结节病专题课件

结节病专题历史回顾1877年Hutchinson首次报道1例结节病。1940年以来称之为结节病。流行病学结节病是世界性分布，地区差别甚大。瑞典最高，为64／100,000。黑种人发病率较白种人可高达10～17倍。我国1958年始报道了第一例，1990年768例。青、中年多见，女性略多于男性。流行病学男性：30-40岁多发（平均38岁），发病率14.8/100,000。女性：两个发病高峰：25-29岁（10.5/100,000）；65–69岁(11.0/100,000)。女性发病率为男性1.06倍。病因感染因素病毒(疱疹病毒、

EB病毒、逆转录病毒、柯萨奇病毒、CMV)伯氏疏螺旋体痤疮丙酸杆菌结核菌和其他分枝杆菌肺炎衣原体理化因素无机物：铍、铝、锆、滑石粉有机物：枫树粉、黏土临床表现全身表现缺乏特异性，30%~40%病例无临床症状。症状轻微：乏力、低热、食欲不振、肌肉及关节疼痛。肺外表现胸内表现病理非干酪性肉芽肿。结节由聚集的巨噬细胞和上皮样细胞组成。上皮样细胞相互溶合则形成朗罕氏多核细胞。淋巴细胞多在结节周边浸润。临床表现全身表现乏力(＞70%)发热(通常为低热)体重减轻(2-6kg/10-12wk)临床表现---肺外表现心脏

5%心律失常和心肌舒张受限肝脏50%~80%受累但触到者不到20%皮肤25%结节红斑、丘疹、斑块眼睛11%~83%畏光、流泪、视力减退、疼痛神经系统10%颅神经麻痹、头痛、癫痫、颅内占位。骨骼及肌肉25%~39%关节痛、肌肉痛。胃肠道系统1.0%腹痛、黄疸、咽下困难血液系统4%~20%贫血、白细胞↓、血小板↓内分泌系统2%~20%高血钙、糖尿病、下丘脑、肾脏6%肾功能衰竭、肾结石腮腺40%肿大、疼痛OcularLesionsEyeinvolvementin11-83%Uveitismostcommon-fluorescenceangiographyifposterioruveitisissuspected-chronicuveitismayleadtogranuloma,cataract,blindnessOthereyelesions:conjunctivalfollicles,lacrimalglandenlargement,keratoconjunctivitissicca,dacryocystitis,retinalvasculitisMacularedemalefteyeofamalesarcoidosispatient,28yrsskeletalsystemJointpains:25-40%ofpatientsDeformingarthritis:rareAcute/transientorchronic/persistentBonecystsoccuronlyinassociationwithchronicskinlesionsNeurologicalmanifestationsofsarcoidosis

Cranialnerveneuropathy/palsyNeuro-ophthalmologicalsyndromesAsepticmeningitisHydrocephalusCerebralsarcoidlesionsSpaceoccupyinglesions;seizuresPsychiatricmanifestationsSpinalcordinvolvementPeripheralneuropathyMuscleinvolvement/myopathyClinicallyrecognizableinvolvementlessthan10%Centralnervoussystemsarcoidosisdiagnosisandmanagement.ZajiceketalQJM;1999Neurosarcoidosisin68patientsNeurosarcoidosis:diagnosticwork-upCerebrospinalfluidanalysis:

usuallynotspecificNeuroimaging:

especiallyMRImostsensitive,butnotspecific(appearanceshighlyvariable)Neurophysiologicalstudies:

EEG;EMGandnerveconductionstudiesBiopsy:

brain,nerve,muscle24人随访7年A-V传导阻滞37%需要装起搏器者29％束支传导阻滞不完全25％完全25％心包积液12％左室功能降低58％猝死8％

OtherManifestationsHaematologicalabnormalities-anaemia:4-20%;haemolyticanaemia:rare-leukopenia:upto40%,rarelysevere;reflectsperipheraldepletionofT-cellsbonemarrowinvolvement:rareLymphnodes:palpablein30-40%Gl-tract:involvementinlessthan1%Kidneys:rarelyinterstitialnephritisbygranulomas;morecommonlyrenalfailurerelatedtohypercalcemiaandnephrocalcinosisLiverInvolvementGranulomasin50-80%ofliverbiopiesLiverenlargementin20%Serumalkalinephosphataseandtranferaseselevatedin30%Portalhypertension,hepaticfailure:rareAsymptomaticpatientswithmildbiochemicalliverabnormalitiesdonotrequiretreatmentGallium-67scintigraphyinsarcoidosis:PandasignIntensetraceruptakeinbothlacrimalandparotidglands临床表现---胸内表现咳嗽胸痛呼吸困难咯血气道高反应性胸腔积液Nonproductivecough,dyspnoeaandchestpainoccurringin30–50%ofpatientsCracklesarepresentin＜20%Clubbing,israrelyobservedinsarcoidosisFatigueandimpairedqualityoflife(QoL)arefarmorecommonChestradiographicstagesofsarcoidosisStageFrequency0Normal5-10%IBHL50%IIBHLandparenchymalinfiltrates25%IIIParenchymalinfiltrateswithoutBHL15%IVSignsoffibrosis5-10%临床表现---临床分期胸片表现CTCT和高分辨CT能较为准确估计结节病的类型、程度和淋巴结的诊断。由于分期是按胸片所见，胸片上定为I期的，在CT特别是高分辨CT上则可能见有肺实质、间质浸润，这种差异是存在的。诊断胸片及胸CTCT常见的典型表现：①广泛的小结节，以胸膜下分布为主②小叶间隔增厚③结构紊乱④有聚集成肿块的表现CT少见的表现：①蜂窝样改变②囊性改变和支气管扩张③肺泡实变CT表现纤维支气管镜检查病理诊断：黏膜活检41%~57%TBLB40%~90%电视引导穿刺or开胸活检90%BALF淋巴细胞比例增加CD4/CD8比值增高Thediagnosticyieldoftransbronchiallungbiopsyishigh,reachingupto80%,iffourtofiveadequatesamplesareobtained.Bronchialmucosalbiopsiesshouldalsobetakensincethehistologicaldemonstrationofgranulomaispossiblein40–60%,evenwhenthebronchialmucosaisgrosslynormal.Whengrossendoscopicfindings,suchasmucosalnodularity,oedemaorhypervascularityarepresent,theyieldmayreach90%Inparticular,thecombinationofthetwomethodswasassociatedwiththehighestdiagnosticyield(93.7%overallsensitivity),TBNAalone(93.7%versus65.6%;p=0.011)TBBalone(93.7%versus62.5%;p=0.005).北京协和医院的资料经病理证实并且行纤支镜检查的结节病患者，共81例，其中男性24例，女性57例；年龄最小25岁，最大70岁，平均47.6±8.5岁。病程最长18年，最短仅20天，平均为14.1±30.5个月。北京协和医院的资料支气管粘膜活检的总阳性率为64.4%，其中以粘膜小结节活检阳性率最高，可达88.0％；TBLB的总阳性率为60.9%，其中以IIa期和I期阳性率最高，分别达到72.0％和55.6％；TBEB和TBLB联合检查对结节病诊断的总阳性率为71.7％。PredictiveModelofBALtoDiagnoseInterstitialLungDiseaseDrentdevelopedasoftwareprogramtoevaluateBALfluid.HighlymphocytesSarcoidosisExtrinsicallergicalveolitisHighplasmacellsandmastcellsExtrinsicallergicalveolitisHighneutrophilsandeosinophilsIPFDrentetalAJRCCM1996;153:736PredictiveValueofBAL

Retrospectivestudyofsixyears1748patientswithinflammatorylungdiseaseslavagedOnlypatientswithspecificfinaldiagnosisanalyzed583(33%)239casesofsarcoidosisAnalysisCelldifferentialCD4:CD8ratioWelkerL,JorresRA,CostabelU,MagnussenH.EurRespirJ.2004;24:1000-1006BALLymphocytesWelkerL,JorresRA,CostabelU,MagnussenH.EurRespirJ.2004;24:1000-1006

N=239N=112N=66N=17BALCD4:CD8WelkerL,JorresRA,CostabelU,MagnussenH.EurRespirJ.2004;24:1000-1006

N=239N=112N=66N=17BALNeutrophilsWelkerL,JorresRA,CostabelU,MagnussenH.EurRespirJ.2004;24:1000-1006

N=239N=112N=66N=17EffectofCD4:CD8LymphocyteratioinBALonProbabilityofaspecificdiagnosisDiagnosisOddspriortoBAL<0.50.5-3.5>3.5Sarc33.79.140.369.1*IPF15.813.612.25.2†EAA9.327.3†17.212.5WelkerL,JorresRA,CostabelU,MagnussenH.EurRespirJ.2004;24:1000-1006*p<0.001†p<0.05Effectof%ofNeutrophilsinBALonProbabilityofaspecificdiagnosisDiagnosisOddspriortoBAL<4%4-20%21-50%Sarc33.742.4*19.6*19.5IPF15.87.3*31.4*22.0EAA9.39.110.312.2WelkerL,JorresRA,CostabelU,MagnussenH.EurRespirJ.2004;24:1000-1006*p<0.001PREDICTIVEACCURACYOFBRONCHOALVEOLARLAVAGEFLUIDCELLRESULTSINSARCOIDOSISLymphocytes(%)CD4/CD8SensitivitySpecificityChi-square15.0↑3.0↑89.762.840.320.0↑4.5↑91.157.030.0Sarcoidosispatients,n=97,others,n=65肺功能检查早期肺功能可正常后可发生弥散功能障碍、限制性通气功能障碍部分患者出现阻塞性通气功能障碍Lungfunctiondisturbances

in1084sarcoidosispatients

whichtypeofventilatoryimpairment

isthemostcommon?P.Boros,M.Martusewicz-Boros,

M.Franczuk,S.WesolowskiMaterial:1084patients(579

M,505

F)age:40.6±11.3(18-78)smokingstatus:activesmokers 19.4%ex-smokers 24.2%neversmokers 56.4%sarcoidosisinstagesI(BBS1,n=113),II(BBS2,n=340),III(BBS3,n=84),IV(BBS4,n=6),nostagegiven(BBS,n=541)

timeperiod:JAN

2002–NOV2005n=543Results(lungvolumes):Results(DLCOandCstinallpatients):Results(DLCOandCstinnon-restrictives):Results(DLCOandCstinnon-restrictives):Results(FEV1/VCandMMEFinallpatients):Airflowlimitation

(loweredFEV1/VCand/orMMEFinallpatients):Airflowlimitation

(loweredFEV1/VCand/orMMEFineverandneversmokers):█

MMEFonly,█

MMEFandFEV1/VC,█

FEV1/VConly,█

noairflowlimitationAirflowlimitation

(loweredFEV1/VCand/orMMEFinallpatientsandacc.tosmokingstatus):19%28%23%Airflowlimitation

(loweredFEV1/VCand/orMMEFinallpatientsandacc.tostage):█

MMEFonly,█

MMEFandFEV1/VC,█

FEV1/VConly,█

noairflowlimitation17%31%23%33%Restrictivepatternexpressed

asloweredlungvolumesindices

wasobservedonlyin7.2%ofpatientsLungparenchymainvolvementpronouncedasdiminishedCst

and/orDLCOwasdetectedin42%

ofnon-restrictivepatientsAirflowlimitation(reducedFEV1/VCand/orMMEF)wasfoundinapproximately23%ofpatientsregardlessoftheyweresmokersornotIn42%ofcaseslungfunctionindiceswereinnormalrangeResults:Summarysmokers:evernever

Expectedrestrictivepatternofventilatoryimpairment

isuncommon,especiallyin

earlystagesofsaroidosis,whileCstandDLCOreductionismoresensitiveinrevealinglung

functiondisturbances.Airflowlimitation(↓FEV1/VCand/or↓MMEF)

isafrequentphenomenoneveninneversmokerssarcoidosis

patients.Conclusions:FREQUENCYOFINCREASEDsACE

LEVELSINVARIOUSDISEASESBerylliumdisease75%Sarcoidosis57%Silicosis42%Leprosy34%Primarybiliarycirrhosis27%Histoplasmosis16%Extrinsicallergicalveolitis14%Asbestosis11%Tuberculosis4%Hodgkin'sdisease3%诊断标准1.胸片示双肺门及纵隔淋巴结肿大（偶见单侧），伴或不伴有肺内网状、结节状、片状阴影。2.组织活检证实或符合结节病。3.Kveim试验阳性反应。4.sACE升高。5.5IUPPD试验阴性或弱阳性反应。6.高血钙、高尿钙、AKP增高、Ig增高、67镓扫描阳性、BALF中TLC及CD4/CD8升高。

具有1，2或1，3条者可诊断为结节病。第4、5、6条为重要的参考指标。注意综合诊断、动态观察。结节病的治疗

NaturalhistoryofsarcoidosisSpontaneousremission:60-70%Chronicorprogressivecourse:10-30%Seriousextrapulmonaryinvolvementatpresentation:4-7%Permanentsequelae:10-20%Mortality:1-5% (respiratory,centralnervous,cardiac)

ATS/ERS/WASOGStatement1999TreatmentforSarcoidosisWhichpatient?Whichdrug?Whichdose?Whichtapering?Whichduration?Whichassessment?Frequencyofresolutionofchestradiographafter2yrsNevilleE,etal.QJMed1983AdversePrognosticFactorsLupuspernioChronicuveitisAgeatonset>40yrChronichypercalcemiaNephrocalcinosisBlackraceProgressivepulmonarysarcoidosisNasalmucosalinvolvementCysticbonelesionsNeurosarcoidosisMyocardialinvolvement哪些病人需要治疗ATS/ERS/WASOG：累及心脏、神经系统、肾脏、或高钙血症，累及眼部、局部用药无效。肺结节病：II～III期的患者、有肺功能损伤（Dlco)、有肺部症状明显。结节病的治疗药物结节病治疗药物：糖皮质激素硫唑嘌呤氨甲蝶呤氯喹CTX己酮可可碱苯丁酸氮芥TNF-a抗体远期疗效远期疗效仍有争议，不能改变自然病程。可能会造成病灶吸收延缓，从而病程延长？

长期使用激素滴眼液延缓结节病的自动缓解ACE(IU/ML)MasayukiNara,etal.TohokuJ.Exp.Med.2004；202：275－282N-10N=14P=0.037NS0.05mg/drop,tidfor1year长期使用激素滴眼液延缓结节病的自动缓解BHL(%)MonthsN-10N=14NSP=0.029MasayukiNara,etal.TohokuJ.Exp.Med.2004；202：275－2820.05mg/drop,tidfor1year激素治疗结节病不利的报道Young,etal.1970Isreal,etal.1973Selroos,etal.1974Gottlieb,etal.1997：74％vs8％复发，可能延长病程（随访4年）Harkleroad,etal.1982Eule,etal.1986：22%复发，对病程无影响Izumi.1994：随访10年，24％vs8％胸片异常Reich.2002循证医学结果

Systematic

CochraneReview目的评价糖皮质激素（口服或吸入）对结节病治疗的益处方法对截止到2004年5月为止所有已公开发表的论文，有二位学者进行独立分析：所有病例均经病理确诊随机对照试验（RCT）观察指标主要指标——CXR次要指标——肺功能（VC、DLCO)、预后ParamothayanNS,etal.Corticosteroidsforpulmonarysarcoidosis.TheCochraneDatabaseofSystematicReviews.2005,Issue2.结果12个符合条件的临床试验，1051病人入组口服强的松龙4～40mg/天（或等效剂量）口服激素：有3个试验报道口服激素3～24个月后，CXR有改善，但结果解释需特别注意；次要观察指标，二组无显著性差异。吸入激素：没有足够的数据，能对CXR的变化进行评价；二个试验肺功能无改善，一个试验弥散有改善；一个试验症状有改善。循证医学结果

Systematic

CochraneReview结论口服激素3～24个月后可以改善CXR和症状评分：但很少有证据表明能改善肺功能。有限的二年观察未发现口服激素对长期病程有改善作用。口服激素对II、III期伴有中－重度或进行性症状加重的患者或胸片有进展的患者有益。循证医学结果

Systematic

CochraneReview结节病激素治疗循证医学建议对于需要治疗的结节病患者来说，糖皮质激素仍是治疗结节病的首选药物；（A)肺功能（VC、DLCO）正常的I期病人不需要激素治疗；(A)伴有肺功能损害的II、III期患者，需要激素治疗；（A)新发现的病例对激素的反应比大于2年病程的好；（A)10mg／天的维持量是有效的，且毒副作用低；（B)如病人维持量＞10mg／天，可以考虑联合其他制剂。（B)吸入激素多数认为对这种病因不明的全身性疾病给予局部治疗并起不到根本性作用目前还缺乏明确的关于吸入激素存在可以取代口服激素的证据，因而不作为常规治疗方法口服激素取得效果后，可以使用吸入激素维持治疗；（B)

剂量及疗程炎症活动性指标：胸片、sACE、Ga67肺显像、肺泡灌洗细胞成分目前无准确反映对治疗的反应、炎症活跃程度、复发的可能性及预后的指标。起始剂量：30～40mg/天（0.5mg／kg体重）治疗时间至少1年Usualprednisonetreatmentschedule

Initialtreatment2wkeachdoselevel40mg(8tabs)dailyor20mgtwicedailyif