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Variability in Baseline Liver Test Values in Clinical Trials: Challenges in Enhancing Drug-Induced Liver Injury Assessment in Subjects with Liver Disease

  • Bereket Tesfaldet
  • Gyorgy Csako
  • Tejas Patel
  • Md Shamsuzzaman
  • Eileen Navarro AlmarioEmail author
Protocol
Part of the Methods in Pharmacology and Toxicology book series (MIPT)

Abstract

Baseline liver test (LT: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin) values were examined in contemporaneous drug product applications for autoimmune disease (Group A), for diseases that could involve the liver (Group B), for hepatobiliary disease (Group C) and in a reference group with no overt liver disease. The upper limit of normal (ULN) values and hence the classification of an LT as a multiple of ULN varied widely across trials. Most baseline LT values were within the ULN, although the distribution curves of LT values in overt hepatobiliary disease gradually diverged from the other disease groups within the range of values considered to be normal, consistent with the exclusion of subjects with baseline LT 1.5–2 × ULN from most studies. Nonetheless, LT values >3 × ULN occurred in all groups, as in the reference group, suggesting underlying liver disease in the populations studied. Drug-induced liver injury (DILI) is challenging to assess in subjects whose baseline LT values are greater than ULN. Detection of DILI in subjects with liver disease will require an assessment of disease status, liver morphology and function, and LT elevations should be interpreted in light of natural disease variation. Population- and disease-specific thresholds predictive of DILI are needed to guide drug use in subjects with liver disease, given the increasing prevalence of nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH) and multidrug and supplement use. Standard definitions of liver cirrhosis and decompensation and standardized data on liver morphology and function can support these assessments.

Key words

Liver injury Adverse reactions Drug trials Data standards Reference standards Diagnosis US Food and Drug Administration 

Notes

Acknowledgments

This chapter reflects the views of the authors and should not be construed to represent FDA’s or NIH’s views or policies.

References

  1. 1.
    Ioannou GN, Boyko EJ, Lee SP (2006) The prevalence and predictors of elevated serum aminotransferase activity in the United States in 1999-2002. Am J Gastroenterol 101(1):76–82. https://doi.org/10.1111/j.1572-0241.2005.00341.x CrossRefPubMedGoogle Scholar
  2. 2.
    Liu Z, Que S, Xu J, Peng T (2014) Alanine aminotransferase-old biomarker and new concept: a review. Int J Med Sci 11(9):925–935. https://doi.org/10.7150/ijms.8951 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bell BP, Manos MM, Zaman A, Terrault N, Thomas A, Navarro VJ, Dhotre KB, Murphy RC, Van Ness GR, Stabach N, Robert ME, Bower WA, Bialek SR, Sofair AN (2008) The epidemiology of newly diagnosed chronic liver disease in gastroenterology practices in the United States: results from population-based surveillance. Am J Gastroenterol 103(11):2727–2736.; quiz 2737. https://doi.org/10.1111/j.1572-0241.2008.02071.x CrossRefPubMedGoogle Scholar
  4. 4.
    Pan WC, Wu CD, Chen MJ, Huang YT, Chen CJ, Su HJ, Yang HI (2016) Fine particle pollution, alanine transaminase, and liver cancer: a Taiwanese prospective cohort study (REVEAL-HBV). J Natl Cancer Inst 108(3). https://doi.org/10.1093/jnci/djv341
  5. 5.
    Fischbein A (1985) Liver function tests in workers with occupational exposure to polychlorinated biphenyls (PCBs): comparison with yusho and yu-cheng. Environ Health Perspect 60:145–150CrossRefGoogle Scholar
  6. 6.
    Chak E, Talal AH, Sherman KE, Schiff ER, Saab S (2011) Hepatitis C virus infection in USA: an estimate of true prevalence. Liver Int 31(8):1090–1101. https://doi.org/10.1111/j.1478-3231.2011.02494.x CrossRefPubMedGoogle Scholar
  7. 7.
    Younossi ZM, Stepanova M, Afendy M, Fang Y, Younossi Y, Mir H, Srishord M (2011) Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 9(6):524–530. e1.; quiz e60. https://doi.org/10.1016/j.cgh.2011.03.020 CrossRefPubMedGoogle Scholar
  8. 8.
    Seeff LB (2015) Drug-induced liver injury is a major risk for new drugs. Dig Dis 33(4):458–463. https://doi.org/10.1159/000374089 CrossRefPubMedGoogle Scholar
  9. 9.
    U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) (July 2009) Guidance for industry. Drug induced liver injury: premarketing clinical evaluation. https://www.fda.gov/downloads/Drugs/.../guidances/UCM174090.pdf. Accessed 23 Feb 2017
  10. 10.
    Senior JR (2015) Drug-induced liver injury: clinical and diagnostic aspects. In: Urban L, Patel VF, Vaz RJ (eds) Antitargets and drug safety. Wiley-VCH Verlag GmbH & Co., KGaA, Weinheim, Germany, pp 83–106. https://doi.org/10.1002/9783527673643.ch05 CrossRefGoogle Scholar
  11. 11.
    Senior JR (2014) Evolution of the Food and Drug Administration approach to liver safety assessment for new drugs: current status and challenges. Drug Saf 37(Suppl 1):S9–17. https://doi.org/10.1007/s40264-014-0182-7 CrossRefPubMedGoogle Scholar
  12. 12.
    Avigan MI, Bjornsson ES, Pasanen M, Cooper C, Andrade RJ, Watkins PB, Lewis JH, Merz M (2014) Liver safety assessment: required data elements and best practices for data collection and standardization in clinical trials. Drug Saf 37(Suppl 1):S19–S31. https://doi.org/10.1007/s40264-014-0183-6 CrossRefPubMedGoogle Scholar
  13. 13.
    Suzuki A, Yuen NA, Ilic K, Miller RT, Reese MJ, Brown HR, Ambroso JI, Falls JG, Hunt CM (2015) Comedications alter drug-induced liver injury reporting frequency: data mining in the WHO VigiBase™. Regul Toxicol Pharmacol 72(3):481–490. https://doi.org/10.1016/j.yrtph.2015.05.004 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Stine JG, Chalasani N (2015) Chronic liver injury induced by drugs: a systematic review. Liver Int 35(11):2343–2353. https://doi.org/10.1111/liv.12958 CrossRefPubMedGoogle Scholar
  15. 15.
    Kappos L, Wiendl H, Selmaj K, Arnold DL, Havrdova E, Boyko A, Kaufman M, Rose J, Greenberg S, Sweetser M, Riester K, O'Neill G, Elkins J (2015) Daclizumab HYP versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 373(15):1418–1428. https://doi.org/10.1056/NEJMoa1501481 CrossRefPubMedGoogle Scholar
  16. 16.
    Marrone A, Signoriello E, Alfieri G, Dalla Mora L, Rinaldi L, Rainone I, Adinolfi LE, Lus G (2014) Epstein Barr virus infection reactivation as a possible trigger of primary biliary cirrhosis-like syndrome in a patient with multiple sclerosis in the course of fingolimod treatment. Infez Med 22(4):331–336PubMedGoogle Scholar
  17. 17.
    Tremlett H, Seemuller S, Zhao Y, Yoshida EM, Oger JD, Petkau J (2006) Liver test abnormalities in multiple sclerosis: findings from placebo-treated patients. Neurology 67(7):1291–1293. https://doi.org/10.1212/01.wnl.0000238515.27055.62 CrossRefPubMedGoogle Scholar
  18. 18.
    Francis GS, Grumser Y, Alteri E, Micaleff A, O'Brien F, Alsop J, Stam Moraga M, Kaplowitz N (2003) Hepatic reactions during treatment of multiple sclerosis with interferon-beta-1a: incidence and clinical significance. Drug Saf 26(11):815–827CrossRefGoogle Scholar
  19. 19.
    Villamil A, Mullen E, Casciato P, Gadano A (2015) Interferon beta 1a-induced severe autoimmune hepatitis in patients with multiple sclerosis: report of two cases and review of the literature. Ann Hepatol 14(2):273–280CrossRefGoogle Scholar
  20. 20.
    Kremer JM (2002) Not yet time to change the guidelines for monitoring methotrexate liver toxicity: they have served us well. J Rheumatol 29(8):1590–1592PubMedGoogle Scholar
  21. 21.
    Kremer JM, Lee RG, Tolman KG (1989) Liver histology in rheumatoid arthritis patients receiving long-term methotrexate therapy. A prospective study with baseline and sequential biopsy samples. Arthritis Rheum 32(2):121–127CrossRefGoogle Scholar
  22. 22.
    Singh JA, Hossain A, Tanjong Ghogomu E, Mudano AS, Tugwell P, Wells GA (2016) Biologic or tofacitinib monotherapy for rheumatoid arthritis in people with traditional disease-modifying anti-rheumatic drug (DMARD) failure: a Cochrane systematic review and network meta-analysis (NMA). Cochrane Database Syst Rev 11:CD012437PubMedGoogle Scholar
  23. 23.
    Ijaz B, Ahmad W, Javed FT, Gull S, Hassan S (2011) Revised cutoff values of ALT and HBV DNA level can better differentiate HBeAg (−) chronic inactive HBV patients from active carriers. Virol J 8:86. https://doi.org/10.1186/1743-422x-8-86 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Ohira H (2016) The liver in systemic diseases [hardcover and eBook]. Springer International Publ. AG, Cham, Switzerland. 978-4-431-55789-0CrossRefGoogle Scholar
  25. 25.
    Clark JM, Brancati FL, Diehl AM (2003) The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 98(5):960–967CrossRefGoogle Scholar
  26. 26.
    Ruhl CE, Everhart JE (2003) Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology 124(1):71–79. https://doi.org/10.1053/gast.2003.50004 CrossRefPubMedGoogle Scholar
  27. 27.
    Gholam PM, Flancbaum L, Machan JT, Charney DA, Kotler DP (2007) Nonalcoholic fatty liver disease in severely obese subjects. Am J Gastroenterol 102(2):399–408. https://doi.org/10.1111/j.1572-0241.2006.01041.x CrossRefPubMedGoogle Scholar
  28. 28.
    Pirttiaho HI, Salmela PI, Sotaniemi EA, Pelkonen RO, Pitkanen U, Luoma PV (1984) Drug metabolism in diabetic subjects with fatty livers. Br J Clin Pharmacol 18(6):895–899CrossRefGoogle Scholar
  29. 29.
    Dutta A, Saha C, Johnson CS, Chalasani N (2009) Variability in the upper limit of normal for serum alanine aminotransferase levels: a statewide study. Hepatology 50(6):1957–1962. https://doi.org/10.1002/hep.23200 CrossRefPubMedGoogle Scholar
  30. 30.
    Gong Z, Tas E, Yakar S, Muzumdar R (2016) Hepatic lipid metabolism and non-alcoholic fatty liver disease in aging. Mol Cell Endocrinol 455:115–130. pii: SO303-7207(16):30545-30547. https://doi.org/10.1016/j.mce.2016.12.022 CrossRefPubMedGoogle Scholar
  31. 31.
    Kwo PY, Cohen SM, Lim JK (2017) ACG clinical guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol 112(1):18–35. https://doi.org/10.1038/ajg.2016.517 CrossRefPubMedGoogle Scholar
  32. 32.
    Weil JG, Bains C, Linke A, Clark DW, Stirnadel HA, Hunt CM (2008) Background incidence of liver chemistry abnormalities in a clinical trial population without underlying liver disease. Regul Toxicol Pharmacol 52(2):85–88. https://doi.org/10.1016/j.yrtph.2008.06.001 CrossRefPubMedGoogle Scholar
  33. 33.
    Xiang Y, Ma L, Wu W, Liu W, Li Y, Zhu X, Wang Q, Ma J, Cao M, Wang Q, Yao X, Yang L, Wubuli A, Merle C, Milligan P, Mao Y, Gu J, Xin X (2014) The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1. PLoS One 9(1):e85905. https://doi.org/10.1371/journal.pone.0085905 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Pradat P, Alberti A, Poynard T, Esteban J-I, Weiland O, Marcellin P, Badalamenti S, Trépo C (2002) Predictive value of ALT levels for histologic findings in chronic hepatitis C: a European collaborative study. Hepatology 36(4):973–977. https://doi.org/10.1053/jhep.2002.35530 CrossRefPubMedGoogle Scholar
  35. 35.
    Ekstedt M, Franzén LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, Kechagias S (2006) Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44(4):865–873. https://doi.org/10.1002/hep.21327 CrossRefPubMedGoogle Scholar
  36. 36.
    Hu Y, Snitker S, Ryan KA, Yang R, Mitchell BD, Shuldiner AR, Zhu D, Gong D-W (2012) Serum alanine aminotransferase is correlated with hematocrit in healthy human subjects. Scand J Clin Lab Invest 72(3):258–264. https://doi.org/10.3109/00365513.2012.660536 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Lee M-H, Yang H-I, Yuan Y, L’Italien G, Chen C-J (2014) Epidemiology and natural history of hepatitis C virus infection. World J Gastroenterol 20(28):9270–9280. https://doi.org/10.3748/wjg.v20.i28.9270 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Seeff LB, Hoofnagle JH (2003) Appendix: the National Institutes of Health consensus development conference Management of Hepatitis C 2002. Clin Liver Dis 7(1):261–287CrossRefGoogle Scholar
  39. 39.
    U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) (December 2014) Guidance for industry. Providing regulatory submissions in electronic format - standardized study data. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292334.pdf. Accessed 23 Feb 2017
  40. 40.
    Ruhl CE, Everhart JE (2013) Diurnal variation in serum alanine aminotransferase activity in the US population. J Clin Gastroenterol 47(2):165–173. https://doi.org/10.1097/MCG.0b013e31826df40a CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Neuschwander-Tetri BA, Unalp A, Creer MH (2008) Influence of local reference populations on upper limits of normal for serum alanine aminotransferase levels. Arch Intern Med 168(6):663–666. https://doi.org/10.1001/archinternmed.2007.131 CrossRefPubMedGoogle Scholar
  42. 42.
    Neuschwander-Tetri BA, Ünalp A, Creer MH (2004) The upper limits of normal for serum ALT levels reported by clinical laboratories depend on local reference populations. Arch Intern Med 168(6):663–666. https://doi.org/10.1001/archinternmed.2007.131 CrossRefPubMedCentralGoogle Scholar
  43. 43.
    Cruz AA, Lima F, Sarinho E, Ayre G, Martin C, Fox H, Cooper PJ (2007) Safety of anti-immunoglobulin E therapy with omalizumab in allergic patients at risk of geohelminth infection. Clin Exp Allergy 37(2):197–207. https://doi.org/10.1111/j.1365-2222.2007.02650.x CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Demirdal US, Ciftci IH, Kavuncu V (2010) Markers of autoimmune liver diseases in postmenopausal women with osteoporosis. Clinics (Sao Paolo) 65(10):971–974. https://doi.org/10.1590/S1807-59322010001000008 CrossRefGoogle Scholar
  45. 45.
    Wang W-B, She F, Xie L-F, Yan W-H, Ouyang J-Z, Wang B-A, Ma H-Y, Zang L, Mu Y-M (2016) Evaluation of basal serum adrenocorticotropic hormone and cortisol levels and their relationship with nonalcoholic fatty liver disease in male patients with idiopathic hypogonadotropic hypogonadism. Chin Med J 129(10):1147–1153. https://doi.org/10.4103/0366-6999.181967 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Artmeier-Brandt U, Boettcher M, Wensing G (2005) Distribution of laboratory values in healthy subjects. [abstract P-56]. Eur J Clin Pharmacol 61(9):701–702Google Scholar
  47. 47.
    Ruhl CE, Everhart JE (2012) Upper limits of normal for alanine aminotransferase activity in the United States population. Hepatology 55(2):447–454. https://doi.org/10.1002/hep.24725 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Kratz A, Ferraro M, Sluss PM, Lewandrowski KB (2004) Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Laboratory reference values. N Engl J Med 351(15):1548–1563. https://doi.org/10.1056/NEJMcpc049016 CrossRefPubMedGoogle Scholar
  49. 49.
    Walker NJ, Zurier RB (2002) Liver abnormalities in rheumatic diseases. Clin Liver Dis 6(4):933–946CrossRefGoogle Scholar
  50. 50.
    Curtis JR, Beukelman T, Onofrei A, Cassell S, Greenberg JD, Kavanaugh A, Reed G, Strand V, Kremer JM (2010) Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide. Ann Rheum Dis 69(1):43–47. https://doi.org/10.1136/ard.2008.101378 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Sheehan NJ, Slavin BM, Kind PR, Mathews JA (1983) Increased serum alkaline phosphatase activity in ankylosing spondylitis. Ann Rheum Dis 42(5):563–565CrossRefGoogle Scholar
  52. 52.
    Jeon CY, Roberts CK, Crespi CM, Zhang Z-F (2013) Elevated liver enzymes in individuals with undiagnosed diabetes in the U.S. J Diabetes Complicat 27(4):333–339. https://doi.org/10.1016/j.jdiacomp.2013.04.005 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Wyld L, Gutteridge E, Pinder SE, James JJ, Chan SY, Cheung KL, Robertson JF, Evans AJ (2003) Prognostic factors for patients with hepatic metastases from breast cancer. Br J Cancer 89(2):284–290CrossRefGoogle Scholar
  54. 54.
    Eskelin S, Pyrhönen S, Hahka-Kemppinen M, Tuomaala S, Kivelä T (2003) A prognostic model and staging for metastatic uveal melanoma. Cancer 97(2):465–475. https://doi.org/10.1002/cncr.11113 CrossRefPubMedGoogle Scholar
  55. 55.
    Jinks MF, Kelly CA (2004) The pattern and significance of abnormal liver function tests in community-acquired pneumonia. Eur J Intern Med 15(7):436–440. https://doi.org/10.1016/j.ejim.2004.06.011 CrossRefPubMedGoogle Scholar
  56. 56.
    Daxboeck F, Gattringer R, Mustafa S, Bauer C, Assadian O (2005) Elevated serum alanine aminotransferase (ALT) levels in patients with serologically verified Mycoplasma pneumoniae pneumonia. Clin Microbiol Infect 11(6):507–510. https://doi.org/10.1111/j.1469-0691.2005.01154.x CrossRefPubMedGoogle Scholar
  57. 57.
    Lens S, Torres F, Puigvehi M, Marino Z, Londono MC, Martinez SM, Garcia-Juarez I, Garcia-Criado A, Gilabert R, Bru C, Sola R, Sanchez-Tapias JM, Carrion JA, Forns X (2016) Predicting the development of liver cirrhosis by simple modelling in patients with chronic hepatitis C. Aliment Pharmacol Ther 43(3):364–374. https://doi.org/10.1111/apt.13472 CrossRefPubMedGoogle Scholar
  58. 58.
    Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC (2000) A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 31(4):864–871. https://doi.org/10.1053/he.2000.5852 CrossRefPubMedGoogle Scholar
  59. 59.
    Baliga P, Merion RM, Turcotte JG, Ham JM, Henley KS, Lucey MR, Schork A, Shyr Y, Campbell DA Jr (1992) Preoperative risk factor assessment in liver transplantation. Surgery 112(4):704–710. discussion 710-701PubMedGoogle Scholar
  60. 60.
    Verma S, Jensen D, Hart J, Mohanty SR (2013) Predictive value of ALT levels for non-alcoholic steatohepatitis (NASH) and advanced fibrosis in non-alcoholic fatty liver disease (NAFLD). Liver Int 33(9):1398–1405. https://doi.org/10.1111/liv.12226 CrossRefPubMedGoogle Scholar
  61. 61.
    Kunde SS, Lazenby AJ, Clements RH, Abrams GA (2005) Spectrum of NAFLD and diagnostic implications of the proposed new normal range for serum ALT in obese women. Hepatology 42(3):650–656. https://doi.org/10.1002/hep.20818 CrossRefPubMedGoogle Scholar
  62. 62.
    Jacoby A, Rannard A, Buck D, Bhala N, Newton JL, James OF, Jones DE (2005) Development, validation, and evaluation of the PBC-40, a disease specific health related quality of life measure for primary biliary cirrhosis. Gut 54(11):1622–1629. https://doi.org/10.1136/gut.2005.065862 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Elman S, Hynan LS, Gabriel V, Mayo MJ (2010) The 5-D itch scale: a new measure of pruritus. Br J Dermatology 162(3):587–593. https://doi.org/10.1111/j.1365-2133.2009.09586.x CrossRefGoogle Scholar
  64. 64.
    Goessling W, Massaro JM, Vasan RS, D'Agostino RB Sr, Ellison RC, Fox CS (2008) Aminotransferase levels and 20-year risk of metabolic syndrome, diabetes, and cardiovascular disease. Gastroenterology 135(6):1935–1944., 1944.e1931. https://doi.org/10.1053/j.gastro.2008.09.018 CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Triger DR, Berg PA, Rodes J (1984) Epidemiology of primary biliary cirrhosis. Liver 4(3):195–200. https://doi.org/10.1111/j.1600-0676.1984.tb00927.x CrossRefPubMedGoogle Scholar
  66. 66.
    Chazouillères OWD, Serfaty L, Montembault S, Rosmorduc O, Poupon R (1998) Primary biliary cirrhosis–autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatology 28(2):296–301. https://doi.org/10.1002/hep.510280203 CrossRefPubMedGoogle Scholar
  67. 67.
    U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) (September 2016) Draft guidance for industry: FDA’s application of statutory factors in determining when a REMS is necessary. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM521504.pdf. Accessed 23 Feb 2017
  68. 68.
    Mercke Odeberg J, Andrade J, Holmberg K, Hoglund P, Malmqvist U, Odeberg J (2006) UGT1A polymorphisms in a Swedish cohort and a human diversity panel, and the relation to bilirubin plasma levels in males and females. Eur J Clin Pharmacol 62(10):829–837. https://doi.org/10.1007/s00228-006-0166-3 CrossRefPubMedGoogle Scholar
  69. 69.
    Olagnier V, Sibille M, Vital Durand D, Deigat N, Baltassat P, Levrat R (1993) Critical value of bilirubin in the selection of healthy volunteers in for phase I. Therapie 48(6):617–622PubMedGoogle Scholar
  70. 70.
    Prati D, Shiffman ML, Diago M, Gane E, Rajender Reddy K, Pockros P, Farci P, O'Brien CB, Lardelli P, Blotner S, Zeuzem S (2006) Viral and metabolic factors influencing alanine aminotransferase activity in patients with chronic hepatitis C. J Hepatol 44(4):679–685. https://doi.org/10.1016/j.jhep.2006.01.004 CrossRefPubMedGoogle Scholar
  71. 71.
    Messier V, Karelis AD, Robillard ME, Bellefeuille P, Brochu M, Lavoie JM, Rabasa-Lhoret R (2010) Metabolically healthy but obese individuals: relationship with hepatic enzymes. Metabolism 59(1):20–24. https://doi.org/10.1016/j.metabol.2009.06.020 CrossRefPubMedGoogle Scholar
  72. 72.
    Breithaupt-Groegler K, Coch C, Coenen M, Donath F, Erb-Zohar K, Francke K, Goehler K, Iovino M, Kammerer KP, Mikus G, Rengelshausen J, Sourgens H, Schinzel R, Sudhop T, Wensing G (2017) Who is a 'healthy subject'?-consensus results on pivotal eligibility criteria for clinical trials. Eur J Clin Pharmacol 73(4):409–416. https://doi.org/10.1007/s00228-016-2189-8 CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Mavrogiannaki AN, Migdalis IN (2013) Nonalcoholic fatty liver disease, diabetes mellitus and cardiovascular disease: newer data. Int J Endocrinol 2013:450639. https://doi.org/10.1155/2013/450639 CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Williams KH, Shackel NA, Gorrell MD, McLennan SV, Twigg SM (2013) Diabetes and nonalcoholic fatty liver disease: a pathogenic duo. Endocr Rev 34(1):84–129. https://doi.org/10.1210/er.2012-1009 CrossRefGoogle Scholar
  75. 75.
    Merz M, Lee KR, Kullak-Ublick GA, Brueckner A, Watkins PB (2014) Methodology to assess clinical liver safety data. Drug Saf 37(Suppl 1):33–45. https://doi.org/10.1007/s40264-014-0184-5 CrossRefPubMedCentralGoogle Scholar
  76. 76.
    de Denus S, Spinler SA, Miller K, Peterson AM (2004) Statins and liver toxicity: a meta-analysis. Pharmacotherapy 24(5):584–591CrossRefGoogle Scholar
  77. 77.
    Chen M, Borlak J, Tong W (2013) High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury. Hepatology 58(1):388–396. https://doi.org/10.1002/hep.26208 CrossRefGoogle Scholar
  78. 78.
    Kullak-Ublick GA, Merz M, Griffel L, Kaplowitz N, Watkins PB (2014) Liver safety assessment in special populations (hepatitis B, C, and oncology trials). Drug Saf 37(Suppl 1):S57–S62. https://doi.org/10.1007/s40264-014-0186-3 CrossRefPubMedGoogle Scholar
  79. 79.
    Schadt S, Simon S, Kustermann S, Boess F, McGinnis C, Brink A, Lieven R, Fowler S, Youdim K, Ullah M, Marschmann M, Zihlmann C, Siegrist YM, Cascais AC, Di Lenarda E, Durr E, Schaub N, Ang X, Starke V, Singer T, Alvarez-Sanchez R, Roth AB, Schuler F, Funk C (2015) Minimizing DILI risk in drug discovery - a screening tool for drug candidates. Toxicol In Vitro 30(1 Pt B):429–437. https://doi.org/10.1016/j.tiv.2015.09.019 CrossRefGoogle Scholar
  80. 80.
    Lopez J, Balasegaram M, Thambyrajah V, Timor J (1996) The value of liver function tests in hepatocellular carcinoma. Malays J Pathol 18(2):95–99PubMedGoogle Scholar
  81. 81.
    Salmela PI, Sotaniemi EA, Niemi M, Maentausta O (1984) Liver function tests in diabetic patients. Diabetes Care 7(3):248–254CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Bereket Tesfaldet
    • 1
  • Gyorgy Csako
    • 2
  • Tejas Patel
    • 1
  • Md Shamsuzzaman
    • 1
  • Eileen Navarro Almario
    • 1
    Email author
  1. 1.Office of Computational Science, Center for Drug Evaluation and ResearchU.S. Food and Drug AdministrationSilver SpringUSA
  2. 2.National Heart, Lung, and Blood InstituteNational Institutes of HealthBethesdaUSA

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