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Advances in Clinical Medicine
Vol. 13  No. 02 ( 2023 ), Article ID: 61764 , 10 pages
10.12677/ACM.2023.132379

原发性胆汁性胆管炎合并干燥综合征患者的 临床特征

赵晨阳1，胡川宁2*

1青岛大学附属医院风湿免疫科，山东 青岛

2青岛大学附属医院护理部，山东 青岛

收稿日期：2023年1月21日；录用日期：2023年2月16日；发布日期：2023年2月23日

摘要

目的：探讨原发性胆汁性胆管炎(PBC)合并干燥综合征(SS)的临床特点。方法：对334例原发性胆汁性胆管炎(PBC)患者进行了筛查，并评估了患者的自身免疫性疾病(AIDs)总体受累程度。然后比较有无SS的PBC病例的实验室和临床结果的差异，讨论了PBC与自身免疫性疾病发病率之间的不同关联。结果：女性PBC患者合并SS的比例高于单纯PBC患者的比例。与单纯PBC患者相比，合并SS的PBC患者的抗Ro-52、抗SSA、抗SSB、抗ds-DNA、ACA、ANuA、AHA抗体阳性率更高(p < 0.05)，出现恶心、下肢水肿、脾大、食管胃静脉曲张的可能性更大(p < 0.05)。伴有SS的PBC患者ALT、AST、ALB、ALP、γ-GT、TBIL、DBIL、IBIL、IgG、IgA水平高于单纯PBC患者，而IgM水平低于单纯PBC患者(p < 0.05)。SLE、RA和HT在合并SS的PBC患者中比单纯PBC患者更常见(p < 0.05)。结论：所取得的研究结果表明，合并SS的PBC患者的预后可能优于没有SS的PBC患者，尽管前者更有可能更易合并其他自身免疫性疾病。

关键词

原发性胆汁性胆管炎，干燥综合征

Clinical Characteristics of Patients with Primary Biliary Cholangitis Complicated with Sjogren’s Syndrome

Chenyang Zhao1, Chuanning Hu2*

1Department of Rheumatology, The Affiliated Hospital of Qingdao University, Qingdao Shandong

2Nursing Department, The Affiliated Hospital of Qingdao University, Qingdao Shandong

Received: Jan. 21st, 2023; accepted: Feb. 16th, 2023; published: Feb. 23rd, 2023

ABSTRACT

Objective: To investigate the clinical characteristics of primary biliary cholangitis (PBC) complicated with Sjogren’s syndrome. Methods: In total, 334 Chinese Primary biliary cholangitis (PBC) cases were screened for autoimmune diseases (AIDs), and overall involvement was evaluated. Discrepancies in the laboratory and clinical achievements were then compared between PBC cases without and with SS, and the diverse associations between PBC and the incidence of AIDs were then discussed. Result: The proportion of women with PBC and SS was higher than that among PBC patients alone. Relative to PBC cases, PBC cases with SS were also more possible to be positive for anti-Ro-52, anti-SSA, anti-SSB, ACA, anti-dsDNA, ANuA, and AHA antibodies (p < 0.05), and were more possible to undergo nausea, lower limb edema, splenomegaly, and esophagogastric varices (p < 0.05). The levels of ALT, AST, ALB, ALP, γ-GT, TBIL, DBIL, IBIL, IgG, and IgA were greater in PBC cases suffering from SS relative to those in patients with PBC alone, whereas the levels of IgM were lesser in the former patients (p < 0.05). The presentation of SLE, RA, and HT was more common in PBC patients with SS relative to patients with PBC alone (p < 0.05). Conclusion: The achieved findings demonstrate that the prognosis of PBC cases suffering from SS tends to be better than that of PBC patients without SS, although the former patient population is more likely to exhibit other comorbid AIDs.

Keywords:Primary Biliary Cholangitis, Sjögren’s Syndrome

Copyright © 2023 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 背景

干燥综合征(SS, Sjögren’s syndrome)和原发性胆汁性胆管炎(PBC, primary biliary cholangitis)均属于慢性器官特异性自身免疫性疾病(AIDs, Autoimmune diseases)，其中，免疫细胞特异性损害唾液腺、泪腺和胆管上皮细胞，最终导致自身免疫性上皮炎和相应组织的进行性免疫介导破坏 [1] [2] 。PBC患者通常伴有其他自身免疫性疾病，包括系统性红斑狼疮(SLE)、类风湿关节炎(RA)、桥本甲状腺炎(HT)和系统性硬化症(SSc)等 [3] 。SS经常出现在PBC和其他AIDs患者中，进一步研究SS、PBC和其他AIDs相互关联性是必要的。本文探讨了单纯PBC患者和PBC患者合并SS患者的临床特点，并分析了这两类患者的肝外AIDs的发生率。

2. 研究对象和方法

2.1. 研究对象纳入标准

本次共纳入中国PBC患者334例(女性309例，男性25例；中位年龄：60岁，年龄范围：20~91岁)，2012年至2020年在青岛大学附属医院初次就诊的患者被纳入本研究数据库，参与本研究前患者均签署知情同意书，且本研究经青岛大学附属医院医学伦理委员会审核批准，这些患者首次就诊时均为PBC患者，均住院接受诊断和治疗。其中，64例(19.16%) PBC患者行肝活检。PBC和其他AIDs的诊断分别根据美国肝病研究协会指南 [4] 、1980年美国风湿病学会(ACR) SSc标准 [5] 、2002年欧洲SS诊断标准 [6] 、2009年ACR修订的SLE分类标准 [7] 、1987年ACR修订的和2010年ACR/欧洲抗风湿病联盟RA标准 [8] [9] ，Bohan和Peter提出的PM和DM的诊断标准 [10] ，IgG-4相关疾病的诊断标准 [11] ，以及日本甲状腺学会HT指南 [12] 。

2.2. 研究对象排除标准

a) 合并其他明确诊断的共病肝病，例如病毒性肝炎、药物相关性肝病或脂肪肝；b) 出现梗阻性胆汁淤积；c) 受其他全身性疾病影响，包括自身免疫性肝炎、原发性硬化性胆管炎和结节病。

2.3. 统计分析

使用SPSS v 25.0 (芝加哥，美国)对结果进行分析。结果以均数 ± 标准差表示，并根据数据类型和正态分布情况采用t检验、Mann-Whitney U检验、2 × 2 χ2检验或Fisher精确检验进行评估。p < 0.05为所有分析的显著性阈值。

3. 结果

3.1. 人口特征

与单纯PBC患者相比，合并SS的PBC患者中女性比例较高(90.25% vs. 97.95%, p = 0.015)。两组患者年龄无明显差异(表1)。

Table 1. Demographic characteristics and serological assay results from PBC cases without and with SS

表1. 合并SS的PBC患者与单纯PBC患者的人口学特征和血清学分析结果

结果以平均值 ± 标准差表示。a符合正态分布的数据用t检验分析结果。

3.2. 血清学化验结果

在合并SS的PBC患者中，RBC、WBC和PLT计数没有明显变化，而单独PBC患者的CRP水平明显高于PBC和SS患者(5.21 ± 12.61 mg/L vs. 5.34 ± 9.24 mg/L, p = 0.040，表1)。

两组患者的ALB或ALT/AST无明显差异，但与合并SS的PBC患者相比，PBC患者的TBIL、DBIL、IBIL、ALT、AST、ALP、γ-GT和IgM水平较高(p < 0.05)。相反，PBC合并SS患者的IgG、IgA和IgE水平高于单纯PBC患者(p < 0.05) (见表1)。

在这些患者的抗可提取性核抗原抗体(ENA)谱中，最常见的自身抗体是抗Ro-52 (66.33%, 65/96)、抗SSA (58.16%, 57/96)、ACA (38.78%, 38/96)和抗SSB (28.57%, 28/96)抗体。

两组患者的ANA、抗RNA、抗sm、抗scl-70、抗PM-Scl、抗jo-1、抗PCNA、AMA、AMA-M2、抗gp210、抗sp100和抗核糖体蛋白P抗体水平相当。与单纯PBC的患者相比，合并SS的患者抗Ro-52、抗SSA、抗SSB、抗ds-DNA、ACA、ANuA和AHA的阳性率更高(见表2)。

Table 2. Anti-ENA antibody profiles from PBC cases with and without SS

表2. 合并SS的PBC患者与单纯PBC患者的抗ENA酶谱分析

结果以比值或n(%)表示。

3.3. 症状和影像学表现

在单纯PBC患者和合并SS的PBC患者中，从出现症状到入院的平均时间间隔分别为943天和1544天(p = 0.009)。疲劳、腹胀、口干、眼干、体重下降、发热、头晕、巩膜黄染、皮肤黄染、瘙痒、消化道出血、肝硬化、门脉高压、腹腔积液发生率在两组患者间无显著差异。然而，恶心和下肢水肿在合并SS的PBC患者中比单纯PBC患者更常见，而食管胃底静脉曲张和脾大的发生率则相反(见表3)。

Table 3. Symptoms and radiographic findings from PBC cases with and without SS

表3. 合并SS的PBC患者与单纯PBC患者的主诉和影像学结果分析

结果以比值或n(%)表示。

3.4. Child-Pugh评分和共病

PBC患者的Child-Pugh评分在单纯PBC和合并SS的PBC患者之间没有显著差异，但合并SS的PBC患者中SLE、RA和HT的共病率明显高于单独合并PBC的患者(见表4)。在这两个患者人群中，未观察到IgG4-RD、SSc或DM发病率的差异。

Table 4. Child-Pugh scores and comorbidities in PBC cases with and without SS

表4. 合并SS的PBC患者与单纯PBC患者的Child-Pugh评分及共病情况

结果以比值或n(%)表示。

4. 讨论

PBC和SS均属于慢性自身免疫性疾病，其共同的特征是免疫介导的上皮细胞破坏 [13] 。这两种疾病的诊断高度依赖于生化指标、自身抗体的检测以及组织病理检查 [1] [2] 。PBC和SS经常同时发生，这与这两种疾病拥有相似的遗传背景和靶器官相关 [13] [14] 。迄今为止，研究主要集中在PBC相关发病机制的器官特异性靶点和非器官特异性并发症，包括高脂血症、骨质疏松症和代谢综合征 [15] ，这些研究为探索PBC潜在发病机制指出了有前景的研究方向。

在意大利进行的一项流行病学分析显示，在361名接受调查的PBC患者中，61.2%的患者表现出至少一种共病的肝外AID，其中SS、HT、SSc和RA是最常见的共病 [16] 。同样，另一项研究发现，大约三分之一的PBC患者患有其他AIDs，其中RA和SS是该研究人群中最常见的疾病 [17] 。本研究纳入的334例PBC患者中，有44.61%的患者同时患有一种或多种AIDs，本研究中患者的SS发生率(29.34%)与以往报道相似。在本研究中，SS是这些自身免疫性疾病中最常见的，这与这两种AIDs的相似致病途径一致。尽管SLE、HT和RA与SS具有相似的发病机制 [18] ，但在三者中，HT在合并SS的PBC患者的发病率更高。甲状腺、泪腺和唾液腺的组织学相似性为这些发现提供了理论支持 [19] 。有趣的是，DM和IgG4-RD在大规模PBC患者研究中很少被讨论 [3] [20] ，尽管先前的病例报告已经确定了患有这些疾病的个体 [21] [22] [23] 。因此，临床医生应该意识到在诊断为PBC的病例中存在这两种AID的可能性。

在本研究中，无论是否患有SS的PBC患者中，女性占比都非常高，且大多数患者在59岁时接受诊断和治疗，这与先前的报道一致 [24] [25] [26] [27] [28] 。与PBC相关的进行性免疫介导的组织破坏优先针对胆道上皮细胞，而在SS中，唾液腺和泪腺是免疫病理损伤的主要靶点 [1] [2] 。胆管和外分泌腺上皮细胞表达的雌激素受体被认为是女性PBC和SS发病率较高的重要原因 [29] ，这可能解释了本研究队列中合并SS的PBC患者女性比例非常高的原因。

与单纯PBC相比，PBC和SS患者抗SSA、抗Ro-52、抗SSB和抗ds-DNA抗体以及ACA、ANuA和AHA抗体的阳性率更高，与本研究中这些患者中AIDs患病率较高的情况一致。自身抗体的存在往往预示着患有AIDs的可能 [30] 。因此，通过分析PBC患者的抗ENA抗体谱来筛查其他AIDs是至关重要的。

之前的研究表明，ALP和TBIL水平升高以及肝硬化的进行性发展与肝病患者预后不良密切相关 [31] [32] 。在本研究队列中，与合并SS的PBC患者相比，单纯PBC患者表现出更高水平的CRP、TBIL、DBIL、IBIL、ALT、AST、ALP、γ-GT和IgM。PBC合并SS患者也不太可能出现肝硬化相关预后较差的并发症，包括脾肿大和食管胃静脉曲张。腹部超声对肝硬化有很高的特异性 [33] 。但是，患者在没有症状的情况下，往往不去医院接受检查。本研究中两组PBC患者的肝硬化患病率高于英国报道的 [34] 。更多的工作仍有待完成，以帮助中国PBC患者的早期诊断。加强对患者的健康教育和定期的年度体检有助于早期发现PBC。本研究结果与先前的证据一致，表明PBC合并AID患者的预后并不一定比单纯PBC患者的预后差 [35] [36] [37] [38] 。

本研究中PBC患者更有可能出现IgM水平异常，而PBC合并SS患者更有可能出现IgG水平异常，其与B细胞功能改变高度相关 [39] [40] [41] [42] 。本研究还对患者最常见的12种主诉进行了额外评估，除恶心和下肢水肿外，患者的其他主诉未见统计学差异，这与中国最近的报道一致 [43] 。在未监测抗ENA抗体谱的情况下，仅根据症状来确定PBC患者是否合并SS仍然具有挑战性。与无SS的PBC患者相比，合并SS的PBC患者TBIL、DBIL、IBIL、ALT、AST、ALP、γ-GT、IgM等生化指标更好，并发症较少，这可能提示该类患者疾病进展相对较慢，预后较好。

本研究可能存在以下的局限性：首先，本研究为单中心研究，样本量受制于地区人口情况，亟需多中心、大样本量的研究来进一步探讨PBC和SS的临床特点。其次，PBC患者仍需长时间、可持续的随访来进一步探索PBC和SS的临床特征。

5. 结论

总的来说，目前的研究结果表明，PBC合并SS患者的预后可能优于PBC患者，因为同时患有这两种疾病的患者在疾病进展的早期，临床、组织学、生化和自身抗体的变化不太明显，患者可以在更早的时间点接受标准化治疗。然而，进一步的前瞻性、多中心、病例对照研究对于深入分析PBC和SS的相互关联性以及探索治疗这些疾病的有效治疗药物至关重要。

文章引用

赵晨阳,胡川宁. 原发性胆汁性胆管炎合并干燥综合征患者的临床特征
Clinical Characteristics of Patients with Primary Biliary Cholangitis Complicated with Sjogren’s Syndrome[J]. 临床医学进展, 2023, 13(02): 2690-2699. https://doi.org/10.12677/ACM.2023.132379

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NOTES

*通讯作者Email: chuanningh@gmail.com

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