Inappropriate production of hepcidin contributes to the pathogenesis of various iron disorders (table ). Relative deficiency in hepcidin is associated with development of iron overload, whereas relative excess of hepcidin causes iron restriction and anemia.
Iron disorders associated with inappropriate hepcidin production
Diseases of Hepcidin Deficiency
Hepcidin deficiency results in the development of systemic iron overload because of excessive iron absorption. In the absence of hepcidin, ferroportin concentrations on the basolateral surface of enterocytes are increased, leading to enhanced transport of dietary iron into plasma. In hepcidin deficiency, macrophages also display increased ferroportin on their cell membranes and thus export more iron. Excess plasma iron accumulates in organs in which iron uptake exceeds the rate of iron export. The liver is most commonly affected by iron overload due to the avid uptake of non-Tf-bound iron by hepatocytes. Iron overload of other organs appears to correlate broadly with the rate of iron absorption. Rapid accumulation of iron, such as seen with severe hepcidin deficiency (juvenile hemochromatosis or thalassemia intermedia), is associated with prominent deposition of iron in the heart and some endocrine organs. Although hepcidin deficiency is the common denominator of several different iron overload disorders, the molecular mechanisms that cause hepcidin deficiency are diverse.
In hereditary hemochromatosis [reviewed by Camaschella and Poggiali in this issue; pp 140–145], hepcidin deficiency results either from mutations in the hepcidin gene itself, or in the genes encoding hepcidin regulators. A very rare form of hemochromatosis is not associated with hepcidin deficiency, but with ferroportin resistance to hepcidin. Hepcidin regulators which are mutated in hereditary hemochromatosis include HFE, TfR2 and HJV, the molecules involved in sensing of iron and subsequent signal transduction. Importantly, the degree of hepcidin deficiency correlates with the severity of iron overload, so that the most severe form of hemochromatosis, juvenile hemochromatosis, develops with mutations in the hepcidin or HJV genes, where hepcidin levels are completely or nearly absent. TfR2 and HFE mutations result in a milder phenotype, particularly HFE mutations, which have a lower clinical penetrance.
Phlebotomy is currently the main treatment for patients with hereditary hemochromatosis. Although this is effective at removing excess iron, complete iron depletion appears to result in a further decrease in hepcidin levels which would be expected to enhance dietary iron absorption and increase the need for phlebotomy. Further studies are needed to establish whether less iron depletion, which would not lower hepcidin levels as much, would still be safe for patients and allow less frequent phlebotomy.
In iron-loading anemias, such as β-thalassemia and congenital dyserythropoietic anemias, urinary and serum hepcidin are severely decreased despite systemic iron overload [22
]. The signal causing hepcidin suppression appears to be generated by high erythropoietic activity and outweighs the effects of iron overload on hepcidin regulation. As mentioned earlier, GDF15 and TWSG1 are two erythroid-produced factors that may contribute to hepcidin suppression in these syndromes. Transfusions increase hepcidin levels, presumably due to both the alleviation of ineffective erythropoiesis and increased iron load. Interestingly, patients with thalassemia intermedia were shown to have liver iron concentrations similar to those of regularly transfused thalassemia major patients, but because of the different hepcidin levels, the cellular distribution of iron in the liver was different. In thalassemia intermedia, similar to hereditary hemochromatosis, iron was heavily deposited in hepatocytes, whereas higher hepcidin levels in thalassemia major caused a shift of iron into macrophages. It is therefore possible that therapeutic hepcidin could be useful in thalassemia to shift the iron from the parenchyma to macrophages, where it is less toxic.
Hepcidin levels were also reported to be low in patients with chronic hepatitis C, a disease frequently accompanied by hepatic iron overload, which worsens liver damage. The mechanism by which hepatitis C virus suppresses hepcidin synthesis is not well understood, but was reported to include the virus-induced oxidative stress.
Diseases of Hepcidin Excess
Human syndromes of hepcidin overproduction suggest, and mouse models demonstrate, that elevated hepcidin is sufficient to cause hypoferremia and anemia [23
]. Mice administered a single intraperitoneal injection of synthetic hepcidin developed hypoferremia within 1 h which lasted for almost 3 days [4
]. Transgenic mice strongly overexpressing hepcidin during embryonic development developed severe microcytic, hypochromic anemia in utero [6
], and weaker hepcidin overexpression caused mild-to-moderate anemia which was associated with iron-restricted erythropoiesis [23
]. The phenotype develops from hepcidin-mediated inhibition of iron recycling and absorption. Decreased flow of iron into plasma results in hypoferremia, and because most of the iron in plasma is destined for the bone marrow, lower iron availability affects hemoglobin synthesis and erythrocyte production. In human disease, elevated hepcidin may contribute to anemia observed in inflammatory disorders, chronic kidney disease (CKD), hepcidin-producing hepatic adenomas and hereditary iron-refractory iron deficiency anemia (IRIDA).
In inflammatory disorders, hepcidin production is stimulated by increased cytokines, prominently including IL-6. Chronic hepcidin-mediated iron restriction would be expected to eventually lead to anemia of inflammation (AI) [for further information, see the review by Agarwal and Prchal in this issue; pp 103–108]. Elevated hepcidin was observed in rheumatologic diseases, inflammatory bowel disease, multiple myeloma, and critical illness, but whether hepcidin is a necessary factor in the pathogenesis of anemia in each of these disorders has not yet been established with certainty. Studies in mice moderately overexpressing hepcidin indicate that increased hepcidin not only causes iron restriction but also blunted erythropoietic response to EPO, characteristic of AI. Hepcidin does not appear to decrease red blood cell survival, another feature associated with AI. The role of hepcidin in the suppression of EPO, sometimes seen in AI, is unclear. Studies of interventions that selectively reduce hepcidin will be necessary to determine how essential the role of hepcidin is in inflammation-induced anemia.
Hepcidin concentrations were reported to be increased in CKD patients [for further information, see the review by Silverberg et al. in this issue; pp 109–119]. This could be caused by inflammation which frequently accompanies CKD, but even patients without significant inflammation had elevated hepcidin levels which progressively increased with the severity of CKD. Because hepcidin is cleared, at least in part, by filtration in the kidney, decreased kidney function is the likely factor contributing to this phenomenon. Indeed, some studies reported an inverse correlation between glomerular filtration rate and serum hepcidin. It has been postulated that high hepcidin may be the reason for EPO resistance commonly observed in CKD patients. Two initial studies, however, reported no correlation between hepcidin-25 levels and EPO dose, raising questions about the usefulness of hepcidin as a predictor of patients' response to EPO. However, the ability of high EPO doses to suppress hepcidin synthesis may confound these studies.
IRIDA is a disease characterized by congenital hypochromic, microcytic anemia, refractory to treatment with oral iron, and only partially responsive to parenteral iron. The phenotype has been described almost 30 years ago, but its molecular basis has only recently been unraveled. IRIDA is caused by increased hepcidin production due to mutations in the hepcidin suppressor, TMPRSS6. The mechanisms are covered in more detail in the review by Lee [this issue; pp 87–96].