Management of drug-induced liver disease.

The treatment and prevention of drug-induced liver injury starts with the recognition of hepatotoxicity at the earliest possible time so that the suspected drug can be discontinued expeditiously. Both liver enzyme monitoring and vigilance for signs of hypersensitivity involving the liver are useful strategies for many agents known to cause hepatocellular necrosis leading to liver failure. Specific antidotes to prevent or limit hepatic damage exist for only a few drugs, the most important being N-acetylcysteine for the treatment of acetaminophen hepatotoxicity. Corticosteroids are of unproven benefit in the setting of fulminant failure. Ursodiol may be helpful in instances of cholestatic injury. For other agents, supportive measures and the increasing use of liver-assist devices as well as emergency liver transplantation are available when drug injury evolves into irreversible liver failure. It is hoped that a better understanding of hepatotoxicity mechanisms will lead to the development of more specific and effective forms of therapy in the near future.

Drug-induced liver disease.

Drug-induced liver disease may account for between 10% and 50% of adult patients with elevated enzymes, especially in patients over age 50 years. It accounts for nearly 25% of patients with fulminant hepatic failure. Liver injury can be cytotoxic, cholestatic, or mixed. A variety of systemic manifestations can accompany drug-induced hepatotoxicity. Drug-induced liver disease can mimic autoimmune hepatitis or it can evolve to cirrhosis. It can also mimic veno-occulusive disorders. The plethora of herbal and traditional agents currently ingested by many people should always be considered in any patient with abnormal hepatic biochemistry.

Drug- and chemical-induced cholestasis.

Cholestasis resulting from drugs is an increasingly recognized cause of liver disease. It produces a broad clinical-pathologic spectrum of injury that includes simple jaundice, cholestatic hepatitis, and bile duct injury that can mimic extrahepatic biliary obstruction, primary biliary cirrhosis, and sclerosing cholangitis. Although the risk of drug-induced cholestasis leading to a fatal outcome is quite rare, knowledge and recognition of the various forms of cholestatic injury assumes an importance whenever clinicians are confronted with jaundice or other manifestations of liver disease in patients receiving medicinal or chemical agents.

Therapeutic misadventures with acetaminophen: hepatoxicity after multiple doses in children.

We compiled reports of acetaminophen hepatotoxicity after multiple overdoses from published cases, cases reported to the Food and Drug Administration, and cases from Children's Hospital Medical Center, Cincinnati, Ohio. Forty-seven children (age range, 5 weeks to 10 years) received 60 to 420 mg/kg/day for 1 to 42 days; 52% had received adult preparations of acetaminophen. The mean peak serum aspartate aminotransferase level was 10,225 IU/L (n = 45), and the mean serum alanine aminotransferase level was 7355 IU/L (n = 31), which were significantly higher (both p < 0.001) than the mean serum aspartate aminotransferase level of 3500 IU/L and alanine aminotransferase level of 3098 IU/L found in children (n = 12) with non-acetaminophen-associated hepatic failure. Serum acetaminophen levels for which an estimate of time from last dose could be calculated were available for 30 patients, of which 22 levels were greater than the toxic range described for acute ingestion. Twenty-four of 43 patients (55%) died, with an additional three surviving after orthotopic liver transplantation. Parents should be advised about the potential hepatotoxicity of acetaminophen when given to ill children in doses exceeding weight-based recommendations.

Risk of acute liver injury associated with the combination of amoxicillin and clavulanic acid.

BACKGROUND: Amoxicillin-clavulanic acid combination-associated hepatitis and jaundice was first identified in 1988. Numerous case reports and case series have been published since then, but there is no precise estimate of this risk. METHODS: A retrospective cohort study in the United Kingdom to estimate the risk of acute liver injury associated with the combination of amoxicillin and clavulanic acid and compare it with the one of amoxicillin alone. Data were derived from a cohort of 93,433 users of the combination drug amoxicillin-clavulanic acid and 360,333 users of amoxicillin alone who were aged between 10 and 79 years and who were followed up from 1991 through 1992. After reviewing the information on subjects with suspected liver injury that was recorded on computer files, the clinical records of 177 patients from the attending general practitioners were requested. RESULTS: They were 35 cases of idiopathic acute liver injury. None was fatal. There were 14 cases of acute liver injury among users of amoxicillin alone. The type of liver injury was hepatocellular in half the cases. There were 21 cases of acute liver injury among users of amoxicillin and clavulanic acid together. The type of liver injury was cholestatic in three quarters of the cases. The incidence rates and 95% confidence intervals (CIs) of developing acute liver injury associated with the combination of amoxicillin and clavulanic acid and amoxicillin alone were 1.7 (1.1-2.7) and 0.3 (.02-0.5) per 10 000 prescriptions, respectively. The rate ratios and 95% CIs of acute liver injury for amoxicillin and clavulanic acid together compared with amoxicillin alone were 6.3 (3.2-12.7) for all patients and 8.4 (3.6-20.8) for patients presenting with jaundice. Among users of amoxicillin and clavulanic acid together, the risk of developing acute liver injury was more than 3 times greater after a course of 2 or more consecutive prescriptions than after a single course of therapy. The risk also increased with age among users of amoxicillin and clavulanic acid together. The combination of advancing age and repeated prescriptions resulted in a risk of developing acute liver injury greater than 1 per 1000 users of amoxicillin and clavulanic acid together.

General aspects of drug-induced liver disease.

Medicinal agents can produce various types of hepatic injury by several mechanisms. Hepatic injury may lead to acute syndromes that resemble viral hepatitis, fatty liver of pregnancy, and obstructive jaundice, as well as to a number of chronic syndromes. Acute liver damage relates, at least in part, to the apparent mechanism of injury. Hepatic injury induced by large single overdose of intrinsically toxic drugs (e.g., acetaminophen, ferrous salts) develops within 24 to 72 hours of intake and usually is accompanied by renal failure. Regular intake of some toxic drugs, (e.g., methotrexate) leads to slowly evolving chronic disease. Liver damage due to hypersensitivity-type idiosyncrasy usually appears after 1 to 5 weeks of taking the drug unless there has been previous exposure and is preceded or accompanied by systemic features that are hallmarks of hypersensitivity. Hepatic injury attributable to metabolic idiosyncrasy may appear after weeks to months of taking the drug and usually presents without the systemic features. Organs other than the liver may be involved in the syndrome of drug-induced injury as the result of selective injury or as part of a hypersensitivity reaction.

Morphologic spectrum of drug-induced hepatic disease.

This article reviews the spectrum of pathologic changes in the liver induced by drugs and toxins. These resemble, and are often indistinguishable from, similar lesions from different origins. The changes are described briefly and examples are illustrated by photomicrographs from the files of the Armed Forces Institute of Pathology.

Chemical- and toxin-induced hepatotoxicity.

Hepatic injury due to chemicals or natural toxins may occur from occupational, household, or environmental exposure. The liver may dominate the syndrome of toxicity from such agents as carbon tetrachloride, poison mushrooms, and toxic alkaloids, or may be only one facet of more generalized toxicity. The entire histologic spectrum of injury, from fulminant acute disease to chronic vascular injury to hepatic neoplasia, is seen with agents in this category.

Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure.

Hepatic injury in alcoholics due to intake of acetaminophen (APAP or acetylparaaminophenol) with therapeutic intent has been reported, but the extent of the phenomenon is not clear, pertinent details of the association remain insufficiently clarified, and the importance of the phenomenon is not widely appreciated. The present report describes 67 patients who developed hepatic injury after ingestion of APAP with therapeutic intent. All were regular users of alcohol. Sixty-four percent of the patients were considered to be "alcoholic" or reported intakes greater than 80 g/d, 35% took 60 g/d or less, and the remainder were vague in their reporting. Doses of APAP were in the "nontoxic" range ( < 6 g/d) in 60% of the group, within the recommended range ( < 4 g/d) in 40%, and at 4.1 to 6 g/d in 20%. Characteristic feature was the towering level reached by aspartate transaminase (AST) with figures ranging from 3,000 to 48,000 IU in more than 90% of cases. Almost 20% of the patients died. The data on these patients were similar to 94 cases of injury from APAP taken with therapeutic intent reported in the literature. This study provides further evidence of hepatic injury in regular uses of alcohol, especially chronic alcoholics, who take APAP with therapeutic intent. Susceptibility is presumably caused by induction of cytochrome P-4502EI by ethanol and by depletion of glutathione (GSH) because of the effects of alcohol, the malnutrition often associated with alcoholism, and the depletion associated with chronic use of APAP and impaired glucuronidation caused by fasting perhaps as well. The syndrome of liver injury is distinctive, marked by uniquely elevated levels of AST, and poses a significant threat.(ABSTRACT TRUNCATED AT 250 WORDS)

Diclofenac-associated hepatotoxicity: analysis of 180 cases reported to the Food and Drug Administration as adverse reactions.

Diclofenac is a nonsteroidal anti-inflammatory drug approved in the United States in 1988 for the treatment of patients with osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis. To characterize the clinical, biochemical, and histological features and possible mechanisms of hepatic injury associated with its use, a retrospective analysis was undertaken of 180 patients whose cases were reported to the Food and Drug Administration from November 1988 through June 1991, as having had possible adverse reactions to diclofenac. Of the reported 180 cases, 79% were female, 71% were 60 years of age or older, and 77% had osteoarthritis. Sixty-seven percent of the cases were detected by symptoms and the remainder by abnormal laboratory tests. Seventy-five percent of the symptomatic patients (90 of 120) were jaundiced. Seven of the 90 icteric patients died. The biochemical pattern of injury was hepatocellular or mixed hepatocellular in 66% of cases. Only 8% had a pattern of cholestatic injury. The remainder, with modestly increased values of both transaminases and alkaline phosphatase, were considered "indeterminate," i.e., either mild hepatocellular or anicteric "cholestatic" injury. Sections of liver from 21 cases were available for study. Hepatic injury was apparent by 1 month after starting the drug in 24%, by 3 months in 63%, and by 6 months in 85% of cases. The latent period in 12% was 6 to 12 months, whereas in 3% it was greater than 12 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Idiosyncratic liver toxicity of nonsteroidal antiinflammatory drugs: molecular mechanisms and pathology.

This review explores the clinical hepatic pathology associated with the use of nonsteroidal antiinflammatory drugs (NSAIDs), possible cellular and molecular mechanisms of injury, and future challenges. NSAIDs comprise a group of widely used compounds that have been associated with rare adverse reactions in the liver, including fulminant hepatitis and cholestasis. These reactions are idiosyncratic, mostly independent of the dose administered, and host-dependent. The mechanisms responsible for the initiation and perpetuation of NSAID-induced hepatotoxicity remain poorly understood and have been largely inferred from clinical manifestation. A mounting body of evidence, however, indicates that many acidic NSAIDs are metabolized to reactive acyl glucuronides that can form covalent adducts with plasma proteins and hepatocellular proteins. In hepatocytes cocultured with lymphocytes, these NSAID-altered proteins can become antigenic. Thus, long-lived, drug-altered proteins may act as immunogens and produce cytotoxic T-cell-mediated or antibody-dependent, cell-mediated toxicity in susceptible patients. Alternatively, individual abnormalities in metabolism or disposition of some NSAIDs may lead to the formation or accumulation of toxic metabolites. Additional work with transgenic animal models is needed to permit better understanding of the general and specific risk factors involved in the pathogenesis of the idiosyncratic liver injuries related to NSAIDs and other drugs.

Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease.

OBJECTIVE: To characterize the hepatic effects of tacrine treatment in patients with Alzheimer's disease. DESIGN: Controlled trials of tacrine therapy consisting of two blinded, parallel-group trials; three blinded, enrichment-design trials; and their respective open-label extensions. SETTING: Multicenter clinical trials in the United States, France, and Canada. PATIENTS: A total of 2446 men and women at least 50 years of age with a diagnosis of probable Alzheimer's disease of mild to moderate severity and in good health without significant hepatic, cardiovascular, or renal disease. INTERVENTION: Administration of tacrine vs placebo, with weekly measurement of serum hepatic enzymes. MAIN OUTCOME MEASURES: Incidence, maximum severity, and timing of event for serum alanine aminotransferase (ALT) elevation. RESULTS: Among the 2446 patients who received tacrine in clinical trials, ALT levels greater than the upper limit of normal (ULN) occurred on at least one occasion in 1203 patients (49%), ALT levels greater than three times the ULN occurred in 621 patients (25%), and ALT levels greater than 20 times the ULN occurred in 40 patients (2%). The elevated ALT levels were generally asymptomatic and occurred more frequently in women than men. The mean time from initiation of tacrine treatment to first ALT level greater than three times the ULN was 50 days, and 90% of all initial ALT levels greater than three times the ULN occurred during the first 12 weeks of treatment. Of 145 patients who discontinued tacrine treatment because of an ALT level greater than three times the ULN and were rechallenged, 127 (88%) were able to resume long-term therapy with the drug. In all instances, discontinuing tacrine completely reversed elevations in ALT levels, and no deaths related to hepatotoxicity occurred. CONCLUSIONS: These data suggest that the potential for serious hepatic toxicity can be reduced through careful monitoring of ALT levels in patients who may benefit from tacrine therapy.

Hepatic sarcoidosis. Clinicopathologic features in 100 patients.

The patterns of hepatic injury were studied in 100 patients with a diagnosis of sarcoidosis and clinical evidence of liver disease that led to diagnostic liver biopsy. Granulomas were present in all patients; they occupied from < 1% to > 90% of the total volume of tissue examined and were most often located in the portal/periportal region. In none of the 100 cases were infectious organisms identified by special stains, culture, or serology. In 99% of cases, these granulomas were noncaseating; in one of the 100 cases central caseation was noted. In addition to the granulomas present in all biopsies, three broad categories of histologic change were found: cholestatic (58%), necroinflammatory (41%), and vascular (20%). Among those with cholestasis, 19 patients had bile duct lesions similar to primary biliary cirrhosis, whereas another 13 had a pattern of periductal fibrosis reminiscent of primary sclerosing cholangitis. In 37 patients with chronic cholestasis, a decrease in the number of bile ducts (ductopenia) was noted. Twelve patients had an acute cholangitis suggestive of mechanical obstruction--although no clinical evidence of ductal obstruction was found. Necroinflammatory changes included spotty necrosis suggesting hepatitis of diverse etiologies (including viral infection and drug reaction) and chronic portal inflammation suggestive of chronic active hepatitis. Vascular changes consisted of sinusoidal dilatation (14 cases) and nodular regenerative hyperplasia (9 cases). In 6% of the patients, the only changes in the biopsy were those of granulomatous inflammation; each of these patients had a dominant mass ("sarcoidoma"), which had been biopsied to rule out tumor. Fibrosis was seen in 21% of the biopsies--periportal (13%), bridging (2%), or cirrhosis (6%). It is clear that sarcoidosis can cause progressive liver disease with a wide array of histologic features that can mimic those of other primary liver diseases.

Hepatotoxicity.

Chemical hepatic injury may result from accidental or suicidal exposure to toxic agents in the home or at work or from adverse reactions to medicinal agents. Chemical hepatic injury can lead to acute or chronic syndromes. Acute injury may be cytotoxic, cholestatic, or mixed. Cytotoxic injury is characterized by necrosis, steatosis, or both. Cholestatic injury is characterized by arrested bile flow and may be associated with portal inflammation or may occur in a setting in which there is no evidence of inflammation. Chronic hepatic injury includes chronic active hepatitis, steatosis, phospholipidosis, veno-occlusive disease, several forms of cirrhosis, peliosis hepatis, and hepatic neoplasms. The mechanism for injury may be intrinsic toxicity of the agent, reaction of an unusually susceptible host, or a combination of the two factors. Unusual susceptibility may be the result of immunologic idiosyncrasy (hypersensitivity reaction) or injury from a toxic metabolite (metabolic idiosyncrasy) of the drug.

Sulindac-associated hepatic injury: analysis of 91 cases reported to the Food and Drug Administration.

BACKGROUND: Recent emphasis on nonsteroidal anti-inflammatory drug (NSAID)-associated hepatic injury blurs differences between NSAIDs. Accordingly, examination of hepatic injury by individual NSAIDs seemed warranted. Sulindac-associated hepatic injury was selected. METHODS: From 338 reports submitted to the Food and Drug Administration, 247 were considered inadequate or unconvincing for sulindac toxicity. The remaining 91 cases of reactions to the drug were analyzed. In 15 there was histological material available. RESULTS: There were four deaths, three attributed to severe hypersensitivity and one to fulminant hepatic failure. Two thirds of the cases had clinical hallmarks of hypersensitivity. The ratio of females to males was 3.5:1; 69% of the patients were over 50 years of age. Jaundice was recorded in 67% of the patients. The pattern was cholestatic in 43%, hepatocellular in 25%, mixed in 12%, and indeterminate in 20% of the patients. Eosinophilia was significantly more frequent in patients with cholestatic injury (40%) than in those with hepatocellular injury (0). CONCLUSION: Sulindac injury involves females more than males. It can lead to cholestatic or hepatocellular injury, most often because of immunological idiosyncrasy. In some patients, metabolic idiosyncrasy may be the mechanism. This study illustrates the utility of analysis of adverse reaction reports in characterizing drug-induced injury.

Effects of bile salt infusion on chlorpromazine-induced cholestasis in the isolated perfused rat liver.

The present study has demonstrated that tauroursodeoxycholate (TUDC), but not taurocholate, can reverse chlorpromazine (CPZ)-induced cholestasis in the isolated perfused rat liver. At an infusion rate of 1.5 mumol/min, TUDC led to restoration of bile flow in the perfused rat liver made cholestatic by the addition of 250 microM CPZ. This reversal was accompanied by an increased excretion of CPZ and its metabolites. A higher infusion rate of 5.0 mumols TUDC/min, however, led to only a transient increase in bile flow and to no increase in CPZ excretion. In contrast to the effects of TUDC, infusion of taurocholate led to an exacerbation of CPZ-induced cholestasis. The differences in the efficacy of the two bile salts may be due to their relative detergent (hydrophobic) properties.

Drug-induced cholestasis in the perfused rat liver and its reversal by tauroursodeoxycholate: an ultrastructural study.

Chlorpromazine at a concentration of 250 microM and estradiol-17 beta-D-glucuronide at 17.5 microM on infusion led to a sharp reduction in bile flow by the in vitro perfused rat liver. This was accompanied by fragmentation and a loss of canalicular microvilli, dilatation of canaliculi, and thickening of pericanalicular ectoplasm. Less prominent were the smooth endoplasmic reticulum dilatation, lysosomal lamination, and the appearance of amorphous bile in hepatocyte cytoplasm. The bile flow and electron microscopy appearance were restored to normal by infusion of tauroursodeoxycholate in a concentration of 5 mumols/min for the estradiol-17 beta-D-glucuronide-induced cholestasis and 1.5 mumol/min for the chlorpromazine-induced cholestasis. Changes in ultrastructure paralleled changes in bile flow. These observations demonstrate the feasibility of electron microscopy studies on the perfused liver, and the rapidity with which cholestatic changes appear.

Alcoholic liver disease: pathologic, pathogenetic and clinical aspects.

Alcoholic liver disease includes steatosis, alcoholic hepatitis and cirrhosis. Other liver diseases of genetic origin, but with a curious association with alcohol intake, are hemochromatosis and porphyria cutanea tarda. The attribution of chronic hepatitis to alcohol intake remains speculative, and the association may reflect hepatitis C infection. Hepatic injury attributed to alcohol includes the changes reported in the fetal alcohol syndrome. Steatosis, the characteristic consequence of excess alcohol intake, is usually macrovesicular and rarely microvesicular. Acute intrahepatic cholestasis, which in rare instances accompanies steatosis, must be distinguished from other causes of intrahepatic cholestasis (e.g., drug-induced) and from mechanical obstruction of the intrahepatic bile ducts (e.g., pancreatitis, choledocholithiasis) before being accepted. Alcoholic hepatitis (steatonecrosis) is characterized by a constellation of lesions: steatosis, Mallory bodies (with or without a neutrophilic inflammatory response), megamitochondria, occlusive lesions of terminal hepatic venules, and a lattice-like pattern of pericellular fibrosis. All these lesions mainly affect zone 3 of the hepatic acinus. Other changes, observed at the ultrastructural level, are of importance in progression of the disease. They include widespread cytoplasmic shedding, and capillarization and defenestration of sinusoids. Progressive fibrosis complicating alcoholic hepatitis eventually leads to cirrhosis that is typically micronodular but can evolve to a mixed or macronodular pattern. Hepatocellular carcinoma occurs in 5 to 15% of patients with alcoholic liver disease. The clinical syndrome of alcoholic liver disease is the result of three factors--parenchymal insufficiency, portal hypertension and the clinical consequences of extrahepatic damage produced by alcohol. At the several phases of the life history of alcoholic liver disease, the individual factors play a different role. The clinical manifestations of alcoholic steatosis are mainly extrahepatic in origin. Those of alcoholic hepatitis reflect mainly parenchymal insufficiency and those of cirrhosis are mainly those of portal hypertension. Alcoholic liver injury appears to be generated by the effects of ethanol metabolism and the toxic effects of acetaldehyde, perhaps the immune responses to alcohol- or acetaldehyde-altered proteins, and questionably enhanced by viral hepatitis. Alcoholic hepatitis may be mimicked histologically, and to a varying degree clinically, by a number of conditions (obesity, diabetes, several drug-induced injuries, jejunoileal bypass, and related "shortcircuiting" of the bowel). Perhaps the most important facet of the hepatotoxicity of alcohol is its enhancement of the effects of a number of other hepatotoxic agents, among which acetaminophen is the prime example.

Hepatotoxicity induced by the Oriental hornet (Vespa orientalis) venom sac extract.

Experiments were performed to investigate the nature of the in vitro and human liver damage exposed to hornets' acute or repeated stings. The hornet investigated is the one ubiquitous in Israel - Vespa orientalis. Experiments were performed in living cats and rats, after single or multiple exposures to venom-sac extracts (VSE) and in various doses. The injury was demonstrated by the increased levels of enzymes, bile acids and cholesterol in serum. Also measured was Beta-N-acetyl hexosaminidase (BNAH) which probably is the only biochemical indicator available of Kupffer-cell function. This, too, was found increased. Other experiments consisted of perfusion of the isolated, intact, rat liver in situ with measurements of enzyme leakage into perfusate and of bile flow. Another set of experiments involved the effects of VSE on in vitro monolayer tissue culture of rat embryos' livers. We examined damage to organelles and compared the damage produced by intact VSE with that produced by the venom sac extract after treatment by heat or dialysis. Light morphology, special stains, electron microscopy and morphometry were all performed. In the first set of experiments no shock was observed in cats and rats exposed to VSE. The increases in enzymes' activity in serum and liver perfusion fluid were significant. Histochemistry indicated decrease of hepatic glycogen and of cellular succinic dehydrogenase as well as hepatic fat infiltration and an increase of alkaline phosphatase activity in liver cells close to the bile capillaries.(ABSTRACT TRUNCATED AT 250 WORDS)