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Year : 2019  |  Volume : 32  |  Issue : 3  |  Page : 818-822

Role of hepcidin in iron metabolism and pathophysiology of different types of anemia

1 Department of Pediatrics, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Pediatrics, Tala Centeral Hospital, Tala, Menoufia, Egypt

Date of Submission12-Jan-2018
Date of Acceptance06-Mar-2018
Date of Web Publication17-Oct-2019

Correspondence Address:
Nehal K El Shennawy
Department of Pediatrics, Tala Centeral Hospital, Tala, Menoufia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mmj.mmj_20_18

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The study aimed to demonstrate the critical role of hepcidin in regulation of iron metabolism in various types of anemia.
Data sources
Medline databases (PubMed, Science Direct, Medscape) and all materials available in the Internet from 2007 to 2017 were searched.
Study selection
The initial search presented 38 articles, of which 11 met the inclusion criteria. The articles studied the relation between hepcidin and iron homeostasis in various types of anemia.
Data extraction
If the studies did not fulfill the inclusion criteria, they were excluded. Study quality assessment included whether ethical approval was gained, eligibility criteria specified, appropriate controls included, adequate information provided, and assessment measures defined.
Data synthesis
Comparisons were made by structured review with the results tabulated.
In total, 11 potentially relevant publications were included. All were human studies. The studies indicated that hepcidin levels were markedly reduced in cases with thalassemia intermedia, which resulted in iron overload. However, hepcidin levels were increased in cases with anemia of chronic disease, which resulted in decreased bioavailability of iron.
Hepcidin has key role in iron regulation and pathogenesis of various types of anemia including anemia of chronic disease and anemia with iron overload. Hepcidin may provide promising therapeutic target in cases with dysregulated iron metabolism.

Keywords: anemia, erythropoiesis, hepcidin, iron homeostasis, therapy

How to cite this article:
El Gendy FM, EL-Hawy MA, El Shennawy NK. Role of hepcidin in iron metabolism and pathophysiology of different types of anemia. Menoufia Med J 2019;32:818-22

How to cite this URL:
El Gendy FM, EL-Hawy MA, El Shennawy NK. Role of hepcidin in iron metabolism and pathophysiology of different types of anemia. Menoufia Med J [serial online] 2019 [cited 2020 May 27];32:818-22. Available from: http://www.mmj.eg.net/text.asp?2019/32/3/818/268815

  Introduction Top

Iron is a key element for virtually all living organisms. Iron is required for synthesis of heme, included in hemoglobin, which is vital for the delivery of oxygen to tissues. Iron is also important constituent of iron-containing proteins that are involved in DNA synthesis and repair, energy production, and cell proliferation [1]. On the contrary, iron overload has harmful effect on cells by iron-generated free radicals and peroxidation of lipid membranes [2].

Regulation of iron metabolism is important for erythropoiesis and normal cellular functions. As there is no certain physiological mechanism of excretion of iron from the body apart from loss from skin and mucosal epithelial cells and menstrual blood loss, iron absorption from diet and utilization from internal iron stores are the major determinants of extracellular iron balance [3].

Iron homeostasis is primarily regulated by the hepcidin/ferroportin axis. Hepcidin is synthesized by liver and considered as the main negative iron regulator. Hepcidin induces ferroportin internalization and degradation in target cells, mostly macrophages and enterocytes, resulting in iron sequestration in macrophages and decreased iron absorption from intestine [4].

Hepcidin synthesis is tightly controlled by both iron concentrations and erythropoietic needs for iron. Hepcidin is induced by increased iron concentration and suppressed by anemia and hypoxia [5].

Hepcidin expression is also induced by inflammation through the action of proinflammatory cytokines such as interleukin-6 (IL-6), which is explained as part of the host defense mechanism to fight infection and tumors by reducing iron availability [6]. In chronic kidney disease (CKD), both inflammation and impaired renal clearance of hepcidin seem to contribute to increased hepcidin levels [7].

Studies focused on hepcidin and its role in iron metabolism may provide novel lines of treatment in disorders of iron deficiency or overload. Therapies that enhance hepcidin activity may be successful in patients with β-thalassemia and disorders with iron overload, whereas therapies that inhibit hepcidin secretion may improve cases with iron-restricted anemia [8].

Disturbed iron balance and iron toxicity are important challenges in patients with β-thalassemia, which must be adequately treated to avoid fatal complications. Therefore, development of new strategies to reduce excessive iron absorption and tissue iron overload is one of the primary goals in management for patients with β-thalassemia [9].

The aim of this study was to demonstrate the essential role of hepcidin in regulation of iron metabolism in various types of anemia.

  Materials and Methods Top

Search strategy

We reviewed papers on hepcidin and iron metabolism from PubMed, Medscape, and Science Direct and also materials available in the Internet. We used hepcidin/hepcidin and iron metabolism/hepcidin, and anemia as searching terms. The search was performed in the electronic databases from 2007 to 2017.

Study selection

All the studies were independently assessed for inclusion. They were included if they fulfilled the following criteria:

Inclusion criteria of the published studies:

  1. Published in English language
  2. Published in peer-reviewed journals
  3. Focused on hepcidin and iron metabolism.

Data extraction

If the studies did not fulfill the aforementioned criteria, they were excluded such as studies not focused on hepcidin role in iron metabolism and pathophysiology of anemia. Moreover, letters, comments, editorials, and news were excluded.

The analyzed publications were evaluated according to evidence-based medicine (EBM) criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM in addition to the Evidence Pyramid.

U.S. preventive services task force classification is as follows:

  1. Level I: Evidence obtained from at least one properly designed randomized controlled trial
  2. Level II-1: Evidence obtained from well-designed controlled trials without randomization
  3. Level II-2: Evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group
  4. Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence
  5. Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

Quality assessment

The quality of all the studies was assessed. Important factors included study design, attainment of ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures.

Data synthesis

A structured systematic review was performed with the results tabulated.

  Results Top

Study selection and characteristics

In total, 38 potentially relevant publications were identified, and 27 articles were excluded as they did not meet our inclusion criteria. A total of 11 studies were included in the review as they were deemed eligible by fulfilling the inclusion criteria. All 11 studies were human studies. The studies investigated the role of hepcidin in iron metabolism. The studies were analyzed with respect to the study design using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM.

Hepcidin role in pathogenesis of iron overload in patients with β-thalassemia and sickle cell anemia

The role of hepcidin in the pathogenesis of iron overload in patients with β-thalassemia and sickle cell disease (SCD) was investigated in three human studies [Table 1] [10],[11],[12] (cross-sectional, which comes in level II-2). Another study [10] assessed urinary hepcidin levels in patients with β-thalassemia intermedia and β-thalassemia major and reported that urinary hepcidin levels were markedly reduced in thalassemia intermedia. In contrast, hepcidin levels were increased in thalassemia major, which was explained by repeated blood transfusions that reduced erythropoietic activity.
Table 1: Hepcidin role in iron homeostasis and pathogenesis of various types of anemia

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In another study [11], hepcidin levels were investigated in serum samples of patients with β-thalassemia major and SCD and healthy controls. The study demonstrated that serum hepcidin level in patients with thalassemia and sickle cell was higher than in controls.

Another cross-sectional study revealed that serum hepcidin levels were significantly increased in patients with thalassemia as compared with control group [12].

Hepcidin role in pathogenesis of anemia of chronic disease

Nine human studies with level II-2 EBM [Table 1] [12],[13],[14],[15],[16],[17],[18],[19],[20] investigated hepcidin role in pathogenesis of anemia of chronic disease (ACD). One of them [12] showed that hepcidin levels were significantly increased in patients with rheumatoid arthritis and chronic liver disease as compared with control group.

Another cross-sectional study [13] investigated serum hepcidin levels by solid-phase enzyme-linked immunosorbent assay in cases with rheumatoid arthritis and iron-deficiency anemia and in healthy adults. The study demonstrated that serum hepcidin levels were significantly higher in patients with rheumatoid arthritis with anemia compared with healthy controls and those with iron-deficiency anemia.

Hepcidin role in anemia in patients with Crohn's disease was investigated in cross-sectional study [14], in which both serum and urinary hepcidin levels in addition to markers of inflammation were evaluated. The study showed that hepcidin levels were increased. Furthermore, a positive correlation between serum hepcidin and IL-6 levels and a negative correlation between serum hepcidin concentrations and hemoglobin levels were demonstrated.

Another cross-sectional study [15] investigated the role of hepcidin in ACD (cases with chronic infection and chronic inflammation including autoimmune disease and malignancy were included in the study) and reported that both serum hepcidin and IL-6 levels were elevated in ACD.

Two cross-sectional and cohort studies [16],[17] respectively evaluated the role of hepcidin in anemia of CKD and found that hepcidin levels were increased in patients as compared with healthy controls possibly owing to increased inflammation and decreased hepcidin clearance. Moreover, hepcidin levels increased with CKD progression.

Role of hepcidin in tumor-related ACD was evaluated in three cross-sectional studies [18],[19],[20], which reported that hepcidin was up-regulated by IL-6. Elevated hepcidin levels resulted in iron restriction and signs of anemia of chronic inflammation.

  Discussion Top

Hepcidin is the main regulator of iron homeostasis. Abnormalities in hepcidin production results in various iron metabolism disorders. Low hepcidin level is the cause of iron overload in iron-loading anemias, such as thalassemia. High hepcidin level is associated with inflammation, chronic renal disease, and iron-refractory iron-deficiency anemia [8].

Patients who have β-thalassemia major require repeated blood transfusions to maintain life and chelation therapy to prevent iron overload. However, those affected by β-thalassemia intermedia do not require chronic blood transfusions but finally develop iron overload owing to ineffective erythropoiesis, which in turn leads to suppression of hepcidin production [21].

SCD is characterized by chronic hemolytic anemia, increased erythropoietic activity, and chronic inflammatory state [22]. There is no evidence of increased iron load in nontransfused patients with SCD, and iron deficiency may occur possibly because of intravascular hemolysis [23].

Hepcidin levels in SCD show marked variability owing to different contrasting stimuli in such condition such as chronic hemolytic anemia and increased erythropoiesis (hepcidin suppression), chronic inflammation, and transfusional iron overload (hepcidin overproduction) [24].

ACD is the most prevalent type of anemia among hospitalized patients. ACD is characterized by decreased iron and increased ferritin and the presence of iron in bone marrow macrophages, indicating impaired iron bioavailability [25].

The pathogenesis of ACD is explained mainly by the essential role of hepcidin. Inflammation induces hepcidin synthesis by IL-6. Hepcidin in turn acts by inhibiting intestional iron absorption and iron release from macrophages by degradation of ferroportin [20].

Hepcidin implication in CKD anemia has been observed in both dialysis and nondialysis patients with CKD: both CKD-related inflammation and lower hepcidin clearance tend to increase hepcidin concentration in these patients [17].

As CKD progresses, the kidneys of most patients eventually fail to synthesize sufficient erythropoietin to maintain adequate erythropoiesis. In patients with systemic inflammation and high hepcidin concentrations, even when iron stores are adequate, iron cannot be released from stores [26].

Considering the master role of the hepcidin–ferroportin axis in iron regulation and in the pathogenesis of different types of anemia, it is not striking that this system has been targeted for new drug development. Hepcidin agonists could be used as a line of treatment in cases with iron overload such as β-thalassemia whereas hepcidin antagonists may be used in treatment of ACD [27].

  Conclusion Top

This review highlights the master role of hepcidin in the regulation of iron metabolism and pathogenesis of various types of anemia.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Ganz T, Nemeth E. Regulation of iron acquisition and iron distribution in mammals. Biochim Biophys Acta 2006; 1763:690–699.  Back to cited text no. 1
Ramm GA, Ruddell RG. Hepatotoxicity of iron overload: mechanisms of iron-induced hepatic fibrogenesis. Semin Liver Dis 2005; 25:433–449.  Back to cited text no. 2
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Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004; 306:2090–2093.  Back to cited text no. 4
Ganz T. Hepcidin and iron regulation, 10 years later. Blood 2011; 117:4425–4433.  Back to cited text no. 5
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Kautz L, Nemeth E. Molecular liaisons between erythropoiesis and iron metabolism. Blood 2014; 124:479–482.  Back to cited text no. 7
Nemeth E, Ganz T. The role of hepcidin in iron metabolism. Acta Haematol 2009; 122:78–86.  Back to cited text no. 8
Gardenghi S, Ramos P, Marongiu MF, Melchiori L, Breda L, Guy E, et al. Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice. J Clin Invest 2010; 120:4466–4477.  Back to cited text no. 9
Origa R, Galanello R, Ganz T, Giagu N, Maccioni L, Faa G, et al. Liver iron concentrations and urinary hepcidin in beta-thalassemia. Haematologica 2007; 92:583–588.  Back to cited text no. 10
Rashidy FH, Abo Elghara HM, Kamal Eldinb SM, Tahac MZ. Hepcidin and iron regulation in chronic hemolytic anemia. Menoufia Med J 2015; 28:463–470.  Back to cited text no. 11
Osman KS, Aly LH, Abd El-Hamid WM, Tawfik MR. Role of hepcidin in the pathogenesis of anemia not caused by iron deficiency. J Clin Cell Immunol 2014; 5:1000193.  Back to cited text no. 12
Demirag MD, Haznedaroglu S, Sancak B, Konca C, Gulbahar O, Ozturk MA, et al. Circulating hepcidin in the crossroads of anemia and inflammation associated with rheumatoid arthritis. Intern Med 2009; 48:421–426.  Back to cited text no. 13
Basseri RJ, Nemeth E, Vassilaki ME, Basseri B, Enayati P, Shaye O, et al. Hepcidin is a key mediator of anemia of inflammation in Crohn's disease. J Crohns Colitis 2013; 7:e286–e291.  Back to cited text no. 14
Suega K. Role of hepcidin in mechanism of anemia chronic disease patients. Bali Med J 2014; 3:89–96.  Back to cited text no. 15
Goyal H, Mohanty S, Sharma M, Rani A. Study of anemia in nondialysis dependent chronic kidney disease with special reference to serum hepcidin. Indian J Nephrol 2017; 27:44–50.  Back to cited text no. 16
Mercadal L, Metzger M, Haymann JP, Thervet E, Boffa JJ, Flamant M, et al. The relation of hepcidin to iron disorders, inflammation and hemoglobin in chronic kidney disease. PLoS One 2014; 9:e99781.  Back to cited text no. 17
Sharma S, Nemeth E, Chen Y, Goodnough J, Huston A, Roodman GD, et al. Involvement of hepcidin in the anemia of multiple myeloma. Clin Cancer Res 2008; 14:3262–3267.  Back to cited text no. 18
Hohaus S, Massini G, Giachelia M, Vannata B, Bozzoli V, Cuccaro A, et al. Anemia in Hodgkin's lymphoma: the role of interleukin-6 and hepcidin. J Clin Oncol 2010; 28:2538–2543.  Back to cited text no. 19
Shu T, Jing C, Lv Z, Xie Y, Xu J, Wu J. Hepcidin in tumor-related iron deficiency anemia and tumor-related anemia of chronic disease: pathogenic mechanisms and diagnosis. Eur J Haematol 2015; 94:67–73.  Back to cited text no. 20
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Stuart MJ, Nagel RL. Sickle-cell disease. Lancet 2004; 364:1343–1360.  Back to cited text no. 22
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