Evaluating the Sensitivity and Specificity of Promising Circulating Biomarkers to Diagnose Liver Injury in Humans
| Autor: | Craig L. Hyde, Gerd A. Kullak-Ublick, James W. Dear, Seda Arat, Vishal S. Vaidya, Jianying Wang, Guruprasad P. Aithal, Roscoe L. Warner, Heather P. Llewellyn, Shashi K. Ramaiah, Kent J. Johnson, David Potter, Katherine Masek-Hammerman, Zhenyu Wang, Matthew Martin, Qing Zong, Qinghai Peng |
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| Přispěvatelé: | University of Zurich, Vaidya, Vishal S |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty acetaminophen overdose 610 Medicine & health Toxicology Gastroenterology 03 medical and health sciences 0302 clinical medicine Internal medicine medicine Animals Humans Osteopontin Acetaminophen Liver injury Gastrointestinal tract Kidney biology business.industry 3005 Toxicology Alanine Transaminase medicine.disease Rats 3. Good health MicroRNAs 030104 developmental biology medicine.anatomical_structure Liver keratin-18 microRNA glutamate dehydrogenase diagnosis liver 10199 Clinic for Clinical Pharmacology and Toxicology Cohort biology.protein Biomarker (medicine) 030211 gastroenterology & hepatology Chemical and Drug Induced Liver Injury business Biomarkers medicine.drug |
| Zdroj: | Toxicological Sciences |
| ISSN: | 1096-0929 1096-6080 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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