Biomarkers for drug-induced liver injury

Drug-Induced Liver Disease

Volumn , Issue , 2013, Pages 275-286

  Watkins, Paul B ^a,b  

^a University of North Carolina at Chapel Hill   (United States)

^b Hamner UNC Institute for Drug Safety Sciences   (United States)

Author keywords

Biomarkers; Metabolomics; MicroRNA; MRNA; Proteomics; Transcriptomics

Indexed keywords

EID: 84882649543     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1016/B978-0-12-387817-5.00017-0     Document Type: Chapter

References (101)

1. Senior J.R. Drug hepatotoxicity from a regulatory perspective. Clin Liver Dis 2007, 11:507-524. [vi].
2. Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 2009. (Accessed at ). http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformati on/Guidances/UCM174090.pdf.
3. Olson S, Robinson, S, Giffin, R. Accelerating the Development of Biomarkers for Drug Safety: Workshop Summary. http://wwwiomedu/Reports/2009/BiomarkersDrugSafetyaspx.
4. Green R.M., Flamm S. AGA technical review on the evaluation of liver chemistry tests. Gastroenterology 2002, 123:1367-1384.
5. Sayuk G.S., Elwing J.E., Lisker-Melman M. Hepatic glycogenosis: an underrecognized source of abnormal liver function tests?. Dig Dis Sci 2007, 52:936-938.
6. Olsson R., Wesslau C., William-Olsson T., Zettergren L. Elevated aminotransferases and alkaline phosphatases in unstable diabetes mellitus without ketoacidosis or hypoglycemia. J Clin Gastroenterol 1989, 11:541-545.
7. Rautou P.E., Cazals-Hatem D., Moreau R., et al. Acute liver cell damage in patients with anorexia nervosa: a possible role of starvation-induced hepatocyte autophagy. Gastroenterology 2008, 135(840-8):8 e1-3.
8. Watkins P.B., Zimmerman H.J., Knapp M.J., Gracon S.I., Lewis K.W. Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease. JAMA 1994, 271:992-998.
9. Carlson M.K., Gleason P.P., Sen S. Elevation of hepatic transaminases after enoxaparin use: case report and review of unfractionated and low-molecular-weight heparin-induced hepatotoxicity. Pharmacotherapy 2001, 21:108-113.
10. Watkins P.B., Kaplowitz N., Slattery J.T., et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 2006, 296:87-93.
11. Radi Z.A., Koza-Taylor P.H., Bell R.R., et al. Increased serum enzyme levels associated with Kupffer cell reduction with no signs of hepatic or skeletal muscle injury. Am J Pathol 2011, 179:240-247.
12. Thulin P., Rafter I., Stockling K., et al. PPARalpha regulates the hepatotoxic biomarker alanine aminotransferase (ALT1) gene expression in human hepatocytes. Toxicol Appl Pharmacol 2008, 231:1-9.
13. Watkins P.B., Whitcomb R.W. Hepatic dysfunction associated with troglitazone. N Engl J Med 1998, 338:916-917.
14. Brown W.V. Safety of statins. Curr Opin Lipidol 2008, 19:558-562.
15. Watkins P.B., Seeff L.B. Drug-induced liver injury: summary of a single topic clinical research conference. Hepatology 2006, 43:618-631.
16. Mitchell J.R., Long M.W., Thorgeirsson U.P., Jollow D.J. Acetylation rates and monthly liver function tests during one year of isoniazid preventive therapy. Chest 1975, 68:181-190.
17. Lee W.M., Larrey D., Olsson R., et al. Hepatic findings in long-term clinical trials of ximelagatran. Drug Saf 2005, 28:351-370.
18. Torti V.R., Cobb A.J., Everitt J.I., Marshall M.W., Boorman G.A., Butterworth B.E. Nephrotoxicity and hepatotoxicity induced by inhaled bromodichloromethane in wild-type and p53-heterozygous mice. Toxicol Sci 2001, 64:269-280.
19. Shayiq R.M., Roberts D.W., Rothstein K., et al. Repeat exposure to incremental doses of acetaminophen provides protection against acetaminophen-induced lethality in mice: an explanation for high acetaminophen dosage in humans without hepatic injury. Hepatology 1999, 29:451-463.
20. Aleksunes L.M., Campion S.N., Goedken M.J., Manautou J.E. Acquired resistance to acetaminophen hepatotoxicity is associated with induction of multidrug resistance-associated protein 4 (Mrp4) in proliferating hepatocytes. Toxicol Sci 2008, 104:261-273.
21. Ros J.E., Libbrecht L., Geuken M., Jansen P.L., Roskams T.A. High expression of MDR1, MRP1, and MRP3 in the hepatic progenitor cell compartment and hepatocytes in severe human liver disease. J Pathol 2003, 200:553-560.
22. Zimmerman H.J. The spectrum of hepatotoxicity. Perspect Biol Med 1968, 12:135-161.
23. Bjornsson E., Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology 2005, 42:481-489.
24. Andrade R.J., Lucena M.I., Kaplowitz N., et al. Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry. Hepatology 2006, 44:1581-1588.
25. Watkins P.B., Desai M., Berkowitz S.D., 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, 34:243-252.
26. Verma S., Kaplowitz N. Diagnosis, management and prevention of drug-induced liver injury. Gut 2009, 58:1555-1564.
27. Jones D.P., Lemasters J.J., Han D., Boelsterli U.A., Kaplowitz N. Mechanisms of pathogenesis in drug hepatotoxicity putting the stress on mitochondria. Mol Interv 2010, 10:98-111.
28. Roth R.A., Luyendyk J.P., Maddox J.F., Ganey P.E. Inflammation and drug idiosyncrasy-is there a connection?. J Pharmacol Exp Ther 2003, 307:1-8.
29. Daly A.K., Day C.P. Genetic association studies in drug-induced liver injury. Drug Metab Rev Drug Metab Rev 2012 Feb, 44(1):116-126.
30. Liu Z.X., Kaplowitz N. Immune-mediated drug-induced liver disease. Clin Liver Dis 2002, 6:755-774.
31. Singer J.B., Lewitzky S., Leroy E., et al. A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat Genet 2010, 42:711-714.
32. Kindmark A., Jawaid A., Harbron C.G., et al. Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J 2008, 8:186-195.
33. Spraggs C.F., Budde L.R., Briley L.P., et al. HLA-DQA102:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol 2011, 29:667-673.
34. Adams D.H., Ju C., Ramaiah S.K., Uetrecht J., Jaeschke H. Mechanisms of immune-mediated liver injury. Toxicol Sci 2010, 115:307-321.
35. McKenzie R., Fried M.W., Sallie R., et al. Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. N Engl J Med 1995, 333:1099-1105.
36. Dykens J.A., Jamieson J.D., Marroquin L.D., et al. In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone. Toxicol Sci 2008, 103:335-345.
37. Xu J.J., Henstock P.V., Dunn M.C., Smith A.R., Chabot J.R., de Graaf D. Cellular imaging predictions of clinical drug-induced liver injury. Toxicol Sci 2008, 105:97-105.
38. Srivastava A., Maggs J.L., Antoine D.J., Williams D.P., Smith D.A., Park B.K. Role of reactive metabolites in drug-induced hepatotoxicity. Handb Exp Pharmacol 2010, 196:165-194.
39. Robertson D.G., Watkins P.B., Reily M.D. Metabolomics in toxicology: preclinical and clinical applications. Toxicol Sci 2011, 120(Suppl 1):S146-S170.
40. Lindon J.C., Nicholson J.K., Holmes E., et al. Contemporary issues in toxicology: the role of metabonomics in toxicology and its evaluation by the COMET project. Toxicol Appl Pharmacol 2003, 187:137-146.
41. Beger R.D., Sun J., Schnackenberg L.K. Metabolomics approaches for discovering biomarkers of drug-induced hepatotoxicity and nephrotoxicity. Toxicol Appl Pharmacol 2010, 243:154-166.
42. Clayton T.A., Lindon J.C., Cloarec O., et al. Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature 2006, 440:1073-1077.
43. Winnike J.H., Li Z., Wright F.A., Macdonald J.M., O'Connell T.M., Watkins P.B. Use of pharmaco-metabonomics for early prediction of acetaminophen-induced hepatotoxicity in humans. Clin Pharmacol Ther 2010, 88:45-51.
44. Clayton T.A., Baker D., Lindon J.C., Everett J.R., Nicholson J.K. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci USA 2009, 106:14728-14733.
45. Andersson U., Lindberg J., Wang S., et al. A systems biology approach to understanding elevated serum alanine transaminase levels in a clinical trial with ximelagatran. Biomarkers 2009, 14:572-586.
46. Blomme E.A., Yang Y., Waring J.F. Use of toxicogenomics to understand mechanisms of drug-induced hepatotoxicity during drug discovery and development. Toxicol Lett 2009, 186:22-31.
47. Bushel P.R., Heinloth A.N., Li J., et al. Blood gene expression signatures predict exposure levels. Proc Natl Acad Sci USA 2007, 104:18211-18216.
48. Umbright C., Sellamuthu R., Li S., Kashon M., Luster M., Joseph P. Blood gene expression markers to detect and distinguish target organ toxicity. Mol Cell Biochem 2010, 335:223-234.
49. Fannin R.D., Russo M., O'Connell T.M., et al. Acetaminophen dosing of humans results in blood transcriptome and metabolome changes consistent with impaired oxidative phosphorylation. Hepatology 2010, 51:227-236.
50. Zhang L, Bushel PR, Chou J, Zhou T, Watkins PB. Identification of identical transcript changes in liver and whole blood during acetaminophen toxicity: implications for blood toxicogenomics. Toxicology; [Submitted].
51. Wang K., Zhang S., Marzolf B., et al. Circulating microRNAs, potential biomarkers for drug-induced liver injury. Proc Natl Acad Sci USA 2009, 106:4402-4407.
52. Wetmore B.A., Brees D.J., Singh R., et al. Quantitative analyses and transcriptomic profiling of circulating messenger RNAs as biomarkers of rat liver injury. Hepatology 2010, 51:2127-2139.
53. Miyamoto M., Yanai M., Ookubo S., Awasaki N., Takami K., Imai R. Detection of cell-free, liver-specific mRNAs in peripheral blood from rats with hepatotoxicity: a potential toxicological biomarker for safety evaluation. Toxicol Sci 2008, 106:538-545.
54. Friedman R.C., Farh K.K., Burge C.B., Bartel D.P. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 2009, 19:92-105.
55. Wang K., Zhang S., Weber J., Baxter D., Galas D.J. Export of microRNAs and microRNA-protective protein by mammalian cells. Nucleic Acids Res 2010, 38:7248-7259.
56. Starkey Lewis P.J., Dear J., Platt V., et al. Circulating microRNAs as potential markers of human drug-induced liver injury. Hepatology 2011, 54:1767-1776.
57. Harrill A.H., Roach J., Fier I., Eaddy J.S., Kurtz C.L., Antoine D.J., et al. The effects of heparins on the liver: application of mechanistic serum biomarkers in a randomized study in healthy volunteers. Clin Pharmacol Therapeut 2012, 92:214-220.
58. Fukushima T., Hamada Y., Yamada H., Horii I. Changes of micro-RNA expression in rat liver treated by acetaminophen or carbon tetrachloride-regulating role of micro-RNA for RNA expression. J Toxicol Sci 2007, 32:401-409.
59. Yang X., Greenhaw J., Shi Q., et al. Identification of urinary microRNA profiles in rats that may diagnose hepatotoxicity. Toxicol Sci 2012 Feb, 125(2):335-344.
60. Antoine D.J., Williams D.P., 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, 112:521-531.
61. Antoine D.J., Williams D.P., Kipar A., Laverty H., Park B.K. Diet restriction inhibits apoptosis and HMGB1 oxidation and promotes inflammatory cell recruitment during acetaminophen hepatotoxicity. Mol Med 2010, 16:479-490.
62. Craig D.G., Lee P., Pryde E.A., Masterton G.S., Hayes P.C., Simpson K.J. Circulating apoptotic and necrotic cell death markers in patients with acute liver injury. Liver Int 2011, 31:1127-1136.
63. Linder S., Havelka A.M., Ueno T., Shoshan M.C. Determining tumor apoptosis and necrosis in patient serum using cytokeratin 18 as a biomarker. Cancer Lett 2004, 214:1-9.
64. Dhupar R., Klune J.R., Evankovich J., et al. Interferon regulatory factor 1 mediates acetylation and release of high mobility group box 1 from hepatocytes during murine liver ischemia-reperfusion injury. Shock 2011, 35:293-301.
65. Pisetsky D.S., Jiang W. Role of Toll-like receptors in HMGB1 release from macrophages. Ann N Y Acad Sci 2007, 1109:58-65.
66. Laverty H.G., Antoine D.J., Benson C., Chaponda M., Williams D., Kevin Park B. The potential of cytokines as safety biomarkers for drug-induced liver injury. Eur J Clin Pharmacol 2010, 66:961-976.
67. Nolan C.M., Goldberg S.V., Buskin S.E. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA 1999, 281:1014-1018.
68. Bell L.N., Vuppalanchi R., Watkins P.B., et al. Serum proteomic profiling in patients with drug-induced liver injury. Alimentary Phamarcology and Therapeutics 2012; Mar, 35(5):600-612.
69. Hoofnagle J.H. Drug-Induced Liver Injury Network (DILIN). Hepatology 2004, 40:773.
70. van der Wiel H.E., Lips P., Huijgens P.C., Netelenbos J.C. Effects of short-term low-dose heparin administration on biochemical parameters of bone turnover. Bone Miner 1993, 22:27-32.
71. Levy S.W. Effects of heparin in vivo on lysosomal enzymes in rat plasma. Can J Biochem 1967, 45:1145-1151.
72. Girolami B., Prandoni P., Rossi L., Girolami A. Transaminase elevations in patients treated with unfractionated heparin or low molecular weight heparin for venous thromboembolism. Clin Appl Thromb Hemost 1998, 4:126-128.
73. Shilo S., Abraham A.S., Breuer R., Sonnenblick M. Hypertransaminasemia with subcutaneous heparin therapy. Isr J Med Sci 1981, 17:1133-1135.
74. Webster P.A., Roberts D.W., Benson R.W., Kearns G.L. Acetaminophen toxicity in children: diagnostic confirmation using a specific antigenic biomarker. J Clin Pharmacol 1996, 36:397-402.
75. Davern T.J., James L.P., Hinson J.A., et al. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology 2006, 130:687-694.
76. James L.P., Capparelli E.V., Simpson P.M., et al. Acetaminophen-associated hepatic injury: evaluation of acetaminophen protein adducts in children and adolescents with acetaminophen overdose. Clin Pharmacol Ther 2008, 84:684-690.
77. James L.P., Letzig L.G., Simpson P.M., et al. Pharmacokinetics of acetaminophen protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab Dispos 2009, 8:1779-1784.
78. Heard K.J., Green J.L., James L.P., et al. Acetaminophen-cysteine adducts during therapeutic dosing and following overdose. BMC Gastroenterol 2011, 11:20.
79. Homberg J.C., Andre C., Abuaf N. A new anti-liver-kidney microsome antibody (anti-LKM2) in tienilic acid-induced hepatitis. Clin Exp Immunol 1984, 55:561-570.
80. Bourdi M., Larrey D., Nataf J., et al. Anti-liver endoplasmic reticulum autoantibodies are directed against human cytochrome P-450IA2. A specific marker of dihydralazine-induced hepatitis. J Clin Invest 1990, 85:1967-1973.
81. Nguyen C., Rose N.R., Njoku D.B. Trifluoroacetylated IgG4 antibodies in a child with idiosyncratic acute liver failure after first exposure to halothane. J Pediatr Gastroenterol Nutr 2008, 47:199-202.
82. Watkins P.B. Antimicrosomal antibodies: what are they telling us?. Hepatology 1991, 13:385-387.
83. Beaune P.H., Lecoeur S., Bourdi M., et al. Anti-cytochrome P450 autoantibodies in drug-induced disease. Eur J Haematol Suppl 1996, 60:89-92.
84. Robin M.A., Le Roy M., Descatoire V., Pessayre D. Plasma membrane cytochromes P450 as neoantigens and autoimmune targets in drug-induced hepatitis. Journal of Hepatology 1997, 26:23-30.
85. Obermayer-Straub P., Strassburg C.P., Manns M.P. Target proteins in human autoimmunity: cytochromes P450 and UDP- glucuronosyltransferases. Canadian Journal of Gastroenterology 2000, 14:429-439.
86. Manns M.P., Obermayer-Straub P. Cytochromes P450 and uridine triphosphate-glucuronosyltransferases: model autoantigens to study drug-induced, virus-induced, and autoimmune liver disease. Hepatology 1997, 26:1054-1066.
87. Beaune P., Dansette P.M., Mansuy D., et al. Human anti-endoplasmic reticulum autoantibodies appearing in a drug-induced hepatitis are directed against a human liver cytochrome P-450 that hydroxylates the drug. Proc Natl Acad Sci USA 1987, 84:551-555.
88. Pichler W.J., Tilch J. The lymphocyte transformation test in the diagnosis of drug hypersensitivity. Allergy 2004, 59:809-820.
89. Merk H.F. Diagnosis of drug hypersensitivity: lymphocyte transformation test and cytokines. Toxicology 2005, 209:217-220.
90. Schreiber J., Zissel G., Greinert U., Schlaak M., Muller-Quernheim J. Lymphocyte transformation test for the evaluation of adverse effects of antituberculous drugs. Eur J Med Res 1999, 4:67-71.
91. Maria V.A., Victorino R.M. Diagnostic value of specific T cell reactivity to drugs in 95 cases of drug induced liver injury. Gut 1997, 41:534-540.
92. 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, 39:427-431.
93. Lindblom P., Rafter I., Copley C., et al. Isoforms of alanine aminotransferases in human tissues and serum-differential tissue expression using novel antibodies. Arch Biochem Biophys 2007, 466:66-77.
94. O'Brien P.J., Slaughter M.R., Polley S.R., Kramer K. Advantages of glutamate dehydrogenase as a blood biomarker of acute hepatic injury in rats. Lab Anim 2002, 36:313-321.
95. Rodrigo L., Hernandez A.F., Lopez-Caballero J.J., Gil F., Pla A. 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, 137:123-137.
96. Kawai M., Hosaki S. Clinical usefulness of malate dehydrogenase and its mitochondrial isoenzyme in comparison with aspartate aminotransferase and its mitochondrial isoenzyme in sera of patients with liver disease. Clin Biochem 1990, 23:327-334.
97. Fukuda M., Yokoyama H., Mizukami T., et al. Kupffer cell depletion attenuates superoxide anion release into the hepatic sinusoids after lipopolysaccharide treatment. J Gastroenterol Hepatol 2004, 19:1155-1162.
98. Horney B.S., Honor D.J., MacKenzie A., Burton S. Stability of sorbitol dehydrogenase activity in bovine and equine sera. Vet Clin Pathol 1993, 22:5-9.
99. 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, 25:47-56.
100. Giffen P.S., Pick C.R., Price M.A., Williams A., York M.J. 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, 30:365-372.
101. Thompson M.B. Bile acids in the assessment of hepatocellular function. Toxicol Pathol 1996, 24:62-71.