Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Current Challenges and Controversies in Drug-Induced Liver Injury

  • 633 Accesses

  • 41 Citations


Current key challenges and controversies encountered in the identification of potentially hepatotoxic drugs and the assessment of drug-induced liver injury (DILI) are covered in this article.

There is substantial debate over the classification of DILI itself, including the definition and validity of terms such as ‘intrinsic’ and ‘idiosyncratic’. So-called idiosyncratic DILI is typically rare and requires one or more susceptibility factors in individuals. Consequently, it has been difficult to reproduce in animal models, which has limited the understanding of its underlying mechanisms despite numerous hypotheses. Advances in predictive models would also help to enable preclinical elimination of drug candidates and development of novel biomarkers.

A small number of liver laboratory tests have been routinely used to help identify DILI, but their interpretation can be limited and confounded by multiple factors. Improved preclinical and clinical biomarkers are therefore needed to accurately detect early signals of liver injury, distinguish drug hepatotoxicity from other forms of liver injury, and differentiate mild from clinically important liver injury. A range of potentially useful biomarkers are emerging, although so far most have only been used preclinically, with only a few validated and used in the clinic for specific circumstances. Advances in the development of genomic biomarkers will improve the prediction and detection of hepatic injury in future.

Establishing a definitive clinical diagnosis of DILI can be difficult, since it is based on circumstantial evidence by excluding other aetiologies and, when possible, identifying a drug-specific signature. DILI signals based on standard liver test abnormalities may be affected by underlying diseases such as hepatitis B and C, HIV and cancer, as well as the concomitant use of hepatotoxic drugs to treat some of these conditions. Therefore, a modified approach to DILI assessment is justified in these special populations and a suggested framework is presented that takes into account underlying disease when evaluating DILI signals in individuals.

Detection of idiosyncratic DILI should, in some respects, be easier in the postmarketing setting compared with the clinical development programme, since there is a much larger and more varied patient population exposure over longer timeframes. However, postmarketing safety surveillance is currently limited by the quantity and quality of information available to make an accurate diagnosis, the lack of a control group and the rarity of cases. The pooling of multiple healthcare databases, which could potentially contain different types of patient data, is advised to address some of these deficiencies.

This is a preview of subscription content, log in to check access.

Table I
Fig. 1
Table II
Table III
Fig. 2


  1. 1.

    Russmann S, Kullak-Ublick GA, Grattagliano I. Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem 2009; 16(23): 3041–53

  2. 2.

    Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 2005; 4(6): 489–99

  3. 3.

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

  4. 4.

    Sgro C, Clinard F, Ouazir K, et al. Incidence of drug-induced hepatic injuries: a French population based study. Hepatology 2002; 36(2): 451–55

  5. 5.

    Kaplowitz N. Drug-induced liver disorders: introduction and overview. In: Kaplowitz N, DeLeve L, editors. Drug-induced liver disease. 2nd ed. New York: Marcel Dekker, 2007: 1–11

  6. 6.

    Verma S, Kaplowitz N. Diagnosis, management and prevention of drug-induced liver injury. Gut 2009; 58(11): 1555–64

  7. 7.

    Jain S, Kaplowitz N. Clinical considerations of drug-induced hepatotoxicity. In: McQueen CA, editor. Comprehensive toxicology. 2nd ed. New York: Elsevier Science and Technology, 2010: 369–81

  8. 8.

    Shapiro MA, Lewis JH. Causality assessment of drug-induced hepatotoxicity: promises and pitfalls. Clin Liver Dis 2007; 11(3): 477–505

  9. 9.

    Andrade RJ, Robles M, Ulzurrun E, et al. Drug-induced liver injury: insights from genetic studies. Pharmacogenomics 2009; 10(9): 1467–87

  10. 10.

    Food and Drug Administration. Guidance for industry. Drug-induced liver injury: Premarketing clinical evaluation. 2009 [online]. Available from URL: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf [Accessed 2011 Sept 20]

  11. 11.

    Temple RJ, Himmel MH. Safety of newly approved drugs: implications for prescribing. JAMA 2002; 287(17): 2273–5

  12. 12.

    Aithal GP, Watkins PB, Andrade RJ, et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther 2011; 89(6): 806–15

  13. 13.

    Roth RA, Ganey PE. Intrinsic versus idiosyncratic drug-induced hepatotoxicity: two villains or one? J Pharmacol Exp Ther 2010; 332(3): 692–7

  14. 14.

    Zimmerman H. Drug-induced liver disease. In: Zimmerman H, editor. Hepatotoxicity, the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia (PA): Lippincott Williams & Wilkins; 1999: 428–33

  15. 15.

    Uetrecht J. Idiosyncratic drug reactions: current understanding. Annu Rev Pharmacol Toxicol 2007; 47: 513–39

  16. 16.

    Lammert C, Einarsson S, Saha C, et al. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology 2008; 47(6): 2003–9

  17. 17.

    Lammert C, Bjornsson E, Niklasson A, et al. Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events. Hepatology 2010; 51(2): 615–20

  18. 18.

    Morita M, Akai S, Hosomi H, et al. Drug-induced hepatotoxicity test using gamma-glutamylcysteine synthetase knockdown rat. Toxicol Lett 2009; 189(2): 159–65

  19. 19.

    Plummer JL, Hall PD, Jenner MA, et al. Hepatic effects of repeated halothane anesthetics in the hypoxic rat model. Anesthesiology 1987; 67(3): 355–60

  20. 20.

    Tasduq SA, Kaiser P, Sharma SC, et al. Potentiation of isoniazid-induced liver toxicity by rifampicin in a combinational therapy of antitubercular drugs (rifampicin, isoniazid and pyrazinamide) in Wistar rats: a toxicity profile study. Hepatol Res 2007; 37(10): 845–53

  21. 21.

    Bourdi M, Amouzadeh HR, Rushmore TH, et al. Halothane-induced liver injury in outbred guinea pigs: role of trifluoroacetylated protein adducts in animal susceptibility. Chem Res Toxicol 2001; 14(4): 362–70

  22. 22.

    Frost L, Mahoney J, Field J, et al. Impaired bile flow and disordered hepatic calcium homeostasis are early features of halothane-induced liver injury in guinea pigs. Hepatology 1996; 23(1): 80–6

  23. 23.

    Lind RC, Gandolfi AJ, Hall PM. Glutathione depletion enhances subanesthetic halothane hepatotoxicity in guinea pigs. Anesthesiology 1992; 77(4): 721–7

  24. 24.

    Lind RC, Gandolfi AJ, Hall PD. Subanesthetic halothane is hepatotoxic in the guinea pig. Anesth Analg 1992; 74(4): 559–63

  25. 25.

    Lind RC, Gandolfi AJ, Hall PM. A model for fatal halothane hepatitis in the guinea pig. Anesthesiology 1994; 81(2): 478–87

  26. 26.

    Lind RC, Gandolfi AJ. Late dimethyl sulfoxide administration provides a protective action against chemically induced injury in both the liver and the kidney. Toxicol Appl Pharmacol 1997; 142(1): 201–7

  27. 27.

    Tennant BC, Baldwin BH, Graham LA, et al. Antiviral activity and toxicity of fialuridine in the woodchuck model of hepatitis B virus infection. Hepatology 1998; 28(1): 179–91

  28. 28.

    Kashimshetty R, Desai VG, Kale VM, et al. Underlying mitochondrial dysfunction triggers flutamide-induced oxidative liver injury in a mouse model of idiosyncratic drug toxicity. Toxicol Appl Pharmacol 2009; 238(2): 150–9

  29. 29.

    Lee YH, Chung MC, Lin Q, et al. Troglitazone-induced hepatic mitochondrial proteome expression dynamics in heterozygous Sod2(+/−) mice: two-stage oxidative injury. Toxicol Appl Pharmacol 2008; 231(1): 43–51

  30. 30.

    Ong MM, Wang AS, Leow KY, et al. Nimesulide-induced hepatic mitochondrial injury in heterozygous Sod2(+/−) mice. Free Radic Biol Med 2006; 40(3): 420–9

  31. 31.

    Ong MM, Latchoumycandane C, Boelsterli UA. Troglitazone-induced hepatic necrosis in an animal model of silent genetic mitochondrial abnormalities. Toxicol Sci 2007; 97(1): 205–13

  32. 32.

    Ulrich RG, Bacon JA, Branstetter DG, et al. Induction of a hepatic toxic syndrome in the Dutch-belted rabbit by a quinoxalinone anxiolytic. Toxicology 1995; 98(1–3): 187–98

  33. 33.

    Knapp AC, Todesco L, Beier K, et al. Toxicity of valproic acid in mice with decreased plasma and tissue carnitine stores. J Pharmacol Exp Ther 2008; 324(2): 568–75

  34. 34.

    Buchweitz JP, Ganey PE, Bursian SJ, et al. Underlying endotoxemia augments toxic responses to chlorpromazine: is there a relationship to drug idiosyncrasy? J Pharmacol Exp Ther 2002; 300(2): 460–7

  35. 35.

    Deng X, Stachlewitz RF, Liguori MJ, et al. Modest inflammation enhances diclofenac hepatotoxicity in rats: role of neutrophils and bacterial translocation. J Pharmacol Exp Ther 2006; 319(3): 1191–9

  36. 36.

    Waring JF, Liguori MJ, Luyendyk JP, et al. Microarray analysis of lipopolysaccharide potentiation of trovafloxacin-induced liver injury in rats suggests a role for proinflammatory chemokines and neutrophils. J Pharmacol Exp Ther 2006; 316(3): 1080–7

  37. 37.

    Zou W, Beggs KM, Sparkenbaugh EM, et al. Sulindac metabolism and synergy with tumor necrosis factor-alpha in a drug-inflammation interaction model of idiosyncratic liver injury. J Pharmacol Exp Ther 2009; 331(1): 114–21

  38. 38.

    Zou W, Devi SS, Sparkenbaugh E, et al. Hepatotoxic interaction of sulindac with lipopolysaccharide: role of the hemostatic system. Toxicol Sci 2009; 108(1): 184–93

  39. 39.

    Lu L, Jones AD, Harkema JR, et al. Amiodarone exposure during modest inflammation induces idiosyncrasy-like liver injury in rats: role of tumor necrosis factor-alpha. Toxicol Sci 2012; 125(1): 126–33

  40. 40.

    Cheng L, You Q, Yin H, et al. Effect of polyI:C cotreatment on halothane-induced liver injury in mice. Hepatology 2009; 49(1): 215–26

  41. 41.

    Shaw PJ, Hopfensperger MJ, Ganey PE, et al. Lipopolysaccharide and trovafloxacin coexposure in mice causes idiosyncrasy-like liver injury dependent on tumor necrosis factor-alpha. Toxicol Sci 2007; 100(1): 259–66

  42. 42.

    Shaw PJ, Fullerton AM, Scott MA, et al. The role of the hemostatic system in murine liver injury induced by co-exposure to lipopolysaccharide and trovafloxacin, a drug with idiosyncratic liability. Toxicol Appl Pharmacol 2009; 236(3): 293–300

  43. 43.

    Shaw PJ, Beggs KM, Sparkenbaugh EM, et al. Trovafloxacin enhances TNF-induced inflammatory stress and cell death signaling and reduces TNF clearance in a murine model of idiosyncratic hepatotoxicity. Toxicol Sci 2009; 111(2): 288–301

  44. 44.

    Shaw PJ, Ganey PE, Roth RA. Trovafloxacin enhances the inflammatory response to a Gram-negative or a Gram-positive bacterial stimulus, resulting in neutrophil-dependent liver injury in mice. J Pharmacol Exp Ther 2009; 330(1): 72–8

  45. 45.

    Shaw PJ, Ditewig AC, Waring JF, et al. Coexposure of mice to trovafloxacin and lipopolysaccharide, a model of idiosyncratic hepatotoxicity, results in a unique gene expression profile and interferon gamma-dependent liver injury. Toxicol Sci 2009; 107(1): 270–80

  46. 46.

    Shaw PJ, Ganey PE, Roth RA. Tumor necrosis factor alpha is a proximal mediator of synergistic hepatotoxicity from trovafloxacin/lipopolysaccharide coexposure. J Pharmacol Exp Ther 2009; 328(1): 62–8

  47. 47.

    Dugan CM, MacDonald AE, Roth RA, et al. A mouse model of severe halothane hepatitis based on human risk factors. J Pharmacol Exp Ther 2010; 333(2): 364–72

  48. 48.

    You Q, Cheng L, Reilly TP, et al. Role of neutrophils in a mouse model of halothane-induced liver injury. Hepatology 2006; 44(6): 1421–31

  49. 49.

    Shenton JM, Chen J, Uetrecht JP. Animal models of idiosyncratic drug reactions. Chem Biol Interact 2004; 150(1): 53–70

  50. 50.

    Caldwell J. The current status of attempts to predict species differences in drug metabolism. Drug Metab Rev 1981; 12(2): 221–37

  51. 51.

    Choudhury AI, Chahal S, Bell AR, et al. Species differences in peroxisome proliferation; mechanisms and relevance. Mutat Res 2000; 448(2): 201–12

  52. 52.

    Guengerich FP. Comparisons of catalytic selectivity of cytochrome P450 subfamily enzymes from different species. Chem Biol Interact 1997; 106(3): 161–82

  53. 53.

    Martignoni M, Groothuis GM, de Kanter R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol 2006; 2(6): 875–94

  54. 54.

    Nebert DW, Dalton TP, Stuart GW, et al. “Gene-swap knock-in” cassette in mice to study allelic differences in human genes. Ann N Y Acad Sci 2000; 919: 148–70

  55. 55.

    Tomlinson ES, Maggs JL, Park BK, et al. Dexamethasone metabolism in vitro: species differences. J Steroid Biochem Mol Biol 1997; 62(4): 345–52

  56. 56.

    Gonzalez FJ. Role of gene knockout and transgenic mice in the study of xenobiotic metabolism. Drug Metab Rev 2003; 35(4): 319–35

  57. 57.

    Lee SS, Buters JT, Pineau T, et al. Role of CYP2E1 in the hepatotoxicity of acetaminophen. J Biol Chem 1996; 271(20): 12063–7

  58. 58.

    Zaher H, Buters JT, Ward JM, et al. Protection against acetaminophen toxicity in CYP1A2 and CYP2E1 double-null mice. Toxicol Appl Pharmacol 1998; 152(1): 193–9

  59. 59.

    Cheung C, Yu AM, Ward JM, et al. The cyp2e1-human-ized transgenic mouse: role of cyp2e1 in acetaminophen hepatotoxicity. Drug Metab Dispos 2005; 33(3): 449–57

  60. 60.

    Cheung C, Gonzalez FJ. Humanized mouse lines and their application for prediction of human drug metabolism and toxicological risk assessment. J Pharmacol Exp Ther 2008; 327(2): 288–99

  61. 61.

    Corchero J, Granvil CP, Akiyama TE, et al. The CYP2D6 humanized mouse: effect of the human CYP2D6 transgene and HNF4alpha on the disposition of debrisoquine in the mouse. Mol Pharmacol 2001; 60(6): 1260–7

  62. 62.

    Gonzalez FJ, Yu AM. Cytochrome P450 and xenobiotic receptor humanized mice. Annu Rev Pharmacol Toxicol 2006; 46: 41–64

  63. 63.

    Dandri M, Burda MR, Torok E, et al. Repopulation of mouse liver with human hepatocytes and in vivo infection with hepatitis B virus. Hepatology 2001; 33(4): 981–8

  64. 64.

    Locke JE, Sun Z, Warren DS, et al. Generation of humanized animal livers using embryoid body-derived stem cell transplant. Ann Surg 2008; 248(3): 487–93

  65. 65.

    Muruganandan S, Sinal CJ. Mice as clinically relevant models for the study of cytochrome P450-dependent metabolism. Clin Pharmacol Ther 2008; 83(6): 818–28

  66. 66.

    van de Steeg E, Stranecky V, Hartmannova H, et al. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest 2012; 122(2): 519–28

  67. 67.

    Begriche K, Massart J, Robin MA, et al. Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver. J Hepatol 2011; 54(4): 773–94

  68. 68.

    Lim PL, Liu J, Go ML, et al. The mitochondrial superoxide/thioredoxin-2/Ask1 signaling pathway is critically involved in troglitazone-induced cell injury to human hepatocytes. Toxicol Sci 2008; 101(2): 341–9

  69. 69.

    Masubuchi Y. Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review. Drug Metab Pharmacokinet 2006; 21(5): 347–56

  70. 70.

    Santos NA, Medina WS, Martins NM, et al. Aromatic antiepileptic drugs and mitochondrial toxicity: effects on mitochondria isolated from rat liver. Toxicol In Vitro 2008; 22(5): 1143–52

  71. 71.

    Tay VK, Wang AS, Leow KY, et al. Mitochondrial permeability transition as a source of superoxide anion induced by the nitroaromatic drug nimesulide in vitro. Free Radic Biol Med 2005; 39(7): 949–59

  72. 72.

    Ganey PE, Luyendyk JP, Maddox JF, et al. Adverse hepatic drug reactions: inflammatory episodes as consequence and contributor. Chem Biol Interact 2004; 150(1): 35–51

  73. 73.

    Deng X, Luyendyk JP, Ganey PE, et al. Inflammatory stress and idiosyncratic hepatotoxicity: hints from animal models. Pharmacol Rev 2009; 61(3): 262–82

  74. 74.

    Shaw PJ, Ganey PE, Roth RA. Idiosyncratic drug-induced liver injury and the role of inflammatory stress with an emphasis on an animal model of trovafloxacin hepatotoxicity. Toxicol Sci 2010; 118(1): 7–18

  75. 75.

    Cosgrove BD, King BM, Hasan MA, et al. Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity. Toxicol Appl Pharmacol 2009; 237(3): 317–30

  76. 76.

    Tukov FF, Maddox JF, Amacher DE, et al. Modeling inflammation-drug interactions in vitro: a rat Kupffer cell-hepatocyte coculture system. Toxicol In Vitro 2006; 20(8): 1488–99

  77. 77.

    Navarro V, Nomenclature Subcommittee Drug Hepatotoxicity Steering Committee. Hepatic adverse event nomenclature document. Jan 2005. Available from URL: http://www.fda.gov/downloads/Drugs/ScienceResearch/.../ucm080365.ppt [Accessed 2011 Sept 20]

  78. 78.

    Cai H, Nguyen N, Peterkin V, et al. A humanized UGT1 mouse model expressing the UGT1A1*28 allele for assessing drug clearance by UGT1A1-dependent glucuronidation. Drug Metab Dispos 2010; 38(5): 879–86

  79. 79.

    Zimmerman HJ. Drug-induced liver disease. Drugs 1978; 16(1): 25–45

  80. 80.

    Benichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol 1990; 11(2): 272–6

  81. 81.

    Watkins PB. Idiosyncratic liver injury: challenges and approaches. Toxicol Pathol 2005; 33(1): 1–5

  82. 82.

    Kaplowitz N. Does elevated alkaline phosphatase exclude Hy’s Law? Drug-induced liver injury: getting the medicine and science together. Mar 2010 Available from URL: http://www.aasld.org/conferences/educationtraining/Pages/2010HepatotoxicitySpecialInterestGroupMeeting.aspx [Accessed 2012 Feb 14]

  83. 83.

    Temple R. Hy’s law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 2006; 15(4): 241–3

  84. 84.

    Hunt CM, Papay JI, Edwards RI, et al. Monitoring liver safety in drug development: the GSK experience. Regul Toxicol Pharmacol 2007; 49(2): 90–100

  85. 85.

    Green RM, Flamm S. AGA technical review on the evaluation of liver chemistry tests. Gastroenterology 2002; 123(4): 1367–84

  86. 86.

    Marrer E, Dieterle F. Impact of biomarker development on drug safety assessment. Toxicol Appl Pharmacol 2010; 243(2): 167–79

  87. 87.

    Ozer JS, Chetty R, Kenna G, et al. Enhancing the utility of alanine aminotransferase as a reference standard bio-marker for drug-induced liver injury. Regul Toxicol Pharmacol 2010; 56(3): 237–46

  88. 88.

    Vanderlinde RE. Review of pyridoxal phosphate and the transaminases in liver disease. Ann Clin Lab Sci 1986; 16(2): 79–93

  89. 89.

    Hall RL. Principles of clinical pathology for toxicology studies. In: Wallace Hayes A, editor. Principles and methods of toxicology. 4th ed. Philadelphia: Taylor & Francis, 2001: 1001–38

  90. 90.

    Antoine DJ, Mercer AE, Williams DP, et al. Mechanism-based bioanalysis and biomarkers for hepatic chemical stress. Xenobiotica 2009; 39(8): 565–77

  91. 91.

    Giffen PS, Pick CR, Price MA, et al. Alpha-glutathione S-transferase in the assessment of hepatotoxicity-its diagnostic utility in comparison with other recognized markers in the Wistar Han rat. Toxicol Pathol 2002; 30(3): 365–72

  92. 92.

    Harrison DJ, Kharbanda R, Cunningham DS, et al. Distribution of glutathione S-transferase isoenzymes in human kidney: basis for possible markers of renal injury. J Clin Pathol 1989; 42(6): 624–8

  93. 93.

    Goldberg DM. Structural, functional, and clinical aspects of gamma-glutamyltransferase. CRC Crit Rev Clin Lab Sci 1980; 12(1): 1–58

  94. 94.

    Keeffe EB, Sunderland MC, Gabourel JD. Serum gamma-glutamyl transpeptidase activity in patients receiving chronic phenytoin therapy. Dig Dis Sci 1986; 31(10): 1056–61

  95. 95.

    Lum G, Gambino SR. Serum gamma-glutamyl transpeptidase activity as an indicator of disease of liver, pancreas, or bone. Clin Chem 1972; 18(4): 358–62

  96. 96.

    Belfield A, Goldberg DM. Normal ranges and diagnostic value of serum 5’nucleotidase and alkaline phosphatase activities in infancy. Arch Dis Child 1971; 46(250): 842–6

  97. 97.

    Hill PG, Sammons HG. An assessment of 5’-nucleotidase as a liver-function test. Q J Med 1967; 36(144): 457–68

  98. 98.

    Seitanidis B, Moss DW. Serum alkaline phosphatase and 5’-nucleotidase levels during normal pregnancy. Clin Chim Acta 1969; 25(1): 183–4

  99. 99.

    Asada M, Galambos JT. Liver disease, hepatic alcohol dehydrogenase activity, and alcohol metabolism in the human. Gastroenterology 1963; 45: 67–72

  100. 100.

    Wiesner IS, Rawnsley HM, Brooks FP, et al. Sorbitol dehydrogenase in the diagnosis of liver disease. Am J Dig Dis 1965; 10: 147–51

  101. 101.

    Brohult J, Fridell E, Sundblad L. Studies on alkaline phosphatase isoenzymes. Relation to gamma-glutamyltransferase and lactate dehydrogenase isoenzymes. Clin Chim Acta 1977; 76(2): 205–11

  102. 102.

    Wroblewski F, Ladue JS. Serum glutamic pyruvic transaminase in cardiac with hepatic disease. Proc Soc Exp Biol Med 1956; 91(4): 569–71

  103. 103.

    Wroblewski F. The clinical significance of transaminase activities of serum. Am J Med 1959; 27: 911–23

  104. 104.

    Jung K, Pergande M, Rej R, et al. Mitochondrial enzymes in human serum: comparative determinations of glutamate dehydrogenase and mitochondrial aspartate aminotransferase in healthy persons and patients with chronic liver diseases. Clin Chem 1985; 31(2): 239–43

  105. 105.

    Berk PD, Javitt NB. Hyperbilirubinemia and cholestasis. Am J Med 1978; 64(2): 311–26

  106. 106.

    Erlinger S. Secretion of bile. In: Schiff L, Schiff ER, editors. Diseases of the liver. 7th ed. Philadelphia: J. B. Lippincott; 1993: 85–107

  107. 107.

    Friedman LS, Martin P, Munoz SJ. Liver function tests and the objective evaluation of the patient with liver disease. In: Zakin D, Boyer TD, editors. Hepatology: a textbook of liver disease. 3rd ed. Philadelphia: W.B. Saunders; 1996: 791–833

  108. 108.

    Adler M, Hoffmann D, Ellinger-Ziegelbauer H, et al. Assessment of candidate biomarkers of drug-induced hepatobiliary injury in preclinical toxicity studies. Toxicol Lett 2010; 196(1): 1–11

  109. 109.

    Camps J, Marsillach J, Joven J. Measurement of serum paraoxonase-1 activity in the evaluation of liver function. World J Gastroenterol 2009; 15(16): 1929–33

  110. 110.

    Ferre N, Camps J, Prats E, et al. Serum paraoxonase activity: a new additional test for the improved evaluation of chronic liver damage. Clin Chem 2002; 48(2): 261–8

  111. 111.

    Rodrigo L, Hernandez AF, Lopez-Caballero JJ, et al. Immunohistochemical evidence for the expression and induction of paraoxonase in rat liver, kidney, lung and brain tissue. Implications for its physiological role. Chem Biol Interact 2001; 137(2): 123–37

  112. 112.

    Mochida S, Arai M, Ohno A, et al. Deranged blood coagulation equilibrium as a factor of massive liver necrosis following endotoxin administration in partially hepatectomized rats. Hepatology 1999; 29(5): 1532–40

  113. 113.

    Misra MK, Khanna AK, Sharma R, et al. Serum malate dehydrogenase (MDH) in portal hypertension-its value as a diagnostic and prognostic indicator. Indian J Med Sci 1991; 45(2): 31–4

  114. 114.

    Ozer J, Ratner M, Shaw M, et al. The current state of serum biomarkers of hepatotoxicity. Toxicology 2008; 245(3): 194–205

  115. 115.

    Bu DX, Hemdahl AL, Gabrielsen A, et al. Induction of neutrophil gelatinase-associated lipocalin in vascular injury via activation of nuclear factor-kappaB. Am J Pathol 2006; 169(6): 2245–53

  116. 116.

    Jayaraman A, Roberts KA, Yoon J, et al. Identification of neutrophil gelatinase-associated lipocalin (NGAL) as a discriminatory marker of the hepatocyte-secreted protein response to IL-1beta: a proteomic analysis. Biotechnol Bioeng 2005; 91(4): 502–15

  117. 117.

    Mori K, Nakao K. Neutrophil gelatinase-associated lipocalin as the real-time indicator of active kidney damage. Kidney Int 2007; 71(10): 967–70

  118. 118.

    Dieterle F, Perentes E, Cordier A, et al. Urinary clusterin, cystatin C, beta2-microglobulin and total protein as markers to detect drug-induced kidney injury. Nat Biotechnol 2010; 28(5): 463–9

  119. 119.

    Rosenberg ME, Silkensen J. Clusterin: physiologic and pathophysiologic considerations. Int J Biochem Cell Biol 1995; 27(7): 633–45

  120. 120.

    Zidek N, Hellmann J, Kramer PJ, et al. Acute hepatotoxicity: a predictive model based on focused illumina microarrays. Toxicol Sci 2007; 99(1): 289–302

  121. 121.

    Tarantino G, Colao A, Capone D, et al. Circulating levels of cytochrome C, gamma-glutamyl transferase, triglycerides and unconjugated bilirubin in overweight/obese patients with non-alcoholic fatty liver disease. J Biol Regul Homeost Agents 2011; 25(1): 47–56

  122. 122.

    Starkey Lewis PJ, Dear J, Platt V, et al. Circulating microRNAs as potential markers of human drug-induced liver injury. Hepatology 2011; 54(5): 1767–76

  123. 123.

    Antoine DJ, Williams DP, Kipar A, et al. High-mobility group box-1 protein and keratin-18, circulating serum proteins informative of acetaminophen-induced necrosis and apoptosis in vivo. Toxicol Sci 2009; 112(2): 521–31

  124. 124.

    Antoine DJ, Williams DP, Kipar A, et al. Diet restriction inhibits apoptosis and HMGB1 oxidation and promotes inflammatory cell recruitment during acetaminophen hepatotoxicity. Mol Med 2010; 16(11–12): 479–90

  125. 125.

    Amacher DE, Adler R, Herath A, et al. Use of proteomic methods to identify serum biomarkers associated with rat liver toxicity or hypertrophy. Clin Chem 2005; 51(10): 1796–803

  126. 126.

    European Medicines Agency. ICH Topic E15. Definitions for genomic biomarkers, pharmacogenomics, pharmacogenetics, genomic data and sample coding categories. [EMEA/CHMP/ICH/437986/2006] Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002880.pdf [Accessed 2011 Sept 20]

  127. 127.

    Fielden MR, Nie A, McMillian M, et al. Interlaboratory evaluation of genomic signatures for predicting carcinogenicity in the rat. Toxicol Sci 2008; 103(1): 28–34

  128. 128.

    Wang K, Zhang S, Marzolf B, et al. Circulating micro-RNAs, potential biomarkers for drug-induced liver injury. Proc Natl Acad Sci U S A 2009; 106(11): 4402–7

  129. 129.

    Laterza OF, Lim L, Garrett-Engele PW, et al. Plasma MicroRNAs as sensitive and specific biomarkers of tissue injury. Clin Chem 2009; 55(11): 1977–83

  130. 130.

    Sukata T, Sumida K, Kushida M, et al. Circulating microRNAs, possible indicators of progress of rat hepatocarcinogenesis from early stages. Toxicol Lett 2011; 200(1–2): 46–52

  131. 131.

    Wolf CR, Smith G. Pharmacogenetics. Br Med Bull 1999; 55(2): 366–86

  132. 132.

    Tarantino G, Conca P, Basile V, et al. A prospective study of acute drug-induced liver injury in patients suffering from non-alcoholic fatty liver disease. Hepatol Res 2007; 37(6): 410–5

  133. 133.

    Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol 2008; 64(12): 1147–61

  134. 134.

    Gupta NK, Lewis JH. Review article: The use of potentially hepatotoxic drugs in patients with liver disease. Aliment Pharmacol Ther 2008; 28(9): 1021–41

  135. 135.

    Hadziyannis SJ, Sette Jr H, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140(5): 346–55

  136. 136.

    Zeuzem S, Hultcrantz R, Bourliere M, et al. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 2004; 40(6): 993–9

  137. 137.

    Thomas HC. Hepatitis B and D. Medicine 2002; 30: 34–6

  138. 138.

    Nunez M. Hepatotoxicity of antiretrovirals: incidence, mechanisms and management. J Hepatol 2006; 44 (1 Suppl.): S132–9

  139. 139.

    Dieterich DT, Robinson PA, Love J, et al. Drug-induced liver injury associated with the use of nonnucleoside reverse-transcriptase inhibitors. Clin Infect Dis 2004; 38 Suppl. 2: S80–9

  140. 140.

    Inductivo-Yu I, Bonacini M. Highly active antiretroviral therapy-induced liver injury. Curr Drug Saf 2008; 3(1): 4–13

  141. 141.

    Ogedegbe AO, Sulkowski MS. Antiretroviral-associated liver injury. Clin Liver Dis 2003; 7(2): 475–99

  142. 142.

    Wit FW, Weverling GJ, Weel J, et al. Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy. J Infect Dis 2002; 186(1): 23–31

  143. 143.

    King PD, Perry MC. Hepatotoxicity of chemotherapeutic and oncologic agents. Gastroenterol Clin North Am 1995; 24(4): 969–90

  144. 144.

    McDonald GB, Frieze D. A problem-oriented approach to liver disease in oncology patients. Gut 2008; 57(7): 987–1003

  145. 145.

    Rodriguez-Frias EA, Lee WM. Cancer chemotherapy I: hepatocellular injury. Clin Liver Dis 2007; 11(3): 641–62, viii

  146. 146.

    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(4): 213–20

  147. 147.

    Llanos L, Moreu R, Ortin T, et al. The existence of a relationship between increased serum alanine aminotransferase levels detected in premarketing clinical trials and postmarketing published hepatotoxicity case reports. Aliment Pharmacol Ther 2010; 31(12): 1337–45

  148. 148.

    Watkins PB, Whitcomb RW. Hepatic dysfunction associated with troglitazone. N Engl J Med 1998; 338(13): 916–7

  149. 149.

    Watkins PB, Desai M, Berkowitz SD, et al. Evaluation of drug-induced serious hepatotoxicity (eDISH): application of this data organization approach to phase III clinical trials of rivaroxaban after total hip or knee replacement surgery. Drug Saf 2011; 34(3): 243–52

Download references


This work was supported financially by F. Hoffmann-La Roche Ltd.

A. Corsini has consultancy agreements with and has received research funding from F. Hoffman-La Roche, NiCox, Novartis, Merck, Kowa, Regeneron and Recordati, and has also received travel funds. C. Ju has received a research grant from Pfizer, Inc., to develop mouse models of DILI; consulting fees from F. Hoffman La Roche for providing advice on DILI and content for associated documents, including her contribution to this manuscript. N. Kaplowitz has consulting agreements with F. Hoffman-La Roche, GSK, Novartis, BMS, JNJ, Otsuka, Daiichi-Sankyo, Merck, Sanofi, Takeda, Hepregen, ISIS and Enanta. R. Roth has consulting agreements with pharmaceutical companies including F. Hoffman-La Roche. D. Pessayre has been a consultant for several other pharmaceutical companies, including recent advices to F. Hoffman-La Roche, Novartis, Pfizer and Astellas. P.B. Watkins has received consulting fees from F. Hoffman-La Roche, Abbott, Actelion, AstraZeneca, Biogen Idec, Bristol Myers Squibb, Cempra, Conatus, Genzyme, Genentech, Gilead, GlaxoSmithKline, Infinity, Merck, Momenta, Janssen & Janssen/McNeil, Novartis, Pfizer, Sanofi-Aventis, UCB and YM Biosciences. M. Albassam, B. Liu, S. Stancic, L. Suter and M. Bortolini are full-time employees of F. Hoffmann-La Roche. P. Ganey has no potential conflicts of interest relevant to the contents of this article.

We thank Dr Stephen Mayall, Dr Ruth Case and Dr Anjan Banerjee of Pope Woodhead & Associates Ltd for providing editorial support.

Author information

Correspondence to Dr Michele Bortolini.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Corsini, A., Ganey, P., Ju, C. et al. Current Challenges and Controversies in Drug-Induced Liver Injury. Drug Saf 35, 1099–1117 (2012). https://doi.org/10.1007/BF03261997

Download citation


  • Liver Injury
  • Nimesulide
  • Acute Liver Failure
  • Tolcapone
  • Clinical Development Programme