Aubrecht Jiri, Potter David, Sauer John Michael, Warner Roscoe, Johnson Kent J, McGill Mitchell R, Peron Katrina, King Nicholas M P
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States.
Nonclinical Statistics, Pfizer R&D, Cambridge, MA 02139, United States.
Toxicol Sci. 2025 Feb 1;203(2):171-180. doi: 10.1093/toxsci/kfae143.
Serum activities of alanine- and aspartate aminotransferases (ALT and AST) are considered the "gold standard" biomarkers of hepatocyte injury in clinical practice and drug development. However, due to the expression of ALT and AST in myocytes, the diagnosis of hepatocellular injury in patients with underlying muscle diseases, including drug-induced muscle injury, is severely limited. Thus, we proposed glutamate dehydrogenase (GLDH) as a liver-specific alternative to serum ALT and AST. In fact, our exploratory studies showed that GLDH has comparable performance to ALT for detecting hepatocyte injury without interference from concomitant muscle injury. Here, we report the results of studies confirming the reference intervals in a healthy human population and the sensitivity and specificity of GLDH for the detection of hepatocyte injury in human subjects. In human subjects, we could not perform liver biopsies due to ethical reasons; we also confirmed the relationship of GLDH and histopathologic lesions using 32 model toxicants in rats. Furthermore, we have shown that injury to tissues that are known to express appreciable levels of GLDH does not affect serum GLDH measurements, indicating excellent liver specificity of serum GLDH. Finally, we observed faster elimination of GLDH than ALT in humans, indicating that decreasing GLDH values could be considered an early sign of recovery. This study provides comprehensive evidence of excellent sensitivity and liver specificity of GLDH for diagnosis of hepatocellular injury, including evaluation of reference intervals, which is essential for the interpretation of serum GLDH in human subjects.
在临床实践和药物研发中，血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶（ALT和AST）的活性被视为肝细胞损伤的“金标准”生物标志物。然而，由于ALT和AST在肌细胞中也有表达，对于患有包括药物性肌肉损伤在内的潜在肌肉疾病的患者，肝细胞损伤的诊断受到严重限制。因此，我们提出将谷氨酸脱氢酶（GLDH）作为血清ALT和AST的肝脏特异性替代指标。事实上，我们的探索性研究表明，在检测肝细胞损伤时，GLDH与ALT具有相当的性能，且不受伴随的肌肉损伤干扰。在此，我们报告了相关研究结果，这些研究确定了健康人群中的参考区间，以及GLDH在检测人类受试者肝细胞损伤时的敏感性和特异性。在人类受试者中，由于伦理原因我们无法进行肝脏活检；我们还利用32种大鼠模型毒物证实了GLDH与组织病理学损伤之间的关系。此外，我们还表明，已知表达相当水平GLDH的组织受到损伤并不会影响血清GLDH的测量结果，这表明血清GLDH具有出色的肝脏特异性。最后，我们观察到在人类中GLDH的清除速度比ALT快，这表明GLDH值下降可被视为恢复的早期迹象。本研究提供了全面的证据，证明GLDH在诊断肝细胞损伤方面具有出色的敏感性和肝脏特异性，包括对参考区间的评估，这对于解读人类受试者的血清GLDH至关重要。
