Low Serum Hepcidin Is Associated With Reduced Short‐Term Survival in Adults With Acute Liver Failure

The liver has an important role in iron homeostasis through the synthesis of the serum transporter transferrin and the iron hormone hepcidin. The aim of this study was to analyze parameters of iron metabolism in a multicenter cohort of adult patients with acute liver failure (ALF) and in an acetaminophen (APAP)‐induced ALF mouse model. A representative subset of 121 adults with ALF (including 66 APAP‐related patients) had baseline serum samples tested for ferritin, transferrin, iron, and hepcidin. Outcomes at 3 weeks after enrollment were categorized as spontaneous survivor (SS) versus death/transplantation (NSS). Mice were assessed before (controls) and 4 and 18 hours after injection of 300 mg/kg APAP. Patients with ALF as well as APAP‐treated mice displayed increased ferritin and diminished serum hepcidin and hepcidin/ferritin ratio. SS had lower iron (29.1% vs. 34.5 µmol/L; P < 0.05) and transferrin saturation (60.9% vs. 79.1%; P < 0.01), but higher hepcidin levels (8.2 vs. 2.7 ng/mL; P < 0.001) and hepcidin/ferritin ratio (0.0047 vs. 0.0009; P < 0.001) than NSS. In a multivariate analysis, a log‐transformed hepcidin‐containing model displayed similar prognostic power as the established Acute Liver Failure Study Group index (C‐statistic 0.87 vs. 0.85) and was better than Model for End‐Stage Liver Disease score (C‐statistic 0.76). In mice, hepcidin levels inversely correlated with the surrogate of liver injury. Conclusion: Our findings demonstrate that several serum iron parameters significantly associate with 3‐week outcomes in adults with ALF. Among them, hepcidin decreases early during experimental APAP‐induced ALF, is an independent predictor and might be a useful component of future prognostic scores.