Iron homeostasis in pregnancy compensates for increased iron requirements and in women of child-bearing age for iron loss in menses. Oral administration of ferrous sulfate, prescribed to cure iron deficiency (ID) and ID anemia (IDA), often fails to increase hematological parameters and causes adverse effects. Recently, we demonstrated safety and efficacy of bovine lactoferrin (bLf) in pregnant women suffering from ID/IDA. Two clinical trials were conducted on pregnant and non-pregnant women of child-bearing age suffering from ID/IDA. In both trials, women received oral administration of bLf 100 mg/twice/day (Arm A), or ferrous sulfate 520 mg/day (Arm B). Hematological parameters, serum IL-6 and prohepcidin were assayed before and after therapy. Unlike ferrous sulfate, bLf increased hematological parameters (P<0.0001). In pregnant women, bLf decreased serum IL-6 (P<0.0001), and increased prohepcidin (P=0.0007). In non-pregnant women bLf did not change the low IL-6 levels while it increased prohepcidin (P<0.0001). Ferrous sulfate increased IL-6 (P<0.0001) and decreased prohepcidin (P=0.093). bLf established iron homeostasis by modulating serum IL-6 and prohepcidin synthesis, whereas ferrous sulfate increased IL-6 and failed to increase hematological parameters and prohepcidin. bLf is a more effective and safer alternative than ferrous sulfate for treating ID and IDA.
SchollTO. Iron status during pregnancy: setting the stage for mother and infant. Am J Clin Nutr2005; 81:1218–22.
2.
BothwellTH. Iron requirements in pregnancy and strategies to meet them. Am J Clin Nutr2000; 72:257–64.
3.
DonovanALimaCAPinkusJLPinkusGSZonLIRobineSAndrewsNC. The iron exporter ferroportin Slc40a1 is essential for iron homeostasis. Cell Metab2005; 1:191–200.
4.
De DomenicoIWardMDKaplanJ. Regulation of iron acquisition and storage: consequences for iron-linked disorders. Nat Rev Mol Cell Biol2008; 9:72–81.
5.
NemethEGanzT. Hepcidin and iron-loading anemias. Hematology J2006; 91:727–32.
6.
KrauseANeitzSMagertHJSchulzAForssmannWGSchulz-KnappePAdermannK. LEAP-1, a novel highly disulfide bonded human peptide, exhibits antimicrobial activity. FEBS Lett2000; 480:147–50.
7.
ParkCHValoreEVWaringAJGanzT. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem2001; 276:7806–10.
8.
LorealOHaziza-PigeonCTroadecMBDetivaudLTurlinBCourselaudBIlyinGBrissotP. Hepcidin in iron metabolism. Curr Protein Pept Sci2005; 6:279–91.
9.
GanzT. Hepcidin regulator of intestinal iron absorption and iron recycling by macrophages. Best Pract Res Clin Haematol2005; 18:171–82.
10.
NemethETurtleMSPowelsonJVaughnMBDonovanAWardDMGanzTKaplanJ. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science2004; 306:2090–93.
11.
De DomenicoIWardDMLangelierCVaughnMBNemethESundquistWIGanzTMusciGKaplanJ. The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell2007; 18:2569–78.
12.
BastinJDrakesmithHReesMSargentITownsendA. Localisation of proteins of iron metabolism in the human placenta and liver. Br J Haematol2006; 134:532–43.
13.
CollardKJ. Iron homeostasis in the neonate. Pediatrics2009; 123:1208–21.
14.
NemethERiveraSGabayanVKellerCTaudorfSPedersenBKGanzT. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest2004; 113:1271–76.
15.
NemethEGanzT. Regulation of iron metabolism by hepcidin. Annu Rev Nutr2006; 26:323–42.
16.
WeinsteinDARoyCNFlemingMDLodaMFWolfsdorfJIAndrewsNC. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood2002; 100:3776–81.
17.
LudwiczekSAignerETheurlIWeissG. Cytokine-mediated regulation of iron transport in human monocytic cells. Blood2003; 101:4148–54.
18.
KadiiskaMBBurkittMJXiangQHMasonRP. Iron supplementation generates hydroxyl radical in vivo. An ESR spin-trapping investigation. J Clin Invest1995; 96:1653–7.
19.
OldenburgBvan Berge HenegouwenGPRennickDVan AsbeckBSKoningsbergerJC. Iron supplementation affects the production of proinflammatory cytokines in IL-10 deficient mice. Eur J Clin Invest2000; 30:505–10.
20.
ReifenRMatasZZeidelLBerkovitchZBujanoverY. Iron supplementation may aggravate inflammatory status of colitis in a rat model. Dig Dis Sci2000; 45:394–97.
21.
PaesanoRPietropaoliMGessaniSValentiP. The influence of lactoferrin, orally administered, on systemic iron homeostasis in pregnant women suffering of iron deficiency and iron deficiency anaemia. Biochimie2009; 91:44–51.
22.
ProvenzanoRSchillerBRaoMCoyneDBrennerLPereiraBJ. Ferumoxytol as an intravenous iron replacement therapy in hemodialysis patients. Clin J Am Soc Nephrol2009; 4:386–93.
23.
PaesanoRTorciaFBerluttiFPacificiEEbanoVMoscariniMValentiP. Oral administration of lactoferrin increases hemoglobin and total serum iron in pregnant women. Biochem Cell Biol2006; 8:377–80.
24.
BakerENBakerHM. Molecular structure, binding properties and dynamics of lactoferrin. Cell Mol Life Sci2005; 62:2531–39.
25.
WeinbergED. Iron availability and infection. Biochim Biophys Acta2009; 1790:600–05.
26.
ValentiPAntoniniG. Lactoferrin: an important host defense against microbial and viral attack. Cell Mol Life Sci2005; 62:2576–87.
27.
MeierPRNickersonHJOlsonKABergRLMeyerJA. Prevention of iron deficiency anemia in adolescent and adult pregnancies. Clin Med Res2003; 1:29–36.
28.
ValentiPPacificiEPietropaoliMPaesanoR. La Lattoferrina per os, un'importante alternativa priva di effetti indesiderati, nella prevenzione e trattamento dell'ipoferremia ed anemia da carenza di ferro in gravidanza. Riv It Ost Gin2008; 17:783–90.
29.
PaesanoRPacificiEErminiBPietropaoliMValentiP. Ipoferremia e anemia da carenza di ferro in gravidanza. Evidenze cliniche della maggiore efficacia della lattoferrina, somministrata per os, rispetto al solfato ferroso. Il Ginecologo Riv Ostet Ginecol2008; 3:1–6.
30.
SchümannKEttleTSzegnerBElsenhansBSolomonsNW. On risks and benefits of iron supplementation recommendations for iron intake revisited. J Trace Elem Med Bio2007; 21:147–68.
31.
DejacoCGascheC. Anemia in chronic inflammatory intestinal disease: an often underestimated problem. Dtsch Med Wochenschr2002; 127:805–08.
32.
BelluzziARodaGTononFSoletiACaponiATuciARodaARodaE. A new iron free treatment with oral fish cartilage polysaccharide for iron deficiency chronic anemia in inflammatory bowel diseases: a pilot study. World J Gastroenterol2007; 13:1575–8.
33.
GanzTOlbinaGGirelliDNemethEWestermanM. Immunoassay for human serum hepcidin. Blood2008; 112:4292–7.
34.
TheurlIMattleVSeifertMMarianiMMarthCWeissG. Dysregulated monocyte iron homeostasis and erythropoietin formation in patients with anemia of chronic disease. Blood2006; 107:4142–8.
