Hepcidin

Last updated
HAMP
Protein HAMP PDB 1m4f.png
Available structures
PDB Human UniProt search: PDBe RCSB
Identifiers
Aliases HAMP , HEPC, HFE2B, LEAP1, PLTR, hepcidin antimicrobial peptide
External IDs OMIM: 606464 HomoloGene: 81623 GeneCards: HAMP
Orthologs
SpeciesHumanMouse
Entrez

57817

n/a

Ensembl

ENSG00000105697

n/a

UniProt

P81172

n/a

RefSeq (mRNA)

NM_021175

n/a

RefSeq (protein)

NP_066998

n/a

Location (UCSC) Chr 19: 35.28 – 35.29 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human
Hepcidin
PDB 1m4f EBI.jpg
Solution structure of hepcidin-25. [3]
Identifiers
SymbolHepcidin
Pfam PF06446
InterPro IPR010500
SCOP2 1m4f / SCOPe / SUPFAM
OPM superfamily 153
OPM protein 1m4e
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
hepcidin antimicrobial peptide
Identifiers
Symbol HAMP
NCBI gene 57817
HGNC 15598
OMIM 606464
RefSeq NM_021175
UniProt P81172
Other data
Locus Chr. 19 q13.1
Search for
Structures Swiss-model
Domains InterPro

Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals. [4]

Contents

During conditions in which the hepcidin level is abnormally high, such as inflammation, serum iron falls due to iron trapping within macrophages and liver cells and decreased gut iron absorption. This typically leads to anemia due to an inadequate amount of serum iron being available for developing red blood cells. When the hepcidin level is abnormally low such as in hemochromatosis, iron overload occurs due to increased ferroportin mediated iron efflux from storage and increased gut iron absorption.

Structure

Hepcidin exists as a preprohormone (84 amino acids), prohormone (60 amino acids), and hormone (25 amino acids). Twenty- and 22-amino acid metabolites of hepcidin also exist in the urine. Deletion of 5 N-terminal amino acids results in loss of function. The conversion of prohepcidin to hepcidin is mediated by the prohormone convertase furin. [5] This conversion may be regulated by alpha-1 antitrypsin. [6]

Hepcidin is a tightly folded polypeptide with 32% beta sheet character and a hairpin structure stabilized by 4 disulfide bonds. The structure of hepcidin has been determined through solution NMR. [3] NMR studies showed a new model for hepcidin: at ambient temperatures, the protein interconverts between two conformations, which could be individually resolved by temperature variation. The solution structure of hepcidin was determined at 325 K and 253 K in supercooled water. X-ray analysis of a co-crystal with Fab revealed a structure similar to the high-temperature NMR structure. [7]

Function

Diagram showing how hepcidin controls ferroportin (FPN) levels which in turn control entry of iron into the circulation Schematic overview of the main elements considered to participate in mammalian iron metabolism.jpg
Diagram showing how hepcidin controls ferroportin (FPN) levels which in turn control entry of iron into the circulation

Hepcidin is a regulator of iron metabolism. It inhibits iron transport by binding to the iron export channel ferroportin which is located in the basolateral plasma membrane of gut enterocytes and the plasma membrane of reticuloendothelial cells (macrophages), ultimately resulting in ferroportin breakdown in lysosomes. [8] [9] It has been shown that hepcidin is able to bind to the central cavity of ferroportin, thus occluding iron export from the cell. This suggests that hepcidin is able to regulate iron export independently of ferroportin endocytosis and ubiquitination, and is thus quickly inducible and reversible. [10] [11] In enterocytes, this prevents iron transmission into the hepatic portal system, thereby reducing dietary iron absorption. In macrophages, ferroportin inhibition causes iron sequestration within the cell. Increased hepcidin activity is partially responsible for reduced iron availability seen in anemia of chronic inflammation, such as kidney failure and that may explain why patient with end stage renal failure may not respond to oral iron replacement. [12]

Any one of several mutations in hepcidin result in juvenile hemochromatosis. The majority of juvenile hemochromatosis cases are due to mutations in hemojuvelin. [13] Mutations in TMPRSS6 can cause anemia through dysregulation of Hepcidin. [14]

Hepcidin has strong antimicrobial activity against Escherichia coli strain ML35P and Neisseria cinerea and weaker antimicrobial activity against Staphylococcus epidermidis , Staphylococcus aureus and Streptococcus agalactiae . It is also active against the fungus Candida albicans , but has no activity against Pseudomonas aeruginosa . [15]

Regulation

Hepcidin synthesis and secretion by the liver is controlled by iron stores, inflammation (hepcidin is an acute phase reactant), hypoxia, and erythropoiesis. [16] In response to large iron stores, production of Bone Morphogenic Protein (BMP) is induced, which binds to receptors on hepatocytes and induces hepcidin expression via the SMAD pathway. [17] Inflammation causes an increase in hepcidin production by releasing the signaling molecule interleukin-6 (IL-6), which binds to a receptor and upregulates the HAMP gene via the JAK/STAT pathway. [17] Hypoxia negatively regulates hepcidin production via production the transcription factor hypoxia-inducible factor (HIF), which under normal conditions is degraded by von Hippel-Lindau (VHL) and prolyl dehydrogenase (PHD). When hypoxia is induced, however, PHD is inactivated, thus allowing HIF to down-regulate hepcidin production. Erythropoiesis decreases hepcidin production via production of erythropoietin (EPO), which has been shown to down-regulate hepcidin production. [17]

Severe anaemia is associated with low hepcidin levels, even in the presence of inflammation. [18] Erythroferrone, produced in erythroblasts, has been identified as inhibiting hepcidin and so providing more iron for hemoglobin synthesis in situations such as stress erythropoiesis. [19] [20]

Vitamin D has been shown to decrease hepcidin, in cell models looking at transcription and when given in large doses to human volunteers. Optimal function of hepcidin may be predicated upon the adequate presence of vitamin D in the blood. [21]

History

The peptide was initially reported in January 1998 by Valore,E., Park,C. and Ganz,T. in the SWISS-PROT database as entry P81172 and named hepcidin [15] after it was observed that it was produced in the liver ("hep-") and appeared to have bactericidal properties ("-cide" for "killing"). Detailed descriptions were published in 2000-2001. [22] [23] [24] Although it is primarily synthesized in the liver, smaller amounts are synthesised in other tissues such as fat cells. [25]

Hepcidin was first discovered in human urine and serum [26] Soon after this discovery, researchers discovered that hepcidin production in mice increases in conditions of iron overload as well as in inflammation. Genetically modified mice engineered to overexpress hepcidin died shortly after birth with severe iron deficiency, again suggesting a central and not redundant role in iron regulation. The first evidence that linked hepcidin to the clinical condition known as the anemia of inflammation came from the lab of Nancy Andrews in Boston when researchers looked at tissue from two patients with liver tumors with a severe microcytic anemia that did not respond to iron supplements. The tumor tissue appeared to be overproducing hepcidin, and contained large quantities of hepcidin mRNA. Removing the tumors surgically cured the anemia.[ citation needed ]

Hepcidin (blue) bound to the central cavity of ferroportin (FPN) Ferroportin with Hepcidin bound.jpg
Hepcidin (blue) bound to the central cavity of ferroportin (FPN)

Taken together, these discoveries suggested that hepcidin regulates the absorption of iron into the body.

Clinical significance

There are many diseases where failure to adequately absorb iron contributes to iron deficiency and iron deficiency anaemia. The treatment will depend on the hepcidin levels that are present, as oral treatment will be unlikely to be effective if hepcidin is blocking enteral absorption, in which cases parenteral iron treatment would be appropriate. Studies have found that measuring hepcidin would be of benefit to establish optimal treatment, [27] although as this is not widely available, C-reactive protein (CRP) is used as a surrogate marker.

β-thalassemia, one of the most common congenital anemias, arises from partial or complete lack of β-globin synthesis. Excessive iron absorption is one of the main features of β-thalassemia and can lead to severe morbidity and mortality. The serial analyses of β-thalassemic mice indicate hemoglobin levels decreases over time, while the concentration of iron in the liver, spleen, and kidneys markedly increases. The overload of iron is associated with low levels of hepcidin. Patients with β-thalassemia also have low hepcidin levels. The observations led researchers to hypothesize that more iron is absorbed in β-thalassemia than is required for erythropoiesis. Increasing expression of hepcidin in β-thalassemic mice limits iron overload, and also decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia. [28] Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis and splenomegaly, and an increase in total hemoglobin levels. From these data, researchers suggested that therapeutics to increase hepcidin levels or act as hepcidin agonists could help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders. [29] In later studies in mice, [30] erythroferrone has been suggested to be the factor that is responsible for the hepcidin suppression. Correcting hepcidin and iron levels in these mice did not improve their anemia. [30]

Related Research Articles

<span class="mw-page-title-main">Hereditary haemochromatosis</span> Medical condition

Hereditary haemochromatosis type 1 is a genetic disorder characterized by excessive intestinal absorption of dietary iron, resulting in a pathological increase in total body iron stores. Humans, like most animals, have no means to excrete excess iron, with the exception of menstruation which, for the average woman, results in a loss of 3.2 mg of iron.

<span class="mw-page-title-main">Thalassemia</span> Medical condition

Thalassemias are inherited blood disorders that result in abnormal hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe. Often there is mild to severe anemia as thalassemia can affect the production of red blood cells and also affect how long the red blood cells live. Symptoms of anemia include feeling tired and having pale skin. Other symptoms of thalassemia include bone problems, an enlarged spleen, yellowish skin, pulmonary hypertension, and dark urine. Slow growth may occur in children. Symptoms and presentations of thalassemia can change over time.

<span class="mw-page-title-main">Ferritin</span> Iron-carrying protein

Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary intracellular iron-storage protein in both prokaryotes and eukaryotes, keeping iron in a soluble and non-toxic form. In humans, it acts as a buffer against iron deficiency and iron overload.

<span class="mw-page-title-main">Transferrin</span> Mammalian protein found in Homo sapiens

Transferrins are glycoproteins found in vertebrates which bind and consequently mediate the transport of iron (Fe) through blood plasma. They are produced in the liver and contain binding sites for two Fe3+ ions. Human transferrin is encoded by the TF gene and produced as a 76 kDa glycoprotein.

<span class="mw-page-title-main">Iron overload</span> Human disease

Iron overload or haemochromatosis indicates increased total accumulation of iron in the body from any cause and resulting organ damage. The most important causes are hereditary haemochromatosis, a genetic disorder, and transfusional iron overload, which can result from repeated blood transfusions.

<span class="mw-page-title-main">Iron-deficiency anemia</span> Medical condition

Iron-deficiency anemia is anemia caused by a lack of iron. Anemia is defined as a decrease in the number of red blood cells or the amount of hemoglobin in the blood. When onset is slow, symptoms are often vague such as feeling tired, weak, short of breath, or having decreased ability to exercise. Anemia that comes on quickly often has more severe symptoms, including confusion, feeling like one is going to pass out or increased thirst. Anemia is typically significant before a person becomes noticeably pale. Children with iron deficiency anemia may have problems with growth and development. There may be additional symptoms depending on the underlying cause.

<span class="mw-page-title-main">Erythropoiesis</span> Process which produces red blood cells

Erythropoiesis is the process which produces red blood cells (erythrocytes), which is the development from erythropoietic stem cell to mature red blood cell.

<span class="mw-page-title-main">Microcytic anemia</span> Medical condition

Microcytic anaemia is any of several types of anemia characterized by smaller than normal red blood cells. The normal mean corpuscular volume is approximately 80–100 fL. When the MCV is <80 fL, the red cells are described as microcytic and when >100 fL, macrocytic. The MCV is the average red blood cell size.

Anemia of chronic disease (ACD) or anemia of chronic inflammation is a form of anemia seen in chronic infection, chronic immune activation, and malignancy. These conditions all produce elevation of interleukin-6, which stimulates hepcidin production and release from the liver. Hepcidin production and release shuts down ferroportin, a protein that controls export of iron from the gut and from iron storing cells. As a consequence, circulating iron levels are reduced. Other mechanisms may also play a role, such as reduced erythropoiesis. It is also known as anemia of inflammation, or anemia of inflammatory response.

<span class="mw-page-title-main">Human iron metabolism</span> Iron metabolism in the body

Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease. Hematologists have been especially interested in systemic iron metabolism, because iron is essential for red blood cells, where most of the human body's iron is contained. Understanding iron metabolism is also important for understanding diseases of iron overload, such as hereditary hemochromatosis, and iron deficiency, such as iron-deficiency anemia.

<span class="mw-page-title-main">Ferroportin</span> Protein

Ferroportin-1, also known as solute carrier family 40 member 1 (SLC40A1) or iron-regulated transporter 1 (IREG1), is a protein that in humans is encoded by the SLC40A1 gene. Ferroportin is a transmembrane protein that transports iron from the inside of a cell to the outside of the cell. Ferroportin is the only known iron exporter.

<span class="mw-page-title-main">African iron overload</span> Iron overload disorder caused by consumption of home-brewed beer

African iron overload is an iron overload disorder first observed among people of African descent in Southern Africa and Central Africa. It is now recognized to actually be two disorders with different causes, possibly compounding each other:

<span class="mw-page-title-main">HFE (gene)</span> Mammalian protein found in Homo sapiens

Human homeostatic iron regulator protein, also known as the HFE protein, is a transmembrane protein that in humans is encoded by the HFE gene. The HFE gene is located on short arm of chromosome 6 at location 6p22.2

<span class="mw-page-title-main">Beta thalassemia</span> Thalassemia characterized by the reduced or absent synthesis of the beta globin chains of hemoglobin

Beta thalassemias are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to clinically asymptomatic individuals. Global annual incidence is estimated at one in 100,000. Beta thalassemias occur due to malfunctions in the hemoglobin subunit beta or HBB. The severity of the disease depends on the nature of the mutation.

<span class="mw-page-title-main">Iron in biology</span> Use of Iron by organisms

Iron is an important biological element. It is used in both the ubiquitous iron-sulfur proteins and in vertebrates it is used in hemoglobin which is essential for blood and oxygen transport.

Juvenile hemochromatosis, also known as hemochromatosis type 2, is a rare form of hereditary hemochromatosis, which emerges in young individuals, typically between 15 and 30 years of age, but occasionally later. It is characterized by an inability to control how much iron is absorbed by the body, in turn leading to iron overload, where excess iron accumulates in many areas of the body and causes damage to the places it accumulates.

<span class="mw-page-title-main">Hemosiderosis</span> Iron metabolism disease

Hemosiderosis is a form of iron overload disorder resulting in the accumulation of hemosiderin.

Haemochromatosis type 3 is a type of iron overload disorder associated with deficiencies in transferrin receptor 2. It exhibits an autosomal recessive inheritance pattern. The first confirmed case was diagnosed in 1865 by French doctor Trousseau. Later in 1889, the German doctor von Recklinghausen indicated that the liver contains iron, and due to bleeding being considered to be the cause, he called the pigment "Haemochromatosis." In 1935, English doctor Sheldon's groundbreaking book titled, Haemochromatosis, reviewed 311 patient case reports and presented the idea that haemochromatosis was a congenital metabolic disorder. Hereditary haemochromatosis is a congenital disorder which affects the regulation of iron metabolism thus causing increased gut absorption of iron and a gradual build-up of pathologic iron deposits in the liver and other internal organs, joint capsules and the skin. The iron overload could potentially cause serious disease from the age of 40–50 years. In the final stages of the disease, the major symptoms include liver cirrhosis, diabetes and bronze-colored skin. There are four types of hereditary hemochromatosis which are classified depending on the age of onset and other factors such as genetic cause and mode of inheritance.

<span class="mw-page-title-main">Erythroferrone</span>

Erythroferrone is a protein hormone encoded in humans by the ERFE gene. Erythroferrone is produced by erythroblasts, inhibits the production of hepcidin in the liver, and so increases the amount of iron available for hemoglobin synthesis. Skeletal muscle secreted ERFE has been shown to maintain systemic metabolic homeostasis.

Hemochromatosis type 4 is a hereditary iron overload disorder that affects ferroportin, an iron transport protein needed to export iron from cells into circulation. Although the disease is rare, it is found throughout the world and affects people from various ethnic groups. While the majority of individuals with type 4 hemochromatosis have a relatively mild form of the disease, some affected individuals have a more severe form. As the disease progresses, iron may accumulate in the tissues of affected individuals over time, potentially resulting in organ damage.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000105697 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 1 2 PDB: 1M4F ​; Hunter HN, Fulton DB, Ganz T, Vogel HJ (October 2002). "The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis". The Journal of Biological Chemistry. 277 (40): 37597–37603. doi: 10.1074/jbc.M205305200 . PMID   12138110.
  4. ↑ Ganz T (August 2003). "Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation". Blood. 102 (3): 783–788. doi: 10.1182/blood-2003-03-0672 . PMID   12663437.
  5. ↑ Valore EV, Ganz T (2008). "Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin". Blood Cells, Molecules & Diseases. 40 (1): 132–138. doi:10.1016/j.bcmd.2007.07.009. PMC   2211381 . PMID   17905609.
  6. ↑ Pandur E, Nagy J, Poór VS, Sarnyai A, Huszár A, Miseta A, Sipos K (April 2009). "Alpha-1 antitrypsin binds preprohepcidin intracellularly and prohepcidin in the serum". The FEBS Journal. 276 (7): 2012–2021. doi: 10.1111/j.1742-4658.2009.06937.x . PMID   19292870. S2CID   28974553.
  7. ↑ PDB: 3H0T ​; Jordan JB, Poppe L, Haniu M, Arvedson T, Syed R, Li V, et al. (September 2009). "Hepcidin revisited, disulfide connectivity, dynamics, and structure". The Journal of Biological Chemistry. 284 (36): 24155–24167. doi: 10.1074/jbc.M109.017764 . PMC   2782009 . PMID   19553669.
  8. ↑ Rossi E (August 2005). "Hepcidin--the iron regulatory hormone". The Clinical Biochemist. Reviews. 26 (3): 47–49. PMC   1240030 . PMID   16450011.
  9. ↑ Gulec S, Anderson GJ, Collins JF (August 2014). "Mechanistic and regulatory aspects of intestinal iron absorption". American Journal of Physiology. Gastrointestinal and Liver Physiology. 307 (4): G397–G409. doi:10.1152/ajpgi.00348.2013. PMC   4137115 . PMID   24994858.
  10. ↑ Aschemeyer S, Qiao B, Stefanova D, Valore EV, Sek AC, Ruwe TA, et al. (February 2018). "Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin". Blood. 131 (8): 899–910. doi:10.1182/blood-2017-05-786590. PMC   5824336 . PMID   29237594.
  11. ↑ Nemeth E, Ganz T (June 2021). "Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis". International Journal of Molecular Sciences. 22 (12): 6493. doi: 10.3390/ijms22126493 . PMC   8235187 . PMID   34204327.
  12. ↑ Ashby DR, Gale DP, Busbridge M, Murphy KG, Duncan ND, Cairns TD, et al. (May 2009). "Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease". Kidney International. 75 (9): 976–981. doi: 10.1038/ki.2009.21 . PMID   19212416.
  13. ↑ Core AB, Canali S, Babitt JL (2014). "Hemojuvelin and bone morphogenetic protein (BMP) signaling in iron homeostasis". Frontiers in Pharmacology. 5: 104. doi: 10.3389/fphar.2014.00104 . PMC   4026703 . PMID   24860505.
  14. ↑ Iron-Deficiency Anemia: New Insights for the Healthcare Professional: 2011 Edition. Scholarly Media LLC. Dec 2012. ISBN   978-1-4649-8960-5.
  15. 1 2 "Hepcidin P81172". UniProt. December 15, 1998.
  16. ↑ Zhao N, Zhang AS, Enns CA (June 2013). "Iron regulation by hepcidin". The Journal of Clinical Investigation. 123 (6): 2337–2343. doi:10.1172/JCI67225. PMC   3668831 . PMID   23722909.
  17. 1 2 3 Rishi G, Wallace DF, Subramaniam VN (March 2015). "Hepcidin: regulation of the master iron regulator". Bioscience Reports. 35 (3). doi:10.1042/bsr20150014. PMC   4438303 . PMID   26182354.
  18. ↑ Abuga KM, Muriuki JM, Uyoga SM, Mwai K, Makale J, Mogire RM, et al. (July 2022). "Hepcidin regulation in Kenyan children with severe malaria and non-typhoidal Salmonella bacteremia". Haematologica. 107 (7): 1589–1598. doi:10.3324/haematol.2021.279316. PMC   9244826 . PMID   34498446. S2CID   237454351.
  19. ↑ Koury MJ. "Erythroferrone: A Missing Link in Iron Regulation". The Hematologist. American Society of Hematology. Archived from the original on 28 January 2019. Retrieved 26 August 2015.
  20. ↑ Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T (July 2014). "Identification of erythroferrone as an erythroid regulator of iron metabolism". Nature Genetics. 46 (7): 678–684. doi:10.1038/ng.2996. PMC   4104984 . PMID   24880340.
  21. ↑ Bacchetta J, Zaritsky JJ, Sea JL, Chun RF, Lisse TS, Zavala K, et al. (March 2014). "Suppression of iron-regulatory hepcidin by vitamin D". Journal of the American Society of Nephrology. 25 (3): 564–572. doi:10.1681/ASN.2013040355. PMC   3935584 . PMID   24204002.
  22. ↑ Krause A, Neitz S, Mägert HJ, Schulz A, Forssmann WG, Schulz-Knappe P, Adermann K (September 2000). "LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity". FEBS Letters. 480 (2–3): 147–150. doi: 10.1016/S0014-5793(00)01920-7 . PMID   11034317. S2CID   9161764.
  23. ↑ Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, Loréal O (March 2001). "A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload". The Journal of Biological Chemistry. 276 (11): 7811–7819. doi: 10.1074/jbc.M008923200 . PMID   11113132.
  24. ↑ Park CH, Valore EV, Waring AJ, Ganz T (March 2001). "Hepcidin, a urinary antimicrobial peptide synthesized in the liver". The Journal of Biological Chemistry. 276 (11): 7806–7810. doi: 10.1074/jbc.M008922200 . PMID   11113131.
  25. ↑ Bekri S, Gual P, Anty R, Luciani N, Dahman M, Ramesh B, et al. (September 2006). "Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH". Gastroenterology. 131 (3): 788–796. doi: 10.1053/j.gastro.2006.07.007 . PMID   16952548.
  26. ↑ Kemna EH, Tjalsma H, Willems HL, Swinkels DW (January 2008). "Hepcidin: from discovery to differential diagnosis". Haematologica. 93 (1): 90–97. doi: 10.3324/haematol.11705 . hdl: 2066/70062 . PMID   18166790.
  27. ↑ Bregman DB, Morris D, Koch TA, He A, Goodnough LT (February 2013). "Hepcidin levels predict nonresponsiveness to oral iron therapy in patients with iron deficiency anemia". American Journal of Hematology. 88 (2): 97–101. doi: 10.1002/ajh.23354 . PMID   23335357. S2CID   42656065.
  28. ↑ Gardenghi S, Ramos P, Marongiu MF, Melchiori L, Breda L, Guy E, et al. (December 2010). "Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice". The Journal of Clinical Investigation. 120 (12): 4466–4477. doi:10.1172/JCI41717. PMC   2993583 . PMID   21099112.
  29. ↑ Kroot JJ, Tjalsma H, Fleming RE, Swinkels DW (December 2011). "Hepcidin in human iron disorders: diagnostic implications". Clinical Chemistry. 57 (12): 1650–1669. doi: 10.1373/clinchem.2009.140053 . hdl: 2066/97956 . PMID   21989113.
  30. 1 2 Moura IC, Hermine O (October 2015). "Erythroferrone: the missing link in β-thalassemia?". Blood. 126 (17): 1974–1975. doi: 10.1182/blood-2015-09-665596 . PMID   26494918.

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