甲状腺功能亢进与肝损害

PAGEPAGE4甲状腺功能亢进与肝损害甲状腺功能亢进症(甲亢)所引起的肝脏损害在临床上相当常见。据GurlekA（1）等观察，60.5％的甲亢病人在确诊原发病时被发现至少有一项肝功能异常，而在台湾进行的一项前瞻性研究（Huang.MJ等）中，这个比例更是高达75.8％（2）。本文就甲亢合并肝脏损害作一综述。甲状腺激素对肝脏的影响甲状腺激素和肝脏之间关系密切。血清甲状腺激素浓度增高，对肝脏功能和胆汁代谢都可产生一定的影响。动物试验证实(3，4)，甲状腺激素可使肝脏重量减轻，肝糖原含量下降，氧耗量增加，其增加肝脏氧耗量的作用仅次于对心脏和横膈膜。血清中过多的甲状腺激素可显著降低细胞色素P450、谷胱甘肽水平及谷胱甘肽-S-转移酶活性，从而改变肝内相关酶的活性（5，6）。T4能使α-磷酸甘油脱氢酶(GPD)的活力增强。甲状腺激素可抑制肝内胆固醇的产生，促进肝内胆固醇从胆道排泄或转化为胆汁酸，从而使血清胆固醇降低，干扰胆汁酸代谢。此外，甲状腺激素还能影响胆汁中胆汁酸盐的组成。研究发现，正常鼠胆汁中的牛磺胆汁酸占胆汁酸的30％左右，给予甲状腺素后，牛磺胆汁酸所占的比例可上升至60％-80％。甲亢时肝脏的改变甲亢引起的肝脏损害多数呈亚临床状态。不过，少数病人也可出现黄疸、腹水、凝血酶原明显延长、肝硬化等严重情况。这一情况多发生于甲亢控制不佳或有心衰、严重感染等患者。至于甲亢严重度与肝损是否存在正相关，目前还有所争论。在血生化检查方面，甲亢肝脏损害患者主要表现为ALT、AST、ALP、γ-GT和胆红素升高，血清白蛋白下降（1，2）。其中，以ALP升高最为明显，ALT次之。白蛋白的下降与基础代谢率和病程相关。不过，鉴于甲亢患者往往骨代谢旺盛，成骨细胞和破骨细胞活性增加，且体外试验证实甲状腺激素有直接使骨吸收的作用，因此，升高的ALP不仅仅来自肝脏，也来自骨骼，它对肝脏的评价意义可能不如ALT。在严重肝脏损害时，由于病人血中甲状腺激素结合蛋白浓度的明显改变，总T4水平并不能如实反映甲状腺功能状态，此时，应监测游离T4和甲状腺刺激素（TSH）以正确评估甲状腺功能（7）。甲亢病人肝脏损害的病理改变多种多样，根据尸检结果，大体上可分为三大类：1、急性退行性肝损害如显著脂肪变性，中心性或局灶性肝坏死；2、局部或弥漫性萎缩；3、硬变。这三种改变可同时存在。其中以脂肪浸润最为常见。Beaver等人的研究表明，甲亢患者出现肝脏脂肪浸润的比例可高达87.8％。在病理切片上，可出现肝细胞气球样改变，肝细胞坏死，残存肝细胞胆色素颗粒沉着，肝小叶中央灶性坏死，结缔组织增生，新生毛细血管出现，局部淋巴细胞、单核细胞浸润，毛细胆管及Kupffer细胞增生等（8）。发病机制肝脏在甲状腺激素的转运、代谢、储存、分泌以及活性的发挥过程中都起着重要的作用，而甲状腺激素水平对于维持肝脏正常功能及胆汁正常代谢也是不可缺少的。虽然甲亢引起肝脏损害的机制目前仍不是很清楚，但高水平的甲状腺激素在肝脏损害的发病中所起的作用是毋庸置疑的（7）。甲亢患者高甲状腺激素（T3、T4）通过以下可能途径影响肝功能：（1）高基础代谢率。它使内脏组织耗氧量增加，而与此同时，内脏动脉血流并不增加，造成相对缺氧状态，尤其是肝小叶中央区域细胞供氧相对不足引起该区域坏死，使谷丙转氨酶（ALT）升高，这与临床上甲亢肝损病人肝穿刺活检结果相一致（8）。（2）由于甲状腺激素大量分泌，分解代谢亢进，肝糖原耗损，必需氨基酸和维生素消耗过多，造成负氮平衡，蛋白质缺乏，营养不良而使肝细胞变性，造成肝内胆汁瘀积而引起γ-GT和碱性磷酸酶（ALP）升高。动物试验证实（12），甲状腺激素除可引起与剂量有依赖关系的肝糖原含量降低外，还同时引起剂量依赖性的肝胞液糖皮质激素受体（GCR）数目增多，Gurlek等的研究进一步证实，甲亢患者ALP和γ-GT升高的比例分别高达44.2％和14％，不过由于甲亢患者骨代谢异常也可引起ALP升高，一定程度上削弱了评价肝损的可靠性（2）。（3）甲状腺激素直接作用于肝脏，包括抑制肝脏中葡萄糖醛酸基转移酶，使胆红素和葡萄糖醛酸结合障碍，进而影响胆红素从胆汁中排泄，导致血中胆红素升高（2，7）。随着免疫学的飞速进展，自身免疫机制在甲亢肝损中的地位日益引起人们的关注。目前认为，甲状腺疾病与肝脏疾病有着共同的发病基础，即自身免疫。研究发现，丙肝病毒感染、干扰素治疗等都可诱发甲亢（13，14，15）。甲亢病人往往存在特异性免疫调节缺陷，其抑制性T细胞功能减弱，B细胞和巨噬细胞数目增多（16，17）。95年，CathebrasPJ等报道了第1例甲亢引起的肉芽肿性肝炎，后者的进展与甲亢的严重程度平行发展，经抗甲状腺药物治疗后好转（18）。从分子水平来看，Graves病等甲状腺疾病和肝炎都存在着细胞因子的异常，它们反应了特定人群对某种疾病的易感性，比如，目前已经证实，HLA-A11和HLA-DR4阳性的病人，甲亢合并肝损的比例可能更高（8,19）。这为将来甲亢肝损易感人群的防治提供了新的思路。甲亢引起肝损及其严重程度与甲亢引起的其它并发症也有密切关系，如心功能不全，休克等。通过病例分析，FongTL等人（20）发现，甲亢和/或甲亢合并CHF患者都可出现严重的肝功能异常，包括重度黄疸、凝血酶原时间延长等。而合并心衰者，出现肝功能异常的比例远比无并发症的甲亢病人多。国内资料也Table4.PrevalenceofthyroidfunctiontestabnormalitiesandmanagementofhyperthyroidismatpresentationwithpropylthiouracilhepatotoxicitySurvivors(n=22)Fatalities(n=7)Thyroidfunctiontests,no.ofcases(%)Hyperthyroid5(19)2(28.6)Normal8(38.1)1(14.3)Hypothyroid1(4.8)0(0)Notreported8(38.1)4(57.1)Treatmentofhyperthyroidism,1no.ofcases(%)Radioactiveiodine12(54.5)20(0)Propranolol10(45.5)4(57.1)Methimazole3(13.6)0(0)Oraliodide4(18.2)1(14.3)Thyroidectomy1(4.5)0(0)Notreported7(31.8)3(42.9)1Patientsmayhavereceivedmorethanoneformoftherapy.2P<0.05comparedtofatalities,byFisher’sexacttest.Nopatientwhodiedreceived131I.Thetimingof131Irangedfrom1–15weeks(mean,32±8days)afterpresentationwithhepatotoxicity.Tenofthe12patientswhoreceived131Itherapyweretreatedbeforethehepaticfunctiontestabnormalitiesresolved.据估计ATD相关的肝毒性发生率小于0.5%；PTU相关的肝毒性发生于各个年龄；女性居多；发生肝毒性的PTU剂量与疗程范围甚广；肝活检示非特异的肝细胞坏死；ATD致肝毒性的机制尚不明了，部分是由于机体对PTU产生免疫反应。在暴发性肝功能衰竭中，一些早期预后因素与生存率低（<20%）有关，其包括病人年龄(<11和>40yr)、脑病发生前黄疸延续时间(>7days)、血清胆红素浓度(>300µmol/L)、凝血酶原时间(>50s)。在对PTU所致肝毒性病人进行严密的临床和实验室观察的基础上（因为停用PTU后肝功能衰竭仍可发展），应考虑肝移植。脑病、低凝血酶原血症、肝肾综合征对肝移植不利。血浆置换、用血流灌注法血透可有效地纠正凝血障碍和脑病，为恢复肝功能或进行肝移植创造时机。因TT4受甲状腺激素结合蛋白、血清胆红素（降低T4与甲状腺激素结合蛋白的亲和）、甲状腺功能正常性病变综合征的影响，所以检测FT4才能真正反映患者甲状腺功能状况。病人接受131I治疗比未接受治疗者较少发生严重的肝毒性。治疗应在做腹部CT（如果需要碘造影剂）或因甲状腺毒症需碘化物治疗前进行。碘化物可在131I治疗1周后服。心得安可用于控制甲亢症状；肝酶正常后也可使用MMI。肝毒性出现后可单独使用碘化物。在多数病人，114mg碘化物在7–14天内对甲状腺激素的产生最大的抑制，作用持续1~50天。但通常与ATD合用，碘化物也可加重甲状腺毒症状况。继往肝功能正常的甲亢病人中，高达72%者至少伴有1个肝酶指标的升高。以AKP升高最常见，转氨酶升高是由于甲状腺毒症导致的肝脏的氧耗增加，而肝血流代偿不足。已报道MMI所致肝毒性21例，死亡3例（14%），死亡率与PTU比较无显著差异。MMI所致肝毒性患者的肝活检更多表现为胆汁淤积。Table5.Summaryofrecommendationsformanagementofpropylthiouracilhepatotoxicity1.尽管肝酶研究无法预测哪些病人将发生肝毒性，但肝酶基值的测定可作为治疗过程中发生肝脏疾病的参考。Althoughliverenzymestudiesmaynotpredictwhichpatientswilldevelophepatotoxicity,baselinestudiesmayserveasareferencevalueifsignsofliverdiseasedevelopduringthecourseoftherapy.2.治疗过程中出现明显的肝酶异常时，需停用PTU，并寻找引起肝并的潜在因素。Significantliverenzymeabnormalitiesdetectedduringthecourseoftherapyrequirepromptdiscontinuationofpropylthiouracilaswellasasearchforanyotherpotentialsourcesofliverdisease.3.怀疑有肝毒性的病人需密切随访，因为肝功能障碍在停用PTU后仍有进展。Patientswithsuspectedhepatotoxicityrequirecloseclinicalfollow-upbecauseliverdysfunctioncanprogressdespitediscontinuationofpropylthiouracil.4.对是否需要肝移植的早期认识可能提高生存。Earlyrecognitionoftheneedforlivertransplantationmayimprovesurvival.5.甲状腺状态的判断需结合临床检查和FT4水平，因为高胆红素血症可负向干扰TT4水平。ThyroidalstatusmustbedeterminedbyacombinationofclinicalexaminationandfreeT4levelsbecausehyperbilirubinemiacanadverselyaffecttheinterpretationoftotalT4levels.6.进一步用放射性碘治疗甲亢，随后配以碘化物可能缓解甲亢的恶化。Prompttreatmentoftheunderlyingthyroiddiseasewithradioactiveiodinefollowedbyiodidemaydiminishthechanceofclinicaldeteriorationfrompersistenthyperthyroidism.7.即使肝酶恢复正常仍不能再次用PTU，因为它的肝毒性存在自身免疫的本性。Propylthiouracilshouldnotbereinstitutedevenaftertheresolutionofliverenzymeabnormalitiesduetothepossibleautoimmunenatureofitshepatotoxicity.甲亢相关的肝功能基值的异常没有必要成为运用ATD的禁忌症，现有的资料无法证实肝功能基值异常的病人更易发生PTU所致的肝毒性。由于自身免疫因素参与PTU所致的肝毒性、肝毒性情况在再次用PTU后又出现，所以肝毒性治疗后和肝移植后仍不能用PTU。fFiftyYearsofExperiencewithPropylthiouracil-AssociatedHepatotoxicity:WhatHaveWeLearned?1KatherineV.Williams,SunilNayak,DorothyBecker,JorgeReyesandLynnA.BurmeisterTheJournalofClinicalEndocrinology&MetabolismVol.82,No.61727-17333．

Toxichepatitis(primarilywithpropylthiouracil)andcholestaticjaundice(primarilywithmethimazole)arefortunatelyuncommon.150Toxichepatitiscanbesevereorfatal,buttheincidenceofseriouslivercomplicationsissolowthatroutinemonitoringoffunctiontestshasnotbeenadvised.151,152Livertransplantationhasbeenusedwithsuccessinseveralpatients152.1.IFN-ainducesthyroiddysfunctionin3to14%ofalltreatedpatientswithchronichepatitisC,leadingtohypothyroidism,hyperthyroidism,orthyroiditis.Inafewpatients,thyroiddiseasewilldevelopintheabsenceofantithyroidantibodies,ascenariothatsuggestsanonimmune-mediatedmechanism.:AmJGastroenterol.2001Jan;96(1):165-9.RelatedArticles,Links

Theincidenceandclinicalcharacteristicsofsymptomaticpropylthiouracil-inducedhepaticinjuryinpatientswithhyperthyroidism:asingle-centerretrospectivestudy.

KimHJ,KimBH,HanYS,YangI,KimKJ,DongSH,KimHJ,ChangYW,LeeJI,ChangR.

DepartmentofInternalMedicine,KyungHeeUniversityCollegeofMedicine,Seoul,Korea.

OBJECTIVES:Althoughsymptomaticpropylthiouracil(PTU)-inducedhepaticinjuryisknowntoberare,therehavebeenfewreportsaboutitsexactincidenceinpatientswithhyperthyroidism.Wetriedtoevaluateitsincidenceinasinglecenteranditsclinicalcourse.METHODS:Medicalrecordsof912hyperthyroidpatientswhohadbeendiagnosedbetweenMarch1990andDecember1998werereviewedaboutclinicalcharacteristics,management,andlaboratoryfindings.SymptomaticPTU-inducedhepaticinjurywasdefinedasthedevelopmentofjaundiceorhepatitissymptomswithatleasta3-timeselevationofliverfunctiontests(LFT)withoutothercauses.RESULTS:Fourhundredninety-sevenpatients(age42.6+/-10.7yr,male/female140/357)wereincluded.Clinicallyoverthepatitisdevelopedinsixpatients(1.2%;age,43.7+/-14.8yr;male:femaleratio,3:3)between12and49daysafterPTUadministration.Jaundiceanditchingdevelopedinfivepatients,feverintwo,rashintwo,andarthralgiainone.Bilirubin,ALT,andALPincreasedinfive,four,andsixpatients,respectively(293+/-288micromol/L,143+/-111U/L,and265+/-81U/L;normal,<117U/L).Thetypeofhepaticinjurywascholestaticinthree,hepatocellularinone,andmixedintwopatients.Noneresultedfromviralhepatitis.Therewerenostatisticaldifferencesinage,sex,PTUdose,orT4andT3levelsatinitialdiagnosisbetweenpatientswithandwithouthepaticinjury.LFTnormalizedinallpatientsbetween16and145(72.8+/-46.4)daysafterthePTUwithdrawal.CONCLUSIONS:SymptomatichepaticinjurydevelopsusuallywithinthefirstfewmonthsofPTUadministrationwithrarefrequency,butitsclinicalcourseisrelativelybenignoncethedrugiswithdrawn.However,itmaybedifficulttopredictitsdevelopment,soallpatientsshouldbemonitoredforriseinLFTsatregularintervals,especiallyduringtheearlyperiod.70:EndocrPract.2000Sep-Oct;6(5):367-9.RelatedArticles,Links

AbnormalresultsofliverfunctiontestsinpatientswithGraves'disease.

BiscoveanuM,HasinskiS.

DivisionofEndocrinologyandMetabolism,DepartmentofMedicine,HahnemannUniversityHospital,Philadelphia,Pennsylvania19102,USA.

OBJECTIVE:Todeterminethefrequencyofliverdysfunctioninpatientswithhyperthyroidism.METHODS:Weanalyzedtheclinicalrecordsof30consecutivepatientswithGraves'diseasetoidentifythespectrumofabnormalresultsofliverfunctiontests.Thevaluesforalkalinephosphatase(AP),aspartateaminotransferase(AST),alanineaminotransferase(ALT),gamma-glutamyltransferase(GGT),andtotalbilirubinwereexamined.RESULTS:ThefrequenciesofincreasedlevelsofAP,AST,ALT,GGT,andbilirubininthecurrentstudygroupweresimilartobutsomewhatlowerthanthosereportedinpreviousstudies.Ofthe30studypatients,11(37%)hadatleastoneabnormalresultofaliverfunctiontest.All30patientsinthestudyhaddeterminationsofAP(notfractionated),ofwhich10values(33%)wereabovenormal(range,124to283U/L).Ofthe30patientswhohaddeterminationsofAST,5(17%)hadincreasedvaluesthatrangedfrom36to71U/L.Sixofthe23patients(26%)withdeterminationsofALThadincreasedvaluesthatrangedfrom45to157U/L.Ofthe25patientswhohadmeasurementsofGGT,6hadabovenormalresults(range,69to331U/L).Inaddition,2ofthe24patients(8%)withdeterminationsoftotalbilirubinhadincreasedlevels.CONCLUSION:Thesefindingsindicatethatabnormalresultsofliverfunctiontestsarecommoninpatientswithhyperthyroidismandmakethediagnosisofconcomitant,unrelatedliverdiseasedifficultuntiltheeuthyroidstatehasbeenestablished.:JRSocHealth.1999Jun;119(2):117-20.RelatedArticles,Links

Lessonstobelearned:acasestudyapproach:severehyponatraemiainducedbyprimaryhypothyroidismandassociatedwithpossibleincreasedhepaticsensitivitytothyroxinereplacement.

OlukogaA,HorsmanG,StewartF.

DepartmentofClinicalBiochemistry,HopeHospital,Salford,Manchester.AOlukoga@

Thecaseispresentedofa74year-oldwomanwhowasadmittedwithseverehypo-osmolarhyponatraemiaassociatedwithinappropriatelyraisedurinaryosmolality,andwhowassubsequentlydiscoveredtohaveprimaryhypothyroidism.Anormalserumsodiumconcentrationwasrestoredbymeansofjudiciousfluidrestrictionandthyroidhormonereplacement.Lowdosethyroxinetherapyledtorapidbutmodestincreasesintheserumactivitiesofalanineaminotransferase(ALT)andalkalinephosphatase(ALP);bothreturnedtonormaloveraperiodofthreeweeks.Thesesub-clinicalenzymechangesmayindicatetissue'hyperthyroidism';andinthiscase,thefactthattheyoccurredacutelyatonlylowdosesofthyroxinepossiblysuggestsanincreasedhepaticsensitivitytothehormone.104:ScandJGastroenterol.1999Jun;34(6):618-22.RelatedArticles,Links

Livervolume,portalveinflow,andclearanceofindocyaninegreenandantipyrineinhyperthyroidismbeforeandafterantithyroidtreatment.

AndersenV,SonneJ,Court-PayenM,SlettingS,PripA,MolholmHansenJ.

Dept.ofEndocrinologyandInternalMedicine,HerlevHospital,Denmark.

BACKGROUND:Theaimofthestudywastoexaminelivervolume,portalveinflow,andindocyaninegreen(ICG)andantipyrineclearanceinhyperthyroidismbeforeandafterantithyroiddrugtreatment.METHODS:LivervolumeandbloodflowintheportalveinwereinvestigatedinninefastingpatientswithhyperthyroidismbymeansofcomputedtomographyscanandDopplerultrasound,respectively.ICGclearancewasestimatedbybolusinjectionofICG(0.5mg/kgbodyweight)andantipyrineclearancewithaone-sampletechnique.Allpatientswereinvestigatedbeforeandafter3monthsofantithyroidtreatment,wheneuthyroidismhadbeenachieved.TheWilcoxonmatched-pairstestwasusedforstatisticalanalysis.RESULTS:Themedianlivervolumeincreasedby238(155-289)ml(median,95%confidenceinterval),correspondingto19%,andtheweightby5.0(0.0-8.0)kg(8%),andtheantipyrineclearancedecreasedby8(3.1-34.4)ml/min(16%).Thesechangeswereallsignificant(P<0.05).Therelationbetweenlivervolumeandbodyweightincreasedfrom19.9(16.5-23.7)ml/kgto21.4(17.1-21.9)ml/kg(P=0.11).TheliverbloodflowasestimatedbyICGclearanceandDopplerultrasoundwasnotalteredsignificantlyafterthetreatmentperiod(P=0.07and0.77,respectively).CONCLUSIONS:Thelivervolumeincreasedby19%inninehyperthyroidpatientsduringtreatmentwithantithyroids.Antipyrineclearancewasreducedby16%,whereasliverbloodflow,asestimatedbyICGclearanceandDopplerultrasoundexaminationofportalveinflow,wasnotsignificantlyaltered.Adifferentialregulationoflivervolumeandoxidativemetaboliccapacityinhyperthyroidismwasseen.

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