Effects of aspirin and acetaminophen on the liver.

The mechanism for aspirin-caused liver injury is not clear. Aspirin produces hepatotoxic reactions as a cumulative phenomenon, requiring days or weeks to develop. Patients with active rheumatic or collagen disease, as well as children, are especially susceptible. Blood levels of salicylate higher than 25 mg/dL are particularly likely to lead to hepatic injury. Levels lower than 15 mg/dL rarely do. The mechanism for acetaminophen liver damage is quite clear. It produces hepatic injury as a result of a large single overdose, usually suicidal in intent. Patients with acetaminophen blood levels higher than 300 mg/dL at four hours after intake are most likely to develop hepatic damage; when N-acetylcysteine is used within the first ten hours after ingestion of an overdose, the recovery rate is reported to be virtually 100%. The conditions of patients receiving long-term full doses of either aspirin or acetaminophen should be intermittently monitored for hepatic injury.

Cholestatic hepatic injury related to warfarin exposure.

Despite the widespread use of oral anticoagulants derived from 4-hydroxycoumarin, there have been only a small number of well-defined cases of hepatotoxicity. We report a well-defined case of cholestasis following exposure to warfarin sodium (Coumadin). Inadvertent rechallenge reproduced the syndrome. Cholestasis may occur in response to exposure to derivations of 4-hydroxycoumarin.

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.

Chlorzoxazone hepatotoxic reactions. An analysis of 21 identified or presumed cases.

A drug rechallenge proved chlorzoxazone to be hepatotoxic in a patient who had been treated with a combination of it and acetaminophen (Parafon Forte) for several months. Failure to demonstrate a toxic response to acetaminophen coupled with a dramatic response to a single dose of chlorzoxazone implicated chlorzoxazone as the hepatotoxic agent. A review of US Food and Drug Administration records and cases reported in the medical literature disclosed 23 cases of chlorzoxazone-associated hepatotoxic reactions occurring since 1970. These cases were examined in terms of age, duration of therapy, other confounding etiologic factors, and ultimate outcome. There were two deaths involving hepatic failure. Reports of adverse reactions among six commonly used analgesic-muscle relaxants in Sweden have indicated a low, but comparatively greater, incidence of hepatotoxic reactions associated with a chlorzoxazone-containing compound.

Liver involvement in the sulfone syndrome.

A patient being treated with dapsone developed a hypersensitivity reaction with typical features of the "sulfone syndrome," including fever, malalse, and hepatitis. All abnormalities rapidly reversed with discontinuance of the dapsone regimen and institution of prednisone therapy. Hepatic involvement may be a prominent feature of the sulfone syndrome and may be of the hepatocellular or cholestatic type. Based on our review of the Food and Drug Administration reports, this syndrome appears to be relatively uncommon, but physicians need to recognize that expression of this syndrome may be incomplete. More clinical data are necessary to better define the incidence and pathogenesis of sulfone-induced liver disease.

Cytotoxic effects of erythromycin estolate and chlorpromazine on hepatocytes isolated from rats of varying ages: a brief note.

Hepatocytes isolated from young (1 month) rats were as sensitive to the cytotoxic effects of erythromycin estolate and chlorpromazine as were liver cells obtained from older (3, 10 and 24 months) rats. The hepatocytes from the 24-month-old rats released aspartate transaminase more slowly than did parenchymal cells isolated from the younger rats.

Chronic intrahepatic cholestasis of sarcoidosis.

The development of the syndrome of chronic intrahepatic cholestasis in five young, black men who had systemic granulomatous disease and clinical features consistent with those of sarcoidosis is described. Clinical and biochemical aspects, similar to those of primary biliary cirrhosis, included pruritus, jaundice, hepatomegaly and striking elevations of serum levels of alkaline phosphatase and cholesterol. (One patient had skin xanthomas.) Mitochondrial antibodies were not found; and survival of the patients (7 to 18 years) exceeded the usual survival of patients with primary biliary cirrhosis. The histologic abnormalities included noncaseating granulomas, chronic intrahepatic cholestasis, increased copper in hepatocytes, progressive diminution in number of interiobular bile ducts, periportal fibrosis and the eventual development of a micronodular "biliary" cirrhosis. The histologic evolution of the disease suggests a slow, progressive destruction of the bile ducts by granulomas. Although the end stage of this syndrome resembles primary biliary cirrhosis, the characteristic nonsuppurative, destructive cholangitis of primary biliary cirrhosis was not present.

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.

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.

Drug-induced liver disease.

The large number of chemical agents administered for therapeutic or diagnostic purposes can produce various types of hepatic injury by several mechanism. Acute injury may be cytotoxic, cholestatic or mixed. Cytotoxic injury may consist of necrosis or steatosis. Cholestatic injury may be cholangiolitic (hepatocanalicular) or bland (canalicular). Chronic hepatic lesions caused by medicinal agents include chronic active hepatitis, steatosis, cirrhosis, fibrosis, hepatoportal sclerosis (non-cirrhotic portal hypertension), hepatic vein thrombosis, peliosis hepatis, adenoma, carcinoma, and angiosarcoma. There is a useful relationship between the type of hepatic injury and the chemical setting in which the drugs are employed. Some agents produce the liver damage because they are intrinsic (true, predictable) hepatotoxins. Other (non-predictable "hepatotoxins"), produce hepatic injury only in the rare and unusually susceptible individual (idiosyncratic injury). Hepatotoxic agents can be recognised by their dose-dependent and experimental reproducibility, properties which are not shared by agents which produce hepatic injury only in idiosyncratic hosts. Intrinsic hepatotoxins may be categorised as direct or indirect. Direct hepatotoxins injure the hepatocyte by direct physiochemical alteration and as a consequence produce metabolic defects. Indirect hepatotoxins selectively block metabolic pathways and, by producing a precise biochemical lesion, lead to structural changes. They may lead to hepatic steatosis or necrosis (cytotoxic indirect hepatotoxins) or block bile flow (cholestatic indirect hepatotoxins). Direct hepatotoxins are rarely encountered as drugs. Overdoses of some drugs and antineoplastic agents appear to be indirect cytotoxic hepatotoxins, and the C-17 alkylated anabolic and contraceptive steroids are indirect, cholestatic hepatotoxins. Idiosyncracy of the host is the mechanism for most types of drug-induced hepatic injury. It may reflect allergy to the drug or a metabolic aberration of the host permitting the production of hepatotoxic metabolites.

Effects of three H2 antagonists on the isolated perfused rat liver. Correlation of bile flow changes with potential for causing hepatic disease in patients.

The adverse effects of oxmetidine, an H2 blocking agent which has been shown to produce hepatic injury in 1-4% of patients, on an in vitro model were compared with those of cimetidine and ranitidine which have led to only rare instances of hepatic injury. Bile flow was measured in the isolated perfused rat liver (Wistar rats), comparing the effects of each of the three drugs with control perfusions. Oxmetidine in concentrations of 3 X 10(-3) M or greater led to a decrease in bile flow within 15 min and, at a concentration of 5 X 10(-3) M, to complete cessation of flow within 5 min. Lower concentrations (5 X 10(-4) M) led to a marked choleresis. Ranitidine and cimetidine in concentrations up to 5 X 10(-3) M produced no decrease in bile flow. Ranitidine, however, led to a choleresis at a concentration of 5 X 10(-3) M. The positive correlation between in vivo and in vitro toxicity supports the view that in vitro testing may prove to be of use in predicting the hepatotoxic potential of a drug.

Various forms of chemically induced liver injury and their detection by diagnostic procedures.

A large number of chemical agents, administered for therapeutic or diagnostic purposes, can produce various types of hepatic injury by several mechanisms. Some agents are intrinsically hepatotoxic, and others produce hepatic injury only in the rare, uniquely susceptible individual. Idiosyncrasy of the host is the mechanism for most types of drug-induced hepatic injury. It may reflect allergy to the drug or a metabolic aberation of the host permitting the accumulation of hepatotoxic metabolites. The syndromes of hepatic disease produced by drugs have been classified hepatocellular, hepatocanalicular, mixed and canalicular. Measurement of serum enzyme activities has provided a powerful tool for studies of hepatotoxicity. Their measurement requires awareness of relative specificity, knowledge of the mechanisms involved, and knowledge of the relationship between known hepatotoxic states and elevated enzyme activities.

The clinician's view of diagnostic electron microscopy.

From the clinician's standpoint, it has become increasingly evident that use of the electron microscope should no longer be confined to research institutes, but should be applied as an adjunct to clinical diagnosis, a guide to therapy, and a means of elucidating pathogenetic mechanisms. The usefulness of electron microscopy is stressed in relation to hematology, nephrology, virology, gastroenterology, and the study of miscellaneous metabolic conditions such as the storage diseases.

Drug-induced chronic hepatic disease.

A number of chronic hepatic lesions can result from adverse reactions to medicinal agents. Such lesions include a form of chronic active hepatitis; hepatic steatosis, phoepholipidosis and granulomatosis; several vascular lesions; two types of noncirrhotic portal hypertension; several types of cirrhosis and several neoplasms.

Drug-induced liver disease.

The relative importance of drug-induced liver disease assumes much significance in certain groups of patients such as the elderly. The majority of cases occur as unexpected reactions to a therapeutic dose of a drug. Factors affecting susceptibility to drug-induced liver disease are diverse and are discussed in this article.

Effects of endotoxin tolerance on hepatic excretory function: in vivo study.

Induction of endotoxin tolerance in rats led to reductions in bile flow and BSP excretion. BSP serum retention or storage of BSP in the liver was not affected. Although serum alanine aminotransferase (ALT) activity was slightly elevated in endotoxin-tolerant rats, the levels of serum aspartate amino-transferase (AST) and hepatic 5'-nucleotidase were normal. These in vivo data support the validity of in vitro studies demonstrating the cholestatic effect of endotoxin and the viewpoint that endotoxin may be responsible for the cholestatic jaundice associated with Gram-negative bacterial infections.

Va cooperative study of post-transfusion hepatitis, 1969-1974: incidence and characteristics of hepatitis and responsible risk factors.

The Veterans Administration has been conducting a cooperative randomized, double-blind, controlled trial to evaluate the efficacy of conventional and hepatitis B immune serum globulin for the prevention of post-transfusion hepatitis. Data collected between 1969 and 1974 provide the opportunity to describe the annual incidence and characteristics of the hepatitis that has developed, and the risk factors which have been identified. Anicteric hepatitis has developed four times more frequently than icteric hepatitis, the total incidence for all six years being 11.3 per cent. The incidence of HBs Ag-associated hepatitis declined dramatically after 1973 with the institution of routine screening of donor blood by radioimmunoassay techniques, although no change in the incidence of antigen-negative hepatitis has occurred. There is indirect evidence to suggest that an undefined agent is responsible for the majority of instances of post-transfusion hepatitis occurring presently. The most important risk factor responsible for the development of hepatitis is the use of commercial blood, and it is strongly urged that this form of blood be removed from general use.

Hepatic disease in asymptomatic parenteral narcotic drug abusers: a Veterans Administration collaborative study.

The Veterans Administration is currently conducting a collaborative study in three hospital-based drug treatment clinics to evaluate asymptomatic parenteral drug addicts for evidence of hepatic disease. Preliminary data are presented on 347 patients who have completed at least three months of follow-up evaluation. On admission, abnormal serum transaminase values were demonstrated in one half, HBs Ag in 7 per cent, and anti-HBs in 59 per cent. The frequency of these findings increased during the follow-up evaluation, only 19 (5.5 per cent) remaining entirely free of one or more of these abnormalities. Definable hepatologic disease (acute or chronic hepatitis, alcoholic hepatitis) developed in 46 per cent of the patients. However, among 60 of them subjected to liver biopsy, a poor correlation was noted between the clinical and histologic diagnoses. In particular, routine liver function and immunologic tests did not discriminate between histologically detected chronic active and chronic persistent hepatitis. However, HBs Ag was present significantly more frequently in those with chronic active hepatitis. Wide variability of histologic diagnoses was seen among patients subjected to more than one biopsy, apparent progression and regression of the lesion being noted. This demonstrates the hazard of attempting to assign a prognosis to the disease on the basis of a single liver biopsy specimen, and suggests that repeated biopsies should be mandatory for the evaluation of chronic liver disease in drug addicts.

Immaturity of the biliary excretory system predisposes neonates to intrahepatic cholestasis.

Intrahepatic cholestasis associated with both gram-negative bacterial infections and total parenteral nutrition (TPN) is observed more frequently in neonates than in older children or adults. Factors involved in the pathogenesis of this syndrome are uncertain. The cholestatic effects of gram-negative bacterial infections appear to result from the inhibitory effects of endotoxin on bile flow. Since the adverse effects of both endotoxin and TPN on bile flow involve primarily the bile acid-independent portion, the immaturity of the neonatal hepatic excretory system which an inadequate bile acid-dependent fraction of bile would explain the increased susceptibility of the neonate to endotoxin- and, perhaps, to TPN-induced cholestasis.