Evaluating the Sensitivity and Specificity of Promising Circulating Biomarkers to Diagnose Liver Injury in Humans. (23rd January 2021)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Toxicological sciences. Volume 181:Number 1(2021)
• Page Start: 23
• Page End: 34
• Publication Date: 2021-01-23
• Subjects: keratin-18 -- microRNA -- glutamate dehydrogenase -- diagnosis -- liver; Toxicology -- Periodicals; Toxicology -- Periodicals; Toxicology; Periodicals; 615.9
• DOI: 10.1093/toxsci/kfab003
• Languages: English
• ISSNs: 1096-6080

Abstract

Abstract: Early diagnosis of drug-induced liver injury (DILI) continues to be a major hurdle during drug development and postmarketing. 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 with healthy volunteers or patients with damage to muscle, pancreas, gastrointestinal tract, and kidney. Expression of K18, GLDH, and 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 7 promising biomarkers and demonstrated that a 3-biomarker multivariate model can accurately detect liver injury.