Hepcidin is decreased in TFR2 hemochromatosis

Abstract

The hepatic peptide hepcidin is the key regulator of iron metabolism in mammals. Recent evidence indicates that certain forms of hereditary hemochromatosis are caused by hepcidin deficiency. Juvenile hemochromatosis is associated with hepcidin or hemojuvelin mutations, and these patients have low or absent urinary hepcidin. Patients with C282Y HFE hemochromatosis also have inappropriately low hepcidin levels for the degree of iron loading. The relationship between the hemochromatosis due to transferrin receptor 2 (TFR2) mutations and hepcidin was unknown. We measured urinary hepcidin levels in 10 patients homozygous for TFR2 mutations, all with increased transferrin saturation. IntroductionThe hepatic peptide hepcidin is the central regulator of iron absorption in mammals. Evidence is accumulating that the pathophysiology of hemochromatosis, a genetic disorder characterized by deregulation of iron absorption, converges on hepcidin. Total hepcidin deficiency characterizes the severe iron overload of juvenile hemochromatosis, which rarely results from hepcidin-inactivating mutations 1 and more frequently from mutations of the HJV gene encoding hemojuvelin. [2][3] Patients with hemojuvelin-related hemochromatosis have low/undetectable urinary hepcidin levels, 2 suggesting that hemojuvelin protein is an important regulator of hepcidin expression. Hepcidin mRNA is also decreased or inappropriately low for the degree of iron overload both in Hfe-deficient or Hfe (845A/ 845A) (C282Y) mice 4 and in patients with HFE hemochromatosis, 5 implying that HFE is another modulator of hepcidin production in response to iron loading.A rare form of hemochromatosis is due to mutations of transferrin receptor 2 (TFR2), 6 a member of the transferrin receptor family with an unclear function in iron metabolism. TFR2 has a capability of binding and internalizing diferric transferrin. 7 However, cellular iron uptake might not be the function of TFR2 in vivo, because mutational disruption of TFR2, both in humans 7 and in animal models, 8 leads to liver iron accumulation and not to iron restriction. In addition, iron overload that follows TFR2 inactivation occurs early in life, 9 as in juvenile hemochromatosis, although TFR2-related disease runs a milder clinical course. Based on these observations, TFR2 could be another regulator of hepcidin, but its relationship with hepcidin in humans has so far remained speculative.To ascertain the involvement of TFR2 in the hepcidin pathway, we measured urinary hepcidin levels in 10 hemochromatosis patients carrying different TFR2 mutations. Our results show low/absent hepcidin in most patients, except for 2 who had concomitant inflammatory conditions. These results confirm the proposed role of TFR2 as a regulator of hepcidin production. Patients, materials, and methodsClinical data and molecular defects of the patients studied have been previously reported. 9-11 Controls were healthy adult subjects from the laboratory staff and their children. Informed consent was obtained from all subjects involved...

Iron storage disease: Facts, fiction and progress

“…In the case of HFE and transferrin receptor-2 mutations some rise of hepcidin levels does occur, and as a consequence iron overload is relatively mild in most cases. In hemojuvelin deficiency, the mutation that causes juvenile hemochromatosis, the defect is more severe [9,10]. It is apparent that these three molecules are involved in some way in the signaling pathway from iron to hepcidin transcription.…”

Hematopoietic deletion of transferrin receptor 2 in mice leads to a block in erythroid differentiation during iron‐deficient anemia

“…Transferrin receptor 2 (TFR2) is involved in the regulation of iron metabolism; patients and mice harboring TFR2 mutations develop type III hereditary hemochromatosis, characterized by inappropriate hepcidin expression relative to body iron levels [9][10][11][12]. Analysis of mice with a hepatocyte-specific deletion of Tfr2 demonstrated the importance of hepatic TFR2 in iron metabolism [13], as they develop similar iron overload as the Tfr2 total knockout (KO) mice.…”

High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis

“…It has not been established how this interaction is related to the observed changes in iron balance. Normal HFE expression is required for regulation of hepcidin, a small hepatic peptide whose production is induced by increased hepatic iron and inflammation [5]. Failure to induce hepcidin in haemochromatosis results in unregulated iron entry into the circulation from the gastrointestinal tract and macrophages [6].…”