Prevention remains the best tool for managing drug-induced liver injury (DILI), as researchers continue to look for optimum methods to diagnose and treat a condition that has a very poor prognosis and is a challenge to diagnose. An in-depth analysis of DILI was published in Clinical Gastroenterology and Hepatology.
DILI is a serious, life-threatening condition that can halt the development of a new drug in its tracks, or lead to further regulatory actions or warnings on a drug product. “Although severe DILI is a relatively rare clinical event, drugs have been the leading cause of acute liver failure (ALF) in the United States and other Westernized countries for several decades,” according to author James H. Lewis, a professor and director of hepatology at Georgetown University Medical Center in Washington, D.C.
Acetaminophen accounts for nearly half of all DILI cases, with dietary supplements, herbal compounds, and other drugs causing roughly 11%—12% of the cases.
The current regulatory definition of liver injury biomarkers reflecting a degree of hepatic functional impairment that could be life-threatening.is as follows: alanine aminotransferase (ALT)/aspartate aminotransferase (AST) > 3x the upper limit of normal (ULN) combined with total bilirubin > 2x ULN in the absence of cholestatic injury, defined as alkaline phosphatase < 2x_ULN, and with no other cause identified.
Lewis noted that progress has been made in identifying DILI in clinical trial and post-approval stages, with the goal of reducing severe hepatotoxicity risk in the general population. In addition, various entities, such as the DILIN database and the federally managed LiverTox website, have offered some guidance on diagnosing and managing DILI.
In general, DILI has been a very difficult condition to properly recognize and diagnose. Three biochemical injury patterns: hepatocellular; cholestatic; and mixed based on the ALT: alkaline phosphatase ratio, have been used to characterize this condition and to determine prognosis. A patient’s age, gender, obesity, alcohol use, and underlying liver disease also influence DILI.
In the absence of a highly sensitive and specific biomarker, DILI fundamentally remains a diagnosis of exclusion.
For many decades, clinicians have relied on ALT and AST to detect hepatocellular injury, but neither is especially specific or sensitive to DILI and only show elevated levels after an injury takes place, meaning they have no value as a predictive marker.
Researchers have been working to find better diagnostic and predictive markers, including markers of necrosis and apoptosis, like microRNA-122 and keratin 18. Apolipoprotein E also has been proposed as a promising predictor of DILI, but neither it nor any other “has yet come to fruition as a true predictor of individual agents causing iDILI,” wrote Lewis.
Meanwhile, biochemical assessment of liver injury remains the first-line method to detect ALF. However, the cost-benefit and compliance with recommended monitoring of ALT levels remain unclear. “Although dozens of drugs have had ALT monitoring recommended, it remains largely unproven that the time, expense, and inconvenience of performing such monitoring is actually effective,” Lewis explained. “Whether the availability of a finger stick test for ALT, akin to home glucose testing, would change attitudes or practice patterns is unknown but remains close to reality.”
Predictive testing ultimately will replace biochemical monitoring, Lewis predicted.