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


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 



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


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Copyright information

© 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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