Evaluating the Sensitivity and Specificity of Promising Circulating Biomarkers to Diagnose Liver Injury in Humans.
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.
['Llewellyn|Heather P|HP|', 'Vaidya|Vishal S|VS|', 'Wang|Zhenyu|Z|', 'Peng|Qinghai|Q|', 'Hyde|Craig|C|', 'Potter|David|D|', 'Wang|Jianying|J|', 'Zong|Qing|Q|', 'Arat|Seda|S|', 'Martin|Matt|M|', 'Masek-Hammerman|Katherine|K|', 'Warner|Roscoe|R|', 'Johnson|Kent|K|', 'Kullak-Ublick|Gerd A|GA|', 'Aithal|Guruprasad P|GP|', 'Dear|James W|JW|', 'Ramaiah|Shashi K|SK|']
D000082:Acetaminophen D000410:Alanine Transaminase D000818:Animals D015415:Biomarkers D056486:Chemical and Drug Induced Liver Injury D006801:Humans D008099:Liver D035683:MicroRNAs D051381:Rats
liver diagnosis glutamate dehydrogenase keratin-18 microRNA