Mechanistic biomarkers in acetaminophen-induced hepatotoxicity and acute liver failure: from preclinical models to patients

Abstract

SUMMARY Introduction Drug hepatotoxicity is a major clinical issue. Acetaminophen (APAP) overdose is especially common. Serum biomarkers used to follow patient progress reflect either liver injury or function, but focus on biomarkers that can provide insight into the basic mechanisms of hepatotoxicity is increasing and enabling us to translate mechanisms of toxicity from animal models to humans. Areas covered We review recent advances in mechanistic serum biomarker research in drug hepatotoxicity. Specifically, biomarkers for reactive drug intermdiates, mitochondrial dysfunction, nuclear DNA damage, mode of cell death and inflammation are discussed, as well as microRNAs. Emphasis is placed on APAP-induced liver injury. Expert Opinion Several serum biomarkers of reactive drug intermediates, mitochondrial damage, nuclear DNA damage, apoptosis and necrosis, and inflammation have been described. These studies have provided evidence that mitochondrial damage is critical in APAP hepatotoxicity in humans, while apoptosis has only a minor role, and inflammation is important for recovery and regeneration after APAP overdose. Additionally, mechanistic serum biomarkers have been shown to predict outcome as well as, or better than, some clinical scores. In the future, such biomarkers will help determine the need for liver transplantation and, with improved understanding of the human pathophysiology, identify novel therapeutic targets.

Drug idiosyncrasy due to pirfenidone presenting as acute liver failure: Case report and mini‐review of the literature

“…There is no single gold standard for the diagnosis, but the armamentarium includes good clinical history, workup for alternative etiologies, causality assessment scores, and liver histology 8, 10. Recently, multiple molecular markers that suggest DILI have been proposed; examples include microRNA‐122 in acetaminophen overdose,13 high mobility group box‐1 and cytokeratin‐18 in the prediction of early liver injury,14 macrophage colony‐stimulating factor receptor 1 in flupirtine toxicity,10 and osteopontin levels or glycodeoxycholic acid in predicting severe DILI 15. Certain autoantibodies, such as anti‐CYP1A2 in dihydralazine DILI, anti‐CYP3A in anticonvulsant DILI, anti‐CYP2E1 in halothane hepatitis, and anti‐isoniazid antibodies in isoniazid‐induced ALF, have been proposed 10.…”

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

“…This led to the recent development of a point-of-care test for the accelerated diagnosis of APAP overdose in patients [243]. Other biomarkers such as miR-122 [244–247], full-length cytokeratin-18 [247–250], high mobility group box 1 (HMGB1) protein [247–249, 251], and argininosuccinate synthetase (ASS) [252] are generally considered indicators of mainly necrotic cell death [253]. On the other hand, increased plasma levels of the caspase-cleaved form of cytokeratin-18 [247, 248, 250, 254, 255] and activated caspases detected as enzyme activity and/or the protein by western blotting [164, 247, 249, 254], are markers of apoptotic cell death.…”

“…miR-122, and that they are even more sensitive indicators of cell injury than the routine parameters of liver cell death plasma ALT and AST activities [252, 256]. The enhanced sensitivity is not only reflected in an earlier increase in the plasma levels of these biomarkers but also in a more rapid decline [248, 252], which makes most of these compounds more accurate indicators of the time course of acute cell death compared to ALT and AST [253]. Another use of biomarkers such as plasma miRNA profiles can be used to distinguish between clinical conditions that are very similar such as acute liver injury after an APAP overdose and hypoxic hepatitis [257].…”

Novel circulating- and imaging-based biomarkers to enhance the mechanistic understanding of human drug-induced liver injury

“…Primarily, by informing on the pathophysiology of injury and identifying an exact mechanism, biomarkers of this kind could by their nature be extremely useful in directing appropriate therapeutic interventions to specific targets and hereby allowing treatment in a stratified and personalised manner [25,26]. In addition, it is logical that mechanistic biomarkers will coincide with the earlier detection of liver injury as the mechanisms induced will inherently preside injury itself and any successive clinical symptoms [25,27]. Finally, biomarkers informing of a mechanism of injury could theoretically hold a characteristic and direct quantitative association with extent of injury, again allowing for improved patient stratification or a more informed evaluation of risk-benefit [27].…”

“…In addition, it is logical that mechanistic biomarkers will coincide with the earlier detection of liver injury as the mechanisms induced will inherently preside injury itself and any successive clinical symptoms [25,27]. Finally, biomarkers informing of a mechanism of injury could theoretically hold a characteristic and direct quantitative association with extent of injury, again allowing for improved patient stratification or a more informed evaluation of risk-benefit [27].…”