Introduction Iron is an essential micronutrient because it plays a vital role in oxygen transport, oxidative metabolism, cellular proliferation and many other physiological processes. It is a redox metal and participates in most of the reversible one-electron oxidation-reduction reactions by switching between the two oxidation states, ferrous and ferric. This redox activity of iron can produce free radicals responsible for cell signalling processes and iron mediated toxicity. Iron is also an essential mineral for all known pathogens, because of which many have developed complex mechanisms for iron acquisition Iron content, bioavailability & factors affecting iron status of Indians K. Madhavan Nair & Vasuprada Iyengar Micronutrient Research Group, National Institute of Nutrition (ICMR), Hyderabad, India Received April 24, 2009 Repeated surveys have shown that the magnitude of nutritional anaemia is of public health concern in India. Though reduced intake of iron is a major aetiological factor, low intake or an imbalance in the consumption of other haematopoietic nutrients, their utilization; increased nutrient loss and/or demand also contribute to nutritional anaemia. In India, cereals and millets form the bulk of the dietaries and are major sources of non-haeme iron. According to the current estimates, the intake of iron is less than 50 per cent of the recommended dietary allowance (RDA) and iron density is about 8.5 mg/1000 Kcal. It is now well established that iron bioavailability from habitual Indian diets is low due to high phytate and low ascorbic acid/iron ratios. These factors determine iron bioavailability and the RDA. There are striking differences in the iron RDAs among the physiological groups, which need to be validated. The other dietary factors affecting iron status are inadequate intake of folic acid and vitamins B 12 , A, C and other vitamins of the B-complex group. Chronic low grade inflammation and infections, and malaria also contribute significantly to iron malnutrition. Recent evidence of the interaction of hepcidin (iron hormone) and inflammatory stimuli on iron metabolism has opened new avenues to target iron deficiency anaemia. Food-based approaches to increase the intake of iron and other haematopoietic nutrients through dietary diversification and provision of hygienic environment are important sustainable strategies for correction of iron deficiency anaemia. Key words Bioavailability - haemopoietic nutrients - intake - iron - iron status - RDA and proliferation in an iron-restricted environment. The human body has therefore developed intricate but exquisitely controlled mechanisms to absorb, transport and store iron, thus ensuring a ready supply for cellular growth and function, but limiting its participation in reactions that produce free radicals and its availability to invading pathogens. However, anaemia is widespread in India in spite of diversity in food habits, particularly in the consumption of cereals and such tight metabolic regulation. The causality between poor dietary iron density, bioavailability and high prevalence of anaemia in our population has not been well established, as anaemia has a multi-factorial aetiology. Albeit, iron 634 Review Article Indian J Med Res 130, November 2009, pp 634-645
Transcript
Introduction
Iron is an essentialmicronutrient because it playsavitalroleinoxygentransport,oxidativemetabolism,cellular proliferation and many other physiologicalprocesses.Itisaredoxmetalandparticipatesinmostofthereversibleone-electronoxidation-reductionreactionsbyswitchingbetweenthetwooxidationstates,ferrousandferric.Thisredoxactivityofironcanproducefreeradicals responsible for cell signalling processes andironmediatedtoxicity.Ironisalsoanessentialmineralforallknownpathogens,becauseofwhichmanyhavedeveloped complex mechanisms for iron acquisition
Micronutrient Research Group, National Institute of Nutrition (ICMR), Hyderabad, India
ReceivedApril24,2009
Repeated surveys have shown that the magnitude of nutritional anaemia is of public health concern in India. Though reduced intake of iron is a major aetiological factor, low intake or an imbalance in the consumption of other haematopoietic nutrients, their utilization; increased nutrient loss and/or demand also contribute to nutritional anaemia. In India, cereals and millets form the bulk of the dietaries and are major sources of non-haeme iron. According to the current estimates, the intake of iron is less than 50 per cent of the recommended dietary allowance (RDA) and iron density is about 8.5 mg/1000 Kcal. It is now well established that iron bioavailability from habitual Indian diets is low due to high phytate and low ascorbic acid/iron ratios. These factors determine iron bioavailability and the RDA. There are striking differences in the iron RDAs among the physiological groups, which need to be validated. The other dietary factors affecting iron status are inadequate intake of folic acid and vitamins B12, A, C and other vitamins of the B-complex group. Chronic low grade inflammation and infections, and malaria also contribute significantly to iron malnutrition. Recent evidence of the interaction of hepcidin (iron hormone) and inflammatory stimuli on iron metabolism has opened new avenues to target iron deficiency anaemia. Food-based approaches to increase the intake of iron and other haematopoietic nutrients through dietary diversification and provision of hygienic environment are important sustainable strategies for correction of iron deficiency anaemia.
and proliferation in an iron-restricted environment.Thehumanbodyhasthereforedevelopedintricatebutexquisitelycontrolledmechanismstoabsorb,transportandstoreiron,thusensuringareadysupplyforcellulargrowth and function, but limiting its participation inreactions thatproducefreeradicalsand itsavailabilitytoinvadingpathogens.However,anaemiaiswidespreadinIndiainspiteofdiversityinfoodhabits,particularlyintheconsumptionofcerealsandsuchtightmetabolicregulation. The causality between poor dietary irondensity,bioavailabilityandhighprevalenceofanaemiain our population has not been well established, asanaemia has a multi-factorial aetiology. Albeit, iron
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deficiency in a population results in consequences that haveseriousimplicationsanditisnowrecognizedthateven mild-to-moderate anaemia, can lead to lowerednational productivity. Therefore it is important to find andaddress the cause(s) so as to enforcemeasures toreduce iron deficiency anaemia in India.
Inthisreview,anattempthasbeenmadetorelatecerealconsumptionpattern,irondensityandanaemiaprevalenceacrosstheIndiansub-continent.Further,anupdateonbioavailabilityofironfromIndiandietsandthe factors that influence iron status of Indians are also included.Finallyanattempthasbeenmadetoanswerthequestionofhowtomeettheironrequirement.
Anaemia in India: iron deficiency alone? Anaemia, defined as a condition where the haemoglobin concentration is less than a defined levelresultingindecreasedoxygencarryingcapacityof blood, is a serious public health problem in Indiaaffectingallsegmentsofthepopulation.Thevulnerablegroups are infants and young children, adolescentboys and girls, women of child bearing age andpregnantwomen1-4.Recent surveysconductedby theNationalNutritionMonitoringBureau (NNMB)1 andNationalFamilyHealthSurvey(NFHS)-32showhighprevalenceofanaemia.NFHS-3hasreportedanaemia
prevalenceof56.2percentinwomenof15-49yr,79.2per cent amongchildrenaged6-35months,57.9percentinpregnantwomenand24.3percentinmenaged15-49yr.Dataobtained fromNNMB1,NFHS-25andNFHS-32showneitheratimetrendnoranappreciabledecrease in anaemia prevalence (Fig. 1). Anaemiaprevalence seems to be the same in urban and ruralareas,butgenderdifferencesexistattheageof15yr,withhigherprevalenceinfemales.
Anaemia in India is not restricted to iron deficiency alone, although a few studies where the role of ironnutrition has been specifically evaluated either by biomarkers or responses to iron administrationindicate that iron deficiency is the predominant cause of anaemia6-8. In pregnant females, sTfR (serumtransferrin receptor) used as a marker of tissue irondeficiency suggested low iron stores and wide spread deficiency4,9.Additionally,morethan40-45percentofpreschoolerspresentwithironbiomarkersindicatingiron deficiency6,10.InanurbansluminIndia,75percentofthechildrenwhopresentedwithanaemiarespondedtoironadministration,22percentofanaemicchildrenalso had biochemical vitamin B12 deficiency, 2.2 per cent had a biochemical folate deficit and 3. 3 per cent weresufferingfrominfection10.
ArecentstudycarriedoutbytheNationalInstituteof Nutrition (NIN), Hyderabad in semi-urban schoolchildrenshowedevidencefortheexistenceofmultiplesub-clinical micronutrient deficiencies11. The linkbetween vitamin A deficiency and anaemia has been recognized for many years12. These can potentiallyinfluence the absorption and metabolism of iron. Also, general undernutrition, haemoglobinopathies andmalariaalsocontribute to theobservedhighanaemiarates13-15.Thusbasedoneithertheprevalenceorimpactofironsupplementationstudiesthereisnodirectproofto demonstrate inadequate intake of iron as the onlymajoraetiologicalfactorofanaemiainIndia.
Dietary iron content in the aetiology of anaemia
Humans derive iron from their every day diet,predominantlyfromplantfoodsandtherestfromfoodsofanimalorigin.Ironisfoundinfoodaseitherhaemornon-haemiron.Haemiron,whichmakesup40percentof the iron in meat, poultry, and fish, is well absorbed. Sixtypercentoftheironinanimaltissue(liver)andalltheironinplants(fruits,vegetables,grains,nuts)isinthe
formofnon-haemironandisrelativelypoorlyabsorbed.Non-haemironcontributesabout90-95percentoftotaldailyironinIndiandiets.Inwesterncountriestheintakeofhaemironfrommeatandmeatproductsaccountsforbulk of the dietary iron and the US dietary referenceintakes(DRIs)arecalculatedonanassumptionof75percenthaemironconsumption16.onthecontrary,haemironconsumptionisminimalinIndiawithmajorityofIndiansobtainingnon-haemironfromcereals,pulses,vegetablesandfruits17.ThustheIndiandietaryisplaguedbylowironcontentandpoorabsorption.
Major sources of non-haem iron: Non-haem ironin plant foods is chemically diverse, ranging fromsimpleironoxidesandsaltstomorecomplexorganicchelates such as hydroxyphosphates in phytoferritin.Therelativecontributionofthesechemicalformsfromplantfoodsisnotyetestablished.
Fig. 2.FoodconsumptionpatternsinIndia(A).PercentcontributionofironfromvariousfoodgroupsinGujarat,Kerala,KarnatakaandTamilNaduascomputedfromNNMBdatabase17(B). Iron density of urban and rural diets from four Indian States. AP (Andhra Pradesh), WB (West Bengal),MP(MadhyaPradesh)andGj(Gujarat)(C).Valuesrepresentirondensityofaday’scompositedietdeterminedbychemicalanalyses.openbarsrepresenturbandietsandstriatedbarsrepresentsruraldiets22.
A
B
C
636 INDIANJMEDRES,NoVEMBER2009
(Fig.2A).According to the recentdiet survey in therural areas of 9 States, rice, wheat, and millets-ragi(Elesine coracana) and sorghum (Sorghum vulgare)arethewidelyconsumedstaplesofvariousregionsofIndia17.Theaveragedailyintakeofcerealsandmilletsrangedfrom320to477gasagainstarecommendedintake of 460 g, providing about 30-82 per cent oftotal dietary non-haem iron. The intake of pulses intheruralareasrangedfrom18to37g,andcontributesto 5-10 per cent of dietary intake of iron while thatfromgreenleafyvegetablesisonly2-5percent.Ironintake(TableI)andrelativecontributionofeachfoodstufftototalironintake(Fig.2B)variesmostwidelyamongtheStatesofGujarat(23mg),Kerala(12mg),Karnataka(12mg),AndhraPradesh(8mg)andTamilNadu(10mg).InGujaratthedietaryintakeofironwasthehighest,arisingoutofconsumptionofbajra(8mgFe/100g)asthemajorstaple22.Therearedifferencesalso in the absolute amount of iron among regions,AndhraPradesh(AP)dietswithriceasthestaplehavelowest (7 mg/1000 Kcal) and Gujarat and MadhyaPradesh (MP) dietswithbajra as the staple have thehighest (16 mg/1000 Kcal) (Fig. 2C). Periodic dietsurveyshaveshownthatthereisanupwardtrendintheirondensityofIndiandietsbuttheintakeofenergyhasreducedovertheyears,implyingcerealintakedoesnotcontributetoincreasedirondensity(Fig.3A,B).Thereisagoodagreementinthemagnitudeofdifferencesintheironcontentacrossdietsfromdifferentregions.
Iron intake and anaemia prevalence: Inter-statedifferences in iron intake and anaemia prevalenceprovide more insight into the complex relationshipbetween these two. In orissa, cereal intake is highwith high anaemia prevalence while Kerala has thelowest anaemia prevalence in spite of lower cereal
intake (Table I). The NNMB survey17 revealed thattheintakeofdietaryironisgrosslyinadequateinmostof the States, meeting less than 50 per cent of RDAof males (28 mg) or females (30 mg). This deficit is highestinAPat72percentandthelowestat23percentinGujarat,inadultfemales.Thesedifferencesiniron intake are attributable to regional differences inthe consumption of staple foods, especially rice andmillets, as millets and wheat have relatively greateriron content when compared to rice.Although thereisamarkedregionaldifferenceinanaemiaprevalenceamong these States, it is surprising to note that theextentofanaemiaprevalenceisnotcorrelatedwiththecurrentintakeofiron,withGujaratshowing55percentanaemia prevalence upon 23 mg/day iron intake and
Asimilarscenarioofnocorrelationemergeswithirondensity.ThedataalsosuggestthattheaverageirondensityofanIndiandietisnotmorethan8.5mg/1000Kcal,withthelowestdensityof4.3andthehighestof15.6 mg/1000 Kcal in the States ofAP and Gujarat,respectively (Table I, Fig. 2C). Despite a lower irondensityof7.1mg/1000Kcalonly,anaemiaprevalenceinKerala isdistinctly lower (8%adultmales,32.8%adult females) compared to other States. Rice is themajor staple in south Indian States but this cannotaccountfortheobserveddifferencesastheotherStatesofAPandTamilNadu(TN)haveanaemiaprevalenceabove 50 per cent, which is comparable to Gujaratwherewheatandmilletsarethemainstaples17.
Bioavailability of non-haem iron
Gastric pH and solubility:Itappearsthatneitherhigherdensity nor intake of iron can adequately accountfor the observed inter-state differences in anaemiaprevalence, necessitating identification of other factors. Themajorityof dietarynon-haem iron enters theGItract in the ferric form, which is insoluble and thusinaccessible.Thisneedstobeconvertedtotheferrousformforabsorptionattheenterocyte.Itiswellknownthat acidic pH is essential and critical for iron to bein the soluble ferrous formwhich in turndeterminesitssubsequentintestinalbioaccessibility.Achlorhydriahas been recognized as an associated feature of irondeficiency anaemia for many years. It is, however, not knownwhethertheextentofacidsecretioninIndiansisassociable with the high prevalence of iron deficiency anaemia. Evidence for enhanced iron absorption inthe presence of normal gastric acidity compared tocasesofachlorhydriapresentsaninterestingoption18.The gastric acidity measured by different groups inDelhi, Vellore and Mumbai was compared with thatreportedfromwesterncountries(TableII)19.Thebasalacid output in normal Indians is significantly lower (~pH3.4)thanthatinwesternsubjects(pH2.5)19.Thisdifferencemaycompromisenon-haemironsolubilityand accessibility in Indians and can therefore beconsideredintheaetiologyofhighanaemiaprevalence.Itispossiblethatthepredominantlyvegetariandietaryhabit of Indians has led to such an adaptation ofdecreasedacidsecretion,asitisknownthattheaminoacidcompositionofproteiningestedplaysanimportantrole in determining acid secretion. It would also beimportanttocorrelateHelicobacterpyloriinfectionin
Indiansongastricacidsecretionandironabsorption,as these have been shown to influence iron absorption inBangladeshichildren20.
Food matrix:Itisverywellknownthatthefoodmatrixcan influence iron solubility in the gastric milieu before itreachestheabsorptivesurfaceoftheintestinalmucosaas numerous dietary factors determine the oxidationstateofiron,especiallyfromatypicalIndiandiet.Thusthepossibilityoffoodmatrixeffectonnon-haemironsolubility is important. In an attempt to evaluate theimpactoffoodmatrix,invitronon-haemironsolubilityfromtypicalIndiancompositedietsofAndhraPradesh,West Bengal, Madhya Pradesh and Gujarat (based on NNMBdiet survey, 2001)21was carriedout.Roleofvariousdietarycomponentsinmodulatingsolubilityofironwasstudiedandironcontent,irondensity,phytateand phytate density showed significant correlation22.
Ironandphytatecontentanddensitywerenegativelycorrelatedtoironavailability.Invitrosolubilityofironfrom thesemealsdecreased from7.9 to1.52per centasphytatecontentincreasedfrom0.3-1.3g/d(Fig.4A).Further, diets with rice (low in iron and phytates) asstaplehadbetteravailabilitycomparedtodietswithBajra(high in iron, phytate) as staple22.Thus adequate ironavailabilitycanbeachievedprincipallybyminimizinginhibitors(phytates, tannins)andenhancingpromoters(ascorbic acid, meat/fish).
Though the essentiality of ascorbic acid for efficient absorption of dietary non-haem iron is generallyaccepted,theintakeisverylowinIndiandietaries.Forexample, intake of ascorbic acid has been shown tobeabout40mginalltheStates17whichisconsidered
sufficient for enhancing iron uptake. It should, however, beborneinmindthattheascorbiccontentderivedfromthe NutritiveValue of Indian Foods23 is for uncookedfood, the content of which, upon cooking may benegligibleduetothethermalinstabilityofascorbicacid.Thus,onlyobservabledifferenceindietpatternsamongtheabovementionedfourstatesistheincreasedintakeof fish, nuts and oilseeds, in Kerala (Fig. 2B), which could have contributed to increased solubility of ironresulting in the lower anaemiaprevalence. Inadequateconsumption of above these food groups can lead toreducedintakeofotherhaematopoieticnutrients,vitaminA, beta carotene (nuts and oil seeds), riboflavin and folic acid,furtheraccentuatinganaemia.
Irondensityofplantfoodscanbeincreasedeitherbychemical fortification or by biofortification. In animals andplanttissues,themajorironstorageproteinisferritin.Therefore,targetingferritinironinstaplecropsthroughconventional plant breeding technique(s), known asbiofortification, is an emerging strategy. However, the bioavailabilityofironcontentsoenhancedisasyetnotknownandtheissueofferritinironbioavailabilityisstillverycontroversial.Studieshaveshownthatferritinironfromplantsourcesareabsorbedtoanextentsimilartothatofferroussulphate24-26. We tested bioavailability of iron frompea ferritinusing theCaco-2cell line,withferroussulphateaspositivecontrol24.Ironbioavailabilityfrom pea ferritin was modulated by the concomitantpresenceofdietaryfactorssuchasphyticandascorbicacid, and gastric pH, suggesting it was similar insolubility and bioaccessibility to ferrous sulphate
(Fig.5).Therefore, it is essential thatall strategiesbeaimed at simultaneously improving endogenous non-haem iron absorption enhancers in plant foods, ratherthanjustincreasingironcontentordensity.
Recommended dietary allowance of iron
Bioavailabilityofnon-haemironfromcommonlyconsumedplantbaseddietsinIndiaisestimatedtobelowdueanabundanceofphyticacidandpolyphenolscoupledwithloweredconsumptionofmeatorascorbicacid. It is thus believed that plant-food based diet
Fig. 5. Ferritinresponseasasurrogatemarkerofpeaferritinironbioavailability inCaco-2cells.Bars thatdonot shareacommonsuperscript are significantly different at P<0.05.Source:Ref.24.
(vegan diet) might predispose to developing irondeficiency anaemia. However, surveys in vegans have found that iron deficiency anaemia is no more common in themthanamongthegeneralpopulation,althoughveganstendtohavelowerironstores27,28.Thereasonfor the adequate iron status of many vegans may bethat commonly eaten vegan foods are high in iron.In fact, the iron density (mg/1000 Kcal) of veganfoods is superior to animal-derived foods and vegandietsarehighinvitaminC27,28.Thuscommonlyeatencombinations,suchaspulsesandcitrusfruitsresultinenhancedironabsorptionanditiseasytoobtainirononavegandietthatwouldmeettheRDAforiron.Studieshave shown that absorption rates can rise significantly fromless than5percent tomorethan15percent ifanimal products and vitamin C are amply providedsimultaneouslyand thatbioavailabilityofmealswithasimilarcontentofiron,energy,protein,fat,etc.,canvary more than ten-fold27,28. Therefore to translatephysiologicalironrequirementsintorecommendationsfordietaryironintakes,thebioavailabilityofiron(i.e.,itsabsorptionforutilizationbythebody)fromdifferentdietsneedstobecalculated.
Iron bioavailability of the Indian diet:Ironabsorptionfrom various Indian diets carried out by chemicalbalancestudiesreportedironabsorptiontovaryfrom7-20per cent (median-10%)29. In1983,detailed ironabsorptionstudiesfromhabitualIndiandietsofsinglestaple(wheat,rice,ragiorsorghum)wereperformedinadultmenbytheextrinsictagtechnique30.Meanironabsorptionfromsinglemealrangedfrom0.8to4.5per
centdependingonthetypeofstapleused.Theextentof absorptionwas the lowest (0.8-0.9%)withmillet-baseddiets,highest (4-5%)with rice-baseddietsandintermediate(1.7-1.9%)withwheat-baseddiets.ApteandIyengar31demonstratedthatduringpregnancyironabsorptionincreasedfromameanof7to30andfurtherto33percentatgestationalweeks8-16,27-32and36-39, respectively, using the chemical balancemethod.The absorption of iron was better among those withlowpercenttransferrinsaturationthaninwomenwithhighpercenttransferrinsaturation.Asmuchas58percentof30mgofdietary iron ingestedperdaycouldbe absorbed by an iron deficient full term pregnant woman.However, themagnitudeof thedifference iniron absorption between non pregnant and pregnantIndianwomenisstrikingevenwhenthesamebalancemethodisused.
ItisimportanttohaveanaccuratemeasureofironcontentaswellasitsbioavailabilityfromtheIndiandiettosuggestRDA.Acomparisonbetweentheextrinsictag and the chemical balance methods indicated thatthe latter overestimated iron absorption32. The ironcontent of whole day’s diet ranged from 29-42 mg,providing high iron/energy ratios (8.2-13 mg/1000Kcal).However,itisknownthatabout1/3rdofthetotalironincerealsandpulsesisduetocontamination,andin vitroavailabilitystudiescarriedoutoncontaminantiron revealed that it was essentially unabsorbable33.Auniformabsorptionvalueof ironof3per cent forIndianmenand5percent for Indianwomen fromamixedcereal-pulsevegetariandietwasconsideredforderiving the iron RDA30,34. RDA of iron (Table III)34
(ii)Even ifan irondensityof10.8mg/1,000Kcal isassumed for all socio-economic groups and age/sexcategories, very few Indians would satisfy RDAsfor ironandenergywith thepresentpatternsof foodconsumption.
These current considerations make it essentiallyimpossiblefor theIndianpopulationtomeettheironrequirementsbynormaldiet alone.
AcomparisonofIndianandUSironRDA(Fig.6)reveals that the US recommendations are 2-3 timeslowerthantheIndianRDA.ThisdifferenceisduetothehigherbioavailabilityofironintheUSdietmainlyattributabletoincreasedascorbicacidcontentandhaemironconsumption16,34.ThismagnitudeofdifferenceinRDA in itself is cause for concern as physiologicalrequirements for the different age/sex categories donotvarytothisextentacrosspopulations.Thisimpliesthat enhancing bioavailability rather than density orcontentisofparamountimportanceforaddressingirondeficiency anaemia in India.
Realistic estimate of Indian iron RDA:TheirondensityofIndiandietisaround8.5mg/1000Kcalbasedondietsurveyrecordsandisaround9mg/1000Kcalbasedonchemicalanalysis22,35whichislowerthanpreviouslyestimated(14.2mg/1000Kcal).Amorerecentironabsorptionstudywascarriedoutusingstate-of-the-artstableisotopesinnormaland iron deficient women consuming a single rice-based meal containing a total of 4.3 mg iron36. The meanfractional absorption in iron-deficient subjects was 17.5 and7.3percentinnormalwomen,whichisgreaterthanabsorptionvalues (5%)usedearlier forcalculating ironRDAofforadultwomen.Consideringthefactthatironabsorptionisinverselyrelatedtobodyironstoresandthat
Indianshavereducedironstorescomparedtotheirpeersindevelopedworld,arealisticestimateofironabsorptionwouldbe5percentforadultmaleand10percentforadult female (Table Iv). These figures are in agreement with the recommendations of WHO/FAO, which for didacticreasons,liststhreebio-availabilitylevelsof5,10,and15percent37.Accordingtotheserecommendations,for developing countries, it may be realistic to use figures of5and10percentandinpopulationsconsumingmoreWestern-type diets, two levels would be adequate - 12 and 15 per cent - mainly depending on meat intake. When the bioavailabilityofirondecreasesto10percent,meanironstoresarereducedtoabout25mgandabout40-50percentofwomenconsumingthisdietwouldhavenoironstores.Those consuming diets with an iron bioavailability of5 per cent have no iron stores and they are iron deficient. Based on the above considerations the RDA of iron isderived(TableV).
Lifecycle approach: Iron requirements are least inadult men and post-menopausal women and highestinthesecondandthirdtrimestersofpregnancyandinthe rapidlygrowing infantbetween6and18monthsof age (Fig. 7). Many studies have established therelationshipbetweenmaternal iron status, foetal ironstores and birth weight. Iyengar and Apte38 showedthat foetal body weight is directly correlated to totaliron, reflecting the essentiality of iron during foetal
Table V. Recommended intakes for iron from meals withbioavailability5-10percentAge(yr) RDAmg/day1-6 6**
7-9 9**
Males10-18 19(10-14yr)*
20(15-18yr)*
Females10-18 17(10-14yr)**
18(15-18yr)**
Males19+ 17*
19-50Adultfemale 16**
Pregnancy It is recommended that iron supplements of100mgironbegiventoallpregnantwomenduring the second half of pregnancy areadequate.Inanemicwomenhigherdosesareusuallyrequired.
Lactation 15
Iron absorption can be significantly enhanced when each meal containsaminimumof25mgofvitaminC,assumingthreemealsperday.Thisisespeciallytrueifthereareironabsorptioninhibitorsinthedietsuchasphytateortannins;*5percentabsorption;**10percentabsorptionSource:Ref.34
development.Thenexthighriskperiodfornutritionaliron deficiency is the adolescent growth spurt and the onsetofmenstruationingirls.Theneedsofwomenofchildbearingagearemuchhigher than thoseofmen,butquitevariablebecauseofthewiderangeinmonthlymenstrualbloodloss,andmayneedtoabsorbasmuchas 2.5 mg each day to replenish losses. In tune withthesephysiologicalneeds,thegovernmenthasrecentlyreviewed theNNACP (NationalNutritionalAnaemiaControlProgramme)toincludeallthevulnerablegroups,known as the ‘lifecycle approach’39. This approachcoversallphysiologicalgroupsexceptadolescentboysand adult men.The amount of dietary iron absorbedis predominantly determined by physiological needwhich increases when body stores are depleted anddecreasesasironstoresarereplenished.
Other determining factors
Althoughitisestablishedthatthemajorcauseofanaemia in India is nutritional iron deficiency, it is indeed difficult to prioritize cause(s) when there are confounding factors such as multiple micronutrientdeficiencies and widespread low grade inflammation. However,asexplainedearlier,theinter-Statedifferencesintheanaemiaprevalencecannotbeexplainedbasedontheironintakeordensityorbioavailabilityalone.Theother factors that will have a profound influence in the aetiology of iron deficiency include (i) simultaneous presence of other micronutrient deficiencies, especially thatofhaematopoieticnutrients(vitaminA,B12,folicacid and riboflavin), and (ii) acute and chronic infections suchasmalaria,tuberculosis,andHIV/AIDS.
Haematopoietic micronutrients: Ascorbic acid isknown to improve the absorption of non-haem ironby reducing ferric iron to ferrous iron thus increasing
its solubility. Vitamin C status is often marginal, asmajordietarysourcesareseasonalvegetablesandfruits.FolateandvitaminB12arenecessaryforerythropoiesisand thesynthesisofDNA.The intakesofgreen leafyvegetables, which are major sources of folate, andanimalproducts,whicharemainsourceofvitaminB12,are meagre in India. Inadequacy in riboflavin intake21alsoreducesabsorptionandutilizationofiron.VitaminB6 is required for haem synthesis and therefore forerythropoiesis.Recentstudies11,17,40have indicated thatthere are other deficiencies that are currently widespread butnotrecognized.Forexample,dietaryintakesurveysshowthatintakeofallthekeymicronutrientsislow21.Sub-clinical deficiencies of riboflavin, pyridoxine and folic acid in pregnant women and children have beenreported40. A study carried out in apparently normalhealthy children also revealed high prevalence ofsub-clinical folate, vitamins B6, B2, C, B12, D and B1deficiencies11.
Folate nutrition in Indians:Folate,asmethyl/methylenetetrahydrafolate (MTHF), acts as a coenzyme inseveral single carbon transfers required for thebiosynthesisofpurineandpyrimidinesinnucleicacidsynthesis. Deficiency of this vitamin decreases several biochemicalfunctions.Therearenodetailedstudiesonfolate nutritional status in the Indian population, butfolate deficiency in the population is known41. Poorfolatecontentofhumanfoetalliverwasreportedwiththemeantotalliverfolateshowinganincreasefrom95to262mgdependingontheage(<28to37-40wk)ofthefoetus42.StudiesconductedinpregnantwomenalsosuggestedpoorfolatestatusbasedonRBCfolatelevelsand deficiency ranged from 40.5-53.3 per cent during different gestational periods43,44. Supplementation offolicacidwasshowntoincreasetheRBCfolate,andinwomenwhodidnotreceivefolicacidsupplements,thelevelsdecreasedfrom329±129nmol/lattermto256 ± 118 nmol/l postpartum45. Significantly higher levelsofRBCfolatewereobservedonlywith200and300mgoffolicacidsupplementation; the incrementswere 91 and 195 nmol/l respectively. A subsequentstudy with 500 mg folic acid given with 60 mg ironshowed a reduction in the per cent of small for datebirths (<2.5 kg) from 30 to 16 per cent43 and RBCfolate levels were higher in infants born to motherswhoreceived300mgoffolicacidthanthoseborntothecontrolgroup.Thebirthweightsofinfantsborntomotherswhohadreceivedeither200or500mgfolicaciddailywerehigherthanthoseborntomotherswhohad not received any supplements46. These studies
clearly indicate folate deficiency in the population, especiallyinthevulnerablegroups.
Vitamin B12 nutrition in Indians: There are not manystudies that have specifically addressed vitamin B12nutrition in Indians and there is no cut-off level for itsdeficiency. The current cut-off in the western countries is 200 pg/ml. However, the available data suggest thatprevalenceofB12deficiency in children is 44 per cent11.
Iron metabolism in inflammation
Anaemia is also a consequence of a synergy ofinflammation and insufficient bioavailable dietary ironandotherhaematinicnutrients. It isnowwidelyrecognized that infection is a much more importantcause of anaemia than previously thought. over andabove the deficit in the intake of these haematopoietic nutrients, disease processes also reduce appetite,resulting in further iron deficit47. With the onset of the inflammatory response, the plasma concentrations of several nutrients, including serum iron, decreasedrastically.Inadditionserumferritinconcentrationwasshown toparallel the rapid rise inC reactiveprotein(CRP),bothaspartoftheacutephaseresponse.
Iron metabolism, infection and inflammation are inextricably linked. Iron deficiency per se has been showntodecreasebothcell-mediatedimmuneresponseandbactericidalactivityofleukocytesinchildren48.ontheotherhand,ironstatusiscompromisedininfection.The influence of malaria, mild and severe respiratory infections in young children on biomarkers of ironstatus has been studied and a significant decrease in haemoglobinwasseeninchildrenwithvaryingdegreeof malaria while no significant changes were observed during upper respiratory tract infections (URTI) andpneumonia. Mean serum transferrin receptor levelschanged in pneumonia affected children but not inchildrenwithURTI49,50.Theseresultssuggestthatmildinfection may not cause any significant disturbance in Hb or transferrin receptor, but this is not true foraggressiveinfections.Inchildrenwithmeagrebodyironstores,infectiontendstoaggravateanaemiabyblockingironutilization. It is hypothesised thatupon infection,ironissequesteredinthemacrophagesandhepatocytesandironabsorptiondecreases,thuslimitingirontotheinvadingpathogen.Thisalsoresultsindecreasedplasmaironlevels,whichifmaintained,leadstoironrestrictederythropoiesisandultimatelyfrankanaemia.
brought on by the action of the inflammatory cytokine IL-6.Hepcidinisa25aminoacidhepatocyte-derivedpeptidethatcanbeincreasedtoupto100-foldduringinfections and inflammation causing a decrease in serum ironlevels51.Urinaryorserumhepcidinconcentrationsarewidelyalteredinanaemiaofchronicinfection,ironoverload, iron deficiency and haemochromatosis52.Hepcidin controls plasma iron concentration andtissuedistributionof ironby inhibiting intestinalandmacrophage iron efflux. Iron per se has also beenshowntomodulatehepcidinlevels51.Thushepcidinisnowconsideredastheironhormone.
Iron and oxidative stress
Multiple micronutrient deficiencies co-exist with anaemia in India. Many of these micronutrients, inadditiontotheirroleintheaetiologyofanaemia,arepro-oranti-oxidant.Ascorbicacidinthepresenceofiron is a pro-oxidant whereas alpha tocopherol is anantioxidant that can quench OH˙. Optimal concentration of glutathione peroxidase, a key antioxidant enzymewhichalsoprotectshaemoglobinagainstoxidationinerythrocyte, requires selenium. However, it is difficult to assess the extent of deficiencies of these micronutrients, their contribution to iron mediated oxidative stressin the vulnerable segments of the population whereiron supplementation is practiced53. It is essential tocondition the system with these micronutrients toachieve optimum impact of the lifecycle approachof iron deficiency control programme. These will not only reduce the anaemia prevalence but alsoreduce the oxidative stress associated with excessiron supplementation. In support of this, we haveshown that preconditioning of iron deficient rats with alpha tocopherol and ascorbic acid protected againstiron mediated oxidative damage54-56. This raises thequestion of whether iron deficient pregnant women aremoresusceptibletooxidativestressresultingfromexcess ironabsorption,particularlywhengivendailypharmacological doses of iron53.The other strategiesto control deleterious effects have been previouslyreviewed57.
Conclusions
Anaemia in India is multifactorial and low ironbioavailabilityisamajoraetiologicalfactor,giventhecurrent irondensityof8.5mg/1000Kcal. Inter-Statedifferences in anaemia prevalence are not correlatedeither with iron intake or density. Intake of fish, fruits, nutsandoilseedsseemstohavecontributed to loweranaemiaprevalenceinKerala.Decreasedgastricacid
production, food matrix interactions, lack of otherhaemopoietic nutrients, low grade inflammation and oxidative stress are factors that contribute toiron dyshomeostasis and need to be addressed. Lowabsorptionreportedfrommixed-cerealdietisthebasisfor the current high RDAs and needs to be verified. Recent stable isotope studies have shown absorptionrateof10percentinadultfemales,thusreducingtheRDAto16mgasagainst30mg.ThustheRDAsfortheothergroupshave tobe re-established.Aholisticapproach that can simultaneously address all theseissuesisthelifecycleapproachtoanaemiacorrection.Anumberofpotentialdietarysourcesthatcontainhighquantities of ascorbic acid, animal products and ironabsorption enhancers need to be urgently promotedincluding many leafy vegetables and legumes. Thisis possible if there is accessibility, availability andaffordabilitytodiversifyfoodtoenhanceabsorbabilityof iron in the general population. For the vulnerablegroups food fortification and food supplementation areimportantalternativesthatcomplementfood-basedapproachestosatisfytheironneeds.
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