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Cited by 623Iron Metabolism and DisordersNeurological diseases and metabolismTrace Elements in Health

Forging a field: the golden age of iron biology.

Open access
Andrews, Nancy C.·2008·Blood
DOI 10.1182/blood-2007-12-077388PMC PMC2442739
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Abstract

Oh what a difference a decade makes! In a landmark paper published in 1996, Feder and colleagues identified the long-sought gene mutated in patients with classical hereditary hemochromatosis. In many ways, this seemed to ignite an explosion in iron biology which, over the next 10 years, led to a

AI snapshot

Written from the paper’s full text.

TL;DR

This review traces the “golden age” of iron biology from 1958 to 2008, emphasizing molecular discoveries in iron transport, regulation, and disease. It argues that understanding hepcidin/ferroportin regulation unified the pathophysiology of hemochromatosis, iron deficiency anemia, and anemia of chronic disease.

Key findings

  • Ferritin is a 24-subunit cage that can hold up to 4500 iron atoms, while transferrin transports iron in plasma; both keep iron nonreactive and are used clinically in iron-status assays.
  • The IRE/IRP posttranscriptional system regulates ferritin and TFR1: IRP binding blocks ferritin translation under low iron, whereas 3′ IRE binding protects TFR1 mRNA from degradation.
  • Hepcidin, a 25-amino-acid liver peptide, binds ferroportin and triggers its internalization and lysosomal degradation, reducing serum iron; hemochromatosis is classified into 3 classes affecting the hepcidin/ferroportin axis.
  • Iron deficiency anemia is estimated to affect 3 billion people worldwide; IRIDA patients fitting strict criteria carried inactivating TMPRSS6 mutations, and mutations in DMT1 or GLRX5 cause rare autosomal recessive microcytic anemia.

Methods

  • Narrative review of iron biology from the birth of ASH in 1958 to 2008, focusing on physiology and inherited/acquired iron disorders.
  • Synthesizes ferrokinetic studies, molecular biology, positional cloning, targeted mouse mutants, zebrafish mutants, and human genetic/clinical observations.
  • No systematic search, meta-analysis, or new primary data are reported.

Limitations

  • Stated by the author: important areas are neglected, including mitochondrial iron metabolism, heme metabolism, brain iron accumulation in neurodegenerative disorders, Fe-S cluster formation, therapeutic chelation, classical ferrokinetics, microbial iron metabolism, and structural characterizations.
  • Stated by the author: topic choice reflects personal expertise and a focus on diseases that have only recently become understood, not a judgment of importance.
  • Evident from the text: as a narrative review, it lacks systematic methods, quantitative synthesis, and formal assessment of evidence quality.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1182/blood-2007-12-077388

Cites

213 of 213 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 179 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Every patient who fit strict criteria for IRIDA carried inactivating mutations in TMPRSS6 that could explain the disease.

    “Every patient who fit our strict criteria for IRIDA carried inactivating mutations in TMPRSS6 that could explain the disease.190,192”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [190] Finberg, 2008, Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)., Nat Genet source

      Not checked in the free run.

    • cites [192] Beutler, 2007, The Mask mutation identifies TMPRSS6 as an essential suppressor of hepcidin gene expression, required for normal uptake of dietary iron., [abstract] Blood

      Not checked in the free run.

  • Findingcitation

    Some patients have congenital, iron-refractory, iron-deficiency anemia (IRIDA) that cannot be explained by mutations in the genes encoding DMT1, GLRX5, TF, or ceruloplasmin.

    “We and others have observed that some patients have congenital, iron-refractory, iron-deficiency anemia (IRIDA) that cannot be explained by mutations in the genes encoding DMT1, GLRX5, TF, or ceruloplasmin.[185][186][187][188][189][190]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [185][186][187][188][189][190]

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  • Findingown data

    The hepatocyte-like cells of the adenomas expressed very high levels of hepcidin.

    “We found that the hepatocytelike cells of the adenomas expressed very high levels of hepcidin 100 and speculated that our results could be generalized-that induction of hepcidin expression in response to inflammation might explain the anemia of chronic disease.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Weinstein, 2002, Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease., Blood source

      Not checked in the free run.

  • Premisecitation

    Transferrin was identified as an abundant plasma iron transport protein a decade after ferritin was crystallized.

    “Transferrin was identified as an abundant plasma iron transport protein a decade later.4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Schade, 1946, An iron-binding component in human blood plasma., Science source

      Not checked in the free run.

  • Premisecitation

    In 1987, investigators observed that conserved sequences in the 5' UTRs of both H- and L-ferritin mRNAs were needed to control a ready but quiescent pool of ferritin mRNA.

    “In 1987, investigators observed that conserved sequences in the 5Ј untranslated regions (UTRs) of both H-and L-ferritin mRNAs were needed to control a ready but quiescent pool of ferritin mRNA in the cell, which could quickly be mobilized to produce ferritin protein when iron was abundant.22,23”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Aziz, 1987, Iron regulates ferritin mRNA translation through a segment of its 5′-untranslated region., PNAS source

      Not checked in the free run.

    • cites [23] Hentze, 1987, A cis-acting element is necessary and sufficient for translational regulation of human ferritin expression in response to iron., Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • May combine two claims. 50
  • Classified as probably not a substantial claim. 17

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    Findingcitation

    Patients with glycogen storage disease type 1a and hepatic adenomas develop anemia resembling anemia of chronic disease, the severity of which correlates directly with the extent of tumor burden.

    “With Weinstein, Roy, and colleagues, we observed that these patients also develop anemia resembling the anemia of chronic disease, the severity of which correlates directly with the extent of tumor burden.100”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Weinstein, 2002, Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease., Blood source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    IRIDA patients appear to have a defect in cellular iron export, but the disorder has an autosomal recessive pattern of inheritance and no mutations have been detected in ferroportin or in the regulatory regions of the hepcidin gene.

    “These individuals appear to have a defect in cellular iron export, 191 but the disorder has an autosomal recessive pattern of inheritance and no mutations have been detected in ferroportin or in the regulatory regions of the hepcidin gene.190”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [190] Finberg, 2008, Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)., Nat Genet source

      Not checked in the free run.

    • cites [191] Andrews, 1999, Commentary on: ferrokinetics in the syndrome of familial hypoferremic microcytic anemia with iron malabsorption., J Pediatr Hematol Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Quigley and colleagues described a heme exporter, FLVCR, which appears to be necessary for normal erythroid development.

    “Recently, however, Quigley and colleagues 20 have described a heme exporter, FLVCR, which appears to be necessary for normal erythroid development.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Quigley, 2004, Identification of a human heme exporter that is essential for erythropoiesis., Cell source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ferritin is the precursor to hemosiderin, a heterogeneous aggregate of iron, lysosomal components, and other products of intracellular digestion.

    “Ferritin is also the precursor to hemosiderin, a heterogeneous aggregate of iron, lysosomal components, and other products of intracellular digestion.8”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Wixom, 1980, Hemosiderin: nature, formation and significance., Int Rev Exp Pathol

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In 1937, horse spleen ferritin was the second of all proteins to be crystallized.

    “In 1937, horse spleen ferritin was the second of all proteins to be crystallized.3”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Laufberger, 1937, Sur la cristallisation de la ferritine., Soc Chim Biol

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Targeted disruption of the Tfr1 gene in mice demonstrated that most tissues develop normally without Tfr1, but erythroid precursors, early lymphoid cells, and neuroepithelial cells require Tfr1 for differentiation.

    “Targeted disruption of the Tfr1 gene in mice demonstrated that most tissues develop normally without Tfr1, but erythroid precursors, early lymphoid cells, and neuroepithelial cells require Tfr1 for differentiation.18,19”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Levy, 1999, Transferrin receptor is necessary for development of erythrocytes and the nervous system., Nat Genet source

      Not checked in the free run.

    • cites [19] Ned, 2003, Transferrin receptor 1 is differentially required in lymphocyte development., Blood source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FLVCR-null mice had a failure of definitive erythropoiesis, resulting in fetal demise.

    “FLVCR-null mice had a failure of definitive erythropoiesis, resulting in fetal demise.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Keel, 2008, A heme export protein is required for red blood cell differentiation and iron homeostasis., Science source

      Not checked in the free run.

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    Premisecitation

    Both STEAP3 and DMT1 were discovered through positional cloning of genes altered in rodents carrying spontaneous mutations impairing iron transport.

    “Both STEAP3 and DMT1 were discovered through positional cloning of genes altered in rodents carrying spontaneous mutations impairing iron transport.10,11”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] Ohgami, 2005, Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells., Nat Genet source

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    • cites [11] Fleming, 1998, Nramp2 is mutated in the anemic Belgrade 11. (b) rat: evidence of a role for Nramp2 in endosomal iron transport., Proc Natl Acad Sci U S A source

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  • May combine two claims.

    Premisecitation

    The mitochondrial iron importer was recently identified as mitoferrin (SLC25A37), a transmembrane protein that plays a critical role in supplying iron to ferrochelatase for insertion into protoporphyrin IX.

    “The mitochondrial iron importer was recently identified as mitoferrin (also known as SLC25A37), a transmembrane protein that plays a critical role in supplying iron to ferrochelatase for insertion into protoporphyrin IX.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Foury, 2002, Deletion of the mitochondrial carrier genes MRS3 and MRS4 suppresses mitochondrial iron accumulation in a yeast frataxin-deficient strain., J Biol Chem source

      Not checked in the free run.

    • cites [17] Shaw, 2006, Mitoferrin is essential for erythroid iron assimilation., Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Liberated inorganic iron is reduced by the ferrireductase STEAP3 to Fe2+, which is the substrate for transmembrane transport by DMT1.

    “Liberated inorganic iron is then reduced by the ferrireductase STEAP3 to Fe 2ϩ , 10 which is the substrate for transmembrane transport by divalent metal transporter 1 (DMT1 or SLC11A2, formerly called NRAMP2, DCT1).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] Ohgami, 2005, Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells., Nat Genet source

      Not checked in the free run.

    • cites [11] Fleming, 1998, Nramp2 is mutated in the anemic Belgrade 11. (b) rat: evidence of a role for Nramp2 in endosomal iron transport., Proc Natl Acad Sci U S A source

      Not checked in the free run.

    • cites [12] Fleming, 1997, Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene., Nat Genet source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Ferritin is a cagelike heteropolymer of 24 subunits of H- and L-types, which can hold up to 4500 iron atoms.

    “Ferritin, which has homologs in all organisms except yeast, is a cagelike heteropolymer of 24 subunits of H-(heavy or heart) and L-(light or liver) types, which can hold up to 4500 iron atoms.5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Harrison, 1967, Ferric oxyhydroxide core of ferritin., Nature source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Mitoferrin was originally discovered in yeast (MRS3/MRS4) and in a mutant zebrafish.

    “Mitoferrin was originally discovered in yeast (called MRS3/MRS4 16 ) and in a mutant zebrafish.17”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Foury, 2002, Deletion of the mitochondrial carrier genes MRS3 and MRS4 suppresses mitochondrial iron accumulation in a yeast frataxin-deficient strain., J Biol Chem source

      Not checked in the free run.

    • cites [17] Shaw, 2006, Mitoferrin is essential for erythroid iron assimilation., Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When the FLVCR gene was inactivated after birth, the animals developed severe, macrocytic anemia, implying that heme export is important for normal erythropoiesis.

    “When the FLVCR gene was inactivated after birth the animals developed severe, macrocytic anemia, implying that heme export is important for normal erythropoiesis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Keel, 2008, A heme export protein is required for red blood cell differentiation and iron homeostasis., Science source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ferritin has homologs in all organisms except yeast.

    “Ferritin, which has homologs in all organisms except yeast, is a cagelike heteropolymer of 24 subunits of H-(heavy or heart) and L-(light or liver) types, which can hold up to 4500 iron atoms.5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Harrison, 1967, Ferric oxyhydroxide core of ferritin., Nature source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Ferritin receptors are present on lymphocytes and some other cell types, but their physiologic function has not been fully defined.

    “Ferritin receptors are present on lymphocytes and some other cell types, but their physiologic function has not been fully defined.7”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Chen, 2005, TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis., J Exp Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DMT1 is electrogenic, requiring proton cotransport to move Fe2+ across the membrane.

    “Gunshin 13 and Hediger 15 showed that DMT1 is electrogenic, requiring proton cotransport to move Fe 2ϩ across the membrane.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13] Gunshin, 1997, Cloning and characterization of a mammalian proton-coupled metal-ion transporter., Nature source

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    • cites [15] Sacher, 2001, Properties of the mammalian and yeast metal-ion transporters DCT1 and Smf1p expressed in Xenopus laevis oocytes., J Exp Biol source

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  • May combine two claims.

    Premisecitation

    The IRE/IRP regulatory system is also used to control expression of other proteins, best studied TFR1, which has multiple IREs in the 3' UTR of its mRNA.

    “The IRE/IRP regulatory system is also used to control expression of other proteins.The best studied is TFR1, which has multiple IREs in the 3Ј UTR of its mRNA.39”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Casey, 1989, Iron regulation of transferrin receptor mRNA levels requires iron-responsive elements and a rapid turnover determinant in the 3′ untranslated region of the mRNA., EMBO J source

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  • May combine two claims.

    Premisecitation

    IRP1 bears strong similarity to aconitase and also has aconitase activity.

    “At the time of its discovery, IRP1 was recognized to bear strong similarity to aconitase, a mitochondrial enzyme of the tricarboxylic acid cycle.Remarkably, IRP1 also has aconitase activity, making it a prime candidate for a previously described cytoplasmic aconitase.29,30”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] Hentze, 1991, Homology between IRE-BP, a regulatory RNA-binding protein, aconitase, and isopropylmalate isomerase., Nucleic Acids Res source

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    • cites [30] Kaptain, 1991, A regulated RNA binding protein also possesses aconitase activity., Proc Natl Acad Sci U S A source

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  • May combine two claims.

    Interpretationreasoning

    Because iron enters the body exclusively through the diet and there is no regulated excretion of iron through the liver or kidneys, iron balance is primarily controlled at the level of intestinal absorption.

    “Because there is no regulated excretion of iron through the liver or kidneys, iron balance is primarily controlled at the level of intestinal absorption.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: In nontransfused individuals, iron enters the body exclusively through the diet.
    • Rests on an assumption: There is no regulated excretion of iron through the liver or kidneys.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CYBRD1 was one of 2 iron transport-related molecules discovered by McKie through a very productive RNA subtraction approach.

    “CYBRD1 was one of 2 iron transport-related molecules discovered by McKie through a very productive RNA subtraction approach.53,54”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [53] McKie, 2001, An iron-regulated ferric reductase associated with the absorption of dietary iron., Science source

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    • cites [54] McKie, 2000, A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation., Mol Cell source

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    Premisecitation

    NRAMP1 was identified by Vidal et al through positional cloning of a mouse locus involved in host defense against intracellular pathogens in mouse macrophages.

    “The sole mammalian homolog of DMT1, designated NRAMP1 for natural resistance associated macrophage protein 1, was identified by Vidal et al through positional cloning of a mouse locus involved in host defense against intracellular pathogens in mouse macrophages.60”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Vidal, 1993, Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg., Cell source

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  • May combine two claims.

    Premisecitation

    There is a siderophore-like iron uptake pathway mediated by lipocalin-2 (NGAL, 24p3) but its physiologic role is not fully worked out.

    “There is a siderophore-like iron uptake pathway mediated by lipocalin-2 (also called NGAL, 24p3) but its physiologic role is not fully worked out.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [74] Goetz, 2002, The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition., Mol Cell source

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    • cites [75] Yang, 2002, An iron delivery pathway mediated by a lipocalin., Mol Cell source

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    • cites [76] Devireddy, 2005, A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake., Cell source

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  • May combine two claims.

    Premisecitation

    Haile and Rouault showed that the aconitase activity of IRP1 is present only when the iron-sulfur cluster is complete; when it is not, IRP1 acts as an RNA binding protein recognizing IREs.

    “Haile and Rouault showed that the aconitase activity of IRP1 is present only when the iron-sulfur cluster is complete; when it is not, IRP1 acts as an RNA binding protein, recognizing IREs.31”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Haile, 1992, Reciprocal control of RNA-binding and aconitase activity in the regulation of the iron-responsive element binding protein: role of the iron-sulfur cluster., Proc Natl Acad Sci U S A source

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  • May combine two claims.

    Premisecitation

    Targeted disruption of the murine gene encoding DMT1 confirmed that DMT1 is the primary transmembrane iron transporter bringing dietary nonheme iron into intestinal epithelial cells and mediating iron uptake through the transferrin cycle in erythroid precursors.

    “Targeted disruption of the murine gene encoding DMT1 confirmed that DMT1 is the primary transmembrane iron transporter bringing dietary nonheme iron into intestinal epithelial cells and mediating iron uptake through the transferrin cycle in erythroid precursors.66”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Gunshin, 2005, Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver., J Clin Invest source

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  • May combine two claims.

    Premisecitation

    Targeted disruption of IRP2 leads to a disorder of iron homeostasis characterized by microcytic, hypochromic anemia, and, at least in one laboratory, a late onset neurodegenerative disorder.

    “In contrast, targeted disruption of IRP2 leads to a disorder of iron homeostasis characterized by microcytic, hypochromic anemia, 42,43 and, at least in one laboratory, a late onset neurodegenerative disorder.42,44,45”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [42] Cooperman, 2005, Microcytic anemia, erythropoietic protoporphyria and neurodegeneration in mice with targeted deletion of iron regulatory protein 2., Blood source

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    • cites [43] Galy, 2005, Altered body iron distribution and microcytosis in mice deficient in iron regulatory protein 2 (IRP2)., Blood source

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    • cites [44] LaVaute, 2001, Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice., Nat Genet source

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  • May combine two claims.

    Premisecitation

    DMT1 may also serve as a physiologically significant portal of entry for other divalent metal cations including Mn2+, Co2+, Zn2+, Cu2+, and Pb2+, though its importance has only been definitively established for Fe2+ in vivo.

    “DMT1 may also serve as a physiologically significant portal of entry for other divalent metal cations including Mn 2ϩ , Co 2ϩ , Zn 2ϩ , Cu 2ϩ , and Pb 2ϩ , though its importance has only been definitively established for Fe 2ϩ in vivo.13”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Gunshin, 1997, Cloning and characterization of a mammalian proton-coupled metal-ion transporter., Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At the time, 6 mouse strains with spontaneous mutations perturbing iron homeostasis had been identified; all are now understood in molecular detail.

    “At the time, 6 strains had been identified; all are now understood in molecular detail.14”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Andrews, 2000, Iron homeostasis: insights from genetics and animal models., Nat Rev Genet source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    NRAMP1 is expressed in phagosomes of professional phagocytes.

    “NRAMP1 is expressed in phagosomes of professional phagocytes.61”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Gruenheid, 1997, Natural resistance to infection with intracellular pathogens: the Nramp1 protein is recruited to the membrane of the phagosome., J Exp Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although Cybrd1 expression is markedly induced in iron-deficient animals, targeted disruption of the murine Cybrd1 gene was not associated with any apparent phenotype in mice fed standard chow.

    “Surprisingly, although Cybrd1 expression is markedly induced in iron-deficient animals, targeted disruption of the murine Cybrd1 gene was not associated with any apparent phenotype in mice fed standard chow.55”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Gunshin, 2005, Cybrd1 (duodenal cytochrome b) is not necessary for dietary iron absorption in mice., Blood

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Beaumont and colleagues showed that disruption of the L-ferritin IRE results in hyperferritinemia-cataract disease, with prominent ocular findings and elevated serum ferritin but no evidence of disturbed iron homeostasis.

    “Beaumont and colleagues 48 showed that disruption of the L-ferritin IRE results in hyperferritinemia-cataract disease, with prominent ocular findings and elevated serum ferritin but no evidence of disturbed iron homeostasis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Beaumont, 1995, Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinemia and cataract., Nat Genet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under low iron conditions IRP2 accumulates, but when iron is abundant it triggers IRP2 degradation.

    “Under low iron conditions IRP2 accumulates, but when iron is abundant it triggers IRP2 degradation.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [32] Guo, 1995, Iron regulates the intracellular degradation of iron regulatory protein 2 by the proteasome., J Biol Chem source

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    • cites [33] Iwai, 1995, Requirements for iron-regulated degradation of the RNA binding protein, iron regulatory protein 2., EMBO J source

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    • cites [34] Iwai, 1998, Iron-dependent oxidation, ubiquitination, and degradation of iron regulatory protein 2: implications for degradation of oxidized proteins., Proc Natl Acad Sci U S A source

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  • May combine two claims.

    Premisecitation

    HFE is an atypical major histocompatibility class I-like molecule that forms a heterodimer with beta-2-microglobulin but is incapable of binding a small peptide.

    “HFE is an atypical major histocompatibility class I-like molecule that forms a heterodimer with ␤2-microglobulin but is incapable of binding a small peptide.145”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] Lebron, 1998, Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor., Cell source

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  • May combine two claims.

    Premisecitation

    Penetrance of HFE hemochromatosis is incomplete, and only a fraction of affected patients have clinical disease, presumably due to both genetic and environmental modifiers.

    “Furthermore, penetrance of HFE hemochromatosis is incomplete, and only a fraction of affected patients have clinical disease, presumably due to both genetic and environmental modifiers. 122”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Allen, 2008, Iron-overload-related disease in HFE hereditary hemochromatosis., N Engl J Med source

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  • May combine two claims.

    Premisecitation

    TFR1 regulates HFE activity and inhibits HFE by sequestering it.

    “However, more recent results suggest a different scenario: that TFR1 regulates HFE activity and inhibits HFE by sequestering it.149”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Schmidt, 2008, The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression., Cell Metab source

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  • May combine two claims.

    Premisecitation

    The amount of hepcidin mRNA in liver cells is decreased in response to hypoxia and ineffective erythropoiesis and induced in response to treatment with lipopolysaccharide or by inflammation of other etiologies.

    “In addition, the amount of hepcidin mRNA in liver cells is decreased in response to hypoxia and ineffective erythropoiesis (overlapping with the response to iron deficiency) 99,105 and induced in response to treatment with lipopolysaccharide or by inflammation of other etiologies.92,99”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [99] Nicolas, 2002, The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation., J Clin Invest source

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    • cites [105] Adamsky, 2004, Decreased hepcidin mRNA expression in thalassemic mice., Br J Haematol source

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    • cites [92] Pigeon, 2001, A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload., J Biol Chem source

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  • May combine two claims.

    Premisecitation

    Several modifier gene candidates have been explored and, in some cases, verified.

    “Several modifier gene candidates have been explored and, in some cases, verified.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [123] Levy, 2000, Genes that modify the hemochromatosis phenotype in mice., J Clin Invest source

      Not checked in the free run.

    • cites [124] Sachot, 2001, Low penetrant hemochromatosis phenotype in eight families: no evidence of modifiers in the MHC region., Blood Cells Mol Dis source

      Not checked in the free run.

    • cites [125] Sproule, 2001, Naturally variant autosomal and sex-linked loci determine the severity of iron overload in beta 2-microglobulin-deficient mice., Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In patients with mutations in hemojuvelin, HFE, or TFR2, intestinal iron absorption and macrophage iron release are not properly controlled, leading to iron overload, increased serum iron, and iron deposition in the liver, heart, and endocrine tissues.

    “As a consequence, intestinal iron absorption and macrophage iron release are not properly controlled, leading to iron overload, increased serum iron, and iron deposition in the liver, heart, and endocrine tissues.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Three classes of hemochromatosis disorders all affect the hepcidin/ferroportin regulatory axis: Class I defects in HAMP preventing production of functional hepcidin; Class II defects in HFE, TFR2, or HFE2 preventing normal hepatic regulation of hepcidin expression; Class III defects in ferroportin preventing normal regulation by hepcidin.

    “Three classes of hemochromatosis disorders all affect the hepcidin/ferroportin regulatory axis: Class I, defects in the hepcidin gene (HAMP) preventing production of functional hepcidin; Class II, defects in HFE, TFR2, or HFE2 genes preventing normal hepatic regulation of hepcidin expression; Class III, defects in ferroportin preventing normal regulation by hepcidin.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Murine hepcidin mRNA is elevated in response to iron overload and decreased in response to iron deficiency.

    “Initially, murine hepcidin mRNA was shown to be elevated in response to iron overload 92 and decreased in response to iron deficiency.99,100”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [92] Pigeon, 2001, A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload., J Biol Chem source

      Not checked in the free run.

    • cites [99] Nicolas, 2002, The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation., J Clin Invest source

      Not checked in the free run.

    • cites [100] Weinstein, 2002, Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease., Blood source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Human iron disorders are invariably disorders of iron balance or iron distribution.

    “Accordingly, human iron disorders are invariably disorders of iron balance or iron distribution.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Hepcidin binds to cell-surface ferroportin, triggering its tyrosine phosphorylation, internalization, and ubiquitin-mediated degradation in lysosomes.

    “Hepcidin binds to cell-surface ferroportin, triggering its tyrosine phosphorylation, internalization, and ubiquitin-mediated degradation in lysosomes.93,94”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [93] Nemeth, 2004, Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization., Science source

      Not checked in the free run.

    • cites [94] De Domenico, 2007, The molecular mechanism of hepcidin-mediated ferroportin down-regulation., Mol Biol Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both retention of iron in intestinal epithelium and interruption of macrophage iron release decrease serum iron.

    “Both events have the same consequence-decreased serum iron.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    BMP treatment is a potent stimulus for hepcidin expression both in cultured cells and in animals.

    “Nonetheless, BMP treatment is a potent stimulus for hepcidin expression both in cultured cells 113,114,116,117 and in animals.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [113] Wang, 2005, A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression., Cell Metab source

      Not checked in the free run.

    • cites [114] Babitt, 2006, Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression., Nat Genet source

      Not checked in the free run.

    • cites [116] Truksa, 2006, Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6., Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In the intestine, inactivation of basolateral ferroportin leads to retention of iron in the intestinal epithelium; in iron-recycling macrophages, inactivation of ferroportin interrupts release of iron recovered from senescent red cells.

    “This is particularly important in the intestine, where inactivation of basolateral ferroportin leads to retention of iron in the intestinal epithelium, and in iron-recycling macrophages of the reticuloendothelial system, where inactivation of ferroportin interrupts release of iron recovered from senescent red cells (Figure 2A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hepcidin has been detected and quantitated in urine samples and, with more difficulty, in serum.

    “It has been detected and quantitated in urine samples, 91,96 and, with more difficulty, in serum.97”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [91] Park, 2001, Hepcidin, a urinary antimicrobial peptide synthesized in the liver., J Biol Chem source

      Not checked in the free run.

    • cites [96] Nemeth, 2003, Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein., Blood source

      Not checked in the free run.

    • cites [97] Kemna, 2007, Mass spectrometry-based hepcidin measurements in serum and urine: analytical aspects and clinical implications., Clin Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The von Hippel-Lindau/hypoxia-inducible transcription factor (HIF) system also appears to control hepcidin expression, with HIF1α acting as a repressor when it binds to the hepcidin promoter.

    “The von Hippel-Lindau/hypoxia-inducible transcription factor (HIF) system also appears to control hepcidin expression, with HIF1␣ acting as a repressor when it binds to the hepcidin promoter.109”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Peyssonnaux, 2007, Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs)., J Clin Invest source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Hepcidin is a 25-amino-acid protein produced by processing of a larger precursor, discovered independently by 3 laboratories and first reported in 2000 and 2001.

    “Discovered independently by 3 laboratories and first reported in 2000 and 2001, hepcidin is a 25-amino-acid protein produced by processing of a larger precursor.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [90] Krause, 2000, LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity., FEBS Lett source

      Not checked in the free run.

    • cites [91] Park, 2001, Hepcidin, a urinary antimicrobial peptide synthesized in the liver., J Biol Chem source

      Not checked in the free run.

    • cites [92] Pigeon, 2001, A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload., J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The basolateral iron transporter, discovered simultaneously by 3 labs, is ferroportin (IREG1, MTP1, SLC39A1, SLC40A1).

    “The basolateral iron transporter, discovered simultaneously by 3 labs, is ferroportin (also called IREG1, MTP1, SLC39A1, and now SLC40A1).54,77,78”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [54] McKie, 2000, A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation., Mol Cell source

      Not checked in the free run.

    • cites [77] Abboud, 2000, A novel mammalian iron-regulated protein involved in intracellular iron metabolism., J Biol Chem source

      Not checked in the free run.

    • cites [78] Donovan, 2000, Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter., Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human patients with DMT1 mutations have similar blood films and erythrocyte abnormalities to the mouse model, but also have hepatic iron overload that is not fully explained by their transfusion histories.

    “The human patients have similar blood films and erythrocyte abnormalities, but also have hepatic iron overload that is not fully explained by their transfusion histories.[172][173][174][175][176]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [172][173][174][175][176]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations in DMT1 (SLC11A2) and glutaredoxin 5 (GLRX5) are associated with autosomal recessive hypochromic, microcytic anemia.

    “Mutations in the genes encoding DMT1 (SLC11A2) and glutaredoxin 5 (GLRX5) are associated with autosomal recessive hypochromic, microcytic anemia.171,172”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [171] Camaschella, 2007, The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload., Blood source

      Not checked in the free run.

    • cites [172] Mims, 2005, Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload., Blood source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The H pylori-associated iron deficiency anemia is typically seen in young women, is associated with gastric atrophy, and can be associated with other autoimmune phenomena.

    “This disorder is typically seen in young women, is associated with gastric atrophy, and can be associated with other autoimmune phenomena.166,167”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [166] Carnicer, 1997, Helicobacter pylori gastritis and sideropenic refractory anemia., J Pediatr Gastroenterol Nutr source

      Not checked in the free run.

    • cites [167] Marignani, 1997, Reversal of long-standing iron deficiency anaemia after eradication of Helicobacter pylori infection., Scand J Gastroenterol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hypotransferrinemia, also called atransferrinemia, has been observed in both human patients and in mice.

    “This disorder, hypotransferrinemia (also called atransferrinemia), has been observed in both human patients and in mice.[180][181][182][183]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [180][181][182][183]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both hypotransferrinemia and ceruloplasmin deficiency are rare, but each can be confused with hemochromatosis if the entire clinical picture is not taken into account.

    “Although both of these disorders are rare, each can be confused with hemochromatosis if the entire clinical picture is not taken into account.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Displacement of HFE from TFR1 by TF may activate HFE to signal through an as-yet-unknown mechanism to increase hepcidin transcription.

    “Because TF and HFE compete for binding to TFR1, displacement of HFE from TFR1 by TF may be a means to activate HFE to signal through an as-yet-unknown mechanism to increase hepcidin transcription.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Deficiency of ceruloplasmin causes mild iron deficiency anemia associated with iron accumulation in the liver and brain.

    “Through a different mechanism, deficiency of another major plasma protein, cerulopasmin, also causes mild iron deficiency anemia associated with iron accumulation in the liver and brain.184”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [184] Harris, 1995, Aceruloplasminemia: molecular characterization of this disorder of iron metabolism., Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Knockout mice heterozygous for a null ferroportin allele had no significant iron phenotype and did not seem to model the human disease.

    “Furthermore, knockout mice heterozygous for a null ferroportin allele had no significant iron phenotype, and did not seem to model the human disease.79”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Donovan, 2005, The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis., Cell Metab source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Anemia of chronic disease may be associated with infection, malignancy, organ failure, trauma, or other causes of inflammation.

    “Elegantly described by Cartwright in a classic review, 194 this condition may be associated with infection, malignancy, organ failure, trauma, or other causes of inflammation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [194] Cartwright, 1966, The anemia of chronic disorders., Semin Hematol

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TFR2 is 43% homologous to TFR1 in its extracellular domain but does not take up diferric-TF efficiently.

    “Although TFR2 is 43% homologous to TFR1 in its extracellular domain, it does not take up diferric-TF efficiently.152”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [152] Kawabata, 1999, Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family., J Biol Chem source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationown data

    HFE, TFR2, and hemojuvelin may be part of a larger BMP signaling complex.

    “These proteins may be part of a larger BMP signaling complex along with hemojuvelin (P.J. Schmidt, F.W. Huang, and N.C.A., unpublished results).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Anemia of chronic disease, also called anemia of inflammation, is an acquired disorder of iron homeostasis.

    “The anemia of chronic disease (also called anemia of inflammation) is an acquired disorder of iron homeostasis (reviewed in Roy and Andrews 193 ).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Roy and Andrews 193

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations in TFR2 are much less common than mutations in HFE, but the clinical disease can be indistinguishable.

    “Mutations in TFR2 are much less common than mutations in HFE, but the clinical disease can be indistinguishable.133”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Camaschella, 2005, Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders., Blood source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Mutations in the 5 genes currently associated with hemochromatosis probably do not account for all patients with the disease.

    “Mutations in the 5 genes currently associated with hemochromatosis probably do not account for all patients with the disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mice expressing a hepcidin transgene are microcytic, similar to IRIDA.

    “Mice expressing a hepcidin transgene are microcytic, similar to IRIDA.104”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Roy, 2007, Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation., Blood source

      Not checked in the free run.

63 of 63

  • The paper relies on this without support.

    In nontransfused individuals, iron enters the body exclusively through the diet.

    “In nontransfused individuals, iron enters the body exclusively through the diet.”

  • The paper relies on this without support.

    There is no regulated excretion of iron through the liver or kidneys.

    “Because there is no regulated excretion of iron through the liver or kidneys, iron balance is primarily controlled at the level of intestinal absorption.”

  • The paper relies on this without support.

    Most dietary nonheme iron is in the ferric (Fe3+) form.

    “Most dietary nonheme iron is in the ferric (Fe 3ϩ ) form.”

  • The paper relies on this without support.

    Only iron exported across the basolateral membrane of the enterocyte is absorbed.

    “Only iron exported across the basolateral membrane of the enterocyte is absorbed.”

  • The paper relies on this without support.

    Hepcidin has primary responsibility for modulating iron availability to meet iron needs.

    “In this context, we now know that hepcidin, a peptide hormone produced in the liver, has primary responsibility for modulating iron availability to meet iron needs.”

  • The paper relies on this without support.

    All ferroportin mutations cause missense changes rather than truncations or frameshifts.

    “Strikingly, all ferroportin mutations caused missense changes, rather than truncations or frameshifts.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Mammalian cellular immunity relies heavily on action of macrophages, which also play critical role in systemic Fe homeostasis.

    “Mammalian cellular immunity relies heavily on the action of macrophages, cells that also play a critical role in systemic Fe homeostasis [13].”

    From Host Iron Withholding Demands Siderophore Utilization for Candida glabrata to Survive Macrophage Killing (2011) · cites this paper as [13]

  • The FPNC326Y disease-associated mutation results in a similar clinical outcome to that observed in patients carrying HFE mutations present in approximately 80% of HH patients and exhibiting an allelic frequency of over 10% in Caucasians of European descent.

    “The FPNC326Y disease-associated mutation results in a similar clinical outcome to that observed in patients carrying HFE mutations present in approximately 80% of HH patients and exhibiting an allelic frequency of over 10% in Caucasians of European descent [13].”

    From Host Iron Withholding Demands Siderophore Utilization for Candida glabrata to Survive Macrophage Killing (2011) · cites this paper as [13]

  • Activation of signaling through HFE, TFR1, TFR2, or HJV increases hepcidin transcription in a SMAD-dependent fashion.

    “Activation of signaling through the hemochromatosis protein HFE, TFR1, TFR2, or hemojuvelin (HJV), which acts as a co-receptor for bone morphogenetic protein 6 (BMP6), increases hepcidin transcription in a SMAD-dependent fashion.”

    From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [190]

  • Constitutively low hepcidin production in the liver due to genetic defects in iron-signaling pathways results in persistent hyperferremia and the development of hemochromatosis.

    “In contrast, constitutively low hepcidin production in the liver, e.g. due to genetic defects in iron-signaling pathways, results in persistent hyperferremia and the development of hemochromatosis.”

    From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [190]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Citation 15 is attributed to the wrong author

    Minor

    The text attributes the cited finding to Hediger, but reference 15 lists Sacher, Cohen, and Nelson as its authors.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 5

  1. Laufberger, 1937, Sur la cristallisation de la ferritine., Soc Chim Biol, 19, 1575
  2. Trousseau, 1865, Glycosurie; diabete sucre., Clinique medicale de l'Hotel-Dieu de Paris, 2, 663
  3. Blaud, 1832, Sur les maladies chlorotiques et sur un mode de traitement specifique dans ces affections., Rev Med Franc Etrang, 45, 357
  4. Faber, 1909, Achylia gastrica mit Anamie., Medizinishe Klinik, 5, 1310
  5. Heilmeyer, 1961, Congenital transferrin deficiency in a seven-year old girl., German Medical Monthly, 86, 1745

Cited by

Sorted by citations

Related

Authors
Andrews, N. C.
Affiliations
Duke University (US)
Corresponding author
Andrews, Nancy C.
ORCID
Andrews, Nancy C.
Venue
Blood
Publisher
American Society of Hematology
Published
2008-07-15
Volume
112
Issue
2
Pages
219-230
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2007-12-077388
PMC
PMC2442739
OpenAlex
W2074040887
Cited by
623
References
213
Citations by year
2026: 12 · 2025: 17 · 2024: 19 · 2023: 9 · 2022: 31 · 2021: 29 · 2020: 31 · 2019: 25 · 2018: 27 · 2017: 28 · 2016: 36 · 2015: 27 · 2014: 31 · 2013: 52 · 2012: 49
FWCI
8.67
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL051057)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK066373, R01DK053813, DK06637, DK053813)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
Keywords
hereditary hemochromatosis, HFE gene, iron metabolism, iron overload
MeSH terms
Iron Deficiencies, Homeostasis, Humans, Iron, Iron Metabolism Disorders, Antimicrobial Cationic Peptides, Hepcidins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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