Blood Res 2019; 54(1): 10-16  https://doi.org/10.5045/br.2019.54.1.10
Molecular perspective of iron uptake, related diseases, and treatments
Negin Shokrgozar, and Habib Allah Golafshan*

Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.

Correspondence to: Correspondence to Habib Allah Golafshan, Ph.D. Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Zand St., Shiraz, Iran. golafshansums@yahoo.com
Received: August 22, 2018; Revised: October 1, 2018; Accepted: October 1, 2018; Published online: March 21, 2019.
© The Korean Journal of Hematology. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Iron deficiency anemia and anemia of chronic disorders are the most common types of anemia. Disorders of iron metabolism lead to different clinical scenarios such as iron deficiency anemia, iron overload, iron overload with cataract and neurocognitive disorders. Regulation of iron in the body is a complex process and different regulatory proteins are involved in iron absorption and release from macrophages into hematopoietic tissues. Mutation in these regulatory genes is the most important cause of iron refractory iron deficiency anemia (IRIDA). This review provides a glance into the iron regulation process, diseases related to iron metabolism, and appropriate treatments at the molecular level.

Keywords: Iron metabolism, Iron deficiency anemia, Iron regulation
INTRODUCTION

Iron is a vital metal not only in hemoglobin synthesis but also in the structure of enzymes, cell growth and proliferation, the immune system, and electron transfer in body chemical interactions [1]. One of the most important causes of iron deficiency is gastrointestinal bleeding and menstruation in women [2]. One milliliter of packed RBCs contains one milligram of iron [3]. Diagnosis of iron deficiency anemia specifically in men is merely the beginning, as gastrointestinal study by endoscopy and colonoscopy must be performed for polyps, ulcers, and cancer [4]. Treatment of anemia resulting from bleeding requires sufficient iron resources for hematopoietic tissues.

Erythroferrone

After bleeding, suppression of hepcidin gene expression causes an increase in gastrointestinal iron absorption and release of iron from cellular storage structures through the ferroportin channel [56]. In response to erythropoietin (EPO), hematopoietic tissue secretes erythroferrone (ERFE). Erythroferrone can rapidly suppress hepcidin gene expression for iron absorption and release of iron from the reticuloendothelial system (Fig. 1) [7]. Disorders of erythroferrone gene expression cause delayed increases in hemoglobin during bleeding and increased erythroferrone expression may lead to iron overload [5]. It is supposed that one of the reasons for iron overload in thalassemia syndromes is the increase in erythroferrone gene expression [8].

Hepcidin and inflammatory disorders

Hepcidin gene expression increases in response to increased iron storage, infections, and inflammation [910]. Hepcidin destroys ferroportin channels (Fpn-1) by connecting to them and thereby prevents gastrointestinal iron absorption and release of iron from macrophages [1112].

Despite the increase in ferritin levels in anemias of inflammatory and rheumatic disorders, IRIDA is observed [13]. Increased IL-6 in inflammatory diseases leads to hepcidin gene expression that eventually prevents iron absorption and release of iron toward erythropoietic tissues (Fig. 2) [1415].

Iron metabolism

Systemic regulation of iron metabolism is presented in Fig. 3. In Fig. 3A, the absorption process through gastrointestinal cells in the duodenum is shown. Iron is imported through DMT1 (Divalent Metal Transporter) and exported through ferroportin [16]. Fig. 3B shows the iron transport to NRBCs (Nucleated red blood cells). Iron is transported by transferrin and upon binding to transferrin receptor (TFR), iron is released to the cytoplasm [1718]. The released iron is delivered to mitochondria by mitoferrin and the “Kiss and Run” process occurs, in which iron in endosomal vacuoles is released to mitochondria by direct contact with the mitochondrial membrane [19].

Fig. 3C shows the hepatocyte that controls iron absorption and release of iron from macrophages by regulating hepcidin secretion (Fig. 3D). Complexes of hemochromatosis proteins (HFE), hemojuvelin (HJV), matriptase-2, transferrin receptor 2 (TFR2), and BMP-6 (Bone morphogenetic protein) receptor on hepatocytes lead to hepcidin gene expression by activating SMAD and ERK-MAPK signaling pathways [202122232425]. Loss or gain of function mutations in these regulatory proteins leads to iron overload by suppressing hepcidin gene expression [26]. Reduction of hepcidin causes iron absorption from ferroportin [27]. GDF15 (growth differentiation factor 15), TWSG1 (twisted gastrulation 1), ERFE, and Matriptase 2 reduce hepcidin synthesis and increase iron absorption in the gastrointestinal system and release of iron from macrophages [28].

Role of microRNAs

Various microRNAs have a role in the expression of iron regulatory proteins. Increased or decreased microRNAs expression interferes in the translation process, causing an increase or decrease in translation and eventually altering the expression of certain proteins [29]. MicroRNAs are composed of about 21 nucleotides and lead to destruction and prevention of mRNA translation by hybridizing to them [30]. For instance, microRNA-130a expression is increased in iron deficiency and targets the mRNA of BMP receptor and causes reduction of hepcidin expression. In another example, reduction of microRNA-199a expression in response to hypoxia causes an increase of HIF-1α and HIF-2α expression that is subsequently accompanied by an increase in EPO synthesis [3132]. HIF factors (hypoxia inducible factors) are transcription factors for EPO gene expression [33].

Iron overload

The most common disorders of iron metabolism are iron overload (type I to IV), iron overload with cataracts, iron deficiency anemia, anemia of chronic disorders, and iron refractory iron deficiency anemia (IRIDA) [343536]. Mutations of hemochromatosis gene (HFE) or classic hemochromatosis appear in women after menopause and in 40–50-year-old men and are accompanied by iron overloads in heart, liver, and exocrine glands [3738]. Bronze skin, diabetes, and liver cirrhosis are complications of hemochromatosis that can lead to hepatocellular carcinoma [39]. Type II hemochromatosis, or juvenile type, is caused by mutations in the hepcidin gene (HAMP) or hemojuvelin (HJV) [4041].

Transferrin saturation ≥55% and ferritin levels ≥200 µg/L are the most important screen tests for hemochromatosis [42]. A certain type of hemochromatosis is accompanied by ferritin more than 1,000 µg/L and cataracts. In this situation, mutation in iron regulatory protein (IRP) prevents its binding to the iron response element of ferritin light chain mRNA so that suppression of ferritin synthesis does not occur [43].

Iron deficiency anemia

Iron deficiency anemia leads to reduction of serum iron, serum ferritin (SFt), and an increase in TIBC in progressive situations [44]. Since ferritin is an acute phase protein and increases in inflammatory and infectious processes, some physicians request CRP and ESR tests along with ferritin. The ferritin test is more reliable in negative CRP and ESR samples [45]. The first parameters of iron deficiency anemia are a reduction of CHR (reticulocyte hemoglobin) and an increase in RDW. Microcytic-hypochromia, an increase in RDW, and hypochromic pencil-shaped RBCs are observed in iron deficiency anemia when the anemia is in a progressive state and iron storage is depleted. In this situation, hemoglobin is below 10 (ferritin<10) and RBC count is <5 million per µL (Table 1) [46]. Iron deficiency anemia rapidly responds to iron therapy and an increase in reticulocyte count is typically observed after 5 days [47]. By beginning treatment, RBCs become dimorphic and populations of hypochromic and normochromic RBCs can be observed in blood smears and after some time, they are converted to normocytic-normochromic (Table 2) [48].

Within 3 weeks of treatment, hemoglobin typically increases to about 2 grams and when the amount of ferritin increases to 50, iron consumption can be stopped [49]. For measuring ferritin, it is not necessary to stop iron consumption and it can be measured any time of the day, whereas measurement of serum iron is suggested in the morning after fasting and daily alterations in serum iron (SFe) has been reported to be 30%. SFe is normal or increased in the morning and physiologically decreases in the evening. TIBC measurement is not highly affected by daily alterations. For measuring TIBC and SFe, iron consumption should be stopped for 2 or 3 days [50]. Any microcytic-hypochromic morphology that does not respond to iron therapy is classified into thalassemia syndromes, hemoglobinopathies, or IRIDA [51].

Iron refractory iron deficiency anemia

Iron refractory iron deficiency anemia can be inherited or acquired. A mutation in the TMPRSS6 gene that leads to disorders of matriptase-2 (MT2) synthesis is the most important inherited cause [5253]. In normal situations, MT2 inhibits the HJV protein's connection with the BMP-6 receptor and causes reduction of hepcidin gene expression [54], which is further accompanied by an increase in gastrointestinal iron absorption [55]. A mutation in MT2 causes an increase in hepcidin expression and destruction of ferroportin and thus iron absorption does not occur in this condition [56].

For children who do not respond to iron therapy despite the confirmation of iron deficiency, an anti-TTG test for diagnosing celiac disease, H. pylori infection, and autoimmune gastritis must be performed [57].

Pregnancy and iron status

In every pregnancy, according to the increased mass of red blood cells, needs of the fetus, and growth of placenta and delivery, the requirement of iron is increased [58]. Ferritin values less than 50 cause iron deficiency anemia in pregnant women, unless it is compensated with daily absorption of 3.5 mg of iron, and daily consumption of 20–30 mg of iron in a biocompatible form is sufficient for compensation [59].

Renal failure and iron deficiency

In renal failure patients who take EPO for treatment of anemia, the response to treatment can be predicted through transferrin saturation, free transferrin receptor in plasma (TFR), and ferritin levels [606162]. Transferrin saturation less than 20% with TFR >8 mg/L and ferritin <50 µg/L is a sign of iron deficiency and requires intravenous iron administration to increase ferritin levels to more than 100 µg/L for a sufficient response in EPO in patients not receiving dialysis, while sufficient ferritin levels for a response in EPO in dialysis patients are more than 200 µg/L [6364].

Inhibitor compounds of iron absorption

Increasing use of proton pump inhibitors (PPIs) for treating ulcers and gastrectomy is an important cause of iron deficiency anemia. Gastric acid secretion is critical for iron absorption [65]. Tannic acid (tannate), phosphate, and phytate compounds prevent oral iron absorption [6667].

Megaloblastic anemia in accompaniment with iron deficiency anemia

Megaloblastic anemia exhibits characteristics of increased ovalomacrocytes (MCV>100), as well as increased RDW, MCH, and normal MCHC [68]. Megaloblastic anemia can be differentiated from cold agglutination by normal MCHC because in cold agglutination, MCV, MCH, and MCHC are increased [69].

Presence of hypersegmented neutrophils with ovalomacrocytes confirms the diagnosis of megaloblastic anemia [70]. If megaloblastic anemia is accompanied by iron deficiency anemia, it will cover macrocytic morphology and hypersegmented neutrophils will typically be observed in peripheral blood [71]. With vitamin B12 or folic acid treatment, microcytic-hypochromic morphology associated with iron deficiency anemia is observed [72].

Treatments

There are different drugs and methods in order to ameliorate the disorders which relate to iron metabolism. In iron deficiency anemia, oral iron is the first-line treatment, but in some conditions it is ineffective or harmful such as in inflammatory diseases and heavy bleeding. In these conditions, intravenous (IV) administration of iron is suggested and usually safe. Ferrous sulfate, gluconate, and fumarate are the most common oral iron formulations [7374]. In patients with non-dialysis-dependent chronic kidney disease and iron deficiency anemia, ferric citrate is effective and can correct anemia [75].

In hemochromatosis, venesection or phlebotomy, iron chelators and erythrocytapheresis are used for treatment but phlebotomy is the most acceptable method. In this method, the initial blood loss causes a reduction in hemoglobin stores of iron which helps erythropoiesis. It removes about 200–250 mg of iron in each session [7677].

In iron refractory iron deficiency anemia, patients do not respond to oral iron treatment appropriately but partial correction of anemia has been seen in some patients after a long period of oral iron administration [78].

CONCLUSION

Different factors play a role in molecular regulation of iron that maintain iron homeostasis by regulating the entrance and exit of iron. Defects or mutations in each of these factors can cause different clinical conditions related to iron metabolism. These disorders may have genetic backgrounds or can be generated by underlying diseases such as infection and inflammation. The most common disorders are iron deficiency anemia and anemia of chronic diseases, which can be diagnosed through hematological indices and genetic tests. Some patients respond to the usual treatments and some are resistant, especially those with IRIDA. Further studies are required to diagnose and treat these disorders.

Figures
Fig. 1.

Erythroferrone is secreted from NRBCs in response to erythropoietin. ERFE causes increased iron absorption in the gastrointestinal system and release of iron from macrophages through ferroportin by decreasing hepcidin synthesis and provides sufficient iron for hematopoietic tissue (Kautz and Nemeth, 2014).

Abbreviations: EPO, erythropoietin; HIF, hypoxia inducible factor; pO2, pressure of oxygen.


Fig. 2.

Hepcidin mechanism. In inflammatory phenomena, increased hepcidin gene expression causes destruction of ferroportin. As a result, iron absorption and release of iron from macrophages is inhibited which eventually leads to anemia of chronic disorders.

Abbreviations: BMP6, bone morphogenetic protein 6; BMPR, bone morphogenetic protein receptor; HFE, human hemochromatosis protein; HJV, hemojuvelin; IL-6, interleukin 6; IL-6R, interleukin 6 receptor; Tfr2, transferrin receptor 2.


Fig. 3.

Systemic regulation of iron absorption through the gastrointestinal system and release of iron from macrophages.

Abbreviations: DcytB, duodenal cytochrome B; Dmt1, divalent metal transporter 1; Fpn1, ferroportin1; GDF15, growth differentiation factor 15; Gpi-Cp, glycosylphosphatidylinositol-linked ceruloplasmin; HAMP, hepcidin anti-microbial peptide; HCP1, heme carrier protein 1; Heph, hephaestin; HO1, heme oxygenase 1; IL-R, interleukin receptor; MT2, matriptase 2; Mtf, metal regulatory transcription factor; PCBP1, poly (rC) binding protein 1; sCp, soluble ceruloplasmin; Tf, transferrin; TfR1, transferrin receptor 1; TWSG1, twisted gastrulation protein homolog 1.


Tables
Table 1 Diagnostic tests of iron deficiency anemia are observed in iron storage depletion, iron limitation for erythropoiesis, and progressive iron deficiency anemia. Note that microcytic-hypochromia is only observed in progressive iron deficiency.

Table 2 Causes of iron deficiency anemia.

References
  1. Gurzau ES, Neagu C, Gurzau AE. Essential metals-case study on iron. Ecotoxicol Environ Saf 2003;56:190-200.
    Pubmed
  2. Goddard AF, James MW, McIntyre AS, Scott BB, British Society of Gastroenterology. Guidelines for the management of iron deficiency anaemia. Gut 2011;60:1309-1316.
    Pubmed
  3. Pandey R, Daloul R, Coyne DW. Iron treatment strategies in dialysis-dependent CKD. Semin Nephrol 2016;36:105-111.
    Pubmed
  4. Joosten E. Iron deficiency anemia in older adults: a review. Geriatr Gerontol Int 2018;18:373-379.
    Pubmed
  5. Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet 2014;46:678-684.
    Pubmed
  6. Kim A, Nemeth E. New insights into iron regulation and erythropoiesis. Curr Opin Hematol 2015;22:199-205.
    Pubmed
  7. Jiang X, Gao M, Chen Y, et al. EPO-dependent induction of erythroferrone drives hepcidin suppression and systematic iron absorption under phenylhydrazine-induced hemolytic anemia. Blood Cells Mol Dis 2016;58:45-51.
    Pubmed
  8. Kautz L, Jung G, Du X, et al. Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-thalassemia. Blood 2015;126:2031-2037.
    Pubmed
  9. Ganz T, Nemeth E. Iron homeostasis in host defence and inflammation. Nat Rev Immunol 2015;15:500-510.
    Pubmed
  10. Michels K, Nemeth E, Ganz T, Mehrad B. Hepcidin and host defense against infectious diseases. PLoS Pathog 2015;11:e1004998.
    Pubmed
  11. Arezes J, Nemeth E. Hepcidin and iron disorders: new biology and clinical approaches. Int J Lab Hematol 2015;37:92-98.
    Pubmed
  12. Wallace DF, McDonald CJ, Ostini L, Iser D, Tuckfield A, Subramaniam VN. The dynamics of hepcidin-ferroportin internalization and consequences of a novel ferroportin disease mutation. Am J Hematol 2017;92:1052-1061.
    Pubmed
  13. Nemeth E, Ganz T. Anemia of inflammation. Hematol Oncol Clin North Am 2014;28:671-681.
    Pubmed
  14. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004;113:1271-1276.
    Pubmed
  15. Ganz T. Hepcidin—a regulator of intestinal iron absorption and iron recycling by macrophages. Best Pract Res Clin Haematol 2005;18:171-182.
    Pubmed
  16. Zoller H, Theurl I, Koch R, Kaser A, Weiss G. Mechanisms of iron mediated regulation of the duodenal iron transporters divalent metal transporter 1 and ferroportin 1. Blood Cells Mol Dis 2002;29:488-497.
    Pubmed
  17. Gkouvatsos K, Papanikolaou G, Pantopoulos K. Regulation of iron transport and the role of transferrin. Biochim Biophys Acta 2012;1820:188-202.
    Pubmed
  18. Bali PK, Zak O, Aisen P. A new role for the transferrin receptor in the release of iron from transferrin. Biochemistry 1991;30:324-328.
    Pubmed
  19. Hamdi A, Roshan TM, Kahawita TM, Mason AB, Sheftel AD, Ponka P. Erythroid cell mitochondria receive endosomal iron by a “kiss-and-run” mechanism. Biochim Biophys Acta 2016;1863:2859-2867.
    Pubmed
  20. Andriopoulos B, Corradini E, Xia Y, et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 2009;41:482-487.
    Pubmed
  21. Babitt JL, Huang FW, Wrighting DM, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 2006;38:531-539.
    Pubmed
  22. Casanovas G, Mleczko-Sanecka K, Altamura S, Hentze MW, Muckenthaler MU. Bone morphogenetic protein (BMP)-responsive elements located in the proximal and distal hepcidin promoter are critical for its response to HJV/BMP/SMAD. J Mol Med (Berl) 2009;87:471-480.
    Pubmed
  23. Gao J, Chen J, Kramer M, Tsukamoto H, Zhang AS, Enns CA. Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab 2009;9:217-227.
    Pubmed
  24. Silvestri L, Pagani A, Nai A, De Domenico I, Kaplan J, Camaschella C. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab 2008;8:502-511.
    Pubmed
  25. Poli M, Luscieti S, Gandini V, et al. Transferrin receptor 2 and HFE regulate furin expression via mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/Erk) signaling. Implications for transferrin-dependent hepcidin regulation. Haematologica 2010;95:1832-1840.
    Pubmed
  26. Camaschella C. Iron and hepcidin: a story of recycling and balance. Hematol Am Soc Hematol Educ Program 2013;2013:1-8.
  27. Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta 2012;1823:1434-1443.
    Pubmed
  28. Makis A, Hatzimichael E, Papassotiriou I, Voskaridou E. 2017 Clinical trials update in new treatments of β-thalassemia. Am J Hematol 2016;91:1135-1145.
    Pubmed
  29. Davis M, Clarke S. Influence of microRNA on the maintenance of human iron metabolism. Nutrients 2013;5:2611-2628.
    Pubmed
  30. Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 2010;11:597-610.
    Pubmed
  31. Zumbrennen-Bullough KB, Wu Q, Core AB, et al. MicroRNA-130a is up-regulated in mouse liver by iron deficiency and targets the bone morphogenetic protein (BMP) receptor ALK2 to attenuate BMP signaling and hepcidin transcription. J Biol Chem 2014;289:23796-23808.
    Pubmed
  32. Joshi HP, Subramanian IV, Schnettler EK, et al. Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis. Proc Natl Acad Sci U S A 2014;111:5331-5336.
    Pubmed
  33. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 1995;270:1230-1237.
    Pubmed
  34. Andrews NC. Disorders of iron metabolism. N Engl J Med 1999;341:1986-1995.
    Pubmed
  35. Bowes O, Baxter K, Elsey T, Snead M, Cox T. Hereditary hyperferritinaemia cataract syndrome. Lancet 2014;383:1520.
    Pubmed
  36. De Falco L, Sanchez M, Silvestri L, et al. Iron refractory iron deficiency anemia. Haematologica 2013;98:845-853.
    Pubmed
  37. Moirand R, Adams PC, Bicheler V, Brissot P, Deugnier Y. Clinical features of genetic hemochromatosis in women compared with men. Ann Intern Med 1997;127:105-110.
    Pubmed
  38. Adams PC, Deugnier Y, Moirand R, Brissot P. The relationship between iron overload, clinical symptoms, and age in 410 patients with genetic hemochromatosis. Hepatology 1997;25:162-166.
    Pubmed
  39. Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011;54:328-343.
    Pubmed
  40. Roetto A, Papanikolaou G, Politou M, et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet 2003;33:21-22.
    Pubmed
  41. Camaschella C, Roetto A, De Gobbi M. Juvenile hemochromatosis. Semin Hematol 2002;39:242-248.
    Pubmed
  42. Adams PC, Chakrabarti S. Genotypic/phenotypic correlations in genetic hemochromatosis: evolution of diagnostic criteria. Gastroenterology 1998;114:319-323.
    Pubmed
  43. Girelli D, Corrocher R, Bisceglia L, et al. Molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome: a mutation in the iron-responsive element of ferritin L-subunit gene (the “Verona mutation”). Blood 1995;86:4050-4053.
    Pubmed
  44. Panagiotou JP, Douros K. Clinicolaboratory findings and treatment of iron-deficiency anemia in childhood. Pediatr Hematol Oncol 2004;21:521-534.
    Pubmed
  45. Liu CP, Liu ZY, Liu JP, Kang Y, Mao CS, Shang J. Diagnostic value of common inflammatory markers on fever of unknown origin. Jpn J Infect Dis 2016;69:378-383.
    Pubmed
  46. Wu AC, Lesperance L, Bernstein H. Screening for iron deficiency. Pediatr Rev 2002;23:171-178.
    Pubmed
  47. Parodi E, Giraudo MT, Ricceri F, Aurucci ML, Mazzone R, Ramenghi U. Absolute reticulocyte count and reticulocyte hemoglobin content as predictors of early response to exclusive oral iron in children with iron deficiency anemia. Anemia 2016;2016:7345835.
    Pubmed
  48. Constantino BT. The red cell histogram and the dimorphic red cell population. Lab Med 2011;42:300-308.
  49. Taylor S, Rampton D. Treatment of iron deficiency anemia: practical considerations. Pol Arch Med Wewn 2015;125:452-460.
    Pubmed
  50. Dale JC, Burritt MF, Zinsmeister AR. Diurnal variation of serum iron, iron-binding capacity, transferrin saturation, and ferritin levels. Am J Clin Pathol 2002;117:802-808.
    Pubmed
  51. Ganz T, Nemeth E. Iron metabolism: interactions with normal and disordered erythropoiesis. Cold Spring Harb Perspect Med 2012;2:a011668.
    Pubmed
  52. Wang CY, Meynard D, Lin HY. The role of TMPRSS6/matriptase-2 in iron regulation and anemia. Front Pharmacol 2014;5:114.
    Pubmed
  53. Jaspers A, Caers J, Le Gac G, Ferec C, Beguin Y, Fillet G. A novel mutation in the CUB sequence of matriptase-2 (TMPRSS6) is implicated in iron-resistant iron deficiency anaemia (IRIDA). Br J Haematol 2013;160:564-565.
    Pubmed
  54. Wahedi M, Wortham AM, Kleven MD, et al. Matriptase-2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway. J Biol Chem 2017;292:18354-18371.
    Pubmed
  55. Zhao N, Zhang AS, Enns CA. Iron regulation by hepcidin. J Clin Invest 2013;123:2337-2343.
    Pubmed
  56. McDonald CJ, Ostini L, Bennett N, et al. Functional analysis of matriptase-2 mutations and domains: insights into the molecular basis of iron-refractory iron deficiency anemia. Am J Physiol Cell Physiol 2015;308:C539-C547.
    Pubmed
  57. Azad SM, Kapoor R, Bannerji R, Ray J, Mitra M. Celiac disease masquerading as refractory iron deficiency anemia. Int J Contemp Pediatr 2017;4:672-673.
  58. Ofei KT. Nutrient intakes and vitamin supplements in early pregnancy in relation to maternal age and body mass index in Umeå. Umeå, Sweden: Umeå International School of Public Health.
  59. Schwartz WJ, Thurnau GR. Iron deficiency anemia in pregnancy. Clin Obstet Gynecol 1995;38:443-454.
    Pubmed
  60. Erslev AJ, Besarab A. Erythropoietin in the pathogenesis and treatment of the anemia of chronic renal failure. Kidney Int 1997;51:622-630.
    Pubmed
  61. Singh AK, Coyne DW, Shapiro W, Rizkala AR, DRIVE Study Group. Predictors of the response to treatment in anemic hemodialysis patients with high serum ferritin and low transferrin saturation. Kidney Int 2007;71:1163-1171.
    Pubmed
  62. Beguin Y, Loo M, R'Zik S, et al. Early prediction of response to recombinant human erythropoietin in patients with the anemia of renal failure by serum transferrin receptor and fibrinogen. Blood 1993;82:2010-2016.
    Pubmed
  63. Silverberg DS, Iaina A, Peer G, et al. Intravenous iron supplementation for the treatment of the anemia of moderate to severe chronic renal failure patients not receiving dialysis. Am J Kidney Dis 1996;27:234-238.
    Pubmed
  64. Van Wyck DB, Stivelman JC, Ruiz J, Kirlin LF, Katz MA, Ogden DA. Iron status in patients receiving erythropoietin for dialysis-associated anemia. Kidney Int 1989;35:712-716.
    Pubmed
  65. Sarzynski E, Puttarajappa C, Xie Y, Grover M, Laird-Fick H. Association between proton pump inhibitor use and anemia: a retrospective cohort study. Dig Dis Sci 2011;56:2349-2353.
    Pubmed
  66. Glahn RP, Wortley GM, South PK, Miller DD. Inhibition of iron uptake by phytic acid, tannic acid, and ZnCl2: studies using an in vitro digestion/Caco-2 cell model. J Agric Food Chem 2002;50:390-395.
    Pubmed
  67. Sandberg AS, Brune M, Carlsson NG, Hallberg L, Skoglund E, Rossander-Hulthén L. Inositol phosphates with different numbers of phosphate groups influence iron absorption in humans. Am J Clin Nutr 1999;70:240-246.
    Pubmed
  68. Croft RF, Streeter AM, O'Neill BJ. Red cell indices in megaloblastosis and iron deficiency. Pathology 1974;6:107-117.
    Pubmed
  69. Walters MC, Abelson HT. Interpretation of the complete blood count. Pediatr Clin North Am 1996;43:599-622.
    Pubmed
  70. Spivak JL. Masked megaloblastic anemia. Arch Intern Med 1982;142:2111-2114.
    Pubmed
  71. Remacha AF, Sardà MP, Canals C, et al. Combined cobalamin and iron deficiency anemia: a diagnostic approach using a model based on age and homocysteine assessment. Ann Hematol 2013;92:527-531.
    Pubmed
  72. Green R. In: Kaushansky K, Lichtman MA, Prchal JT. Williams hematology. 9th ed. New York, NY: McGraw-Hill; 2017. p. 596-641.
  73. Auerbach M, Adamson JW. How we diagnose and treat iron deficiency anemia. Am J Hematol 2016;91:31-38.
    Pubmed
  74. Schröder O, Mickisch O, Seidler U, et al. Intravenous iron sucrose versus oral iron supplementation for the treatment of iron deficiency anemia in patients with inflammatory bowel disease-a randomized, controlled, open-label, multicenter study. Am J Gastroenterol 2005;100:2503-2509.
    Pubmed
  75. Fishbane S, Block GA, Loram L, et al. Effects of ferric citrate in patients with nondialysis-dependent ckd and iron deficiency anemia. J Am Soc Nephrol 2017;28:1851-1858.
    Pubmed
  76. Ekanayake D, Roddick C, Powell LW. Recent advances in hemochromatosis: a 2015 update : a summary of proceedings of the 2014 conference held under the auspices of hemochromatosis Australia. Hepatol Int 2015;9:174-182.
    Pubmed
  77. Harrison SA, Bacon BR. Hereditary hemochromatosis: update for 2003. J Hepatol 2003;38:S14-S23.
    Pubmed
  78. Hershko C, Camaschella C. How I treat unexplained refractory iron deficiency anemia. Blood 2014;123:326-333.
    Pubmed


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