Need for New Biomarkers

Drug-induced hepatotoxicity can present in variable manifestations, such as cell death (necrosis, apoptosis), infiammation, degeneration (steatosis), fibrosis/cirrho-sis and the development of tumors. The manifestations of drug toxicity may not be mutually exclusive and may occur sequentially, or in combination. ALT and ALP can be used to generally classify the pattern of liver injury as either hepatocellular (ALT 3x ULN), cholestatic (ALP 2x ULN, ALT/ALP 2) or mixed (elevated ALP and ALT). The successful monitoring of hepatotoxicity would identify cases before irreversible injury occurs. The activity levels of ALT, AST and ALP only increase after hepatic or cholestatic injury has occurred. Waiting for activity levels to exceed the established thresholds may be too late [3]. New biomarkers are needed to monitor/predict the specific sequence of events for different classes of hepatotoxic compounds. 

Many patients have underlying liver disease with liver function abnormalities. It may be difficult to determine superimposed drug-induced liver injury in patients with viral hepatitis, passive congestion of the liver from heart failure, fatty liver 

Changes in serum ALT may not aWays be indicative ofa true hepatotoxic response. Mild dose-related ALT elevations (2x to 3x ULN) are observed in some patients taking lovastatin as a result of an adaptive response [139]. As another example, isoniazid, an anti-tuberculosis agent, leads to a high incidence of ALT and AST elevations, but is tolerated chronically without severe hepatotoxicity. This suggests that more specific and sensitive biomarkers are still needed to predict serious liver injury. 

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