沈 博
美國克利夫蘭醫(yī)學中心胃腸病學和肝病學系
炎癥性腸病(IBD)主要包括克羅恩病(CD)和潰瘍性結腸炎(UC)兩種疾病,目前其診斷和治療仍是難題?;啬c結腸鏡檢查是該病最重要的診斷手段,主要用于明確診斷、鑒別診斷、癌變監(jiān)控以及評估病灶范圍、疾病活動度和治療應答。
結腸回腸鏡能直接觀察直腸、結腸和末端回腸,并可取黏膜行活檢。除非有禁忌證,如暴發(fā)性結腸炎或中毒性巨結腸,否則對臨床表現疑似IBD的患者均應行結腸鏡檢查,以充分觀察整個直腸、結腸和末端回腸。由于磷酸鈉[1,2]和非甾體消炎藥(NSAIDs)[3]可能致腸黏膜損傷,使腸黏膜發(fā)生類似于IBD的組織學改變,因此在行結腸鏡前應避免使用磷酸鈉作為腸道準備以及服用NSAIDs。
多種腸道疾病的臨床和內鏡下表現與IBD類似,包括感染性腸炎、藥物性腸炎、憩室結腸炎、缺血性結腸炎、器官移植后結腸炎、自身免疫性腸炎和放射性腸炎。組織病理學檢查不僅能為鑒別IBD與非IBD疾病提供有價值的線索,而且對CD和UC亦有一定的鑒別價值。這是因為一旦開始治療后,原本的病灶分布會發(fā)生改變,變得不典型,如UC原本彌漫分布的病灶可能變成片狀分布,甚至發(fā)生直腸未受累的情況,而這類型的病灶原本在CD中更常見[4,5]。在一項包含 39 例 UC 患者的臨床研究[5]中,經局部或系統治療后,內鏡下44%的患者病灶呈片狀分布,13%直腸未受累;33%的患者組織學可見片狀病灶,15%組織學未受累。行結腸鏡檢查時,應特別注意肛門和肛周病變,如膿腫、線狀裂隙、瘺管和大皮贅(“象耳”狀),上述病變多見于CD。CD最典型的內鏡下特征表現為病灶呈節(jié)段性分布(如斑片狀病灶)、直腸未受累、累及末端回腸和回盲瓣、肛門和肛周病灶,可與UC進行鑒別。內鏡下阿弗他潰瘍、非連續(xù)性潰瘍、匐行性潰瘍和黏膜呈鵝卵石樣改變亦可提示CD,但需指出的是,上述特征性改變對診斷CD和UC缺乏特異性。
回腸鏡對鑒別回腸末端的炎癥為CD回腸炎還是倒灌性回腸炎具有重要意義。倒灌性回腸炎在活動性UC中所占的比例約為10%,尤其是并發(fā)原發(fā)性硬化性膽管炎(PSC)的患者[6]。倒灌性回腸炎的內鏡和組織學表現與彌漫性右半結腸炎十分相似,其回盲瓣常保持開放狀態(tài),呈“魚嘴”樣(見圖1)。而CD回腸炎的主要特征為非連續(xù)性潰瘍、末端回腸或回盲瓣變形和狹窄[6~8]。
遠端型UC可能會逐漸向近端發(fā)展[9]。闌尾孔周圍的炎癥稱為“斑片狀盲腸炎”或“斑片狀闌尾周圍炎”,常并發(fā)左半結腸炎而右半結腸正常,應避免與 CD 混淆[10,11]。
結腸鏡結合其他檢查可有效鑒別CD與UC,準確率≥85%[12]。一項對350例IBD患者隨訪超過22個月的前瞻性研究[13]發(fā)現,結腸鏡結合黏膜活檢能準確鑒別89%的CD與UC,4%的患者排除了IBD的診斷,7%診斷為未定型結腸炎。但目前對未定型結腸炎的診斷標準尚未達成共識。
黏膜活檢對診斷和鑒別診斷疑似IBD患者十分重要。雖然目前尚缺乏能明確診斷UC或CD的病理學標準,但黏膜組織病理學評估仍是診斷和鑒別診斷IBD的首要步驟。結腸鏡檢查的進鏡深度應達回腸末端,回腸末端和直腸必須取活檢,右半結腸和左半結腸亦應取活檢。對病灶和病灶周圍看似正常的組織,均應取活檢。不同部位的活檢標本應分瓶標記,這是因為即使是正常黏膜,不同腸段,如結腸與直腸、左半結腸與右半結腸的組織學表現并不相同。Paneth細胞是特殊分化的小腸細胞,但在部分正常人中可出現于右半結腸,而左半結腸和(或)直腸黏膜中的 Paneth細胞則提示為IBD所致的慢性黏膜損傷。需指出的是,內鏡下炎癥的嚴重程度與組織學表現可能并不平行。組織學檢查示黏膜慢性炎癥改變的患者,內鏡下可表現為正常黏膜,反之亦然。
各種急性或活動性炎癥的組織學表現,如嗜中性或嗜酸性粒細胞浸潤、內鏡下糜爛和潰瘍均缺乏特異性,僅反映炎癥的嚴重程度,對診斷IBD無特殊價值?!熬衷钚曰顒有匝装Y”是個令人費解的組織學術語,“局灶性”的描述常被誤解為CD的“節(jié)段性”或“斑片狀”病灶。局灶性活動性炎癥常因服用NSAIDs、感染或使用磷酸鈉行腸道準備所致。
圖1 UC倒灌性回腸炎與CD回腸炎的區(qū)別
目前認為組織學缺乏慢性非特異性炎癥,就不能作出IBD的診斷。這是因為IBD的診斷一旦確立就是終身的。慢性炎癥的組織學特征性改變包括隱窩結構扭曲變形、基底層淋巴細胞增多、絨毛鈍化、細胞固有層單核細胞聚集、幽門腺化生、Paneth細胞化生和黏膜肌層增生[14~16]。非干酪樣肉芽腫提示CD,但內鏡標本中肉芽腫的檢出率僅為15% ~36%[17]。潰瘍和阿弗他糜爛邊緣取活檢能提高肉芽腫的檢出率[18]。肉芽腫對診斷CD缺乏特異性,其還可見于腸結核、真菌和細菌感染、改道性結腸炎、結節(jié)病[19]和排異反應(主要發(fā)生于腸切除術后的縫線處)。對新診斷的CD,尤其是病灶位于末端回腸處,推薦采用AFB染色或黏膜樣本PCR法排除腸結核。在慢性腸炎患者中(無論是否為IBD),腸黏膜上皮破壞(特別是杯狀細胞)可導致黏蛋白樣物質溢出,導致黏液性肉芽腫或異物肉芽腫。
黏膜活檢有助于發(fā)現結腸炎癥,并可對炎癥的范圍和程度進行分級。炎癥范圍可分級為直腸炎、左半結腸炎(炎癥自下向上發(fā)展到脾區(qū))和廣泛性結腸炎(從近端發(fā)展到脾區(qū))。結腸鏡下炎癥嚴重程度與和組織學結果并沒有相關性。與組織學檢查相比,結腸鏡觀察常會低估IBD的嚴重程度[20],尤其是處于治療中的患者。炎癥范圍(廣泛性腸炎、左半結腸炎或直腸炎)的評判更應依賴組織學診斷,而非內鏡檢查[20,21]。
組織學檢查對評估難治性IBD患者和應用免疫抑制劑患者的巨細胞病毒和EB病毒重復感染具有十分重要的意義。在三級醫(yī)療機構中,已常規(guī)開展應用免疫組化判斷巨細胞病毒感染和染色體原位雜交診斷EB病毒感染的工作。
黏膜活檢的主要缺點是無法評價CD透壁性腸炎。手術可獲取理想的腸壁全層病理學標本,但具有創(chuàng)傷性,使其臨床應用受到局限。此外,重度UC患者可發(fā)生淋巴細胞聚集的透壁性腸炎,尤其是在深潰瘍區(qū)域,病理醫(yī)師常將其診斷為未定型結腸炎。
內鏡下UC直腸炎或左半結腸炎的發(fā)生率約為1/3 ~1/2[22,23],隨著病程的延長(如病程 > 20 ~30年),全結腸炎的病變范圍會逐漸縮小[22]。
結腸鏡能客觀評估IBD的疾病活動度,與此相反,主觀癥狀并不能準確判斷疾病的嚴重程度。此外,癥狀評分與內鏡下炎癥程度的相關性以及臨床緩解與黏膜愈合的相關性均較弱[24]。結腸鏡檢查有助于指導藥物治療和判斷是否需手術干預[25,26]。目前有不少基于臨床表現和(或)內鏡檢查結果的疾病活動性評分系統[26~29]。結腸鏡檢查常用于判斷免疫抑制劑和生物制劑抗腫瘤壞死因子治療IBD的療效[30,31]。在最近的一些藥物臨床研究[32,33]中,應用結腸鏡判斷黏膜愈合情況已成為評估IBD結局的重要指標,黏膜愈合預示疾病復發(fā)和日后需外科手術的可能性較低。
病程長、受累腸段廣泛的IBD患者發(fā)展為異型增生甚至結直腸癌(CRC)的危險性明顯增高。CRC風險與長期病程、廣泛重度UC病變范圍、CRC家族史、發(fā)病年齡、倒灌性回腸炎以及并發(fā)PSC呈正相關[34~37]。超過1/3全結腸受累的 CD患者的 CRC風險亦升高[38,39]。受累腸段范圍的評估需由內鏡檢查和病理學檢查共同完成[40]。一項UC的病例對照研究[41]發(fā)現,長期結腸鏡隨訪可明顯降低CRC的死亡率。
病變范圍廣泛的IBD患者在發(fā)病8~10年后應每1~2年復查一次結腸鏡,而對伴有PSC者,UC確診時應即刻定期復查結腸鏡。確診為全結腸炎的患者,應從盲腸至直腸每隔10 cm行4象限活檢,至少取33塊標本[40]?;顧z標本應包括狹窄、大面積病變、肉眼可見的異常,而不必包括假息肉[42,43]。由于分級的一致性較差,對異型增生的診斷需2名病理專家確認,特別是低級別異型增生[40]。如平坦型黏膜中發(fā)現高級別異型增生或多灶性低級別異型增生,應考慮結腸切除術。單發(fā)病灶的低級別異型增生是否需手術目前尚存爭議。對腺瘤樣息肉,應采用息肉切除術徹底切除,并對鄰近黏膜取活檢判斷是否存在異型增生。如非炎癥活動區(qū)發(fā)現一個異型增生性息肉,且鄰近黏膜無異型增生,則按照非IBD的散發(fā)性息肉進行處理。如異型增生性息肉發(fā)生在活動性炎癥區(qū)(發(fā)育不良相關性損害和團塊)且息肉多為扁平型、鄰近黏膜可見異型增生,但又不適合采用內鏡下息肉切除術治療,則應行結腸切除術[34~36,44~46]。如在活動性炎癥區(qū)發(fā)現一個邊界清晰且適合行內鏡下切除的息肉,病灶徹底切除后應取鄰近黏膜行活檢,標本應單獨保存[47]。
IBD患者應常規(guī)行回腸結腸鏡檢查,可評估病情并鑒別UC與CD。回腸結腸鏡可為評估病變范圍和程度提供有價值的信息。黏膜活檢同樣有非常重要的診斷價值,并可鑒別CD和UC。CD和UC的組織學特征均可表現為慢性炎癥。如內鏡下結腸炎或末端回腸炎未表現出相應的組織學慢性改變,則確診IBD存在一定難度。病程長、范圍廣的IBD發(fā)生異型增生的概率明顯增高,定期接受結腸鏡檢查監(jiān)控病情十分必要。
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