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DOI: 10.1055/s-2002-30103
Hepatotoxicity of Antimicrobial Agents
Publication History
Publication Date:
16 May 2002 (online)
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ABSTRACT
Antimicrobial agents are a common and important cause of hepatotoxicity. As a class, the antimicrobials contain many and varied structures, leading to a wide clinical spectrum of hepatotoxicity. Minor liver injury, manifest only as liver enzyme elevations, is common with some antimicrobials. Clinically significant injury is unusual but can adopt almost any form. Classical acute hepatocellular, cholestatic, or mixed reactions are most often seen. Other forms of hepatotoxicity including granulomatous reactions, steatosis, chronic hepatitis, and cirrhosis have also been described. Generally, antimicrobial-associated hepatotoxicity is mild and self-limited; most cases resolve after withdrawal of the offending medication. Occasionally, however, liver injury presents as a fulminant life-threatening condition or may develop into a chronic illness with significant morbidity. This article presents a summary of reported hepatotoxicity associated with the major classes of antimicrobials and, where possible, identifies potential risk factors and management strategies to assist clinical practice.
KEYWORDS
Liver - human - hepatitis - toxic hepatitis - hepatotoxicity - toxicity - drug - medication - side effect - infection - tuberculosis - human immunodeficiency virus - antimicrobials - antibiotics - antifungals - antivirals - antiparasitic agents - review
REFERENCES
- 1 Benichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol . 1990; 11 272-276
- 2 Farrell G C. Drug-induced hepatic injury. J Gastroenterol Hepatol . 1997; 12 S242-S250
- 3 Maria V A, Victorino R M. Diagnostic value of specific T cell reactivity to drugs in 95 cases of drug induced liver injury. Gut . 1997; 41 534-540
- 4 Zimmerman H J. Drug-induced liver disease. In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff's Diseases of the Liver Philadelphia: Lippincott-Raven 1999: 973
- 5 Goldstein L I, Ishak K G. Hepatic injury associated with penicillin therapy. Arch Pathol . 1974; 98 114-117
- 6 Reddy K R, Schiff E R. Hepatotoxicity of antimicrobial, antifungal, and antiparasitic agents. Gastroenterol Clin North Am . 1995; 24 923-936
- 7 Presti M E, Janney C G, Neuschwander-Tetri B A. Nafcillin-associated hepatotoxicity. Report of a case and review of the literature. Dig Dis Sci . 1996; 41 180-184
- 8 Derby L E, Jick H, Henry D A. Cholestatic hepatitis associated with flucloxacillin. Med J Aust . 1993; 158 596-600
- 9 Devereaux B M, Crawford D H, Purcell P. Flucloxacillin associated cholestatic hepatitis. An Australian and Swedish epidemic?. Eur J Clin Pharmacol . 1995; 49 81-85
- 10 Hewitt J, Hammond L. Adverse hepatic events associated with drug therapy. Med J Aust . 1996; 165 347-350
- 11 Fairley C K, McNeil J J, Desmond P. Risk factors for development of flucloxacillin associated jaundice. BMJ . 1993; 306 233-235
- 12 Desmond P V. Flucloxacillin hepatitis-an Australian epidemic. Aust N Z J Med . 1995; 25 195-196
- 13 Eckstein R P, Dowsett J F, Lunzer M R. Flucloxacillin induced liver disease: histopathological findings at biopsy and autopsy. Pathology . 1993; 25 223-228
- 14 Olsson R, Wiholm B E, Sand C. Liver damage from flucloxacillin, cloxacillin and dicloxacillin. J Hepatol . 1992; 15 154-161
- 15 Bolzan H, Spatola J, Castelletto R. Intrahepatic cholestasis induced by amoxicillin alone. Gastroenterol Hepatol . 2000; 23 237-239
- 16 Larrey D, Vial T, Micaleff A. Hepatitis associated with amoxycillin-clavulanic acid combination report of 15 cases. Gut . 1992; 33 368-371
- 17 Thomson J A, Fairley C K, Ugoni A M. Risk factors for the development of amoxycillin-clavulanic acid associated jaundice. Med J Aust . 1995; 162 638-640
- 18 Hautekeete M L, Brenard R, Horsmans Y. Liver injury related to amoxycillin-clavulanic acid: interlobular bile-duct lesions and extrahepatic manifestations. J Hepatol . 1995; 22 71-77
- 19 Hautekeete M L, Horsmans Y, Van Waeyenberge C. HLA association of amoxicillin-clavulanate-induced hepatitis. Gastroenterology . 1999; 117 1181-1186
- 20 O'Donohue J, Oien K A, Donaldson P. Co-amoxiclav jaundice: clinical and histological features and HLA class II association. Gut . 2000; 47 717-720
- 21 Quattropani C, Schneider M, Helbling A. Cholangiopathy after short-term administration of piperacillin and imipenem/cilastatin. Liver . 2001; 21 213-216
- 22 Parry M F, Neu H C. A comparative study of ticarcillin plus tobramycin versus carbenicillin plus gentamicin for the treatment of serious infections due to gram- negative bacilli. Am J Med . 1978; 64 961-966
- 23 Ryan J, Dudley F J. Cholestasis with ticarcillin-potassium clavulanate (Timentin). Med J Aust . 1992; 156 291
- 24 Thompson J W, Jacobs R F. Adverse effects of newer cephalosporins. An update. Drug Saf . 1993; 9 132-142
- 25 Ammann R, Neftel K, Hardmeier T, Reinhardt M. Cephalosporin-induced cholestatic jaundice. Lancet . 1982; 2 336-337
- 26 Meyers B R. Comparative toxicities of third-generation cephalosporins. Am J Med . 1985; 79 96-103
- 27 Lee W M. Drug-induced hepatotoxicity. N Engl J Med . 1995; 333 1118-1127
- 28 Kim Y S, Kestell M F, Lee S P. Gall-bladder sludge: lessons from ceftriaxone. J Gastroenterol Hepatol . 1992; 7 618-621
- 29 Shiffman M L, Keith F B, Moore E W. Pathogenesis of ceftriaxone-associated biliary sludge. In vitro studies of calcium-ceftriaxone binding and solubility. Gastroenterology . 1990; 99 1772-1778
- 30 Westphal J F, Vetter D, Brogard J M. Hepatic side-effects of antibiotics. J Antimicrob Chemother . 1994; 33 387-401
- 31 Gough A, Chapman S, Wagstaff K. Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome. BMJ . 1996; 312 169-172
- 32 Breen K J, Schenker S, Heimberg M. Fatty liver induced by tetracycline in the rat. Dose-response relationships and effect of sex. Gastroenterology . 1975; 69 714-723
- 33 Lawrenson R A, Seaman H E, Sundstrom A. Liver damage associated with minocycline use in acne: a systematic review of the published literature and pharmacovigilance data. Drug Saf . 2000; 23 333-349
- 34 Davies M G, Kersey P J. Acute hepatitis and exfoliative dermatitis associated with minocycline. BMJ . 1989; 298 1523-1524
- 35 Teitelbaum J E, Perez-Atayde A R, Cohen M. Minocycline-related autoimmune hepatitis: case series and literature review. Arch Pediatr Adolesc Med . 1998; 152 1132-1136
- 36 Goldstein N S, Bayati N, Silverman A L. Minocycline as a cause of drug-induced autoimmune hepatitis. Report of four cases and comparison with autoimmune hepatitis. Am J Clin Pathol . 2000; 114 591-598
- 37 Knowles S R, Shapiro L, Shear N H. Serious adverse reactions induced by minocycline. Report of 13 patients and review of the literature. Arch Dermatol . 1996; 132 934-939
- 38 Bjornsson E, Lindberg J, Olsson R. Liver reactions to oral low-dose tetracyclines. Scand J Gastroenterol . 1997; 32 390-395
- 39 Lienart F, Morissens M, Jacobs P. Doxycycline and hepatotoxicity. Acta Clin Belg . 1992; 47 205-208
- 40 Carson J L, Strom B L, Duff A. Acute liver disease associated with erythromycins, sulfonamides, and tetracyclines. Ann Intern Med . 1993; 119 576-583
- 41 Degott C, Feldmann G, Larrey D. Drug-induced prolonged cholestasis in adults: a histological semiquantitative study demonstrating progressive ductopenia. Hepatology . 1992; 15 244-251
- 42 Periti P, Mazzei T, Mini E. Adverse effects of macrolide antibacterials. Drug Saf . 1993; 9 346-364
- 43 Cascaval R I, Lancaster D J. Hypersensitivity syndrome associated with azithromycin. Am J Med . 2001; 110 330-331
- 44 Wallace Jr J R, Brown B A, Griffith D E. Drug intolerance to high-dose clarithromycin among elderly patients. Diagn Microbiol Infect Dis . 1993; 16 215-221
- 45 Pedersen F M, Bathum L, Fenger C. Acute hepatitis and roxithromycin. Lancet . 1993; 341 251-252
- 46 Easton-Carter K L, Hardikar W, Smith A L. Possible roxithromycin-induced fulminant hepatic failure in a child. Pharmacotherapy . 2001; 21 867-870
- 47 Larrey D, Amouyal G, Danan G. Prolonged cholestasis after troleandomycin-induced acute hepatitis. J Hepatol . 1987; 4 327-329
- 48 Pessayre D, Larrey D, Funck-Brentano C. Drug interactions and hepatitis produced by some macrolide antibiotics. J Antimicrob Chemother . 1985; 16(Suppl A) 181-194
- 49 Tonder M, Nordoy A, Elgjo. Sulfonamide-induced chronic liver disease. Scand J Gastroenterol . 1974; 9 93-96
- 50 Konttinen A, Perasalo J O, Eisalo A. Sulfonamide hepatitis. Acta Med Scand . 1972; 191 389-391
- 51 Phillips-Howard P A, West L J. Serious adverse drug reactions to pyrimethamine-sulphadoxine, pyrimethamine-dapsone and to amodiaquine in Britain. J R Soc Med . 1990; 83 82-85
- 52 Zitelli B J, Alexander J, Taylor S. Fatal hepatic necrosis due to pyrimethamine-sulfadoxine (Fansidar). Ann Intern Med . 1987; 106 393-395
- 53 Lazar H P, Murphy R L, Phair J P. Fansidar and hepatic granulomas. Ann Intern Med . 1985; 102 722
- 54 Alberti-Flor J J, Hernandez M E, Ferrer J P. Fulminant liver failure and pancreatitis associated with the use of sulfamethoxazole-trimethoprim. Am J Gastroenterol . 1989; 84 1577-1579
- 55 van der Ven J A, Koopmans P P, Vree T B. Adverse reactions to co-trimoxazole in HIV infection. Lancet . 1991; 338 431-433
- 56 Levy M. Role of viral infections in the induction of adverse drug reactions. Drug Saf . 1997; 16 1-8
- 57 Munoz S J, Martinez-Hernandez A, Maddrey W C. Intrahepatic cholestasis and phospholipidosis associated with the use of trimethoprim-sulfamethoxazole. Hepatology . 1990; 12 342-347
- 58 Tanner A R. Hepatic cholestasis induced by trimethoprim. Br Med J (Clin Res Ed) . 1986; 293 1072-1073
- 59 Medina I, Mills J, Leoung G. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med . 1990; 323 776-782
- 60 Martines G, Butturini L, Menozzi I. Amikacin-induced liver toxicity: correlations between biochemical indexes and ultrastructural features in an experimental model. Rev Med Univ Navarra . 1988; 32 41-45
- 61 Ball P, Mandell L, Niki Y. Comparative tolerability of the newer fluoroquinolone antibacterials. Drug Saf . 1999; 21 407-421
- 62 Bjornsson E, Olsson R, Remotti H. Norfloxacin-induced eosinophilic necrotizing granulomatous hepatitis. Am J Gastroenterol . 2000; 95 3662-3664
- 63 George D K, Crawford D H. Antibacterial-induced hepatotoxicity. Incidence, prevention and management. Drug Saf . 1996; 15 79-85
- 64 Hautekeete M L. Hepatotoxicity of antibiotics. Acta Gastroenterol Belg . 1995; 58 290-296
- 65 Sharp J R, Ishak K G, Zimmerman H J. Chronic active hepatitis and severe hepatic necrosis associated with nitrofurantoin. Ann Intern Med . 1980; 92 14-19
- 66 Berson A, Freneaux E, Larrey D. Possible role of HLA in hepatotoxicity. An exploratory study in 71 patients with drug-induced idiosyncratic hepatitis. J Hepatol . 1994; 20 336-342
- 67 Hinthorn D R, Baker L H, Romig D A. Endocarditis treated with clindamycin: relapse and liver dysfunction. South Med J . 1977; 70 823-826
- 68 Kutty K P, Nath I V, Kothandaraman K R. Fusidic acid-induced hyperbilirubinemia. Dig Dis Sci . 1987; 32 933-938
- 69 Christiansen K. Fusidic acid adverse drug reactions. Int J Antimicrob Agents . 1999; 12(Suppl 2) S3-S9
- 70 van den Brande P, van Steenbergen W, Vervoort G. Aging and hepatotoxicity of isoniazid and rifampin in pulmonary tuberculosis. Am J Respir Crit Care Med . 1995; 152 1705-1708
- 71 Devoto F M, Gonzalez C, Iannantuono R. Risk factors for hepatotoxicity induced by antituberculosis drugs. Acta Physiol Pharmacol Ther Latinoam . 1997; 47 197-202
- 72 Dossing M, Wilcke J T, Askgaard D S, Nybo B. Liver injury during antituberculosis treatment: an 11-year study. Tuber Lung Dis . 1996; 77 335-340
- 73 Wong W M, Wu P C, Yuen M F. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology . 2000; 31 201-206
- 74 Ungo J R, Jones D, Ashkin D. Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus. Am J Respir Crit Care Med . 1998; 157 1871-1876
- 75 Singh J, Garg P K, Tandon R K. Hepatotoxicity due to antituberculosis therapy. Clinical profile and reintroduction of therapy. J Clin Gastroenterol . 1996; 22 211-214
- 76 Pande J N, Singh S P, Khilnani G C. Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study. Thorax . 1996; 51 132-136
- 77 Nolan C M, Goldberg S V, Buskin S E. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA . 1999; 281 1014-1018
- 78 Black M, Mitchell J R, Zimmerman H J. Isoniazid-associated hepatitis in 114 patients. Gastroenterology . 1975; 69 289-302
- 79 Durand F, Jebrak G, Pessayre D. Hepatotoxicity of antitubercular treatments. Rationale for monitoring liver status. Drug Saf . 1996; 15 394-405
- 80 Altman C, Biour M, Grange J D. Hepatic toxicity of antitubercular agents. Role of different drugs. 199 cases. Presse Med . 1993; 22 1212-1216
- 81 Durand F, Bernuau J, Pessayre D. Deleterious influence of pyrazinamide on the outcome of patients with fulminant or subfulminant liver failure during antituberculous treatment including isoniazid. Hepatology . 1995; 21 929-932
- 82 Pessayre D, Bentata M, Degott C. Isoniazid-rifampin fulminant hepatitis. A possible consequence of the enhancement of isoniazid hepatotoxicity by enzyme induction. Gastroenterology . 1977; 72 284-289
- 83 Mitchell J R, Zimmerman H J, Ishak K G. Isoniazid liver injury: clinical spectrum, pathology, and probable pathogenesis. Ann Intern Med . 1976; 84 181-192
- 84 Girling D J. The hepatic toxicity of antituberculosis regimens containing isoniazid, rifampicin and pyrazinamide. Tubercle . 1978; 59 13-32
- 85 Singh J, Arora A, Garg P K. Antituberculosis treatment-induced hepatotoxicity: role of predictive factors. Postgrad Med J . 1995; 71 359-362
- 86 Farrell F J, Keeffe E B, Man K M. Treatment of hepatic failure secondary to isoniazid hepatitis with liver transplantation. Dig Dis Sci . 1994; 39 2255-2259
- 87 Stuart R L, Grayson M L. A review of isoniazid-related hepatotoxicity during chemoprophylaxis. Aust N Z J Med . 1999; 29 362-367
- 88 Severe isoniazid-associated hepatitis-New York 1991- 1993. MMWR Morb Mortal Wkly Rep . 1993 42: 545-547
- 89 Tahaoglu K, Atac G, Sevim T. The management of anti-tuberculosis drug-induced hepatotoxicity. Int J Tuberc Lung Dis . 2001; 5 65-69
- 90 Centers for Disease Control and Prevention. Fatal and severe hepatitis associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection-New York and Georgia, 2000. JAMA . 2001; 285 2572-2573
- 91 Lewis J H, Zimmerman H J, Benson G D. Hepatic injury associated with ketoconazole therapy. Analysis of 33 cases. Gastroenterology . 1984; 86 503-513
- 92 Garcia Rodriguez A L, Duque A, Castellsague J. A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs. Br J Clin Pharmacol . 1999; 48 847-852
- 93 Bercoff E, Bernuau J, Degott C. Ketoconazole-induced fulminant hepatitis. Gut . 1985; 26 636-638
- 94 Lavrijsen A P, Balmus K J, Nugteren-Huying W M. Liver damage during administration of itraconazole (Trisporal). Ned Tijdschr Geneeskd . 1993; 137 38-41
- 95 Trujillo M A, Galgiani J N, Sampliner R E. Evaluation of hepatic injury arising during fluconazole therapy. Arch Intern Med . 1994; 154 102-104
- 96 Gupta A K, del Rosso Q J, Lynde C W. Hepatitis associated with terbinafine therapy: three case reports and a review of the literature. Clin Exp Dermatol . 1998; 23 64-67
- 97 Vivas S, Rodriguez M, Palacio M A. [Acute hepatitis associated with terbinafine]. Gastroenterol Hepatol . 1997; 20 456-458
- 98 Gill J, Sprenger H R, Ralph E D. Hepatotoxicity possibly caused by amphotericin B. Ann Pharmacother . 1999; 33 683-685
- 99 Ellis M, Shamoon A, Gorka W. Severe hepatic injury associated with lipid formulations of amphotericin B. Clin Infect Dis . 2001; 32 E87-E89
- 100 Vermes A, Guchelaar H J, Dankert J. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother . 2000; 46 171-179
- 101 Kreisberg R. Clinical problem-solving. We blew it. N Engl J Med . 1995; 332 945-949
- 102 Hernandez L V, Gilson I, Jacobson J. Antiretroviral hepatotoxicity in human immunodeficiency virus-infected patients. Aliment Pharmacol Ther . 2001; 15 1627-1632
- 103 Gisolf E H, Dreezen C, Danner S A. Risk factors for hepatotoxicity in HIV-1-infected patients receiving ritonavir and saquinavir with or without stavudine. Prometheus Study Group. Clin Infect Dis . 2000; 31 1234-1239
- 104 Sulkowski M S, Thomas D L, Chaisson R E. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA . 2000; 283 74-80
- 105 Reisler K. High hepatotoxicity rate seen among HAART patients. Aids Alert . 2001; 16 118-119
- 106 den Brinker M, Wit F W, Wertheim-van Dillen M P. Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. AIDS . 2000; 14 2895-2902
- 107 Velasco M, Guijarro C. Elevated liver enzymes following initiation of antiretroviral therapy. JAMA . 2000; 283 2526-2527
- 108 Gradon J D, Chapnick E K, Sepkowitz D V. Zidovudine-induced hepatitis. J Intern Med . 1992; 231 317-318
- 109 Freiman J P, Helfert K E, Hamrell M R. Hepatomegaly with severe steatosis in HIV-seropositive patients. AIDS . 1993; 7 379-385
- 110 Olano J P, Borucki M J, Wen J W. Massive hepatic steatosis and lactic acidosis in a patient with AIDS who was receiving zidovudine. Clin Infect Dis . 1995; 21 973-976
- 111 Chattha G, Arieff A I, Cummings C. Lactic acidosis complicating the acquired immunodeficiency syndrome. Ann Intern Med . 1993; 118 37-39
- 112 Pessayre D, Mansouri A, Haouzi D. Hepatotoxicity due to mitochondrial dysfunction. Cell Biol Toxicol . 1999; 15 367-373
- 113 Shriner K, Goetz M B. Severe hepatotoxicity in a patient receiving both acetaminophen and zidovudine. Am J Med . 1992; 93 94-96
- 114 Lai K K, Gang D L, Zawacki J K. Fulminant hepatic failure associated with 2′,3′-dideoxyinosine (ddI). Ann Intern Med . 1991; 115 283-284
- 115 Bissuel F, Bruneel F, Habersetzer F. Fulminant hepatitis with severe lactate acidosis in HIV-infected patients on didanosine therapy. J Intern Med . 1994; 235 367-371
- 116 Hill J B, Sheffield J S, Zeeman G G. Hepatotoxicity with antiretroviral treatment of pregnant women. Obstet Gynecol . 2001; 98 909-911
- 117 Martinez E, Blanco J L, Arnaiz J A. Hepatotoxicity in HIV-1-infected patients receiving nevirapine-containing antiretroviral therapy. AIDS . 2001; 15 1261-1268
- 118 Serious adverse events aSerious adverse events attributed to nevirapine regimens for postexposure prophy. Serious adverse events attributed to nevirapine regimens for postexposure prophylaxis after HIV exposures-worldwide 1997-2000. MMWR Morb Mortal Wkly Rep . 2001; 49 1153-1156
- 119 McKenzie R, Fried M W, Sallie R. Hepatic failure lactic acidosis due to fialuridine (FIAU) an investigational nucleoside analogue for chronic hepatitis B. N Engl J Med . 1995; 333 1099-1105
- 120 Ormseth E J, Holtzmuller K C, Goodman Z D. Hepatic decompensation associated with lamivudine: a case report review of lamivudine-induced hepatotoxicity. Am J Gastroenterol . 2001; 96 1619-1622
- 121 Renkes P, Trechot P, Blain H. Valaciclovir-induced hepatitis. Acta Clin Belg . 1999; 54 17-18
- 122 Styrt B, Freiman J P. Hepatotoxicity of antiviral agents. Gastroenterol Clin North Am . 1995; 24 839-852
- 123 el Mufti M, Kamag A, Ibrahim H. Albendazole therapy of hydatid disease: 2-year follow-up of 40 cases. Ann Trop Med Parasitol . 1993; 87 241-246
- 124 Eland I A, Kerkhof S C, Overbosch D. Cholestatic hepatitis ascribed to the use of thiabendazole. Ned Tijdschr Geneeskd . 1998; 142 1331-1334
- 125 Skandrani K, Richardet J P, Duvoux C. Hepatic transplantation for severe ductopenia related to ingestion of thiabendazole. Gastroenterol Clin Biol . 1997; 21 623-625
- 126 Reshef R, Lok A S, Sherlock S. Cholestatic jaundice in fascioliasis treated with niclofolan. Br Med J (Clin Res Ed) . 1982; 285 1243-1244
- 127 O'Brien J G, Dong B J, Coleman R L. A 5-year retrospective review of adverse drug reactions their risk factors in human immunodeficiency virus-infected patients who were receiving intravenous pentamidine therapy for Pneumocystis carinii pneumonia. Clin Infect Dis . 1997; 24 854-859
- 128 Larrey D, Castot A, Pessayre D. Amodiaquine-induced hepatitis. A report of seven cases. Ann Intern Med . 1986; 104 801-803
- 129 Bernuau J, Larrey D, Campillo B. Amodiaquine-induced fulminant hepatitis. J Hepatol . 1988; 6 109-112
- 130 Farrell G C. Drug-Induced Liver Disease. London: Churchill Livingstone 1994