Iron overload in the Asian community

Lok, Chun Yu; Merryweather‐Clarke, Alison T.; Viprakasit, Vip; Chinthammitr, Yingyong; Srichairatanakool, Somdet; Limwongse, Chanin; Oleesky, D A; Robins, Anthony J.; Hudson, John L.; Wai, P; Premawardhena, Anuja; Silva, H. Janaka de; Dassanayake, Anuradha S; McKeown, Carole; Jackson, Maurice; Gama, Rousseau; Khan, Nasaim; Newman, William G.; Banait, Gurvinder; Chilton, Andrew; Wilson-Morkeh, Isaac; Weatherall, D. J.; Robson, Kathryn

doi:10.1182/blood-2009-01-199109

Cited by 92 publications

(65 citation statements)

References 43 publications

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“…Because genetic iron overload syndromes showed an ethnic difference with regard to prevalence, 19,37,38 the patient population was intentionally expanded to a wider range than the general population. Four Italian patients with HFE hemochromatosis and 3 Japanese patients with aceruloplasminemia were included in the study with 13 Japanese patients with a variety of iron overload syndromes referred to 2 institutes in central Japan.…”

Section: Discussionmentioning

confidence: 99%

Measurement of serum hepcidin-25 levels as a potential test for diagnosing hemochromatosis and related disorders

et al. 2010

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Background. Iron overload syndromes include a wide spectrum of genetic and acquired conditions. Recent studies suggest suppressed hepcidin synthesis in the liver to be the molecular basis of hemochromatosis. However, a liver with acquired iron overload synthesizes an adequate amount of hepcidin. Thus, hepcidin could function as a biochemical marker for differential diagnosis of iron overload syndromes.Methods. We measured serum iron parameters and hepcidin-25 levels followed by sequencing HFE, HJV, HAMP, TFR2, and SLC40A1 genes in 13 Japanese patients with iron overload syndromes. In addition, we performed direct measurement of serum hepcidin-25 levels using liquid chromatography-tandem mass spectrometry in 3 Japanese patients with aceruloplasminemia and 4 Italians with HFE-hemochromatosis. Results.One patient with HJV-hemochromatosis, 2 with TFR2-hemochromatosis, and 3 with ferroportin disease were found among the 13 Japanese patients. The remaining 7 Japanese patients showed no evidence for genetic basis of iron overload syndrome. As far as the serum hepcidin-25 was concerned, seven patients with hemochromatosis and 3 with aceruloplasminemia showed markedly decreased serum hepcidin-25 levels. In contrast, 3 patients with ferroportin disease and 7 with secondary iron overload syndromes showed serum hepcidin levels parallel to their hyperferritinemia. Patients with iron overload syndromes were divided into 2 phenotypes presenting as low and high hepcidinemia. These were then associated with their genotypes. Conclusion.Determining serum hepcidin-25 levels may aid differential diagnosis of iron overload syndromes prior to genetic analysis. (231 words)

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Section: Discussionmentioning

confidence: 99%

Measurement of serum hepcidin-25 levels as a potential test for diagnosing hemochromatosis and related disorders

et al. 2010

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“…[7][8][9][10]22 The less common phenotype with parenchymal iron loading similar to classical hemochromatosis results from mutations that cause a gain of function, because they interfere with hepcidin-mediated internalization and degradation of Fpn (N144D/ T/H, C326S/Y, Y64N). 8,[11][12][13][14][15][16][17] Some mutations (eg, A77D) appear to cause a mixed phenotype, with both parenchymal and macrophage iron deposition, and normal to high transferrin saturation. 23,24 In vitro, A77D mutation was reported to cause Fpn mislocalization and a loss of function, 7,25 but additional studies are needed to explain the development of the phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…8,11 Such patients develop a phenotype similar to classical hemochromatosis caused by hepcidin deficiency, with increased duodenal iron absorption, high transferrin saturation, and iron deposition in hepatic parenchyma and other tissues. [12][13][14][15][16][17] The most severe form with an early age of onset is associated with substitutions in C326 residue (C326S/Y), 13,17 whereas a milder hemochromatosis phenotype was observed with substitutions at N144 (N144D/T/H) 12,14,15 and Y64 (Y64N) 16 residues. A letter published in this issue of Blood reports that serum and urinary hepcidin levels in patients carrying C326S mutation are at the upper limit of the normal range or above, confirming that this form of hemochromatosis is hepcidin-resistant.…”

Section: Introductionmentioning

confidence: 99%

The molecular basis of hepcidin-resistant hereditary hemochromatosis

Fernandes

Preza

Phung

et al. 2009

Blood

151

139

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The interaction between the hormone hepcidin and the iron exporter ferroportin (Fpn) regulates plasma iron concentrations. Hepcidin binds to Fpn and induces its internalization and degradation, resulting in decreased iron efflux from cells into plasma. Fpn mutations in N144, Y64N, and C326 residue cause autosomal dominant disease with parenchymal iron overload, apparently due to the resistance of mutant Fpn to hepcidin-mediated internalization. To define the mechanism of resistance, we generated human Fpn constructs bearing the pathogenic mutations. The mutants localized to the cell surface and exported iron normally, but were partially or completely resistant to hepcidinmediated internalization and continued to export iron despite the presence of hepcidin. The primary defect with exofacial C326 substitutions was the loss of hepcidin binding, which resulted in the most severe phenotype. The thiol form of C326 was essential for interaction with hepcidin, suggesting that C326-SH homology is located in or near the binding site of hepcidin. In contrast, N144 and Y64 residues were not required for hepcidin binding, but their mutations impaired the subsequent internalization of the ligandreceptor complex. Our observations explain why the mutations in C326 Fpn residue produce a severe form of hemochromatosis with iron overload at an early age. (Blood. 2009;114:437-443) IntroductionHereditary hemochromatosis is a disease characterized by high transferrin saturation and parenchymal iron overload. Most forms are caused by autosomal-recessive mutations in HFE, transferrin receptor 2, hemojuvelin, or hepcidin. These mutations lead to deficiency of the iron-regulatory hormone hepcidin. Rarely, hereditary hemochromatosis is caused by autosomal-dominant mutations in the hepcidin receptor ferroportin (Fpn). 1 Fpn is the only known cellular iron exporter in vertebrates and is expressed on all tissues that handle major iron flows, including absorptive enterocytes, iron-recycling macrophages, and iron-storing hepatocytes. 2 The rate of iron efflux from these cells is a major determinant of iron concentration in plasma and is directly proportional to the number of Fpn molecules on the cell surface. Furthermore, by controlling the absorption of dietary iron, Fpn expression on the basolateral membranes of enterocytes ultimately determines total body iron. The concentration of cell surface Fpn is regulated mainly by the interaction with its ligand hepcidin. Hepcidin binding to Fpn results in internalization and degradation of the ligand-receptor complex and leads to decreased iron efflux from cells into plasma. 3 The hepcidin-Fpn interaction is critical for normal iron homeostasis and underlies the pathogenesis of iron disorders, including not only hereditary hemochromatosis, but also anemia of inflammation and iron-loading anemias. 4 Although the complete loss of Fpn is embryonic lethal in zebrafish and mice, 2,5 some heterozygous missense mutations in the Fpn gene result in an autosomal-dominant form of iron overload disease called ...

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“…The same mutation was found in the Huh-7 hepatoma cell line and was shown to prevent the translocation of HFE to the cell surface [88]. In addition, families with various types of HH were sporadically reported from Asian countries, including Japan, China, and Pakistan [67,87,[89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104]. In Japan, mutations in HFE2 (type 2A), TFR2 (type 3), and SLC40A1 (type 4) seem relatively common causes of HH [97].…”

Section: Various Types Of Hhmentioning

confidence: 85%

The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis

Kawabata

2017

Int J Hematol

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Hereditary hemochromatosis (HH) is a group of genetic iron overload disorders that manifest with various symptoms, including hepatic dysfunction, diabetes, and cardiomyopathy. Classic HH type 1, which is common in Caucasians, is caused by bi-allelic mutations of HFE. Severe types of HH are caused by either bi-allelic mutations of HFE2 that encodes hemojuvelin (type 2A) or HAMP that encodes hepcidin (type 2B). HH type 3, which is of intermediate severity, is caused by bi-allelic mutations of TFR2 that encodes transferrin receptor 2. Mutations of SLC40A1 that encodes ferroportin, the only cellular iron exporter, causes either HH type 4A (loss-of-function mutations) or HH type 4B (gain-of-function mutations). Studies on these gene products uncovered a part of the mechanisms of the systemic iron regulation; HFE, hemojuvelin, and TFR2 are involved in iron sensing and stimulating hepcidin expression, and hepcidin downregulates the expression of ferroportin of the target cells. Phlebotomy is the standard treatment for HH, and early initiation of the treatment is essential for preventing irreversible organ damage. However, because of the rarity and difficulty in making the genetic diagnosis, a large proportion of patients with non-HFE HH might have been undiagnosed; therefore, awareness of this disorder is important.

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Iron overload in the Asian community

Abstract: Hereditary hemochromatosis is an iron overload disorder that can lead to the impairment of multiple organs and is caused by mutations in one or more different genes.

Cited by 92 publications

References 43 publications

Measurement of serum hepcidin-25 levels as a potential test for diagnosing hemochromatosis and related disorders

Measurement of serum hepcidin-25 levels as a potential test for diagnosing hemochromatosis and related disorders

The molecular basis of hepcidin-resistant hereditary hemochromatosis

The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis

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