THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 9, No.5, 1996

Everyday Practice227

Drug-induced hepatotoxicity

AVTARLAL.J.S.BAPNA

INTRODUCTIONThe liver is the most important site of drug metabolism in the bodyand thus it is vulnerable to their toxic effects. More than 900 drugsare known to be associated with liver injury.'?

The diagnosis of drug-induced hepatotoxicity may be obviousbut is sometimes difficult, because it can closely mimic liverillnesses due to other causes.

TYPES OF LIVER INJURYDrug-induced hepatotoxicity can be divided into two categories:(i) dose-dependent (intrinsic) hepatotoxic reactions, and (ii) idio-syncratic (sensitization) reactions.

The typical features of dose-dependent hepatotoxic reactionsare:

I. production of a predictable and reproducible reaction when thedrug is administered to man or animal;

2. dose-related severity of reaction;3. appearance of clinical manifestations of reaction at a predictable

interval after exposure;4. laboratory tests compatible with hepatocellular damage; and5. findings of zonal necrosis with little parenchymal and inflam-

matory reaction on liver biopsy.

Hepatic necrosis induced by acetaminophen. carbon tetrachlo-ride and chloroform are typical examples of intrinsic hepatotoxicreactions.

Idiosyncratic drug reactions are characterized by:

I. occurrence of hepatic injury in a small number of personsreceiving the drug;

2. absence of hepatic injury when administered to animals;3. absence of correlation between the dose of the drug and extent

of reaction produced;4. unpredictable time interval from exposure to the onset of

reaction;5. other signs of hypersensitivity such as eosinophilia, fever,

arthralgia and rashes; and6. unknown pathogenesis.

Hepatic injuries induced by phenytoin, sulphonamides andhalothane are of the idiosyncratic type. 1

MECHANISMS OF LIVER INJURYMost drugs are non-polar compounds that are not easily elimi-nated from the body in their natural form as they are avidly

University College of Medical Sciences and Guru Teg Bahadur Hospital.Shahdara, New Delhi 110095. India

AVT AR LAL. J. S. BAPNA Department of Pharmacology

Correspondence to J. S. BAPNA

@ The National Medical Journal of India 1996

reabsorbed across renal tubular and bile ductular epithelium.Drug metabolizing systems convert these substances to polar,water-soluble derivatives that are efficiently excreted in the urineand bile. The liver plays an important role in this biotransforma-tion mainly by way of the mixed-function oxidase enzymesalthough other less important enzyme systems also contribute.

Biotransformation consists of two phases: Phase I is thetoxification phase. The introduction of polar groups yields meta-bolites which may produce hepatic injury. The enzymes respon-sible for the reaction are mixed function oxidases which containP450 and NADPH-cytochrome reductase. Exposure of the patientto drugs or chemicals that induce cytochrome P4S0 increases thelikelihood of hepatotoxic effects of drugs.' Drugs which alreadypossess a polar group bypass the phase I reaction.'

In phase II the metabolic product of the phase I reaction isconjugated with glucuronide. sulphate, glycine, glutathione or amethyl group so that it becomes water-soluble and can be ex-creted.

FACTORS INFLUENCING DRUG-INDUCEDHEPATOTOXICITYIndividual susceptibility to drug-induced liver injury may beaffected by genetic factors, age, sex, food, other drugs andobesity.

Genetic factorsThe expression of certain enzymes is genetically-mediated.Genetic predisposition may increase susceptibility to liver dam-age by isoniazid," phenytoin and halothane.'

Age and sexAdults are more susceptible than children to the toxic effects ofisoniazid. halothane and acetaminophen. On the other hand,children are more susceptible to hepatic injury by aspirin andsodium valproate.s'

Females appear more vulnerable than males to the hepato-toxicity of methyldopa and halothane.v?

Food and drugsBarbecued food, alcohol, tobacco. DDT, other insecticides,phenobarbitone, phenytoin and rifampicin induce cytochromeP450 enzyme which could potentially enhance the conversion ofdrugs to their toxic metabolites. A deficient intake of proteinsleads to depletion of glutathione which aggravates the toxicity ofacetaminophen. ).10

ObesityObesity may increase halothane-induced liver injury by storingthe drug in fatty tissue.

Drug interactionsSodium valproate and chlorpromazine can add on to the cholestasisinduced by oral contracepti ves. 10.11

CLINICAL PATfERNS OF LIVER INJURYLiver injury can take the form of hepatocellular damage, cholestaticdisease or exhibit a mixed pattern.

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Hepatocellular damageThis is usually indistinguishable from viral hepatitis or ischaemia.Drug history and laboratory investigations may aid the diagnosis.Acetaminophen and isoniazid are examples of drugs causinghepatocellular injury.

Cholestatic hepatitisThe common features of this are jaundice, direct reactinghyperbilirubinaemia, pruritus, light coloured stools, absence ofurobilinogen in the urine and an increase in serum alkalinephosphatase. Liver biopsy demonstrates cholestasis. Chlorpro-mazine and oestrogen are examples.

Mixed patternOccasionally features of both hepatocellular and cholestatic hepa-titis are present and the liver injury is then classified as mixedpattern hepatitis. Moderate abnormalities of serum transaminasesand alkaline phosphatase and a variable degree of jaundice maybe present. Phenytoin causes mixed pattern liver disease.

Granulomatous, fibrosing, vascular and neoplastic injurieshave also been reported with the use of drugs.I.5·IO·11

HEPATIC INJURY CAUSED BY SPECIFIC DRUGSA variety of pharmacological agents are associated with liverinjury.

Anaesthetic agentsSome of the volatile anaesthetics (halothane, methoxyflurane,enflurane, fluroxene, and isoflurane) induce idiosyncratic hepaticinjury .~.12Previous exposure to halothane, particularly if recent.'increases the chance of toxic reaction on re-exposure.

The onset is usually abrupt with fever, diffuse rash, myalgia,anorexia, nausea and chills and can occur up to two weeks afterexposure. Later, hepatomegaly, jaundice, liver failure and ascitesmay develop. Treatment consists of supportive measures anddealing with complications." Methoxyflurane also damages thekidneys.'? The incidence of hepatic damage with enflurane,fluroxene and isoflurane is less than that with halothane.t'"!':"

AntimicrobialsTetracyclines lead to dose-related hepatic injury. Most reportedcases have occurred in pregnant women given large doses intra-venously for pyelonephritis.' The histological lesion is identicalwith that of fatty Iiver of pregnancy. 5 As a general rule, not morethan I g of tetracycline should be given intravenously, nor morethan 2 g orally in 24 hours, and if renal function is impaired lowerdoses should be used.'

Erythromycin salts (estolate, succinate, propionate and stear-ate) cause hepatic injury (usually cholestatic) by hypersensitivity.Jaundice, pruritus and abdominal pain occur 2-21 days afterinitiation of therapy. Symptoms usually subside on withdrawal ofthe drug. 10Cholestatic liver injury has been reported with the useof cloxacillin, oxacillin and amoxicillin-clavulanic acid" combi-nation but not with amoxicillin alone.":" Cephalosporins havelittle hepatotoxicity but ceftriaxone can induce gallstone forma-tion."

Sulphonamides can cause acute hepatitis, granulomatous liverdisease, chronic active hepatitis, hepatic necrosis and cholestaticjaundice due to hypersensitivity. Trimethoprim has been associ-ated with cholestasis." Sulphamethoxazole-trimethoprim com-bination can cause severe hepatotoxicity, especially in patientswith the acquired immunodeficiency syndrome (AIDS). 14Sulpha-

THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 9, No.5, 1996

salazine and a combination of pyrimethamine-sulphadoxine canlead to liver damage." Nitrofurantoin causes cholestasis, hepato-cellular reaction and chronic hepatitis mimicking autoimmunehepatitis." Resolution is slow and incomplete even after with-drawal of the drug.'? Quinolones have been suspected to causecholestasis."

Antituberculous agentsThe identification of independent antitubercular agents respon-sible for the causation of hepatic injury is often difficult, as twoor more of these are given in combination. Isoniazid causes anasymptomatic elevation of serum aminotransferase levels in 10%-20% of patients which reverts to normal in a few weeks despitecontinuation of therapy. The incidence of clinically overt hepati-tis with jaundice is much less (about 0.1%). The illness is oftenindistinguishable from viral hepatitis and can be severe. Rifampicincauses hepatocellular and cholestatic damage. It is a potentenzyme-inducing agent which accelerates the metabolism ofisoniazid and can thus enhance its hepatotoxicity. Patients withAIDS are at greater risk of toxicity from these drugs. Ii

Antifungal and antiviral agentsHepatocellular necrosis (and less commonly cholestatic jaundice)can occur within 1-6 months of treatment with ketoconazole,though the incidence (1:15 000) is 10w.1OGriseofulvin is knownto produce cholestatic injury and porphyria. Fluocytosine causesfrank hepatic necrosis. II Antiviral agents such as idoxuridine,vidarabine and cytarabine cause cholestatic as well as hepato-cellular injury.!"!'

Analgesic and anti-inflammatory drugsIngestion of more than IS g of acetaminophen invariably leads tohepatic damage.' There is considerable variation in susceptibilitybut individuals suffering from alcohol abuse are particularly atrisk.' Initially, the patient is nauseated, vomiting and diaphoreticand this is followed by a period of apparent recovery until signsof hepatic failure supervene 48-72 hours later. Toxic metabolites(probably N-acetyl-p-benzoquinoneimine)5 are produced by cyto-chrome P450 enzymes. Because these exceed the scavengingcapacity of the glutathione system, hepatic injury occurs. N-acetylcysteine, a precursor of glutathione, if administered withinthe first ten hours of injury gives the best results. Cimetidine mayalso help by inhibiting cytochrome P450 enzyme activity .I~Livertransplantation is the final option."

Aspirin-induced focal liver necrosis occurs in patients withjuvenile rheumatoid arthritis, systemic lupus erythematosus andhypoalbuminaemia. Hepatic damage usually resolves rapidlyafter withdrawal of the drug." Aspirin may cause Reye's syn-drome in children 4-12 years of age especially those who haveinfluenza B and respiratory tract infection after chickenpox. Fattyinfiltration of the liver and kidneys develops rapidly. Manypatients die within 2-4 days if supportive care, glucose supple-ments and efforts to lower the blood ammonia level and raisedcerebrospinal pressure remain unsuccessful.v'?

Phenylbutazone and oxyphenbutazone have been reported tocause hepatocellular necrosis, cholestatic jaundice and granulo-matous injury in about 0.25% of patients within 6 months ofstarting therapy. Diclofenac sodium causes hepatic injury whichmay be fatal. Patients with osteoarthritis and females are particu-larly susceptible. Indomethacin causes hepatocellular and chole-static jaundice.P" Ibuprofen, naproxen and piroxicam have a lowincidence of hepatic injury.

LAL, BAPNA : DRUG-INDUCED HEPATOTOXICITY

Drugs used/or musculoskeletal diseasesIntrahepatic cholestasis and hepatocellular necrosis are rare com-plications of gold and allopurinol therapy and usually resolvewithin 3 months of cessation.":" Colchicine is hepatotoxic. II

AnticonvulsantsHepatocellular necrosis is a well-documented complication ofphenytoin therapy. It is commoner in females and occurs within6 weeks of treatment. Allergic features like rash, fever, lymph-adenopathy and eosinophilia are frequently present and there maybe manifestations of Stevens-Johnson syndrome. Sodium val-proate causes serious and occasionally fatal hepatocellular necro-sis and bile duct injury. Epileptic children below the age of2 yearsare more susceptible.' Other risk factors are concomitant therapywith anticonvulsant drugs, mental retardation and other congeni-tal abnormalities.' Carbamazepine causes hepatocellular, chole-static and granulomatous injury usually within one month ofinitiating therapy. 23

Psychotropic drugsChlorpromazine has been associated with cholestatic hepatitisand hepatocelllar injury which occurs in I% of patients and within1-5 weeks of onset of therapy. Cross-reacti vity with other pheno-thiazines has been observed. The patient may develop fever,chills, malaise, anorexia, itching, arthralgia, lymphadenopathyand eosinophilia. The damage is immunologically mediated andprognosis is usually good. Cholestyramine may help in reducingpruritus." Iproniazid causes hepatic necrosis in I% of patientswithin 3 months.' The symptoms consist of anorexia, malaise,fatigue and jaundice. Mortality in clinically jaundiced patients isabout 15%. Tricyclic antidepressants and trazadone have alsobeen incriminated in several instances of hepatic injury .10.24

Anabolic and contraceptive steroidsAnabolic and androgenic steroids and oral contraceptives induceacute cholestatic jaundice, peliosis hepatis and hepatic tumours.Jaundice usually appears 1-6 months after starting oral contra-ceptives. Complete recovery occurs within a few months ofstopping the drug."

Cardiovascular agentsCalcium channel blocker such as verapamil and diltiazem cancause hepatocellular necrosis within 2-3 weeks of the initiation oftherapy. 10

Methyldopa has been associated with acute and chronic he-patic injury, usually weeks to months after commencement oftherapy. Paradoxically, there may be a gradual return to normaldespite continuation of the drug suggesting some alternativepathway of toxic metabolite disposal. Hydralazine causes hepato-cellular necrosis and hepatic granuloma, which reverses rapidlyon withdrawal of the drug." Angiotensin-converting enzymeinhibitors (captopril, enalapril and lisinopril) and some beta-adrenergic blockers (atenolol, acebutolol and metoprolol) havebeen associated with injury to the liver. 10 Amiodarone can causeisolated increases in transaminase levels during long term treat-ment but acute liver intoxication has also been reported whichmay have a fatal outcome." Other antiarrhythmics (quinidine,procainamide and disopyramide) cause hepatocellular injury within6-12 days of the initiation of treatment. Heparin, warfarin,phenindione and ticlopidine used as anticoagulants have alsobeen associated with hepatic injury. Clofibrate causes mildcholestasis. Nicotinic acid induces dose-related cholesatic

229

hepatic injury which resolves within one month of cessation of thedrug. Some evidence of hepatic injury has been seen with HMG-CoA reductase inhibitors such as lovastatin, simvastatin andpravastatin.!"!'

Drugs used/or peptic ulcerCimetidine and ranitidine induce cholestatic and hepatocellularinjury but the incidence is low. Rapid reversal occurs afterwithdrawal of the offending drug. II

Oral hypoglycaemic agentsChlorpropamide, tolbutamide and tolazamide induce cholestaticjaundice. Acetohexamide causes hepatocellular, mixed and chole-static injury which reverts to normal on withdrawal.lO.1I

Antithyroid drugsThiourea, methimazole, carbimazole and methyl-thiouracil causecholestatic jaundice. Propyl-thiouracil induces hepatocellularinjury due to hypersensitivity. Resolution of liver damage occurson drug withdrawal."

Antineoplastic drugsAntimetabolites cause dose-related liver damage. Methotrexatehas been associated with liver damage which correlates withcumulative dose, duration of therapy and length of intervalbetween doses.' Antipyramidines produce fatty liver and hepato-cellular necrosis. Cytarabine, 5-fluorouracil and floxuridine alsocause hepatic injury. Antipurines such as mercaptopurine,azathioprine and thioguanine cause hepatocellular necrosis.Asparaginase, cyclosporine and cytotoxic drugs namely dactino-mycin, doxorubicin, daunomycin and cycloheximide also inducehepatic lesions. Vinca alkaloids rarely cause hepatic injury.Alkylating agents like nitrogen mustard, mechlorethane, mel-phalan, chlorambucil, and cyclophosphamide lead to hepatocel-lular necrosis. Busulphan causes cholestasis whereas tamoxifencauses peliosis hepatis."

Miscellaneous drugsStreptokinase, penicillamine, disulfiram, emetine and etretinateinduce hepatic injury.v-!'

Herbal. ayurvedic and unani medicinesMany herbal preparations contain hepatotoxic alkaloids.' Bushteas, seatone, pennyroyal oil and mistletoe cause liver damage.'Alternative medicine preparations used in India need to be evalu-ated for hepatotoxicity. Known hepatotoxic agents are Sameera-panag, which forms the base for many other preparations, andMallasindoor. Both these agents contain mercury and arsenic, andshould be dispensed only by qualified practitioners. If correctlyprepared, neither should cause liver damage.

CONCLUSIONThe clinical picture of drug-induced hepatotoxicity is varied andmay be non-specific. Awareness of the hepatotoxic potential ofdrugs commonly used in clinical practice is important. A thor-ough history and a high index of suspicion are probably the mostimportant aids to diagnosis. Other causes of Iiver disease must beeliminated. On suspicion of hepatic injury, the offending drugshould be withdrawn. Until extensive experience with any newcompound has evolved, it is best to maintain a healthy paranoia-there are very few totally safe agents.

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