佝偻病维生素d缺乏（rickets of vitamin d deficiency）课件

RicketsofvitaminDdeficiency Dr YanHaoDeptofPediatricsTongjiHospital HUSTTel 83662684e mail haoyaner Rickets ThetermricketsevolvedfromtheoldEnglishwordwrick meaningtotwist ThistwistingorbendingoftheboneshasbeenknownsinceantiquityandwasdescribedindetailbyF Glissonin1650atermsignifyingfailuretomineralizegrowingboneorosteoidtissuemanycauses mainlyvitaminDdeficiencySynonymofrachitis VitaminD Fatsoluble stabletoheat acidalkali andoxidationbilenecessaryforabsorptionIn1824 cod liveroilwasfirstlybeprescribedforthetreatmentofricketsbyD Scheutte In1906 Hopkinspostulatedtheexistenceofessentialdietaryfactorsnecessaryforthepreventionofrickets In1928 theNobelprizeforchemistrywasawardedtoAdolfWindausforhisdiscoveryofvitaminD absorpable blood 1 alpha hydroxylase 25 alpha hydroxylase PTHLowP3 VitaminD actuallyreferstoagroupofsteroidmoleculesTwoforms vitaminD2 calciferol andvitaminD3 cholecalciferol Bothareproducedsyntheticallyandareavailableasdietarysupplements EachoftheformsofvitaminDishydrophobic andistransportedinbloodboundtocarrierproteins mainlyvitaminD bindingprotein Thehalflifeof25 hydroxycholecalciferolisseveralweeks whilethatof1 25 dihydroxycholecalciferolisonlyafewhours 1 25 dihydroxycholecalciferol Receptorsarepresentinmostcellsifnotallmostdramaticeffectistofacilitateintestinalabsorptionofcalcium althoughitalsostimulatesabsorptionofphosphateandmagnesiumionsfacilitaterenalreabsorptionofphosphoruspossiblyadirecteffectonbonedepositionandreabsorptionofcalciumandphosphorusCoordinatedwithparathormone PTH andcalcitonin TheVitaminDReceptorandMechanismofAction TheactiveformofvitaminDbindstointracellularreceptorswhichformsheterodimerwithanotherintracellularreceptor theretinoid Xreceptor andbindstoDNAtomodulategeneexpressionInmostcasesstudied theeffectistoactivatetranscription butsituationsarealsoknowninwhichvitaminDsuppressestranscription affinityfor1 25 dihydroxycholecalciferolisroughly1000timesthatfor25 hydroxycholecalciferol whichexplainstheirrelativebiologicalpotencies EffectsofVitaminDonintestine VitaminDstimulatestheexpressionofanumberofproteinsinvolvedintransportingcalciumfromthelumenoftheintestine acrosstheepithelialcellsandintoblood Thebest studiedofthesecalciumtransportersiscalbindin 钙结合蛋白 anintracellularproteinthatferriescalciumacrosstheintestinalepithelialcell EffectsofVitaminDonbone VitaminDinducestheexpressionofosteocalcin 骨钙蛋白 andsuppressessynthesisoftypeIcollagen itstimulatesdifferentiationofosteoclasts However studiesofhumansandanimalswithvitaminDdeficiencyormutationsinthevitaminDreceptorsuggestthattheseeffectsareperhapsnotofmajorphysiologicimportance andthatthecrucialeffectofvitaminDonboneistoprovidetheproperbalanceofcalciumandphosphorustosupportmineralization vitaminDreceptorsarepresentinmostifnotallcellsinthebody potenteffectsonthegrowthanddifferentiationofmanytypesofcellsinvitro physiologiceffectsmuchbroaderotherthanmineralhomeostasisandmineralizationofboneThisisanactiveareaofresearchandamuchbetterunderstandingofthisareawilllikelybeavailableinthenearfuture Parathyroidhormone themostimportantendocrineregulatorofcalciumandphosphorusBone stimulateosteoclaststoreabsorbbonemineral liberatecalciumintoblood Intestine indirectlyenhancesabsorptionofcalciumKidney stimulatesrenaltubularreabsorptionofcalciumbutlossofphosphatereleasedinresponsetolowextracellularconcentrationsoffreecalciumthroughcalcium sensingreceptor Calcitonin synthesizedmainlyinparafollicularorCcellsinthethyroidgland butalsoinawidevarietyofothertissues includingthelungandintestinaltract Bone Calcitoninsuppressesreabsortionofbonebyinhibitingtheactivityofosteoclasts thuspreventseffluxofcalciumandphosphorusfrombone Kidney Calciuminhibitstubularreabsorptionofcalciumandphosphorus CausesofvitaminDdeficiency inadequatedirectexposuretosunlightinadequatevitaminDintakeDiseases steatorrhea hepaticandrenaldiseasesDrugs P450 stimulatingdrugsmaydecreasehydroxylationofvitaminD glucocorticoids anticonvulsant phenytoins phenobarbitalRapidgrowth Bonemetabolism Osteoblasts initiatenewboneformation secretecollagen andsubsequentbonemineralizationinthepresenceofadequatecalciumandphosphorus Osteoclasts secreteenzymeswhichdissolveandremovebothbonematrixandmineral Osteocytes bothresorbandredepositbone manyfactorsaffectbonegrowth phosphorus calcium fluoride andgrowthhormoneareknowntobeinvolved Bonegrowth Intramembranousorossification 膜内成骨 bonetissuereplacesmembranousfibroustissue bywhichthediaphysis 骨干 increasesinwidththroughoutpostnatalgrowthandflatbonesofthecalvarium 颅盖骨 areformedentirely Endochondralorintracartilaginousossification 软骨成骨 bonetissuereplacescartilage bywhichthelongitudinalgrowthofthelongbonesoccursintheepiphyseal 骨骺 growthplate VitaminD deficientricketscanbeconceptualizedasthebody sattempttomaintainnormalserumcalciumlevels whichresultsinhaltedbonemineralization VitD CaPabsorptioninintestine SerumCa Parathyroidgland PTH Osteoclast Boneresorption SerumCarisestonormal Presorptionintubules SerumP Ca P Mineralization Rickets SerumCaremainslow Tetany PTH mechanismofbonedeformities Ca P cartilagecellsgrowthfailure patchycapillarypenetrationfailure frayedandirregularepiphysealline uncalcifiedosteoid therachiticmetaphysis 佝偻病骨骺 skeletaldeformitiesItbecomescompressedandbulgeslaterally producingflaringoftheendsofthebonesandtherachiticrosary 佝偻病串珠 Ifthisprocesscontinues theshaftlosesitsrigidityandisreadilydistortedbystress resultingindeformitiesaswellasfractures Linetestsinrats proximalendofthetibia calcifiedtissuestainedwithsilverappearsblack A Activerickets Thelightbroadzonebetweentheepiphysisandtheshaftrepresentstherachiticmetaphysis R M 佝偻病骨骺 C cartilage O osteoid B Healingrickets Thelineofpreparatorycalcification L P C betweenthezoneofcartilage C andtheosteoid O C Healedrickets Cartilaginousdisc C betweentheepiphysisandthenormalshaft Clinicalmanifestation bonedeformitiesMuscleweakness potbellyIrritationofnervoussystemEvenabnormalindigestion heartandlungfunctionandimmunity mentaldevelopment Bonedeformities 6m occiputorposteriorparietalbonePing Pongballsensation 乒乓颅 7 8m Craniotabes 方颅 flatteninghead1y rachiticrosary 佝偻病串珠 Harrisongroove 郝氏沟 pigeonchest 鸡胸 funnelchest 漏斗胸 1y thickeningofthewristsandankles bowlegs 0型腿 knock knees X型腿 scoliosis 脊柱侧弯 kyphosis 驼背 rachiticdwarfism 佝偻病性侏儒 deformityofthepelvis overextensionofthekneejoints weakankles donotstandorwalkattheusualages Others enlargedanddelayedclosureofanteriorfontanel 前囟 delayederuptionofteeth defectsoftheenamelandextensivecaries etc Palpableenlargementofthecostochondraljunctions rachiticrosary inayounginfant Deformitiesinrickets showingthecurvatureofthelimbs potbelly andHarrisongroove Harrisongroovemeansagrooveinthechestmanifestingadeformityoftheribscausedbythepullofthediaphragm 隔肌 onribs Diagnosis SerumCa maybenormalorlowSerumP almostalwaysislessthan4mg dLserumalkalinephosphatase inevitablyelevatedtomorethan500IU d butmaybenormalinproteinorzincdepletedinfantswithrickets urinarycyclicAMP elevatedSerum25 hydroxycholecalciferol usually 8ug ml normally10 50ug ml 25 125nmol l Nonspecificfindings generalizedaminoaciduria alowbonecitratelevelwithelevatedurinarycitrateexcretion impairedrenalacidification phosphaturia and occasionally glucosuria Radiographyofbone thechangesofricketsareearlyseenradiographicallyattheendsoflongbones Cupping frayingandflaringofepiphysisinsteadofcalcificationlinerachiticmetaphyses 2mm bonedeformities greenstickfractures osteoporosisFraying 磨损 flaring 闪烁 发亮 A Activerickets cuppingandfrayingofthedistalendsoftheradiusandulna doublecontouralongthelateraloutlineoftheradius periostealosteoid Thetwodensezonesintheshaftoftheulnaarecallusesofgreenstickfractures B Healingricketsafter12daysoftreatmentwithvitaminD Zonesofpreparatorycalcification ZPC abovethemintherachiticmetaphysesthereisbeginningcalcification C Healingricketsafter18daysoftreatment Thezonesofpreparatorycalcificationarewelldefined andtherachiticmetaphysesappearwellcalcified Theepiphysisoftheradiushasbecomevisible D Healingricketsafter29daysoftreatment Zonesofpreparatorycalcification rachiticmetaphyses andshaftshavebecomeunited Differentialdiagnosis Differfromricketsofothercauseslikerenaltubularacidosis hereditaryhypophosphatemiawithrickets vitaminD dependentrickets renalrickets hepaticrickets Differfromdiseaseswithbonedeformitieslikecongenitalchestdeformities scurvy 坏血病 chondrodystrophy 软骨发育不良 mucopolysaccharidosis 粘多糖病 Hereditaryhypophosphatemiawithrickets X linkedtype PHEXmutationresultinginlow1hydroxylaseand24hydroxylaseactivityinkidney rickets limbdeformities muscleweakness andbonepain SerumP 0 8mmol L 2 5mg dl autosomalrecessiveinheritance mutationofSLC34A3 thegeneencodingtherenalsodium phosphatecotransporterNaP i Iic hypercalciuria andincreasedserum1 25 dihydroxyvitaminDlevels autosomaldominantform Treatment calcitriol50 70ng kg d phosphate10mg kg d amiloride0 210mg kg d GH0 18 0 37510mg kg w VitaminDresistantrickets familialhypophosphataemiawithricketsvitaminDdependentricketst