UCLA

Drug-induced liver failure is a significant indication for a liver transplant, and unexpected liver toxicity is a major reason that otherwise effective therapies are removed from the market. Various methods exist for monitoring liver injury but are often inadequate to predict liver failure. New diagnostic tools are needed. Methods: We evaluate in a preclinical model whether ¹⁸F-2-deoxy-2-fluoroarabinose (¹⁸F-DFA), a PET radiotracer that measures the ribose salvage pathway, can be used to monitor acetaminophen-induced liver injury and failure. Mice treated with vehicle, 100, 300, or 500 mg/kg acetaminophen for 7 or 21 h were imaged with ¹⁸F-FDG and ¹⁸F-DFA PET. Hepatic radiotracer accumulation was correlated to survival and percentage of nonnecrotic tissue in the liver. Mice treated with acetaminophen and vehicle or N-acetylcysteine were imaged with ¹⁸F-DFA PET. ¹⁸F-DFA accumulation was evaluated in human hepatocytes engrafted into the mouse liver. Results: We show that hepatic ¹⁸F-DFA accumulation is 49%-52% lower in mice treated with high-dose acetaminophen than in mice treated with low-dose acetaminophen or vehicle. Under these same conditions, hepatic ¹⁸F-FDG accumulation was unaffected. At 21 h after acetaminophen treatment, hepatic ¹⁸F-DFA accumulation can distinguish mice that will succumb to the liver injury from those that will survive it (6.2 vs. 9.7 signal to background, respectively). Hepatic ¹⁸F-DFA accumulation in this model provides a tomographic representation of hepatocyte density in the liver, with a R² between hepatic ¹⁸F-DFA accumulation and percentage of nonnecrotic tissue of 0.70. PET imaging with ¹⁸F-DFA can be used to distinguish effective from ineffective resolution of acetaminophen-induced liver injury with N-acetylcysteine (15.6 vs. 6.2 signal to background, respectively). Human hepatocytes, in culture or engrafted into a mouse liver, have levels of ribose salvage activity similar to those of mouse hepatocytes. Conclusion: Our findings suggest that PET imaging with ¹⁸F-DFA can be used to visualize and quantify drug-induced acute liver injury and may provide information on the progression from liver injury to hepatic failure.