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鲁琼, 贺铮雯, 张乐之, 沈茜, 唐古生. 血清IgG4和CA199联合检测在自身免疫性胰腺炎和胰腺癌鉴别诊断中的意义. 2011, 26(11): 746-749
LU Qiong, HE Zhengwen, ZHANG Lezhi, SHEN Qian, TANG Gusheng. Significance on the combination determination of serum IgG4 and CA199 in differential diagnosis between autoimmune pancreatitis and pancreatic cancer. Labratory Medicine, 2011, 26(11): 746-749  
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《检验医学》编辑部
血清IgG4和CA199联合检测在自身免疫性胰腺炎和胰腺癌鉴别诊断中的意义
鲁琼, 贺铮雯, 张乐之, 沈茜, 唐古生
第二军医大学附属长海医院实验诊断科,上海 200433

通讯作者:唐古生,联系电话:021-81873612-8609。

作者简介:鲁琼,女,1984年生,学士,技师,主要从事临床免疫检验工作。

摘要
目的

研究血清IgG4在中国人自身免疫性胰腺炎(AIP)中的诊断价值,并探讨联合检测血清糖类抗原199(CA199)在AIP和胰腺癌鉴别诊断中的作用。

方法

750例慢性胰腺炎患者和30例胰腺癌患者血样采自2009年8月至2010年7月消化科门诊或住院患者;30名正常健康人血样取自血站和体检部。血清IgG4浓度采用速率散射比浊法测定,血清CA199浓度采用电化学免疫发光法测定。各组间血清IgG4和CA199浓度变化的差异采用非参数统计分析。

结果

750例慢性胰腺炎患者血清中有28例血清IgG4浓度高于正常参考值上限(>2.0 g/L),其中11例 (1.4%)患者经影像学和胰腺穿刺活检病理检查等确诊为AIP,其IgG4浓度中位数为11.10(4.1237.20)g/L;胰腺癌患者IgG4浓度为0.51(0.061.12)g/L,正常对照组IgG4浓度为0.56(0.181.50)g/L 。AIP患者组血清中的IgG4浓度明显高于正常参考值上限,且明显高于胰腺癌患者和正常对照组(P<0.000 1)。胰腺癌组血清IgG4水平均低于正常参考值上限,与正常对照组比较差异无统计学意义。所有确诊AIP患者血清CA199浓度7例患者轻、中度升高,余低于正常参考值上限(<37 U/L),浓度中位数为41.48(0.60136.40)U/L;然而胰腺癌组血清CA199浓度中位数为533.60(4.251 000)U/L,明显高于AIP患者组(P<0.01)。

结论

血清IgG4明显升高,用于辅助诊断AIP具有较高的特异性和敏感性,提示将IgG4水平纳入AIP的诊断标准对中国人也适用;在AIP和胰腺癌难以鉴别时,同时检测血清IgG4和CA199有助于临床对AIP和胰腺癌的鉴别诊断。

关键词: IgG4; 糖类抗原199; 自身免疫性胰腺炎; 胰腺癌; 鉴别诊断
中图分类号:R446.62 文献标志码:A 文章编号:1673-8640(2011)011-0746-04
Significance on the combination determination of serum IgG4 and CA199 in differential diagnosis between autoimmune pancreatitis and pancreatic cancer
LU Qiong, HE Zhengwen, ZHANG Lezhi, SHEN Qian, TANG Gusheng
Department of Laboratory Diagnosis,Changhai Hospital, Second Military Medical University, Shanghai 200433, China
Abstract
Objective

To investigate the diagnostic value of the serum IgG4 in autoimmune pancreatitis (AIP) in Chinese people and the differential diagnosis value of the combination determination of serum IgG4 and carbohydrate antigen 199(CA199) between AIP and pancreatic cancer.

Methods

A total of 750 patients with chronic pancreatitis and 30 patients with pancreatic cancer were enrolled from patients and inpatients of digestion department during August 2009 to July 2010. The 30 healthy blood samples were collected from the blood bank and health examination department. Serum IgG4 was determined by rate nephelometry assay, and serum CA199 was detected by electrochemiluminescence assay. Non-parametric statistical analysis was performed to analyze the concentration differences of serum IgG4 and CA199 in each group.

Results

In serum samples from 750 patients with chronic pancreatitis, 28 cases had IgG4 levels exceeding the upper limit of normal reference(>2.0 g/L), among which 11 cases (1.4%) were finally identified as AIP according to imaging and pathological examination. The median concentration of IgG4 was 11.10(4.12-37.20)g/L. The median concentrations of serum IgG4 in patients with pancreatic cancer and healthy control group were 0.51(0.06-1.12)g/L and 0.56(0.18-1.50)g/L, respectively. Serum IgG4 concentrations in AIP patients exceeding the upper limit of normal reference were significantly higher than those in patients with pancreatic cancer and healthy control group (P<0.000 1). All serum IgG4 concentrations in patients with pancreatic cancer were lower than the upper limit of normal reference and had no statistical significance with the healthy control group. Serum CA199 in 7 out 11 of AIP patients were higher, while the other 4 patients were lower than the upper limit of normal reference (<37 U/L). The median concentration was 41.48(0.60-136.40)U/L. Serum CA199 in patients with pancreatic cancer was significantly higher than that in AIP patients with a median concentration of 533.60(4.25-1 000)U/L (P<0.01).

Conclusions

High specificity and sensitivity of serum IgG4 obvious increasing in AIP diagnosis is further confirmed in Chinese people. The combination determination of serum IgG4 and CA199 contributes to the differential diagnosis of AIP and pancreatic cancer.

Keyword: IgG4; Carbohydrate antigen 199; Autoimmune pancreatitis; Pancreatic cancer; Differential diagnosis

自身免疫性胰腺炎 (AIP)是一种由免疫机制介导的特殊类型的慢性胰腺炎,常伴有胰腺外症状如唾液腺炎、腹膜后纤维化、腹腔及肺门淋巴结肿大、慢性甲状腺炎及间质性肾炎等,其病理机制尚不清楚[[ 1]。1961年,Sarles 等[ 2]发现了第1例伴有高γ-球蛋白血症的胰腺炎,称之为“慢性炎症性硬化性胰腺炎”。1992年,Toki 等[ 3]报道了4例罕见的主胰腺管不规则狭窄且胰腺淋巴细胞弥漫性浸润的病例。1995年,Yoshida等[ 4]首次提出“AIP”的概念。 虽然AIP的发病机制尚不明确,但其临床表现及放射影像学检查与胰腺癌极为相似,易造成两者的误诊而选错治疗方案,组织病理活检虽可有效地鉴别两者,但有时很难获得有效的胰腺组织。本研究就血清IgG4联合糖类抗原199(CA199)检测在两者鉴别诊断中所起的作用做出相关评价。

材料和方法
一、研究对象

收集长海医院2009年8月至2010年7月的门诊或住院750例慢性胰腺炎患者血清,以1987年桂林慢性胰腺炎会议提出的慢性胰腺炎诊断标准评定,男、女比例为 1.3∶1,平均年龄为50岁(1085岁);30例胰腺癌患者(均经病理学确诊)血清,男、女比例为1∶1,平均年龄为59岁(3678岁);30名正常健康人血清取自长海医院血站和体检部作为正常对照组,排除肝、肾、心脏等主要器官疾患和自身免疫性疾病,在年龄和性别与上述试验组匹配。本研究得到长海医院医学伦理委员会批准。

二、样本采集

患者于治疗前清晨空腹采集全血3 mL于真空采血促凝管,静置30 min,3 000 r/min(离心半径15 cm)离心20 min,分离出血清(无溶血、脂血),置-20 ℃冰箱保存待检。

三、方法

1.血清IgG4的测定 采用速率散射比浊法(DADE BEHRING BNII系统)测定血清IgG4含量,所用试剂有: N 乳胶免疫球蛋白G4试剂(编号:OPAU03);N蛋白标准品SL(编号:OQIM);N蛋白质控品SL/L(编号:OQIN);N蛋白质控品SL/M(编号:OQIO);N蛋白质控品SL/H(编号:OQIP);N辅助试剂/沉淀剂(编号:OUMU);N稀释液(编号:OUMT)。

2.血清CA199测定 采用Roche Cobas e601系统使用配套的糖类抗原CA199定量测定试剂盒(电化学免疫发光法)测定血清CA199浓度。主要试剂组成包括:M 包被链霉亲和素的磁珠微粒;R1 生物素化的抗CA199抗体;生物素化的抗CA199单克隆抗体(小鼠)浓度3 mg/L;磷酸盐缓冲液100 mmol/L(pH值6.5);防腐剂;R2 Ru(bpy 标记的抗CA199抗体;钌标记的抗CA199单克隆抗体(小鼠)浓度4 mg/L;磷酸盐缓冲液100 mmol/L(pH值6.5),防腐剂。

四、统计学方法

数据处理应用Graphpad 5.0绘图统计软件包,血清IgG4和CA199检测结果呈偏态分布,采用中位数(范围)表示。组间差异采用Mann-Whitney非参数统计分析, P<0.05表示差异有统计学意义。

结果
一、胰腺癌组、正常对照组与AIP组之间的IgG4浓度比较

750例慢性胰腺炎患者血清中有28例(3.7%)血清IgG4浓度高于正常参考值上限(>2.0 g/L,生产厂家推荐、我科验证)。经影像学和胰腺穿刺活检病理检查等确诊11例为AIP(1.4%),男、女比例为9∶2,平均年龄63岁(5176岁),且IgG4浓度显著升高(>4.0 g/L),其中有1例高达37.6 g/L,见 图1。而其余17例慢性胰腺炎患者血清IgG4浓度均为2.04.0 g/L之间。AIP患者组血清中的IgG4浓度[11.10(4.1237.20) g/L]明显高于正常参考值上限(>2.0 g/L),且明显高于胰腺癌患者[0.51(0.061.12) g/L]与正常对照组[0.56(0.181.50) g/L],差异有统计学意义( P<0.000 1)。

图1 胰腺癌组、正常对照组和AIP组血清IgG4浓度水平(g/L)注:与正常对照组比较,*** P<0.000 1

胰腺癌患者组血清IgG4水平均低于正常参考值上限(<2.0 g/L),与正常对照组比较差异无统计学意义,见 图1。

二、胰腺癌组、正常对照组与AIP组之间的CA199浓度比较

胰腺癌组患者血清CA199浓度[533.60(4.251000.00) U/L]明显高于AIP患者组[41.48(0.60136.40) U/L],差异具有统计学意义( P<0.01)。AIP组中有7例CA199浓度高于正常参考值上限(37 U/L,生产厂家推荐、我科验证),但与正常对照组[12.45(0.8624.84) U/L]差异无统计学意义,见 图2。

图2 胰腺癌组、正常对照组和AIP组血清CA199浓度对照(U/L)注:与正常对照组比较,* P<0.01

研究中发现1例AIP患者血清IgG4水平持续明显升高,CA199水平也逐渐、明显升高,影像学高度提示胰腺肿瘤存在,但尚未获得病理确诊,目前在随访中。

讨论

AIP是一种与IgG4相关的自身免疫机制介导的慢性胰腺炎,其在慢性胰腺炎中所占的比例为1.86%6.60%,多发于老年男性。AIP较难诊断,诊断标准主要有日本胰腺协会(JPS)2006年修改后标准[ 5]、韩国Kim标准(2006年)[ 6, 7]、美国Mayo Clinic的2006年HISORt标准[ 8]和2008年的亚洲标准[ 9],尚无统一的诊断标准。虽然AIP诊治标准不尽相同,但总体而言不外乎影像学、血清学、组织学、激素治疗和胰腺外器官受累等几个方面。在各诊断标准中血清学指标均包括血清IgG4水平升高。由此可见,血清IgG4 水平升高对AIP的诊断非常重要。目前我国对AIP的认识尚处于起步阶段,也未制定相关诊断标准,使得临床医生对诊断AIP尤为谨慎。本研究中11例AIP的诊断均依据亚洲标准[ 9]。

Hamano等[ 10]报道,以1.35 g/L为诊断临界值,血清IgG4升高诊断AIP 的敏感性为95%、特异性为97%、准确性为97%。本研究分析了750例慢性胰腺炎患者血清IgG4水平,28例(3.7%)出现IgG4水平高于正常参考值上限,其中符合影像学和病理检查等诊断标准确诊为AIP有11例,占本组病例数的1.4%,与日本等文献报道[ 5]基本相符。其余17例慢性胰腺炎患者血清IgG4水平虽高于正常参考值上限,但均为落在2.04.0 g/L之间。以血清IgG4水平>4.0 g/L为诊断临界值,诊断AIP的敏感性、特异性和准确性均达到 100%,优于文献报道[ 10]的数据。这种差异很可能由于病例数较少造成,但也不能排除人种差异的因素存在。

由于AIP常需与胰腺癌进行鉴别诊断,且AIP一旦误诊为胰腺癌,患者可能遭受不必要的手术治疗。有文献报道[ 11]至少有5%因胰腺癌手术患者最终发现是良性炎症性胰腺疾病,其中包括AIP。因此,AIP和胰腺癌的鉴别诊断直接影响患者的治疗方案。为此,本研究对30例经病理学确诊的胰腺癌患者血清和11例AIP患者血清分别检测IgG4和CA199,以观察和评价这2个指标在胰腺癌和AIP鉴别诊断中的实用价值。研究发现30例胰腺癌血清IgG4水平均低于正常参考值上限,与AIP患者组差异有统计学意义。血清CA199的水平在2组之间差异也有统计学意义,表现为胰腺癌组CA199水平明显升高,多例高达1 000 U/L;AIP组仅有7例出现CA199的轻中度升高,可能与慢性胰腺炎和部分患者出现轻度胆汁淤积有关。可见,同时检测IgG4和CA199对AIP和胰腺癌的鉴别诊断有一定的实用价值。

近来有文献报道[ 12, 17],AIP患者可发展为胰腺癌,两者可同时存在,也可在首发AIP35年后出现胰腺癌。另外,也有一些个案报道[ 18],胰腺癌患者血清中IgG4浓度升高,这些血清IgG4升高的胰腺癌是否由AIP发展而来?目前尚不清楚。本研究也发现1例AIP患者血清IgG4和CA199均明显升高,影像学高度提示胰腺肿瘤存在,但未获病理学确诊,目前尚在随访中。这些均提示,尽管血清IgG4和CA199水平对AIP与胰腺癌的鉴别诊断具有较好的实用价值,但是对一些特殊病例仍需综合判断和分析,进一步提高诊断的准确性。

The authors have declared that no competing interests exist.

参考文献
[1] Pezzilli R, Corinaldesi R. IgG4 as a serological marker of autoimmune pancreatitis: the latest news[J]. JOP, 2004, 5(6): 531-533. [本文引用:1]
[2] Sarles H, Sarles J, Muratore R, et al. Chronic inflammatory sclerosis of the pancreas——an autonomous pancreatic disease[J]. Am J Dig Dis, 1961, 6: 688-698. [本文引用:1]
[3] Toki F, Kozu T, Oi I. An usual type of chronic pancreatitis showing diffuse irregular narrowing of the entire main pancreatic duct on ERCP. A report of four cases[J]. Endoscopy, 1992, 24(3): 640. [本文引用:1] [JCR: 5.735]
[4] Yoshida K, Toki F, Takeuchi T, et al. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis[J]. Dig Dis Sci, 1995, 40(7): 1561-1568. [本文引用:1]
[5] Okazaki K, Kawa S, Kamisawa T, et al. Clinical diagnostic criteria of autoimmune pancreatitis: revised proposal[J]. J Gastroenterol, 2006, 41(7) : 626-631. [本文引用:2] [JCR: 3.788]
[6] Kim KP, Kim MH, Kim JC, et al. Diagnostic criteria for autoimmune chronic pancreatitis revisited[J]. World J Gastroenterol, 2006, 12(16): 2487-2496. [本文引用:1]
[7] Kim MH, Lee TY. Diagnostic criteria for autoimmune pancreatitis(AIP); a proposal of revised Kim criteria[J]. J Gastroenterol Hepatol, 2007, 22(2): 104. [本文引用:1]
[8] Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience[J]. Clin Gastroenterol Hepatol, 2006, 4(8): 1010-1016. [本文引用:1]
[9] Otsuki M, Chung JB, Okazaki K, et al. Asian diagnostic criteria for autoimmune pancreatitis: consensus of the Japan-Korea symposium on autoimmune pancreatitis[J]. J Gastroenterol, 2008, 43(6): 403-408. [本文引用:2] [JCR: 3.788]
[10] Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis[J]. N Engl J Med, 2001, 344(10): 732-738. [本文引用:2]
[11] Van Gulik TM, Reeders JW, Bosma A, et al. Incidence and clinical findings of benign, inflammatory disease in patients resected for presumed pancreatic head cancer[J]. Gastrointest Endosc, 1997, 46(5): 417-423. [本文引用:1] [JCR: 5.21]
[12] Inoue H, Miyatani H, Sawada Y, et al. A case of pancreas cancer with autoimmune pancreatitis[J]. Pancreas, 2006, 33(2): 208-209. [本文引用:1] [JCR: 2.953]
[13] Fukui T, Mitsuyama T, Takaokama M, et al. Pancreatic cancer associated with autoimmune pancreatitis in remission[J]. Intern Med, 2008, 47(3): 151-155. [本文引用:1] [JCR: 0.973]
[14] Ghazale A, Chari S. Is autoimmune pancreatitis a risk factor for pancreatic cancer[J]. Pancreas, 2007, 35(4): 376. [本文引用:1] [JCR: 2.953]
[15] Witkiewicz AK, Kennedy EP, Kennyon L, et al. Synchronous autoimmune pancreatitis and infiltrating pancreatic ductal adenocarcinoma: case report and review of the literature[J]. Hum Pathol, 2008, 39(10): 1548-1551. [本文引用:1] [JCR: 2.843]
[16] Sakashita F, Tanahashi T, Yamaguchi K, et al. Case of pancreatic tail cancer associated with autoimmune pancreatitis[J]. Jpn J Gastroenterol Surg, 2006, 39(1): 78-83. [本文引用:1]
[17] Iida H, Kubota K, Yoneda M, et al. A case of autoimmune pancreatitis developed pancreatic tail cancer[J]. Pancreas, 2009, 38(5): 483-484. [本文引用:1] [JCR: 2.953]
[18] Hiroyuki M, Kazuya M, Katsuhiko U, et al. A case of pancreatic carcinoma with suspected autoimmune pancreatitis[J]. Clin J Gastroenterol, 2009, 12(2): 59-63. [本文引用:1]