigen that triggers humoral and cell-mediated responses that combine to produce necrosis. Biotransformation in a low oxygen environment occurs along a reductive pathway and yields a free radical metabolite capable of producing necrosis. These same investigators believe that reductive metabolites play a role in provoking minor injury, while the immunologic reaction leads to the severe injury. We would suggest that the minor injury produced by toxic metabolites is converted to severe injury when immunological factors are added.106 Cousins and associates l8 have long taken a somewhat similar view and have provided evidence that toxic metabolites do play a key role in halothane necrosis. There is evidence that genetic factors also modify metabolism and toxicity of halothane. That a particular isozyme of P450 may be relevant is suggested by the observations that phenobarbital induction enhances halothane toxicity in animals and humans, while phenytoin induction does not 68 ; by the enhancement of halothane toxicity in rats by alcohopo3 (alcohol is an enhancer of a particular P450 isozyme 64 );

786

JA"-'IES H. LEWIS AND HY',IAN

J.

ZIM\IERMAN

that cimetidine inhibits halothane toxicity for animals'2; and by the genetic studies of Farrell et aP' who showed a familial metabolic defect in patients susceptible to halothane injury. Isoniazid. Isoniazid (INH) hepatic injury has been amply studied and is clearly relatable to metabolism of the drug and, probably, conversion to an active metabolite of acetyl hydrazine. The debate of the past 15 years regarding the role of acetylator phenotype is almost resolved; the early suggestion that "rapid" metabolizers are more susceptible 61 has been largely dismissed with a near consensus that "slow" acetylators are as (or even more) susceptible. 24 Occasional dissent, however, continues to appear. 100 In any event, it remains clear that INH metabolism is relevant to its hepatotoxicity. Moreover, it appears that specific P450 isoenzymes may ultimately be identified in view of the enhancement of toxicity by alcohol, 103 by other drugs (rifampicin),'O and by the enhancing effect of advancing age. 62 It is also of interest that biotransformation of INH is inhibited by cimetidine in rats, but not in humans. 4o Acetaminophen. The development of severe injury after ACM overdose is well known with hepatotoxic effects dependent on the dose of drug, the activity of the cytochrome P450 system, stores of glutathione (GSH), and the activity of the glucuronidating system. 104 The enhancement of toxic effects of modest doses of ACM in chronic alcoholics has been explained on the basis that chronic alcoholic ingestion depletes GSH, enhances ACM metabolism, and perhaps enhances hepatocyte vulnerability.85 The enhancement of ACM toxicity after chronic ethanol consumption in experimental animals,82 and apparently in humans, 11. 85 becomes even more interesting based on recent data showing that the isoenzyme of cytochrome P450 most active in the metabolism of ACM is the one mainly induced by ethanol in the rabbit,64 rat,93 and probably humans. '2 There is evidence that the conversion of ACM to an active metabolite can be inhibited by cimetidine in experimental animals. 40 While the role of cimetidine alone in treating a human ACM overdose has not been defined,3 experimentally, the combination of cimetidine with N-acetylcysteine (Mucomyst) may be beneficial,B9 In animals, ACM combined with methionine also has prevented toxic injury.67 Whether or not ACM will ever be manufactured for human use with methionine to prevent toxicity remains speculative. 99 An additional factor affecting ACM toxicity is the rate of glucuronication. 11 Enhancement of glucuronidation decreases toxicity by enhancing disposition of the drug away from the toxic pathway while blockade of glucuronidation could enhance toxicity. 14

Alcohol and Drug Metabolism The effects of alcohol consumption on the toxicity of ACM, INH, and halothane are presumably but the tip of the iceberg. The toxicity of other agents is also enhanced (for example, carbon tetrachloride, chloroform, cocaine, trichloroethane) and in some cases even decreased by alcohol. 103 Interestingly, the acute administration of ethanol to rats has prevented hepatic injury from ACM,81 presumably due to decreased production of reactive ACM metabolites, most likely due to a direct inhibiting effect of ethanol on ACM production. In contrast, injury induced by carbon tetrachloride is markedly increased by acute ethanol administration" and can be potentiated following withdrawal of chronic ethanol consumption in animals. The meaning of these influences may become clear as cytochrome P450 isoenzymology becomes increasingly clarified. 50 More than 20 P450 isoenzymes have been identified in animals and humans to date, which may account for the many differences in species-related, age-related, and other susceptibility factors.

DBue-INDUCED LIVER DISEASE

787

DILD DUE TO INDIVIDUAL AGENTS Table 5 lists many of thc drugs known to cause hcpatic injury according to thcir morphologic pattern of injury. Drugs of reccnt vintage and thosc newly recognized as causes of DILD are discussed below.

Anesthetics Among thc halogcnated inhalational agents, halothanc,66, 106 methoxyflurane,35 and enflurane!9 in decreasing order, are capable of producing rarc (often fatal) instances of hepatic necrosis. The issue of a prior sensitizing cxposure has taken on new meaning in light of reccnt observations suggcsting that rcsidual halothane may bccome trappcd in the anesthesia apparatus. 96 Cross-sensitivity of halothane with methoxyflurane and eriflurane is probable,49 raising important questions concerning rep cat exposure to any of the three. '3 Isoflurane, which undergocs negligible metabolism, and nitrous oxide appear devoid of hepatotoxic potcntial, 98 although a few instances of isoflurane injury report cd to the Food and Drug Administration cannot be readily dismissed. 13

Antimicrobials Ketoconazole rarely causes severe hepatocellular necrosis; pcrhaps one in 10,000 to 15,000 patients according to the manufacturer. 47 Subclinical cnzyme abnormalities that do not progress are seen in 10 to 15 per cent. Most instances of liver toxicity from the erythromycins have been due to the estolate formulation, but injury from E. ethylsuccinate and E. proprionate has been recently reported. 19 A clinical illness resembling acute cholelithiasis or cholecystitis points out the importance of recognizing thc drug-induced etiology with erythromycin. llo Hepatic dysfunction, including fatal massive necrosis, has been reccntly described with pyrimethamine-sulfadoxine (Fansidar), which is being used prophylactically against Pneumocystis carinii pncumonia in patients with AIDS.ll3

Anticonvulsants Injury from VPN 08 and phcnytoin (DPH)90 has been discussed in the context of metabolic idiosyncracy. DPH-induced injury may mimic infectious mononucleosis or lymphoma (pscudolymphoma),29 while VPA toxicity rcsembles Jamaican vomiting sickness and Reyc's syndrome. 48 . lOb

Antiarrhythmic and Cardiovascular Drugs PHM and AD produce PL in a majority and PsALD in a small proportion of susceptible patients rcceiving chronic doses. 44 . 46.55. 71 Approximately 25 per ccnt of AD recipients develop elevated hcpatic enzymes that do not progrcss. 44 Howcver, a number of hepatic-related fatalities have been reported with AD!4, 51 and cxtrahcpatic toxicity also may limit its usefulness. 44 , 55 Among the calcium channel blockers, nifedipine has been implicated in a few instances of cholestatic injury79 and verapamil with possiblc hepatocellular injury. IS Warfarin may cause extrahepatic cholestasis ' as may captopril. 75 Ticrynafen, a uricosuric diuretic, was withdrawn aftcr severe hepatocellular injury was recognized. 1I2

Analgesics and Anti-in8ammatory Agents Aspirin and other salicylates can causc dose-dependent hepatic injury correlated with high scrum levels (greater than 15 mg per dl), especially in younger persons enhanccd by active rheumatic fever, juvcnile rhcumatoid arthritis, or systemic

788

JA~1ES H. LEWIS AND HYMAN J. ZIMMERMAN

lupus erythematosus.106 . 107 In contrast to the centrizonal nccrosis seen with ACM, aspirin injury is a nonzonal, diffusc degeneration, usually of lesser clinical import and rarely fatal. Among the various other nonsteroidal antiinfiammatory drugs, most instances of D ILD ar~ cytotoxic. 42 Notoriety was achieved several years ago by benoxaprofen when it was incriminated in a number of fatal reactions associated with cholestatic injury.2 42 The paradoxically high case fatality rate was distinctly unusual; indeed, the cause of death has been the subject of speculation but remains largely unexplained. J09

Antiulcer Drugs Yluch attention has been recently focused on the injury attributed to several H2 blockers.41 Of interest is the fact that oxmetidine was withdrawn prior to marketing because of unexpected (although apparently intrinsic) toxicity that developed during chronic therapy. 30 More recently, further investigation was suspended with zaltidine, an H2 receptor antagonist with a diaryl structure, due to a high incidence (8 per cent) of hepatocellular necrosis seen within a 4-week treatment period. 28 The attention given to the hepatic injury seen with the currently available agents appears to be well out of proportion to the incidence and degree of actual injury. Provcn instances of clinically acute hepatic injury from cimetidine and ranitidine are exceedingly rare, consistent with a metabolic type of idiosyncratic drug reaction. 41 The limited histologic and rechallenge data indicate injury with cytotoxic, cholestatic, or mixed features, with no significant clinical differences having cmerged between the two, when administered either orally or intravenously. No cases of chronic hepatitis and no fatalities have been reported. Injury from famotidine and nizatidine was reported during their respective clinical trials and, although the true incidence has not been determined, it also appears to be quite low. By virtue of its imidazole ring structure, cimetidine inhibits the hepatic P450 system. This accounts for both its important drug interaction potential,88 as well as for its potcntially hepatoprotective effects. 40. 72, 89

Antineoplastics While most antineoplastic drugs have some hepatotoxic potential, 58. 102 liver injury often assumes a somewhat lesser importance in the context of treating malignancy. Ylethotrexate deserves special mention because of its propensity to cause steatosis, fibrosis, and cirrhosis in the setting of long-term treatment of psoriasis and rheumatoid arthritis. 43 Hepatic injury from MTX is clearly dose-, frequency-, and duration-dependent, with active alcoholism abetting the injury. Efforts to devise single weekly dosing regimens of less than 15 mg have been successful in reducing the incidence of significant injury. However, monitoring for potential MTX-induced hepatotoxicity generally requires periodic liver biopsy as serum enzymes do not correlate with histologic abnormalities. 43

Miscellaneous Drugs Disulfiram continues to be implicated in an occasional instance of hepatitis that resolves rapidly after drug withdrawal. 5 A curious chronic lesion resembling Lafora bodies also has been described in association with a related compound, cyanamide. 92 Lovastatin, a cholesterol synthesis inhibitor, has come under scrutiny because of aminotransferase elevations that may necessitate discontinuation of the drug. 52 Recent observations have demonstrated hepatotoxicity from cocaine in animals, 25 with an instance of severe hepatic necrosis in humans. 69 A few suspected cases of acute hepatitis due to azidothymidine have been reported,22. 51 although the difficulties in differentiating DILD from the underlying hepatic lesions associated with AIDS84 are obvious.

789

DRUG-INDUCED LIVER DISEASE

REFERENCES 1. Adler E, Benjamin SB, Zimmerman HJ: Cholestatic hepatic injury related to warfarin exposure. Arch Intern Med 145:1837-1839, 1986 2. Anonymous: Benoxaprofen. Br Med J 285:456-460, 1982 3. Anonymous: H2 receptor antagonists, cytochrome P450 and paracetamol-induced hepatotoxicity. Lancet 2:868-870, 1985 4. Bagheri SA, Boyer JL: Peliosis hepatis associated with androgenic-anabolic steroid therapy: A severe form of hepatic injury. Ann Intern Med 81:610-618, 1974 5. Bartle WR, Fisher MM, Kerenyi N: Disulfiram-induced hepatitis. Report of two cases and review of the literature. Dig Dis Sci 30:834-837, 1985 6. Benhamou JP: Drug-induced hepatitis: Clinical aspects. In Fillastre JP (ed): Hepatotoxicity of Drugs. Rouen, University de Rouen, 1986, pp 23-30 7. Benjamin SB, Goodman ZD, Ishak KG, et al: The morphologic spectrum of halothaneinduced hepatic injury: Analysis of 77 cases. Hepatology 5: 1163-1171, 1985 8. Benjamin SB, Ishak KG, Zimmerman JH, et al: Phenylbutazone liver injury: A clinicalpathologic survey of 23 cases and review of the literature. Hepatology 1:255-263, 1981 9. Benson GD, Anderson PK, Combes B, et al: Prolonged jaundice following ketoconazoleinduced hepatic injury. Dig Dis Sci 33:340-346, 1988 10. Bernuau J, Rueff B, Benhamou JP: Fulminant and subfulminant liver failure: Definitions and causes. Semin Liver Dis 6:97-106, 1986 11. Black M: Acetaminophen hepatotoxicity. Annu Rev Med 35:577-593, 1984 12. Black M, Rauey J: Acetaminophen, alcohol and cytochrome P-450. Ann Intern Med 104:427, 1986 13. Blogg CE: Halothane and the liver: The problem revisited and made obsolete. Br Med J 292:1691-1692, 1986 14. Bolton JS, Bowen JC: Biliary sclerosis associated with hepatic artery infusion of floxuridine. Surgery 99:119-122, 1986 15. Bras G, Jelliffe DB, Stuart KL: Veno-occlusive disease of liver with nonportal type of cirrhosis, occurring in Jamaica. Arch Pathol 57:285-300, 1954 16. Brodsky SJ, Cutler SS, Weiner DA, et al: Hepatotoxicity due to treatment with verapamil. Ann Intern Med 94:490-491, 1981 17. Camuto P, Shupack J, Orbuch P, et al: Long-term effects of etretinate on the liver in psoriasis. Am J Surg Pathol 11:30-37, 1987 18. Cousins MJ, Plummer JL, Hall P, et al: Toxicity of volatile anesthetic agents. Can Anaesth Soc J 32:552-555, 1985 19. Diehl AM: Cholestatic hepatitis from erythromycin ethylsuccinate. Am J Med 76:931934, 1984 20. Dienstag JL: Halothane hepatitis. Allergy or idiosyncracy? N Engl J Med 303:102-104, 1980 21. Dossing M, Buch Andreasen P: Drug-induced liver disease in Denmark. An analysis of 572 cases of hepatotoxicity reported to the Danish Board of Adverse Reactions to Drugs. Scand J GastroenteroI17:205-211, 1982 22. Dubin G, Brafl'man MN: Zidovudine-induced hepatotoxicity. Ann Intern Med 110:8586, 1989 23. Eastwood HOH: Causes of jaundice in the elderly: A survey of diagnosis and investigation. Geront Clin 13:69, 1971 24. Ellard GA: The potential clinical significance of the isoniazid acetylator phenotype in the treatment of pulmonary tuberculosis. Tubercle 65:211-227, 1984 25. Evans MA, Barbison RD: Cocaine-induced hepatotoxicity in mice. Toxicol Appl Pharmacol 45:739-754, 1978 26. Faich GA, Knapp D, Dreis M, et al: National Adverse Drug Reaction Surveillance: 1985. JAMA 257:2068-2070, 1987 27. Farrell G, Prendergast D, Murray M: Halothane hepatitis. Detection of a constitutional susceptibility factor. N Engl J Med 313:1310-1314, 1985 28. Farup PG and other members of the European Zaltidine study group: Zaltidine: An effective but hepatotoxic H2-receptor antagonist. Scand J Gastroenterol 23:655-688, 1988 29. Harinasuta U, Zimmerman HJ: Diphenylhydantoin sodium hepatitis. JAMA 203:10151018, 1968 30. Helfrich HM, Evers PW, Schriver RC, et al: Role of nocturnal acid suppression on the

790

JAMES H. LEWIS AND HYMAN J. ZIMMERMAN

rate of duodenal ulcer healing: Clinical dose-range trials with oxmetidine. Am J Gastroenterol 80:959-963, 1985 31. Hostetler KY, Giordano JR, Jellison EJ: In vitro inhibition of phospholipase Al of rat lung by amiodarone and desethylamiodarone. Biochim Biophys Acta 959:316-321,

1988 32. Ishak KG: Hepatic lesions caused by anabolic and contraceptive steroids. Semin Liver Dis 1:116-124, 1981 33. Ishak KG, Sesterhenn LA, Goodman ZD, et aI: Epithelioid hemangioendothelioma of the liver: A cliniopathologic and follow-up study of 32 cases. Hum Pathol 55:839-852, 1984 34. Jacqz E, Hall SD, Branch RA: Genetically determined polymorphisms in drug oxidation. Hepatology 6:1020-1032, 1986 35. Joshi PH, Conn HO: The syndrome of methoxyflurane-associated hepatitis. Ann Intern Med 80:395-401, 1974 36. Kesterson JW, Granneman GR, Machinist JM: The hepatotoxicity of valproic acid and its metabolites in rats. I. Toxicologic, biochemical and histopathologic studies. Hepatology 4:1143-1152, 1984 37. Koff RS, Gardner R, Harinasuta U, et al: Profile ofhyperbilirubinemia in three hospital populations. Clin Res 18:680, 1970 38. Larrey D, Amouyal G, Pessayre D, et aI: Amitriptyline-induced prolonged cholestasis. Gastroenterology 94:200-203, 1988 39. Larrey D, Henrion J, Helier F: Metoprolol-induced hepatitis: Rechallenge and drug oxidation phenotyping. Ann Intern Med 108:67-68, 1988 40. Lauterburg BH, Todd EL, Smith CV, et al: Cimetidine inhibits the formation of the reactive toxic metabolite of isoniazid in rats but not in man. Hepatology 5:607, 1985 41. Lewis JH: Hepatic effects of drugs used in the treatment of peptic ulcer disease. Am J Gastroenterol 82:987-1003, 1987 42. Lewis JH: Hepatotoxicity of non-steroidal anti-inflammatory drugs. Clin Pharmacy 3:128138, 1984 43. Lewis JH, Schiff ER: Methotrexate-induced chronic liver injury: Guidelines for detection and prevention. Am J Gastroenterol 83:1337-1345, 1988 44. Lewis JH, Ranard RC, Caruso A, et al: Amiodarone hepatotoxicity: Prevalence and clinicopathologic correlations among 104 patients. Hepatology, in press 45. Lewis JH, Tice HL, Zimmerman HJ: Budd-Chiari syndrome associated with oral contraceptive steroids: Review of treatment of 47 cases. Dig Dis Sci 28:673-683, 1983 46. Lewis D, Wainwright HC, Kew MC, et al: Liver damage associated with perhexiline maleate. Gut 20:186-189, 1979 47. Lewis JH, Zimmerman HJ, Benson GD, et aI: Hepatic injury associated with ketoconazole therapy. Analysis of 33 cases. Gastroenterology 86:503-513, 1984 48. Lewis JH, Zimmerman HJ, Garrett CT, et al: Valproate-induced hepatic steatogenesis in rats. Hepatology 2:870-873, 1982 49. Lewis JH, Zimmerman HJ, Ishak KG, et al: Enflurane hepatotoxicity. A clinicopathologic study of 24 cases. Ann Intern Med 98:984-992, 1983 50. Lieber CS: Biochemical and molecular basis of alcohol-induced injury to liver and other tissues. N Engl J Med 319:1639-1650, 1988 51. Lim PK, Trewby PN, Storey GCA, et aI: Neuropathy and fatal hepatitis in a patient receiving amiodarone. Br Med J 288:1638-1639, 1984 52. Lovastatin for hypercholesterolemia: Med Lett 29:99-101, 1987 53. Lullmann H, Lullmann-Rauch R, Wassermann 0: Drug-induced phospholipidoses. CRC Crit Rev Toxicol 4:185-218, 1975 54. Maddrey W: Granulomatous liver disease. In Seeff LB, Lewis JH (eds): Current Perspectives in Liver Disease: Festschrift for Hyman J. Zimmerman. New York, Plenum Publishing, in press 55. Mason JW: Amiodarone. N Engl J Med 316:455-466, 1987 56. McDonald GB, Sharma P, Matthews DE, et al: Venoocclusive disease of the liver after bone marrow transplantation: Diagnosis, incidence, and predisposing factors. Hepatology 4:116-122, 1984 57. Melamed AJ, Muller RJ, Gold JWM, et al: Possible zidovudine-induced hepatotoxicity. JAM A 258:2063, 1987 58. Menard DB, Gisselbrecht C, Marty M, et aI: Antineoplastic agents and the liver. Gastroenterology 78:142-164, 1979

DRl!C-INDL'CED LIVER DISEASE

791

59. Milhas AA, Holley P, Koff RS, et al: Fulminant hepatitis and Iymphocyte sensitization due to propylthiouracil. Gastroenterology 70:770-774, 1976 60. Miller RR: Hospital admissions due to adverse drug reactions. A report from the Boston Collaborative Drug Surveillance Program. Arch Intern Med 134:219-223, 1974 61. Mitchell JR, Thorgeirsson VP, Black M, et al: Increased incidence of isoniazid hepatitis in rapid acetylators: Possible relation to hydrazine metabolites. Clin Pharmacol Ther 18:70-79, 1975 62. Mitchell JR, Zimmerman HJ, Ishak KG, et al: Isoniazid liver injury: Clinical spectrum, pathology and provable pathogenesis. Ann Intern Med 84:181-192, 1976 63. Moore DH, Benson GD: Prolonged halothane hepatitis: prompt resolution of severe lesion with corticosteroid therapy. Dig Dis Sci 31:1269-1272, 1986 64. Morgan ET, Koop DR, Coon MJ: Comparison of six rabbit liver cytochrome P-450 isozymes in formation of a reactive metabolite of acetaminophen. Biochem Biophys Res Commun 112:8-13, 1983 65. Morgan NY, Reshef R, Shah RR, et al: Impaired oxidation of debrisoquine in patients with perhexiline liver injury. Gut 25:1057-1064, 1984 66. Neuberger J, Williams R: Halothane anesthesia and liver damage. Br Med J 289:1135, 1984 67. Neuvonen PI, Tokola 0, Toivonen ML, et al: Methionine in paracetamol tablets, a tool to reduce paracetamol toxicity. Int J Clin Pharmacol Ther Toxicol 23:497-500, 1985 68. Nomura F, Hatano H, Ohnishi K, et al: Effects of anticonvulsant agents on halothaneinduced liver injury in human subjects and experimental animals. Hepatology 6:952956, 1986 69. Perino LE, Warren GH, Levine IS: Cocaine-induced hepatotoxicity in humans. Gastroenterology 93:176-180, 1987 70. Pessayre D, Bentana M, Degott C, et al: Isoniazid-rifampicin fulminant hepatitis: A possible consequence of enhancement of isoniazid hepatotoxicity by enzyme induction. Gastroenterology 72:284-289, 1977 71. Pessayre D, Bichara M, Feldmann G, et al: Perhexiline maleate-induced cirrhosis. Gastroenterology 76:170-177, 1979 72. Plummer JL, Wanwimolruk S, Jenner M, et al: Effects of cimetidine and ranitidine on halothane metabolism and hepatoxicity in an animal model. Drug Metab Disp 12:106110, 1984 73. Popper H, Thomas LB, Telles NC, et al: Development of hepatic angiosarcoma in man induced by vinyl chloride, Thorotrast and arsenic. Am } Pathol 92:349-369, 1978 74. Price VF, Jolliew DJ: Role of VDPGA flux in acetaminophen clearance and toxicity. Xenobiotica 14:553, 1984 75. Rahmat }, Gelfand RL, Gelfimd MC, et al: Captopril-associated cholestatic jaundice. Ann Intern Med 102:56-58, 1985 76. Read AE, Wiesner RH, LaBrecque DR, et al: Hepatic veno-occlusive disease associated with renal transplantation and azathioprine therapy. Ann Intern Med 104:651-655, 1986 77. Reasor MJ, Ogle CL, Walker ER, et al: Amiodarone-induced phospholipidosis in rat alveolar macrophages. Am Rev Resp Dis 137:510-518, 1988 78. Reynolds TB, Peters RL, Yamada S: Chronic active and lupoid hepatitis caused by a laxative, oxyphenisatin. N Engl J Med 285:813-820, 1971 79. Richter WO, Schwandt P: Serious side effect of nifedipine. Arch Intern Med 147:1852, 1987 80. Rodman IS, Deutch DJ, Gutman SI: Methyldopa hepatitis: A report of six cases and review of the literature. Am} Med 60:941-948, 1976 81. Sato C, Lieber CS: Mechanism of the preventive effect of ethanol on acetaminopheninduced hepatotoxicity. J Pharmacol Exper Ther 218:811-815, 1981 82. Sato C, Matsuda Y, Lieber CS: Increased hepatotoxicity of acetaminophen after chronic ethanol consumption in the rat. Gastroenterology 80:140-148, 1981 83. Sato C, Nakano M, Lieber ES: Prevention of acetaminophen-induced hepatotoxicity by acute ethanol administration in the rat: Comparison with carbon tetrachloride-induced hepatotoxicity. } Pharmacol Exper Ther 218:805-810, 1981 84. Schneiderman DJ, Arenson DM, Cello JP, et al: Hepatic disease in patients with the acquired immune deficiency syndrome (AIDS). Hepatology 7:925-930, 1987 85. Seeff LB, Cuccherini BA, Zimmerman HJ, et al: Acetaminophen hepatotoxicity in alcoholics: A therapeutic misadventure. Ann Intern Med 104:399-404, 1986

792

JAMES H. LEWIS AND HYMAN

J.

ZIMMERMAN

86. Setchell KDR, Gosselin SJ, Welsh MB, et al: Dietary estrogens-a probable cause of infertility and liver disease in captive cheetahs. Gastroenterology 93:225~233, 198'7 87. Shikata T, Kanetaka T, Endo Y, et al: Drug-induced generalized phospholipidosis. Acta Pathol Jpn 22:517~531, 1972 88. Somogyi A, Muirhead M: Pharmacokinetic interactions of cimetidine. Clin Pharmacokinetic 12:321 ~366, 1987 89. Speeg KV Jr, Mitchell MC, Maldonado AL: Additive protection of cimetidine and Nacetylcysteine treatment against acetaminophen-induced hepatic necrosis in the rat. J Pharmacol Exper Ther 234:550~554, 1985 90. Spielberg SP, Gordon GB, Blake DA, et al: Predisposition to phenytoid hepatotoxicity assessed in vitro. N Engl J Med 305:722~727, 1981 91. Stricker GHC, Blok APR, Claas FHJ, et al: Hepatic injury associated with the use of nitrofurans: A clinicopathological study of 52 reported cases. Hepatology 3:599~606, 1988 92. Thomsen P, Reinicke V: Ground glass inclusions in liver cells in an alcoholic treated with cyanamide (Dipsan). Liver 1:67~73, 1981 93. Tu YY, Peng R, Chang ZF, et al: Induction of a high affinity nitrosamine de methylase in rat liver microsomes by acetine and isopropanol. Chem Bioi Interact 44:247, 1983 94. Valla D, Casadevall N, Lacombe C, et al: Primary myeloproliferative disorder and hepatic vein thrombosis: A prospective study of erythroid colony formation in vitro in 20 patients with Budd-Chiari syndrome. Ann Intern Med 103:329~334, 1985 95. Valla D, Le MG, Poynard T, et al: Risk of hepatic vein thrombosis in relation to recent use of oral contraceptives. Gastroenterology 90:807~811, 1986 96. Varma RR, Whitsell RC, Iskandarani MM: Halothane hepatitis without halothane: Role of inapparent circuit contamination and its prevention. Hepatology 5:1159~1162, 1985 97. Villeneuve JP, Huet PM, Joly JG, et al: Idiopathic portal hypertension. Am J Med 6l:459~464, 1976 98. Wade JG, Stevens WC: Isoflurane: An anesthetic for the eighties? Anesth Analg 60:666~ 682, 1981 99. Williams R: Paracetamol hepatotoxicity: A built-in antidote? Hepatology 6:751~ 752, 1986 100. Yamamoto T, Snou T, Hirayama C: Elevated serum aminotransferase induced by isoniazid in relation to isoniazid acetylator phenotype. Hepatology 6:295~298, 1986 101. Zab'ani ES, Pinaudeau Y, Dhumeaux D: Drug-induced vascular lesions of the liver. Arch Intern Med 143:495~502, 1983 102. Zimmerman HJ: Hepatotoxic effects of oncotherapeutic agents. Prog Liver Dis 8:621~ 642, 1986 103. Zimmerman HJ: Effects of alcohol on other hepatotoxins. Alcoholism. Clin Exper Res 1O:3~15, 1986 104. Zimmerman HJ: Effects of aspirin and acetaminophen on the liver. Arch Intern Med 14l:333~342, 1981 105. Zimmerman HJ: Drug-induced chronic hepatic disease. Med Clin North Am 63:567~ 582, 1979 106. Zimmerman HJ: Hepatotoxicity. The Adverse Effects of Drugs and Other Chemicals on the Liver. New York, Appleton-Century-Crofts, 1978 107. Zimmerman HJ: Aspirin-induced hepatic injury. Ann Intern Med 80:74~ 76, 1974 108. Zimmerman HJ, Ishak KG. Valproate-induced hepatic injury: Analyses of 23 fatal cases. Hepatology 2:591~597, 1982 109. Zimmerman HJ, Lewis JH: Drug-induced cholestasis. Med ToxicoI2:ll2~160, 1987 110. Zimmerman HJ, Lewis JH: Hepatic toxicity of antimicrobial agents. In Root RK, Sande MA (eds): New Dimensions in Antimicrobial Therapy. New York, Churchill Livingstone, 1984, pp 153~202 ll1. Zimmerman HJ, Maddrey WC: Toxic and drug-induced hepatitis. In Schiff L, Schiff ER (eds): Diseases of the Liver, ed 5. Philadelphia, JB Lippincott, 1987, pp 591~667 112. Zimmerman HJ, Lewis JH, Ishak KG, et al: Ticrynafen-associated hepatic injury. Analysis of 340 cases. Hepatology 4:315~323, 1984 ll3. Zitelli BN, Alexander J, Taylor S, et al: Fatal hepatic necrosis due to pyrimethaminesulfadoxine (Fansidar). Ann Intern Med 106:393~395, 1987 Division of Gastroenterology Department of Medicine Georgetown University Medical Center 3800 Reservoir Road NW Washington, DC 20007-2197