Skip to main content
SpringerLink
Log in

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

  • Protocol
  • First Online:
Drug-Induced Liver Toxicity

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

  • 2256 Accesses

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.

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

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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. Fischbein A (1985) Liver function tests in workers with occupational exposure to polychlorinated biphenyls (PCBs): comparison with yusho and yu-cheng. Environ Health Perspect 60:145–150

    Article  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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. 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

    Chapter  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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):331–336

    PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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):815–827

    Article  CAS  Google Scholar 

  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):273–280

    Article  CAS  Google Scholar 

  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):1590–1592

    CAS  PubMed  Google Scholar 

  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):121–127

    Article  CAS  Google Scholar 

  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:CD012437

    PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ohira H (2016) The liver in systemic diseases [hardcover and eBook]. Springer International Publ. AG, Cham, Switzerland. 978-4-431-55789-0

    Book  Google Scholar 

  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):960–967

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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):895–899

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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):261–287

    Article  Google Scholar 

  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. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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):701–702

    Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  49. Walker NJ, Zurier RB (2002) Liver abnormalities in rheumatic diseases. Clin Liver Dis 6(4):933–946

    Article  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sheehan NJ, Slavin BM, Kind PR, Mathews JA (1983) Increased serum alkaline phosphatase activity in ankylosing spondylitis. Ann Rheum Dis 42(5):563–565

    Article  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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):284–290

    Article  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 710-701

    CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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. 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

    Article  CAS  PubMed  Google Scholar 

  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):617–622

    CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed Central  Google Scholar 

  76. de Denus S, Spinler SA, Miller K, Peterson AM (2004) Statins and liver toxicity: a meta-analysis. Pharmacotherapy 24(5):584–591

    Article  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  80. Lopez J, Balasegaram M, Thambyrajah V, Timor J (1996) The value of liver function tests in hepatocellular carcinoma. Malays J Pathol 18(2):95–99

    CAS  PubMed  Google Scholar 

  81. Salmela PI, Sotaniemi EA, Niemi M, Maentausta O (1984) Liver function tests in diabetic patients. Diabetes Care 7(3):248–254

    Article  CAS  Google Scholar 

Download references

Acknowledgments

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

Author information

Authors and Affiliations

  1. Office of Computational Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA

    Bereket Tesfaldet, Tejas Patel, Md Shamsuzzaman & Eileen Navarro Almario

  2. National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Gyorgy Csako

Authors
  1. Bereket Tesfaldet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gyorgy Csako
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tejas Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Md Shamsuzzaman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eileen Navarro Almario
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eileen Navarro Almario .

Editor information

Editors and Affiliations

  1. Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA

    Minjun Chen

  2. Drug Safety Research and Development, Pfizer Inc., Groton, CT, USA

    Yvonne Will

Rights and permissions

Reprints and permissions

Copyright information

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

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Tesfaldet, B., Csako, G., Patel, T., Shamsuzzaman, M., Almario, E.N. (2018). Variability in Baseline Liver Test Values in Clinical Trials: Challenges in Enhancing Drug-Induced Liver Injury Assessment in Subjects with Liver Disease. In: Chen, M., Will, Y. (eds) Drug-Induced Liver Toxicity. Methods in Pharmacology and Toxicology. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-7677-5_21

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-7677-5_21

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-7676-8

  • Online ISBN: 978-1-4939-7677-5

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation