title: Diagnostic and predictive performance and standardized threshold of traditional biomarkers for drug-induced liver injury in rats.
abstract: Traditional biomarkers such as alanine and aspartate aminotransferase (ALT, AST) and total bilirubin (TBIL) have been widely used for detecting drug-induced liver injury (DILI). Although the Food and Drug Administration (FDA) proposed standardized thresholds for human as Hy's law, those for animals have not been determined, and predictability of these biomarkers for future onset of hepatic lesions remains unclear. In this study, we investigated these diagnostic and predictive performance of 10 traditional biomarkers for liver injury by receiver-operating characteristic (ROC) curve, using a free-access database where 142 hepatotoxic or non-hepatotoxic compounds were administrated to male rats (n=5253). Standardization of each biomarker value was achieved by calculating the ratio to control mean value, and the thresholds were determined under the condition of permitting 5% false positive. Of these 10 biomarkers, AST showed the best diagnostic performance. Furthermore, ALT and TBIL also showed high performance under the situation of hepatocellular necrosis and bile duct injury, respectively. Additionally, the availability of the diagnostic thresholds in difference testing facility was confirmed by the application of these thresholds to in-house prepared dataset. Meanwhile, incorrect diagnosis by the thresholds was also observed. Regarding prediction, all 10 biomarkers showed insufficient performance for future onset of hepatic lesions. In conclusion, the standardized diagnostic thresholds enable consistent evaluation of traditional biomarkers among different facilities, whereas it was suggested that novel biomarker is required for more accurate diagnosis and prediction of DILI.
authors.affiliation: Drug Safety Evaluation, Research Laboratory for Development, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tonomura
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kato
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hanafusa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Morikawa
authors.forename: Keigo
authors.initials: K
authors.lastname: Matsuyama
authors.forename: Takeki
authors.initials: T
authors.lastname: Uehara
authors.forename: Motonobu
authors.initials: M
authors.lastname: Ueno
authors.forename: Mikinori
authors.initials: M
authors.lastname: Torii
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000175:diagnosis*; D002784:Cholesterol / Q000097:blood; D005189:False Positive Reactions; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D010743:Phospholipids / Q000097:blood; D011237:Predictive Value of Tests; D012372:ROC Curve; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012709:Serum Albumin / Q000032:analysis; D014280:Triglycerides / Q000097:blood; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: D015415:Biomarkers; D010743:Phospholipids; D012709:Serum Albumin; D014280:Triglycerides; D002784:Cholesterol; D007770:L-Lactate Dehydrogenase; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin
keywords: diagnostic performance; drug-induced liver injury; predictive performance; receiver-operating characteristic curve; standardized diagnostic threshold; traditional biomarker