resurrection of vitamin d deficiency and rickets...resurrection of vitamin d deficiency and rickets...
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Resurrection of vitamin D deficiency and rickets
Michael F. Holick
J Clin Invest. 2006;116(8):2062-2072. https://doi.org/10.1172/JCI29449.
The epidemic scourge of rickets in the 19th century was caused by vitamin D deficiency dueto inadequate sun exposure and resulted in growth retardation, muscle weakness, skeletaldeformities, hypocalcemia, tetany, and seizures. The encouragement of sensible sunexposure and the fortification of milk with vitamin D resulted in almost complete eradicationof the disease. Vitamin D (where D represents D2 or D3) is biologically inert andmetabolized in the liver to 25-hydroxyvitamin D [25(OH)D], the major circulating form ofvitamin D that is used to determine vitamin D status. 25(OH)D is activated in the kidneys to1,25-dihydroxyvitamin D [1,25(OH)2D], which regulates calcium, phosphorus, and bonemetabolism. Vitamin D deficiency has again become an epidemic in children, and ricketshas become a global health issue. In addition to vitamin D deficiency, calcium deficiencyand acquired and inherited disorders of vitamin D, calcium, and phosphorus metabolismcause rickets. This review summarizes the role of vitamin D in the prevention of rickets andits importance in the overall health and welfare of infants and children.
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2062 TheJournalofClinicalInvestigationâ â â http://www.jci.orgâ â â Volumeâ116â â â Numberâ8â â â Augustâ2006
Historical perspectiveInâtheâmid-1600s,âmostâchildrenâwhoâlivedâinâtheâcrowdedâandâpol-lutedâindustrializedâcitiesâofânorthernâEuropeâdevelopedâaâsevereâbone-deformingâdiseaseâthatâwasâcharacterizedâbyâgrowthâretarda-tion,âenlargementâofâtheâepiphysesâofâtheâlongâbones,âdeformitiesâofâtheâlegs,âbendingâofâtheâspine,âknobbyâprojectionsâofâtheâribcage,âandâweakâandâtonelessâmusclesâ(1,â2)â(Figureâ1).âInâtheâlatterâpartâofâtheâ19thâcentury,âautopsyâstudiesâdoneâinâBostonâandâLeiden,âTheâNetherlands,âshowedâthatâ80â90%âofâchildrenâhadârickets.
Inâ1822,âSniadeckiâ(3)ârecognizedâtheâimportanceâofâsunâexpo-sureâforâtheâpreventionâandâcureâofârickets.âPalmâ(4)âextendedâtheseâobservationsâinâ1890âandâpromotedâsystemicâuseâofâsunâbathsâtoâpreventârickets.âInâ1919,âHuldschinskiâ(5,â6)âfoundâthatâexposingâchildrenâtoâradiationâfromâaâsunâquartzâlampâ(mercuryâarcâlamp)âorâcarbonâarcâlampâforâoneâhourâ3âtimesâaâweekâwasâeffectiveâinâtreatingârickets,âasâdemonstratedâbyâaâmarkedâincreaseâinâtheâmineralizationâofâtheâskeleton,âespeciallyâtheâendsâofâtheâlongâbones,âevidentâinâtheâchildâsâx-rayâ(Figureâ2).âAâsimilarâgroupâofâchildrenânotâexposedâtoâUVâradiationâshowedânoâcureâorâonlyâaâslightâimprovementâ(6).âHeâconcludedâthatâexposureâtoâUVâradi-ationâwasâanââinfallibleâremedyââagainstâallâformsâofâricketsâinâchildren.âTwoâyearsâlater,âHessâandâUngerâ(7)âexposedâ7ârachiticâchildrenâinâNewâYorkâCityâtoâvaryingâperiodsâofâsunshineâandâreportedâmarkedâimprovementâinâtheâricketsâofâeachâchildâasâevi-dencedâbyâcalcificationâofâtheâepiphyses.
Inâ1918,âMellanbyâetâal.â(8)âpreventedâricketsâinâpuppiesâwithâcodâliverâoil.âMcCollumâetâal.â(9)âcalledâthisânewânutritionalâfactorâvitaminâD.âHessâandâWeinstockâ(10)âandâSteenbockâandâBlackâ(11)âobservedâthatâUVâirradiationâofâvariousâfoodsâandâoilsâimpartedâanti-rachiticâactivity.âThisâledâtoâenhancementâofâtheâantirachiticâactivityâofâmilkâbyâexposingâmilkâtoâUVâradiationâorâfeedingâcowsâUV-irradi-
atedâyeast.âOnceâvitaminâDâwasâstructurallyâidentifiedâandâchemi-callyâsynthesizedâinexpensivelyâfromâyeast,âitâwasâdirectlyâaddedâtoâmilkâatâaâstandardâofâ400âIUâ(1âIUâ=â25âng)âperâquartâ(12,â13).âItâwasâthoughtâthatâtheâvitaminâDâobtainedâfromâirradiatedâyeastâwasâtheâsameâvitaminâDâthatâwasâproducedâinâtheâskin.âHowever,âwhenâitâwasâobservedâthatâvitaminâDâfromâirradiatedâyeastâhadâlittleâantirachiticâactivityâinâchickens,âwhereasâcodâliverâoilâwasâeffective,âitâwasâcon-cludedâthatâtheâvitaminâDâproducedâinâtheâskinâmustâbeâdifferentâ(14).âVitaminâDâwasâisolatedâandâidentifiedâfromâpigâskinâandâshownâtoâoriginateâfromâ7-dehydrocholesterolâ(1,â2,â14).âToâdistinguishâtheâtwoâvitaminâDs,âtheâvitaminâDâfromâyeastâwasâcalledâvitaminâD2âandâtheâoneâfromâpigâandâhumanâskinvitaminâD3â(1,â2).
Photobiology of vitamin D3
Sunlightâwasârecommendedâasâaâtherapeuticâmethodâtoâpreventâricketsâinâinfants,âandâaâdetailedâdescriptionâwasâpublishedâinâtheâUnitedâStatesâChildrenâsâBureauâFolderâinâ1931â(13,â14).âItâwasârecognizedâthatâinâtheâtemperateâzone,âsunlightâwasâfeebleâinâitsâantirachiticâpropertiesâinâtheâwinter,âandâthus,âitâwasârecommend-edâthatâchildrenâbeâexposedâtoâUVâradiationâfromâaâmercuryâarcâorâcarbonâarcâlampâinâtheâwinterâ(5,â6,â13,â14)â(Figureâ2).âDuringâexposureâtoâsunlight,âtheâultravioletâBâ(UVB)âradiationâ(290â315ânm)âisâabsorbedâbyâ7-dehydrocholesterolâinâtheâskinâtoâformâprevi-taminâD3â(1,â15).âPrevitaminâD3â(1,â15)âisâinherentlyâunstableâandârapidlyâconvertsâbyâaâtemperature-dependentâprocessâtoâvitaminâD3â(Figureâ3).âOnceâformed,âitâisâejectedâoutâofâtheâskinâcellâintoâtheâextracellularâspace,âwhereâitâisâdrawnâintoâtheâdermalâcapillaryâbedâbyâtheâvitaminâDâbindingâproteinâ(DBP)â(1).
TheâefficiencyâofâvitaminâD3âsynthesisâinâtheâskinâisâdependentâonâtheânumberâofâUVBâphotonsâthatâpenetrateâintoâtheâepidermis.âAnâincreaseâinâskinâmelaninâpigmentationâ(16)âandâtheâtopicalâapplicationâofâaâsunscreenâ(17),âbothâofâwhichâefficientlyâabsorbâUVBâphotons,âcanâmarkedlyâdiminishâbyâmoreâthanâ90%âtheâpro-ductionâofâvitaminâD3.âExcessiveâexposureâtoâsunlightâcannotâcauseâvitaminâDâintoxicationâbecauseâsunlightâdestroysâanyâexcessâvitaminâD3âproducedâinâtheâskinâ(18,â19).âMostâUVBâphotonsâfromâtheâsunâareâabsorbedâbyâstratosphericâozone.âAnâincreaseâinâtheâsunâsâzenithâangleâresultsâinâanâincreasedâpathâlengthâforâtheâUVBâphotonsâtoâtravel,âandâthisâexplainsâwhyâatâhigherâlatitudesâ(aboveâ
Resurrection of vitamin D deficiency and ricketsMichael F. Holick
Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, and Vitamin D, Skin and Bone Research Laboratory, Boston University Medical Center, Boston, Massachusetts, USA.
Theepidemicscourgeofricketsinthe19thcenturywascausedbyvitaminDdeficiencyduetoinadequatesunexposureandresultedingrowthretardation,muscleweakness,skeletaldeformi-ties,hypocalcemia,tetany,andseizures.Theencouragementofsensiblesunexposureandthefor-tificationofmilkwithvitaminDresultedinalmostcompleteeradicationofthedisease.VitaminD(whereDrepresentsD2orD3)isbiologicallyinertandmetabolizedintheliverto25-hydroxyvi-taminD[25(OH)D],themajorcirculatingformofvitaminDthatisusedtodeterminevitaminDstatus.25(OH)Disactivatedinthekidneysto1,25-dihydroxyvitaminD[1,25(OH)2D],which
regulatescalcium,phosphorus,andbonemetabolism.VitaminDdeficiencyhasagainbecomeanepidemicinchildren,andricketshasbecomeaglobalhealthissue.InadditiontovitaminDdeficiency,calciumdeficiencyandacquiredandinheriteddisordersofvitaminD,calcium,andphosphorusmetabolismcauserickets.ThisreviewsummarizestheroleofvitaminDinthepreventionofricketsanditsimportanceintheoverallhealthandwelfareofinfantsandchildren.
Nonstandardabbreviationsused:â1-OHase,â25-hydroxyvitaminâD-1Îą-hydroxylase;â1,25(OH)2D,â1,25-dihydroxyvitaminâD;â25(OH)D,â25-hydroxyvitaminâD;âDBP,âvitaminâDâbindingâprotein;âFGF23,âfibroblastâgrowthâfactorâ23;âPHEX,âphosphate-regulatingâendopeptidaseâhomolog,âX-linked;PTH,âparathyroidâhormone;âRANKL,âreceptorâacti-vatorâofâNF-ÎşBâligand;âRXR,âretinoicâacidâXâreceptor;âSPF,âsunâprotectionâfactor;âUVB,âultravioletâB;âVDR,âvitaminâDâreceptor;âVDRE,âvitaminâDâresponsiveâelement.
Conflictofinterest:âTheâauthorâhasâdeclaredâthatânoâconflictâofâinterestâexists.
Citationforthisarticle:âJ. Clin. Invest.â116:2062â2072â(2006).âdoi:10.1172/JCI29449.
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TheJournalofClinicalInvestigationâ â â http://www.jci.orgâ â â Volumeâ116â â â Numberâ8â â â Augustâ2006â 2063
~35°âlatitude),âveryâlittle,âifâany,âvitaminâD3âisâproducedâinâtheâskinâfromâNovemberâthroughâMarchâ(19,â20).
Vitamin D metabolism and its role in calcium and phosphorus metabolismVitaminâD2âandâvitaminâD3â(DârepresentsâeitherâD2âorâD3)âderivedâfromâsupplements,âfortifiedâfoods,âandâfishâingestedâfromâtheâdietâ(Tableâ1)âareâincorporatedâintoâchylomicronsâandâabsorbedâintoâtheâlymphaticâsystem.âFromâhereâtheyâenterâtheâcirculation,âwhereâtheyâareâboundâtoâtheâDBPâandâlipoproteinsâ(1,â20â22).âVitaminâDâisâreleasedâfromâDBPâtoâtheâliverâandâundergoesâaâhydroxylationâonâC-25âbyâtheâvitaminâD-25-hydroxylasesâ(25-OHase;âalsoâknownâasâCYP27A1,âCYP3A4,âCYP2R1,âCYP2J3)âtoâ25-hydroxyvitaminâDâ[25(OH)D]â(20â22)â(Figureâ3).â25(OH)DâisâtheâmajorâcirculatingâformâofâvitaminâDâthatâisâmeasuredâtoâdetermineâaâpersonâsâvitaminâDâstatusâbecauseâitâhasâaâhalf-lifeâinâtheâcirculationâofâ2âweeksâandâitâcorrelatesâwithâsecondaryâhyperparathyroidism,ârickets,âandâosteo-malaciaâ(20,â22â24).â25(OH)DâisâboundâtoâDBP,âandâthisâcomplexâbindsâtoâmegalinâonâtheâplasmaâmembraneâofâtheârenalâtubuleâcellâandâisâtransportedâintoâtheâcellâ(20,â22).âOnceâinside,â25(OH)Dâisâreleasedâandâisâconvertedâinâtheâmitochondriaâbyâtheâ25-hydroxyvi-taminâD-1Îą-hydroxylaseâ[1-OHase;âalsoâknownâasâCYP27B1]âtoâformâ1,25-dihydroxyvitaminâDâ[1,25(OH)2D].â1,25(OH)2DâisâtheâbiologicallyâactiveâformâofâvitaminâDâresponsibleâforâmaintainingâcalciumâandâphosphorusâhomeostasis.âItâaccomplishesâthisâbyâinter-actingâwithâitsânuclearâreceptor,âtheâvitaminâDâreceptorâ(VDR)âinâtheâsmallâintestinalâcellsâ(22,â25).âTheâ1,25(OH)2DâVDRâstructureâcomplexesâwithâretinoicâacidâXâreceptorâ(RXR)âinâtheânucleus.âTheâ1,25(OH)2D-VDR-RXRâcomplexâbindsâtoâtheâvitaminâDâresponsiveâelementâ(VDRE)âforâtheâepithelialâcalciumâchannelâ(22,â25).âTheâincreasedâexpressionâofâtheâcalciumâchannelâpermitsâmoreâcalciumâtoâenterâtheâcell,âwhereâtheâvitaminâDâdependentâcalcium-bindingâproteinâcalbindinâ9Kâhelpsâcalciumâsâtranslocationâintoâtheâblood-stream.â1,25(OH)2Dâalsoâenhancesâphosphorusâabsorptionâinâtheâsmallâintestineâ(1,â22,â25).
Whenâdietaryâcalciumâisâinadequate,âvitaminâDâhelpsâmain-tainâcalciumâhomeostasisâbyâinteractingâwithâtheâVDRâinâosteo-blastsâtoâinduceâtheâexpressionâofâtheâplasmaâmembraneâproteinâreceptorâactivatorâofâNF-ÎşBâligandâ(RANKL).âTheâRANKâonâtheâplasmaâmembraneâofâpreosteoclastsâbindsâRANKL,âwhichâinducesâ
theâpreosteoclastâtoâbecomeâaâmatureâosteoclastâ(20,â22,â26).âTheâmatureâosteoclastâreleasesâhydrochloricâacidâandâcollagenasesâtoâdissolveâboneâandâreleaseâitsâpreciousâcalciumâandâphosphorusâstoresâintoâtheâcirculation.âThus,âtheâmajorâphysiologicâfunctionâofâvitaminâDâisâtoâmaintainâserumâcalciumâandâphosphorusâlevelsâwithinâtheânormalâphysiologicârangeâtoâsupportâmostâmetabolicâfunctions,âneuromuscularâtransmission,âandâboneâmineralizationâ(1,â20,â22,â24)â(Figureâ3).
Vitamin D and calcium deficiencies as a cause of ricketsVitaminâDâdeficiencyâisâtheâmostâcommonâcauseâofârickets.âVitaminâDâdeficiencyâpreventsâtheâefficientâabsorptionâofâdietaryâcalciumâandâphosphorus.âInâaâvitaminâDâdeficientâstate,âonlyâ10â15%âofâdietaryâcalciumâandâ50â60%âofâdietaryâphosphorusâareâabsorbed.âTheâpoorâabsorptionâofâcalciumâcausesâaâdecreaseâinâserum-ionizedâcalciumâlevels.âThisâisâimmediatelyârecognizedâbyâtheâcalciumâsensorâinâtheâparathyroidâglands,âresultingâinâanâincreaseâinâtheâexpression,âsynthesis,âandâsecretionâofâparathyroidâhormoneâ(PTH)â(1,â20,â22,â27).âPTHâconservesâcalciumâbyâincreasingâtubularâreabsorptionâofâcalciumâinâbothâtheâproximalâandâdistalâconvolutedâtubules.âPTH,âlikeâ1,25(OH)2D,âenhancesâtheâexpressionâofâRANKLâonâosteoblastsâtoâincreaseâtheâproductionâofâmatureâosteoclastsâtoâmobilizeâcal-ciumâstoresâfromâtheâskeleton.âPTHâalsoâdecreasesâphosphorusâreabsorptionâinâtheâkidney,âcausingâlossâofâphosphorusâintoâtheâurineâ(Figureâ4).âTheâserumâcalciumâlevelâisâusuallyânormalâinâaâvitaminâDâdeficientâinfantâorâchild.âHowever,âtheâserumâphospho-rusâlevelâisâlow,âandâthusâthereâisâinadequateâcalcium-phosphorusâproduct,âwhichâisânecessaryâtoâmineralizeâtheâosteoidâlaidâdownâbyâosteoblastsâ(1,â20,â22,â24,â28)â(Figureâ4).âThus,âtypically,âinfantsâwithâvitaminâDâdeficiencyâricketsâhaveâaânormalâserumâcalciumâlevel,âlowânormalâorâlowâfastingâserumâphosphorusâlevels,âelevatedâalkalineâphosphataseâlevels,âandâlowâ25(OH)Dâlevelsâ(<15âng/ml)â(23,â28â31)â(Tableâ2).âTheâsecondaryâhyperparathyroidismâstimu-latesâtheâkidneysâtoâproduceâ1,25(OH)2D,âandâthus,â1,25(OH)2Dâlevelsâareânormalâorâoftenâelevated,âwhichâisâwhyâtheâmeasurementâofâ1,25(OH)2DâisâofânoâvalueâinâdeterminingâaâstateâofâvitaminâDâdeficiencyâ(24).âOnlyâwhenâtheâcalciumâstoresâinâtheâskeletonâareâtotallyâdepletedâwillâtheâinfantâorâchildâbecomeâhypocalcemic.
Vitaminâ Dâ deficiencyâ causesâ globalâ poorâ mineralizationâ ofâtheâskeleton.âClinicalâandâradiologicalâboneâmanifestationsâpre-dominateâinâareasâofârapidâboneâgrowth,âincludingâtheâlongâboneâepiphysesâandâtheâcostochondralâjunctionsâ(5,â6,â12â14,â30â32).âThisâisâwhyâricketsâisâmostlyâobservedâbeforeâ18âmonthsâofâage,âwithâmaximumâfrequencyâbetweenâtheâagesâofâ4âandâ12âmonths.âSkeletalâdeformitiesâareâusuallyâaâresultâofâlong-standingârickets.â
Figure 2UV radiation therapy for rickets. (A) Photograph from the 1920s of a child with rickets being exposed to UV radiation. (B) Radiographs dem-onstrating florid rickets of the hand and wrist (left) and the same wrist and hand taken after treatment with 1 hour UV radiation 2 times a week for 8 weeks. Note mineralization of the carpal bones and epiphyseal plates (right). Reproduced from ref. 126.
Figure 1Skeletal deformities observed in rickets. (A) Photograph from the 1930s of a sister (left) and brother (right), aged 10 months and 2.5 years, respectively, showing enlargement of the ends of the bones at the wrist, carpopedal spasm, and a typical âTaylorwiseâ posture of rick-ets. (B) The same brother and sister 4 years later, with classic knock-knees and bow legs, growth retardation, and other skeletal deformities. Reproduced from ref. 14.
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2064 TheJournalofClinicalInvestigationâ â â http://www.jci.orgâ â â Volumeâ116â â â Numberâ8â â â Augustâ2006
Hypertrophyâofâtheâcostochondralâjunctionsâleadsâtoâbeadingâandâtheâclassicârachiticârosaryâthatâprogressesâwithâinvolutionâofâtheâribsâandâprotrusionâofâtheâsternumâ(pigeonâchest)âandârecessionâofâtheâcostochondralâjunctionsâandâtraverseâdepressionsâcausingâHarrisonâsâgroove.âOnceâtheâchildâbeginsâtoâstand,âgravityâpushingâonâtheâlowerâlimbsâresultsâinâeitherâinwardâ(genuâvalgum)âorâout-
wardâ(genuâvarum)âtibialâandâfemoralâbowing.âMuscleâpullâcanâalsoâcauseâboneâdeformitiesâinâbothâupperâandâlowerâlimbsâevenâbeforeâtheâinfantâbeginsâtoâwalk.âMuscleâtractionâonâtheâsoftenedâribcageâisâresponsibleâforâtheâchestâdeformation,âleadingâtoâpectusâcarinatum,âthoracicâasymmetry,âandâwideningâofâtheâthoracicâbase.âSofteningâofâtheâoccipitalâareaâ(rachiticâcraniotabes),âenlargedâsuturesâandâ
Figure 3The photoproduction and metabolism of vitamin D and the various biologic effects of 1,25(OH)2D on calcium, phosphorus, and bone metabolism. Vitamin D is either produced in the skin by exposure to UVB radiation or is ingested in the diet. Vitamin D (D represents vitamin D2 or vitamin D3) is converted by the vitamin D-25-hydroxylase (25-OHase) in the liver to 25(OH)D. 25(OH)D is converted in the kidneys by 1-OHase to 1,25(OH)2D. Once formed, 1,25(OH)2D enhances intestinal calcium and phosphorus absorption and stimulates the expression of RANKL on the osteoblasts to interact with its receptor RANK on preosteoclasts to induce mature osteoclastic activity, which releases calcium and phosphorus (HPO4
2â). In addition, 1,25(OH)2D inhibits the renal 1-OHase and stimulates the expression of the renal 25(OH)D-24-hydroxylase (24-OHase). The induction of the 24-OHase results in the destruction of 1,25(OH)2D into a water-soluble inactive metabolite calcitroic acid. PreD3, previtamin D.
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TheJournalofClinicalInvestigationâ â â http://www.jci.orgâ â â Volumeâ116â â â Numberâ8â â â Augustâ2006â 2065
fontanelles,âdelayedâclosingâofâfontanelles,âandâoccipitalâorâparietalâflatteningâcanâbeâobservedâ(5,â6,â12,â13,â30â32)â(Figureâ1).âToothâdevelopmentâisâimpaired,âwithâdelayedâeruption,âenamelâhypopla-sia,âandâearlyâdentalâcariesâ(12â14).âTheâpelvicâboneâstructureâisâflat-tenedâinârachiticâchildren.âBecauseâofâtheâhighâincidenceâofâinfantâandâmaternalâmorbidityâandâmortalityâinârachiticâwomen,âchildrenâwereâoftenâdeliveredâbyâCaesarianâsectionâ(1,â2).
Extraskeletalâmanifestationsâassociatedâwithâhypocalcemiaâleadâtoâtetany,âseizures,âlaryngospasm,âandâhypocalcemicâmyocardiopa-thyâandâdeathâ(6,â12â14,â32).âOftenâthereâisâdelayedâmotorâdevelop-mentâwithâhypotoniaâinâtheâabsenceâofâhypocalcemia.âWeaknessâofâtheâthoracicâmusclesâtogetherâwithâsofteningâofâtheâribcageâresultsâinâdefectiveâventilationâwithârespiratoryâobstructionâandâinfection.âInâolderâchildrenâandâadolescents,âsymptomsâsimilarâtoâthoseâobservedâinâadultâosteomalacia,âincludingâboneâpain,âwad-dlingâgait,âandâfatigue,âmayâbeâpresentâ(12â14,â24,â30â32).âHema-tologicâdisordersâareâoftenâobservedâinâcommonârickets,âincludingâhypochromicâanemiaâandâtheârareâVonâJackschâLuzetâsyndrome.âThisâsyndromeâisâassociatedâwithâsevereâanemiaâandâaâprofileâofâchronicâmyeloidâleukemiaâwithâerythroblastosis,â leukocytosis,âmyelocytosis,âandâpossibleâmyeloblastosis.âTheâspleenâandâliverâcanâbeâenlargedâasâaâresultâofâextramedullaryâhematopoiesis.âTheâboneâmarrowâisâhypoplastic.âThisâsyndromeâisâoftenâcuredâwithâsimpleâvitaminâDâtherapyâ(31).
SevereâcalciumâdeficiencyâcanâleadâtoâricketsâinâmuchâtheâsameâwayâasâvitaminâDâdeficiencyâ(32â35).âVeryâlowâdietaryâcalciumâintakeâleadsâtoâdecreasedâionizedâcalciumâandâsecondaryâhyper-parathyroidism.âThisâcausesâaâmineralizationâdefectâinâtheâskeletonâthatâresultsâinâgrowthâretardationâandâmanyâofâtheâskeletalâmani-festationsâseenâinâvitaminâDâdeficiency,âbutâtheseâareâofâgreaterâseverityâdueâtoâtheâhypocalcemiaâ(31â35)â(Figureâ4).
Inadequateâcalciumâintakeâduringâtheâ3rdâtrimesterâofâpregnan-cyâcanâcauseâaâseriousâcalciumâdeficitâinâtheâfetalâskeletonâthatâisârapidlyâbeingâmineralizedâduringâtheâlastâ7âweeksâinâutero.âTypi-callyâatâ28âweeks,â100âmg/dâofâcalciumâisâbeingâdepositedâinâtheâskeleton,âwhereasâatâ35âweeksâ350âmg/dâisâbeingâdepositedâ(30,â31,â
36).âTherefore,âmotherâsâmilkâcontainingâ240â340âmg/lâofâcalciumâisâunableâtoâmeetâtheâdemandsâofâpostnatalâaccretionâratesâofâaâpretermâinfantâ(30,â31).
Youngâchildrenâandâadolescents,âespeciallyânon-whiteâindivid-uals,âonâaâstrictâvegetarianâdietâorâaâdietâthatâisâhighâinâphytate,âwhichâbindsâcalcium,âcanâalsoâbeâcalciumâdeficient,âwhichâleadsâtoâricketsâ(33â35).âThis,âinâcombinationâwithâvitaminâDâdeficiency,âisâoftenâtheâprecipitatingâcauseâofâricketsâinâchildrenâofâMiddleâEast-ernâdescentâlivingâinâGreatâBritainâandâAfricanâAmericanâchildrenâinâtheâUnitedâStatesâ(32â35).
Theâcalciumâdeficiencyâandâassociatedâsecondaryâhyperparathy-roidismâincreaseâtheârequirementâforâvitaminâD,âsinceâtheâvitaminâDâisârapidlyâmetabolizedâtoâ1,25(OH)2D.âTheâcombinationâofâcal-ciumâdeficiencyâandâvitaminâDâdeficiencyâacceleratesâandâmakesâmoreâsevereâtheâskeletalâabnormalitiesâandâhypocalcemia.
Prevalence of subclinical vitamin D deficiencySevereâchronicâvitaminâDâdeficiencyâ[25(OH)Dâlevelâlessâthanâ15âng/ml]âleadsâtoâovertâskeletalâabnormalitiesâinâchildrenâthatâisâtypi-callyâdefinedâasâricketsâ(23,â30â32).âHowever,âthereâisâaâlargeânumberâofâinfants,âchildren,âandâadolescentsâwhoâareâvitaminâDâinsufficientâbutâhaveânoâapparentâskeletalâorâcalciumâmetabolismâabnormalitiesâ(Tableâ2).âWeâobservedâthatâofâ40ââhealthyââmother-infantâpairsâthatâwereâpredominantlyânon-white,â73%âofâmothersâandâ80%âinfantsâhadâ25(OH)Dâlevelsâofâlessâthanâ20âng/mlâdespiteâtheâfactâthatâ80%âofâtheâmothersâtookâaâdailyâprenatalâmultivitaminâthatâcontainedâ400âIUâofâvitaminâDâ(37).âSullivanâetâal.â(38)âreportedâthatâ48%âofâwhiteâgirlsâagedâ9â11âyearsâinâMaineâhadâ25(OH)Dâlevelsâlessâthanâ20âng/mlâatâtheâendâofâtheâwinterâandâ17%âremainedâvitaminâDâdefi-cientâatâtheâendâofâtheâsummerâdueâeitherâtoâavoidingâsunâexposureâorâalwaysâwearingâsunâprotection.âForty-twoâpercentâofâadolescentâAfricanâAmericanâandâHispanicâchildrenâhadâ25(OH)Dâlevelsâlessâthanâ20âng/mlâinâBostonâ(39),âwhichâisâconsistentâwithâtheâobserva-tionâbyâtheâCentersâforâDiseaseâControlâthatâ48%âofâAfricanâAmeri-canâwomenâagedâ15â49âyearsâthroughoutâtheâentireâUnitedâStatesâhadâ25(OH)Dâlevelsâofâlessâthanâ15âng/mlâatâtheâendâofâtheâwinterâ(40).âSimilarâobservationsâhaveâbeenâmadeâinâCanadaâandâEurope,âwhereâfewâfoodsâareâfortifiedâwithâvitaminâDâandâtheâhighâlatitudeâlimitsâvitaminâDâproductionâinâtheâskinâ(41â45).âRemarkably,âinâtheâsunniestâareasâofâtheâworld,âricketsâisâaâmajorâhealthâproblem.âBecauseâofâtheâpracticeâofâpurdahâorâwearingâaâburkaâ(45,â46),âavoid-anceâofâexposureâofâanyâskinâtoâsunlight,âandâtheâfactâthatâfewâfoodsâareâfortifiedâwithâvitaminâD,âupwardâofâ35â80%âofâchildrenâinâSaudiâArabiaâ(46,â47),âIndiaâ(48),âTurkeyâ(29),âNewâZealandâ(49),âIsraelâ(50),âEgyptâ(51),âHongâKongâ(52),âChinaâ(53),âLibyaâ(54),âLebanonâ(55),âSpainâ(56),âAustraliaâ(57),âSanâDiego,âCaliforniaâ(58),âandâtheâsoutheasternâUnitedâStatesâ(59)âareâvitaminâDâdeficient.âWhenâtheâdeficiencyâoccursâduringâfetalâlife,âthereâisâdataâtoâsuggestâthatâthisâmayâcauseâanâincreasedâriskâofâhipâfracturesâandâboneâlossâlaterâinâlifeâ(56,â60,â61).âSubclinicalâvitaminâDâdeficiencyâinâneonatesâisâassociatedâwithâaânormalâserumâcalciumâlevel,âlowâ25(OH)Dâcon-centrationâ(typicallyâbetweenâ10âandâ20âng/ml),âandâelevatedâserumâPTH,â1,25(OH)2Dâandâalkalineâphosphataseâlevelsâ(30â32).
Inherited causes of ricketsOnceâitâwasârecognizedâthatâvitaminâDâmustâbeâmetabolizedâinâtheâliverâandâkidneysâbeforeâitâcanâcarryâoutâitsâbiologicâeffectsâonâcal-cium,âphosphorus,âandâboneâmetabolism,âitâwasâhypothesizedâthatâaâdefectâinâtheâhepaticâ25-hydroxylationâorârenalâ1Îą-hydroxylationâstepsâwouldâleadâtoâanâinabilityâtoâactivateâvitaminâD,âthusâcausingâ
Table 1Dietary sources of vitamin D
Source VitaminDcontentFortified milk 100 IU/8 ozFortified orange juice 100 IU/8 ozInfant formulas 100 IU/8 ozFortified yogurts 100 IU/8 ozFortified butter 56 IU/3.5 ozFortified margarine 429 IU/3.5 ozFortified cheeses 100 IU/3 ozFortified breakfast cereals ~100 IU/servingEgg yolk ~20 IU/yolkShiitake mushrooms, fresh 100 IU/3.5 ozTuna, canned 236 IU/3.5 ozMackerel, canned ~250 IU/3.5 ozSardines, canned ~300 IU/3.5 ozSalmon, canned ~300â600 IU/3.5 ozSalmon, fresh ~400â500 IU/3.5 ozShiitake mushrooms, sun-dried 1,600 IU/3.5 ozDrisdol (vitamin D2) liquid 8,000 IU/ccCod liver oil 400 IU/tsp
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aâvitaminâDâdeficiencyâlikeâstateâthatâwasâresistantâtoâphysiologicâdosesâofâvitaminâDâ(Figureâ4).âThereâisâonlyâoneâdocumentedâcaseâofâ25-OHaseâdeficiencyâricketsâ(62).âTheâmostâlikelyâreasonâwhyâmoreâcasesâareânotâreportedâisâthatâthereâareâatâleastâ4âdifferentâenzymesâthatâhaveâtheâabilityâtoâconvertâvitaminâDâtoâ25(OH)Dâ(63).
SinceâvitaminâDâundergoesâitsâfinalâactivationâinâtheâkidneys,âseveralâstudiesâofâindividualsâwithââvitaminâDâresistantââdiseasesâcausingâricketsâinâwhichâpatientsâwereâevaluatedâforâaâdefectâinâtheâmetabolismâofâ25(OH)Dâtoâ1,25(OH)2Dâhaveâbeenâreported.âPseu-dovitaminâDâdeficiencyâricketsâ(alsoâknownâasâhereditary,âvitaminâDâdependentâricketsâtypeâ1),âaârareâhereditaryâdisorder,âwasâfoundâtoâbeâassociatedâwithâveryâlowâorâundetectableâlevelsâofâ1,25(OH)2Dâinâtheâcirculationâ(64).âTheseâchildrenârespondedâtoâorallyâadminis-teredâ1,25(OH)2D3â(64).âTheâcloningâofâtheârenalâ1-OHaseâenzymeâledâtoâtheâidentificationâofâaâmultitudeâofâpointâmutationsâofâtheâCYP27B1âgene,âwhichâresultâinâeitherâaâpoorlyâfunctionalâ1-OHaseâorâtheâcompleteâabsenceâofâ1-OHaseâactivityâ(65).
Severalâinvestigatorsâreportedâchildrenâwithâsevereâricketsâwhoâoftenâhadâalopeciaâandâextremelyâelevatedâlevelsâofâ1,25(OH)2Dâ
(65,â66).âSomeâchildrenâwithâthisâdisease,âvitaminâDâresistantârick-etsâ(hereditary,âvitaminâDâdependentâricketsâtypeâ2),ârespondedâtoâpharmacologicâdosesâofâvitaminâDâorâ1,25(OH)2D3,âwhileâoth-ersâdidânotâ(66,â67).âPointâmutationsâinâtheâVDRâgeneâareârespon-sibleâforâtheâvitaminâDâresistance.âChenâetâal.â(68)âreportedâaânewâformâofâvitaminâDâresistance,âhereditaryâvitaminâDâdependentâricketsâtypeâ3,âcausedâbyâtheâabnormalâexpressionâofâaâhormoneâresponseâelementâbindingâproteinâ(HRBP)âthatâbindsâtoâtheâVDREâandâthereforeâpreventsâtheâ1,25(OH)2D-VDR-RXRâcomplexâfromâbindingâtoâitsâresponsiveâelement.âThisâpatientâhadânormalâVDRâexpressionâandâwasâcompletelyâresistantâtoâ1,25(OH)2D3âaction.âChildrenâwithâtheseâvitaminâDâresistanceâsyndromesâoftenâsufferâfromâsevereâboneâdeformitiesâandâmoreâmarkedâhypocalcemiaâthanâchildrenâwithâvitaminâDâdeficiencyârickets.âTreatmentâdependsâonâtheâcauseâandâseverityâofâtheâvitaminâDâresistance.âChildrenâhaveârespondedâtoâpharmacologicâdosesâofâvitaminâD,âphysiologicâandâpharmacologicâdosesâofâ1,25(OH)2D3âandâitsâanalogâ1Îą-hydroxyvi-taminâD3,âasâwellâasâintravenousâinfusionsâofâcalciumâandâphos-phorusâ(30,â64,â66â69).
Figure 4Biochemical changes in calcium and phosphorus metabolism due to vitamin D or calcium deficiency, vitamin Dâresistant syndromes, or hypo-phosphatemic syndromes that cause rickets or osteomalacia. Vitamin D and/or calcium deficiency leads to a decrease in the level of ionized calcium (Ca2+), resulting in an increase in PTH. PTH increases tubular reabsorption of calcium to correct the serum calcium into the normal range. However, in severe calcium and vitamin D deficiency, the serum calcium is below normal. In addition, PTH causes phosphorus loss via the urine, resulting in a decrease in serum HPO4
2â. An inadequate calcium-phosphorus product (Ca+2 Ă HPO42â) leads to a defect in bone miner-
alization that causes rickets in children and osteomalacia in adults. There are various inherited and acquired disorders that can disrupt calcium and phosphorus metabolism that can also result in defective mineralization of the skeleton. There are 3 inherited syndromes that cause vitamin D resistance. Vitamin Dâdependent rickets type 1 (DDR-1) is due to a mutation of the 1-OHase. A mutation of the VDR gene results in an inef-fective recognition of 1,25(OH)2D, causing DDR-2. A genetic defect that results in the overproduction of hormone response elementâbinding protein (HRBP) eliminates the interaction of 1,25(OH)2D with its VDR, resulting in DDR-3. There are also inherited and acquired disorders that cause severe hypophosphatemia and decrease renal production of 1,25(OH)2D. The acquired disorders X-linked hypophosphatemic rickets (XLH) and autosomal dominant hypophosphatemic rickets (ADHR) are caused by the increased production or decreased destruction, respec-tively, of phosphatonins that include FGF23. Tumor-induced osteomalacia (TIO) is caused by the tumorâs production of FGF23, which results in phosphaturia and a decrease in the renal production of 1,25(OH)2D.
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Inherited and acquired hypophosphatemic ricketsTheseâ disordersâ areâ characterizedâ byâ hypophosphatemia,âdecreasedâ reabsorptionâ ofâ phosphorusâ byâ theâ renalâ tubule,âdecreasedâabsorptionâofâcalciumâandâphosphorusâfromâtheâgas-trointestinalâtract,âandâvaryingâdegreesâofâricketsâorâosteomalaciaâ(70,â71).âPatientsâoftenâhaveânormalâorâreducedâserumâlevelsâofâ1,25(OH)2D,âwhichâisâconsideredâtoâbeâabnormal,âsinceâhypophos-phatemiaâcausesâanâincreaseâinâserumâ1,25(OH)2Dâlevelsâbecauseâitâenhancesâtheârenalâproductionâofâ1,25(OH)2Dâ(70,â72).âOriginallyâitâwasâthoughtâthatâhypophosphatemicâdisordersâwereâcausedâbyâaâdefectâinâaârenalâphosphateâtransportâprotein.âHowever,ârecentâevidenceâsuggestsâthatâotherâfactorsâofâboneâoriginâparticipateâinâmaintainingâphosphorusâhomeostasis,âincludingâfibroblastâgrowthâfactorâ23â(FGF23),âmatrixâextracellularâphosphoglyco-protein,âandâfrizzled-relatedâproteinâ4.âTheseâfactorsâareâcollec-tivelyâknownâasâphosphatoninsâ(73).âWhenâFGF23âisâelevated,âitâcausesâanâinternalizationâofâtheâsodiumâphosphateâcotransporterâinâbothâtheâkidneysâandâintestine,âtherebyâcausingâphosphaturiaâandâdecreasedâintestinalâphosphateâabsorptionâ(74).âItâalsoâinhib-itsâCYP27B1âactivity.âPatientsâwithâautosomalâdominantâhypo-phosphatemicâricketsâ(ADHR)âhaveâaâmutationâinâtheâFGF23 geneâthatâpreventsâorâreducesâFGF23âmetabolicâbreakdown,âleadingâtoâelevatedâFGF23âlevelsâ(70,â75).âTumor-inducedâosteomalaciaâisâcausedâbyâaâsmallâtumorâthatâisâoftenâbenignâandâsecretesâFGF23â(70,â71,â73,â74).âTheâexactâcauseâofâX-linkedâhypophosphatemicâricketsâisâlessâwellâunderstood.âItâhasâbeenâlinkedâtoâaâmutationâofâtheâphosphate regulating endopeptidase homolog, X-linkedâ(PHEX)âgene.âLossâofâitsâexpressionâcausesâoverexpressionâofâFGF23âandâpos-siblyâotherâphosphatoninsâinâbone,âleadingâtoâincreasedâlevelsâofâcirculatingâFGF23â(74).
Thus,âhypophosphatemicâricketsâisâcausedâbyâanâinabilityâtoâmetabolizeâFGF23âorâtheâexcessiveâproductionâofâFGF23â(70,â71,â73,â74)â(Figureâ4).âIntravenousâphosphateâdeliveryâhasâbeenâeffectiveâinâtreatingâricketsâandâosteomalaciaâ(70,â71,â76),âandâremovalâofâtheâtumorâisâcurativeâ(77,â78).âTreatmentâincludesâfrequentâoralâphosphateâadministration,âtypicallyâ250â500âmgâupâtoâ5âtimesâaâday,âasâwellâasâtwiceâdailyâoralâdeliveryâofâ0.5â1.0âÎźgâofâ1,25(OH)2D3â(70,â71,â76).âLessâfrequentâadministrationâofâhigherâdosesâofâphosphateâisâtoâbeâdiscouraged,âsinceâtheâtran-sientâincreaseâinâserumâphosphateâcausesâaâdecreaseâinâionizedâcalciumâandâanâincreaseâinâPTHâlevelâandâcausesâparathyroidâglandsâtoâbecomeâhyperplasticâandâautonomous,âwhichâleadsâtoâtertiaryâhyperparathyroidism.
Prevention and treatment of vitamin Dâ and calcium-deficiency ricketsInâtheâ1940s,âtheârecommendedâintakeâofâvitaminâDâforâinfantsâwasâ100âIU/dâtoâpreventâricketsâ(14).âHowever,âtheâcurrentâaccept-edârecommendationâtoâpreventâricketsâisâaâdailyâ400âIUâdoseâofâvitaminâDâandâadequateâcalciumâintakeâ(32â35,â79).âClinicalâtrialsâinâpretermâinfantsâ(16âdaysâofâage)âwereârandomizedâtoâdailyâvita-minâDâintakesâofâ200âIUâ(90âIU/kg),â400âIUâ(180âIU/kg),âorâ800âIUâ(360âIU/kg)âforâupâtoâoneâmonth.âNoâradiologicalâdifferencesâwereâobservedâbetweenâgroupsâ(80).âTheâ25(OH)Dâlevelsâinâtheâgroupâreceivingâ200âIUâvitaminâDâforâ24â29âdaysâdidânotâchange,âwhereasâtheâgroupsâreceivingâ400âIUâandâ800âIUâforâtheâsameâperiodâofâtimeâshowedâanâincreaseâinâ25(OH)Dâlevelsâofâapproximatelyâ30%.âSimi-larâstudiesâalsoâsuggestedâthatâpretermâinfantsââplasmaâ25(OH)Dâlevelsâwereâmaintainedâfromâearlyâneonatalâlifeâtoâ3âmonthsâwithâadministrationâofâsupplementalâvitaminâDâofâ400âIU/d.âNoâbenefitâinâvitaminâDâstatusâorâforearmâboneâmineralâdensityâwasâobservedâatâaâhigherâdoseâofâ900âIU/dâ(30,â81).âInâEurope,âtheâNutritionâCommitteeâforâtheâEuropeanâSocietyâofâPediatricâGastroenterol-ogy,âHepatologyâandâNutritionârecommendedâaâvitaminâDâintakeâofâ800â1,600âIU/dâ(36).âMawerâetâal.â(36)âgaveâeitherâ1,000âorâ3,000âIUâofâvitaminâD2âdailyâtoâlow-birth-weightâinfantsâwithâaâmeanâweightâofâ1.36âkgâandâfoundâthatâtheâ25(OH)Dâlevelâincreasedâfromâaâbaselineâofâ6â10âng/mlâtoâaâmeanâofâ33âng/mlâinâbothâdoseâgroupsâafterâ7âweeks.âTheyâalsoâobservedâthatâtheâ25(OH)Dâlevelsârapidlyâroseâduringâtheâfirstâweekâandâbeganâtoâplateauâatâ7âweeksâatâapproximatelyâ33âng/ml.âMarkestadetâal.â(23)âtreatedâchildrenâwithâ1,700â4,000âIUâvitaminâD2/dayâforâupâtoâ10âweeksâandâshowedâanâaverageâ25(OH)Dâlevelâofâapproximatelyâ30âng/mlâandâcorrec-tionâofâtheirâbiochemicalâandâskeletalâabnormalities.âPrematureâneonatesâtreatedâwithâ1,200âIUâvitaminâD3/dayâforâ7âdaysâraisedâtheirâ25(OH)Dâlevelâfromâ8âng/mlâtoâ18âng/mlâ(81).âAlthoughâitâisânotâknownâwhatâtheâminimumânormalâlevelâofâ25(OH)Dâshouldâbeâforâinfantsâandâneonatesâbasedâonâtheseâobservations,âitâisânotâunreasonableâforâtheâbloodâlevelâtoâbeâatâleastâ20âng/ml.âHowever,âsinceâthoseâstudiesâshowedâthatâ25(OH)Dâlevelsâreachedâaâplateauâatâapproximatelyâ33âng/ml,âthisâisâlikelyâtheâidealâhealthyâlevelâforâinfantsâandâchildrenâandâisâsimilarâforâadultsâ(23,â24,â30,â36,ââ81â84).âToâachieveâaâhealthyâ25(OH)Dâlevelâofâgreaterâthanâ30âng/ml,ââinfantsârequireâatâleastâ400â1,000âIUâofâvitaminâD/dayâdependingâonâtheirâ25(OH)Dâlevelsâatâbirth.
InfantsâwhoâareâvitaminâDâdeficientâshouldânotâsimplyâreceiveâwhatâisâtheârecommendedâUSâadequateâintakeâ(200âIU/d)â(85)âorâ
Table 2Vitamin D status and associated biochemistries: serum levels of 25(OH)D, 1,25(OH)2D, Ca, HPO42â, alkaline phosphatase (Alk. phos.), PTH, and FGF23
25(OH)D,ng/ml 1,25(OH)2D Ca HPO42â Alk.phos. PTH FGF23 SkeletaldiseaseVitamin D deficiency <20 â â NL â â â NL Rickets/osteomalaciaVitamin D insufficiency 21â29 â or NL NL NL â or NL â or NL NL â BMDVitamin D sufficiency >30 NL NL NL NL NL NL NoneXLH NL â NL ââ â NL â or NL RicketsADHR NL â NL ââ â NL ââ RicketsTIO NL â NL ââ â NL ââ Rickets
The upward-pointing arrows (â and ââ) indicate that the level is moderately or markedly above the normal range, respectively, and the downward-point-ing arrows (â and ââ) indicate that the serum level is moderately or markedly below the normal range, respectively. NL represents levels within the normal range. BMD, bone mineral density; XLH, X-linked hypophosphatemic rickets; ADHR, autosomal dominant hypophosphatemic rickets; TIO, tumor-induced osteomalacia.
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evenâ400âIU/dâbutâratherâshouldâbeâaggressivelyâtreatedâwithâphar-macologicâdosesâofâvitaminâDâinâorderâtoâbuildâupâtheâbodyâstoresâofâvitaminâDâandâquicklyâcorrectâtheâvitaminâDâdeficiency.âTheâbestâmethodâtoâeffectivelyâtreatâandâcureâricketsâisâtoâgiveâaâtotalâofâ5â15âmgâ(200,000â600,000âIU)âofâvitaminâD2âorâvitaminâD3âorallyâwithâadequateâdietaryâcalciumâ(86).âTheseâdosesâcanâbeâgivenâsafelyâeitherâasâaâsingle-dayâtherapyâorâasâdailyâdosesâofâ2,000â4,000âIU/dâ(50â100âÎźg/d)âforâ3â6âmonthsâ(30,â86,â87).âTypicallyâthereâisârapidâcorrectionâofâbothâserumâcalciumâandâphosphorusâlevelsâwithinââ6â10âdaysâandânormalizationâofâPTHâlevelsâwithinâ1â2âmonths.âAlkalineâphosphataseâdeclineâandâhealingâofâradiologicâsignsâofârick-etsâareâobservedâwithinâ3â6âmonthsâdependingâonâtheâseverityâofâtheâdeficiencyâ(30,â86).âForâthoseâwhoâmayânotâcomplyâwithâthisâregime,âitâisârecommendedâthatâ5âmgâ(200,000âIU)âofâvitaminâDâbeâgivenâasâaâsingleâoralâdose,âwithâaâfollow-upâdoseâofâ5âmgâ3âmonthsâlater.âItâisâimperativeâtoâinitiateâtherapyâwithâlargeâdosesâofâvitaminâD,ââsinceâgivingâsmallâdailyâdosesâofâ200â400âIU/dâwillânotârestoreâade-quateâstoresâofâvitaminâDâasârapidlyâasâeitherâaâsingleâlargeâdoseâorâdailyâdosesâthatâareâ10-âtoâ20-foldâhigherâthanâtheârecommendedâadequateâintakeâ(AI)â(30,â85,â86,â87).âForâinfantsâandâchildrenâwhoâhaveâfatâmalabsorption,âincludingâcysticâfibrosisâpatientsâ(88),âitâisârecommendedâthatâsubcutaneousâorâintramuscularâadministrationâbeâused.âAlternatively,âcontrolledâexposureâtoâsunlightâorâUVâradia-tionâfromâaâcommercialâlampâisâadvisableâ(5,â6,â12â14,â30,â33,â88).
Sunlight, UV irradiation, and neonatal and maternal vitamin D supplementationRegularâandâsensibleâsunâexposureâduringâtheâmonthsâofâtheâyearâwhenâvitaminâDâproductionâisâpromotedâisâstillâtheâmostâphysi-ologicâwayâtoâpreventâvitaminâDâdeficiencyâinâinfantsâandâyoungâchildrenâ(1,â24,â80,â89).âSeasonalâvariationsâinâserumâ25(OH)Dâinâchildrenâandâadultsâisâwellâdocumented,âwithâlevelsâreachingâaâpeakâinâtheâmiddleâofâtheâsummerâandânadirâatâtheâendâofâtheâwinterâinâbothâtheâNorthernâandâSouthernâHemispheresâ(1,â19,â24,â57,â89).âSinceâbreastâmilkâhasâveryâlittle,âifâany,âvitaminâDâ(usuallyânoâmoreâthanâ25âIU/l),âitâisâusuallyâinadequateâinâsatisfyingâtheâinfantâsârequirementâ(85,â87,â90).âThus,âifâtheâinfantâisâreceivingânutritionâsolelyâfromâbreast-feedingâandâifâtheâmotherâisâvitaminâDâdeficient,âtheâinfantâwillâbecomeâvitaminâDâdeficientâandâwillâlikelyâdevelopâricketsâ(30,â37,â90).
Neonatesâandâyoungâchildrenâwhoâdoânotâreceiveâadequateâvita-minâDâfromâtheirâdietârespondâwellâtoâoralâdosesâofâ1,000â1,500âIU/dâallâyearâupâtoâtheâageâofâ2âandâduringâtheâwinterâupâtoâageâ5âyearsâwithoutâanyâsignâofâvitaminâDâintoxicationâ(30).âThisâpreven-tionâschemeâhasâbeenâveryâeffectiveâinâEuropeâforâat-riskâinfantsâwhoâareâexclusivelyâbreast-fedâorâwhoâareâtooâoldâtoâtakeâformulaâ(30).âPreventionâwithâlowerâdailyâdosesâofâ400â500âIU/dâisârecom-mendedâforâotherâbreast-fedâinfantsâandâforâat-riskâneonatesâandâyoungâinfantsâreceivingâformula.âTheâeffectâofâprovidingâmotherâorâinfantâduringâlactationâwithâsupplementsâofâ400âIUâofâvitaminâDâshowedâthatâitâisâmostâeffectiveâtoâgiveâtheâinfantâvitaminâDâsup-plementationâdaily.âHowever,âHollisâetâal.â(90)âreportedâthatâgivingâlactatingâfemalesâ4,000âIUâvitaminâD3âdailyâprovidesâadequateâvita-minâDâinâbreastâmilkâtoâsatisfyâtheâinfantâsârequirement.
Noncalcemic and nonskeletal consequences of vitamin D deficiency in childrenChildrenâwithâvitaminâDâdeficiencyâoftenâsufferâfromâsevereâmuscleâweaknessâwithâtonelessâandâflabbyâlegsâ(1,â2,â12â14,â30â32).âItâisânowârecognizedâthatâskeletalâmuscleâhasâaâVDRâandâthatâ1,25(OH)2Dâ
improvesâmuscleâfunctionâ(91).âSerumâ25(OH)Dâlevelsâaboveâ30âng/mlâmaximizeâproximalâmuscleâlegâfunctionâinâadultsâ(92).âItâwasâobservedâinâhealthyâadultsâthatâifâtheâserumâ25(OH)Dâwasâgreaterâthanâ20âng/ml,âthereâwasâaâsignificantâincreaseâinâlungâfunction,âwithâanâaverageâincreaseâinâforcedâexpiratoryâvolumeâofâ176âmlâ(93).âCamargoâetâal.â(94)âreportedâaâprospectiveâstudyâofâmaternalâintakeâofâvitaminâDâduringâpregnancyâandâobservedâthatâvitaminâDâdefi-ciencyâwasâhighlyâpredictiveâofâincreasedâriskâforâasthma.
TheâVDRâisâpresentânotâonlyâinâtissuesâthatâregulateâserumâcal-cium,âincludingâtheâsmallâintestine,âboneâcells,âandâkidney,âbutâalsoâinâessentiallyâallâtissuesâandâcellsâinâtheâbody,âincludingâbrain,âcolon,âbreast,âprostate,âpancreas,âheart,â skin,â skeletalâmuscle,âmonocytes,âandâactivatedâTâandâBâlymphocytesâ(1,â20â22,â24).âTheâfirstâinsightâintoâtheânoncalcemicâroleâofâ1,25(OH)2D3âwasâobservedâwhenâ1,25(OH)2D3âwasâincubatedâwithâmouseâandâhumanâleuke-micâcells.â1,25(OH)2D3âinhibitedâleukemicâcellâproliferationâandâinducedâtheâcellsâtoâmatureâ(20â22,â95,â96).âManyâcancerâcellâlinesâandâprimaryâcancerâcellâculturesâthatâpossesâaâVDRâdemonstrateâmarkedâinhibitionâofâgrowthâandâinductionâofâmaturationâwhenâexposedâtoâ1,25(OH)2D3âorâitsâactiveâanaloguesâ(1,â20â22,â24,â96)â(Figureâ5).â1,25(OH)Ddoesâthisâbyâinducingâcellularâmaturation,âregulatingâtheâexpressionâofâp21âandâp27âandâapoptosis,âandâact-ingâasâanâantiangiogenicâfactorâ(20â22,â24,â95,â96).
LivingâatâhigherâlatitudesâandâbeingâproneâtoâvitaminâDâdefi-ciencyâincreaseâriskâofâcancersâofâtheâcolon,âprostate,âbreast,âovary,âesophagus,âandâseveralâotherâtissuesâ(1,â24,â97â99).âItâhasâbeenâsuggestedâthatâmaintenanceâofâaâ25(OH)Dâlevelâgreaterâthanâ20âng/mlâreducesâriskâofâcolon,âprostate,âbreast,âandâovarianâcancerâbyâasâmuchâasâ30â50%â(24,â97â99).âAlthoughâitâisâunknownâwheth-erâvitaminâDâdeficiencyâinâuteroâandâduringâinfancyâandâchild-hoodâwouldâimprintâonâtheâchildâforâtheârestâofâhisâorâherâlifeâanâincreasedâriskâofâtheseâdeadlyâcancers,âtheârecentâobservationâthatâchildrenâexposedâtoâtheâmostâsunlightâhadâaâ40%âreducedâriskâofâdevelopingânon-Hodgkinâlymphomaâ(100)âandâincreasedâsurvivalâfromâmalignantâmelanomaâ(101)âsuggestsâthatâmaintenanceâofâadequateâ25(OH)Dâlevelsâthroughoutâlifeâmayâhelpâreduceâriskâofâmanyâdeadlyâcancersâ(24,â97â99,â102).
Livingâaboveâtheâ35°âlatitudeâforâtheâfirstâ10âyearsâofâlifeâimprintsâonâaâchildâforâtheârestâofâhisâorâherâlifeâaâ100%âincreasedâriskâofâdevelopingâmultipleâsclerosisânoâmatterâwhereâtheyâliveâthereaf-terâ(24,â103,â104).âLivingâatâhigherâlatitudeâandâbeingâproneâtoâvitaminâDâdeficiencyâincreasesâriskâofâseveralâotherâautoimmuneâdiseasesâincludingâtypeâ1âdiabetesâandâCrohnâdiseaseâ(105,â106).âChildrenâinâFinlandâinâtheâ1960sâwhoâreceivedâtheârecommendedâ2,000âIUâofâvitaminâD/dayâatâleastâduringâtheâfirstâyearâofâlifeâandâfollowedâforâtheânextâ31âyearsâdemonstratedâaâreducedâriskâofâdevelopingâtypeâ1âdiabetesâbyâ80%â(105).âFurthermore,âchildrenâfromâtheâsameâcohortâwhoâwereâvitaminâDâdeficientâatâoneâyearâofâageâhadâaâ2.4-foldâincreasedâriskâofâdevelopingâtypeâ1âdiabe-tes.âVitaminâDâdeficiencyâinâuteroâandâduringâtheâfirstâyearâofâlifeâhasâalsoâbeenâlinkedâtoâincreasedâriskâofâtypeâ1âdiabetesâ(107).â1,25(OH)2Dâaffectsâtheâimmuneâsystemâ(106,â108),âand,âasâpan-creaticâisletâβâcellsâhaveâaâVDR,âitâalsoâstimulatesâinsulinâsecre-tionâ(20â22,â24)â(Figureâ5).âThus,âhypovitaminosisâDâinâchildrenâmayâincreaseâtheirâriskânotâonlyâofâtypeâ2âdiabetesâbutâalsoâinsulinâresistanceâandâisletâβâcellâdysfunctionâ(109).
LivingâatâhigherâlatitudeâandâvitaminâDâdeficiencyâareâalsoâasso-ciatedâwithâhypertensionâandâcardiovascularâheartâdiseaseâ(24,â110,â111).âLiâetâal.â(112)âreportedâthatâ1,25(OH)2D3âisâanâeffectiveâregulatorâofâreninâproduction,âwhichâcontrolsâbloodâpressure.âAâ
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studyâinâhypertensiveâadultsâexposedâtoâsimulatedâsunlightâ3âtimesâaâweekâforâ3âmonthsâresultedâinâanâincreaseâinâtheirâ25(OH)Dâlevelsâbyâmoreâthanâ150%âandâaâsignificantâ(6âmmHg)âreductionâinâbothâsystolicâandâdiastolicâbloodâpressureâ(113).
Autocrine production and function of 1,25(OH)2DCirculatingâlevelsâofâ1,25(OH)2Dâareâveryâlowâorâundetectableâinâpatientsâwithâchronicâkidneyâdiseaseâ(114).âItâhasâbeenâassumedâthatâtheâkidneysâareâtheâsoleâsourceâofâ1,25(OH)2D.âHowever,âjustâasâmostâtissuesâandâcellsâinâtheâbodyâhaveâaâVDR,âsoâtooâdoâtheseâtissuesâandâcellsâpossessâtheâabilityâtoâexpressâCYP27B1.âThus,âtheâskin,âprostate,âbreast,âcolon,âlung,âbrain,âandâplacentaânotâonlyâexpressâtheâVDRâbutâalsoâhaveâtheâcapacityâtoâproduceâ1,25(OH)2Dâ(22,â24,â115,â116).âItâisânowârecognizedâthatâ1,25(OH)2Dâhelpsâcon-trolâtheâexpressionâofâmoreâthanâ200âgenesâ(20â22,â24,â117).âItâisâthoughtâthatâ1,25(OH)2Dâmaintainsâcellularâhealthâbyâactingâasâaâsentinelâforâpreventingâmalignancyâ(24,â95,â96)â(Figureâ5).
ActivatedâmacrophagesâalsoâexpressâCYP27B1âandâthusâpro-duceâ1,25(OH)2D.âThisâisâtheâmechanismâbyâwhichâpatientsâwithâ
chronicâgranulomatousâdiseasesâsuchâasâsarcoidosisâandâtubercu-losisâdevelopâaâdisorderâinâcalciumâmetabolismâthatâcausesâhyper-calcuriaâandâhypercalcemiaâ(1,â22,â24).âWhyâmacrophagesâproduceâ1,25(OH)2DâwasâunknownâuntilâLiuâetâal.â (118)âreportedâthatâactivationâofâTLRsâwithâLPSâresultedâinâtheâupregulationâofâtheâexpressionâofânotâonlyâVDRâbutâalsoâtheâCYP27B1âgene.âTheâlocalâproductionâofâ1,25(OH)2Dâinducedâtheâexpressionâofâtheâantimi-crobialâpeptideâcathelicidinâ(LL-37),âwhichâisâthoughtâtoâbeâaâkeyâfactorâinâtheâinnateâimmuneâresponseâwhenâTLRâisâactivatedâbyâanâinfectiveâagentâsuchâasâMycobacterium tuberculosisâ(Figureâ5).âThisâremarkableâobservationâexplainsâwhyâpatientsâwithâTBâoftenâdoâbetterâwhenâplacedâinâaâsolariumâandâexposedâtoâsunlightâorâtakenâtoâhigherâaltitudesâwhereâtheâvitaminâD3âproductionâinâtheâskinâisâmoreâefficientâ(14).âThisâalsoâisâtheâlikelyâreasonâwhyâAfricanâAmericans,âwhoâareâoftenâvitaminâDâdeficient,âandâchildrenâwithâvitaminâDâdeficiencyâhaveâincreasedâsusceptibilityâtoâTBâinfec-tionâ(118).âThisâalsoâmayâexplainâwhyâitâwasâwidelyâreportedâthatâchildrenâwithâricketsâoftenâareâmoreâproneâtoâinfectiousâdiseases,âincludingâtheâcommonâcoldâvirusâ(12â14,â119).
Figure 5Noncalcemic functions of 1,25(OH)2D. Vitamin D coming from the photoproduction of previtamin D or coming from the diet is converted in the liver to 25(OH)D by the vitamin 25-OHase. 25(OH)D is converted in the kidneys by 1-OHase. 1,25(OH)2D not only regulates calcium and phosphorus metabolism but can stimulate the pancreas to produce insulin and to downregulate the renal production of renin. 1,25(OH)2D also interacts with its nuclear receptor (VDR) in a wide variety of tissues and cells and helps maintain normal cell proliferation and differentiation. 25(OH)D can also be converted to 1,25(OH)2D in a wide variety of cells, including colon, prostate, and breast, for the autocrine production of 1,25(OH)2D. It is believed that the autocrine production of 1,25(OH)2D is important for regulating cell growth and maturation, which decreases risk of the cell becoming malignant. 25(OH)D also is metabolized in macrophages by the 1-OHase to produce 1,25(OH)2D. The expression of the VDR and 1-OHase is upregulated when TLR2/1 is stimulated by LPS. This results in an increase in the expression of the VDR and the 1-OHase. The increase production of 1,25(OH)2D increases the nuclear expression of cathelicidin (CD) in the macrophage, which is a cationic peptide that causes the destruction of infective agents including M. tuberculosis.
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ConclusionVitaminâDâdeficiencyâricketsâisâaâsunlightâdeficiencyâdisease.âTheâinabilityâtoâappreciateâtheâbeneficialâeffectâofâsunlightâforâhealthâhadâdevastatingâconsequencesâforâbothâchildrenâandâadultsâforâmoreâthanâ300âyears.âWhenâitâwasâfinallyârealizedâthatâexposureâtoâsunlightâcouldâpreventâandâtreatârickets,âthisâledâtoâtheârecom-mendationâthatâallâchildrenâbeâexposedâtoâsensibleâsunlightâtoâmaximizeâboneâhealth.âTheâfortificationâofâmilkâwithâvitaminâDâeradicatedâricketsâasâaâmajorâhealthâproblem,âand,âtherefore,âitâwasâthoughtâtoâhaveâbeenâconquered.
Ricketsâhas,âhowever,âmadeâanâunfortunateâcomebackâ(120).âTheâmajorâcauseâofâricketsâinâtheâUnitedâStatesâisâaâlackâofâappreciationâthatâhumanâmilkâcontainsâveryâlittleâifâanyâvitaminâDâtoâsatisfyâtheâinfantâsârequirement.âAfricanâAmericanâwomenâareâoftenâvitaminâDâdeficient,âandâwomenâwhoâalwaysâwearâsunâprotectionâandâonlyâtakeâaâprenatalâmultivitaminâareâalsoâatâaâhighâriskâofâvitaminâDâinsufficiency.âIfâtheyâprovideâbreastâmilkâtoâtheirâinfantâasâtheâsoleâsourceâofânutrition,âtheâinfantâwillâbecomeâvitaminâDâdeficient.âIfâtheâinfantâisânotâexposedâtoâsunlightâorâdoesânotâreceiveâaâvitaminâDâsupplement,âtheâinfantâwillâinevitablyâdevelopârickets.âHowever,âtheâskeletalâmanifestationsâofâricketsârepresentâonlyâtheâtipâofâtheâvitaminâDâdeficiencyâiceberg.âVitaminâDâdeficiencyâinâuteroâandâduringâtheâfirstâyearâofâlifeâhasâdevastatingâconsequencesâandâmayâimprintâonâtheâchildâsâlifeâchronicâdiseasesâthatâwillâshortenâhis/herâlifeâspanâ(24,â57).âInâutero,âvitaminâDâdeficiencyâresultsâinâreducedâintrauterineâlongâboneâgrowthâandâslightlyâshorterâgestationâ(121).âThisâhasâbeenâlinkedâtoâincreasedâriskâofâosteoporosisâandâfrac-turesâlaterâinâlifeâ(24,â60,â61,â82,â122).âChildrenâbornâandâraisedâatâlatitudesâbelowâ35°âforâtheâfirstâ10âyearsâhaveâaâ50%âreducedâriskâofâdevelopingâmultipleâsclerosisâlaterâinâlifeâ(103,â104).âNeonatesâwhoâareâvitaminâDâdeficientâduringâtheâfirstâyearâofâlifeâareâ2.4-foldâmoreâlikelyâtoâdevelopâtypeâ1âdiabetesâcomparedâwithâchildrenâwhoâreceivedâ2,000âIUâofâvitaminâD3/dayâ(105).âItâhasâbeenâsuggestedâthatâtheâincreasedâriskâofâdevelopingâschizophreniaâmayâbeâinitiatedâinâuteroâandâduringâchildhoodâdueâtoâvitaminâDâdeficiencyâ(102).âMuscleâfunction,âinnateâimmunity,âcellularâgrowthâandâmatura-tion,âimmunomodulation,âinsulinâsecretion,âasâwellâasâregulationâofâcalcium,âphosphorus,âandâboneâmetabolismâareâallâaffectedâorâcontrolledâbyâvitaminâD.âThus,âensuringâthatâwomenâduringâpreg-nancyâareâvitaminâDâsufficientâandâthatânewbornsâeitherâbeâimme-diatelyâevaluatedâforâtheirâvitaminâDâstatusâbyâmeasuringâ25(OH)DâlevelsâinâcordâbloodâorâgivenâvitaminâDâprophylacticallyâshouldâbeâaâhighâpriority.âVitaminâDâdeficiencyâshouldâbeâimmediatelyâtreatedâwithâatâleastâ1,000âIUâofâvitaminâD2âorâvitaminâD3/dayâforâtheâfirstâweekâofâlife.âAlternatively,âaâsingleâdoseâofâ200,000âIUâofâvitaminâDâshouldâsufficeâforâtheâfirstâfewâmonthsâofâlife.
ThereâhasâbeenâaâgreatâfearâaboutâcausingâvitaminâDâintoxicationâinâneonates.âThisâresultedâfromâtheâpoorlyâdescribedâoutbreakâofâneonatalâhypercalcemiaâinâtheâ1950sâinâGreatâBritainâ(123),âwhichâledâtoâtheâenactmentâofâlawsâinâEuropeâforbiddingâtheâfortificationâofâdairyâproductsâasâwellâasâallâotherâproductsâwithâvitaminâD.âInâ1997âtheâInstituteâofâMedicineârecommendedâthatâtheâAIâforâinfantsâ
andâchildrenâofâallâagesâbeâ200âIU/d.âTheâsameârecommendationâwasâmadeâforâpregnantâandâlactatingâwomen.âTheâsafeâupperâlimitâforâinfantsâagesâ0â12âmonthsâwasâ1,000âIU/dâandâforâchildrenâolderâthanâ1âyearâofâage,â2,000âIU/d.âHowever,âitâisânowâobviousâbasedâonâtheâhistoricalâliteratureâ(14â16)âasâwellâasâtheârecentâliteratureâ(23,â24,â30,â36,â81,â86,â87)âthatâtheseârecommendationsâareâinadequateâwithoutâsensibleâsunâexposure.âItâisâwellâdocumentedâthatâneonatesâandâchildrenâcanâtolerateâaâsingleâdoseâofâ200,000âIUâofâvitaminâD2âorâvitaminâD3âorâdosesâofâvitaminâDâupâtoâ3,000âIU/dâwithoutâanyâuntowardâsideâeffects.âIndeedâ400â1,000âIU/dâtoâmaintainâserumâ25(OH)Dâlevelsâbetweenâ30â50âng/mlâshouldâbeâtheâgoal,âjustâasâitâisâinâadults.âInfantsâandâchildrenâhaveâroutinelyâreceivedâ400â2,000âIUâvitaminâD2âorâvitaminâD3/dayâforâtheâfirstâyearsâofâlifeâwithoutâanyâreportsâofâtoxicityâ(23,â80,â105,â107).âTypically,âdosesâofâmoreâthanâ50,000âIU/dâofâvitaminâD2âwereâfoundâtoâcauseâtoxicityâ(12â14).
InâCanada,âitâisârecommendedâthatâallâinfantsâreceiveâ400âIU/dâfromâbirth.âThisârecommendationâhasâbeenâsuccessfullyâimple-mentedâandâhasânotâresultedâinâanyâreportedâcasesâofâvitaminâDâintoxicationâorâhypercalcemia.âIâbelieveâthatâtheâ200âIUâofâvitaminâDââthatâisârecommendedâbyâtheâAmericanâAcademyâofâPediatricsâisâsuboptimalâ(124).âThisâdoseâmayâpreventâovertâricketsâbutâwillânotâpreventâvitaminâDâdeficiency.
Hopefully,âhistoryâwillânotârepeatâitself.âTheâwidespreadâconcernâaboutâanyâdirectâsunâexposureâincreasingâtheâriskâofâtheârelativelyâbenignâandânonlethalâsquamousâandâbasalâcellâcancersâneedsâtoâbeâputâintoâperspective.âItâisâchronicâexcessiveâexposureâtoâsunlightâandâsunburningâexperiencesâduringâchildhoodâthatâincreasesâriskâofânonmelanomaâskinâcancerâ(125).âMelanoma,âoneâofâtheâmostâfearedâcancersâbecauseâofâitsâabilityâtoârapidlyâmetastasizeâbeforeâitâisâobviousâtoâeitherâtheâpatientâorâphysician,âhasâbeenâbrandedâasâaâsun-inducedâskinâcancer.âHowever,âmostâmelanomasâoccurâonâtheâleastâsun-exposedâareas,âandâitâhasâbeenâreportedâthatâoccupationalâexposureâtoâsunlightâdecreasesâriskâofâmelanomaâ(125).
Theâ30-yearâcampaignâtoârecommendâabstinenceâfromâsunâexpo-sureâhasânotâstemmedâtheâincreaseâinâskinâcancerâincidenceâ(125).âItâisâcuriousâthatâinâtheâ1930sâandâ1940s,âwhenâchildrenâwereâencour-agedâtoâbeâexposedâtoâsunlightâandâartificialâUVâradiationâtoâtreatârickets,âtheâincidenceâofâskinâcancerâdidânotâincrease.âThus,âthereâneedsâtoâbeâaâreevaluationâofâtheâbeneficialâeffectâofâsensibleâexpo-sureâtoâsunlightâasânotedâbyâtheâAustralianâCollegeâofâDermatolo-gistsâandâtheâCancerâCouncilâAustralia,âwhichârecommendâaâbal-anceâbetweenâavoidingâanâincreaseâriskâofâskinâcancerâandâachievingâenoughâUVâradiationâtoâmaintainâadequateâvitaminâDâlevels.
AcknowledgmentsThisâworkâwasâsupportedâinâpartâbyâNIHâgrantsâM01RR00533âandâAR36963âandâtheâUVâFoundation.
Addressâcorrespondenceâto:âMichaelâF.âHolick,âBostonâUniversityâSchoolâofâMedicine,â715âAlbanyâStreet,âM-1013,âBoston,âMassa-chusettsâ02118,âUSA.âPhone:â(617)â638-4545;âFax:â(617)â638-8882;âE-mail:â[email protected].
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