贫血治疗：铁代谢与贫血

铁代谢与贫血

铁代谢与贫血

铁稳态调节缺铁性贫血先天性小细胞低色素贫血铁限制性红细胞生成荷铁性贫血铁过载对造血影响生理状态下铁的吸收、转运、再循环利用及丢失

正常成人铁含量3～4g

每日需要1-2mg

主要通过肠道吸收调节膳食铁含量

男8mg,女18mg红细胞生成需要20～25mg

体内铁的再循环

上皮脱落每日1-2mg

缺乏铁排除机制

二种形态存在

Fe(II)Fe(III)二者生理pHF溶解度差机体合成许多铁蛋白携带铁通过细胞膜或以非毒性易代谢形式储存*十二指肠刷状缘细胞*正常人每日善食含铁13～18mg,吸收1～2mg*无机铁吸收：

1.还原为Fe(II)：Dcytb属细胞色素b561家族，膜结合型还原酶，铁缺乏诱导其表达增加

2.Fe(II)转运至肠粘膜细胞内：

Nramp2/DMT1transporter*血红素铁吸收与无机铁吸收不同:

通过血红素携带蛋白：HCP1*通过Ferroportin

输出细胞进入血浆同时经穿膜蛋白hephaestin氧化为Fe(III)肠道吸收铁IronAbsorptionFromDietaryAbsorptionofIntestinalIronHepecidin胃肠道铁吸收:剂量与效率IDA正常IOLIronRecyclingIronAbsorption/Recycling1~2mg/day25mg/day细胞获得铁：Tf-Fe/TfR细胞获得铁：非Tf-Fe/TfR*幼红细胞与骨髓巨噬细胞直接接触*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铁稳态的维持：

两个调节系统HEPCIDIN起中心的调节作用肝脏产生调节肠道吸收巨噬细胞铁循环肝脏贮存铁释放肠腔血液缺铁时Hepcidin合成减少，Ferroportin表达增加铁过多时，肝脏Hepcidin合成增加，与Ferroportin作用，内化、降解后者RegulationofHepcidinExpression

RegulationbySystemicIronAvailabilityNormalIronAbsorptionIronDeficiencyIronOverload铁代谢与贫血

铁稳态调节缺铁性贫血先天性小细胞低色素贫血铁限制性红细胞生成荷铁性贫血铁过载对造血影响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诊断*小细胞低色素贫血*相应病史/时期状态*铁代谢指标*BM铁染色*网织红细胞Hgb含量*

铁剂治疗反应铁代谢与贫血

铁稳态调节缺铁性贫血先天性小细胞低色素贫血铁限制性红细胞生成荷铁性贫血铁过载对造血影响体质性铁吸收与转运异常DMT1diseaseIRIDA铜蓝蛋白缺乏症先天性转铁蛋白缺乏症儿童/自幼发病小细胞低色素贫血铁过载生化检查/二代基因测序基因表达/蛋白功能

TMPRSS6Mutation&IRIDAF21TMPRSS6基因7号外显子18970位碱基A>G纯合突变（K253E)小细胞低色素MCV51.8flSI1.58umol/LSF114.63ug/LISAT3%Hepcidin213.77ug/LThefathercarriedaheterozygousnovelsplicingmutationc.1113G>Ainexon9.Themotherwasheterozygousfortwocommonpolymorphismsrs2235321andrs855791inexon17.铁失利用：SideroblasticAnemiaHeme

合成Fe-S簇生成线粒体编码蛋白翻译异常SideroblasticAnemia先天性环状铁粒幼细胞贫血先天性环状铁粒幼细胞贫血先天性小细胞低色素贫血获得性环状铁粒幼细胞贫血铁代谢与贫血

铁稳态调节缺铁性贫血先天性小细胞低色素贫血铁限制性红细胞生成荷铁性贫血铁过载对造血影响RegulationofHepcidinExpression

RegulationbyInfammatory

StimuliInflammationIncreasesHepcidinSynthesisHepcidinsynthesisbyhepatocytesTranscriptionallyRegulatedbyIL-6STAT-3SignalingPathwayIncreaseHepcidinProductionBloodConcentrationHypoferremia

ToLimitIron-dependentExtracellularMicrobesLimittheAvailabilityofIronforErythropoiesisAnemiaofInflammation

(AnemiaofChronicDisease)AnemiaofInflammationAI/ACDMultifactorialanemia

AssociatedwithincreasedcytokineproductionUp-regulationofhepcidinAbnormalironhomeostasisIron-RestrictedErythropoiesis铁限制性红细胞生成Iron-RestrictedErythropoiesis肝脏合成Hepcidin增多，血浓度增高铁吸收减少&铁释放减少血清铁浓度减低幼红细胞可利用铁减少单核巨噬细胞铁阻留

Hepcidin抑制剂Anemiaofinflammation/Anemiaofcancer

慢性肾病，Hepcidin

肾小球滤过减少

IRIDA,FerroportinDiseaseLaboratoryDifferentiationofIDAvsACDIDA实验室检查铁代谢与贫血

铁稳态调节缺铁性贫血先天性小细胞低色素贫血铁限制性红细胞生成荷铁性贫血铁过载对造血影响RegulationofHepcidinExpression

RegulationbyErythropoietic

SignalsMolecularMechanismsofIronHomeostasisYun,etal.CriticalReviewsinOncology/Hematology,2015GDF-11、GDF-15、TWSG1、ERFE荷铁性贫血Iron-loadinganemias骨髓红系无效造血

β地中海贫血

MDSCDAGDF-11/GDF-15/TWSG1/ERFE

低血浆Hepcidin水平继发铁过载祛铁治疗/Hepcidin

治疗铁代谢与贫血

铁稳态调节缺铁性贫血先天性小细胞低色素贫血铁限制性红细胞生成荷铁性贫血铁过载对造血影响铁过载对造血影响?

原发血色病&再障：压力承受与结局TheeffectofironoverloadandchelationonerythroiddifferentiationTheeffectofironoverloadandchelationonerythroiddifferentiationIronoverloadincreasesintracellularROSlevelsandpromotesapoptosisBCL2IOLEnhanceIntracellularROSBMMNCHPCHSCIOLDamageClonogenicCapacityofHSPCsCFU-EBFU-ECFU-GMCFU-mixSingleCellColony-formingCounts血液学反应可评价疗效72例去铁+IST19/48(39.6%)去铁