Liver iron concentrations and urinary hepcidin in  -thalassemia

Origa, Raffaella; Galanello, Renzo; Ganz, Tomas; Giagu, Nicolina; Maccioni, Liliana; Faa, Gavino; Nemeth, Elizabeta

doi:10.3324/haematol.10842

Cited by 344 publications

(315 citation statements)

References 22 publications

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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%

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

Kautz¹,

Jung²,

Du³

et al. 2015

Blood

265

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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Section: Introductionmentioning

confidence: 99%

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

265

262

View full text Add to dashboard Cite

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“…Ferritin is increased in iron overload secondary to chronic blood transfusions irrespective of the reason and also in the so called iron loading anemias, which include beta-thalassemia syndromes 8 and congenital sideroblastic or dyserythropoietic anemias, 9 characterized by high levels of ineffective erythropoiesis and low hepcidin production. All these conditions are usually well known from the patient's history and may be diagnosed by specific tests.…”

Section: Clara Camaschella and Erika Poggialimentioning

confidence: 99%

Towards explaining "unexplained hyperferritinemia"

Camaschella¹,

Poggiali²

2009

Haematologica

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© F e r r a t a S t o r t i F o u n d a t i o nIron (NTBI), the toxic moiety of iron, responsible for liver damage and eventually damage to the heart, pancreas and pituitary gland. Very high levels of ferritin may be found in hemochromatosis type 4 or ferroportin disease which does not result from impaired hepcidin but rather from heterozygous mutations of the hepcidin receptor ferroportin. 5 The disease is autosomal dominant and has a variable clinical phenotype. The true ferroportin disease (hemochromatosis type 4a in Table 1) is due to mutant proteins that are not correctly targeted to the cell surface and is characterized by macrophage iron accumulation, low/normal transferrin saturation and iron-restricted erythropoiesis.6 A second form (hemochromatosis type 4b), due to mutant ferroportins that reach the cell surface but are resistant to hepcidin-induced internalization, 7 is characterized by hepatocyte iron accumulation and high transferrin saturation, as in hemochromatosis. The distinction is clinically relevant, because the true ferroportin disease seems not to be associated with clinical complications. These observations strengthen the relevance of assessing serum ferritin always in the context of transferrin saturation ( Figure 1).Ferritin is increased in iron overload secondary to chronic blood transfusions irrespective of the reason and also in the so called iron loading anemias, which include beta-thalassemia syndromes 8 and congenital sideroblastic or dyserythropoietic anemias, 9 characterized by high levels of ineffective erythropoiesis and low hepcidin production. All these conditions are usually well known from the patient's history and may be diagnosed by specific tests. Several methods such as magnetic resonance imaging (MRI) 10 or SQUID 11 have become available to non-invasively assess hepatic iron concentration: however, serial ferritin determinations remain a useful guide to assess iron overload and to monitor iron chelation therapy in these patients. 12Moderate increase of serum ferritin with normal/high transferrin saturation and mild/moderate liver iron accumulation may be common in chronic liver disorders, such as alcoholic liver disease and chronic viral hepatitis. These conditions require attention because iron may amplify the toxic effect of alcohol and viruses, accelerating the evolution towards fibrosis and cirrhosis. In porphyria cutanea tarda hyperferritinemia is a sign of iron overload (in some cases due to HFE mutations) 13 and, like alcohol and chronic hepatitis, is a trigger of porphyria attacks.In the metabolic syndrome (variable combination of hypertension, diabetes, hypertrigliceridemia, obesity, steatohepatitis or fatty liver) moderate elevation of ferritin is common, but usually ferritin levels are disproportionately high in comparison with iron stores, 14 whereas transferrin saturation is not increased.In recent years, new forms of inherited hyperferritinemia not associated with iron overload have been identified, adding new elements for differential diagnosis. A rare d...

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“…8 Normally, these signals are balanced to provide an appropriate level of iron to meet erythropoietic demand, but in thalassemia, excessive erythropoiesis suppresses hepcidin, increasing iron absorption. 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.…”

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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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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Liver iron concentrations and urinary hepcidin in -thalassemia

Cited by 344 publications

References 22 publications

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

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

Towards explaining "unexplained hyperferritinemia"

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

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