Hepcidin response to acute iron intake and chronic iron loading in dysmetabolic iron overload syndrome

Abstract

Background The pathogenesis of dysmetabolic iron overload syndrome (DIOS) is still unclear. Hepcidin is the key regulator of iron homeostasis controlling iron absorption and macrophage release. Aim To investigate hepcidin regulation by iron in DIOS. Methods We analysed urinary hepcidin at baseline and 24 h after a 65 mg oral iron dose in 24 patients at diagnosis and after iron depletion (n=13) and compared data with those previously observed in 23 healthy controls. Serum iron indices, liver histology and metabolic data were available for all patients. Results At diagnosis, hepcidin values were significantly higher than in controls (P<0.001). After iron depletion, hepcidin levels decreased to normal values in all patients. At baseline, a significant response of hepcidin to iron challenge was observed only in the subgroup with lower basal hepcidin concentration (P=0.007). In iron-depleted patients, urinary hepcidin significantly increased after oral iron test (P=0.006). Conclusions Ours findings suggest that in DIOS, the progression of iron accumulation is counteracted by the increase in hepcidin production and progressive reduction of iron absorption, explaining why these patients develop a mild–moderate iron overload that tends to a plateau.

Increased Serum Hepcidin Levels in Subjects with the Metabolic Syndrome: A Population Study

“…On the other hand, pilot studies have found high hepcidin levels in either serum [24] or urine [25] of few DIOS subjects (n = 16 to 24), suggesting a distinct pathogenesis. Supporting and extending these observations, our results establish for the first time at population level that subjects with MetS have increased serum levels of hepcidin.…”

Iron Homeostasis in the Liver

“…Several pathways in the liver regulate hepcidin, the master hormone for maintaining systemic iron homeostasis. Recent studies have shown that these pathways can have redundancy or act independently based on the stimuli (172). The challenge will be to understand how these pathways crosstalk and are regulated in a coordinate manner to maintain hepcidin levels.…”

Hepcidin resistance in dysmetabolic iron overload

“…These results have been later criticized based on contrasting findings of reduced iron absorption in still iron‐overloaded DIOS patients , with the amount of iron stores being a major confounder of iron metabolism regulation. Indeed, strong upregulation of hepcidin release when hepatic iron stores begin to accumulate may counteract the development of severe iron overload in DIOS .…”

“…Although variants in genes implicated in HH are predisposing factors , the mechanism underpinning iron accumulation in DIOS is still unclear. Previous studies indicated that circulating hepcidin concentration at diagnosis is upregulated coherently with iron stores . Conversely, HH is caused by decreased hepcidin release in response to iron overload .…”