高钙血症与原发性甲状旁腺功能亢进

高钙血症与原发性甲状旁腺功能亢进 Vo1.6,No.6June,2006Endocrinedisorders15 Hypercalcaemiaandprimary hyperparathyroidismiiii--- EmmaHatfield JeremyTurner Ofthenumerouscausesofhypercalcaemia,primary hyperparathyroidism(PHPT)isthemostcommoninout—patient settingsandmalignancyismostcommoninin—patients.Other causesofhypercalcaemiainclude: ?tertiaryhyperparathyroidism ?thyrotoxicosis ?Addison?sdisease ?milk—alkalisyndrome ?sarcoidosis ?rarely,Paget?sdiseaseofbone. PHPTischaracterizedbyhypercalcaemiawithelevatedorinappro— priatelynormallevelsofparathyroidhormone(PTH)andelevated urinarycalcium.Theprevalenceis1-3/1000.Itismorecommon infemales(3:1)andmostcommonlypresentsaftertheageof 50years.Hypercalcaemiaofmalignancyisreadilydistinguished fromPHPTbyreducedPTHlevels. Aetiology PHPTiscausedbyasolitaryadenomain80—85%ofcases.The remaining15—20%ariseasaresultofmultipleadenomasorfour— glandhyperplasia.Carcinomaoftheparathyroidglandisavery rarecauseofPHPT(<0.5%).PHPTisusuallysporadic,butmay beassociatedwithinheritedsyndromes,mostcommonlymultiple endocrineneoplasia(MEN)typelandtype2a.1nMENl,90—95% ofpatientsdevelopPHPTbytheageof50years,associatedwith pancreaticendocnnetumoursf30—80%)andpituitan,adenomas (15-50%J.InMEN2a,10—25%havemildparathyroidhyperplasia, associatedwithmedullarythyroidcarcinomaf100%1andphaeo chromocytoma(s0%1.otherrareformsofPHPTincludefamilial isolatedhyperparathyroidismandhyperparathyroidism—jaw tumoursyndrome.Thelattercomprisesfibre—osseoustumours oftheiawassociatedwithrenalcystsorWilms?tumour.These inheritedformstendtopresentatayoungerage. Emmana~etdisConsultantinDiabe~sandEndocrinologyat HammersmithHospitalsNHS』s?London,UKandHonorarySenior LecturerintheDepartmentofEndocrinologyatImperialCollegeLondon Conflictsofinterest:nonedeclared. 1eremyTurnerisConsultantEndocrinologistatHammersmithand ChafingCrassHospitals,London,UK.HequalifiedfromtheUniversflyof London,andtrainedinendocrinology,diabetesandgeneralmedicinein LondonandOxford.Hisresearchinterestsincludethemoleculargenetics ofdisordersofcalciumanduratehomeostasis.Confiictsofinterest:none. MEDICINEINTERNAT10NAL ?In2002,theUSNationalInstitutesofHealthpublished guidelinesonwhichgroupsofpatientswithPHP下 shouldundergoparathyroidectomy ?Minimallyinvasivesurgeryisperformedinsome centres,followinggreateruseofpreoperative localizationtechniques ?Incarefullyselectedpatients.conservative managementofPHPrrisanarernativetosurgery ClinicaIfeatures PresentationofPHPThaschangedsincetheintroductionof multichannelaut0analvsers.Mostpatients(75—80%)arenow asymptomaticatdiagnosis,withserumcalciumlessthan 0.25mmol/litreabovethereferencerange. Symptomaticpatientstypicallyhaveplasmacalciumlevelsof 3mmol/litreormoreandmaypresentwithgeneralfeaturesof hypercalcaemiawithorwithoutfeaturesofend—organdamage. Symptomsofhypercalcaemiaincludepolyuria,polydipsiaand renalcolic(ifstoneshaveformed).Otherfeaturestraditionally associatedwithPHPTincludedepression.pepticulcerdiseaseand generalizedachesandpains(„moans,bones,stonesandgroans?), butthesearecommoninthegeneralpopulationanditisunclear whethertheyarecausallyrelatedtoPHPFeaturesofendorgan damageincludeosteoporosis,osteitisfibrosacystica,nephro— lithiasisandneDhr0calcin0sis.Classicalskeletalchanges(Brown tumours,osteitisfibrosacystica)occurinlessthan2%ofpatients, butosteoporosisisacommonfeatureofhyperparathyroidismand predominantlyaffectscorticalbonefe.g.distalradius1morethan trabecularbonefe.g.vertebralbodies1. Diagnosisandinvestigations(Figure1) Elevatedorinappr0priatelynormalPTHwithelevatedserum calciumfcorrectedforserumalbuminc0ncentrati0n1isalmost diagnosticofPHPTheexceptionistherareconditionfamil— ialhypocalciurichypercalcaemia(FHH),whichcanmimicthe serumbiochemistryofPHPTandisdistinguishableonlyonurine biochemistry.FHHisanautosomaldominantconditioncaused byinactivatingmutationsinthecalcium—sensingreceptorgene. Thereismildresistanceoftheparathyroidcellstocalcium,and reducedcapacityofthekidneystoup??regulaterenalcalciumexcre-- tion.Thisresultsinamodestincreaseinserumcalciumwithan inappr0priatelynormalPTHconcentration(slightelevationin 5—10%ofpatients). Thecalcium:creatinineclearanceratioisusedtodistinguish PHPTfromFHH.Thisiscalculatedframsimultaneousmeasure— mentsofurineandserumcalciumandcreatininec0ncentrati0ns. usingthefollowingformula: calciumclearance/creatinineclearance=urinecalciumx plasmacreatinine/plasmacalciumxurinecreatinine Theplasmac0ncentrati0nmustbeconve~edtothesameunits astheotherparameters(mmol/litre).Theratioislessthan0.01 inFHHandmorethan0.01inPHP ?2006TheMedicinePublishingCompanyLtd 16EndocrinedisordersVOI.6.NO.6June.2006 1 InvestigationofhypercaIcaemia Low Highcalcium(ontwooccasions) Ensurenodrugcauses(e.g.thiazides,lithium) NormaIrenaIfunction CheckFrrH MaUgnancy(mostcommoninhospitalsettin Multlplemyeloma Bonymetastases HumoraIhypercalcaemia Sarcoidosis(highlevelsof1,25?dihydroxyvitaminDleadtoincreased gastrointestinalcalciumabsorption)andothergranulomatousdisease VitamlnDtoxicity M?【_alkalisyndrome AddIson?sdisease High.turnoverbonediseasewithimmobilization ?Paget?sdisease ?Thyrotoxicosis VitaminAtoxicity PTH,parathyroidhormone Management Surgeryistheonlycurativetreatment,butisnotappropriateinall patients;thepotentialbenefitsmtlstbeweigbedagainsttherisks ineachcase.Thisprocesshasbeensimplifiedbythepublication ofguidelinesfromtheUSNationa1InstitutesofHeahhfFigure2) However,theseguidelinesdonotapplyintbefamilialPHPTsyn— dromesdescribedabove. Surgery Surgeryisindicatedinallsymptomaticpatientsandasymptomatic patientswithevidenceofend—organdamage,specifically: ?impairedrenalfunction ?highurinarycalciumexcretion【>400mg/day)isarelative indicationforsurgery(thoughitisrecognizedthaturinecalcium excretioncorrelatespoorlywithdevelopmentofrenalstones) .age<50yearsfinaprospectivestudyofconservativelyman— agedpatientswithPHPTfollowedover10years,thedisease progressedinonly27%ofthosewithasylnptomaticPHPT;most oftbosewhoprogressedwere<50yearsofage,andagewas theonlypredictiveindex) .reducedboneminera1density(BMD)(Tscore<一2.5)(results post—surgeryshowanincreaseinBMDof12—14%atlumbar spineandhipthatissustainedover10years.thoughitisunclear whetherreducedBMDinPHPTcorrelateswithreducedbone strengthorincreasedfracturerisk;somestudieshaveshown anincreasedfractureriskassociatedwithPHPTtbatmay declinepost-surgery,butotherstudiesinmildPHPTshowed noincreasedfracturerisk]. MED【C【NE【NTERNATIONAL NormaI MeasurecaIcium:creattnineclearanceratio „0.01 FamillaI hypocalciuric hypercalcaemia 》0.01 Primary hyperparathyroidism Choiceofsurgery:thestandardoperationhasbeenfullneckexplo— ration,withidentificationofallfourglands.However,minimally invasivesurgeryisnowperformedinsomecentres,iftechnetium 2 USNationalInstitutesofHeaLthguidelines Indicationsforsurgeryinprimaryhyperparathyroidism 5ymptomatic Asymptomatic ?Serumcalcium?0.25mmol/litreaboveupperlimitofnormal ?24-hoururinarycalcium,400mg ?Creatinineclearancereducedby3O% ?BonemineraldensityTscore《-2.5(hip,spine,forearm) .Age《50years ?PatientsinwhommedicaIsurveillanceisnotpracticalor deslred Follow?uDofprimaryhyperparathymidismmanaged conservativeiy ?Serumcalcium—biannually ?24.hoururinecalcium—baseline ?Creatinineclearance—baseline ?Serumcreatinine—annuaUy ?Bonemineraldensity一2-3-yearly(hip,spine,forearm) ?RenaluItras0n0graphy—baseline(forassessmentofrenal stones) 2006TheMedicinePublishingCompanyLtd Vo1.6No6June2o06Endocrinedisordersl7 seslanubiSgallnill~lFigure3】attdulIrasollographyshowall ddeBo[1lai1Ithesameloca【iOlclie51e?concorfJaii【?iTheIocaliL/I1 CallbemarkedollthesklrlandsLlrrvperInr】l_e【llIIider10[aI anaesthelicPatlentsinwh[]Inimajis_I,wh0,qiig110concordant haveillldtiglanddisease01whohavetltldergonesurgerybefore areyenerallynolcandidatesforillillilllallyinvasiresurgery ReCtlrrelllPHPTandcasest?onlplicaletIbyecLopicparathyroid adelloii1a【nlediaslina1.iiitracl1vro.1a【er.1lii[kaI1,ltelrl1 oesopJ1ageaIJreqtllrei1i0rextensivePreoperaIiVPInIaglng IhatmayincludeMRI,angiographv,1lidselective,?enous sampling PatielItswid1forJr-glandhyperplasiaareIrealedwifllsubtolal ortelaIparaIhyroideclemy.fo?owedbyI_iet1iL.1【【leatmelllfor l1yp0【1ra111yr0idls【]Tol一lparalhyroidocttll11VandSLIIgicalre inLpIantatioIIofparal}lyroidlisstleiI1tIleforeari11isalla1terllalive stiJIProe[„sPdillsoIllecentl?es PafienIswithsevelehyperparathyroidismw?hsymploBIdtic hvpercalcaeniiarequirelargevolL]rilesOlinlrave]LOLLSI?luid【eg 09nornlaIslllie,3—6liiresOVelthefirst24】lOLlrs)tostdbilize ca】口til1]leve]sOncethepalientjsadeqtlalYjwdrated.aIoop diurelicnla~,I)cddedtoeliCOUFIjgecalciuresis,~dministrationof inlravellOLlSl?1phospl_01]ate【gpalriidronate30—90mgJresults ii1ddecljliei11plasmacalciu_11over3—5Llays..titisnotnormally ilecessarvIIthepaliell【j1asbeellfu】lvrehvdraledandshou【dbe roidediisUleryisil11Illlhen1.becausebispbospl1011dloscanIead IoprofouiiLJpos1operativehypocaIcaeII1ia Antires0rptivcagentsinpHmanagedCOllSerl,ativelv:studies oIaleIldrollaleiiiPHP1showaL/ilicreasei11BMDat2VedrsI11 1hIunlbarsplliewj山【essergai[】satIJlehipandradiLLS.SIIIdies ofIheselectiveoeslrogenreceptormodulatorraloxifenesuggesta beneficiaIeffL~.?l0I1BMDa[1dredtlcedcalciumandbonehirnover, wi1lII10effect(11iPrH Cornplications:postoperatJveIra【]sienthypoparathyroidiSIT)fl/aV dovelopiI1IIPto7001lIienisdsaco[1sequeltceofSllpprestCalcimimetjcagentsinPHPTmanagedCOI lservativelv:『1a— sionollheremainillgglandsThisusuallyresolveswithinlweekcadetisacalcimimelicagenttlfathlcrease sthesensitivityof andmayrequireoralcalciulnsut!plemeIllsIlluS1lhydroxylt1teltcalcittlntsensingreceptorsIoextracell ularcalciun1. therebydirecdy vitaminDinetabolilesMoreseverehvpocaIcaemiainayariseIrentIeducillgPr14secretionAstudyinPH PG?showedreducedcalcium .hungry【lO]les?.icOCCUrsli1pal[enw【lhpre一 12xistiIlg[1oRediseasant1PTH,111ItI10changeii1BMDal12rllOnths? andmayrequileiulravenotlscalcilI111tocorreclIllehypocac~ea PerlnanenthypoparathyroidiSillisrdre【(2.I【hesepatiell【 requirelife—longcalciumstipp[ellieltlSall(]1flIlydroxylatedvihl _】_irlDlllelabol1los Medicalmanagement 1iipa【ienIsw】1hhvPerparall1vr0ldisitlwiIl1oiIyilloderaIcIv elevatedcalciuln.generaIvlceincIhidesellStIr…EadeqLid【eluk1 intakea_1c1noriliaIdietaWcdIciuIT)c1000—1200川Rdayandvl【a. nlltlD(400—800[tJ/day)IPveIs,andavoidingihlazidediuretics ReguIaTnioii】todngwjth6一inoliI…1vsortiIllcaIciLI111alllluaJcreaIi tlilleand3-yearlyBMDIlleastlrelllelilsisrecoI11INle11dedcFiglii-e2: Abonl25%ofPttPTpaleliisnlaILagedCOlIservaiirelyfor10Pars developallindicalionforsLIi?gery1iterestI_elnai11S{.IbIeall{1we1I andrequire[10specificJnlerve[1tions 3Technetiumsestamibiscanshowingarightlowerparathyroid adenoma(BycourtesyofDrJFrank.ChafingCrossHospita1. London,UK.】 MEDICINEINTERNATIONAL REFEREHCES 1TLtrner1J.LeotlelaPD,PanneltAAetalFrequent0c[UrrenEeof anintron4mutationinmuItipleendocrinerieoplasiatype1,[ffn d0crD?We[ab2OO2:B7:2688—93 2panneftAKennedyAM,TurnerIJefMu…p【巳end0ne neop_asIatype1(MEN1)germIinemutationsinm…alI50Iated ma_vhvpeparathyD5mE门出0Jfn坩2D03:58: 639—46 3car口tenJD.RobbinsCM.v1llab【ancaA口LHRP.encodln parabromin,lsmulatedmhyper阳ra【hymldism—faw-IJmor sVndrOme船6即20O2:32:676—80 4Peac0ckM.日lIekianJK【assenPS0J[inacalc巳1hvdrochloride mdin[afn510ng?cermnOrmOcalcemiainpat1ent5wjth口rimarv hype叩arathvr0ism,[m?dDcm0』招02005:90:135—41 FuRTHERREADIN6 Bi}ezIanJ8randlMLRubinM口』prjma叫hypeparachyrojdl5m: nec0ncepbl兀c1J…ca【,densItOmetrj[andbl0[hemica【features fer”Med2005:257:6—17. 引IeJanIRPD【tsJTJFuLeihan6?HaSummarvstatement rT0maworkoponasymptomaticpfimaryhypefparatToidism: aperpectIvef0r【he21stcenr,口,r口20O丑日 5,53—61 0?2.D6The?ed?nePub?sh.ngC?L 内分泌疾病国际内科双语杂志2t)06.Vo1.6,No.6 高钙血症与原发性甲状旁 腺功能亢进 EmmaHatfield~ JeremyTurner~ MEDICINE,2005,33(12):52,54 引起高钙血症的原因很多,门诊病人最常见的 是原发性甲状旁腺功能亢进(PH),而住院病人最 常见的则是恶性肿瘤.其他引起高钙血症的原因还 包括: ?三发性甲状旁腺功能亢进 ?甲状腺毒症 ?Addison病 ?乳碱综合征 ?结节病 ?罕见的,骨Paget病. PH以高钙血症伴甲状旁腺素(H)升高或不 恰当的正常水平及高尿钙为特征.发病率为1/1000, 3/1000.女性多见(3:1),多在50岁以后发病.恶性 肿瘤引发的高钙血症H下降,可以很容易地与 PHPT鉴别. 病因 约80%,85%的PH由单个腺瘤引起.其余 15%,20%源于多发性腺瘤或甲状旁腺4腺体增生. 甲状旁腺癌引起的PH甚为罕见(<0.5%).PH 多散发,但可能与一些遗传综合征有关,最常见的 是多发性内分泌瘤病(MEN)1型和2a型.MEN1 型患者90%,95%于50岁出现PH,伴发胰腺内分 ?EmmaHatfield是英国伦敦Hammersmith医院国家卫生院信托基金 的糖尿病和内分泌学顾问医师,以及伦敦帝围学院内分泌系荣誉高级 讲师.利益冲突,未声明. (JeremyTurner是英国伦敦Hammersmith和ChafingCross医院的顾 问内分泌学家,他毕业于伦敦大学,并在伦敦和牛津进修内分泌学, 糖尿病学和普通内科,他的研究兴趣包括钙和尿酸盐内环境稳定疾病 的分子遗传学.利益冲突,未声明. MEDICINEJNTERNATIONAL 泌肿瘤(30%,80%)和垂体瘤(15%,50%). MEN2a型患者10%,25%有轻度甲状旁腺增生,同时 伴发甲状腺髓样瘤(100%)和嗜铬细胞瘤(50%). 其他罕见的PH还包括家族性单纯甲状旁腺功能亢 进及甲状旁腺功能亢进一颌肿瘤综合征.后者包括颌 纤维骨瘤及肾囊肿或Wilms瘤.这些遗传形式的 PHPT倾向于较年轻时发病. 临床现 自从多通道自动分析仪出现之后,PH的表现 也发生改变.现在多数患者(75%,80%)在诊断时没 有症状,伴血清钙低于正常参考范围上限以上 0.25mmol/L. 具有典型症状的患者血浆钙?3mmol/L,可以出 现高钙血症的一般特征,伴或不伴终末器官破坏的特 征.高钙血症的症状包括多尿,烦渴多饮及肾绞痛 (如果有结石形成).其他传统认为与PHVI?相关的特 征还包括抑郁,消化性溃疡及全身疼痛(“呜咽,骨, 结石,呻吟”),但这些并不特异,且这些是否由PH— VI?引起还不清楚.终末器官破坏的特征包括骨质疏 松,纤维囊性骨炎,肾结石和肾钙质沉着.经典骨改 变(Brown瘤,纤维囊性骨炎)在患者中的发生率小 于2%,但骨质疏松是甲状旁腺功能亢进的一个常见 特征,主要累及骨密质(如桡骨远端)而松质骨(如 椎体)较少累及. 诊断和检查(图1) P1H升高或不恰当的正常水平伴血清钙升高(以 血清白蛋白浓度校正)即可诊断为PH,但需除外 ?2OO6TheMedicinePublishingCompanyLtd 国际内科双语杂志2006,Voi.6,No.6坌鲨49 下降 高钙(两次) 确认非药物引起(如噻嗪类,锂) 肾功能正常 检澳9删 恶性肿瘤(住院病人常见) 多发性骨髓瘤 骨转移 恶性体液性高钙血症 结节病(高水平1,25(OH)VitD,导致胃肠道钙吸收增加) 和其他肉芽肿疾病 维生素D毒性 乳碱综合征 Addison病 高骨转换疾病伴制动 ?Paget?S病 ?甲状腺毒症 维生素A毒性 PTH,甲状旁腺激素 图1高钙血症的检查 罕见的家族性低钙尿高钙血症(FHH).该病血清生 化与PHPT相似,仅能根据尿生化区分.FHH是钙感 受器受体基因失活突变引起的常染色体显性遗传病. 甲状旁腺细胞对钙有轻度抵抗,肾排钙上调能力下 降.这导致血钙中度升高而PTH正常(5%一10%患者 轻度升高). 可以用钙:肌酐清除率比来区分PHPT和FHH. 钙:肌酐清除率比需要同时测定血清和尿中钙和肌酐浓 度,使用如下公式计算: 钙清除率椰酐清除率:尿钙×血浆肌酐/血浆钙×尿 肌酐 血浆浓度必须转化为同一单位(mmol/L).FHH 患者该比值小于0.01而PHPT患者大于0.01. 治疗 外科手术是惟一根治方法,但并不是所有患者均 适合手术;对每个患者必须权衡其手术利弊.美国国 立卫生研究所指南使这一过程简单化(表1).但是该 MEDIClNElNTERNATIONAL 正常 <0.01 . 升藕 i9雌窜丐:肌圈谰懵露蓼比t 家族性低钙 尿高钙血症 { 礞援姓潭被旁 腺功能亢进. 指南不适用于前面介绍的家族性PHPT综合征. 手术 所有有症状及虽无症状但有终末器官破坏证据的 患者均为手术适应证,尤其是: ?肾功能受损 ?高尿钙排泄(>400mg/day)是手术的相对指征 (尽管尿钙排泄与肾结石有较少联系) ?年龄<50岁(一项对经过保守治疗的PHPT患 者跟踪随访10年的前瞻性研究表明仅有27%无症状 PHPT患者疾病进展,多数疾病进展的患者年龄<50 岁,年龄是惟一预测指标) ?骨矿物质密度(BMD)下降(T积分<一2.5) (手术后结果显示腰椎和髋BMD升高12%,14%并持 续10年以上,但PH患者BMD下降与骨强度下降 及骨折危险I生增加是否相关还不清楚;一些研究显示 PH盯相关的骨折危险性手术后可下降,但其他一些 研究显示轻度PHPT不造成骨折危险I生增加). 手术选择术式为全颈部探查确认所有四 个腺体.现在一些机构对锝sestamibi扫描(图3) 和超声检查显示同一部位的腺瘤采用微创手术.在 ?2006TheMedicinePublishingCompanyLtd 内分泌疾病国际内科双语杂志2006— ,Vo1.6— ,No.6 皮肤上进行定位标记并在局部麻醉下进行手术.对 成像不一致,多腺体疾病及有手术史的患者一般不 选用微创手术. PHPT复发和合并异位甲状旁腺腺瘤(纵隔,甲 状腺内,侧颈部,食管后)患者术前需要进行更多 的成像检查,包括MRI,CT,血管造影和选择性静 脉取样. 四腺体增生患者采用甲状旁腺全切或次全切术治 疗,随后内科治疗甲状旁腺功能低下.甲状旁腺全切 和甲状旁腺组织前臂再植入作为另一选择,在一些中 心仍在进行. 并发症70%患者手术后出现一过性甲状旁腺功 能减退,这是剩余腺体被抑制的结果.通常于1周内 恢复,可能需要口服补充钙及let(OH)VitD代谢产 物.”饥饿骨”可能引起严重的低钙血症;见于有原 发骨病的患者,可能需要静脉补钙以纠正低钙血症. 永久性甲状旁腺功能低下罕见(<2%).这些患者需 要终生补钙和10【(OH)VitD代谢产物. 表1美国国立卫生研究所指南 原发性甲状旁腺功能亢进手术指征 有症状者 无症状者 ?血清钙大于正常上限o.25mmol/l ?24小时尿钙>400mg ?肌酐清除率下降30% ?骨矿物质密度T积分<一2.5(髋,椎体,前臂) ?年龄<50岁 ?不易实现或不愿接受内科监护的患者 原发性甲状旁腺功能亢进保守治疗患者随访 ?血清钙——每半年1次 ?24小时尿钙——基线 ?肌酐清除率——基线 ?血清肌酐——每年1次 ?骨矿物质密度——2,3年1次(髋,椎体,前臂) ?肾超声检查——基线(检测肾结石) 内科治疗 对甲状旁腺功能亢进伴血钙仅中度升高的患者, 一 般建议包括确保足量的液体摄入,正常饮食补钙 (1000,1200m~d)及维生素D(400,800IU/d),忌用 噻嗪类利尿剂.推荐6个月定期监测血清钙,每年检 查肌酐,3年检查一次BMD(表1).约25%PHPT患 者保守治疗l0年出现手术指征;其余病情平稳,不 需要特殊干预. 严重的甲状旁腺功能亢进伴有症状性高钙血症患 者需要大量静脉补液(如第一个244,z,-Db充0.9%生 理盐水3,6L)以稳定血钙水平.充分补液后可加用 袢利尿剂促进尿钙排出.静脉给予双磷酸盐(如帕米 磷酸二钠,30,90mg)可使血浆钙在3,5天内下降, 但对经过充分水化的患者并不是