慢性胰腺炎患者血液免疫指標(biāo)的檢測(cè)和分析

·論著·

慢性胰腺炎患者血液免疫指標(biāo)的檢測(cè)和分析

鄭兆泓趙九龍杜婷婷胡良皞廖專(zhuān)葉博李白容季鈞淘王丹林金歡李兆申

【摘要】目的檢測(cè)慢性胰腺炎(CP)患者各項(xiàng)血液自身免疫指標(biāo)的陽(yáng)性率，探討其臨床價(jià)值。方法檢測(cè)上海長(zhǎng)海醫(yī)院消化科就診的409例CP患者的抗可提取性核抗原抗體(抗ENA抗體)、抗胞漿型中性粒細(xì)胞抗體、抗β2-糖蛋白1抗體(anti-β2-GPI)、抗心磷脂抗體(ACA)、抗單鏈-DNA抗體等25項(xiàng)血清相關(guān)自身免疫指標(biāo)，并與系統(tǒng)檢索的Pubmed數(shù)據(jù)庫(kù)內(nèi)相關(guān)文獻(xiàn)的健康人群陽(yáng)性率進(jìn)行比較。結(jié)果409例CP患者中僅檢出anti-β2-GPI、ACA、抗雙鏈-DNA抗體陽(yáng)性患者，陽(yáng)性率分別為11.7%、1.4%、1.9%，其余指標(biāo)均為陰性。其中anti-β2-GPI陽(yáng)性率與健康人群相比有顯著提高(11.7%比3.4%)，ACA陽(yáng)性率低于健康人群(1.4%比4.1%)，差異均有統(tǒng)計(jì)學(xué)意義(P值均<0.05)。而抗單鏈-DNA抗體陽(yáng)性率與健康人群的差異無(wú)統(tǒng)計(jì)學(xué)意義。結(jié)論anti-β2-GPI對(duì)于CP的診療具有潛在價(jià)值，ACA的臨床意義尚不確定。

【關(guān)鍵詞】胰腺炎，慢性；自身免疫疾?。簧飳W(xué)標(biāo)記；抗β2-糖蛋白1抗體

DOI:10.3760/cma.j.issn.1674-1935.2015.02.006

收稿日期：(2015-01-08)

Detection and analysis of blood immune parameters in patients with chronic pancreatitisZhengZhaohong,ZhaoJiulong,DuTingting,HuLianghao,LiaoZhuang,YeBo,LiBairong,JiJuntao,WangDan,LinJinhuan,LiZhaoshen.DepartmentofGastroenterology,ChanghaiHospital,SecondMilitaryMedicalUniversity,Shanghai200433,China

Correspondingauthor:LiZhaoshen,Email:zhaoshen-li@hotmail.com

Abstract【〗ObjectiveTo explore the positive rate of each autoimmunity parameters in patients with chronic pancreatitis. MethodsFour hundred and nine chronic pancreatitis patients treated in Department of Gastroenterology of Changhai Hospital were selected and the 25 autoimmunity parameters included anti-ENA antibody, anti-neutrophil cytoplasmic antibody, anti-β2-GPI, anticardiolipin antibody (ACA), anti dsDNA antibody were determined, then a literature search was performed to compare the autoimmune positive rate of healthy people in Pubmed database with chronic pancreatitis patients. ResultsAmong 409 patients, the positive rates of anti β2-GPI, ACA, and anti dsDNA antibody were 11.7%, 1.4%, and 1.9%, respectively, whereas other indicators were negatively expressed. The positive rate of anti β2-GPI in CP patients was significantly higher than that of healthy group (11.7%vs3.4%), and the positive rate of ACA was lower than that of healthy group (1.4%vs4.1%), and the difference between the two groups was statistically significant (P<0.05). ConclusionsAnti β2-GPI shows some potential value in the diagnosis and treatment of chronic pancreatitis, but the clinical significance of ACA is uncertain.

【Key words】Pancreatits, chronic;Autoimmune diseases;Biological markers;anti-β2 glycoprotein 1

慢性胰腺炎(chronic pancreatitis，CP)是胰腺的一種進(jìn)行性炎癥性疾病。隨著國(guó)人生活水平的提高，CP的發(fā)病率有增長(zhǎng)的趨勢(shì)，嚴(yán)重地影響了人們的工作和生活。目前關(guān)于CP的病因除了攝入酒精較為明確[1]外，其他致病因素尚不明確，影響了疾病的診斷和治療。自身免疫性胰腺炎(autoimmune pancreatitis, AIP)作為CP的一種亞型，自身免疫指標(biāo)IgG4對(duì)于其診斷的價(jià)值已得到明確[2]。對(duì)于其他特發(fā)性CP患者，自身免疫因素是不是其致病因素，是否需要對(duì)CP患者行血液自身免疫指標(biāo)檢測(cè)，目前尚無(wú)明確的相關(guān)研究。本研究檢測(cè)CP患者(AIP除外)的血液自身免疫指標(biāo)，以明確CP與自身免疫是否相關(guān)。

作者單位：200433上海，第二軍醫(yī)大學(xué)長(zhǎng)海醫(yī)院消化內(nèi)科

通信作者：李兆申，Email: zhaoshen-li@hotmail.com

資料與方法

一、一般資料

選取2008年1月至2013年12月在上海長(zhǎng)海醫(yī)院消化內(nèi)科就診并同意接受檢測(cè)的CP患者(AIP與有免疫性疾病史除外)共409例，其中男性291例，女性118例，平均年齡(34±8)歲。青少年(<18歲)患者55例。

二、檢測(cè)指標(biāo)

檢測(cè)的血指標(biāo)包括抗可提取性核抗原抗體(抗ENA抗體)，抗SS-A，抗SS-B，抗JO-1，抗RNP，抗Scl-70，抗Sm，抗胞漿型中性粒細(xì)胞抗體，抗多發(fā)性肌炎硬皮病抗體，抗蛋白酶3抗體IgG，抗髓過(guò)氧化物酶抗體，抗線粒體M2抗體，抗核糖體抗體，抗腎小球基底膜抗體，抗增殖細(xì)胞核抗原抗體，抗β2-糖蛋白1抗體(anti-β2-GPI )，抗核小體抗體，抗組蛋白抗體，抗核周型中性粒細(xì)胞抗體，抗雙鏈-DNA抗體，抗單鏈-DNA抗體，抗核抗體，抗平滑肌抗體，抗線粒體抗體，抗心磷脂抗體(ACA)，免疫球蛋白G4亞型(IgG4)，共25項(xiàng)自身免疫指標(biāo)。

三、對(duì)照組的設(shè)置

因本研究基于大樣本的臨床檢測(cè)，未設(shè)置相關(guān)對(duì)照組，且部分抗體在健康人群中陽(yáng)性率的相關(guān)研究較少，并且尚無(wú)準(zhǔn)確、統(tǒng)一的數(shù)值，故系統(tǒng)檢索Pubmed，選取庫(kù)內(nèi)所有涉及健康人群相關(guān)自身免疫陽(yáng)性率的文獻(xiàn)作為對(duì)照。例如以anti-β2 glycoprotein I和anti-β2-GPI作為關(guān)鍵詞檢索Pubmed數(shù)據(jù)庫(kù)，選取庫(kù)內(nèi)所有涉及健康人群anti-β2-GPI陽(yáng)性率的相關(guān)文獻(xiàn)共16篇[3-18]，anti-β2-GPI分為IgA、IgG、IgM3型，本次檢測(cè)為anti-β2-GPI總值，故單獨(dú)檢測(cè)anti-β2-GPI 3種分型之一的相關(guān)文獻(xiàn)未列入統(tǒng)計(jì)。

四、統(tǒng)計(jì)學(xué)處理

結(jié)　　果

一、CP患者血液自身免疫指標(biāo)的陽(yáng)性率

409例CP患者中48例患者的anti-β2-GPI呈陽(yáng)性，陽(yáng)性率11.7%。48名陽(yáng)性患者中anti-β2-GPI的平均值為38.51RU/ml，預(yù)測(cè)他們的anti-β2-GPI 值分布在33.40～43.63RU/ml(95%CI)，明顯高于≤20RU/ml的正常參考值[19]。Pubmed數(shù)據(jù)庫(kù)內(nèi)所有涉及健康人群anti-β2-GPI陽(yáng)性率的相關(guān)文獻(xiàn)共16篇，納入2 438名健康者，其中88名陽(yáng)性，陽(yáng)性率為3.4%。CP 患者陽(yáng)性率顯著高于文獻(xiàn)報(bào)道的健康人群，差異有統(tǒng)計(jì)學(xué)意義(χ2=50.85，P<0.001)。

本組6例患者ACA呈陽(yáng)性，陽(yáng)性率1.4%。數(shù)據(jù)庫(kù)涉及的健康人群陽(yáng)性率的相關(guān)文獻(xiàn)共12篇[20-31]，納入7 269名健康者，其中299例陽(yáng)性，陽(yáng)性率為4.1%。CP患者陽(yáng)性率顯著低于文獻(xiàn)報(bào)道的健康人群，差異有統(tǒng)計(jì)學(xué)意義(χ2=7.07，P<0.001)

本組8例患者抗雙鏈-DNA抗體陽(yáng)性，陽(yáng)性率1.9%。數(shù)據(jù)庫(kù)涉及健康人群的陽(yáng)性率的相關(guān)文獻(xiàn)共5篇[32-36]，納入368名健康者，其中8名陽(yáng)性，陽(yáng)性率為2.1%。CP患者與健康人群的差異無(wú)統(tǒng)計(jì)學(xué)意義(χ2=0.01，P>0.05)。

其余22項(xiàng)自身免疫指標(biāo)均未發(fā)現(xiàn)陽(yáng)性者。

CP患者血anti-β2-GPI、ACA、抗雙鏈-DNA抗體的陽(yáng)性率之間有相關(guān)性(F=29.33，P<0.001)。

二、anti-β2-GPI陰性與陽(yáng)性CP患者的比較

anti-β2-GPI陽(yáng)性CP患者胰腺發(fā)育異常(胰腺分裂、胰管匯流異常、環(huán)狀胰腺等)發(fā)生率高于陰性的CP患者，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)，其他指標(biāo)的差異均無(wú)統(tǒng)計(jì)學(xué)意義(表1)。

表1　anti-β2-GPI陰性與陽(yáng)性CP患者的臨床資料比較

三、胰腺發(fā)育異常者與正常者的比較

23例CP患者存在胰腺發(fā)育異常。胰腺發(fā)育異常CP患者的男性占比低于胰腺發(fā)育正常的CP患者，血清anti-β2-GPI陽(yáng)性率顯著高于胰腺發(fā)育正常的CP患者，差異均有統(tǒng)計(jì)學(xué)意義(P值均<0.05)，其他指標(biāo)的差異均無(wú)統(tǒng)計(jì)學(xué)意義(表2)。

表2　胰腺發(fā)育異常與正常的CP患者的臨床資料比較

討　　論

本研究檢測(cè)了CP患者25項(xiàng)血清自身免疫指標(biāo)，其中anti-β2-GPI、ACA、抗雙鏈-DNA抗體呈現(xiàn)陽(yáng)性。CP患者的anti-β2-GPI陽(yáng)性率高于健康人群，提示該指標(biāo)與CP有相關(guān)性。anti-β2-GPI為肝細(xì)胞合成并影響甘油三酯和膽固醇的代謝，它還參與凝血過(guò)程，促進(jìn)微血栓形成[37-39]。Wanless等[40]報(bào)道，肝微血栓的形成與肝臟纖維化相關(guān)。CP作為一種胰腺實(shí)質(zhì)萎縮、纖維化的疾病，anti-β2-GPI引起微血栓形成亦可能與CP的胰腺纖維化相關(guān)。但anti-β2-GPI的檢測(cè)對(duì)于CP患者是否具有早期診斷的價(jià)值，其數(shù)值的變化是否具有評(píng)價(jià)疾病預(yù)后及判斷治療效果的價(jià)值都需要進(jìn)一步研究證實(shí)。anti-β2-GPI在胰腺發(fā)育異常的患者中也顯著升高，提示該指標(biāo)與胰腺發(fā)育異常的相關(guān)性。anti-β2-GPI檢測(cè)目前主要應(yīng)用于習(xí)慣性流產(chǎn)，系統(tǒng)性紅斑狼瘡，腦卒中等疾病，其中在系統(tǒng)紅斑狼瘡的陽(yáng)性率較高，其余疾病的陽(yáng)性率大部分在10%～20%之間[3-18]，與本研究所得陽(yáng)性率數(shù)值相近?？剐牧字贵w作為一種以血小板和內(nèi)皮細(xì)胞膜上帶負(fù)電荷的心磷脂作為靶抗原的自身抗體，其陽(yáng)性率增高常見(jiàn)于系統(tǒng)性紅斑狼瘡、血栓形成相關(guān)疾病、習(xí)慣性流產(chǎn)等。本研究該抗體陽(yáng)性率低于健康人群，其原因尚不明確，有無(wú)臨床意義有待進(jìn)一步探討?；谧陨砻庖咭蛩夭⒉皇荂P常見(jiàn)的致病因素，且全面篩查自身免疫指標(biāo)費(fèi)用較高，故對(duì)CP患者無(wú)需全面檢查各項(xiàng)免疫指標(biāo)，僅檢測(cè)anti-β2-GPI單項(xiàng)指標(biāo)即可。

參考文獻(xiàn)

[1]Strate T, Knoefel WT, Yekebas E, et al. Chronic pancreatitis: etiology, pathogenesis, diagnosis, and treatment[J]. Int J Colorectal Dis, 2003, 18(2): 97-106.

[2]Chari ST, Smyrk TC, Levy MJ. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience[J]. Clin Gastroenterol Hepatol, 2006, 4(8): 1010-1016.

[3]Chilcott IT, Margara R, Cohen H, et al. Pregnancy outcome is not affected by antiphospholipid antibody status in women referred for in vitro fertilization[J]. Fertil Steril, 2000, 73(3): 526-530.

[4]Lee RM, Emlen W, Scott JR, et al. Anti-beta2-glycoprotein I antibodies in women with recurrent spontaneous abortion, unexplained fetal death, and antiphospholipid syndrome[J]. Am J Obstet Gynecol, 1999, 181(3): 642-648.

[5]Stern C, Chamley L, Hale L, et al. Antibodies to beta2 glycoprotein I are associated with in vitro fertilization implantation failure as well as recurrent miscarriage: results of a prevalence study[J]. Fertil Steril, 1998, 70(5): 938-944.

[6]Koudriavtseva T, D′Agosto G, Mandoj C, et al. High frequency of antiphospholipid antibodies in relapse of multiple sclerosis:a possible indicator of inflammatory-thrombotic processes[J]. Neurol Sci, 2014, 35(11): 1737-1741.

[7]Alkaabi JK, Gravell D, Al-Haddabi H, et al. Haemostatic Parameters in Patients with Behcet′s Disease[J]. Sultan Qaboos Univ Med J, 2014, 14(2): 190-196.

[8]Etemadifar M, Fatemi A, Hashemijazi H, et al. Is it necessary to perform connective tissue disorders laboratory tests when a patient experiences the first demyelinating attack[J]? J Res Med Sci, 2013, 18(7): 617-620.

[9]Sater MS, Finan RR, Abu-Hijleh FM, et al. Anti-phosphatidylserine, anti-cardiolipin, anti-β2 glycoprotein I and anti-prothrombin antibodies in recurrent miscarriage at 8-12 gestational weeks[J]. Eur J Obstet Gynecol Reprod Biol, 2012, 163(2): 170-174.

[10]Spinillo A, Beneventi F, Ramoni V, et al. Prevalence and significance of previously undiagnosed rheumatic diseases in pregnancy[J]. Ann Rheum Dis, 2012, 71(6): 918-923.

[11]Manka? A, Achour A, Thabet Y, et al. Anti-cardiolipin and anti-beta 2-glycoprotein I antibodies in celiac disease[J]. Pathol Biol(Paris), 2012, 60: 291-295.

[12]Fanopoulos D, Teodorescu MR, Varga J, et al. High frequency of abnormal levels of IgA anti-beta2-glycoprotein I antibodies in patients with systemic lupus erythematosus: relationship with antiphospholipid syndrome[J]. J Rheumatol, 1998, 25(4): 675-680.

[13]Farsi A, Domeneghetti MP, Fedi S, et al. High prevalence of anti-beta2 glycoprotein I antibodies in patients with ischemic heart disease[J]. Autoimmunity, 1999, 30(2): 93-98.

[14]Bruce IN, Clark-Soloninka CA, Spitzer KA, et al. Prevalence of antibodies to beta2-glycoprotein I in systemic lupus erythematosus and their association with antiphospholipid antibody syndrome criteria: a single center study and literature review[J]. J Rheumatol, 2000, 27(12): 2833-2837.

[15]Faden D, Tincani A, anzi P, et al. Anti-beta 2 glycoprotein I antibodies in a general obstetric population: preliminary results on the prevalence and correlation with pregnancy outcome. Anti-beta2 glycoprotein I antibodies are associated with some obstetrical complications, mainly preeclampsia-eclampsia[J]. Eur J Obstet Gynecol Reprod Biol, 1997, 73(1): 37-42.

[16]Koutroubakis IE,Petinaki E, Anagnostopoulou E, et al. Anti-cardiolipin and anti-beta2-glycoprotein I antibodies in patients with inflammatory bowel disease[J]. Dig Dis Sci, 1998, 43(11): 2507-2512.

[17]Helgadottir LB, Skjeldestad FE, Jacobsen AF, et al. The association of antiphospholipid antibodies with intrauterine fetal death: a case-control study[J]. Thromb Res, 2012, 130(1): 32-37.

[18]Roldán V, Marín F, Pineda J, et al. Annexin V levels in survivors of early myocardial infarction[J]. Rev Esp Cardiol, 2002,55(12): 1230-1234.

[19]熊艷,崔天盆，吳建民.SLE患者血清抗心磷脂抗體和抗β2糖蛋白Ⅰ抗體水平及關(guān)系[J].臨床皮膚科雜志, 2001,30(6):351-352.

[20]Butkiewicz F, Kaszuba M, Brzeziński M, et al. Associations between the incidence of antiphosphatidylserine and antiphosphatidylethanolamine antibodies and clinical manifestations of systemic lupus erythematosus[J]. Pol Arch Med Wewn, 2014,124(11):573-578.

[21]Palomo IG, Mujica VE, Alarcón ML, et al. Prevalence of antiphospholipid antibodies is not different in Chilean diabetic patients and normal individuals[J]. J Diabetes Complications, 2005,19(3):133-137.

[22]Yaseen Al, Khayat ZA, Waheda NE, et al. The prevalence of positive serum anticardiolipin antibodies and asymptomatic bacteriuria in women with recurrent abortions[J]. Eurasian J Med, 2013,45(1):39-42.

[23]Ferrer-Oliveras R, Llurba E, Cabero-Roura L, et al. Prevalence and clinical usefulness of antiphospholipid and anticofactor antibodies in different Spanish preeclampsia subsets[J]. Lupus, 2012,21(3):257-263.

[24]Elefsiniotis IS, Diamantis ID, Dourakis SP, et al. Anticardiolipin antibodies in chronic hepatitis B and chronic hepatitis D infection, and hepatitis B-related hepatocellular carcinoma. Relationship with portal vein thrombosis[J]. Eur J Gastroenterol Hepatol, 2003,15(7):721-726.

[25]Rajewski M, Skrzypczak J. Frequency of antiphospholipid antibodies and antiphospholipid syndrome in women with recurrent miscarriages[J].Ginekol Pol, 2011,82(1):32-38.

[26]Markic′ J, Mestrovic′ M, Valic′ I, et al. Frequency of anticardiolipin, antinuclear and anti-beta2 glycoprotein I antibodies in children with epilepsy[J]. Coll Antropol, 2007,31(3):739-742.

[27]Karoui S, Sellami MK, Laatar AB, et al. Prevalence of anticardiolipin and anti-beta2-glycoprotein I antibodies in celiac disease[J]. Dig Dis Sci, 2007,52(4):1096-1100.

[28]Chen WH, Kao YF, Lan MY, et al. The increase of blood anticardiolipin antibody depends on the underlying etiology in cerebral ischemia[J]. Clin Appl Thromb Hemost, 2006,12(1):69-76.

[29]Wang Z, Fan Y, Wu G. Relation between fetal intrauterine growth retardation and anticardiolipin antibodies[J]. Zhonghua Fu Chan Ke Za Zhi, 1997,32(10):623-625.

[30]Liozon F, Jauberteau-Marchan MO, Boutros-Toni F, et al. Anticardiolipin antibodies and Horton disease[J]. Ann Med Interne (Paris), 1995,146(8):541-547.

[31]Pattison NS, Chamley LW, McKay EJ, et al. Antiphospholipid antibodies in pregnancy: prevalence and clinical associations[J]. Br J Obstet Gynaecol, 1993,100(10):909-913.

[32]Saigal R, Goyal LK, Agrawal A, et al. Anti-nucleosome antibodies in patients with systemic lupus erythematosus: potential utility as a diagnostic tool and disease activity marker and its comparison with anti-dsDNA antibody[J].J Assoc Physicians India, 2013,61(6):372-377.

[33]Kekow M, Barleben M, Drynda S, et al. Long-term persistence and effects of fetal microchimerisms on disease onset and status in a cohort of women with rheumatoid arthritis and systemic lupus erythematosus[J]. BMC Musculoskelet Disord, 2013, 14:325.

[34]Blondin DA, Zhang Z, Shideler KK, et al. Prevalence of non-organ-specific autoantibodies in patients with pemphigus vulgaris[J]. J Cutan Med Surg,2009,13(2):82-87.

[35]Chen HY, Guo JL, Li ZG. Significance of anti-cell membrane-associated DNA (mDNA) antibodies in systemic lupus erythematosus[J]. Clin Rheumatol, 2008,27(2):183-187.

[36]Croquefer S, Renaudineau Y, Jousse S, et al. The ananti-alpha-actinin test completes ananti-DNA determination in systemic lupus erythematosus[J]. Ann N Y Acad Sci, 2005,1050:170-175.

[37]McNally T, Crook M, Mackie IJ, et al. Beta 2 glycoprotein-I antigen is increased in primary hyperlipidaemia[J]. Br J Haematol, 1994, 88(2): 424-426.

[38]Schousboe I, Rasmussen MS. The effect of beta 2-glycoprotein I on the dextran sulfate and sulfatide activation of the contact system (Hageman factor system) in the blood coagulation[J]. Int J Biochem, 1988, 20(8): 787-792.

[39]Balasubramanian K, Killion JJ, Schroit AJ. Estimation of plasma beta-2-glycoprotein levels by competitive ELISA[J]. Thromb Res, 1998, 92(2): 91-97.

[40]Wanless IR, Liu JJ, Butany J. Role of thrombosis in the pathogenesis of congestive hepatic fibrosis (cardiac cirrhosis) [J〗. Hepatology, 1995, 21(5): 1232-1237.

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