In hereditary hemochromatosis the fault lies in the regulation of iron: the body keeps absorbing iron instead of matching absorption to its needs, and the surplus is deposited in the tissues. The pathway that normally prevents this begins with the HFE protein and ends with the hormone hepcidin.
HFE and the control of hepcidin
Hepcidin is a small peptide made by the liver and the principal regulator of how much iron enters the blood. It acts on ferroportin, the exporter on the surface of the cells that release iron; when hepcidin binds, ferroportin is taken into the cell and degraded, so iron export falls. Hepcidin production rises when iron stores are full or when inflammation is present, and it falls in iron deficiency, in hypoxia, and in ineffective erythropoiesis, when the marrow is demanding more iron.
The HFE protein helps the hepatocyte read the amount of iron in the blood. HFE is attached to the transferrin receptors, TfR1 and TfR2. When circulating iron is low and iron is carried by transferrin, HFE has more affinity for TfR1, the receptor that takes transferrin-bound iron into the cell. When circulating transferrin is high, diferric transferrin displaces HFE from TfR1 and HFE instead binds TfR2, which is involved in the intracellular signalling that increases hepcidin production. In this way a high concentration of iron promotes hepcidin, and hepcidin in turn reduces the export of iron from the intracellular compartment by causing the ubiquitination of ferroportin. Hemojuvelin participates in the same pathway and is needed for the signal that switches hepcidin on, which is why losing it markedly lowers hepcidin production.
How the intestine absorbs iron
The iron in food comes mainly from meat and exists in two forms: the free iron ion, and iron bound inside the heme group. The iron ion is taken up by DMT-1 (divalent metal transporter 1) in the small intestine. Iron bound to heme is taken up as the whole complex by a heme carrier protein, and the iron is then released inside the cell by the enzyme heme oxygenase. Iron absorbed into the duodenal enterocyte is stored in ferritin; when it is needed, it leaves the cell across the basolateral membrane through ferroportin and passes into the blood.
Ferroportin and the export of iron
Ferroportin is the iron exporter of the cell. It spans the membrane twelve times and carries three functionally important regions: an extracellular site where hepcidin binds, a cytoplasmic loop that becomes ubiquitinated when hepcidin signals, and an adaptor-binding motif that is used for clathrin-dependent endocytosis during that downregulation. Export is thought to work through a change in the protein’s conformation that carries Fe2+ from the inside to the outside of the cell. There, a ferroxidase converts Fe2+ to Fe3+, the form transferrin can carry, so the exported iron is loaded onto transferrin rather than left free.
Ferroportin is expressed in the cells that handle the body’s iron traffic: duodenal cells, which export absorbed iron; hepatocytes, which release stored iron; macrophages, which release iron recovered from phagocytosed red blood cells; and erythroblasts, which release iron from non-functional red cell precursors.
What goes wrong in HFE-related hemochromatosis
In HFE-related HH the pathophysiology rests on reduced expression of hepcidin for the amount of iron in the body, which has two consequences: an increase in the intestinal absorption of iron, and a higher activity of ferroportin that allows iron to accumulate in the tissues and drive fibrogenesis. With little hepcidin to restrain it, ferroportin stays on the cell surface, so iron keeps leaving the enterocytes and macrophages.
Once the accumulating iron exceeds the capacity of transferrin to carry it, free iron ions circulate in the blood and are taken up by the hepatocytes. Inside the hepatocytes this free iron produces oxidative stress and lipid peroxidation. The resulting radicals damage the hepatocytes, and this is followed by activation of the Kupffer cells and of the stellate cells of the liver, which produce inflammation and fibrosis within the liver.