结节病专题

概述,结节病（Sarcoidosis）是一种原因未明、可累及多系统的以非干酪性坏死性肉芽肿为病变特征的疾病。临床上最常影响的是双侧肺门淋巴结肿大及肺脏浸润，其次为眼和皮肤受累。病变也可影响淋巴结、肝、脾、心脏、腮腺、骨骼等其它器官。,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64100,000。黑种人发病率较白种人可高达1017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 ）；6569 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 (2-6 kg / 10-12 wk),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,Ocular Lesions,Eye involvement in 11-83%Uveitis most common - fluorescence angiography if posterior uveitis is suspected - chronic uveitis may lead to granuloma, cataract, blindnessOther eye lesions: conjunctival follicles, lacrimal gland enlargement, keratoconjunctivitis sicca, dacryocystitis, retinal vasculitis,Macular edema left eye of a male sarcoidosis patient, 28 yrs,skeletal system,Joint pains: 25-40% of patientsDeforming arthritis: rareAcute/transient or chronic/persistentBone cysts occur only in association with chronic skin lesions,Neurological manifestations of sarcoidosis,Cranial nerve neuropathy/palsy Neuro-ophthalmological syndromes Aseptic meningitis Hydrocephalus Cerebral sarcoid lesions Space occupying lesions; seizures Psychiatric manifestations Spinal cord involvement Peripheral neuropathy Muscle involvement/myopathy,Clinically recognizable involvement less than 10%,Central nervous system sarcoidosis diagnosis and management. Zajicek et al QJM; 1999,Neurosarcoidosis in 68 patients,Neurosarcoidosis: diagnostic work-up,Cerebrospinal fluid analysis: usually not specific Neuroimaging: especially MRI most sensitive, but not specific (appearances highly variable)Neurophysiological studies: EEG; EMG and nerve conduction studiesBiopsy: brain, nerve, muscle,24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,Other Manifestations,Haematological abnormalities - anaemia: 4-20%; haemolytic anaemia: rare - leukopenia: up to 40%, rarely severe; reflects peripheral depletion of T-cells bone marrow involvement: rareLymph nodes: palpable in 30-40%Gl-tract: involvement in less than 1%Kidneys: rarely interstitial nephritis by granulomas; more commonly renal failure related to hypercalcemia and nephrocalcinosis,Liver Involvement,Granulomas in 50-80% of liver biopiesLiver enlargement in 20%Serum alkaline phosphatase and tranferases elevated in 30%Portal hypertension, hepatic failure: rareAsymptomatic patients with mild biochemical liver abnormalities do not require treatment,Gallium-67 scintigraphy in sarcoidosis:Panda sign,Intense tracer uptake in both lacrimal and parotid glands,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,Nonproductive cough, dyspnoea and chest pain occurring in 3050% of patientsCrackles are present in20%Clubbing, is rarely observed in sarcoidosisFatigue and impaired quality of life (QoL) are far more common,Chest radiographic stages of sarcoidosis,临床表现-临床分期,胸片表现,CT,CT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：广泛的小结节，以胸膜下分布为主 小叶间隔增厚 结构紊乱 有聚集成肿块的表现CT少见的表现： 蜂窝样改变 囊性改变和支气管扩张 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%TBLB 40%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,The diagnostic yield of transbronchial lung biopsy is high, reaching up to 80%, if four to five adequate samples are obtained .Bronchial mucosal biopsies should also be taken since the histological demonstration of granuloma is possible in 4060%, even when the bronchial mucosa is grossly normal.When gross endoscopic findings, such as mucosal nodularity, oedema or hypervascularity are present, the yield may reach 90%,In particular, the combination of the two methods was associated with the highest diagnostic yield (93.7% overall sensitivity), TBNA alone (93.7% versus 65.6%; p=0.011) TBB alone (93.7% versus 62.5%; 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47.68.5岁。病程最长18年，最短仅20天，平均为14.130.5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。,Predictive Model of BAL to Diagnose Interstitial Lung Disease,Drent developed a software program to evaluate BAL fluid. High lymphocytesSarcoidosis Extrinsic allergic alveolitisHigh plasma cells and mast cellsExtrinsic allergic alveolitisHigh neutrophils and eosinophilsIPF,Drent et al AJRCCM 1996; 153: 736,Predictive Value of BAL,Retrospective study of six years1748 patients with inflammatory lung diseases lavagedOnly patients with specific final diagnosis analyzed583 (33%)239 cases of sarcoidosisAnalysisCell differentialCD4:CD8 ratio,Welker L, Jorres RA, Costabel U, Magnussen H. Eur Respir J. 2004;24:1000-1006,BAL Lymphocytes,Welker L, Jorres RA, Costabel U, Magnussen H. Eur Respir J. 2004;24:1000-1006,N=239 N=112 N=66 N=17,BAL CD4:CD8,Welker L, Jorres RA, Costabel U, Magnussen H. Eur Respir J. 2004;24:1000-1006,N=239 N=112 N=66 N=17,BAL Neutrophils,Welker L, Jorres RA, Costabel U, Magnussen H. Eur Respir J. 2004;24:1000-1006,N=239 N=112 N=66 N=17,Effect of CD4:CD8 Lymphocyte ratio in BAL on Probability of a specific diagnosis,Welker L, Jorres RA, Costabel U, Magnussen H. Eur Respir J. 2004;24:1000-1006,* p0.001 p0.05,Effect of % of Neutrophils in BAL on Probability of a specific diagnosis,Welker L, Jorres RA, Costabel U, Magnussen H. Eur Respir J. 2004;24:1000-1006,* p 40 yrChronic hypercalcemiaNephrocalcinosisBlack race,Progressive pulmonary sarcoidosisNasal mucosal involvementCystic bone lesionsNeurosarcoidosisMyocardial involvement,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：IIIII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),Masayuki Nara,et al. Tohoku J.Exp.Med. 2004；202：275282,N-10,N=14,P=0.037,NS,0.05 mg/drop, tid for 1 year,长期使用激素滴眼液延缓结节病的自动缓解,BHL(%),Months,N-10,N=14,NS,P=0.029,Masayuki Nara,et al. Tohoku J.Exp.Med. 2004；202：275282,0.05 mg/drop, tid for 1 year,激素治疗结节病不利的报道,Young, et al. 1970Isreal, et al. 1973Selroos, et al. 1974Gottlieb, et al. 1997：74 vs 8复发，可能延长病程（随访4年）Harkleroad, et al. 1982Eule, et al. 1986 ：22% 复发，对病程无影响Izumi. 1994：随访10年，24 vs 8胸片异常Reich. 2002,循证医学结果 Systematic Cochrane Review,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,Paramothayan NS,et al. Corticosteroids for pulmonary sarcoidosis. The Cochrane Database of Systematic Reviews. 2005, Issue 2.,结果12个符合条件的临床试验，1051病人入组口服强的松龙440mg/天（或等效剂量）口服激素：有3个试验报道口服激素324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 Cochrane Review,结论口服激素324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 Cochrane Review,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：3040mg/天 （0.5mgkg体重）治疗时间至少1年,Usual prednisone treatment schedule,Initial treatment 2 wk each dose level 40 mg (8 tabs) daily or 20 mg twice daily if fever is prominent 30 mg (6 tabs) daily-single 8 AM dose 25 mg (5 tabs) daily-single AM dose 20 mg (4 tabs) daily-single AM dose Daily maintenance after 8 wk 15 mg (3 tabs) daily at 8 AM Later-10 mg (2 tabs) may be adequate Complete 8 mo of treatment Monthly tapering after 8 mo 7.5 mg (1 1/2 tabs) daily 1 mo 5 mg (1 tab) daily 1 mo 2.5 mg (1/2 tab) daily 1 mo 2.5 mg every other day 1 mo,激素剂量,时间,起始剂量,减量,维持量,减量,观察期