Review Article

Risks of iron supplements S. Umadevi*, A. Mohamed Akram, K. Mugesh, R. Mukilan

ABSTRACT

Iron is a vital mineral that is included in many over the counter multivitamin and mineral supplements and is used therapeutically in higher doses to treat or prevent iron deficiency anemia. When taken at the usual recommended daily doses or in replacement doses, iron has little or no adverse effect on the liver. However, in high doses or accidental overdoses, iron causes severe toxicities. Today different types of iron supplements are available in the market without mentioning the individual compound. These supplements are based on at least 20 different iron compounds and sold under a wide range of brands. Iron supplements are good for women and children, but when we focus on individual compound, not all supplements are created equal potency, as some compounds may actually do more harm than good. From the recent research, it was found that two iron compounds, ferric citrate and ferric ethylenediaminetetraacetic acid are often used in dietary supplements and as a food additive, respectively, in worldwide markets can increase the biomarkers for colon cancer, suggesting a link to the death toll. This review reports the cautious of iron supplements and serious disorders of an overdose of ionic compounds.

KEY WORDS: Amphiregulin, Ferric citrate, Ferric ethylenediaminetetraacetic acid, Ferritin, Iron overload

INTRODUCTION used, iron will enhance immunity, and it provides anticarcinogenic and cognition-enhancing activities.[1] Iron is a metallic element which is present in most of soils, mineral waters, and certain minerals. Iron The majority of the iron that is required for the body is an essential mineral that is compulsory for life. is obtained during food items such as meat, fish, Every living species, stating as of bacteria to humans, vegetables, fruits, and whole grains. However, from contain iron. It is found mainly in blood as the main time to time, this is not sufficient for pregnant women, component, and it is a fundamental component of they may need additional iron, as people who have hemoglobin, cytochrome, and other components of lost their blood or comprise of low hemoglobin levels respiratory enzyme systems. The most important for other reasons. Patients with kidney disease, they function of iron is to transport oxygen to tissues require a high dose of iron to bind phosphates into the (hemoglobin) and in cellular oxidation mechanisms. bloodstream.[2] Reduction of iron stores may lead to iron deficiency anemia. Iron is used as a building block to make up Two types of iron, such as ferric and ferrous form the blood in anemia. Iron is important to regulate are normally prescribed. However, ferrous iron is our metabolic pathways such as rofecoxib pathway, absorbed better than ferric iron. Accordingly, most magnesium salicylate action pathway, etodolac iron supplements contain ferrous iron. Three types of ferrous iron are usually given, ferrous sulfate, ferrous pathway, and diclofenac pathway. Iron is also fumarate, and ferrous gluconate. These supplements involved in several metabolic disorders, some of are existing in different forms, which includes tablets, which include adenine phosphoribosyltransferase capsules, liquids, drops, and extended-release.[3,4] deficiency, porphyria variegata, adenylosuccinate lyase deficiency, and AICA-ribosiduria. To cure or Ferric iron is not well absorbed like ferrous iron; prevent iron deficiency, anemia iron supplements are hence, ferric iron is not prescribed as regularly like ferrous. In total, reports recommend that ferrous iron Access this article online is tolerated better in patients than ferric iron. Since the gastrointestinal tract has a reduced amount of ability Website: jprsolutions.info ISSN: 0975-7619 to decrease ferric iron to its ferrous form, there is a

Department of Pharmaceutics, School of Pharmaceutical Sciences, VELS Institute of Sciences, Technology and Advanced Studies, Chennai, Tamil Nadu, India

*Corresponding author: Dr. S. Umadevi, Department of Pharmaceutics, School of Pharmaceutical Sciences, VELS Institute of Sciences, Technology and Advanced Studies, Pallavaram, Chennai - 600 117, Tamil Nadu, India. Mobile: +91-8667469884, Phone: +91-44 2266 2500/01/02/03. E-mail: [email protected]

Received on: 12-02-2019; Revised on: 16-03-2019; Accepted on: 22-04-2019

Drug Invention Today | Vol 12 • Issue 8 • 2019 1785 S. Umadevi, et al. condensed chance of iron poisoning with iron citrate, the stomach and small intestine. It forms ferritin when which is the most commonly used form of ferric iron.[5] united with apoferritin. Ferritin is stored in the liver, spleen, red bone marrow, and intestinal mucosa as The World Health Organization estimates that a storage form of iron. This transport oxygen to the more than 25% of population (1.62 billion) have tissues by hemoglobin and this iron is also found in iron deficiency anemia.[6] Persons from developing myoglobin, transferrin, and ferritin and is component countries are affected by this problem.[7] of a number of enzymes such as catalase, peroxidase, and cytochromes. Ferrous gluconate is also used as DIETARY SUPPLEMENTS food additives, color retention agent, and nutrient supplement. Iron is existing in various dietary enhancements such as multivitamin/multimineral supplements extraordinarily Ferrous fumarate is an alternate salt type of the those are considered for ladies, kids, and seniors. By mineral iron utilized in dietary expansion to treat and large utilized types of iron in the enhancements iron insufficiency related disorder. Ferrous fumarate incorporate of ferrous and ferric iron salts, for example, increases serum ion concentration, which is then ferrous sulfate, ferrous gluconate, ferric citrate, and assimilated into hemoglobin that is required for the ferric sulfate. Because its higher dissolvability, ferrous transport of oxygen. The overabundance iron is put iron in dietary enhancements is included bioavailable away in reticuloendothelial cells. It is utilized as a source than ferric iron.[3,4] High portions of advantageous iron of dietary iron in uncommon dietary sustenances. cause gastrointestinal reactions, for example, sickness and constipation.[8] Other types of supplemental iron, Ferric citrate is another compound which is normally for example, heme iron polypeptides, carbonyl iron, utilized in iron enhancement. It is an acknowledged iron amino-corrosive chelates, and polysaccharide- option in contrast to ferrous sulfate since it is gentler iron buildings, may have little sum gastrointestinal on the stomach and is all the more effectively symptoms than the ferrous or ferric salts.[4] consumed by the body.[12] Ferric citrate is promoted in a brand name Auryxia and is a usually realistic iron Each iron enhancement contains a diverse measure of enhancement used to delight pallor in individuals with natural particle. For instance, ferrous fumarate is 33% unending kidney malady.[2] natural iron by weight, while ferrous sulfate is 20% and ferrous gluconate is 12% basic iron.[4] However, Ferric ethylenediaminetetraacetic acid (EDTA) is as a rule convergences of extraordinary type of iron beneficial into different nourishment things, for is planned for the Supplement Facts plate, while the example, grains, flour, and powdered beverages, as a clients are not obligatory to gauge the amount of iron sustaining operator. As a dietary enhancement, ferric provided by different types of iron enhancements. EDTA included numerous nations, as the U.S., China, Mexico, the Philippines, and a few European states. Since the literature survey, it was discovered that To overcome iron inadequacy, it is added to kids’ 14–18% of Americans are with iron enhancement. drug in the U.K. what is more, France. The Food 12–19 years children are in a scope of 6% use, lactating and Drug Administration endorsed the utilization of ladies are 60% utilization extend and pregnant ladies ferric EDTA, as a sustenance added substance to an are in 72% usage.[9-11] assortment of sauces, including soy sauce, sweet and sharp sauces, and fish sauce in the United States.[2,13] COMMONLY USED IRONIC Ferrous succinate as supplemental iron is in the COMPOUND IN IRON anticipation and treatment of iron insufficiency SUPPLEMENTS frailty. Iron has putative invulnerable improving, anticarcinogenic, and discernment upgrading Ferrous sulfate is also famous as green vitriol. This is exercises. used to treat or prevent the iron deficiency throughout pregnancy and anemia. While ferrous gluconate Iron dextran is a dark colored, somewhat viscous or ferrous fumarate tablets are complete double, fluid complex of ferric hydroxide and dextran for the quantity is compulsory to meet the demand of intravenous or intramuscular use. Iron dextran is elemental iron in ferrous sulfate tablets. However, if utilized for the treatment of patients with reported iron any unabsorbed dietary iron is present in our body, inadequacy in which oral organization is unsuitable or it may increase free radical production in the colon incredible.[13] to concentrations which would lead to mucosal cell damage or increased construction of carcinogens. Ferric pyrophosphate is an iron substitution item. The presence of free iron causes various reactions as it Ferrous gluconate is a type of mineral iron used in oral can catalyze free extreme course of action and lipid iron supplement, and ferrous gluconate is absorbed in peroxidation just as the event of associations of iron

1786 Drug Invention Today | Vol 12 • Issue 8 • 2019 S. Umadevi, et al. in plasma. The ferric particle is firmly complexed by are often used in dietary supplements and as a food pyrophosphate. It shows a developing interest as this additive correspondingly, in worldwide markets can insoluble structure can be milder in the gastrointestinal increase the biomarkers for colon cancer, signifying tract and present higher bioavailability. Ferric a link to the deadly disease.[16-19] They have identified pyrophosphate is utilized for the treatment of iron two iron compounds such as ferric citrate and ferric misfortune or iron inadequacy as detailing with a EDTA could increase the production of amphiregulin, milder gastrointestinal impact. This is affirmed by the a biomarker for colon cancer. American Cancer Food and Drug Administration as sustenance added Society estimated 50,630 deaths are due to colon substance and utilized in fortifier. cancer in the previous year in the U.S. alone.

Iron (II) sulfate heptahydrate is a hydrate that is As of the literature survey, ferric citrate and ferric heptahydrate type of iron (2+) sulfate. It is utilized EDTA have been ever-increasing tumor formation in as a wellspring of iron in the treatment of iron mice by developing colon cancer. The learning was insufficiency sickliness, utilized in nutraceutical, carried out only in the animal model, and the possible and diminishing operator. This is normally utilized effects on human cells were not earlier investigated. in fluid measurement medicines. In any case, for strong measurement medications, the monohydrate Recently, the study was carried out in two types of is regularly utilized. It contains an iron (2+) sulfate cultured human colon cancer cells to come across (anhydrous). the effect of normal supplemental doses. The effect of ferric citrate and ferric EDTA was compared Reinforcing of nourishment with iron is one with ferrous sulfate, which is normally used ion progressively elective strategy to support the dietary supplement on two types of cultured human fundamental mineral like iron. For instance, fortress colon cancer cells by cell proliferation assays and of flour with iron is the act of purposely expanding Western blot analysis. Ferrous sulfate exhibited no the substance of a basic mineral in nourishment, to effect whatsoever, whereas both ferric citrate and recuperate the healthful nature of the sustenance. ferric EDTA led to increases in cellular levels of This is the perform dependent on general well-being amphiregulin, a biomarker used for cancer and its to profit them with negligible hazard to well-being. receptors. The effect is noted even at very low doses Fortress of nourishments with folic corrosive has been of the two compounds.[12,20] commanded in numerous nations solely to advance the folate status of pregnant ladies to forestall neural The total quantity of 3–4 g of body iron in ordinary [12] tube defect. adults is in hemoglobin. The excess iron is stored in the form of ferritin or hemosiderin in the liver, spleen, RESULTS and bone marrow or is located in myoglobin in muscle [21] Iron deficiency occurs either due to chronic blood tissue. Just the little measures of iron are discharged loss or intake of food which is not sufficient to meet in urine, feces, the gastrointestinal tract, and skin. our body’s requirement. Normally ferritin which Misfortunes are more noteworthy in discharging [22-24] is an iron store that is sufficient for accelerated ladies as a result of blood misfortune. Hepcidin, erythropoiesis and restoration of iron homeostasis. a coursing peptide hormone, is the key controller of If homeostasis remains for a long period in weeks both iron retention notwithstanding the dissemination to months, then the iron supplement is required to of iron all through the body, incorporating into [25-27] treat this disorder. Iron deficiency may be due to plasma. ectoparasitism, endoparasitism, hematuria, epistaxis, Hence, intense admissions of in excess of 20 mg/kg hemorrhagic skin, coagulopathy, thrombocytopenia, iron from enhancements or drugs can prompt gastric thrombocytopathia, and gastrointestinal hemorrhage. bombshell, clogging, queasiness, stomach agony, Heme iron from supplements or red meat may increase heaving, and faintness, particularly if sustenance is the formation of cancer-causing N-nitroso compounds not taken in the meantime.[8,28,29] Taking enhancements in the digestive tract which was revealed in clinical containing 25 mg natural iron or more can likewise trials in humans.[14,15] decrease zinc ingestion and plasma zinc fixations.[3,30,31] Overdoses of iron, once ingestions of 60 mg/kg, can Added reports suggest that taking iron supplements is prompt multisystem organ disappointment, trance-like well and good, especially for women. However, some state, seizures, and even death.[4,32] of the iron supplements be causing more harmful. Researchers from Chalmers University of Technology Iron over-burden happens in certain grown-ups in Sweden and collaboration with the UK Medical who have ingested iron enhancements for delayed Research Council and Cambridge University found interims.[33] Iron over-burden issue is genetic two iron compounds, ferric citrate and ferric EDTA, hemochromatosis, which bit by bit construct iron

Drug Invention Today | Vol 12 • Issue 8 • 2019 1787 S. Umadevi, et al. in tissues and organs.[34,35] Ultimately, untreated blood, and patients with chronic kidney disease and hemochromatosis makes the danger of joint cancer. The researchers inform that these groups of inflammation, malignancy, diabetes, and heart people might be at a higher risk of overwhelming harmful failure.[36] Still in little overabundance measure of levels of the carcinogenic chemical.[2] Ferric citrate and iron may expand the hazard for a liver ailment, for ferric EDTA increase the formation of amphiregulin, example, cirrhosis and disease, heart assault or heart that is known cancer marker. Hence, people use these disappointment, diabetes mellitus, osteoarthritis, two supplements might often be connected with long- osteoporosis, metabolic disorders, hypothyroidism, term cancer with poor prognosis. However, consumers hypogonadism, and inexhaustible indications. Once in do not know the type of compounds present in the a while, it prompts sudden passing. Neurodegenerative supplement; it can repeatedly be complex to identify illnesses, for example, Alzheimer’s, early-beginning what accurately they are buying. Many stores and Parkinson’s, Huntington’s, epilepsy and numerous suppliers, even pharmacies, do not point toward what sclerosis are quickened by abundance iron.[37] kind of iron compound is current. Prescribed label contain iron, or iron mineral to facilitate is not easy Fortress of flour with iron was cultivated before for consumers to recognize if their iron supplement is [38] in created nations to fight iron deficiency. Some safe for them. However, this study has its limitations; of these nations gloat been repressed iron braced the outcome is completed based only on lab-cultured flour since of conceivable antagonistic impacts of cancer cells. However, the clinical trial in human being [39-42] abundance iron. Various increasingly broad reveals the exact mechanisms in the human body, which surveys are reachable with arranging of potential is yet to study. dangers in private nations with weight control plans contain an assortment of iron-rich foods.[40-47] However, iron is an essential mineral for our body, but particularly toxic when excess amount is consumed. People with genetic or secure clutters may influence Numerous blood transfusions due to blood loss or iron retention. Iron fortress will give to press load anemia, getting iron shots or injections, or consuming anyway the extra addition in body iron load in many high levels of supplemental may overload iron [48] people would be minor. To maintain a strategic compound. As the body has no active excretion distance from neural cylinder deserts in pregnant pathways for iron, a continuous load of iron exceeding ladies, a stronghold of sustenances with folic 1–2 mg/day will result in iron overload, and organ corrosive has been commanded in numerous nations failures counting liver and heart.[57] Therefore, iron to show signs of improvement, the folate status of supplement and a high folic acid intake due to to pregnant ladies. Neural tube defect-a birth deformity fortification may be harmful to more people than the which influenced 0.5% (1 out of 200) US births before policy is calculated to help.[53] fortress began.[49-52] A different way of eliminating excess iron is blood loss. In general, the admission of folic corrosive in As a result, menstruating women and those who donate pregnancy to challenge neural tube forms. Along blood frequently be at lower risk of iron overload. these lines in all people, this fortress prompts raised Measures to abolish iron toxicity are by accepting blood convergences of true to form happening folates individual body iron metabolism. Development of and of unmetabolized folic corrosive. High blood patients’ outcome is suitable promising if a right early centralizations of folic corrosive may diminish diagnosis is made, and suitable management of these common killer cell cytotoxicity, and high folate inflexible conditions by means of iron chelation with status may decrease the reaction to drugs used to treat high compliance is conducted.[57] intestinal sickness, rheumatoid joint pain, psoriasis, and malignant growth. High folate may lessen Although iron deficiency is able to occur to anyone, nutrient B-12 status, which prompts expanded danger women are at major risk gender and as such, are in of intellectual weakness and iron deficiency in the greater danger from the effects of these carcinogenic older and, in pregnant ladies, through an expanded iron compounds. Recurrently during menstruation danger of insulin obstruction and stoutness in their and pregnancy women will lose more iron, as a result, youngsters. This way, a high folic corrosive admission they have to depend on iron supplements to attain the because of stronghold likely could be hurtful for a minerals they cannot get from presently their diet. larger number of individuals than the arrangement is Food is a natural source of iron than any type of iron intended to help.[53-56] supplement.

DISCUSSION CONCLUSION Iron supplements are used medically by pregnant To finish up as of our perceptions, just patients among women, breastfeeding mothers, people who have lost reported iron lack, iron consumption, or endless blood

1788 Drug Invention Today | Vol 12 • Issue 8 • 2019 S. Umadevi, et al. misfortune ought to ingest iron enhancements. Still compound/iron. [Last accessed on 2019 Jan 15]. nourishing iron over-burden can be created behind 14. Cross AJ, Pollock JR, Bingham SA. Haem, not protein or inorganic iron, is responsible for endogenous the long periods of supplementation. Patients could intestinal N-nitrosation arising from red meat. Cancer Res assume control over the counter arrangements of iron 2003;63:2358-60. enhancements for an alleged medical advantage and 15. Bingham SA, Hughes R, Cross AJ. Effect of white versus red be uninformed that it conveys potential dangers as meat on endogenous N-nitrosation in the human colon and further evidence of a dose response. J Nutr 2002;132:3522S-5. taken for an extensive stretch of time. Doctors ought 16. Liao J, Seril DN, Yang AL, Lu GG, Yang GY. Inhibition to manage the impacts and term of supplemental iron of chronic ulcerative colitis associated adenocarcinoma treatment and sever it if there is no therapeutic sign. development in mice by inositol compounds. Carcinogenesis People among hemochromatosis-related changes 2007;28:446-54. 17. Radulescu S, Brookes MJ, Salgueiro P, Ridgway RA, or specific sorts of sickliness may have expanded McGhee E, Anderson K, et al. Luminal iron levels govern hazard to create iron over-load with ingestion of iron intestinal tumorigenesis after apc loss in vivo. Cell Rep enhancements. Since overabundance body iron in any 2016;17:2805-7. structure is to be required to be hurtful and can manual 18. Seril DN, Liao J, Yang CS, Yang GY. Systemic iron supplementation replenishes iron stores without enhancing for organ harm, patients with iron over-burden from colon carcinogenesis in murine models of ulcerative iron enhancements ought to likewise be blessed to colitis: Comparison with iron-enriched diet. Dig Dis Sci receive dispose of the over-burden iron. 2005;50:696-707. 19. Seril DN, Liao J, Ho KL, Warsi A, Yang CS, Yang GY. Dietary iron supplementation enhances dss-induced colitis and REFERENCES associated colorectal carcinoma development in mice. Dig Dis Sci 2002;47:1266-78. 1. The Human Metabolome Database (HMDB) Available 20. Scheers NM, Pereira DIA, Faria N, Powell JJ. Ferric citrate from: https://www.pubchem.ncbi.nlm.nih.gov/compound/ and ferric EDTA but not ferrous sulfate drive amphiregulin- iron#section=Top; http://www.hmdb.ca/metabolites/HMDB mediated activation of the MAP kinase ERK in gut epithelial 0015531. [Last accessed on 2019 Jan 15]. cancer cells. Oncotarget 2018;9:17066-77. 2. Sandoiu A. Two Common Iron Supplements May Cause 21. Andrews NC. Disorders of iron metabolism. N Engl J Med Cancer. Brighton, UK: Medical News Today, Healthline Media 1999;341:1986-95. UK Ltd.; 2018. 22. Alleyne M, Horne MK, Miller JL. Individualized treatment for 3. Kolbe LE, Beard J. Iron. In: Coates PM, Betz JM, Blackman MR, iron-deficiency anemia in adults. Am J Med 2008;121:943-8. Cragg GM, Levine M, Moss J, et al. editors. Encyclopedia 23. Hunt JR, Zito CA, Johnson LK. Body iron excretion by healthy nd of Dietary Supplements. 2 ed. London, New York: Informa men and women. Am J Clin Nutr 2009;89:1792-8. Healthcare; 2010. p. 432-8. 24. Fairbanks VF. Iron in medicine and nutrition. In: Shils ME, 4. Manoguerra AS, Erdman AR, Booze LL, Christianson G, Shike M, Ross AC, Caballero B, Cousins RJ, editors. Modern Wax PM, Scharman EJ, et al. Iron ingestion: An evidence- Nutrition in Health and Disease. 10th ed. Baltimore: Lippincott based consensus guideline for out-of-hospital management. Williams and Wilkins; 1999. p. 193-221. Clin Toxicol (Phila) 2005;43:553-70. 25. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary 5. Gulec S, Anderson GJ, Collins JF. Mechanistic and regulatory antimicrobial peptide synthesized in the liver. J Biol Chem aspects of intestinal iron absorption. Am J Physiol Gastrointest 2001;276:7806-10. Liver Physiol 2014;307:G397-409. 26. Inamura J, Ikuta K, Jimbo J, Shindo M, Sato K, Torimoto Y, 6. Available from: https://www.who.int/vmnis/anaemia/ et al. Upregulation of hepcidin by interleukin-1beta in human prevalence/summary/anaemia_data_status_t2/en/WHO hepatoma cell lines. Hepatol Res 2005;33:198-205. (VMNIS). [Last accessed on 2019 Jan 15]. 27. Ganz T. Hepcidin in iron metabolism. Curr Opin Hematol 7. Ludwig H, Evstatiev R, Kornek G, Aapro M, Bauernhofer T, 2004;11:251-4. Buxhofer-Ausch V, et al. Iron metabolism and iron 28. Aggett PJ. Iron. In: Erdman JW, Macdonald IA, Zeisel SH, supplementation in cancer patients. Wien Klin Wochenschr editors. Present Knowledge in Nutrition. 10th ed. Washington 2015;127:907-19. DC: Wiley-Blackwell; 2012. p. 506-20. 8. Institute of Medicine. Food and Nutrition Board. Dietary 29. Jafarbegloo E, Ahmari Tehran H, Dadkhah Tehrani T. Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Gastrointestinal complications of ferrous sulfate in pregnant Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, women: A randomized double-blind placebo-controlled trial. Nickel, Silicon, Vanadium, and Zinc: A Report of the Panel Iran Red Crescent Med J 2015;17:e15001. on Micronutrients. Washington, DC: National Academy Press; 30. Solomons NW. Competitive interaction of iron and zinc 2001. in the diet: Consequences for human nutrition. J Nutr 9. U.S. Department of Agriculture, Agricultural Research Service; 1986;116:927-35. 2012. What We Eat in America; 2009-2010. Available from: 31. Whittaker P. Iron and zinc interactions in humans. Am J Clin http://www.ars.usda.gov/ba/bhnrc/fsrg. [Last accessed on 2019 Nutr 1998;68:442S-6. Jan 15]. 32. Chang TP, Rangan C. Iron poisoning: A literature-based review 10. Bailey RL, Gahche JJ, Lentino CV, Dwyer JT, Engel JS, of epidemiology, diagnosis, and management. Pediatr Emerg Thomas PR, et al. Dietary supplement use in the united states, Care 2011;27:978-85. 2003-2006. J Nutr 2011;141:261-6. 33. Barton JC, Lee PL, West C, Bottomley SS. Iron overload and 11. Cogswell ME, Kettel-Khan L, Ramakrishnan U. Iron prolonged ingestion of iron supplements: Clinical features and supplement use among women in the United States: Science, mutation analysis of hemochromatosis-associated genes in four policy and practice. J Nutr 2003;133:1974S-1977S. cases. Am J Hematol 2006;81:760-7. 12. Chalmers University of Technology. Certain Iron Supplements 34. Kowdley KV. Iron, hemochromatosis, and hepatocellular May Influence the Development of Colon Cancer. Science carcinoma. Gastroenterology 2004;127:S79-86. Daily. 12 April 2018. Available from: http://www.sciencedaily. 35. Pietrangelo A. Hereditary hemochromatosis: Pathogenesis, com/releases/2018/04/180412140623.htm. [Last accessed on diagnosis, and treatment. Gastroenterology 2010;139:393-408. 2019 Jan 15]. 36. Fleming RE, Ponka P. Iron overload in human disease. N Engl 13. Available from: https://www.pubchem.ncbi.nlm.nih.gov/ J Med 2012;366:348-59.

Drug Invention Today | Vol 12 • Issue 8 • 2019 1789 S. Umadevi, et al.

37. Kew MC. Hepatic iron overload and hepatocellular carcinoma. Christakis J, et al. Mutant antimicrobial peptide hepcidin is Liver Cancer 2014;3:31-40. associated with severe juvenile hemochromatosis. Nat Genet 38. Ramakrishnan U, Yip R. Experiences and challenges in 2003;33:21-2. industrialized countries: Control of iron deficiency in 49. National Institute of Child Health and Human Development. industrialized countries. J Nutr 2002;132:820S-4S. How Many People are Affected by or are at Risk for Neural 39. Hallberg L, Hulthén L. Perspectives on iron absorption. Blood Tube Defects? 2012. U.S. National Institutes of Health. Cells Mol Dis 2002;29:562-73. Available from: http://www.Nichd.nih.gov. [Last accessed on 40. Milman N, Byg KE, Ovesen L, Kirchhoff M, Jürgensen KS. 2019 Jan 15]. Iron status in danish women, 1984-1994: A cohort comparison 50. Prevention of neural tube defects: Results of the medical of changes in iron stores and the prevalence of iron deficiency research council vitamin study. MRC vitamin study research and iron overload. Eur J Haematol 2003;71:51-61. group. Lancet 1991;338:131-7. 41. Milman N, Byg KE, Ovesen L, Kirchhoff M, Jürgensen KS. 51. Czeizel AE, Dudás I. Prevention of the first occurrence of neural- Iron status in danish men 1984-94: A cohort comparison of tube defects by periconceptional vitamin supplementation. changes in iron stores and the prevalence of iron deficiency and N Engl J Med 1992;327:1832-5. iron overload. Eur J Haematol 2002;68:332-40. 52. Refsum H, Smith AD. Are we ready for mandatory fortification 42. Hallberg L. Advantages and disadvantages of an iron-rich diet. with vitamin B-12? Am J Clin Nutr 2008;88:253-4. Eur J Clin Nutr 2002;56 Suppl 1:S12-8. 53. Smith AD, Kim YI, Refsum H. Is folic acid good for everyone? 43. Schümann K. Safety aspects of iron in food. Ann Nutr Metab Am J Clin Nutr 2008;87:517-33. 2001;45:91-101. 54. Rosenberg IH. Science-based micronutrient fortification: 44. Milman N, Byg KE, Ovesen L. Iron status in danes 1994. II: Which nutrients, how much, and how to know? Am J Clin Nutr Prevalence of iron deficiency and iron overload in 1319 danish 2005;82:279-80. women aged 40-70 years. Influence of blood donation, alcohol 55. Powers HJ. Folic acid under scrutiny. Br J Nutr 2007;98:665-6. intake and iron supplementation. Ann Hematol 2000;79:612-21. 56. Crider KS, Bailey LB, Berry RJ. Folic acid food fortification- 45. Milman N, Pedersen AN, Ovesen L, Schroll M. Iron status in its history, effect, concerns, and future directions. Nutrients 358 apparently healthy 80-year-old danish men and women: 2011;3:370-84. Relation to food composition and dietary and supplemental iron 57. Kohgo Y, Ikuta K, Ohtake T, Torimoto Y, Kato J. Body iron intake. Ann Hematol 2004;83:423-9. metabolism and pathophysiology of iron overload. Int J 46. Sempos CT. Do body iron stores increase the risk of developing Hematol 2008;88:7-15. coronary heart disease? Am J Clin Nutr 2002;76:501-3. 47. Wood RJ. The iron-heart disease connection: Is it dead or just hiding? Ageing Res Rev 2004;3:355-67. Source of support: Nil; Conflict of interest: None Declared 48. Roetto A, Papanikolaou G, Politou M, Alberti F, Girelli D,

1790 Drug Invention Today | Vol 12 • Issue 8 • 2019