Iron Matryoshka—Haemochromatosis nested in Ferroportin Disease?

Viveiros, André; Schaefer, Benedikt; Tilg, Herbert; Zoller, Heinz

doi:10.1111/liv.14061

Cited by 4 publications

(7 citation statements)

References 16 publications

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“…Globally, allele frequency has been estimated at 0.0008-0.0009 (128). The former and most frequent type-4A is characterized by atypical manifestations that do not correspond to hemochromatosis (139,140). Owing to this, it should be considered as a distinct disorder (ferroportin disease).…”

Section: Hemochromatosis Type-4 (Omim #606069)mentioning

confidence: 99%

“…Owing to this, it should be considered as a distinct disorder (ferroportin disease). Type-4B shows typical serum iron indices alterations and pattern of iron overload and should be now listed as hemochromatosis type-4 (31,140). Nevertheless, it differs from the other three forms of hemochromatosis from the genetic (autosomal dominant phenotype) and physiopathological point of view (hepcidin resistance).…”

Section: Hemochromatosis Type-4 (Omim #606069)mentioning

confidence: 99%

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Inherited iron overload disorders

Piperno

Pelucchi

Mariani

2020

Transl Gastroenterol Hepatol

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Hereditary iron overload includes several disorders characterized by iron accumulation in tissues, organs, or even single cells or subcellular compartments. They are determined by mutations in genes directly involved in hepcidin regulation, cellular iron uptake, management and export, iron transport and storage. Systemic forms are characterized by increased serum ferritin with or without high transferrin saturation, and with or without functional iron deficient anemia. Hemochromatosis includes five different genetic forms all characterized by high transferrin saturation and serum ferritin, but with different penetrance and expression. Mutations in HFE, HFE2, HAMP and TFR2 lead to inadequate or severely reduced hepcidin synthesis that, in turn, induces increased intestinal iron absorption and macrophage iron release leading to tissue iron overload. The severity of hepcidin down-regulation defines the severity of iron overload and clinical complications. Hemochromatosis type 4 is caused by dominant gain-of-function mutations of ferroportin preventing hepcidin-ferroportin binding and leading to hepcidin resistance. Ferroportin disease is due to loss-of-function mutation of SLC40A1 that impairs the iron export efficiency of ferroportin, causes iron retention in reticuloendothelial cell and hyperferritinemia with normal transferrin saturation.Aceruloplasminemia is caused by defective iron release from storage and lead to mild microcytic anemia, low serum iron, and iron retention in several organs including the brain, causing severe neurological manifestations. Atransferrinemia and DMT1 deficiency are characterized by iron deficient erythropoiesis, severe microcytic anemia with high transferrin saturation and parenchymal iron overload due to secondary hepcidin suppression. Diagnosis of the different forms of hereditary iron overload disorders involves a sequential strategy that combines clinical, imaging, biochemical, and genetic data. Management of iron overload relies on two main therapies: blood removal and iron chelators. Specific therapeutic options are indicated in patients with atransferrinemia, DMT1 deficiency and aceruloplasminemia.

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Section: Hemochromatosis Type-4 (Omim #606069)mentioning

confidence: 99%

Section: Hemochromatosis Type-4 (Omim #606069)mentioning

confidence: 99%

Inherited iron overload disorders

Piperno

Pelucchi

Mariani

2020

Transl Gastroenterol Hepatol

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“…In patients with early disease onset and severe clinical manifestations recessive mutations in HAMP, TFR2 and HJV have been identified (12,13). In contrast, dominant mutations in SLC40A1 are associated with iron overload in patients with ferroportin disease or hemochromatosis type 4 (13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

MRI‐Based Iron Phenotyping and Patient Selection for Next‐Generation Sequencing of Non–Homeostatic Iron Regulator Hemochromatosis Genes

et al. 2021

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“…[1][2][3] SLC40A1 mutations can cause two different clinical phenotypes differentiated by transferrin saturation and patterns of iron storage. 4 Mutations leading to reduced iron export function cause ferroportin disease (FD), which presents with low to normal transferrin saturation and splenic and Kupffer cell iron overload, 5 whereas mutations conferring resistance of ferroportin to hepcidin cause haemochromatosis type 4 (HH4). 6,7 In the latter, patients present with high transferrin saturation and predominant iron accumulation in the hepatocytes.…”

Section: Introductionmentioning

confidence: 99%

“…Mutations in SLC40A1 have been identified in patients with hepatic iron overload and are considered the second most common genetic cause of hemochromatosis after the disease‐associated polymorphism C282Y in HFE 1‐3 . SLC40A1 mutations can cause two different clinical phenotypes differentiated by transferrin saturation and patterns of iron storage 4 . Mutations leading to reduced iron export function cause ferroportin disease (FD), which presents with low to normal transferrin saturation and splenic and Kupffer cell iron overload, 5 whereas mutations conferring resistance of ferroportin to hepcidin cause haemochromatosis type 4 (HH4) 6,7 .…”

Section: Introductionmentioning

confidence: 99%

Reduced iron export associated with hepcidin resistance can explain the iron overload spectrum in ferroportin disease

Viveiros

Panzer

Baumgartner

et al. 2020

Liver International

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Background & Aims: Ferroportin disease (FD) and hemochromatosis type 4 (HH4) are associated with variants in the ferroportin-encoding gene SLC40A1. Both phenotypes are characterized by iron overload despite being caused by distinct variants that either mediate reduced cellular iron export in FD or resistance against hepcidininduced inactivation of ferroportin in HH4. The aim of this study was to assess if reduced iron export also confers hepcidin resistance and causes iron overload in FD associated with the R178Q variant. Methods: The ferroportin disease variants R178Q andA77D and the HH4-variant C326Y were overexpressed in HEK-293T cells and subcellular localization was characterized by confocal microscopy and flow cytometry. Iron export and cytosolic ferritin were measured as markers of iron transport and radioligand binding studies were performed. The hepcidin-ferroportin axis was assessed by ferritin/hepcidin correlation in patients with different iron storage diseases. Results: In the absence of hepcidin, the R178Q and A77D variants exported less iron when compared to normal and C326Y ferroportin. In the presence of hepcidin, the R178Q and C326Y, but not the A77D-variant, exported more iron than cells expressing normal ferroportin. Regression analysis of serum hepcidin and ferritin in patients with iron overload are compatible with hepcidin deficiency in HFE hemochromatosis and hepcidin resistance in R178Q FD. Conclusions: These results support a novel concept that in certain FD variants reduced iron export and hepcidin resistance could be interlinked. Evasion of mutant ferroportin from hepcidin-mediated regulation could result in uncontrolled iron absorption and iron overload despite reduced transport function.

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Iron Matryoshka—Haemochromatosis nested in Ferroportin Disease?

Abstract: See Article on Page 1120

Cited by 4 publications

References 16 publications

Inherited iron overload disorders

Inherited iron overload disorders

MRI‐Based Iron Phenotyping and Patient Selection for Next‐Generation Sequencing of Non–Homeostatic Iron Regulator Hemochromatosis Genes

Reduced iron export associated with hepcidin resistance can explain the iron overload spectrum in ferroportin disease

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