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Drug-induced liver injury: an overview over the most critical compounds

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Abstract

There has been a substantial interest in drug-induced liver injury (DILI) recently. National Institutes of Health has sponsored a multicenter study in the USA for the last 10 years, which has collected valuable information in this context. Idiosyncratic DILI is like other adverse effects of drugs underestimated and underreported in most epidemiological studies. A recent prospective population-based study from Iceland found a crude incidence of approximately 19 cases per 100,000 and year. Antibiotic is the class of drugs most commonly implicated in patients with DILI. Amoxicillin–clavulanate continues to be the most commonly implicated agent occurring in approximately 1 out of 2,300 users. Drugs with the highest risk of DILI in the Icelandic study were azathioprine and infliximab. Although rare, statin-induced hepatotoxicity has been well documented. Liver injury associated with the use of herbal medicines and dietary supplements seems to be increasing. Information on the documented hepatotoxicity of drugs has recently been made easier by a website available in the public domain: LiverTox (http://livertox.nlm.nih.gov). Unfortunately, at the current time, pre-therapy risk assessment for DILI in the individual patient is difficult but previous well-documented hepatotoxicity is usually a contraindication for a subsequent treatment with the same drug.

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References

  • Aithal GP, Ramsay L, Daly AK, Sonchit N, Leathart JB, Alexander G, Kenna JG, Caldwell J, Day CP (2004) Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity. Hepatology 39:1430–1440

    Article  CAS  PubMed  Google Scholar 

  • Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H et al (2011) Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther 89:806–815

    Article  CAS  PubMed  Google Scholar 

  • Andrade RJ, Lucena MI, Fernandez MC et al (2005) Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 129:512–521

    Article  PubMed  Google Scholar 

  • Benichou C, Danan G, Flahault A (1993) Causality assessment of adverse reactions to drugs-II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol 46:1331–1336

    Article  CAS  PubMed  Google Scholar 

  • Björnsson E, Olsson R (2005) Outcome and prognostic markers in severe drug-induced liver disease. Hepatology 42:481–489

    Article  PubMed  Google Scholar 

  • Björnsson E, Davidsdottir L (2009) The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice. J Hepatology 50:511–517

    Article  Google Scholar 

  • Björnsson E, Kalaitzakis E, Olsson R (2007) The impact of eosinophilia and hepatic necrosis on prognosis in patients with drug-induced liver injury. Aliment Pharmacol Ther 25:1411–1421

    Article  PubMed  Google Scholar 

  • Björnsson E, Jacobsen EI, Kalaitzakis E (2012) Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing. J Hepatol 56:374–380

    Article  PubMed  Google Scholar 

  • Björnsson ES, Bergmann OM, Bjornsson HK, Kvaran RB, Olafsson S (2013) Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 144:1419–1425

    Article  PubMed  Google Scholar 

  • Björnsson ES, Gunnarsson BI, Gröndal G, Jonasson JG, Einarsdottir R, Ludviksson BR, Gudbjörnsson B, Olafsson O (2014) The risk of drug-induced liver injury from Tumor Necrosis Factor (TNF)-alpha-antagonists. Clin Gastroenterol Hepatol. doi:10.1016/j.cgh.2014.07.062

  • Chalasani N, Fontana RJ, Bonkovsky HL et al (2008) Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 135:1924–1934

    Article  PubMed Central  PubMed  Google Scholar 

  • Charles EC, Olson KL, Sandhoff BG, McClure DL, Merenich JA (2005) Evaluation of cases of severe statin-related transaminitis within a large health maintenance organization. Am J Med 118:618–624

    Article  CAS  PubMed  Google Scholar 

  • Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe’er I, Floratos A, Daly MJ, Goldstein DB, John S, Nelson MR, Graham J, Park BK, Dillon JF, Bernal W, Cordell HJ, Pirmohamed M, Aithal GP, Day CP (2009) Nat Genet 41:816–819

    Article  CAS  PubMed  Google Scholar 

  • Danan G, Benichou C (1993) 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 46:1323–1330

    Article  CAS  PubMed  Google Scholar 

  • Davies MH, Harrison RF, Elias E, Hübscher SG (1994) Antibiotic-associated acute vanishing bile duct syndrome: a pattern associated with severe, prolonged, intrahepatic cholestasis. J Hepatol 20:112–116

    Article  CAS  PubMed  Google Scholar 

  • de Abajo FJ, Montero D, Madurga M, de García Rodríguez LA (2004) Acute and clinically relevant drug-induced liver injury: a population based case-control study. Br J Clin Pharmacol 58(1):71–80

    Article  PubMed Central  PubMed  Google Scholar 

  • De Valle MB, Av Klinteberg V, Alem N, Olsson R, Björnsson E (2006) Drug induced liver injury in a Swedish University hospital out-patient hepatology clinic. Aliment Pharmacol Ther 24(8):1187–1195

    Article  PubMed  Google Scholar 

  • Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK (2010) Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol 105:2396–2404

    Article  PubMed  Google Scholar 

  • Fairley CK, McNeil JJ, Desmond P, Smallwood R, Young H, Forbes A, Purcell P, Boyd I (1993) Risk factors for development of flucloxacillin associated jaundice. BMJ 306:233–235

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fontana RJ, Shakil AO, Greenson JK, Boyd I, Lee WM (2005) Acute liver failure due to amoxicillin and amoxicillin/clavulanate. Dig Dis Sci 50:1785–1790

    Article  PubMed  Google Scholar 

  • Fontana R, Seef LB, Andrade RJ, Bjornsson E, Day CP, Serrano J, Hoofnagle JH (2010) Standardization of nomenclature and causality assessment in drug-induced liver injury: summary of a clinical research workshop. Hepatology 52:730–742

    Article  PubMed Central  PubMed  Google Scholar 

  • Fontana RJ, Hayashi PH, Gu J, Reddy KR, Barnhart H, Watkins PB, Serrano J, Lee WM, Chalasani N, Stolz A, Davern T, Talwakar JA (2014) Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology 147(1):96–108

    Article  CAS  PubMed  Google Scholar 

  • García Rodríguez LA, Stricker BH, Zimmerman HJ (1996) Risk of acute liver injury associated with the combination of amoxicillin and clavulanic acid. Arch Intern Med 156:1327–1332

    Article  PubMed  Google Scholar 

  • García Rodríguez LA, Ruigómez A, Jick H (1997) A review of epidemiologic research on drug-induced acute liver injury using the general practice research data base in the United Kingdom. Pharmacotherapy 17:721–728

    PubMed  Google Scholar 

  • Ghabril M, Bonkovsky HL, Kum C et al (2013) Liver injury from tumor necrosis factor-α antagonists: analysis of thirty-four cases. Clin Gastroenterol Hepatol 11:558–564

    Article  CAS  PubMed  Google Scholar 

  • Hussaini SH, O’Brien CS, Despott EJ, Dalton HR (2007) Antibiotic therapy: a major cause of drug-induced jaundice in southwest England. Eur J Gastroenterol Hepatol 19:15–20

    Article  CAS  PubMed  Google Scholar 

  • Ibanez L, Perez E, Vidal X, Laporte JR (2002) Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 37:592–600

    Article  PubMed  Google Scholar 

  • Lammert C, Einarsson S, Saha C et al (2008) Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology 47:2003–2009

    Article  CAS  PubMed  Google Scholar 

  • Lee WM (2008) Acetaminophen-related acute liver failure in the United States. Hepatol Res 38:S3–S8

    Article  CAS  PubMed  Google Scholar 

  • Lucena MI, Andrade RJ, Fernández MC, Pachkoria K, Pelaez G, Durán JA et al (2006) Determinants of the clinical expression of amoxicillin–clavulanate hepatotoxicity: a prospective series from Spain. Hepatology 44:850–856

    Article  CAS  PubMed  Google Scholar 

  • Martinez MA, Vuppalanchi R, Fontana RJ, Stolz A, Kleiner DE, Hayashi PH, Gu J, Hoofnagle JH, Chalasani N (2014) Clinical and histologic features of azithromycin-induced liver injury. Clin Gastroenterol Hepatol. doi:10.1002/hep.27542

    Google Scholar 

  • Navarro VJ, Lucena MI (2014) Hepatotoxicity induced by herbal and dietary supplements. Semin Liver Dis 34(2):172–193

    Article  CAS  PubMed  Google Scholar 

  • Navarro VJ, Barnhart H, Bonkovsky HL, Davern T, Fontana RJ, Grant L, Reddy KR, Seeff LB, Serrano J, Sherker AH, Stolz A, Talwalkar J, Vega M, Vuppalanchi R (2014) Liver injury from herbals and dietary supplements in the U.S. drug-induced liver injury network. Hepatology 60(4):1399–1408

    Article  PubMed  Google Scholar 

  • Olsson R, Wiholm BE, Sand C, Hultcrantz R, Myrhed M (1992) Liver damage from flucloxacillin, cloxacillin and dicloxacillin. J Hepatol 15:154–161

    Article  CAS  PubMed  Google Scholar 

  • Pauli-Magnus C, Meier PJ (2006) Hepatobiliary transporters and drug-induced cholestasis. Hepatology 44:778–787

    Article  CAS  PubMed  Google Scholar 

  • Pérez Gutthann S, García Rodríguez LA (1993) The increased risk of hospitalizations for acute liver injury in a population with exposure to multiple drugs. Epidemiology 4(6):496–501

  • Reuben A, Koch DG, Lee WM (2010) Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 52:2065–2076

    Article  PubMed Central  PubMed  Google Scholar 

  • Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P (2004) Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl 10:1018–1023

    Article  PubMed  Google Scholar 

  • Russo MW, Scobey M, Bonkovsky HL (2009) Drug-induced liver injury associated with statins. Review. Semin Liver Dis 29:412–422

    Article  CAS  PubMed  Google Scholar 

  • Sgro C, Clinard F, Ouazir K et al (2002) Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology 36:451–455

    Article  PubMed  Google Scholar 

  • Suk KT, Kim DJ, Kim CH, Park SH, Yoon JH, Kim YS, Baik GH, Kim JB, Kweon YO, Kim BI, Kim SH, Kim IH, Kim JH, Nam SW, Paik YH, Suh JI, Sohn JH, Ahn BM, Um SH, Lee HJ, Cho M, Jang MK, Choi SK, Hwang SG, Sung HT, Choi JY, Han KH (2012) A prospective nationwide study of drug-induced liver injury in Korea. Am J Gastroenterol 107(9):1380–1387

    Article  PubMed  Google Scholar 

  • Suzuki A, Andrade RJ, Bjornsson E, Lucena MI, Lee WM, Yuen NA, Hunt CM, Freston JW (2010) Unified list of drugs causing hepatotoxicity and the reporting frequency of liver events in the WHO vigibaset: international collaborative work. Drug Saf 33:503–522

    Article  CAS  PubMed  Google Scholar 

  • Wai CT, Tan BH, Chan CL, Sutedja DS, Lee YM, Khor C, Lim SG (2007) Drug-induced liver injury at an Asian center: a prospective study. Liver Int 27:465–474

    Article  PubMed  Google Scholar 

  • Turner IB, Eckstein RP, Riley JW, Lunzer MR (1989) Prolonged hepatic cholestasis after flucloxacillin therapy. Med J Aust 151:701–705

    CAS  PubMed  Google Scholar 

  • Wei G, Bergquist A, Broome U, Lindgren S, Wallerstedt S, Almer S, Sangfeldt P, Danielsson A Sandberg-Gertzen H, Loof L, Prytz H, Björnsson E (2007) Acute liver failure in Sweden: etiology and prognosis. J Internal Med 262:393–401

    Article  CAS  PubMed  Google Scholar 

  • Zimmerman HJ (1999) Drug-induced liver disease. In: Sciff ER, Sorrell MF, Maddrey WC (eds) Schiff´s diseases of the liver, 8th edn. Lippincott-Raven Publishers, Philadelphia, pp 973–1064

    Google Scholar 

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, The National University Hospital of Iceland, 101, Reykjavík, Iceland

    Einar S. Björnsson

  2. Faculty of Medicine, University of Iceland, Reykjavík, Iceland

    Einar S. Björnsson

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  1. Einar S. Björnsson
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Correspondence to Einar S. Björnsson.

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Björnsson, E.S. Drug-induced liver injury: an overview over the most critical compounds. Arch Toxicol 89, 327–334 (2015). https://doi.org/10.1007/s00204-015-1456-2

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  • DOI: https://doi.org/10.1007/s00204-015-1456-2

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