Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives

Gastroenterology

Volumn 146, Issue 4, 2014, Pages 914-928.e1

  Fontana, Robert J ^a  

^a UNIVERSITY OF MICHIGAN   (United States)

Author keywords

Acetaminophen; Epidemiology; Liver Failure; Side Effect

Indexed keywords

AMOXICILLIN PLUS CLAVULANIC ACID; ANTIINFECTIVE AGENT; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; BIOLOGICAL MARKER; CALCIUM CHANNEL BLOCKING AGENT; CHEMOKINE; CYTOKINE; FELODIPINE; FLUCLOXACILLIN; GLUTAMATE DEHYDROGENASE; HEPARIN; HIGH MOBILITY GROUP B1 PROTEIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; ISONIAZID; LAPATINIB; MICRORNA; MICRORNA 122; NITROFURANTOIN; OXALIPLATIN; PHENYTOIN; PIPERACILLIN; PROPRANOLOL; PSYCHOTROPIC AGENT; TAMOXIFEN; TETRACYCLINE; TRANSCRIPTOME; VALPROIC ACID; XIMELAGATRAN;

ADAPTIVE IMMUNITY; CLINICAL PRACTICE; DIET SUPPLEMENTATION; DRUG SAFETY; EPIDEMIOLOGY; EXOME; GENE SEQUENCE; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENOME; HEREDITY; HLA SYSTEM; HUMAN; IDIOSYNCRATIC DRUG INDUCED LIVER DISEASE; IMMUNE SYSTEM; IN VITRO STUDY; IN VIVO STUDY; LIVER HISTOLOGY; LIVER INJURY; LIVER TOXICITY; LYMPHOCYTE PROLIFERATION; METABOLOME; METABOLOMICS; MICROBIOME; NONHUMAN; PATHOGENESIS; PHARMACOGENETICS; PHENOTYPE; PRESCRIPTION; PRIORITY JOURNAL; PROGNOSIS; PROTEIN EXPRESSION; PROTEOMICS; RARE DISEASE; REGISTER; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; TOXIC HEPATITIS; TRANSCRIPTOMICS;

ACETAMINOPHEN; EPIDEMIOLOGY; LIVER FAILURE; SIDE EFFECT;

ANIMALS; BIOLOGICAL MARKERS; DRUG-INDUCED LIVER INJURY; GENETIC PREDISPOSITION TO DISEASE; HUMANS; LIVER; PHARMACOGENETICS; PREDICTIVE VALUE OF TESTS; PROGNOSIS; REGISTRIES; RISK FACTORS; TERMINOLOGY AS TOPIC;

EID: 84896450857     PISSN: 00165085     EISSN: 15280012     Source Type: Journal    
DOI: 10.1053/j.gastro.2013.12.032     Document Type: Review

References (146)

1. A.E. Guttmacher, and F.S. Collins Realizing the promise of genomics in biomedical research JAMA 294 2005 1399 1402
2. D. Ge, J. Fellay, and A.J. Thompson et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance Nature 461 2009 399 401
3. A.J. Thompson, A.J. Muir, and M.S. Sulkowski et al. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus Gastroenterology 139 2010 120 129.e18
4. G.D. Demetri, M. von Mehren, and C.D. Blanke et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors N Engl J Med 347 2002 472 480
5. S. Mallal, D. Nolan, and C. Witt et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir Lancet 359 2002 727 732
6. D. Zucman, P. deTruchis, and C. Majerholc et al. Prospective screening for human leukocyte antigen-B*5701 avoids abacavir hypersensitivity reaction in the ethnically mixed French HIV population J Acquir Immune Defic Syndr 45 2007 1 3
7. P.B. Watkins Drug safety sciences and the bottleneck in drug development Clin Pharmacol Ther 89 2011 788 790
8. P. Watkins, and L.B. Seeff Drug-induced liver injury: summary of a single topic clinical research conference Hepatology 43 2006 618 631
9. R.J. Fontana, L.B. Seeff, and R.J. Andrade et al. Standardization of nomenclature and causality assessment in drug-induced liver injury: summary of a clinical research workshop Hepatology 52 2010 730 742
10. R.A. Roth, and P.E. Ganey Intrinsic versus idiosyncratic drug-induced hepatotoxicity: two villains or one? J Pharmacol Exp Ther 332 2010 692 697
11. R.J. Fontana Approaches to the study of drug-induced liver injury Clin Pharmacol Ther 88 2010 416 419
12. M.V. Galan, J.A. Potts, and A.L. Silverman et al. The burden of acute non-fulminant drug-induced hepatitis in a United States tertiary care referral center J Clin Gastroenterol 39 2005 64 67
13. G. Ostapowicz, R.J. Fontana, and F.V. Schiodt et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States Ann Intern Med 137 2002 947 954
14. R. Vuppalanchi, S. Liangpunsakul, and N. Chalasani Etiology of new-onset jaundice: how often is it caused by idiosyncratic DILI in the United States? Am J Gastroenterol 102 2007 558 562
15. Y. Meier, M. Cavallaro, and M. Roos et al. Incidence of drug-induced liver injury in medical inpatients Eur J Clin Pharmacol 61 2005 135 153
16. M.S. Duh, A.M. Walker, and K.H. Kronlund Descriptive epidemiology of acute liver enzyme abnormalities in the general population of central Massachusetts Pharmacoepidemiol Drug Saf 8 1999 275 283
17. S.J. Bielinski, H.S. Chai, and J. Pathak et al. Mayo Genome Consortia: a genotype-phenotype resource for genome-wide association studies with an application to the analysis of circulating bilirubin levels Mayo Clin Proc 86 2011 606 614
18. C.A. McCarty, R.L. Chisholm, and C.G. Chute et al. The eMERGE Network: a consortium of biorepositories linked to electronic medical records data for conducting genomic studies BMC Med Genomics 4 2011 13
19. K. Jinjuvadia, W. Kwan, and R.J. Fontana Searching for a needle in a haystack: use of ICD-9-CM codes in drug induced liver injury Am J Gastroenterol 102 2007 2437 2443
20. C.L. Overby, J. Pathak, and O. Gottesman et al. A collaborative approach to developing an electronic health record phenotyping algorithm for drug-induced liver injury J Am Med Inform Assoc 20 2013 e243 e252
21. S. Sembera, C. Lammert, and J.A. Talwalkar et al. Frequency, clinical presentation, and outcomes of drug-induced liver injury after liver transplantation Liver Transpl 18 2012 803 810
22. R.J. Fontana, P.B. Watkins, and H.L. Bonkovsky et al. Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct Drug Saf 32 2009 55 68
23. R.J. Fontana Drug induced Liver Injury Networks N. Kaplowtiz, L. DeLeve, Drug Induced Liver Disease 3rd ed 2013 Elsevier San Diego, CA 713 723
24. R.J. Andrade, M.J. Lucena, and M.C. Fernandez et al. Drug induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10 year period Gastroenterology 129 2005 512 521
25. E.S. Bjornsson, O.M. Bergmann, and H.K. Bjornsson et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the General population of Iceland Gastroenterology 144 2013 1419 1425
26. M. Molookhia, and P. McKeigue EUDRAGENE: European collaboration to establish a case-control DNA collection for studying the genetic basis of adverse drug reactions Pharmacogenomics 7 2006 633 638
27. H. Takikawa, Y. Murata, and N. Horiike et al. Drug-induced liver injury in Japan: an analysis of 1676 cases between 1997 and 2006 Hepatol Res 39 2009 427 431
28. G.P. Aithal, P.B. Watkins, and R.J. Andrade et al. Case definition and phenotype standardization in drug-induced liver injury Clin Pharmacol Ther 89 2011 806 815
29. V. Agarwal, J.G. McHutchison, and J.H. Hoofnagle Important elements for the diagnosis of drug-induced liver injury Clin Gastroenterol Hepatol 8 2010 463 470
30. D.C. Rockey, L.B. Seeff, and J. Rochon et al. Causality assessment in drug-induced liver injury using a structured expert opinion process: comparison to the Roussel-Uclaf Assessment method Hepatology 51 2010 2117 2126
31. M. Pirmohamed, G.P. Aithal, and E. Behr et al. The phenotype standardization project: improving pharmacogenetic studies of serious adverse drug reactions Clin Pharmacol Ther 89 2011 784 785
32. J.H. Hoofnagle, J. Serrano, and J.E. Knoben et al. LiverTox: a website on drug-induced liver injury Hepatology 57 2013 873 874
33. N. Chalasani, R.J. Fontana, and H.L. Bonkovsky et al. Causes, clinical features, and outcomes from a prospective study of drug induced liver injury in the United States Gastroenterology 135 2008 1924 1934
34. C. Sgro, F. Clinard, and K. Quazir et al. Incidence of drug-induced hepatic injuries: a French population-based study Hepatology 36 2002 451 455
35. V.J. Navarro, H.X. Barnhart, and H.L. Bonkovsky et al. The rising burden of herbal and dietary supplement induced hepatotoxicity in the U.S.A. (abstr) Hepatology 58 suppl 2013 264A
36. G. Galati, A. Lin, and A.M. Sultan et al. Cellular and in vivo hepatotoxicity caused by green tea phenolic acids and catechins Free Radic Biol Med 40 2006 570 580
37. V.J. Navarro, H.X. Barnhart, and H.L. Bonkovsky et al. Green tea extract containing herbal and dietary supplements are frequently mislabelled in the US: the US DILIN experience (abstr 336) Hepatology 54 suppl 2011 526A
38. T.J. Davern, N. Chalasani, and R.J. Fontana et al. Role of acute hepatitis E in suspected drug-induced liver injury Gastroenterology 141 2011 1665 1672
39. H.R. Dalton, H.J. Fellows, and W. Stableforth et al. The role of hepatitis E virus testing in drug-induced liver injury Aliment Pharmacol Ther 26 2007 1429 1435
40. Hoofnagle JH, Nelson KE, Purcell RH. Hepatitis E. N Engl J Med 2012;367:1237-1244.
41. R.J. Fontana, J. Gu, and H. Barnhart et al. Subject race and liver biochemical profile are strongly associated with clinical outcomes and chronic liver injury: results from the DILIN Prospective Study (abstr) Hepatology 56 suppl 2012 600A
42. R.J. Andrade, M.I. Lucena, and N. Kaplowitz et al. Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry Hepatology 44 2006 1581 1588
43. E.S. Bjornsson, and L. Davidsdottir The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice J Hepatol 50 2009 511 517
44. A. Reuben, D.G. Koch, W.M. Lee Acute Liver Failure Study Group Drug induced acute liver Study Group: results of a US multicenter, prospective study Hepatology 52 2010 2065 2076
45. Q.M. Anstee, and C.P. Day S-adenosylmethionine (SAMe) therapy in liver disease: a review of current evidence and clinical utility J Hepatol 57 2012 1097 1109
46. S.J. Patel, J.M. Milwid, and K.R. King et al. Gap junction inhibition prevents drug-induced liver toxicity and fulminant hepatic failure Nat Biotechnol 30 2012 179 183
47. C. Lammert, S. Einarsson, and C. Saha et al. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals Hepatology 47 2009 2003 2009
48. M. Chen, J. Borlak, and W. Tong High lipophilicity and high daily dose of oral medication are associated with significant risk for drug-induced liver injury Hepatology 58 2013 388 396
49. N. Kaplowitz Avoiding idiosyncratic DILI: two is better than one Hepatology 58 2013 15 17
50. C. Lammert, E. Bjornsson, and A. Niklasson et al. Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events Hepatology 51 2010 615 620
51. Y. Low, T. Uehera, and Y. Minowa et al. Predicting drug-induced hepatotoxicity using QSAR and toxicogenomics approaches Chem Res Toxicol 24 2011 1251 1262
52. A.D. Rodgers, H. Zhu, and D. Fourches et al. Modeling liver-related adverse effects of drugs using nearest neighbor quantitative structure-activity relationship methods Chem Res Toxicol 23 2010 724 732
53. P.J. Shaw, P.E. Ganey, and R.A. Roth Idiosyncratic drug-induced liver injury and the role of inflammatory stress with an emphasis on an animal model of trovafloxacin hepatotoxicity Toxicol Sci 118 2010 7 18
54. J.H. Lewis, M.E. Mortensen, and S. Zweig et al. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well compensated chronic liver disease: results of a prospective, randomized, double-blind placebo-controlled multicenter trial Hepatology 46 2007 1453 1463
55. FDA drug safety communication: important safety label changes to cholesterol lowering statin drugs. April 13, 2013. http://www.fda.gov/Drugs/ DrugSafety/ucm293101.htm.
56. J.D. Stewart, R. Horvath, and E. Baruffini et al. Polymerase G gene, POLG, determines the risk of sodium-valproate-induced liver toxicity Hepatology 52 2010 1791 1796
57. D. Kleiner, N. Chalasani, and W.M.L. Lee et al. Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations Hepatology 59 2014 661 670
58. E. Bjornsson, E. Kalaitzakis, and R. Olsson The impact of eosinophilia and hepatic necrosis on prognosis in patients with drug-induced liver injury Aliment Pharmacol Ther 25 2007 1411 1421
59. A. Katoonizadeh, F. Nevens, and C. Verslype et al. Liver regeneration in acute severe liver impairment: a clinicopathological correlation study Liver Int 26 2006 1225 1233
60. A. Suzuki, E.M. Brunt, and D.E. Kleiner et al. The use of liver biopsy evaluation in the discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury Hepatology 54 2011 931 939
61. N. Kaplowitz Drug-induced liver injury Clin Infect Dis 38 suppl 2 2004 S44 S48
62. M.P. Holt, L. Cheng, and C. Ju Identification and characterization of infiltrating macrophages in acetaminophen-induced liver injury J Leukoc Biol 84 2008 1410 1421
63. P. Krishnan, Z.Z. Feng, and S. Gordon Prolonged intrahepatic cholestasis and renal failure secondary to anabolic androgenic steroid-enriched dietary supplements. A review of the literature J Clin Gastroenterol 43 2009 672 675
64. M.J. Robinson, and A.M. Rywlin Tetracycline-associated fatty liver in the male. Report of an autopsied case Am J Dig Dis 15 1970 857 862
65. C. Bleeker-Rovers, S. Kadir, and R. van Leusen et al. Hepatic steatosis and lactic acidosis caused by stavudine in an HIV-infected patient Neth J Med 57 2000 190 193
66. I. Larosche, P. Letteron, and B. Fromenty et al. Tamoxifen inhibits topoisomerases, depletes mitochondrial DNA, and triggers steatosis in mouse liver J Pharmacol Exp Ther 321 2007 526 535
67. M. Narita, E. Oussoultzoglou, and M.P. Chenard et al. Liver injury due to chemotherapy-induced sinusoidal obstruction syndrome is associated with sinusoidal capillarization Ann Surg Oncol 19 2012 2230 2237
68. N.O. Vieto, and B.J. George Oxaliplatin-induced hepatocellular injury and ototoxicity: a review of the literature and report of unusual side effects of a commonly used chemotherapeutic agent J Oncol Pharm Pract 18 2012 355 359
69. Committee on Toxicity Testing and Assessment of Environmental Agents, National Research Council Toxicity testing in the 21st century: a vision and a strategy 2007 National Academies Press Washington, DC
70. M. Grompe, and S. Strom Mice with human livers Gastroenterology 145 2013 1209 1214
71. M.R. McGill, H.U. Yan, and A. Ramachandran et al. HepaRG cells: a human model to study mechanisms of acetaminophen hepatotoxicity Hepatology 53 2011 974 982
72. K. Si-Tayeb, K.N. Fallon, and M. Nagaoka et al. Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells Hepatology 51 2010 297 305
73. Z. Song, J. Cai, and Y. Liu et al. Efficient generation of hepatocyte-like cells from human induced pleuripotent stem cells Cell Res 19 2009 1233 1242
74. C. Guguen-Guillouzo, A. Corlu, and A. Guillouzo Stem cell-derived hepatocytes and their use in toxicology Toxicology 270 2010 3 9
75. W. Jozefczuk, A. Prigione, and L. Chavez et al. Comparative analysis of human embryonic stem cell and induced pluripotent stem-cell derived hepatocyte like cells reveals current drawbacks and possible strategies for improved differentiation Stem Cells Dev 20 2011 1259 1275
76. L. Faulkner, K. Martinsson, and A. Santoyo-Castelazo et al. The development of in vitro culture methods to characterize primary T-cell responses to drugs Toxicol Sci 127 2012 150 158
77. S. El-Chaiesh, M.M. Monshi, and P. Whitaker et al. Characterization of the antigen specificity of T-cell clones from piperacillin-hypersensitive patients with cystic fibrosis J Pharmacol Exp Ther 341 2012 597 610
78. D. Chessman, L. Kostenko, and T. Lethborg et al. Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity Immunity 28 2008 822 832
79. G. Porebski, A. Gschwend-Azwodniak, and W.J. Pichler In vitro diagnosis of T cell-mediated drug allergy Clin Exp Allergy 4 2011 461 470
80. P.B. Watkins Biomarkers for the diagnosis and management of drug-induced liver injury Semin Liver Dis 29 2009 394 400
81. R.M. Green, and S. Flamm AGA technical review on the evaluation of liver chemistry tests Gastroenterology 123 2002 1367 1384
82. G.S. Sayuk, J.E. Elwing, and M. Lisker-Melman Hepatic glycogenosis: an underrecognized source of abnormal liver function tests? Dig Dis Sci 52 2007 936 938
83. J.R. Senior Monitoring for hepatotoxicity: what is the predictive value of liver "function" tests? Clin Pharmacol Ther 85 2009 331 334
84. J.R. Mitchell, M.W. Long, and U.P. Thorgeisson et al. Acetylation rates and monthly liver function tests during one year of isoniazid preventive therapy Chest 68 1975 181 190
85. H. M'Kada, H. Perazzo, and M. Munteanu et al. Real time identification of drug-induced liver injury (DILI) through daily screening of ALT results: a prospective, pilot cohort study PLoS One 7 2012 e42418
86. A.E. Rutherford, L.S. Hynan, and C.B. Borges et al. Serum apoptosis markers in acute liver failure: a pilot study Clin Gastroenterol Hepatol 5 2007 1477 1483
87. H. Bantel, A. Lugering, and J. Hidemnan et al. Detection of apoptotic caspase activation in sera from patients with chronic HCV infection is associated with fibrotic liver injury Hepatology 40 2004 1078 1087
88. A. Rutherford, L.Y. King, and L.S. Hynan et al. Development of an accurate index for predicting outcomes of patients with acute liver failure Gastroenterology 143 2012 1237 1243
89. R.T. Chung, T. Stravitz, and R.J. Fontana et al. Pathogenesis of liver injury in acute liver failure Gastroenterology 143 2012 e1 e7
90. M. Monreal, E. Lafoz, and R. Salvador et al. Adverse effects of three different forms of heparin therapy: thrombocytopenia, increased transaminases, and hyperkalemia Eur J Clin Pharmacol 37 1989 415 418
91. A.H. Harrill, J. Roach, and I. Fier et al. The effects of heparins on the liver: application of mechanistic serum biomarkers in a randomized study in healthy volunteers Clin Pharmacol Ther 92 2012 214 220
92. D.S. Pisetsky, and W. Jiang Role of Toll-like receptors in HMGB1 release from macrophages Ann N Y Acad Sci 1109 2007 58 65
93. P. Kubes, and W.Z. Mehal Sterile inflammation in the liver Gastroenterology 143 2012 1158 1172
94. J. Uetrecht Mechanisms of immune-mediated liver injury Toxicol Sci 115 2010 307 321
95. P.B. Watkins, N. Kaplowitz, and J.T. Slattery et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized, controlled trial JAMA 296 2006 87 93
96. B.A. Wetmore, D.J. Brees, and R. Singh et al. Quantitative analyses and transcriptomic profiling of circulating messenger RNAs as biomarkers of rat liver injury Hepatology 51 2010 2127 2139
97. D. Antoine, J.W. Dear, and P.S. Lewis et al. Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital Hepatology 58 2013 777 787
98. D.J. Antoine, R.E. Jenkins, and J.W. Dear et al. Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity J Hepatol 56 2012 1070 1079
99. T.J. Davern, L.P. James, and J.A. Hinson et al. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure Gastroenterology 130 2006 687 694
100. N. Khandelwal, L.P. James, and C. Sanders et al. Unrecognized acetaminophen toxicity as a cause of indeterminate acute liver failure Hepatology 53 2011 567 576
101. L.P. James, P. Simpson, and M. Russo et al. Detection of acetaminophen-protein adducts in serum during therapeutic exposure to acetaminophen in healthy volunteers (abstract) Hepatology 46 suppl 1 2007 812A
102. D.J. Antoine, D.P. William, and B.K. Parke Understanding the role of reactive metabolites in drug-induced hepatotoxicity. State of the science Expert Opin Drug Metab Toxicol 4 2008 1415 1427
103. L.N. Bell, R. Vuppalanchi, and P.B. Watkins et al. Serum proteomic profiling in patients with drug-induced liver injury Aliment Pharmacol Ther 35 2012 600 612
104. R. Maniratanachote, A. Shibata, and S. Kaneko et al. Detection of autoantibody to aldolase B in sera from patients with troglitazone-induced liver dysfunction Toxicology 216 2005 15 23
105. U. Andersson, J. Lindberg, and S. Wang et al. A systems biology approach to understanding elevated serum alanine transaminase levels in a clinical trial with ximelagatran Biomarkers 14 2009 572 586
106. Q. Shi, H. Hong, and J. Senior et al. Biomarkers for drug-induced liver injury Exp Rev Gastroenterol Hepatol 4 2010 225 234
107. N.M. Steuerwald, D.M. Foureau, and H.J. Norton et al. Profiles of serum cytokines in acute drug-induced liver injury and their prognostic significance PLoS One 8 2013 e81974
108. L. Hammerich, F. Heymann, and F. Tacke Role of IL-17 and Th17 cells in liver diseases Clin Dev Immunol 345 2011 803
109. J. Li, X. Zhu, and F. Liu et al. Cytokine and autoantibody patterns in acute liver failure J Immunotoxicol 7 2010 157 164
110. E.K. Lobenhofer, J.T. Auman, and P.E. Blackshear et al. Gene expression response in target organ and whole blood varies as a function of target organ injury phenotype Genome Biol 9 2008 R100
111. P.R. Bushel, A.N. Heinloth, and J. Li et al. Blood gene expression signatures predict exposure levels Proc Natl Acad Sci U S A 104 2007 18211 18216
112. R.D. Fannin, M. Russo, and T.M. O'Connell et al. Acetaminophen dosing of humans results in blood transcriptome and metabolome changes consistent with impaired oxidative phosphorylation Hepatology 51 2010 227 236
113. J.H. Winnike, Z. Li, and F.A. Wright et al. Use of pharmco-metabonomics for early prediction of acetaminophen-induced hepatotoxicity in humans Clin Pharmacol Ther 88 2010 45 50
114. T.A. Clayton, D. Baker, and J.C. Lindon et al. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism Proc Natl Acad Sci U S A 106 2009 14728 14733
115. T.M. O'Connell, and P.B. Watkins The application of metabonomics to predict drug-induced liver injury Clin Pharmacol Ther 88 2010 384 399
116. D.G. Robertson, P.B. Watkins, and M.D. Reily Metabolomics in toxicology: preclinical and clinical applications Toxicol Sci 120 2011 S146 S170
117. K. Wang, S. Zhang, and B. Marzolf et al. Circulating microRNA's, potential biomarkers for DILI Proc Natl Acad Sci U S A 106 2009 4402 4407
118. M.R. McGill, M.R. Sharpe, and C.D. Williams et al. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation J Clin Invest 122 2012 1574 1583
119. L.P.J. Starkey, J. Dear, and V. Platt et al. Circulating microRNA's as potential markers of human drug-induced liver injury Hepatology 54 2011 1767 1776
120. Y.S. Huang, H.D. Chern, and W.J. Su et al. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis Hepatology 35 2002 883 889
121. Y.S. Huang, H.D. Chern, and W.J. Su et al. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis Hepatology 37 2003 924 930
122. M.L. Hautekeete, Y. Horsmans, and C. Van Waeyenberge et al. HLA association of amoxicillin clavulanate-induced hepatitis Gastroenterology 117 1999 1181 1186
123. A.K. Daly, and C.P. Day Genetic association studies in drug-induced liver injury Semin Liver Dis 29 2009 400 411
124. A.K. Daly, P.T. Donaldson, P. Bhatnagar DILIGEN Study; International SAE Consortium HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin Nat Genet 41 2009 816 819
125. A. Kindmark, A. Jawaid, and C.G. Harbron et al. Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis Pharmacogenomics J 8 2008 186 195
126. J.B. Singer, S. Lewitzky, and E. Leroy et al. A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury Nat Genet 42 2010 711 714
127. C.F. Spraggs, L.R. Budde, and L.P. Briley et al. HLA-DQA1*01:01 is a major risk factor for lapatanib-induced hepatotoxicity in women with advanced breast cancer J Clin Oncol 29 2011 667 673
128. S. Russmann, J.A. Kaye, and S.S. Jick et al. Risk of cholestatic liver disease associated with flucloxacillin and flucloxacillin prescribing habits in the UK: cohort study using data from the UK General Practice Research Database Br J Clin Pharmacol 60 2005 76 82
129. E.J. Phillips, and S.A. Mallal HLA-B*5701 and flucloxacillin associated drug-induced liver disease AIDS 27 2013 491 492
130. E. Andrews, M. Armstrong, and J. Tugwood et al. A role for the pregnane X receptor in flucloxacillin-induced liver injury Hepatology 51 2010 1656 1664
131. M. Monshi, L. Faulkner, and A. Gibson et al. Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T-cells provides the immunological basis for flucloxacillin-induced liver injury Hepatology 57 2013 727 739
132. P.T. Illing, J.P. Vivain, and N.L. Dudek et al. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire Nature 486 2012 554 558
133. N. Wuillemin, J. Adam, and S. Fontana et al. HLA haplotype determines hapten or p-I T cell reactivity to flucloxacillin J Immunol 190 2013 4956 4964
134. T.J. Urban, Y. Shen, and A. Stolz et al. Limited contribution of common genetic variants to risk of liver injury due to a variety of drugs Pharmacogenet Genomics 22 2012 784 795
135. M.I. Lucena, M. Molokhia, and Y. Shen et al. Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA Class I and II alleles Gastroenterology 131 2011 338 347
136. T.J. Urban, D.B. Goldstein, and P.B. Watkins Genetic basis of susceptibility to drug-induced liver injury: what have we learned and where do we go from here? Pharmacogenomics 13 2012 735 738
137. N.T. Ventham, N.A. Kennedy, and E.R. Nimmo et al. Beyond gene discovery in inflammatory bowel disease: the emerging role of epigenetics Gastroenterology 145 2013 293 308
138. P. Parham, and T. Onta Population biology of antigen presentation by MHC class I molecules Science 272 1996 67 74
139. M. Bharadwaj, P. Iling, and A. Theodossis et al. Drug hypersensitivity and human leukocyte antigens of the major histocompatibility complex Annu Rev Pharmacol Toxicol 52 2012 401 431
140. P. Chen, J.J. Lin, and C.S. Lu et al. Carbamazepine-induced toxic effects and HLA-B*5802 screening in Taiwan N Engl J Med 364 2011 1126 1133
141. M. McCormack, A. Alfirevic, and S. Bourgeois et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans N Engl J Med 364 2011 1134 1143
142. J.G. Markle, D.N. Frank, and S. Mortin-Toth et al. Sex differences in the gut microbiome drive hormone dependent regulation of autoimmunity Science 339 2013 1084 1088
143. J. Henao-Mejia, E. Elinav, and C. Jin et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity Nature 482 2012 179 185
144. G.M. Hirschfield, R.W. Chapman, and T.H. Karlsen et al. The genetics of complex cholestatic disorders Gastroenterology 144 2013 1357 1374
145. E. Holmes, J.V. Li, and J.R. Marchesi et al. Gut microbiota composition and activity in relation to host metabolic phenotype and disease risk Cell Metab 16 2012 559 564
146. X. Zheng, A. Zhao, and G. Xie et al. Melamine-induced renal toxicity is mediated by the gut microbiota Sci Transl Med 5 2013 172ra22