貧血治療：鐵代謝與貧血

鐵代謝與貧血

鐵代謝與貧血

鐵穩(wěn)態(tài)調(diào)節(jié)缺鐵性貧血先天性小細(xì)胞低色素貧血鐵限制性紅細(xì)胞生成荷鐵性貧血鐵過載對(duì)造血影響生理狀態(tài)下鐵的吸收、轉(zhuǎn)運(yùn)、再循環(huán)利用及丟失

正常成人鐵含量3～4g

每日需要1-2mg

主要通過腸道吸收調(diào)節(jié)膳食鐵含量

男8mg,女18mg紅細(xì)胞生成需要20～25mg

體內(nèi)鐵的再循環(huán)

上皮脫落每日1-2mg

缺乏鐵排除機(jī)制

二種形態(tài)存在

Fe(II)Fe(III)二者生理pHF溶解度差機(jī)體合成許多鐵蛋白攜帶鐵通過細(xì)胞膜或以非毒性易代謝形式儲(chǔ)存*十二指腸刷狀緣細(xì)胞*正常人每日善食含鐵13～18mg,吸收1～2mg*無機(jī)鐵吸收：

1.還原為Fe(II)：Dcytb屬細(xì)胞色素b561家族，膜結(jié)合型還原酶，鐵缺乏誘導(dǎo)其表達(dá)增加

2.Fe(II)轉(zhuǎn)運(yùn)至腸粘膜細(xì)胞內(nèi)：

Nramp2/DMT1transporter*血紅素鐵吸收與無機(jī)鐵吸收不同:

通過血紅素?cái)y帶蛋白：HCP1*通過Ferroportin

輸出細(xì)胞進(jìn)入血漿同時(shí)經(jīng)穿膜蛋白hephaestin氧化為Fe(III)腸道吸收鐵IronAbsorptionFromDietaryAbsorptionofIntestinalIronHepecidin胃腸道鐵吸收:劑量與效率IDA正常IOLIronRecyclingIronAbsorption/Recycling1~2mg/day25mg/day細(xì)胞獲得鐵：Tf-Fe/TfR細(xì)胞獲得鐵：非Tf-Fe/TfR*幼紅細(xì)胞與骨髓巨噬細(xì)胞直接接觸*DMT1

*MetaltransporterZIP14*L-typevoltage-gated

calciumchannel

cardiomyocytesandneuronalcells*Receptor-mediatedendocytosisofotherformsofprotein-boundiron*Ferritinreceptors:theScara5(scavengerreceptorclassA,member5)andTIM-2(Tcellimmunoglobulinandmucindomaincontaining2)*Hemeimporter:enterocytic,SLC48A1*Cellsalsoacquirehemeindirectly:intravascularhemolysisTransferrin-independentRoutesofIronUptake√

Functionssystemically:

Hepcidin/Ferroportin√

Cellularironmetabolism:

IRP/IRE鐵穩(wěn)態(tài)的維持：

兩個(gè)調(diào)節(jié)系統(tǒng)HEPCIDIN起中心的調(diào)節(jié)作用肝臟產(chǎn)生調(diào)節(jié)腸道吸收巨噬細(xì)胞鐵循環(huán)肝臟貯存鐵釋放腸腔血液缺鐵時(shí)Hepcidin合成減少，F(xiàn)erroportin表達(dá)增加鐵過多時(shí)，肝臟Hepcidin合成增加，與Ferroportin作用，內(nèi)化、降解后者RegulationofHepcidinExpression

RegulationbySystemicIronAvailabilityNormalIronAbsorptionIronDeficiencyIronOverload鐵代謝與貧血

鐵穩(wěn)態(tài)調(diào)節(jié)缺鐵性貧血先天性小細(xì)胞低色素貧血鐵限制性紅細(xì)胞生成荷鐵性貧血鐵過載對(duì)造血影響PrevalenceofAnemia,ID,andIDACausesofIDAIncreasedIronlossAcutehemorrhageChronicorocculthemorrhageMenstruationHemolysisBlooddonationDecreasedIroninDietVegetariandietMalnutritionDecreasedIronAbsorptionCeliacdiseaseInflammatoryboweldiseasePartialgastrectomyIncreasedIronRequirementsPregnancyLactationSymptomsofIDAVeryFrequent?Paleness(45–50%)?Fatigue(44%)?Dyspnoea?Headache(63%)Frequent?Diffuseandmoderatealopecia(30%)?Atrophicglossitis(27%)?Restlesslegssyndrome(24%)Rare?Haemodynamicinstability(2%)?Koilonychia?Plummer-Vinsonsyndrome(<0·1%)IDA診斷*小細(xì)胞低色素貧血*相應(yīng)病史/時(shí)期狀態(tài)*鐵代謝指標(biāo)*BM鐵染色*網(wǎng)織紅細(xì)胞Hgb含量*

鐵劑治療反應(yīng)鐵代謝與貧血

鐵穩(wěn)態(tài)調(diào)節(jié)缺鐵性貧血先天性小細(xì)胞低色素貧血鐵限制性紅細(xì)胞生成荷鐵性貧血鐵過載對(duì)造血影響體質(zhì)性鐵吸收與轉(zhuǎn)運(yùn)異常DMT1diseaseIRIDA銅藍(lán)蛋白缺乏癥先天性轉(zhuǎn)鐵蛋白缺乏癥兒童/自幼發(fā)病小細(xì)胞低色素貧血鐵過載生化檢查/二代基因測(cè)序基因表達(dá)/蛋白功能

TMPRSS6Mutation&IRIDAF21TMPRSS6基因7號(hào)外顯子18970位堿基A>G純合突變（K253E)小細(xì)胞低色素MCV51.8flSI1.58umol/LSF114.63ug/LISAT3%Hepcidin213.77ug/LThefathercarriedaheterozygousnovelsplicingmutationc.1113G>Ainexon9.Themotherwasheterozygousfortwocommonpolymorphismsrs2235321andrs855791inexon17.鐵失利用：SideroblasticAnemiaHeme

合成Fe-S簇生成線粒體編碼蛋白翻譯異常SideroblasticAnemia先天性環(huán)狀鐵粒幼細(xì)胞貧血先天性環(huán)狀鐵粒幼細(xì)胞貧血先天性小細(xì)胞低色素貧血獲得性環(huán)狀鐵粒幼細(xì)胞貧血鐵代謝與貧血

鐵穩(wěn)態(tài)調(diào)節(jié)缺鐵性貧血先天性小細(xì)胞低色素貧血鐵限制性紅細(xì)胞生成荷鐵性貧血鐵過載對(duì)造血影響RegulationofHepcidinExpression

RegulationbyInfammatory

StimuliIn?ammationIncreasesHepcidinSynthesisHepcidinsynthesisbyhepatocytesTranscriptionallyRegulatedbyIL-6STAT-3SignalingPathwayIncreaseHepcidinProductionBloodConcentrationHypoferremia

ToLimitIron-dependentExtracellularMicrobesLimittheAvailabilityofIronforErythropoiesisAnemiaofIn?ammation

(AnemiaofChronicDisease)AnemiaofInflammationAI/ACDMultifactorialanemia

AssociatedwithincreasedcytokineproductionUp-regulationofhepcidinAbnormalironhomeostasisIron-RestrictedErythropoiesis鐵限制性紅細(xì)胞生成Iron-RestrictedErythropoiesis肝臟合成Hepcidin增多，血濃度增高鐵吸收減少&鐵釋放減少血清鐵濃度減低幼紅細(xì)胞可利用鐵減少單核巨噬細(xì)胞鐵阻留

Hepcidin抑制劑Anemiaofin?ammation/Anemiaofcancer

慢性腎病，Hepcidin

腎小球?yàn)V過減少

IRIDA,FerroportinDiseaseLaboratoryDifferentiationofIDAvsACDIDA實(shí)驗(yàn)室檢查鐵代謝與貧血

鐵穩(wěn)態(tài)調(diào)節(jié)缺鐵性貧血先天性小細(xì)胞低色素貧血鐵限制性紅細(xì)胞生成荷鐵性貧血鐵過載對(duì)造血影響RegulationofHepcidinExpression

RegulationbyErythropoietic

SignalsMolecularMechanismsofIronHomeostasisYun,etal.CriticalReviewsinOncology/Hematology,2015GDF-11、GDF-15、TWSG1、ERFE荷鐵性貧血Iron-loadinganemias骨髓紅系無效造血

β地中海貧血

MDSCDAGDF-11/GDF-15/TWSG1/ERFE

低血漿Hepcidin水平繼發(fā)鐵過載祛鐵治療/Hepcidin

治療鐵代謝與貧血

鐵穩(wěn)態(tài)調(diào)節(jié)缺鐵性貧血先天性小細(xì)胞低色素貧血鐵限制性紅細(xì)胞生成荷鐵性貧血鐵過載對(duì)造血影響鐵過載對(duì)造血影響?

原發(fā)血色病&再障：壓力承受與結(jié)局TheeffectofironoverloadandchelationonerythroiddifferentiationTheeffectofironoverloadandchelationonerythroiddifferentiationIronoverloadincreasesintracellularROSlevelsandpromotesapoptosisBCL2IOLEnhanceIntracellularROSBMMNCHPCHSCIOLDamageClonogenicCapacityofHSPCsCFU-EBFU-ECFU-GMCFU-mixSingleCellColony-formingCounts血液學(xué)反應(yīng)可評(píng)價(jià)療效72例去鐵+IST19/48(39.6%)去鐵