Evaluating the sensitivity and specificity of promising circulating biomarkers to diagnose liver injury in humans

Llewellyn, Heather P.; Vaidya, Vishal S.; Wang, Zhenyu; Peng, Qinghai; Hyde, Craig; Potter, David; Wang, Jianying; Zong, Qing; Arat, Seda; Martin, Matt; Masek-Hammerman, Katherine; Warner, Roscoe; Johnson, Kent; Kullak-Ublick, Gerd A.; Aithal, Guruprasad P.; Dear, James W.; Ramaiah, Shashi K.

Abstract

Early diagnosis of drug-induced liver injury (DILI) continues to be a major hurdle during drug development and post marketing. The objective of this study was to evaluate the diagnostic performance of promising biomarkers of liver injury - glutamate dehydrogenase (GLDH), cytokeratin-18 (K18), caspase-cleaved K18 (ccK18), osteopontin (OPN), macrophage colony-stimulating factor (MCSF), MCSF receptor (MCSFR), and microRNA-122 (miR-122) in comparison to the traditional biomarker alanine aminotransferase (ALT). Biomarkers were evaluated individually and as a multivariate model in a cohort of acetaminophen overdose (n=175) subjects and were further tested in cohorts of healthy adults (n=135), patients with liver damage from various causes (n=104), and patients with damage to the muscle (n=74), kidney (n=40), gastrointestinal tract (n=37) and pancreas (n=34). In the acetaminophen cohort, a multivariate model with GLDH, K18 and miR-122 was able to detect DILI more accurately than individual biomarkers alone. Furthermore, the three-biomarker model could accurately predict patients with liver injury compared to healthy volunteers or patients with damage to muscle, pancreas, gastrointestinal tract and kidney. Expression of K18, GLDH ad miR-122 was evaluated using a database of transcriptomic profiles across multiple tissues/organs in humans and rats. K18 mRNA (Krt18) and MiR-122 were highly expressed in liver whereas GLDH mRNA (Glud1) was widely expressed. We performed a comprehensive, comparative performance assessment of seven promising biomarkers and demonstrated that a three-biomarker multivariate model can accurately detect liver injury.

Citation

Llewellyn, H. P., Vaidya, V. S., Wang, Z., Peng, Q., Hyde, C., Potter, D., …Ramaiah, S. K. (2021). Evaluating the sensitivity and specificity of promising circulating biomarkers to diagnose liver injury in humans. Toxicological Sciences, 181(1), 23-34. https://doi.org/10.1093/toxsci/kfab003

• Journal Article Type: Article
• Acceptance Date: Jan 3, 2021
• Online Publication Date: Jan 23, 2021
• Publication Date: May 1, 2021
• Deposit Date: Jan 6, 2021
• Publicly Available Date: Jan 24, 2022
• Journal: Toxicological Sciences
• Print ISSN: 1096-6080
• Electronic ISSN: 1096-0929
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 181
• Issue: 1
• Pages: 23-34
• DOI: https://doi.org/10.1093/toxsci/kfab003
• Keywords: keratin-18, microRNA, glutamate dehydrogenase, diagnosis, liver
• Public URL: https://nottingham-repository.worktribe.com/output/5203235
• Publisher URL: https://academic.oup.com/toxsci/article/181/1/23/6112709
• Additional Information: This is a pre-copyedited, author-produced version of an article accepted for publication in Toxicological Sciences following peer review. The version of record [insert complete citation information here] is available online at: https://academic.oup.com/toxsci/article/181/1/23/6112709 and https://doi.org/10.1093/toxsci/kfab003.