Diagnostic Performance of Traditional Hepatobiliary Biomarkers of Drug-Induced Liver Injury in the Rat

Nonclinical studies provide the opportunity to anchor biochemical with morphologic findings; however, liver injury is often complex and heterogeneous, confounding the ability to relate biochemical changes with specific patterns of injury. The aim of the current study was to compare diagnostic performance of hepatobiliary markers for specific manifestations of drug-induced liver injury in rat using data collected in a recent hepatic toxicogenomics initiative in which rats (n = 3205) were given 182 different treatments for 4 or 14 days. Diagnostic accuracy of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (Tbili), serum bile acids (SBA), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total cholesterol (Chol), and triglycerides (Trig) was evaluated for specific types of liver histopathology by Receiver Operating Characteristic (ROC) analysis. To assess the relationship between biochemical and morphologic changes in the absence of hepatocellular necrosis, a second ROC analysis was performed on a subset of rats (n = 2504) given treatments (n = 152) that did not cause hepatocellular necrosis. In the initial analysis, ALT, AST, Tbili, and SBA had the greatest diagnostic utility for manifestations of hepatocellular necrosis and biliary injury, with comparable magnitude of area under the ROC curve and serum hepatobiliary marker changes for both. In the absence of hepatocellular necrosis, ALT increases were observed with biochemical or morphologic evidence of cholestasis. In both analyses, diagnostic utility of ALP and GGT for biliary injury was limited; however, ALP had modest diagnostic value for peroxisome proliferation, and ALT, AST, and total Chol had moderate diagnostic utility for phospholipidosis. None of the eight markers evaluated had diagnostic value for manifestations of hypertrophy, cytoplasmic rarefaction, inflammation, or lipidosis.