Clinical meaning
The NP must understand iron metabolism as a tightly regulated system governed by the hepcidin-ferroportin axis. Total body iron in adults is approximately 3-4 grams: 65% in hemoglobin, 10% in myoglobin, 20-30% in storage forms (ferritin and hemosiderin in hepatocytes and macrophages), and less than 1% in enzymes and plasma transferrin. Daily iron losses are approximately 1-2 mg through desquamation of intestinal and skin epithelial cells and trace losses in urine and bile; there is no regulated excretion pathway, making absorption control essential. Dietary iron is absorbed in the duodenum: non-heme iron (Fe3+) is reduced to Fe2+ by duodenal cytochrome b (DcytB) on the apical brush border, then transported into the enterocyte via divalent metal transporter 1 (DMT1). Heme iron is absorbed intact by the heme carrier protein (HCP1) and liberated intracellularly by heme oxygenase. Inside the enterocyte, iron is either stored as ferritin (if body stores are replete) or exported across the basolateral membrane by ferroportin (the ONLY cellular iron exporter). HEPCIDIN, a 25-amino-acid peptide hormone synthesized by hepatocytes, is the master regulator of systemic iron homeostasis. Hepcidin binds to ferroportin, causing its internalization and degradation, thereby blocking iron export from enterocytes (reducing absorption), macrophages (reducing iron recycling from senescent RBCs), and hepatocytes (reducing release from stores). Hepcidin synthesis is INCREASED by iron overload (via the HFE/TfR2/hemojuvelin-BMP6 pathway), inflammation (via IL-6 activating the JAK-STAT3 pathway), and infection. Hepcidin synthesis is DECREASED by iron deficiency, erythropoietic drive (erythroferrone released by erythroblasts suppresses hepcidin during active erythropoiesis), hypoxia (via HIF pathway), and in hereditary hemochromatosis (HFE gene mutations disrupt hepcidin signaling). In the plasma, iron circulates bound to transferrin (each molecule binds two Fe3+ atoms). Transferrin-bound iron is delivered to cells via the transferrin receptor (TfR1), which is ubiquitously expressed with highest density on erythroblasts. In conditions of iron overload exceeding transferrin binding capacity, non-transferrin-bound iron (NTBI) appears in plasma and is taken up by hepatocytes, cardiomyocytes, and pancreatic beta cells, generating reactive oxygen species via the Fenton reaction (Fe2+ + H2O2 → Fe3+ + OH• + OH−) that causes oxidative tissue damage. This explains the pattern of organ damage in iron overload: liver cirrhosis, dilated cardiomyopathy, and diabetes mellitus.