Urinary hepcidin in congenital chronic anemias

Kearney, Susan; Nemeth, Elizabeta; Neufeld, Ellis J.; Thapa, Dharma R.; Ganz, Tomas; Weinstein, David A.; Cunningham, Melody J.

doi:10.1002/pbc.20616

Cited by 156 publications

(146 citation statements)

References 16 publications

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“…Previous studies have indicated that suppression of hepcidin is greater in patients with thalassemia intermedia than TM, 14 suggesting that by suppressing erythropoiesis, transfusion permits hepcidin levels to increase 12,13 ; this effect occurs dynamically across the transfusion cycle in patients with TM. 16 However, in our population, hepcidin concentrations were similarly suppressed in patients with both severe and moderate clinical phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…9,10 Iron from transfusions compounds iron loading. Hepcidin concentrations are suppressed in b-thalassemia, 11,12 as is hepatic HAMP mRNA expression in patients with thalassemia major (TM) 13,14 and in the C57Bl/6 Hbb th3/1 thalassemia mouse model. 15 However, patients with thalassemia intermedia exhibit lower liver HAMP mRNA than those with TM, 14 probably because of the transfusions that are required to stabilize TM disease.…”

Section: Introductionmentioning

confidence: 99%

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Hepcidin is suppressed by erythropoiesis in hemoglobin E β-thalassemia and β-thalassemia trait

Jones

Pasricha

Allen

et al. 2015

Blood

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Key Points• Expanded erythropoiesis strongly drives hepcidin suppression in severe transfusion-dependent HbE b-thalassemia.• b-thalassemia carriers, but not HbE carriers, have enhanced erythropoiesis associated with mildly suppressed hepcidin.Hemoglobin E (HbE) b-thalassemia is the most common severe thalassemia syndrome across Asia, and millions of people are carriers. Clinical heterogeneity in HbE b-thalassemia is incompletely explained by genotype, and the interaction of phenotypic variation with hepcidin is unknown. The effect of thalassemia carriage on hepcidin is also unknown, but it could be relevant for iron supplementation programs aimed at combating anemia. In 62 of 69 Sri Lankan patients with HbE b-thalassemia with moderate or severe phenotype, hepcidin was suppressed, and overall hepcidin inversely correlated with iron accumulation. On segregating by phenotype, there were no differences in hepcidin, erythropoiesis, or hemoglobin between severe or moderate disease, but multiple linear regression showed that erythropoiesis inversely correlated with hepcidin only in severe phenotypes. In moderate disease, no independent predictors of hepcidin were identifiable; nevertheless, the low hepcidin levels indicate a significant risk for iron overload. In a population survey of Sri Lankan schoolchildren, b-thalassemia (but not HbE) trait was associated with increased erythropoiesis and mildly suppressed hepcidin, suggesting an enhanced propensity to accumulate iron. In summary, the influence of erythropoiesis on hepcidin suppression associates with phenotypic disease variation and pathogenesis in HbE b-thalassemia and indicates that the epidemiology of b-thalassemia trait requires consideration when planning public health iron interventions. (Blood. 2015;125(5):873-880)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hepcidin is suppressed by erythropoiesis in hemoglobin E β-thalassemia and β-thalassemia trait

Jones

Pasricha

Allen

et al. 2015

Blood

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“…8,9 In contrast to human patients who have dramatically reduced hepcidin production even in adulthood, [2][3][4][5] in the Th3/1 model, liver hepcidin mRNA expression is only low in young mice compared with wild-type (WT) mice of the same age; in adult Th3/1 mice, hepcidin expression becomes similar to that of WT mice. 10,11 However, even in adult Th3/1 mice, hepcidin levels are inappropriately low, considering their iron overload, consistent with the concept that inadequate levels of hepcidin cause the iron overload in thalassemic mice.…”

Section: Introductionmentioning

confidence: 99%

“…1 In b-thalassemia intermedia, patients do not require regular blood transfusions. 1 Even without the added iron load of transfusions, pathological suppression of the iron-regulatory hormone hepcidin [2][3][4][5] in patients with b-thalassemia syndromes results in excessive iron absorption. Subsequent iron accumulation in the liver, endocrine glands, and other organs leads to oxidative damage and severe clinical complications predominantly involving hepatic, endocrine, and vascular systems, but sparing the heart, at least compared with transfused patients.…”

Section: Introductionmentioning

confidence: 99%

Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-thalassemia

Kautz¹,

Jung²,

Du³

et al. 2015

Blood

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263

262

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Inherited anemias with ineffective erythropoiesis, such as β-thalassemia, manifest inappropriately low hepcidin production and consequent excessive absorption of dietary iron, leading to iron overload. Erythroferrone (ERFE) is an erythroid regulator of hepcidin synthesis and iron homeostasis. Erfe expression was highly increased in the marrow and spleen of HbbTh3/+ mice (Th3/+), a mouse model of thalassemia intermedia. Ablation of Erfe in Th3/+ mice restored normal levels of circulating hepcidin at 6 weeks of age, suggesting ERFE could be a factor suppressing hepcidin production in β-thalassemia. We examined the expression of Erfe and the consequences of its ablation in thalassemic mice from 3 to 12 weeks of age. The loss of ERFE in thalassemic mice led to full restoration of hepcidin mRNA expression at 3 and 6 weeks of age, and significant reduction in liver and spleen iron content at 6 and 12 weeks of age. Ablation of Erfe slightly ameliorated ineffective erythropoiesis, as indicated by reduced spleen index, red cell distribution width, and mean corpuscular volume, but did not improve the anemia. Thus, ERFE mediates hepcidin suppression and contributes to iron overload in a mouse model of β-thalassemia.

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“…If hepcidin synthesis is switched on after hemochromatosis already developed, then increased hepcidin causes redistribution of iron from parenchymal cells to macrophages, where iron is relatively nontoxic (57). In iron-loading anemias (␤-thalassemia and congenital dyserythropoietic anemia), the suppressive effect of erythropoiesis on hepcidin production (22,58) and the resulting increase in dietary iron absorption is sufficient to cause systemic iron overload and iron-mediated damage to the liver and myocardium even without blood transfusions. It remains to be seen whether exogenous hepcidin can correct the iron pathology in iron-loading anemias as well.…”

Section: Role Of Hepcidin In Iron Overload Disordersmentioning

confidence: 99%

Molecular Control of Iron Transport

Ganz

2007

Journal of the American Society of Nephrology

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322

225

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The iron-regulatory hormone hepcidin is a 25-amino acid peptide that is synthesized in hepatocytes. Hepcidin binds to the cellular iron export channel ferroportin and causes its internalization and degradation and thereby decreases iron efflux from iron exporting tissues into plasma. By this mechanism, hepcidin inhibits dietary iron absorption, the efflux of recycled iron from splenic and hepatic macrophages, and the release of iron from storage in hepatocytes. Hepcidin synthesis is stimulated by plasma iron and iron stores and is inhibited by erythropoietic activity, ensuring that extracellular plasma iron concentrations and iron stores remain stable and the erythropoietic demand for iron is met. During inflammation, increased hepcidin concentrations cause iron sequestration in macrophages, resulting in hypoferremia and eventually anemia of inflammation. Hepcidin deficiency plays a central role in most iron overload disorders. The role of hepcidin abnormalities in anemias that are associated with renal disease and in resistance to erythropoietic therapies remains to be elucidated.

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Urinary hepcidin in congenital chronic anemias

Cited by 156 publications

References 16 publications

Hepcidin is suppressed by erythropoiesis in hemoglobin E β-thalassemia and β-thalassemia trait

Hepcidin is suppressed by erythropoiesis in hemoglobin E β-thalassemia and β-thalassemia trait

Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-thalassemia

Molecular Control of Iron Transport

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