Impact of Vitamin D Enteral Supplementation on Hepcidin Serum Levels and Transfusion Requirements in Surgical and Critically Ill Patients

Patient blood management has become an important concept for the perioperative care of the surgical patients and in septic patients, aiming to improve outcomes. Hepcidin might be a potential target to reduce transfusion requirements after major abdominal surgery and in patients with sepsis. Major surgery and sepsis induce complex immune dysregulations, characterised by a pro-inflammatory state (the postoperative acute-phase reaction). Excess hepcidin values in acute inflammatory conditions might represent an exaggerated response that leads to iron-sequestration anemia, a functional iron deficiency anemia. Vitamin D supplementation might constitute a novel strategy to modulate the hepcidin-ferroportin-iron axis in surgery and sepsis-induced acute inflammation. Thus, vitamin D might impact hepcidin values and might reduce transfusion requirements.

I. Inflammation-induced regulation of the hepcidin-ferroportin-iron axis

Surgery and sepsis are associated with iron-restricted anemia. After major abdominal surgery and sepsis, a prototypical inflammatory syndrome, often complicated by the development of anemia, appears. Inflammatory cytokines (like interleukin 6) released during acute infection alter iron metabolism by inducing excess synthesis of hepcidin. Anemia after major abdominal surgery and sepsis may be the expression of impaired erythropoiesis as a result of hepcidin up-regulation. Hepcidin plays a role in the development of anemia, together with the inhibition of erythropoietin production, a decreased lifespan of erythrocytes, and a blunted erythropoietic response. Functional iron deficiency is increasingly recognised as a cause of anemia in the general surgical patient and in patients with sepsis.

Iron is a two-faced element. First, iron is essential for living as it is incorporated in the "breathing" molecule haemoglobin and in the mitochondrial respiratory chain. On the other hand, iron is detrimental due to the generation of oxidative stress and its availability for the growing of bacteria. Low serum iron level is considered detrimental as it leads to anemia and low tissue oxygen delivery. Iron deficiency and anemia are associated with poor outcomes in surgical and septic patients. Also, transfusion is associated with immune suppression and other adverse reactions. Thus, other approaches to the correction of anemia are advocated, even though not yet included in the clinical practice.

Hepcidin is the master regulator of iron metabolism and hence, a modulator of anemia in states of inflammation. Hepcidin is an acute phase protein synthetised in the liver and which acts as an hyposideremia inducing hormone. It binds to ferroportin (an iron exporter) and prevents the release of iron from the cells: prevents the absorption of dietary iron from enterocytes and prevents iron release from macrophages, where it is stored. Thus, the effect of hepcidin would be iron sequestration, lowering the serum iron concentrations. The beneficial result would be a low availability of iron for bacterial growth (thus, a direct antimicrobial effect) and less oxidative stress. The detrimental result is the limited possibility for the synthesis of new haemoglobin molecules and the occurrence of anemia. The up-regulation of hepcidin, as a pro-inflammatory biomarker, characterises both acute and chronic inflammatory conditions. The induction of hepcidin synthesis may be the cause for the iron-restricted erythropoiesis in the surgical population and in patients with sepsis. The induction of hepcidin synthesis may contribute to the development of anemia, which is detrimental for tissue oxygenation and might increase transfusion requirements and the aggravation of immune suppression after blood transfusion. In animal models of anemia due to inflammation, hepcidin knockout mice had milder anemia and faster recovery.