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DOI: 10.1055/s-2002-30105
Epidemiology and Individual Susceptibility to Adverse Drug Reactions Affecting the Liver
Publication History
Publication Date:
16 May 2002 (online)
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ABSTRACT
Adverse drug reactions affecting the liver represent an important challenge for safety in drug development. Drugs can reproduce practically the whole spectrum of liver diseases, but acute hepatitis is the most common syndrome. Drug hepatotoxicity is one of the most common causes of fulminant hepatitis. Most hepatic drug reactions occur in only a small proportion of individuals, making them difficult to detect at the time of drug development. Liver injury is principally recognized on the basis of spontaneous reports within the first 2 years of marketing a new drug. The prevalence of drug hepatotoxicity is poorly documented by a small number of retrospective studies. Despite the development of international analytical methods to allow standardized evaluation, the diagnosis remains indeterminate in many cases. Acquired and genetic factors influence the individual susceptibility to drug hepatotoxicity. Important directions for the future include prospective studies of the incidence of hepatic adverse drug reactions, finding specific markers that augment or replace causality assessment, and further elucidating the role of the genetic and environmental factors that contribute to individual susceptibility.
KEYWORDS
Adverse drug reactions - liver - drug hepatotoxicity - drug safety - epidemiology - hepatitis - individual susceptibility pharmacogenetics
REFERENCES
- 1 Watkins P B, Whitcomb R W. Hepatic dysfunction associated with troglitazone. N Engl J Med . 1998; 13 916-917
- 2 Lee W M. Assessing causality in drug-induced liver injury. J Hepatol . 2000; 33 1003-1005
- 3 Biour M, Poupon R, Grangé J D, Chazouilleres O. Hépatotoxicité des médicaments. Gastroenterol Clin Biol . 2000; 11 1052-1091
-
4 Stricker B H C H. Drug-Induced Hepatic Injury, 2nd ed. Amsterdam: Elsevier; 1992
- 5 Farrell O C. Drug-Induced Liver Disease. London: Churchill Livingstone; 1994
- 6 Pessayre O, Larrey D, Biour M. Drug-induced liver injury. In: Bircher J, Benhamou JP, McIntyre N, et al, eds. Oxford Textbook of Clinical Hepatology, 2nd ed, vol 2 Oxford: Oxford University Press 1999: 1261-1315
- 7 Zimmerman H J. The Adverse Effects of Drugs and Other Chemicals on the Liver, 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 1999 .
- 8 Larrey D. Drug-induced liver diseases. J Hepatol . 2000; 32 77-88
- 9 Negro F, Mondardini A, Palmas E. Hepatotoxicity of saccharin. N EngI J Med . 1994; 331 134-135
- 10 Larrey D. Hepatotoxicity of herbal medicines. J Hepatol . 1997; 26(Suppl 1) 47-51
- 11 Schuppan D, Jia J D, Brinkhaus B, Hahn E G. Herbal products for liver diseases: a therapeutic challenge for the new millennium. Hepatology . 1999; 30 1099-1104
- 12 Seeff L B, Lindsay K L, Bacon B R. Complementary and alternative medicine in chronic liver disease. Hepatology . 2001; 34 595-603
- 13 Watkins P B, Zimmerman H J, Knapp M J. Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease. JAMA . 1994; 271 992-998
- 14 Hammel F, Larrey D, Bernau J. Acute hepatitis after tetrahydroaminoacridine administration for Alzheimer's disease. J Clin Gastroenterol . 1990; 12 329-331
- 15 Larrey D. Hépatites médicamenteuses: aspects épidémiologiques, cliniques, diagnostiques, et physiopathologiques en 1995. Rev Med Interne . 1995; 16 752-758
- 16 Jean-Pastor M J, Jouglard J. Bilan des accidents hépatiques médicamenteux recueillis par la pharmacovigilance française. Therapie . 1984; 39 453-500
- 17 Dossing M, Andreasen B P. Drug-induced liver disease in Denmark. An analysis of 572 cases of hepatotoxicity reported to the Danish board of adverse reaction to drugs. Scand J Gastroenterol . 1982; 17 205-211
- 18 Bernuau J, Benhamou J P. Fulminant and subfulminant liver failure. In: Bircher J, Benhamou JR, McIntyre N, et al, eds. Oxford Textbook of Clinical Hepatology, 2nd ed, vol 2 Oxford: Oxford University Press 1999: 1341-1372
- 19 Takahashi Y, Okuda K. Fulminant hepatitis in Japan: etiology and prognostic prediction. Chin J Gastroenterol . 1993; 10 337-350
- 20 Criteria of drug-inducedCriteria of drug-induced liver disorders. Report of an internationa Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol . 1990; 11 272-276
- 21 Lucena I, Camargo R, Andrade J. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology . 2001; 33 123-130
- 22 Kaplowitz N. Causality assessment versus guilt-by-association in drug hepatotoxicity. Hepatology . 2001; 33 308-309
- 23 Bissell D M, Gores G J, Laskin D L, Hoofnagle J H. Drug-induced liver injury: mechanism test systems. Hepatology . 2001; 33 1009-1013
- 24 Danan G, Benichou C. Causality assessment of adverse reactions to drugs-I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol . 1993; 46 1331-1336
- 25 Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drug-II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol . 1993; 46 1331-1336
- 26 Maria V AJ, Victorino R MM. Development validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology . 1997; 26 664-669
- 27 Aithal G P, Rawlins M D, Day C P. Clinical diagnostic scale: a useful tool in the evaluation of suspected hepatotoxic adverse drug reactions. J Hepatol . 2000; 33 949-952
- 28 Knowles S R, Uetrecht J, Shear N H. Idiosyncratic drug reactions: the reactive metabolite syndromes. Lancet . 2001; 356 1587-1591
- 29 Dansette P M, Bonierbale F, Minoletti C. Drug-induced immunotoxicity. Eur J Drug Metab Pharmacokinet . 1998; 23 443-451
- 30 Bourdi M, Larrey D, Natal J. Anti-liver endoplasmic reticulum autoantibodies are directed against human cytochrome P-450 1A2: a specific marker of dihydralazine-induced hepatitis. J Clin Invest . 1990; 85 1967-1973
- 31 Fromenty B, Pessayre D. Impaired mitochondrial function in microvesicular steatosis. Effects of drugs ethanol, hormones cytokines. J Hepatol . 1997; 26 43-53
- 32 Krähenbühl S. Mitochondria: important target for drug toxicity?. J Hepatol . 2001; 34 334-336
- 33 Larrey D, Letteron P, Foliot A. Effects of pregnancy on the toxicity metabolism of acetaminophen in mice. J Pharmacol Exp Ther . 1986; 237 283-291
- 34 Rodriguez-Rosado R, Garcia-Samaniego J, Soriano V. Hepatotoxicity after introduction of highly active antiretroviral therapy. AIDS . 1998; 12 1256
- 35 Morgan M Y, Reshef R, Shah R R. Impaired oxidation of debrisoquine in patients with perhexiline liver injury. Gut . 1984; 25 1057-1064
- 36 Larrey D, Pageaux G P. Genetic predisposition to drug-induced hepatotoxicity. J Hepatol . 1997; 26 12-21
- 37 Shimada T, Tsumura F, Yamazaki H. Characterization of (±)-bufuralol hydroxylation activities in liver microsomes of Japanese Caucasian subjects genotyped for CYP2D6 Pharmacogenetics . 2001; 11 143-156
- 38 Roddam P L, Rollinson S, Kane E. Poor metabolizers at the cytochrome P450 2D6 2C19 loci are at increased risk of developing adult acute leukaemia. Pharmacogenetics . 2000; 10 605-615
- 39 Larrey D, Tinel M, Amouyal G. Genetically determined oxidation polymorphism drug hepatotoxicity. Study of 51 patients. J Hepatol . 1989; 8 158-164
- 40 Horsmans Y, Lannes B, Pessayre D, Larrey D. Possible association between poor metabolism of mephenytoin hepatotoxicity caused by Atrium℗ a fixed combination preparation containing phenobarbital febarbamate and difebarbamate. J Hepatol . 1994; 21 1075-1079
- 41 Xie H G, Stein M, Kim R B. Allelic genotypic and phenotypic distributions of S-mephenytoin 4′-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world. Pharmacogenetics . 1999; 9 539-549
- 42 Kumashiro R, Kubota T, Iga T. Homozygous mutation of cytochrome P-450 2C19 is associated with troglitazone-induced hepatitis. Hepatology . 2000; 32 197A
- 43 Shear N H, Spielberg S P, Grant D M. Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med . 1986; 105 179-184
- 44 Rieder M J, Shear N H, Kance A. Prominence of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions. Clin Pharmacol Ther . 1991; 49 13-17
- 45 Grant D M. Molecular genetics of the N-acetyltransferases. Pharmacogenetics . 1993; 3 45-50
- 46 Fretland A J, Leff M A, Doll M A, Hein D W. Functional characterization of human N-acetyltransferase 2 (NAT2) single nucleotide polymorphisms. Pharmacogenetics . 2001; 11 207-215
- 47 Watson R GP, Olomu A, Clements D. A proposed mechanism for chlorpromazine jaundice-defective hepatic sulphoxidation combined with rapid hydroxylation. J Hepatol . 1988; 7 72-78
- 48 Spielberg S P. In vitro assessment of pharmacogenetic susceptibility to toxic drug metabolites in humans. Fed Proc . 1984; 43 2308-2313
- 49 Larrey D, Berson A, Hebersetzer F. Genetic predisposition to drug hepatotoxicity. Role in hepatitis caused by amineptine a tricyclic antidepressant. Hepatology . 1989; 10 168-173
- 50 Bequemont L, Lecoeur S, Simon T. Glutathione S-transferase ;gu genetic polymorphism might influence tacrine hepatotoxicity in Alzheimer's patients. Pharmacogenetics . 1997; 7 251-253
- 51 De Sousa M, Pirmohamed M, Kitteringham N R. No association between tacrine transaminitis the glutathione transferase ;gu genotype in patients with Alzheimer's disease. Pharmacogenetics . 1998; 8 353-355
- 52 Berson A, Fréneaux 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
- 53 Hautekeete M L, Horsmans Y, Van Waeyenberge C. HLA association of amoxicillin-clavulanate-induced hepatitis. Gastroenterology . 1999; 117 1181-1186
- 54 Donohue J O, Oien K A, Underhill J. Co-amoxiclav jaundice: clinical histological features HLA class II association. Gut . 2000; 47 717-720