An update on iron physiology

Table 1 Main proteins involved in iron homeostasis in mammals

Protein name (alternative name)	Acronyms	Function	Localization
Divalent metal transporter 1 (divalent cation transporter 1, NRAMP 1 and 2)	DMT1	Traffics divalent metal ions such as iron, zinc, copper and cobalt across the membrane by a proton coupled mechanism	Enterocyte (apical membrane)
	DCT1		Erythroblast (siderosome)
	NRAMP1*		Macrophage (plasma membrane, phagocytic vesicles*)
	NRAMP2
			Hepatocyte
			Kidney cells
Ferrireductase	Dcytb	Reduction of Fe3+ to Fe2+	Enterocyte (apical membrane)
	STEAP3*		Erythroblast (siderosome*)
Heme carrier protein 1	HCP1	Putative transporter that traffics heme across the membrane by an unknown mechanism	Enterocyte (apical membrane)
			Hepatocyte
			Kidney cells
Heme oxygenase		An enzyme that disassembles heme to liberate iron	Enterocyte (microsomal fraction)
			Macrophages
Ferroportin 1 (Iron regulatory protein 1)	FPN 1	Transmembrane Fe2+ transporter (exporter)	Enterocyte (basolateral membrane)
	Ireg1		Macrophages
	MTP1		Hepatocytes
Hephaestin	Hp	Membrane-bound multicopper ferroxidase, similar to plasma ceruloplasmin, which oxidizes Fe2+ to Fe3+ to load it onto transferrin	Enterocyte (basolateral)
		Maintenance of cell-surface localization of ferroportin	Macrophage
			Hepatocyte?
Transferrin	Tf	Plasma Fe3+ binding protein	Plasma
		Ligand for transferrin receptors 1 and 2
Transferrin receptor 1	TfR1	Cellular uptake of transferrin bound iron	Ubiquitously expressed
Transferrin receptor 2	TfR2	Sensor for diferric transferrin; regulates hepcidin expression; may participate in a signaling complex with HFE	Enterocyte
			Hepatocyte
			Erythroblast
Mitoferrin	SLC25A37	Mitochondrial iron importer that plays a critical role in supplying iron to ferrochelatase for insertion in protoporphyrin IX to form heme	Erythroblast (mitochondria)
Ferritin	Ft	Iron storage protein (H and L chains)	Enterocyte
		Ferroxidase activity (H chain)	Erythroblast
			Macrophage
			Hepatocyte
			Myocytes and cardiomyocytes
Hemosiderin		Iron storage protein; breakdown product of ferritin that occurs when iron levels are high	Macrophage (lysosomes)
			Hepatocytes (lysosomes)
Heme exporters	LFLVCR*	ATP-independent heme export at the cell membrane* ATP-dependent heme export at the cell membrane** and mitochondrial membrane***	Erythroblast*
	Bcrp/Abcg2**		Ubiquitously expressed**,***
	Abcb6***
HFE	HFE	Regulates hepcidin expression, mechanism uncertain; may participate in a signaling complex with TfR2; interacts with TfR1 & β-2-microglobulin	Enterocyte
			Macrophage
			Hepatocyte
Hemojuvelin	HFE2	Acts as a BMP co-receptor to stimulate hepcidin transcription	Hepatocytes
Lipocalin 2		Mediates a siderophore-like iron uptake pathway. Its an innate immune response to bacterial infection by sequestrating iron, but its physiologic role in iron absorption is not fully worked out	Enterocytes (apical membrane)
			Macrophages
			Adipocyte
Hepcidin	HEP	Iron regulatory hormones, binds ferroportin to cause its internalization and degradation	Hepatocytes
	HAMP		Adipocytes (low secretion)
	LEAP1		Enterocytes?
Erythropoietin	EPO	Upregulates the expression ferroportin in macrophages, TfR1 in erythroblasts, and DMT1 and hephaestin in enterocytes	Kidney (interstitial peritubular cells)
		Downregulates hepcidin expression in hepatocytes and DMT1 expression in macrophages	Hepatocytes (low secretion)

BMP: Bone morphogenetic protein.

Table 2 Main laboratory tests for the diagnosis of anemia and iron deficiency

Laboratory test	Normal values, units	Conversion to SI units
Iron depletion in the body
Serum iron	50-180 μg/dL	× 0.179 μmol/L
Transferrin	200-360 mg/dL	× 0.01 g/L
TSAT	20%-50%
Ferritin	30-300 ng/mL	× 2.247 pmol/L
sTfR	0.76-1.76 mg/L	6.4-25.7 nmol/L
Ratio of sTfR to serum ferritin (sTfR/log ferritin)	< 1
Iron deficient red cell production
Hemoglobin	12-16 g/dL (female)	× 0.6206 mmol/L
	13-17 g/dL (male)
MCV	80-100 fL
RDW	11-15
MCH	28-35 pg
HYPO	< 5%
CHr	28-35 pg

TSAT: Transferrin saturation; sTfR: Soluble transferrin receptors; MCV: Mean corpuscular volume; RDW: Red cell distribution width; MCH: Mean corpuscular Hb; HYPO: Hypochromic red cells; CHr: Reticulocyte Hb content.