IBD与结核

克罗恩病与肠结核的鉴别,王 新第四军医大学西京消化病医院2010-06-23,现状与挑战,Its reported 21% of patients eventually diagnosed with CD were initially thought of ITB (J Gastroenterol Hepatol, 1998),In China, Liu reported up to 65% of CD had been misdiagnosed as ITB (Zhonghua Nei Ke Za Zhi, 1981),The delay in diagnosis affect both the patient individually and the society (Am J Gastroenterol, 2003),Diagnostic Challenge for ITB and CD,Marker for differential diagnosis of ITB and CD!,A major concern when treating patients with CD using anti-TNF agents is the development of TB, even more so when the diagnosis is not definite,Epidemiology of CD,Epidemiology of ITB,Both intestinal tuberculosis (ITB) and Crohns disease (CD) are chronic granulomatous disorder with a lot of similarities,Change in epidemiology of ITB and CD make it more difficult in discriminating the two diseases,ITB and CD,(Am J Gastroenterol,2009),克罗恩病 (Crohns disease, CD),Burrill Crohn在1932年最早描述该病, 1973年WHO将其定为Crohn病是一种病因尚不十分明确的肠道慢性炎症性肉芽肿性疾病欧美国家发病率高, 近几年我国发病率呈增加趋势临床表现呈多样性内镜下主要特点为纵行溃疡、铺路石样外观和非干酪性肉芽肿次要特点为线样、阿弗他溃疡样改变。,肠结核 (Intestinal tuberculosis, ITB),由结核分枝杆菌侵犯肠道引起的慢性特异性感染我国常见病之一，发病率较高主要临床表现为腹痛、排便习惯改变、腹部包块和低热、盗汗、消瘦等全身症状诊断金标准：病原学检查和病变组织干酪样坏死部分肠结核与CD患者临床表现、内镜及病理学改变极为相似，鉴别诊断十分困难两种疾病相互误诊率达50%70%,鉴别诊断,ITB内镜下改变,横向溃疡包绕肠腔,回盲瓣多发溃疡瘢痕形成,CD内镜下表现,粘膜鹅卵石样改变,直肠口疮样粘膜溃疡,CD？ITB？,CD患者内镜下横向溃疡,ITB患者鹅卵石样改变,ITB患者直肠口疮样溃疡,ITB病理学表现,肉芽肿形成,干酪样坏死肉芽肿,淋巴肉芽肿,上皮组织基底溃疡,CD病理学表现,模糊的肉芽肿形成,小肉芽肿形成,Caseous necrosis,TB最突出的特征： 肉芽肿最大直径大于400m； 每个活检位点多于四处炎性肉芽肿； 裂隙样溃疡(cessation)； 溃疡基底部上皮样巨噬细胞带；回盲部肉芽肿CD最突出的特征： 无上述肉芽肿特点；局限性结肠炎加重； 隐窝旁炎性肉芽肿；存在组织结构改变/慢性炎症无肉芽肿的病灶 临近部位的深大溃疡 CD肉芽肿比TB更常见于结直肠,病理学特征分析的鉴别诊断价值,Pulimood AB, et al. J Gastroenterol Hepatol. 2005;20(5):688-96,对疑似肠结核患者回肠末段和回盲部大体表现正常的粘膜组织行活检标本组织病理学检查有助于不可忽略的一小部分患者明确诊断,Misra SP, et al. Endoscopy. 2004;36(7):612-6,回顾性分析临床、影像学和组织学确诊的CD (n=25, 104块) 和肠结核(n=18, 41块)结肠镜活检标本,Kirsch R, et al. J Clin Pathol. 2006;59(8):840-4,病理学特征分析的鉴别诊断价值,110例确诊胃肠道结核患者纳入研究，观察全形态学表现谱 (entire morphological spectrum)结果：除了典型的结核病灶如横向溃疡、狭窄、 增生性病损和浆膜结节，肠穿孔发生频率高(32.6%)，并存在肠缺血(7.3%)组织病理学：干酪样、非干酪样、融合型、散在型甚至化脓性肉芽肿等各种类型的上皮样细胞肉芽肿均可见同一病例中出现不同类型肉芽肿并存的现象是重要发现多达44.5%的病例粘膜下层可见肉芽肿病灶85.5%病例的粘膜固有层炎症类型为淋巴浆细胞型,Tripathi PB, et al. Trop Gastroenterol. 2009;30(1):35-9,病理学特征分析的鉴别诊断价值,30例初发内镜活检疑似CD并后续行肠切除的成人患者（25例CD/3例结核/2例憩室并发炎症），长期随访内镜活检。标本经三位病理学医生盲评以下指标：粘膜结构改变、上皮异常、慢性活动性炎症和粘膜下层及粘膜基层改变结果：主要表现为活动性慢性回结肠炎粘膜固有层的慢性炎症，敏感性最好（92.7%），活动性炎症、基层浆细胞增多、结构改变、上皮异常也具有较好的敏感性肉芽肿可见于部分CD患者和所有肠结核患者CD患者的肉芽肿较小、致密、边界清晰；TB为大而融合型肉芽肿,病理学特征分析的鉴别诊断价值,Kumarasinghe MP, et al. Pathology. 2010;42(2):131-7,Clinical, endoscopic, and histological features aid in the differentiation,(Am J Gastroenterol,2009),Serological Tests and Culture,ESR CRP,p-ANCA and c-ANCA,IgA and IgC subtypes of anti-Saccharomyces cerevisiae antibodies,Most reliable- evidence of M. tuberculosis in the intestinal tissues,Acid-fast bacilli staining lacks sensitivity and specificity!,Biopsy culture for M. tuberculosis is time consuming (3-8weeks),Results are frequently negative (accuracy 25-35%),(Word J Gastroenterol,2008;Dig Dis Sci, 2007; ),(Am J Gastroenterol,2009),Fetal Biomarkers,Lactoferrin (Am J Gastroenterol, 1998),Calprotectin,No difference between IBS (Am J Gastroenterol,2003),Controversy in predictive value of UC versus CD (Gut,2005),S100A12 (Gut, 2007),Mostly done in children patients, need more for verification (Gut,2009),Multi-marker panelsCommercial available panel: “IBD first-step” pANCA and ASCA; Pilot study: anti-OmpW, anti-I2, and ASCA,Proteomic approaches for biomarkers,(Inflamm Bowel Dis 2010 ahead of print),Proteomic approaches for biomarkers,(Inflamm Bowel Dis 2010 ahead of print),The tuberculin skin test (TST),The PPD skin test has been extensively studied in cases of pulmonary TB. - e value of this test is unknown for ITB, but from these studies we can conclude that diagnostic value of this test varies according to the population that is being tested.,(Am J Gastroenterol,2009),Promising New Approach,TB-PCR (World J Gastroenterol, 2008),Amplification of insertion element IS6110 that is specific for the M. tuberculosis (J Clin Microbiol, 2006),In situ PCR (Am J Clin Pathol, 2008),方法：原位PCR法检测粘膜活检标本：结核分枝杆菌复合物特异性引物检测IS6110结果：阳性率：肠结核30%(6/20); CD 5%(1/20)结论：如检测敏感性得到提高，原位PCR可有助于区分ITB和CD,Pulimood AB, et al. Am J Clin Pathol. 2008;129(6):846-51,PCR检测肠黏膜结核杆菌DNA的鉴别诊断价值,Image Studies,Chest X-ray,Negative can not exclude ITB,MRI,Not helpful in discriminating CD from ITB Cannot detect small calcification within node or masses,CT,Helpful,(Am J Gastroenterol, 2009),Anti-TB medication trial,The use of anti-TB medications comes with the risk of signifcant side effects and morbidity and can cause unnecessary delay in the management of patients with CD.,(Am J Gastroenterol,2009),Quantiferon-TB gold (QFT-G),QFT-G is a blood test that uses an IFN-r-release assay to measure release of IFN after stimulation in vitro by M. tuberculosis antigen Approved by FDA for diagnosis of latent TB in 2005 May (MMWR Recomm Rep, 2005),ESAT-6,即6kDa早期分泌性抗原，是从结核分枝杆菌短期培养滤液中分离纯化出的一种低分子量分泌性蛋白，具有较强的细胞免疫活性，在抗结核感染的免疫回忆应答中起重要作用。ESAT-6仅存在于致病性分枝杆菌中，包括人型结核杆菌、牛型结核杆菌、非洲分枝杆菌以及苏尔加分枝杆菌、海水分枝杆菌和堪萨斯分枝杆菌等非典型分枝杆菌，BCG及其他非致病性分枝杆菌缺失。,CFP-10,即培养滤液蛋白10，与ESAT-6位于同一基因簇上，两者分布相同，都是RDl区编码的。ESAT-6和CFP10能刺激机体产生特异性IgG，利用ESAT-6和CFP10蛋白抗原能与结核分枝杆菌感染者血中特异性 IgG结合的特点，采用ELISA等方法可特异性区分是真正的结核分枝杆菌感染或是接种BCG后所致敏，该方法明显优于PPD作包被抗原的ELISA法。,QuantiferonTB金标法（QFT-G）PPD:纯化的蛋白衍生物酶联免疫斑点(Elispot)检测外周血中结核分枝杆菌性抗原特异性干扰素(IFN-)水平 结核菌素皮内测试(TST)特异性较低，而QFT-G和结核感染T细胞斑点试验 (T-SPOT.TB)是基于干扰素-Gamma对于结核分枝杆菌特异性抗原的反应。,How Quantiferon Is Performed,QFT vs. TST,In vitroMultiple antigensNo boosting1 patient visitMinimal inter-reader variability Results in 1 dayStimulate 12 hrs,In vivoSingle antigen Boosting2 patient visitsInter-reader variability Results in 2 - 3 daysRead