Epidemiology of Idiosyncratic Drug-Induced Liver Injury

ABSTRACT

Idiosyncratic drug-induced liver injury (DILI) is a significant health problem because of its unpredictable nature, poorly understood pathogenesis, and potential to cause fatal outcomes. It is also a significant hurdle for drug development and marketing of safe prescription medications. Idiosyncratic DILI is generally rare, but its occurrence is likely underappreciated due to the lack of active reporting or surveillance systems and substantial challenges involved in its recognition and diagnosis. Nonetheless, DILI is a common cause of potentially serious and fatal acute liver failure in both children and adults. Population-based studies that accurately estimate the incidence and full spectrum of DILI are limited. However, using a prospective, population-based French study with an annual estimated incidence of 13.9 ± 2.4 DILI cases per 100,000 inhabitants, it has been extrapolated that nearly 44,000 individuals in the United States will suffer from DILI each year. Although increasing numbers of patients are also being seen with DILI due to herbal and dietary supplements, the epidemiology of this entity requires further investigation. In this article, the epidemiology of DILI, both in the general population and in potentially high-risk subgroups, is reviewed.

KEYWORDS

Idiosyncratic - hepatotoxicity - acute liver failure - adverse drug reaction

REFERENCES

• 1 Ostapowicz G, Fontana R J, Schiødt F V U.S. Acute Liver Failure Study Group et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States.  Ann Intern Med. 2002;  137(12) 947-954
• 2 Watkins P B, Seeff L B. Drug-induced liver injury: summary of a single topic clinical research conference.  Hepatology. 2006;  43(3) 618-631
• 3 Navarro V J, Senior J R. Drug-related hepatotoxicity.  N Engl J Med. 2006;  354(7) 731-739
• 4 Abboud G, Kaplowitz N. Drug-induced liver injury.  Drug Saf. 2007;  30(4) 277-294
• 5 Lazarou J, Pomeranz B H, Corey P N. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies.  JAMA. 1998;  279(15) 1200-1205
• 6 Murray K F, Hadzic N, Wirth S, Bassett M, Kelly D. Drug-related hepatotoxicity and acute liver failure.  J Pediatr Gastroenterol Nutr. 2008;  47(4) 395-405
• 7 Nourjah P, Ahmad S R, Karwoski C, Willy M. Estimates of acetaminophen (paracetomal)-associated overdoses in the United States.  Pharmacoepidemiol Drug Saf. 2006;  15(6) 398-405
• 8 Rowden A K, Norvell J, Eldridge D L, Kirk M A. Updates on acetaminophen toxicity.  Med Clin North Am. 2005;  89(6) 1145-1159
• 9 Lee W M. Acetaminophen toxicity: changing perceptions on a social/medical issue.  Hepatology. 2007;  46(4) 966-970
• 10 Larson A M, Polson J, Fontana R J Acute Liver Failure Study Group et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study.  Hepatology. 2005;  42(6) 1364-1372
• 11 Fontana R J. Acute liver failure due to drugs.  Semin Liver Dis. 2008;  28(2) 175-187
• 12 Andrade R J, Robles M, Fernández-Castañer A, López-Ortega S, López-Vega M C, Lucena M I. Assessment of drug-induced hepatotoxicity in clinical practice: a challenge for gastroenterologists.  World J Gastroenterol. 2007;  13(3) 329-340
• 13 De Valle M B, Av Klinteberg V, Alem N, Olsson R, Björnsson E. Drug-induced liver injury in a Swedish University hospital out-patient hepatology clinic.  Aliment Pharmacol Ther. 2006;  24(8) 1187-1195
• 14 Hussaini S H, O'Brien C S, Despott E J, Dalton H R. Antibiotic therapy: a major cause of drug-induced jaundice in southwest England.  Eur J Gastroenterol Hepatol. 2007;  19(1) 15-20
• 15 Meier Y, Cavallaro M, Roos M et al.. Incidence of drug-induced liver injury in medical inpatients.  Eur J Clin Pharmacol. 2005;  61(2) 135-143
• 16 Russo M W, Galanko J A, Shrestha R, Fried M W, Watkins P. Liver transplantation for acute liver failure from drug induced liver injury in the United States.  Liver Transpl. 2004;  10(8) 1018-1023
• 17 Vuppalanchi R, Liangpunsakul S, Chalasani N. Etiology of new-onset jaundice: how often is it caused by idiosyncratic drug-induced liver injury in the United States?.  Am J Gastroenterol. 2007;  102(3) 558-562, quiz 693
• 18 Jinjuvadia K, Kwan W, Fontana R J. Searching for a needle in a haystack: use of ICD-9-CM codes in drug-induced liver injury.  Am J Gastroenterol. 2007;  102(11) 2437-2443
• 19 Duh M S, Walker A M, Kronlund Jr K H. Descriptive epidemiology of acute liver enzyme abnormalities in the general population of central Massachusetts.  Pharmacoepidemiol Drug Saf. 1999;  8(4) 275-283
• 20 de Abajo F J, Montero D, Madurga M, García Rodríguez L A. Acute and clinically relevant drug-induced liver injury: a population based case-control study.  Br J Clin Pharmacol. 2004;  58(1) 71-80
• 21 Hartleb M, Biernat L, Kochel A. Drug-induced liver damage—a three-year study of patients from one gastroenterological department.  Med Sci Monit. 2002;  8(4) CR292-CR296
• 22 Andrade R J, Lucena M I, Fernández M C Spanish Group for the Study of Drug-Induced Liver Disease et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period.  Gastroenterology. 2005;  129(2) 512-521
• 23 Chalasani N, Fontana R J, Bonkovsky H L Drug Induced Liver Injury Network (DILIN) et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.  Gastroenterology. 2008;  135(6) 1924-1934, 1934.e1–e4
• 24 Hoofnagle J H. Drug-induced liver injury network (DILIN).  Hepatology. 2004;  40(4) 773
• 25 Sgro C, Clinard F, Ouazir K et al.. Incidence of drug-induced hepatic injuries: a French population-based study.  Hepatology. 2002;  36(2) 451-455
• 26 Takikawa H, Murata Y, Horiike N, Fukui H, Onji M. Drug-induced liver injury in Japan: an analysis of 1676 cases between 1997 and 2006.  Hepatol Res. 2009;  39(5) 427-431
• 27 Tameda T, Adachi Y, Watanabe A. National survey of drug-induced liver injury. In: Watanabe A, Higuchi K Newest Hepatology. Tokyo; Shinko-Igaku 2001: 50-61
• 28 Wai C T, Tan B H, Chan C L et al.. Drug-induced liver injury at an Asian center: a prospective study.  Liver Int. 2007;  27(4) 465-474
• 29 Shapiro M A, Lewis J H. Causality assessment of drug-induced hepatotoxicity: promises and pitfalls.  Clin Liver Dis. 2007;  11(3) 477-505, v
• 30 Lucena M I, Andrade R J, Kaplowitz N Spanish Group for the Study of Drug-Induced Liver Disease et al. Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex.  Hepatology. 2009;  49(6) 2001-2009
• 31 Elinav E, Pinsker G, Safadi R et al.. Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity.  J Hepatol. 2007;  47(4) 514-520
• 32 García-Cortés M, Borraz Y, Lucena M I et al.. [Liver injury induced by “natural remedies”: an analysis of cases submitted to the Spanish Liver Toxicity Registry].  Rev Esp Enferm Dig. 2008;  100(11) 688-695
• 33 Ibáñez L, Pérez E, Vidal X, Laporte J R. Grup d'Estudi Multicènteric d'Hepatotoxicitat Aguda de Barcelona (GEMHAB) . Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs.  J Hepatol. 2002;  37(5) 592-600
• 34 Abebe W. Herbal medication: potential for adverse interactions with analgesic drugs.  J Clin Pharm Ther. 2002;  27(6) 391-401
• 35 Estes J D, Stolpman D, Olyaei A et al.. High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure.  Arch Surg. 2003;  138(8) 852-858
• 36 Schenker S, Bay M. Drug disposition and hepatotoxicity in the elderly.  J Clin Gastroenterol. 1994;  18(3) 232-237
• 37 Fountain F F, Tolley E, Chrisman C R, Self T H. Isoniazid hepatotoxicity associated with treatment of latent tuberculosis infection: a 7-year evaluation from a public health tuberculosis clinic.  Chest. 2005;  128(1) 116-123
• 38 Grönhagen-Riska C, Hellstrom P E, Fröseth B. Predisposing factors in hepatitis induced by isoniazid-rifampin treatment of tuberculosis.  Am Rev Respir Dis. 1978;  118(3) 461-466
• 39 Onji M, Fujioka S, Takeuchi Y et al.. Clinical characteristics of drug-induced liver injury in the elderly.  Hepatol Res. 2009;  39(6) 546-552
• 40 Pelkonen O, Turpeinen M, Hakkola J, Honkakoski P, Hukkanen J, Raunio H. Inhibition and induction of human cytochrome P450 enzymes: current status.  Arch Toxicol. 2008;  82(10) 667-715
• 41 Lucena M I, Andrade R J, Fernández M C Spanish Group for the Study of Drug-Induced Liver Disease (Grupo de Estudio para las Hepatopatías Asociadas a Medicamentos (GEHAM)) et al. Determinants of the clinical expression of amoxicillin-clavulanate hepatotoxicity: a prospective series from Spain.  Hepatology. 2006;  44(4) 850-856
• 42 Squires Jr R HJ, Shneider B L, Bucuvalas J et al.. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group.  J Pediatr. 2006;  148(5) 652-658
• 43 Maddrey W C. Drug-induced hepatotoxicity: 2005.  J Clin Gastroenterol. 2005;  39(4, Suppl 2) S83-S89
• 44 Soriano V, Puoti M, Garcia-Gascó P et al.. Antiretroviral drugs and liver injury.  AIDS. 2008;  22(1) 1-13
• 45 Núñez M J, Martín-Carbonero L, Moreno V et al.. Impact of antiretroviral treatment-related toxicities on hospital admissions in HIV-infected patients.  AIDS Res Hum Retroviruses. 2006;  22(9) 825-829
• 46 Akhtar A J, Shaheen M. Jaundice in African-American and Hispanic patients with AIDS.  J Natl Med Assoc. 2007;  99(12) 1381-1385
• 47 Ungo J R, Jones D, Ashkin D et al.. Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus.  Am J Respir Crit Care Med. 1998;  157(6 Pt 1) 1871-1876
• 48 Tostmann A, Boeree M J, Aarnoutse R E, de Lange W C, van der Ven A J, Dekhuijzen R. Antituberculosis drug-induced hepatotoxicity: concise up-to-date review.  J Gastroenterol Hepatol. 2008;  23(2) 192-202
• 49 Núñez M, Lana R, Mendoza J L, Martín-Carbonero L, Soriano V. Risk factors for severe hepatic injury after introduction of highly active antiretroviral therapy.  J Acquir Immune Defic Syndr. 2001;  27(5) 426-431
• 50 Sulkowski M S, Thomas D L, Chaisson R E, Moore R D. 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(1) 74-80
• 51 Rodríguez-Rosado R, García-Samaniego J, Soriano V. Hepatotoxicity after introduction of highly active antiretroviral therapy.  AIDS. 1998;  12(10) 1256
• 52 Savès M, Vandentorren S, Daucourt V et al.. Severe hepatic cytolysis: incidence and risk factors in patients treated by antiretroviral combinations. Aquitaine Cohort, France, 1996–1998. Groupe dEpidémiologie Clinique de Sida en Aquitaine (GECSA).  AIDS. 1999;  13(17) F115-F121
• 53 Savès M, Raffi F, Clevenbergh P The APROCO Study Group et al. Hepatitis B or hepatitis C virus infection is a risk factor for severe hepatic cytolysis after initiation of a protease inhibitor-containing antiretroviral regimen in human immunodeficiency virus-infected patients.  Antimicrob Agents Chemother. 2000;  44(12) 3451-3455
• 54 Bonfanti P, Landonio S, Ricci E CISAI study group et al. Risk factors for hepatotoxicity in patients treated with highly active antiretroviral therapy.  J Acquir Immune Defic Syndr. 2001;  27(3) 316-318
• 55 Monforte Ade A, Bugarini R, Pezzotti P ICONA (Italian Cohort of Naive for Antiretrovirals) Study Group et al. Low frequency of severe hepatotoxicity and association with HCV coinfection in HIV-positive patients treated with HAART.  J Acquir Immune Defic Syndr. 2001;  28(2) 114-123
• 56 Aceti A, Pasquazzi C, Zechini B, De Bac C. LIVERHAART Group . Hepatotoxicity development during antiretroviral therapy containing protease inhibitors in patients with HIV: the role of hepatitis B and C virus infection.  J Acquir Immune Defic Syndr. 2002;  29(1) 41-48
• 57 Wit F W, Weverling G J, Weel J, Jurriaans S, Lange J M. Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy.  J Infect Dis. 2002;  186(1) 23-31
• 58 Servoss J C, Kitch D W, Andersen J W, Reisler R B, Chung R T, Robbins G K. Predictors of antiretroviral-related hepatotoxicity in the adult AIDS Clinical Trial Group (1989–1999).  J Acquir Immune Defic Syndr. 2006;  43(3) 320-323
• 59 Núñez M, Ríos P, Martín-Carbonero L, Pérez-Olmeda M, González-Lahoz J, Soriano V. Role of hepatitis C virus genotype in the development of severe transaminase elevation after the introduction of antiretroviral therapy.  J Acquir Immune Defic Syndr. 2002;  30(1) 65-68
• 60 Maida I, Babudieri S, Selva C et al.. Liver enzyme elevation in hepatitis C virus (HCV)-HIV-coinfected patients prior to and after initiating HAART: role of HCV genotypes.  AIDS Res Hum Retroviruses. 2006;  22(2) 139-143
• 61 Torti C, Lapadula G, Puoti M et al.. Influence of genotype 3 hepatitis C coinfection on liver enzyme elevation in HIV-1-positive patients after commencement of a new highly active antiretroviral regimen: results from the EPOKA-MASTER Cohort.  J Acquir Immune Defic Syndr. 2006;  41(2) 180-185
• 62 Aranzabal L, Casado J L, Moya J et al.. Influence of liver fibrosis on highly active antiretroviral therapy-associated hepatotoxicity in patients with HIV and hepatitis C virus coinfection.  Clin Infect Dis. 2005;  40(4) 588-593
• 63 Zimmerman H J. Hepatotoxicity. The Adverse Effects of Drugs and Other Chemicals on the Liver, 2nd ed. Philadelphia, PA; Lippincott Williams & Wilkins 1999
• 64 Wong W M, Wu P C, Yuen M F et al.. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection.  Hepatology. 2000;  31(1) 201-206
• 65 Wu J C, Lee S D, Yeh P F et al.. Isoniazid-rifampin-induced hepatitis in hepatitis B carriers.  Gastroenterology. 1990;  98(2) 502-504
• 66 Gupta N K, Lewis J H. Review article: The use of potentially hepatotoxic drugs in patients with liver disease.  Aliment Pharmacol Ther. 2008;  28(9) 1021-1041
• 67 Labarga P, Soriano V, Vispo M E et al.. Hepatotoxicity of antiretroviral drugs is reduced after successful treatment of chronic hepatitis C in HIV-infected patients.  J Infect Dis. 2007;  196(5) 670-676
• 68 Dalton H R, Fellows H J, Stableforth W et al.. The role of hepatitis E virus testing in drug-induced liver injury.  Aliment Pharmacol Ther. 2007;  26(10) 1429-1435
• 69 Chalasani N. Statins and hepatotoxicity: focus on patients with fatty liver.  Hepatology. 2005;  41(4) 690-695
• 70 Chalasani N, Aljadhey H, Kesterson J, Murray M D, Hall S D. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity.  Gastroenterology. 2004;  126(5) 1287-1292
• 71 Vuppalanchi R, Teal E, Chalasani N. Patients with elevated baseline liver enzymes do not have higher frequency of hepatotoxicity from lovastatin than those with normal baseline liver enzymes.  Am J Med Sci. 2005;  329(2) 62-65
• 72 Tarantino G, Conca P, Basile V et al.. A prospective study of acute drug-induced liver injury in patients suffering from nonalcoholic fatty liver disease.  Hepatol Res. 2007;  37(6) 410-415
• 73 Rutherford A, Davern T, Hay J E Acute Liver Failure Study Group et al. Influence of high body mass index on outcome in acute liver failure.  Clin Gastroenterol Hepatol. 2006;  4(12) 1544-1549