炎癥性腸病相關(guān)性肝病的研究進(jìn)展

炎癥性腸病(inflammatory bowel disease，IBD)是一種慢性自身免疫介導(dǎo)的炎癥性疾病，包括潰瘍性結(jié)腸炎(ulcerative colitis，UC)和克羅恩病(Crohn’s disease，CD)。確切病因尚不清楚，認(rèn)為是由環(huán)境、微生物和遺傳因素相互作用引發(fā)異常免疫反應(yīng)導(dǎo)致腸道炎癥

。IBD已成為21世紀(jì)全球發(fā)病率不斷上升的全球性疾病

。

與很多免疫相關(guān)性疾病一樣，IBD并不局限于胃腸道，是一種可以累及任何器官的全身性疾病

。國(guó)外文獻(xiàn)報(bào)道超過30%的IBD患者伴有腸外表現(xiàn)

，雖然亞洲與歐洲的IBD患者有著相似的腸外表現(xiàn)危險(xiǎn)因素，亞洲IBD患者腸外表現(xiàn)患病率卻低于西方國(guó)家患者

。腸外表現(xiàn)是IBD患者發(fā)病率和致殘率的重要來源，也是一個(gè)確定的危險(xiǎn)因素

。研究發(fā)現(xiàn)，腸外表現(xiàn)可在IBD診斷數(shù)年前出現(xiàn)，臨床醫(yī)師應(yīng)了解其各種表現(xiàn)，以期幫助早期發(fā)現(xiàn)、診斷、治療IBD患者，改善患者預(yù)后

。

因肝臟和胃腸道之間存在密切的解剖和生理關(guān)系，肝臟受累常發(fā)生在胃腸道疾病中

。常見的IBD相關(guān)性肝病分為：(1)與代謝相關(guān)：非酒精性脂肪性肝病(non-alcoholic fatty liver disease， NAFLD)；(2)與致病機(jī)制相關(guān)：原發(fā)性硬化性膽管炎(primary sclerosing cholangitis， PSC)、自身免疫性肝炎(autoimmune hepatitis， AIH)、原發(fā)性膽汁性肝硬化(autoimmune hepatitis， PBC)、重疊綜合征；(3)與治療相關(guān)：藥物性肝炎、病毒性肝炎；(4)與生理學(xué)變化相關(guān)：門靜脈血栓、肝膿腫。IgG4相關(guān)膽管炎(IgG4-associated cholangitis，IAC)、肉芽腫性肝炎和淀粉樣變性較少見

，接下來就常見的、嚴(yán)重的IBD相關(guān)性肝病的流行病學(xué)、發(fā)病機(jī)制、臨床特點(diǎn)、治療方面的最新研究進(jìn)展作一概述。

1 IBD并發(fā)NAFLD

NAFLD是最常見的IBD相關(guān)性肝病，關(guān)于其患病率各研究報(bào)道不一(8.2%～44%)

，明顯高于一般人群

。年齡、BMI、糖尿病、IBD病程和既往腸切除史是目前公認(rèn)的IBD患者發(fā)生NAFLD的危險(xiǎn)因素

。一項(xiàng)關(guān)于IBD患者肌少癥和NAFLD的臨床相關(guān)性的研究發(fā)現(xiàn)，肌少癥比值比為2.99，是IBD患者并發(fā)NAFLD的一個(gè)重要、獨(dú)立的危險(xiǎn)因素

。部分IBD患者接受硫唑嘌呤治療后出現(xiàn)肝脂肪變性，故認(rèn)為高水平的甲基巰基嘌呤可能是肝脂肪變性另一個(gè)潛在危險(xiǎn)因素

。IBD合并NAFLD具體的發(fā)病機(jī)制尚不明確，影像學(xué)檢查發(fā)現(xiàn)肝臟脂肪變性在IBD患者中較為常見，提示腸道炎癥和肝-腸軸紊亂可能在NAFLD的病理生理學(xué)中起著重要作用

。接受抗腫瘤壞死因子(tumor necrosis factor, TNF)治療的IBD患者中NAFLD的患病率很高?？肆_恩疾病活動(dòng)指數(shù)(the Crohn’s disease activity index，CDAI)與肝脂肪變性獨(dú)立相關(guān)，提示IBD治療藥物與自身腸道炎癥參與了NAFLD的發(fā)生發(fā)展

。利用NAFLD評(píng)分對(duì)有上述危險(xiǎn)因素的IBD患者進(jìn)行篩查，有助于疾病的早期診斷和治療

。近期一項(xiàng)研究發(fā)現(xiàn)，在采用地中海飲食(mediterranean diet，MD)的基礎(chǔ)上進(jìn)行短期飲食干預(yù)后，CD和UC患者營(yíng)養(yǎng)不良相關(guān)參數(shù)和肝臟脂肪變性顯著降低，對(duì)IBD并發(fā)NAFLD治療提供了參考

。

2 IBD并發(fā)PSC

PSC是一種以慢性、進(jìn)行性肝內(nèi)和/或肝外膽管炎癥、擴(kuò)張、狹窄和閉塞為病理表現(xiàn)的肝病，診斷基于內(nèi)窺鏡逆行胰膽管造影或磁共振胰膽管造影

。約80%的PSC患者同時(shí)患有IBD

，PSC是IBD患者最常見、最特異的肝膽表現(xiàn)

。伴有PSC的結(jié)腸炎具有特定的臨床和病理學(xué)特征，被認(rèn)為是IBD的一種獨(dú)特表現(xiàn)型，常被稱為“PSC-IBD”，通常表現(xiàn)為輕度廣泛結(jié)腸炎，以右側(cè)為主

。IBD與PSC之間的病理生理相互作用尚不清楚，與單純的IBD相比，伴有PSC的IBD患者病變范圍更廣，發(fā)生結(jié)直腸癌的風(fēng)險(xiǎn)增加

，PSC-IBD患者如果在40歲以下就被診斷患有IBD，患結(jié)直腸癌的風(fēng)險(xiǎn)將增加4倍，對(duì)于這類患者，建議每年篩查結(jié)腸鏡

。一項(xiàng)關(guān)于有PSC的UC和無PSC的UC橫斷面研究發(fā)現(xiàn)，前者谷草轉(zhuǎn)氨酶(aspartate aminotransferase， AST)、谷丙轉(zhuǎn)氨酶(alanine aminotransferase， ALT)、γ-谷氨酰轉(zhuǎn)肽酶(gamma glutamyl transpeptidase，γ-GGT)、血清堿性磷酸酶(alkaline phosphatase， ALP)和血清IgG4較后者顯著升高，推薦使用GGT和IgG4檢測(cè)方法評(píng)估UC合并PSC的風(fēng)險(xiǎn)

。IBD伴發(fā)PSC的發(fā)病機(jī)制不清，研究發(fā)現(xiàn)合并PSC的UC患者CD4

、CD25

T細(xì)胞升高，提示CD4

、CD25

調(diào)節(jié)性T細(xì)胞可能在UC相關(guān)PSC的發(fā)病機(jī)制中發(fā)揮關(guān)鍵作用，也為這一疾病的治療提供了新的思路

。但目前肝移植仍然是治療PSC唯一有效的方法

。

現(xiàn)實(shí)主義為了解國(guó)際社會(huì)提供了真實(shí)的一面，但其更側(cè)重于描述以國(guó)家間相互實(shí)力的對(duì)比為核心的層面，在這種無政府狀態(tài)下，國(guó)家之間并非完全處于一種無政府狀態(tài)下的混亂局勢(shì)，各個(gè)國(guó)際組織、國(guó)際法會(huì)對(duì)主權(quán)國(guó)家間的行為進(jìn)行相應(yīng)的約束和遏制。但現(xiàn)實(shí)主義并未對(duì)國(guó)際關(guān)系中各國(guó)之間的合作與發(fā)展作出必要的解釋和分析，建立在對(duì)現(xiàn)實(shí)主義批判基礎(chǔ)之上的自由主義將從理論層面對(duì)這些問題進(jìn)行相應(yīng)的彌補(bǔ)和梳理。

3 IBD并發(fā)AIH、PBC及重疊綜合征

免疫調(diào)節(jié)劑和生物制劑的使用使得IBD的治療發(fā)生了革命性的變化。在這種免疫抑制的情況下，機(jī)會(huì)性感染是IBD患者的一個(gè)重要安全問題

。IBD患者全身嚴(yán)重病毒感染的發(fā)生率是普通人群的3倍

。一項(xiàng)回顧性研究提示：中國(guó)IBD患者的乙型肝炎病毒(hepatitis B virus，HBV)感染率高于歐洲、美國(guó)和中國(guó)普通人群，但HCV感染率與本研究中普通人群相似

。免疫抑制和生物療法相關(guān)的乙型肝炎再活化正在成為當(dāng)前或先前接觸過HBV感染的患者發(fā)病和死亡的重要原因

。已報(bào)道的病毒性肝炎再活化病例具有廣泛的臨床表現(xiàn)，從無臨床表現(xiàn)的病毒血癥到危及生命的暴發(fā)性肝炎不等

。因此，在開始使用這些藥物之前，識(shí)別有重新激活風(fēng)險(xiǎn)的患者，并開始以預(yù)防HBV重新激活為目標(biāo)的治療，是管理這些患者的最佳策略

。接種疫苗對(duì)IBD患者至關(guān)重要，并且對(duì)IBD患者應(yīng)該常規(guī)進(jìn)行乙型和丙型肝炎病毒感染的篩查

。

4 IBD并發(fā)藥物性肝損傷(drug-induced liver injury，DILI)

用于治療IBD的多種藥物如磺胺嘧啶、硫嘌呤、甲氨蝶呤、TNF、抗整合素、5-氨基水楊酸、小分子JAK抑制劑等均可能引起肝損傷

。不同的藥物所致的DILI有著不同的特點(diǎn)，如：在TNF拮抗劑中，英夫利昔單抗和依那西普最常與肝損傷相關(guān)，包括無癥狀血清轉(zhuǎn)氨酶升高、臨床上明顯的AIH的誘導(dǎo)和乙型肝炎的再激活

；硫鳥嘌呤治療的IBD患者中，可以觀察到肝臟的血管異常，特別是結(jié)節(jié)性再生增生(nodular regenerative hyperplasia，NRH)

；硫唑嘌呤常常表現(xiàn)為肝細(xì)胞損傷和膽汁淤積二者混合

；甲氨蝶呤主要表現(xiàn)為轉(zhuǎn)氨酶升高

。早期診斷DILI是重要的，因?yàn)樗绊懙交颊呶磥淼呐R床管理。當(dāng)肝臟檢查異常時(shí)，臨床醫(yī)師應(yīng)進(jìn)行全面的診斷檢查，以確定肝臟異常是否與IBD有關(guān)

。研究發(fā)現(xiàn)，硫唑嘌呤和巰基嘌呤治療IBD患者1周6-甲基巰基嘌呤核糖核苷酸(6-methylmercaptopurine ribonucleotide，6-MMPR)濃度對(duì)肝毒性發(fā)展有著較好的預(yù)測(cè)價(jià)值

；利用RUCAM評(píng)分可以幫助臨床醫(yī)師辨別肝損傷是否由服用的藥物所致

。近年來關(guān)于DILI治療的研究層出不窮，部分取得了階段性的成果，低劑量硫嘌呤-別嘌呤醇聯(lián)合治療對(duì)IBD患者是一種安全、有益的優(yōu)化策略

；單激肽可減輕2%右旋糖酐硫酸鈉引起的肝臟病理損傷、肝臟參數(shù)、巨噬細(xì)胞浸潤(rùn)和細(xì)胞因子水平

；半乳糖蛋白酶-1對(duì)肝損傷小鼠具有增殖、抗凋亡、抗炎和抗氧化作用，有望作為一種抗肝毒性的保護(hù)劑

。目前肝毒性仍然是治療IBD患者的一個(gè)重要臨床問題。臨床醫(yī)師需要對(duì)不同藥物類別下肝臟相關(guān)不良事件的特點(diǎn)，根據(jù)患者情況制定合理、個(gè)體化治療方案以及結(jié)合危險(xiǎn)因素制定適當(dāng)?shù)念A(yù)防和管理策略。

IBD發(fā)生血管并發(fā)癥的風(fēng)險(xiǎn)增加，最重要的是動(dòng)脈和靜脈血栓栓塞，被認(rèn)為是IBD的特殊腸外表現(xiàn)。PVT在IBD患者中并不常見，但其發(fā)病率仍高于普通人群

。PVT主要發(fā)生在結(jié)腸次全切除術(shù)后，最常見的初始癥狀為腹痛，可在出院數(shù)周后發(fā)生，術(shù)前C反應(yīng)蛋白(C-reactive protein，CRP)與其相關(guān)，最佳預(yù)測(cè)CRP閾值為45 mg/L，CRP>45 mg/L的患者PVT發(fā)生率更高，需要進(jìn)一步的研究來確定高?；颊咝g(shù)后合適的門診血栓預(yù)防方案

。早期和積極地使用抗凝治療可對(duì)IBD相關(guān)性PVT起到良好的治療效果，特別是選擇直接口服抗凝藥物的研究對(duì)象未出現(xiàn)腸缺血、門脈高壓癥、大出血和死亡等不良反應(yīng)，與較高的完全緩解率(96%)相關(guān)

。為IBD患者并發(fā)PVT的抗凝治療方案提供了參考。

5 IBD并發(fā)病毒性肝炎

相比PSC，IBD合并AIH、PBC及重疊綜合征較為少見。PSC是最常見的肝膽表現(xiàn)，其他AIH可能在后者的演變過程中發(fā)生發(fā)展，稱為重疊綜合征

。臨床診療發(fā)現(xiàn)伴有AIH的IBD患者比不伴有AIH的IBD患者治療失敗的頻率更高

。同時(shí)，最近一研究報(bào)道可溶性抑制性受體PD1(soluble programmed death 1，sPD1)水平與AIH和IBD的活動(dòng)性相關(guān)，這一受體與PSC無關(guān)，而PSC合并AIH或IBD顯示較高的sPD1水平。說明可溶性sPD1水平可作為評(píng)估AIH患者活動(dòng)性的臨床生物標(biāo)志物，可前瞻性監(jiān)測(cè)、評(píng)估PSC患者發(fā)生IBD或AIH的可能性

。PBC是另一種自身免疫性膽汁淤積性肝病，二者并存的情況很少見，但在IBD患者肝功能異常篩查時(shí)也應(yīng)考慮PBC

。

6 IBD并發(fā)門靜脈血栓(portal vein thrombosis，PVT)

兩試驗(yàn)均采用大區(qū)對(duì)比設(shè)計(jì)，每處理1 320 m2（22 m×60 m）不設(shè)重復(fù)。試驗(yàn)田施種肥磷酸二銨525.0 kg/hm2+尿素 112.5 kg/hm2，追施尿素 750.0 kg/hm2。生育期間澆4水。

“中國(guó)特色社會(huì)主義”是何時(shí)提出的？目前，絕大多數(shù)學(xué)者一致認(rèn)為這一命題是在黨的第十六次代表大會(huì)被正式提出和使用的，而鄧小平在黨的第十二次代表大會(huì)開幕詞中的講話則被普遍認(rèn)為是中國(guó)特色社會(huì)主義內(nèi)涵的首次鋪墊。此后，黨的歷次代表大會(huì)均圍繞“中國(guó)特色社會(huì)主義”的主題開展，并對(duì)其內(nèi)涵進(jìn)行不斷的豐富與發(fā)展。

7 IBD并發(fā)肝膿腫

肝膿腫雖然是IBD的罕見并發(fā)癥，但卻是潛在的嚴(yán)重威脅患者生命的嚴(yán)重疾病。由于癥狀往往不典型，可能會(huì)誤以為IBD病情加重，導(dǎo)致診斷和治療延遲，對(duì)患者的生命造成嚴(yán)重的威脅

。綜合目前研究結(jié)果，每年住院兩次或兩次以上、剖腹手術(shù)、糖尿病患者、行經(jīng)皮膽囊和膽道穿刺、內(nèi)鏡下膽道引流管置入、免疫抑制治療、瘺管形成和腹腔內(nèi)膿腫是IBD發(fā)生肝膿腫的危險(xiǎn)因素，UC患者比CD患者更容易發(fā)病，在IBD人群中，年齡和性別不影響肝膿腫發(fā)生

。最常見的致病微生物為中間鏈球菌。治療方案包括抗生素抗感染、針吸、導(dǎo)管引流、膽道引流、手術(shù)引流等，應(yīng)根據(jù)患者病情、病灶范圍、位置等綜合判斷和選擇個(gè)體化治療方案

。

IBD伴有肝臟并發(fā)癥并不少見，其對(duì)IBD患者的病情發(fā)展和預(yù)后有著重要的影響。對(duì)于肝功能異常的IBD患者，臨床應(yīng)常規(guī)篩查是否與原發(fā)病相關(guān)以及積極查找肝損傷的原因。肝病作為IBD的常見并發(fā)癥，多先于IBD發(fā)生，對(duì)IBD的早期發(fā)現(xiàn)、診斷、治療有著重要的意義，通過學(xué)習(xí)各型IBD相關(guān)性肝病的特點(diǎn)及研究進(jìn)展，可為科學(xué)的治療和管理患者奠定基礎(chǔ)。

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