Hepcidin and iron parameters determine disease outcome

Abstract

Iron represents both an essential and toxic element and its metabolism is regulated via hepcidin, the master regulator of iron in human body. Inappropriately low hepcidin levels result in iron accumulation in parenchymal tissues, whereas an overproduction of hepcidin leads to anemia of chronic inflammation. Accordingly, hepcidin knockout (KO) mice represent a model of severe iron overload. Increased iron availability may predispose to development of bacterial infection whereas hepatic iron overload may accelerate the progression of liver disease and development of hepatocellular carcinoma. Ryan et al. suggested that the extent of pegylated interferon- induced hypoferremia correlates with the reduction of hepatitis C viral load. We evaluated the role and prognostic significance of hepcidin and other iron parameters as outcome predictors in multiple patients’ cohorts with different human conditions. To further understand the downstream consequences of iron overload we analyzed the changes that occur in pancreas of hepcidin KO mice. In our intensive care unit cohort, parameters of iron metabolism at admission constituted strong outcome predictors. In Kaplan-Meier analyses, low iron levels (cutoff 10.5 μmol/mL), low transferrin saturation (cutoff 55%), and high serum transferrin concentrations (cutoff 1.6 g/L) were associated with short- and long-term survival. In patients with alcoholic liver cirrhosis, lower serum hepcidin was independently associated with death and this association remained significant in multivariate analysis [HR = 2.84 (1.29– 6.25), P = 0.009]. In a third patients cohort, dual therapy of hepatitis C infection with pegylated interferon and ribavirin led to a marked up-regulation of hepcidin level, however, no association between hepcidin levels and the virological response was noted. Aged hepcidin KO mice exhibited massive cytoplasmic acinar iron overload, acinar atrophy, macrophage infiltration, fatty changes and fibrosis as sign of chronic pancreatitis. As potential underlying mechanisms, increased oxidative stress with elevated DNA damage, apoptosis and activated NF-kB signaling were observed. Treatment of the mice with daily minihepcidin injections led to iron redistribution from acinar cells to macrophages and to an overall improvement in health status. In conclusion, parameters of iron metabolism constitute attractive predictors of disease course in several human disorders. Severe iron overload seen in hepcidin KOs leads to development of chronic pancreatitis that the iron overload-induced chances become rapidly reversed after minihepcidin supplementation.