Skip to main content
SpringerLink
Log in
Book cover

Liver Immunology pp 389–399Cite as

Nonimmune-Mediated Drug-Induced Hepatotoxicity

  • Chapter
  • First Online:

  • 2456 Accesses

Abstract

Although drug-mediated hepatotoxicity is of considerable importance and an important factor in the differential diagnosis of biochemical and structural liver disease, not much of its epidemiology in clinical practice is backed by high-quality data. It is assumed that the incidence of drug reactions leading to hepatic toxicity ranges from 1 in 10,000 to 1 in 100,000 of drug-exposed individuals or patients [1, 2].

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Andrade RJ, Lucena MI, Fernandez MC, Pelaez G, Pachkoria K, Garcia-Ruiz E, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology. 2005;129:512–21.

    PubMed  Google Scholar 

  2. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135:1924–34, 1934 e1921–4.

    Article  PubMed  Google Scholar 

  3. Lozano-Lanagran M, Robles M, Lucena MI, Andrade RJ. Hepatotoxicity in 2011—advancing resolutely. Rev Esp Enferm Dig. 2011;103:472–9.

    Article  PubMed  Google Scholar 

  4. Andrade RJ, Robles M, Fernandez-Castaner A, Lopez-Ortega S, Lopez-Vega MC, Lucena MI. Assessment of drug-induced hepatotoxicity in clinical practice: a challenge for gastroenterologists. World J Gastroenterol. 2007;13:329–40.

    PubMed  CAS  Google Scholar 

  5. Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology. 2002;36:451–5.

    Article  PubMed  Google Scholar 

  6. Yang XX, Hu ZP, Duan W, Zhu YZ, Zhou SF. Drug-herb interactions: eliminating toxicity with hard drug design. Curr Pharm Des. 2006;12:4649–64.

    Article  PubMed  CAS  Google Scholar 

  7. Hu Z, Yang X, Ho PC, Chan SY, Heng PW, Chan E, et al. Herb-drug interactions: a literature review. Drugs. 2005;65:1239–82.

    Article  PubMed  CAS  Google Scholar 

  8. 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;39:427–31.

    Article  PubMed  Google Scholar 

  9. Hadem J, Tacke F, Bruns T, Langgartner J, Strnad P, Denk GU, et al. Etiologies and outcomes of acute liver failure in Germany. Clin Gastroenterol Hepatol. 2012;10:664–9.e2.

    Article  PubMed  Google Scholar 

  10. Reuben A, Koch DG, Lee WM. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology. 2010;52:2065–76.

    Article  PubMed  Google Scholar 

  11. Andrade RJ, Lucena MI, Kaplowitz N, Garcia-Munoz B, Borraz Y, Pachkoria K, et al. Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry. Hepatology. 2006;44:1581–8.

    Article  PubMed  CAS  Google Scholar 

  12. Lucena MI, Andrade RJ, Kaplowitz N, Garcia-Cortes M, Fernandez MC, Romero-Gomez M, et al. Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex. Hepatology. 2009;49:2001–9.

    Article  PubMed  Google Scholar 

  13. Pande JN, Singh SP, Khilnani GC, Khilnani S, Tandon RK. Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study. Thorax. 1996;51:132–6.

    Article  PubMed  CAS  Google Scholar 

  14. Heubi JE, Partin JC, Partin JS, Schubert WK. Reye’s syndrome: current concepts. Hepatology. 1987;7:155–64.

    Article  PubMed  CAS  Google Scholar 

  15. Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe’er I, Floratos A, et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet. 2009;41:816–9.

    Article  PubMed  CAS  Google Scholar 

  16. Stewart JD, Horvath R, Baruffini E, Ferrero I, Bulst S, Watkins PB, et al. Polymerase gamma gene POLG determines the risk of sodium valproate-induced liver toxicity. Hepatology. 2010;52:1791–6.

    Article  PubMed  CAS  Google Scholar 

  17. Ramachandran A, Lebofsky M, Weinman SA, Jaeschke H. The impact of partial manganese superoxide dismutase (SOD2)-deficiency on mitochondrial oxidant stress, DNA fragmentation and liver injury during acetaminophen hepatotoxicity. Toxicol Appl Pharmacol. 2011;251:226–33.

    Article  PubMed  CAS  Google Scholar 

  18. Fujimoto K, Kumagai K, Ito K, Arakawa S, Ando Y, Oda S, et al. Sensitivity of liver injury in heterozygous Sod2 knockout mice treated with troglitazone or acetaminophen. Toxicol Pathol. 2009;37:193–200.

    Article  PubMed  CAS  Google Scholar 

  19. Lucena MI, Garcia-Martin E, Andrade RJ, Martinez C, Stephens C, Ruiz JD, et al. Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury. Hepatology. 2010;52:303–12.

    Article  PubMed  CAS  Google Scholar 

  20. Lucena MI, Andrade RJ, Martinez C, Ulzurrun E, Garcia-Martin E, Borraz Y, et al. Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury. Hepatology. 2008;48:588–96.

    Article  PubMed  Google Scholar 

  21. Zaher H, Buters JT, Ward JM, Bruno MK, Lucas AM, Stern ST, et al. Protection against acetaminophen toxicity in CYP1A2 and CYP2E1 double-null mice. Toxicol Appl Pharmacol. 1998;152:193–9.

    Article  PubMed  CAS  Google Scholar 

  22. Daly AK, Aithal GP, Leathart JB, Swainsbury RA, Dang TS, Day CP. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology. 2007;132:272–81.

    Article  PubMed  CAS  Google Scholar 

  23. Strassburg CP, Kalthoff S. UDP-glucuronosyltransferases. In: Anzenbacher P, Zanger UM, editors. Metabolism of drugs and other xenobiotics. Weinheim: Wiley; 2012. p. 67–116.

    Chapter  Google Scholar 

  24. Tukey RH, Strassburg CP. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol. 2000;40:581–616.

    Article  PubMed  CAS  Google Scholar 

  25. Castiella A, Lucena MI, Zapata EM, Otazua P, Andrade RJ. Drug-induced autoimmune-like hepatitis: a diagnostic challenge. Dig Dis Sci. 2011;56:2501–2; author reply 2502–3.

    Article  PubMed  Google Scholar 

  26. Lankisch TO, Moebius U, Wehmeier M, Behrens G, Manns MP, Schmidt RE, et al. Gilbert’s disease and atazanavir: from phenotype to UDP-glucuronosyltransferase haplotype. Hepatology. 2006;44:1324–32.

    Article  PubMed  CAS  Google Scholar 

  27. Lammert C, Einarsson S, Saha C, Niklasson A, Bjornsson E, Chalasani N. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology. 2008;47:2003–9.

    Article  PubMed  CAS  Google Scholar 

  28. Lu Y, Zhuge J, Wang X, Bai J, Cederbaum AI. Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice. Hepatology. 2008;47:1483–94.

    Article  PubMed  CAS  Google Scholar 

  29. Muriel P. Role of free radicals in liver diseases. Hepatol Int. 2009;3:526–36.

    Article  PubMed  Google Scholar 

  30. Dreifuss FE, Santilli N, Langer DH, Sweeney KP, Moline KA, Menander KB. Valproic acid hepatic fatalities: a retrospective review. Neurology. 1987;37:379–85.

    Article  PubMed  CAS  Google Scholar 

  31. Walgren JL, Mitchell MD, Thompson DC. Role of metabolism in drug-induced idiosyncratic hepatotoxicity. Crit Rev Toxicol. 2005;35:325–61.

    Article  PubMed  CAS  Google Scholar 

  32. Mitchell MD, Elrick MM, Walgren JL, Mueller RA, Morris DL, Thompson DC. Peptide-based in vitro assay for the detection of reactive metabolites. Chem Res Toxicol. 2008;21:859–68.

    Article  PubMed  CAS  Google Scholar 

  33. Agundez JA, Lucena MI, Martinez C, Andrade RJ, Blanca M, Ayuso P, et al. Assessment of nonsteroidal anti-inflammatory drug-induced hepatotoxicity. Expert Opin Drug Metab Toxicol. 2011;7:817–28.

    Article  PubMed  CAS  Google Scholar 

  34. Goldkind L, Laine L. A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity: lessons learned from the bromfenac experience. Pharmacoepidemiol Drug Saf. 2006;15:213–20.

    Article  PubMed  CAS  Google Scholar 

  35. Harrill AH, Watkins PB, Su S, Ross PK, Harbourt DE, Stylianou IM, et al. Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res. 2009;19:1507–15.

    Article  PubMed  CAS  Google Scholar 

  36. Laine L, Goldkind L, Curtis SP, Connors LG, Yanqiong Z, Cannon CP. How common is diclofenac-associated liver injury? Analysis of 17,289 arthritis patients in a long-term prospective clinical trial. Am J Gastroenterol. 2009;104:356–62.

    Article  PubMed  Google Scholar 

  37. Lankisch TO, Behrens G, Ehmer U, Mobius U, Rockstroh J, Wehmeier M, et al. Gilbert’s syndrome and hyperbilirubinemia in protease inhibitor therapy—an extended haplotype of genetic variants increases risk in indinavir treatment. J Hepatol. 2009;50:1010–8.

    Article  PubMed  CAS  Google Scholar 

  38. Strassburg CP. Pharmacogenetics of Gilbert’s syndrome. Pharmacogenomics. 2008;9:903–15.

    Article  Google Scholar 

  39. Ehmer U, Kalthoff S, Fakundiny B, Pabst B, Freiberg N, Naumann R, et al. Gilbert syndrome redefined: a complex genetic haplotype influences the regulation of glucuronidation. Hepatology. 2012;55:1912–21.

    Article  PubMed  CAS  Google Scholar 

  40. Dhakshinamoorthy S, Long 2nd DJ, Jaiswal AK. Antioxidant regulation of genes encoding enzymes that detoxify xenobiotics and carcinogens. Curr Top Cell Regul. 2000;36:201–16.

    Article  PubMed  CAS  Google Scholar 

  41. Jaiswal AK. Regulation of genes encoding NAD(P)H:quinone oxidoreductases. Free Radic Biol Med. 2000;29:254–62.

    Article  PubMed  CAS  Google Scholar 

  42. Yu X, Kensler T. Nrf2 as a target for cancer chemoprevention. Mutat Res. 2005;591:93–102.

    Article  PubMed  CAS  Google Scholar 

  43. Itoh K, Tong KI, Yamamoto M. Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles. Free Radic Biol Med. 2004;36:1208–13.

    Article  PubMed  CAS  Google Scholar 

  44. Nguyen T, Sherratt PJ, Huang HC, Yang CS, Pickett CB. Increased protein stability as a mechanism that enhances Nrf2-mediated transcriptional activation of the antioxidant response element. Degradation of Nrf2 by the 26 S proteasome. J Biol Chem. 2003;278:4536–41.

    Article  PubMed  CAS  Google Scholar 

  45. Chan K, Kan YW. Nrf2 is essential for protection against acute pulmonary injury in mice. Proc Natl Acad Sci U S A. 1999;96:12731–6.

    Article  PubMed  CAS  Google Scholar 

  46. Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto M, Talalay P, et al. Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci U S A. 2001;98:3410–5.

    Article  PubMed  CAS  Google Scholar 

  47. Kalthoff S, Ehmer U, Freiberg N, Manns MP, Strassburg CP. Interaction between oxidative stress sensor Nrf2 and xenobiotic-activated aryl hydrocarbon receptor in the regulation of the human phase II detoxifying UDP-glucuronosyltransferase 1A10. J Biol Chem. 2010;285:5993–6002.

    Article  PubMed  CAS  Google Scholar 

  48. Arnesen E, Huseby NE, Brenn T, Try K. The Tromso Heart Study: distribution of, and determinants for, gamma-glutamyltransferase in a free-living population. Scand J Clin Lab Invest. 1986;46:63–70.

    Article  PubMed  CAS  Google Scholar 

  49. Tanaka K, Tokunaga S, Kono S, Tokudome S, Akamatsu T, Moriyama T, et al. Coffee consumption and decreased serum gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers. Int J Epidemiol. 1998;27:438–43.

    Article  PubMed  CAS  Google Scholar 

  50. Ruhl CE, Everhart JE. Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States. Gastroenterology. 2005;128:24–32.

    Article  PubMed  CAS  Google Scholar 

  51. Klatsky AL, Morton C, Udaltsova N, Friedman GD. Coffee, cirrhosis, and transaminase enzymes. Arch Intern Med. 2006;166:1190–5.

    Article  PubMed  Google Scholar 

  52. Modi AA, Feld JJ, Park Y, Kleiner DE, Everhart JE, Liang TJ, et al. Increased caffeine consumption is associated with reduced hepatic fibrosis. Hepatology. 2009;51:201–9.

    Article  Google Scholar 

  53. Freedman ND, Everhart JE, Lindsay KL, Ghany MG, Curto TM, Shiffman ML, et al. Coffee intake is associated with lower rates of liver disease progression in chronic hepatitis C. Hepatology. 2009;50:1360–9.

    Article  PubMed  CAS  Google Scholar 

  54. Kalthoff S, Ehmer U, Freiberg N, Manns MP, Strassburg CP. Coffee induces expression of glucuronosyltransferases via the aryl hydrocarbon receptor and Nrf2 in liver and stomach. Gastroenterology. 2010;139:1699–710.

    Article  PubMed  CAS  Google Scholar 

  55. Gressner OA. In the search of the magic bullet. Gastroenterology. 2010;139:1453–7.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine I, University of Bonn Medical Center, Sigmund-Freud-Straße 25, 53127, Bonn, Germany

    Christian P. Strassburg M.D.

Authors
  1. Christian P. Strassburg M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christian P. Strassburg M.D. .

Editor information

Editors and Affiliations

  1. Division of Rheumatology, Allergy and Clinical Immunology, University of California School of Medicine, Davis, California, USA

    M. Eric Gershwin

  2. Medicine and Surgery, Baylor College of Medicine, Houston, Texas, USA

    John M. Vierling

  3. Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Germany

    Michael P. Manns

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Strassburg, C.P. (2014). Nonimmune-Mediated Drug-Induced Hepatotoxicity. In: Gershwin, M., Vierling, J., Manns, M. (eds) Liver Immunology. Springer, Cham. https://doi.org/10.1007/978-3-319-02096-9_26

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-02096-9_26

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-02095-2

  • Online ISBN: 978-3-319-02096-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation