修回日期: 2013-09-30
接受日期: 2013-10-15
在线出版日期: 2013-11-18
自身免疫性胰腺炎(autoimmunepancreatitis, AIP)是一种慢性胰腺炎症, 以慢性阻塞性黄疸、淋巴浆细胞组织浸润、纤维化以及对类固醇激素治疗应答为特征. AIP分2个亚型, 1型为淋巴浆细胞硬化性胰腺炎(lymphoplasmacytic sclerosingpancreatitis, LPSP), 2型为特发性导管中心性胰腺炎(idiopathic duct centric pancreatitis, IDCP). AIP的发病机制可能涉及遗传易感性、自身抗体、分子模拟、T细胞免疫调节失衡以及基因突变等. 本文系统地阐述了AIP患者的临床、影像及组织病理学的典型及非典型特征. 此外, 本文还重点阐述了AIP的诊断和治疗进展.
核心提示: 自身免疫性胰腺炎(autoimmunepancreatitis, AIP)的发病机制可能涉及遗传易感性、免疫异常、分子模拟及基因突变等, 尽管类固醇治疗AIP有效, 但治疗后复发以及其与胰腺癌(pancreatic cancer)的鉴别诊断仍面临挑战.
引文著录: 黄颖秋. 自身免疫性胰腺炎的研究进展. 世界华人消化杂志 2013; 21(32): 3505-3513
Revised: September 30, 2013
Accepted: October 15, 2013
Published online: November 18, 2013
Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis characterized clinically by frequent presentation with obstructive jaundice, histologically by lymphoplasmacytic infiltration with fibrosis, and therapeutically by a dramatic response to steroids. AIP have recently been classified into two subtypes, lymphoplasmacytic sclerosing pancreatitis (LPSP) and idiopathic duct centric pancreatitis (IDCP). The pathogenesis of AIP may involve genetic susceptibility, autoantibodies, molecular mimicry, imbalance of T-cell-mediated immune regulation, and gene mutation. In this article, we will systematically review typical and atypical clinical, imaging and histopathological features of AIP, with an emphasis placed on the advances in the diagnosis and treatment of this disease.
- Citation: Huang YQ. Current status of research on autoimmune pancreatitis. Shijie Huaren Xiaohua Zazhi 2013; 21(32): 3505-3513
- URL: https://www.wjgnet.com/1009-3079/full/v21/i32/3505.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v21.i32.3505
自身免疫性胰腺炎(autoimmune pancreatitis, AIP)是由自身免疫介导的慢性胰腺炎症, 以慢性阻塞性黄疸、淋巴浆细胞组织浸润、纤维化以及对类固醇激素治疗应答为特征[1]. 最近, AIP国际共识诊断标准(International Consensus Diagnostic Criteria, ICDC)将AIP分为1、2两个亚型[1,2]. 1型AIP是以胰腺为表现形式的多器官疾病, 属IgG4相关性疾病(IgG4-related disease, IgG4-RD), 其对类固醇敏感, 但易复发, 长期应用小剂量类固醇可减少其复发[1]. 2型AIP与IgG4无关, 常见于年轻患者, 同样伴有阻塞性黄疸和胰腺炎症, 对类固醇敏感, 但罕有复发[1]. ICDC分别将1型AIP称为淋巴浆细胞硬化性胰腺炎(lymphoplasmacytic sclerosing pancreatitis, LPSP), 2型AIP称为特发性导管中心性胰腺炎(idiopathic duct-centric chronic pancreatitis, IDCP)[2,3], 前者不伴粒细胞上皮损伤(granulocyte epithelial lesions, GELs), 而后者伴有GELs, 并可致中小胰管或腺泡的破坏和闭塞[3]. Kamisawa等[4]研究显示, AIP存在地域差异, LPSP与IDCP不仅病理特征不同, 临床表现也各异. Wang等[5]认为, 胰腺外表现在AIP常见, 1型AIP常伴有硬化性胆管炎、硬化性涎腺炎及腹膜后纤维化, 2型AIP常伴有溃疡性结肠炎. 此外, 限局性AIP(focalautoimmunepancreatitis, f-AIP)[6]或弥漫性AIP(diffuse autoimmunepancreatitis, d-AIP)[7]的影像特征有时酷似胰腺癌(pancreatic cancer, PC)应予鉴别. AIP的发病机制尚未明确, IgG4可能至关重要, 也可能与自身免疫功能紊乱而致对胰腺组织异常免疫应答有关[8]. 本文就AIP的最新研究进展概述如下.
Zen等[9]认为, 数个人类白细胞抗原(human leukocyte antigen, HLA)及非HLA的单体型/基因型与IgG4-RD或类固醇治疗后的疾病复发相关. HLA-DRB1*0405、-DQB1*0401可能与AIP的遗传易感性相关[10]. Ota等[10]对43例AIP患者基因组的DNA分析显示, 2个对AIP易感的关键HLA区域局限在Ⅱ类HLA的-DRB1*0405-DQB1*0401位点以及Ⅰ类HLA-E临近C3-2-11的ABCF1位点. Freitag等[11]对转基因小鼠研究发现, 由于HLA-DR*0405表达不能保护小鼠免于AIP, HLA-DR*0405等位基因似乎是AIP重要的风险因素. Park等[12]发现, 门冬氨酸(aspartic acid)在HLA-DQ β1的57位点替代非门冬氨酸(nonaspartic acid)似乎代表了AIP治疗后复发的关键遗传因素. 细胞毒性T淋巴细胞相关蛋白4(cytotoxic T-lymphocyte-associated protein 4, CTLA4)是T细胞免疫反应的关键负调节蛋白, CTLA4的单核苷多态性与多种自身免疫性疾病的易感性相关[13]. Chang等[13]研究显示, CTLA-4 49A多态性以及-318C/+49A/CT60G单体型与中国人群的AIP易感性显著相关. Umemura等[14]证实, 日本人群的AIP易感性也与CTLA-4的多态性以及血清sCTLA-4的水平显著相关. 钾电压阀门通道混合器相关亚家族成员3(potassium voltage-gated channel, shaker-related subfamily, member 3, KCNA3)基因可能参与调节效应和记忆T细胞介导的自身免疫性疾病[15]. Ota等[15]发现, KCNA3与AIP相关, 提示KCNA3可能影响AIP的风险. 此外, Toll样受体(Toll-like receptor, TLR)为先天性免疫和获得性免疫的重要中介, TLR基因多态性与几种自身免疫性疾病相关, 但是否与AIP有关尚不清楚[16]. Umemura等[16]应用等位基因频率分析发现, TLR基因多态性与AIP的易感性及复发均无关.
Smyk等[17]认为, 抗乳铁蛋白(antilactoferrin, anti-LF)抗体、抗碳酸酐酶Ⅱ、Ⅳ(anticarbonic anhydrase Ⅱ, Ⅳ, anti-CA-Ⅱ, Ⅳ)抗体、抗胰腺分泌型胰蛋白酶抑制因子(antipancreas secretory trypsin inhibitor, anti-PSTI)抗体、抗胰蛋白酶原(antitrypsinogens)抗体、抗α-淀粉酶(antiamylase alpha)抗体、抗热休克蛋白10(anti-heat shock protein 10, anti-HSP10)抗体以及抗纤溶酶原结合蛋白(antiplasminogen-binding protein peptide, anti-PBP)抗体在AIP患者常呈阳性, 但他们均非AIP的特异性抗体[17]. 此外, 近40%的AIP患者类风湿因子(rheumatoid factor, RF)及抗核杭体(antinuclear antibody, ANA)也呈阳性[17]. Okazaki等[18]推测, AIP的发病机制可能在于, 天然调节性T细胞(natural ocurring regulatory T cells, nTregs)的减少致使自身抗原(诸如LF、CA-Ⅱ、CA-Ⅳ、PSTI、α-淀粉酶、PBP)产生初始反应, 进而引发Th1的促炎症性反应并释放干扰素-γ(interferon-γ, IFN-γ)、白介素-1β(interleukin-1β, IL-1β)、IL-2和肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α). 继发于Th1初始反应的Th2反应促进疾病进一步恶化, 并使IgG、IgG4增加以及自身抗体产生[18]. IL-10和转化生长因子-β(transforming growth factor-β, TGF-β)可调节IgG4及纤维化, IgG1免疫复合物也可激活经典的补体途径[18]. Löhr等[8]通过基因组学、蛋白组学、免疫组织化学、免疫印记以及免疫分析等方法研究发现, AIP组包括编码免疫球蛋白、趋化因子及其受体基因在内的272种基因上调, 而包括编码胰源性蛋白酶原3种异构体基因在内的86种基因下调. AIP组胰蛋白酶原及其他胰酶含量均显著下降, 胰蛋白酶阳性的腺泡细胞缺失, 血浆抗胰蛋白酶原(protease serine 1, PRSS1)、PRSS2以及抗PSTI(SPINK1基因的产物)自身抗体的滴度升高[8]. 此研究表明, AIP的自身免疫过程可能涉及胰腺腺泡细胞及其分泌的各种酶[8]. Frulloni等[19]研究发现, 20例AIP患者中19例(95%)血清anti-PBP抗体阳性, 40例PC中4例(10%)anti-PBP抗体阳性, 而慢性胰腺炎(chronic pancreatitis, CP)及胰管内乳头状黏液瘤患者均为阴性. 提示anti-PBP抗体在AIP的发病机制中可能起重要作用.
分子模拟是指病原体的抗原表位与人体组织蛋白的表位相同或相似, 致使免疫系统在清除病原体的同时会攻击与之相似的自体成分, 导致自身免疫性疾病. AIP的发病机制可能涉及分子模拟[9]. Haruta等[20]每周给C57BL/6小鼠接种高温灭活的大肠杆菌共计8 wk, 接种结束后1 wk和12 mo分别处死小鼠获取样本, 1 wk及12 mo的胰腺外分泌腺组织可见明显的细胞浸润和纤维化, 接种结束后10 mo的胰管中心纤维化十分明显, 唾液腺管周围的炎症也可看到, 此外, 血清中拥有anti-CA抗体、anti-LF抗体及ANA, 接种灭活大肠杆菌触发C57BL/6小鼠产生了AIP样胰腺炎. 据此, Haruta等[20]推测, 在疾病的初始阶段, 悄然浸润的病原体相关分子模式(pathogen-associated molecular pattern, PAMP)和/或抗原(如灭活细菌)可能触发和上调先天免疫系统. 随后, 通过分子模拟机制, 此类PAMP的持续攻击或刺激致使针对靶抗原的宿主免疫应答上调, 这些缓慢渐进的步骤可能导致AIP的形成及相关的胰腺外损伤[20]. 幽门螺杆菌(Helicobacter pylori, H. pylori)被认为参与AIP的发病机制[21]. 为此, Jesnowski等[21]对AIP患者胰腺组织及胰液中H. pylori的DNA保守序列检测发现, 胰腺组织及胰液中均未检测出H. pylori的DNA序列, 提示H. pylori似乎不可能直接感染导致AIP, 而是通过分子模拟参与AIP的发病机制[21]. Okazaki等[22]认为,在早期阶段, nTregs的减少诱发H. pylori分子模拟, Th1细胞释放促炎症细胞因子IFN-γ、IL-1b、IL-2及TNF-α. 在慢性阶段, 通过记忆性Tregs的增加及Th2型免疫反应促进疾病进展, 补体系统的经典途径可能被IgG1免疫复合物激活[22].
IgG4-RD可见大量的IgG4+浆细胞浸润, CD4+ CD25+ Tregs参与IgG4-RD的发病机制[23]. Fukumura等[23]分别采用IgG4/Foxp3(CD4+ CD25+ Tregs特殊标记物)免疫染色及双重荧光免疫组织化学方法对4例AIP患者研究发现, AIP的组织中富含IgG4+浆细胞及CD4+ CD25+ Tregs, 这可能与AIP的炎症活动有关. Kusuda等[24]发现, AIP患者Foxp3+细胞与浸润性单核细胞(Foxp3/Mono)的比率显著高于对照组, 且Foxp3/Mono与IgG4/Mono呈正相关, 诱导性共刺激分子阳性的Tregs显著高于对照组, IL-10阳性的Tregs也显著高于对照组. 提示诱导性共刺激分子阳性的Tregs大量增加可能影响AIP患者的IgG4产生. Kubota等[25]对32例AIP患者研究发现, 18例可见十二指肠乳头Foxp3+细胞显著浸润, 27例可见IgG4+浆细胞显著浸润, 提示检测十二指肠乳头的Foxp3+细胞数有助于AIP与PC的鉴别诊断. Li等[26]研究显示, AIP患者的胰腺及胰腺外组织中可见大量的CD8+ T淋巴细胞浸润, 表明这些细胞群在介导AIP的发病机制中可能更为重要. 此外, Schwaiger等[27]对MRL/Mp小鼠的AIP模型研究发现, MRL/Mp小鼠的CTLA-4堵塞不仅可抑制Tregs功能而且可提高效应T细胞与后续的组织形态学损伤的应答, 提示AIP为T细胞驱动性疾病. Seleznik等[28]对AIP患者及小鼠模型研究发现, AIP患者淋巴毒素(lymphotoxin, LT)α、β的mRNA水平以及趋化因子(CXCL13、CCL19、CCL21、CCL1、B细胞活化因子)的表达均显著高于对照组; 小鼠腺泡LTαβ的特异性超表达可诱导产生具有AIP各种特征的小鼠模型. 提示小鼠腺泡细胞的LTαβ超表达可导致AIP.
Gao等[29]研究发现, AIP患者的PRSS1基因存在2个新突变(p.81Leu→Met和p.91Ala→Ala). PRSS1_p.81Leu→Met基因突变导致胰蛋白酶与苯基琼脂糖结合减少76.2%, 然而, AIP患者的胰蛋白酶/淀粉酶比率显著高于PC和其他胰腺炎患者, 并可见胆管内大量的淋巴细胞和浆细胞浸润以及肌成纤维细胞的增殖. 提示AIP可能与PRSS1基因突变有关[29]. AIP患者在随访期间可能并发胃癌或结肠癌[30]. Kamisawa等[30]分别对12例AIP患者的十二指肠乳头(8例)、胃黏膜(5例)、结肠黏膜(3例)、胰腺组织(5例)、胆总管(5例)以及胆囊上皮(4例)的K-ras基因突变检测发现, 4例十二指肠乳头、2例胃黏膜、2例结肠黏膜、5例胰腺组织、4例胆总管及3例胆囊上皮可见显著的K-ras基因突变. 而且, K-ras基因突变与组织的纤维化、IgG4+ T淋巴细胞及Foxp3+细胞浸润相关. 提示AIP可能有胃癌和结肠癌的风险. Kamisawa等[31]的另一项研究显示, AIP患者的胰腺和胆道组织常有显著的K-ras基因突变. 表明AIP可能是胰腺和胆道癌症的风险因素[31]. AIP的临床及影像特征有时酷似PC, 检测超声内镜引导下-细针穿刺(endoscopic ultrasound-guided fine needle aspiration, EUS-FNA)标本的K-ras基因突变、抑癌基因丢失及端粒酶活性等或许有助于AIP与PC的鉴别诊断[32]. Khalid等[32]对14例AIP和11例PC患者EUS-FNA标本的K-ras基因突变检测发现, AIP患者无一例K-ras基因突变, 而11例PC患者中10例出现K-ras基因突变, 提示EUS-FNA标本的K-ras基因突变检测有助于AIP与PC的鉴别[32]. 此外, DiMagno等[33]认为, 囊性纤维化转膜传导调节因子(cystic fibrosis transmembrane conductance regulator, CFTR)基因错位于胰管黏膜可能与AIP的发病机制有关. Patel等[34]研究显示, AIP患者的CFTR基因突变可能引发坏死性胰腺炎.
Kanno等[35]对日本全国范围内AIP患者的流行病学调查资料显示, 2007年AIP患者的预估数为2790例(95%CI: 2540-3040), 总体患病率为2.2/100000人. 新近被诊断为AIP的患者数预估为1120例(95%CI: 1000-1240), 年均发病率为0.9/100000人. 男女性别比例为3.7, 平均年龄为63.0岁±11.4岁. 546例获取临床信息的AIP患者中, 87.6%患者的血清IgG4水平升高(≥135 mg/dL), 83%的患者接受类固醇治疗. Li等[36]对636例CP的回顾性分析显示, 1990-2000年的CP数为215例, 而AIP为0例; 2001-2010年的CP数为421例, AIP为15例. AIP的发病率呈逐年上升趋势可能与人们对其认识加深有关. Shiokawa等[37]发现, 108例AIP患者中有15例(13.9%)在平均3.3年的随访期间发生18个癌症. 癌症的标准化发病率(standardized incidence ratio, SIR)为2.7%(95%CI: 1.4%-3.9%), AIP患者在其诊断时的相对癌症风险为4.9%(95%CI: 1.7%-14.9%). 提示AIP患者有罹患各种癌症的风险.
Zhang等[38]发现, AIP患者可出现上腹痛、黄疸、尿黄、上腹不适、腹胀、厌食、消瘦、虚弱、脐周痛及腰背痛等症状, 1型AIP患者血清ALT、ALP、γ-GT、AST水平显著低于2型AIP患者(分别P = 0.044、0.025、0.013、0.072). Kamisawa等[4]研究显示, 1型AIP阻塞性黄疸较2型常见(75% vs 47%, P<0.001), 而腹痛(41% vs 68%, P<0.001)和急性胰腺炎(5% vs 34%, P<0.001)较2型少见. 1型AIP弥漫性胰腺肿大(40% vs 25%, P = 0.037)及血清IgG4升高(63% vs 23%, P<0.001)也较2型常见, 但伴发溃疡性结肠炎少于2型(1% vs 16%, P<0.001). Detlefsen等[39]及Czakó等[40]对欧洲AIP患者的研究与上述结论基本一致. AIP常累及其他器官, 如胆管、胆囊、肾脏、腹膜后、甲状腺、唾液腺、肺、纵隔淋巴结以及前列腺等[41,42].
此外, 米古利兹病(Mikulicz's disease, MD)是唾液腺、泪腺受累的自身免疫性疾病, 以淋巴细胞浸润并取代腺泡为特征, 部分AIP患者可伴发MD, 使临床表现更为复杂[43]. Kuruma等[43]发现, AIP伴发MD者其复发率显著高于不伴发MD者.
Rehnitz等[44]应用磁共振成像(magnetic resonance imaging, MRI)和CT对36例AIP患者的影像学特征评估显示, 胰腺肿大有3种类型: (1)局限型(focal type, F型)(28%); (2)弥漫型(diffuse type, D型)(11%); (3)混合型(combined type, C型)(56%). 67%的AIP主胰管扩张并伴有局限性或弥漫性狭窄. Tabata等[45]根据胰腺肿大的部位将F型进一步分为头型(head type, H型)、体和/或尾型(body and/or tail type, B/T型), 67例AIP中D型34例, H型19例, B/T型14例. Sun等[6]研究显示, F型AIP常见5种影像结果: (1)腊肠型肿大; (2)延迟均匀增强; (3)低衰减胶囊样边缘; (4)不规则主胰管(main pancreatic duct, MPD)和/或胆总管(common bile duct, CBD)狭窄; (5)MPD上段扩张≤5 mm. 提示CT和MRI联合分析有助于F型AIP与PC的准确鉴别[6]. Zhang等[46]对7例AIP患者行全身正电子发射计算机断层显像(positron emission tomography/computed tomography, PET/CT)常规及胰腺延迟扫描发现, 6例胰腺弥漫性肿大, 1例节段性肿大, 病变部位氟脱氧葡萄糖(fluorodeoxyglucose, FDG)条状摄取增高, 最大标准化摄取值(maximum standardized uptake value, SUVmax)平均4.38±0.90, 延迟扫描后SUVmax增加至5.31±1.08, 4例胰腺周围炎性渗出. 7例均有胰腺外病损, 4例肿大淋巴结伴FDG摄取增高; 4例合并涎腺肿大伴代谢增高; 4例合并胆管炎; 3例合并间质性肺炎; 5例前列腺出现倒"V"形FDG摄取增高. 提示18F-FDG PET/CT不仅能显示胰腺病灶, 还能发现胰腺外受累, 在AIP诊断及全身评估中发挥独特作用[46]. 但Nakatani等[47]认为, PET/CT仅为诊断要素之一, AIP的诊断还应结合其他检查结果. Santhosh等[48]报道1例经超声及血清学诊断为壶腹周围癌拟行Whipple手术后经PET/CT扫描疑诊AIP并经细胞学证实的AIP病例. 此外,Imazu等[49]采用时间-强度曲线(time intensity curve, TIC)软件及谐波造影增强超声内镜技术(contrast-enhanced harmonic-endoscopic ultrasound, CEH-EUS)研究发现, AIP与PC胰腺病灶的TIC模式显著不同, 以CEH-EUS制作TIC这种新的诊断程序有助于准确鉴别AIP与PC的胰腺病灶.
1型和2型AIP的组织病理学特征不完全相同[2,50]. Detlefsen等[51]认为, 二者除淋巴浆细胞浸润及席纹状纤维化特征相同外, 2型有其特殊的胰管改变, 即所谓的GELs, 但没有或罕有IgG4+浆细胞(<10个细胞/高倍视野)浸润[51]. Zhang等[52]发现,上述特征不仅能区别AIP与其他类型CP, 而且也能准确鉴别1型和2型AIP.Deshpande等[53]进一步证实, 1型是以胰腺为表现的IgG4-RD,2型则仅局限于胰腺组织. EUS-FNA能否准确诊断AIP尚不清楚[54]. Iwashita等[54]研究显示, EUS-FNA获取的胰腺标本对于AIP的组织学分析安全可靠, 尽管其诊断率不高, 但可能有助于非典型特征的AIP患者免于外科手术.
Shimosegawa等[2]起草的"AIP诊断标准的最新国际共识"将AIP分为LPSP和IDCP 2种类型, 二者均有胰管周围淋巴浆细胞浸润和席纹状纤维化的组织病理学特征, 其最主要区别在于LPSP不伴有GELs, 而IDCP伴有GELs, 并可致中小胰管或腺泡的破坏和闭塞. 此外, LPSP还可见大量的IgG4+浆细胞浸润(>10个细胞/每高倍镜视野)及闭塞性淋巴浆细胞性小静脉炎等组织学特征; 而IDCP很少有IgG4+浆细胞浸润(<10个细胞/每高倍镜视野). 鉴于胰腺组织病理学结果难以获得, 基于LPSP和IDCP的临床特征, 又将AIP分为1型和2型, 分别与之对应. LPSP(1型)多见于亚洲老年男性, 常有阻塞性黄疸, 为IgG4-RD的胰腺表现, 血清IgG4水平显著升高, 胰腺外器官可受累, 如IgG4相关硬化性胆管炎(immunoglobulin G4-related sclerosing cholangitis, IgG4-SC)、硬化性涎腺炎及腹膜后纤维化等, 对激素治疗反应敏感. 而IDCP(2型)常见于欧美患者, 平均发病年龄比1型小10岁, 无性别倾向, 血清IgG4正常, 多并发炎症性肠病(inflammatory bowel disease, IBD), 对激素有应答. 尽管AIP诊断已取得国际共识, 但各区域AIP特征仍存差异. Kamisawa等[4]证实, AIP存在地域差异, LPSP和IDCP不仅病理特征不同, 临床表现也各异. AIP有时酷似PC而致不必要的手术治疗[55]. 倘若AIP与PC共存于同一患者无疑使术前确诊更为困难[56]. Chandrasegaram等[56]及Yoneda等[57]分别报道1例PC与AIP共存以及1例胰腺导管腺癌(pancreatic ductal adenocarcinoma, PDA)与AIP共存的病例. Matsumoto等[58]认为, PET/CT无助于PDA诊断. Wu等[59]发现, 血清γ-球蛋白升高可作为AIP与PC的术前鉴别指标, 对于γ-球蛋白升高者, 应进一步检测血清IgG或IgG4, 以避免AIP患者接受不必要的手术.
近期研究结果推荐, 0.5-0.6 mg/(kg·d)为初始治疗AIP的标准口服剂量, 但对于激素治疗无效或治疗当中再被诊断为PC的患者, 激素停用是否会增加术后肾上腺皮质功能低下风险尚不清楚, 也几乎缺乏激素冲击治疗AIP的相关报道[60]. Tomiyama等[60]对11例激素冲击治疗及10例传统口服治疗的AIP回顾性分析发现, 前者初始静脉注射甲强龙500 mg/d, 每周3 d, 2 wk后改用口服强的松龙20 mg/d维持并逐渐减停; 后者初始口服强的松龙30-40 mg/d, 2 wk后同样改用口服强的松龙20 mg/d维持并逐渐减停. 结果显示, 前者治疗后的GTP及ALT水平均较后者显著改善. 此外, 1例低位胆总管狭窄经传统口服激素治疗无效的AIP患者却在激素冲击治疗后得以缓解. 提示激素冲击治疗对AIP是一种行之有效的初始治疗选择, 对低位胆总管狭窄程度的改善可能优于传统的口服激素治疗[60]. Liu等[61]对28例类固醇治疗的AIP及40例接受胰腺切除术、射频消融术、经皮肝穿胆汁引流术以及内镜胆汁引流术的AIP对比研究发现, 类固醇治疗AIP的缓解率(96.4%)显著高于无类固醇治疗者(75%). 同样, 前者的复发率(28.6%)也显著低于后者(42.5%)[61]. 无论是否曾接受过类固醇治疗, 对复发者重新类固醇治疗依然有效[61]. 但Miura等[62]对13例行胰腺切除术的AIP长期随访发现, 无确切证据表明AIP复发. 腹部超声是检查胰腺形态学的最便捷方法, 类固醇反应是AIP的关键特征[63]. Matsubayashi等[63]应用超声对33例AIP患者类固醇治疗前以及治疗后2 wk、1 mo的胰腺、胰腺外病变的可视化评估显示, 86%及97%患者的胰腺病变分别于类固醇治疗2 wk及1 mo内明显回缩, 其中, 2 wk内胰腺病变的最大回缩厚度从28 mm减至22 mm(P<0.0001), 48%的胰腺周围肿大淋巴结、12%的主动脉壁厚也在2 wk内明显回缩(P = 0.005). 提示多数AIP的类固醇反应于2 wk内发生[63]. 此外, Matsubayashi等[64]在另一项研究发现, 部分AIP伴有脾肿大, 尤其是弥漫性胰腺肿大及脾静脉狭窄者, 类固醇可使其回缩或缓解. Kamisawa等[1]认为,AIP类固醇治疗后复发常见, 小剂量类固醇长期应用可减少复发, 免疫抑制剂(硫唑嘌呤、6-巯基嘌呤和霉酚酸酯)及生物制剂(CD20抗体、利妥昔单抗)可能在维持缓解1型AIP的复发中发挥作用. Hart等[65]研究证实, 利妥昔单抗对免疫调节剂抵抗及类固醇不耐受的AIP患者有治疗效果.
AIP的发病机制尚不清楚, 可能涉及遗传易感性、免疫异常、分子模拟及基因突变等因素, 虽然1型AIP也被称为IgG4-RD, 但IgG4在AIP的致病作用仍不得而知. AIP被发现不过10余年的时间, 但其临床、影像及组织病理学的研究已取得长足进步. AIP的最新国际诊断共识为AIP的进一步研究奠定了基础. AIP类固醇治疗后的复发以及最佳治疗方案的选择仍是目前急需解决的问题.
1995年, 日本学者Yoshida首次报道了以血清IgG4水平升高、胰腺肿大及IgG4+淋巴浆细胞组织浸润为特征的一种慢性纤维炎症性疾病, 即自身免疫性胰腺炎(autoimmune pancreatitis, AIP). 近年来, AIP已成新的国际研究热点. 随着研究不断深入, AIP的基础与临床研究已取得飞速进展.
陈卫昌, 教授, 苏州大学附属第一医院消化内科
自身免疫性胰腺炎(autoimmune pancreatitis, AIP)的临床及影像学特征有时酷似胰腺癌(pancreatic cancer, PC), 因此迫切需要精确的诊断方法予以鉴别, 检测EUS-FNA标本内K-ras基因的突变、抑癌基因的丢失及端粒酶活性等或许有助于AIP与PC的鉴别诊断. 因此, 研究EUS-FNA标本中K-ras基因突变及抑癌基因杂合子的丢失情况应是目前努力的方向.
Shimosegawa等报道了AIP的最新国际诊断共识, 对AIP的诊断、规范化治疗以及进一步研究有重要意义.
本文详尽阐述了AIP的发病机制、临床特征、影像学特征、组织病理学特征以及AIP的最新国际诊断共识, 重点阐述了AIP治疗取得的最新进展, 为该领域的进一步研究提供了大量有价值的参考信息.
本文详尽阐述了AIP近5年的最新研究进展, 提供了大量有价值的参考信息, 对该领域的基础与临床研究具有重要的指导意义.
谐波造影增强超声内镜技术(CEH-EUS): 指EUS检查时, 利用超声造影剂, 增强病灶中的血流信号, 连续实时和动态观察病灶组织中血流灌注状态, 从而达到诊断目的. CEH-EUS是一项全新技术, 可检测<2 cm的胰腺肿瘤, 敏感性达95%, 最近被用于AIP与PC的鉴别诊断.
本文结合最新文献资料详细阐述了AIP的最新进展, 内容丰富, 科学性及可读性较好, 对临床工作有指导意义.
编辑:郭鹏 电编:闫晋利
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