DOI: 10.1182/blood-2002-04-1260. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease

Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease

10.1182/blood-2002-04-1260

Crossref journal-article

American Society of Hematology

Blood (234)

Abstract

The anemia of chronic disease is a prevalent, poorly understood condition that afflicts patients with a wide variety of diseases, including infections, malignancies, and rheumatologic disorders. It is characterized by a blunted erythropoietin response by erythroid precursors, decreased red blood cell survival, and a defect in iron absorption and macrophage iron retention, which interrupts iron delivery to erythroid precursor cells. We noted that patients with large hepatic adenomas had severe iron refractory anemia similar to that observed in anemia of chronic disease. This anemia resolved spontaneously after adenoma resection or liver transplantation. We investigated the role of the adenomas in the pathogenesis of the anemia and found that they produce inappropriately high levels of hepcidin mRNA. Hepcidin is a peptide hormone that has been implicated in controlling the release of iron from cells. We conclude that hepcidin plays a major, causative role in the anemia observed in our subgroup of patients with hepatic adenomas, and we speculate that it is important in the pathogenesis of the anemia of chronic disease in general.

Bibliography

Weinstein, D. A., Roy, C. N., Fleming, M. D., Loda, M. F., Wolfsdorf, J. I., & Andrews, N. C. (2002). Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood, 100(10), 3776â3781.

Authors 6

David A. Weinstein (first)
Cindy N. Roy (additional)
Mark D. Fleming (additional)
Massimo F. Loda (additional)
Joseph I. Wolfsdorf (additional)
Nancy C. Andrews (additional)

References 26 Referenced 463

10.1053/beha.1999.0065 / Baillieres Best Pract Res Clin Haematol. / The anaemia of infection. by Means (2000)
{'key': '2019111822315035100_B2', 'first-page': '61', 'article-title': 'The anemia of chronic disease.', 'volume': '20', 'author': 'Lee', 'year': '1983', 'journal-title': 'Semin Hematol.'} / Semin Hematol. / The anemia of chronic disease. by Lee (1983)
10.1152/ajplegacy.1967.213.1.43 / Am J Physiol. / Effect of endotoxin on iron absorption. by Cortell (1967)
10.1016/0024-3205(92)90279-X / Life Sci. / Iron depletion: a defense against intracellular infection and neoplasia. by Weinberg (1992)
10.1086/515549 / Clin Infect Dis. / Iron, infections and anemia of inflammation. by Jurado (1997)
10.1096/fasebj.3.5.2784116 / FASEB J. / Cachectin/tumor necrosis factor-α alters red blood cell kinetics and induces anemia in vivo. by Moldawer (1989)
10.1046/j.1523-1755.1999.055Suppl.69012.x / Kidney Int Suppl. / Iron and anemia of chronic disease. by Weiss (1999)
10.1002/stem.5530130105 / Stem Cells. / Pathogenesis of the anemia of chronic disease: a cytokine-mediated anemia. by Means (1995)
10.1073/pnas.161296298 / Proc Natl Acad Sci U S A. / Hepcidin: a putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease. by Fleming (2001)
10.1074/jbc.M008922200 / J Biol Chem. / Hepcidin, a urinary antimicrobial peptide synthesized in the liver. by Park (2001)
10.1016/S0014-5793(00)01920-7 / FEBS Lett. / LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. by Krause (2000)
10.1074/jbc.M008923200 / J Biol Chem. / A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. by Pigeon (2001)
10.1073/pnas.072632499 / Proc Natl Acad Sci U S A. / Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. by Nicolas (2002)
10.1073/pnas.151179498 / Proc Natl Acad Sci U S A. / Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. by Nicolas (2001)
{'key': '2019111822315035100_B15', 'first-page': '1521', 'article-title': 'Glycogen storage diseases.', 'volume-title': 'The Metabolic and Molecular Bases of Inherited Disease.', 'author': 'Chen', 'year': '2001', 'edition': '8th ed.'} / The Metabolic and Molecular Bases of Inherited Disease. / Glycogen storage diseases. by Chen (2001)
10.7326/0003-4819-120-3-199402010-00008 / Ann Intern Med. / Glycogen storage disease in adults. by Talente (1994)
{'key': '2019111822315035100_B17'}
{'key': '2019111822315035100_B18', 'first-page': '104', 'article-title': 'Tissue iron stores.', 'volume': '1', 'author': 'Torrance', 'year': '1980', 'journal-title': 'Methods in Hematology.'} / Methods in Hematology. / Tissue iron stores. by Torrance (1980)
10.1126/science.7667636 / Science. / CDC25 phosphatases as potential human oncogenes. by Galaktionov (1995)
10.1038/35042073 / Nat Rev Genet. / Iron homeostasis: insights from genetics and animal models. by Andrews (2000)
10.1038/5979 / Nat Genet. / Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. by Vulpe (1999)
10.1038/ng0897-383 / Nat Genet. / Microcytic anemia mice have a mutation in Nramp2, a candidate iron transporter gene. by Fleming (1997)
10.1182/blood.V96.3.1113 / Blood. / The molecular defect in hypotransferrinemic mice. by Trenor (2000)
10.1056/NEJM199912233412607 / N Engl J Med. / Medical progress: disorders of iron metabolism. by Andrews (1999)
10.1046/j.1432-1033.2002.02881.x / Eur J Biochem. / Bass hepcidin is a novel antimicrobial peptide induced by bacterial challenge. by Shike (2002)
{'key': '2019111822315035100_B26', 'first-page': '7', 'article-title': 'Advances in the anemia of chronic disease.', 'volume': '70', 'author': 'Means', 'year': '1999', 'journal-title': 'Int J Hematol.'} / Int J Hematol. / Advances in the anemia of chronic disease. by Means (1999)

Dates

Type	When
Created	22 years, 10 months ago (Oct. 30, 2002, 9:43 a.m.)
Deposited	5 years, 9 months ago (Nov. 18, 2019, 5:32 p.m.)
Indexed	1 month, 1 week ago (July 26, 2025, 4:48 a.m.)
Issued	22 years, 9 months ago (Nov. 15, 2002)
Published	22 years, 9 months ago (Nov. 15, 2002)
Published Print	22 years, 9 months ago (Nov. 15, 2002)

Funders 0

None

BibTeX

@article{Weinstein_2002, title={Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease}, volume={100}, ISSN={0006-4971}, url={http://dx.doi.org/10.1182/blood-2002-04-1260}, DOI={10.1182/blood-2002-04-1260}, number={10}, journal={Blood}, publisher={American Society of Hematology}, author={Weinstein, David A. and Roy, Cindy N. and Fleming, Mark D. and Loda, Massimo F. and Wolfsdorf, Joseph I. and Andrews, Nancy C.}, year={2002}, month=nov, pages={3776–3781} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        7,
        26
      ]
    ],
    "date-time": "2025-07-26T08:48:27Z",
    "timestamp": 1753519707392
  },
  "reference-count": 26,
  "publisher": "American Society of Hematology",
  "issue": "10",
  "content-domain": {
    "domain": [
      "ashpublications.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        2002,
        11,
        15
      ]
    ]
  },
  "abstract": "<jats:p>The anemia of chronic disease is a prevalent, poorly understood condition that afflicts patients with a wide variety of diseases, including infections, malignancies, and rheumatologic disorders. It is characterized by a blunted erythropoietin response by erythroid precursors, decreased red blood cell survival, and a defect in iron absorption and macrophage iron retention, which interrupts iron delivery to erythroid precursor cells. We noted that patients with large hepatic adenomas had severe iron refractory anemia similar to that observed in anemia of chronic disease. This anemia resolved spontaneously after adenoma resection or liver transplantation. We investigated the role of the adenomas in the pathogenesis of the anemia and found that they produce inappropriately high levels of hepcidin mRNA. Hepcidin is a peptide hormone that has been implicated in controlling the release of iron from cells. We conclude that hepcidin plays a major, causative role in the anemia observed in our subgroup of patients with hepatic adenomas, and we speculate that it is important in the pathogenesis of the anemia of chronic disease in general.</jats:p>",
  "DOI": "10.1182/blood-2002-04-1260",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2002,
        10,
        30
      ]
    ],
    "date-time": "2002-10-30T14:43:16Z",
    "timestamp": 1035988996000
  },
  "page": "3776-3781",
  "update-policy": "http://dx.doi.org/10.1182/blood.2019cm0000",
  "source": "Crossref",
  "is-referenced-by-count": 463,
  "title": "Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease",
  "prefix": "10.1182",
  "volume": "100",
  "author": [
    {
      "given": "David A.",
      "family": "Weinstein",
      "sequence": "first",
      "affiliation": [
        {
          "name": "From Children's Hospital, Harvard Medical School; Brigham and Women's Hospital and Harvard Medical School; Dana-Farber Cancer Institute; and Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School; all of Boston, MA."
        }
      ]
    },
    {
      "given": "Cindy N.",
      "family": "Roy",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "From Children's Hospital, Harvard Medical School; Brigham and Women's Hospital and Harvard Medical School; Dana-Farber Cancer Institute; and Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School; all of Boston, MA."
        }
      ]
    },
    {
      "given": "Mark D.",
      "family": "Fleming",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "From Children's Hospital, Harvard Medical School; Brigham and Women's Hospital and Harvard Medical School; Dana-Farber Cancer Institute; and Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School; all of Boston, MA."
        }
      ]
    },
    {
      "given": "Massimo F.",
      "family": "Loda",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "From Children's Hospital, Harvard Medical School; Brigham and Women's Hospital and Harvard Medical School; Dana-Farber Cancer Institute; and Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School; all of Boston, MA."
        }
      ]
    },
    {
      "given": "Joseph I.",
      "family": "Wolfsdorf",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "From Children's Hospital, Harvard Medical School; Brigham and Women's Hospital and Harvard Medical School; Dana-Farber Cancer Institute; and Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School; all of Boston, MA."
        }
      ]
    },
    {
      "given": "Nancy C.",
      "family": "Andrews",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "From Children's Hospital, Harvard Medical School; Brigham and Women's Hospital and Harvard Medical School; Dana-Farber Cancer Institute; and Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School; all of Boston, MA."
        }
      ]
    }
  ],
  "member": "234",
  "reference": [
    {
      "key": "2019111822315035100_B1",
      "doi-asserted-by": "crossref",
      "first-page": "151",
      "DOI": "10.1053/beha.1999.0065",
      "article-title": "The anaemia of infection.",
      "volume": "13",
      "author": "Means",
      "year": "2000",
      "journal-title": "Baillieres Best Pract Res Clin Haematol."
    },
    {
      "key": "2019111822315035100_B2",
      "first-page": "61",
      "article-title": "The anemia of chronic disease.",
      "volume": "20",
      "author": "Lee",
      "year": "1983",
      "journal-title": "Semin Hematol."
    },
    {
      "key": "2019111822315035100_B3",
      "doi-asserted-by": "crossref",
      "first-page": "43",
      "DOI": "10.1152/ajplegacy.1967.213.1.43",
      "article-title": "Effect of endotoxin on iron absorption.",
      "volume": "213",
      "author": "Cortell",
      "year": "1967",
      "journal-title": "Am J Physiol."
    },
    {
      "key": "2019111822315035100_B4",
      "doi-asserted-by": "crossref",
      "first-page": "1289",
      "DOI": "10.1016/0024-3205(92)90279-X",
      "article-title": "Iron depletion: a defense against intracellular infection and neoplasia.",
      "volume": "50",
      "author": "Weinberg",
      "year": "1992",
      "journal-title": "Life Sci."
    },
    {
      "key": "2019111822315035100_B5",
      "doi-asserted-by": "crossref",
      "first-page": "888",
      "DOI": "10.1086/515549",
      "article-title": "Iron, infections and anemia of inflammation.",
      "volume": "25",
      "author": "Jurado",
      "year": "1997",
      "journal-title": "Clin Infect Dis."
    },
    {
      "key": "2019111822315035100_B6",
      "doi-asserted-by": "crossref",
      "first-page": "1637",
      "DOI": "10.1096/fasebj.3.5.2784116",
      "article-title": "Cachectin/tumor necrosis factor-\u03b1 alters red blood cell kinetics and induces anemia in vivo.",
      "volume": "3",
      "author": "Moldawer",
      "year": "1989",
      "journal-title": "FASEB J."
    },
    {
      "key": "2019111822315035100_B7",
      "doi-asserted-by": "crossref",
      "first-page": "S12",
      "DOI": "10.1046/j.1523-1755.1999.055Suppl.69012.x",
      "article-title": "Iron and anemia of chronic disease.",
      "volume": "69",
      "author": "Weiss",
      "year": "1999",
      "journal-title": "Kidney Int Suppl."
    },
    {
      "key": "2019111822315035100_B8",
      "doi-asserted-by": "crossref",
      "first-page": "32",
      "DOI": "10.1002/stem.5530130105",
      "article-title": "Pathogenesis of the anemia of chronic disease: a cytokine-mediated anemia.",
      "volume": "13",
      "author": "Means",
      "year": "1995",
      "journal-title": "Stem Cells."
    },
    {
      "key": "2019111822315035100_B9",
      "doi-asserted-by": "crossref",
      "first-page": "8160",
      "DOI": "10.1073/pnas.161296298",
      "article-title": "Hepcidin: a putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease.",
      "volume": "98",
      "author": "Fleming",
      "year": "2001",
      "journal-title": "Proc Natl Acad Sci U S A."
    },
    {
      "key": "2019111822315035100_B10",
      "doi-asserted-by": "crossref",
      "first-page": "7806",
      "DOI": "10.1074/jbc.M008922200",
      "article-title": "Hepcidin, a urinary antimicrobial peptide synthesized in the liver.",
      "volume": "276",
      "author": "Park",
      "year": "2001",
      "journal-title": "J Biol Chem."
    },
    {
      "key": "2019111822315035100_B11",
      "doi-asserted-by": "crossref",
      "first-page": "147",
      "DOI": "10.1016/S0014-5793(00)01920-7",
      "article-title": "LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity.",
      "volume": "480",
      "author": "Krause",
      "year": "2000",
      "journal-title": "FEBS Lett."
    },
    {
      "key": "2019111822315035100_B12",
      "doi-asserted-by": "crossref",
      "first-page": "7811",
      "DOI": "10.1074/jbc.M008923200",
      "article-title": "A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload.",
      "volume": "276",
      "author": "Pigeon",
      "year": "2001",
      "journal-title": "J Biol Chem."
    },
    {
      "key": "2019111822315035100_B13",
      "doi-asserted-by": "crossref",
      "first-page": "4596",
      "DOI": "10.1073/pnas.072632499",
      "article-title": "Severe iron deficiency anemia in transgenic mice expressing liver hepcidin.",
      "volume": "99",
      "author": "Nicolas",
      "year": "2002",
      "journal-title": "Proc Natl Acad Sci U S A."
    },
    {
      "key": "2019111822315035100_B14",
      "doi-asserted-by": "crossref",
      "first-page": "8780",
      "DOI": "10.1073/pnas.151179498",
      "article-title": "Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice.",
      "volume": "98",
      "author": "Nicolas",
      "year": "2001",
      "journal-title": "Proc Natl Acad Sci U S A."
    },
    {
      "key": "2019111822315035100_B15",
      "first-page": "1521",
      "article-title": "Glycogen storage diseases.",
      "volume-title": "The Metabolic and Molecular Bases of Inherited Disease.",
      "author": "Chen",
      "year": "2001",
      "edition": "8th ed."
    },
    {
      "key": "2019111822315035100_B16",
      "doi-asserted-by": "crossref",
      "first-page": "218",
      "DOI": "10.7326/0003-4819-120-3-199402010-00008",
      "article-title": "Glycogen storage disease in adults.",
      "volume": "120",
      "author": "Talente",
      "year": "1994",
      "journal-title": "Ann Intern Med."
    },
    {
      "key": "2019111822315035100_B17"
    },
    {
      "key": "2019111822315035100_B18",
      "first-page": "104",
      "article-title": "Tissue iron stores.",
      "volume": "1",
      "author": "Torrance",
      "year": "1980",
      "journal-title": "Methods in Hematology."
    },
    {
      "key": "2019111822315035100_B19",
      "doi-asserted-by": "crossref",
      "first-page": "1575",
      "DOI": "10.1126/science.7667636",
      "article-title": "CDC25 phosphatases as potential human oncogenes.",
      "volume": "269",
      "author": "Galaktionov",
      "year": "1995",
      "journal-title": "Science."
    },
    {
      "key": "2019111822315035100_B20",
      "doi-asserted-by": "crossref",
      "first-page": "208",
      "DOI": "10.1038/35042073",
      "article-title": "Iron homeostasis: insights from genetics and animal models.",
      "volume": "1",
      "author": "Andrews",
      "year": "2000",
      "journal-title": "Nat Rev Genet."
    },
    {
      "key": "2019111822315035100_B21",
      "doi-asserted-by": "crossref",
      "first-page": "195",
      "DOI": "10.1038/5979",
      "article-title": "Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse.",
      "volume": "21",
      "author": "Vulpe",
      "year": "1999",
      "journal-title": "Nat Genet."
    },
    {
      "key": "2019111822315035100_B22",
      "doi-asserted-by": "crossref",
      "first-page": "383",
      "DOI": "10.1038/ng0897-383",
      "article-title": "Microcytic anemia mice have a mutation in Nramp2, a candidate iron transporter gene.",
      "volume": "16",
      "author": "Fleming",
      "year": "1997",
      "journal-title": "Nat Genet."
    },
    {
      "key": "2019111822315035100_B23",
      "doi-asserted-by": "crossref",
      "first-page": "1113",
      "DOI": "10.1182/blood.V96.3.1113",
      "article-title": "The molecular defect in hypotransferrinemic mice.",
      "volume": "96",
      "author": "Trenor",
      "year": "2000",
      "journal-title": "Blood."
    },
    {
      "key": "2019111822315035100_B24",
      "doi-asserted-by": "crossref",
      "first-page": "1986",
      "DOI": "10.1056/NEJM199912233412607",
      "article-title": "Medical progress: disorders of iron metabolism.",
      "volume": "341",
      "author": "Andrews",
      "year": "1999",
      "journal-title": "N Engl J Med."
    },
    {
      "key": "2019111822315035100_B25",
      "doi-asserted-by": "crossref",
      "first-page": "2232",
      "DOI": "10.1046/j.1432-1033.2002.02881.x",
      "article-title": "Bass hepcidin is a novel antimicrobial peptide induced by bacterial challenge.",
      "volume": "269",
      "author": "Shike",
      "year": "2002",
      "journal-title": "Eur J Biochem."
    },
    {
      "key": "2019111822315035100_B26",
      "first-page": "7",
      "article-title": "Advances in the anemia of chronic disease.",
      "volume": "70",
      "author": "Means",
      "year": "1999",
      "journal-title": "Int J Hematol."
    }
  ],
  "container-title": "Blood",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "http://ashpublications.org/blood/article-pdf/100/10/3776/1252915/h82202003776.pdf",
      "content-type": "application/pdf",
      "content-version": "vor",
      "intended-application": "syndication"
    },
    {
      "URL": "http://ashpublications.org/blood/article-pdf/100/10/3776/1252915/h82202003776.pdf",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2019,
        11,
        18
      ]
    ],
    "date-time": "2019-11-18T22:32:03Z",
    "timestamp": 1574116323000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://ashpublications.org/blood/article/100/10/3776/106328/Inappropriate-expression-of-hepcidin-is-associated"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2002,
        11,
        15
      ]
    ]
  },
  "references-count": 26,
  "journal-issue": {
    "issue": "10",
    "published-print": {
      "date-parts": [
        [
          2002,
          11,
          15
        ]
      ]
    }
  },
  "URL": "http://dx.doi.org/10.1182/blood-2002-04-1260",
  "relation": {},
  "ISSN": [
    "1528-0020",
    "0006-4971"
  ],
  "subject": [],
  "published": {
    "date-parts": [
      [
        2002,
        11,
        15
      ]
    ]
  }
}