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世界华人消化杂志. 2016-10-28; 24(30): 4156-4161
在线出版日期: 2016-10-28. doi: 10.11569/wcjd.v24.i30.4156
IgG4相关性硬化性胆管炎的研究进展
李哲夫, 范海静, 孙良金, 宋敏
李哲夫, 平度市人民医院肝胆外科 山东省平度市 266700
范海静, 孙良金, 青岛市中心医院(青岛大学医学院第二附属医院)肝胆外科 山东省青岛市 266042
宋敏, 青岛市市立医院内镜室 山东省青岛市 266011
李哲夫, 教授, 主任医师, 硕士生导师, 主要从事肝胆胰脾疾病的基础与临床研究.
作者贡献分布: 李哲夫负责撰写; 范海静与孙良金负责资料检索和采集; 宋敏审校.
通讯作者: 宋敏, 主管护师, 266011, 山东省青岛市市北区胶州路1号, 青岛市市立医院内镜室. 13808950917@163.com
电话: 0532-82789261
收稿日期: 2016-05-02
修回日期: 2016-05-27
接受日期: 2016-06-21
在线出版日期: 2016-10-28

免疫球蛋白G4(immunoglobulin G4, IgG4)相关性硬化性胆管炎是一种特殊类型的胆管炎, 是一种慢性自身免疫性疾病. 该类型的胆管炎其发病机制目前尚不清楚, 无特异性的临床表现, 生化特点是血清IgG4浓度升高, 影像学上胆道成像表现为弥漫性或部分肝内/或肝外胆道壁增厚相关的狭窄, 伴有自身免疫性胰腺炎等自身免疫性疾病, 组织病理学检查显示有大量的IgG4阳性浆细胞的浸润和广泛的胆管壁的纤维化. 该类型胆管炎临床上难以与原发性硬化性胆管炎、继发性硬化性胆管炎和胆管癌等疾病相鉴别, 但他对糖皮质激素治疗有效的一类硬化性胆管炎, 本文将这一特殊疾病的现状和研究进展概括如下.

关键词: 免疫球蛋白G4; 硬化性胆管炎; 胆管癌; 自身免疫性疾病

核心提要: 免疫球蛋白G4相关性硬化性胆管炎发病率低, 临床病例少见, 定性诊断困难, 极易误诊, 对激素治疗敏感, 预后不明确, 因此仍需要进行深入的研究, 以期提高对该病的诊断及治疗水平.
引文著录: 李哲夫, 范海静, 孙良金, 宋敏. IgG4相关性硬化性胆管炎的研究进展. 世界华人消化杂志 2016; 24(30): 4156-4161
Advances in research of immunoglobulin G4-related sclerosing cholangitis
Zhe-Fu Li, Hai-Jing Fan, Liang-Jin Sun, Min Song
Zhe-Fu Li, Department of Hepatobiliary Surgery, People's Hospital of Pingdu City, Pingdu 266700, Shandong Province, China
Hai-Jing Fan, Liang-Jin Sun, Department of Hepatobiliary Surgery, Qingdao Central Hospital (the Second Affiliated Hospital of Qingdao University), Qingdao 266042, Shandong Province, China
Min Song, Department of Endoscopy, Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China
Correspondence to: Min Song, Nurse-in-Charge, Department of Endoscopy, Qingdao Municipal Hospital, 1 Jiaozhou Road, Shibei District, Qingdao 266011, Shandong Province, China. 13808950917@163.com
Received: May 2, 2016
Revised: May 27, 2016
Accepted: June 21, 2016
Published online: October 28, 2016

Immunoglobulin G4 (IgG4)-related sclerosing cholangitis is a special form of cholangitis. As an autoimmune disease, IgG4-related sclerosing cholangitis has no specific clinical manifestations, and its pathogenesis remains unclear. In patients with this disease, serum concentration of IgG4 is elevated, intrahepatic or extrahepatic bile duct stenosis associated with biliary wall thickening is often revealed by biliary imaging, autoimmune diseases such as autoimmune pancreatitis may be present, and massive IgG4 positive plasma cell infiltration and widespread bile duct wall fibrosis are often showed by histopathological examination. It is often difficult to differentiate IgG4-related sclerosing cholangitis from primary sclerosing cholangitis, secondary sclerosing cholangitis and bile duct cancer. However, the disease is sensitive to hormone therapy. This article will review the current advances in research of IgG4-related sclerosing cholangitis.

Key Words: Immunoglobulin G4; Sclerosing cholangitis; Bile duct cancer; Autoimmune diseases
0 引言

免疫球蛋白G4相关性硬化性胆管炎(immunoglobulin G4-related sclerosing cholanitis, IgG4-SC)是一种发病机制不明, 具有临床生化学特点[血清免疫球蛋白G4(immunoglobulin G4, IgG4)升高]以及胆管影像学特殊表现(弥漫性或部分肝内/肝外胆道的与胆道壁增厚相关的狭窄)[1-7], 管壁有大量的IgG4阳性浆细胞的浸润和广泛的胆管壁的纤维化[8-11], 对糖皮质激素治疗有效的一类特殊的胆管炎, 伴有其他慢性自身免疫性疾病如自身免疫性胰腺炎(autoimmune pancreatitis, AIP)等.

IgG4相关性疾病是近年逐渐被认识的一种慢性自身免疫性疾病, 1995年最早报道累及胰腺[12], 后来陆续发现该病可累及胆管、胆囊、肝脏、后腹膜、纵膈、肾脏、肺脏、胃肠等多种器官[13,14]. 由于AIP常存在胰腺外表现, 最多见的是肝内外胆管狭窄并合并梗阻性黄疸, 同时组织标本上存在大量IgG4阳性的浆细胞浸润胆管壁, 故将该病称为AIP相关性硬化性胆管炎.

Björnsson等[15,16]于2007年首次将该病命名为免疫球蛋白G4相关性胆管炎, 2009年被改称为IgG4-SC, 现已在国际上被认为是不同于原发性硬化性胆管炎(primary sclerosing cholangitis, PSC)和继发性硬化性胆管炎(secondary sclerosing cholangitis, SSC)的一类特殊的病因不明的免疫相关性胆管炎.

1 IgG4-SC的病因及发病机制

目前对于IgG4-SC的发病原因尚不明确, 而对于发病机制的研究仍少. 目前有初步研究认为, IgG4-SC的发病机制与Th1占主导免疫反应的PSC或原发性胆汁性肝硬化(primary biliary cirrhosis, PBC)有很大区别. IgG4-SC患者中可见其Th2和可调节性T细胞免疫反应明显增加[17,18]. 虽然IgG4-SC中IgG4明显升高, 但对于IgG4在此病中所发挥的确切作用仍不明朗.

2 IgG4-SC的临床特点

该病多发于60余岁男性[19,20], 临床表现为轻度黄疸, 偶伴随有腹胀、纳差等不适. 实验室检查方面均存在总胆红素、结合胆红素、碱性磷酸酶及γ-谷氨酰基转移酶的轻度升高, 约90%患者血清IgG4明显高于135 mg/dL, 最高可达2560 mg/dL[21-24]. 肿瘤标志物检测中绝大多数在正常范围. 自身抗体检测(检测指标包括抗线粒体抗体、抗核抗体、抗中性粒细胞胞浆抗体、抗平滑肌抗体均为阴性. 在影像学检查方面, 核磁共振胆道成像检查, 病变范围可累及肝内外胆管的各个部位, 尤其是肝门部与胆总管下段胆管, 其受累胆管管壁明显增厚, 纤维化及管腔狭窄, 影像学表现与PSC极为类似, 但部分ISC患者可发现胆管外器官, 特别是胰腺炎性病变. 在组织学上可见胆管壁的IgG4阳性浆细胞大量浸润和严重纤维化, 其常见的特征是闭塞性静脉炎和胆管炎伴有胆管周围轮幅状纤维化, 而相应动脉不受累, 同时一般无胆管上皮损伤. 术后组织学检查发现大量浆细胞浸润胆管壁, 以及可见大量IgG4阳性浆细胞.

3 IgG4-SC的临床分型

有作者按照胆管狭窄部位将IgG4-SC分为4型: Ⅰ型为狭窄仅位于远端胆管; Ⅱ型为肝内外胆管狭窄弥漫性分布, 其中Ⅱa型为存在肝内胆管扩张, Ⅱb型为肝内胆管不扩张; Ⅲ型为狭窄部位同时位于肝门部和远端胆管; Ⅳ型为狭窄部位仅位于肝门部胆管. 通过该分型对IgG4-SC累及胆管部位有一致的认识, 同时为有助于与PSC、SSC、PBC和胆管癌的鉴别[25-27].

4 IgG4-SC的临床诊断标准

欧洲肝病学会建议IgG4-SC的诊断标准包括: 胆管造影有典型的硬化性胆管炎的表现, 同时具有: (1)组织学上有AIP或IgG4-RD的表现; (2)或影像学上典型的AIP表现及IgG4升高; (3)或满足下列标准中的两条(血清IgG4升高; 提示性的胰腺影像学表现; 其他脏器的表现包括: 硬化性唾液腺炎、腹膜后纤维变性、胃肠道受累、腹腔淋巴结有IgG4阳性浆细胞浸润; 胆管活检IgG4阳性浆细胞>10个/高倍视野), 同时对糖皮质激素治疗有应答, 治疗4 wk后可以取出胆管支架而无梗阻性胆汁淤积、肝功能转氨酶<2倍正常值上限[28-32].

美国肝病学会建议对所有疑似PSC的患者, 检测血清IgG4水平以除外IgG4-SC. IgG4升高(>135 mg/dL)具有诊断特异性.

日本2012年IgG4-SC诊断标准[33,34]: 诊断项目(1)胆道成像表现为弥漫性或部分肝内/或肝外胆道的与胆道壁增厚相关的狭窄; (2)血清学检查提示了血清IgG4浓度的增高(≥135 mg/dL); (3)与AIP、IgG4相关泪腺炎/涎腺炎或IgG4-SC相关的腹膜后纤维化共存; (4)组织病理学检测显示: a: 显著的淋巴细胞和浆细胞浸润和纤维化; b: IgG4阳性浆细胞的浸润(10个IgG4阳性浆细胞/高倍视野); c: 席纹状纤维化; d: 闭塞性静脉炎. <选择>类固醇激素治疗的有效性: 一个专门的医院, 能够进行详细的检查如内镜下胆道活检、超声内镜引导下细针穿刺活检, 一旦排除了胰腺或胆管癌, 诊断中也可包括类固醇激素治疗的有效性. 诊断: 明确诊断: (1)+(3); (1)+(2)+(4)a, b; (4)a, b, c; (4)a, b, d. 可能诊断: (1)+(2)+<选择>. 疑似诊断: (1)+(2)(注: 有必要排除PSC、恶性疾病如胰腺或胆道癌以及有明显发病机制引起的继发性胆管炎. 当与恶性疾病鉴别困难时, 不能采取类固醇激素治疗, 必须建议患者去专业性医院).

5 IgG4-SC的鉴别诊断

所有胆管狭窄的病例均应考虑到IgG4-SC的可能性, 而对于所有怀疑IgG4-SC的病例则应警惕恶性肿瘤、PSC和SSC的可能. 因此应常规行胆道相关的影像学检查及肝功能、血清IgG4、血清相关自身抗体等检测, 结合影像学表现与实验室检查结果做出正确的诊断. 对于IgG4正常的Ⅰ型ISC病例, 如果怀疑恶性肿瘤的可能, 可考虑通过超声内镜, 胆管内超声, 甚至内镜下胆管活检进行鉴别, 对于难以在术前取到确切的病理结果, 必要时仍需通过手术治疗或手术活检进行组织学检测以明确诊断. 对于Ⅳ型IgG4-SC病例, 因与肝门胆管癌的影像学表现上很相似, 极易误诊. Ⅳ型IgG4-SC所致的黄疸多为轻度黄疸, 且病程中无明显升高趋势, 而肝门部胆管癌病例呈现重度黄疸, 且进行增高明显, 影像学上虽两者均合并有肝内胆管扩张, 但IgG4-SC病例扩张程度较轻, 甚至不扩张, 而肝门胆管癌病例则扩张非常明显. 结合血清学检测, 多可诊断IgG4-SC.

有研究[35]表明, 127例PSC患者血清IgG4升高(>140 mg/dL)的比例为9%. 另有报道[36-39]显示, PSC患者肝组织IgG4免疫染色阳性率为23%. 但是PSC病例的IgG4值仅轻度升高, 多不超过正常值的2倍, 而联合IgG4/IgG1比值检测可能对于鉴别有更高的敏感性[40-43]. 目前有研究[44]表明超过80%的PSC病例合并有炎症性肠病, 多数为溃疡性结肠炎, 且多数病例中自身抗体呈阳性表现, PSC这些特点有助于和IgG4-SC的鉴别. 有研究[45]认为, IgG4-SC与PSC、胰腺癌和胆管癌的鉴别诊断仅凭胆管影像学特征是困难的, 往往需要全面考虑, 必要时手术探查或手术切除, 最后需要病理检查才能确诊. 另外, 还应与胆道手术后胆管狭窄、先天性胆管变异、胆管缺血性狭窄、获得性免疫缺乏综合征相关性胆管炎以及胆管损伤所致的SSC相鉴别.

6 IgG4-SC的治疗

IgG4-SC的急性期胆道梗阻引起黄疸明显时, 可通过胆道支架缓解胆道梗阻, 也可行诊断性检查进行活检以及对病变胆管的成像. IgG4-SC的有效治疗是糖皮质激素[46-49]. 当胆管梗阻有胆管炎时, 需预防性应用抗生素. 推荐的治疗方案是泼尼松0.6 mg/kg, 2-4 wk后开始减量, 每1-2 wk减量5 mg, 直至症状缓解, 血清IgG4水平恢复正常水平. 随访期间血清IgG4水平再提升常常预示着复发. IgG4-SC糖皮质激素治疗的有效性应谨慎评估, 因为一些恶性病变服用激素后改善[50]. 已有研究, 利妥昔单抗对那些糖皮质激素抵抗、依赖或复发的患者的疗效[51,52], 目前正在开展该药的临床多中心的研究.

7 结论

IgG4-SC发病率低, 临床病例少见, 近年来随着诊断技术的进步, 该病的临床检出率越来越多, 是医学界近年来关注的疾病. IgG4病的病因及发病机制不清, 定性诊断困难, 极易误诊, 对激素治疗敏感, 预后不明确, 因此仍需要进行深入的研究, 从而提高对该病的诊断及治疗水平.

评论
背景资料

免疫球蛋白G4相关性硬化性胆管炎(immunoglobulin G4-related sclerosing cholanitis, IgG4-SC)临床上极易误诊, 难以与原发性硬化性胆管炎(primary sclerosing cholangitis, PSC)、继发性硬化性胆管炎和胆管癌等疾病相鉴别, 需要加强这方面的研究.

研发前沿

IgG4-SC临床上极易误诊, 临床确诊困难, 需要研发相关的特异标志物和检查手段, 以期早期诊断该疾病.

相关报道

目前有研究表明超过80%的PSC病例合并有炎症性肠病, 多数为溃疡性结肠炎, 且多数病例中自身抗体呈阳性表现, PSC这些特点有助于IgG4-SC的鉴别.

应用要点

本文对临床医生认识该疾病, 避免误诊有着重要的指导意义.

同行评议者

张倜, 主任医师, 天津肿瘤医院肝胆科, 天津医科大学肿瘤医院; 崔立红, 教授, 主任医师, 博士生导师, 海军总医院消化内科

同行评价

IgG4-SC是近年逐渐被认识的一种慢性自身免疫性疾病, 本综述基本上反映了该领域的发展概况, 对临床有一定的指导价值. 文章书写层次分明, 结构合理, 逻辑清晰.

手稿来源: 邀请约稿

学科分类: 胃肠病学和肝病学

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