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原发性胆汁性胆管炎患者发生桥本氏甲状腺炎的临床特征及预后分析
DOI: 10.3969/j.issn.1001-5256.2022.07.013
伦理学声明：本研究经由昆明医科大学第二附属医院伦理委员会批准，批号：审-PJ-2019-38。所纳入患者均知情同意。
利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。
作者贡献声明：张静怡负责课题设计，收集数据，资料分析，拟定写作思路，撰写论文；唐映梅负责指导撰写文章并最后定稿。
Features and prognosis of Hashimoto's thyroiditis in patients with primary biliary cholangitis
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摘要:
目的 探索原发性胆汁性胆管炎(PBC)患者发生桥本氏甲状腺炎(HT)的临床特征、相关因素以及预后特点。 方法 回顾性选取2018年1月—2020年12月就诊于昆明医科大学第二附属医院确诊为PBC且甲状腺功能检查资料完善的患者301例。根据患者甲状腺疾病累及情况，分为HT组患者83例，非HT组患者88例。对比两组患者的一般资料、临床特征及实验室检查，分析PBC患者发生HT的相关因素及预后特征。计量资料两组间比较采用独立样本t检验或Mann-Whitney U检验，计数资料两组间比较采用χ2检验和Bonferroni校正检验；相关性分析采用Spearman相关性分析，多因素分析采用二元logistic回归分析或多元线性回归分析。 结果 PBC患者常合并肝外自身免疫性疾病，其中HT患病率为27.6%，PBC患者中HT组较非HT组女性患者数量(χ2=9.547)、Child-Pugh评分(Z=-3.100)、IgA(Z=-1.992)、IL-6(Z=-1.969)、TgAb(Z=-9.612)、TPOAb(Z=-9.739)水平明显增加，肝硬化(χ2=8.807)、乏力(χ2=4.951)、纳差(χ2=6.636)、腹胀(χ2=7.977)发生率明显增加(P值均＜0.05)，HT组患者较非HT组患者TC(Z=-2.743)、TG(Z=-2.332)、LDL(Z=-2.604)、C3(t=5.063)水平明显降低(P值均＜0.05)。Child-Pugh评分[比值比(OR)=1.486, 95%CI: 1.060~2.083, P＜0.05]、TgAb(OR=1.032, 95%CI: 1.012~1.052, P＜0.05)、TPOAb(OR=1.007, 95%CI: 1.002~1.012, P＜0.05)水平升高是PBC患者发生HT的独立危险因素。高龄(t=9.147)、UDCA治疗不应答(t=-2.727)，AST(t=2.121)、ALP(t=2.446)、总胆红素(t=10.114)、IgA(t=4.162)、IL-6(t=2.033)水平升高，总蛋白(t=-3.384)、HDL(t=-3.887)、C3(t=-2.440)、C4(t=-2.422)水平降低，合并肝性脑病(t=3.685)、腹水(t=6.744)、gp210抗体阳性(t=3.125)是Mayo风险评分升高的独立危险因素(P值均＜0.05)，提示预后不良。PBC患者合并HT不是Mayo风险评分升高的独立危险因素(t=-0.077，P＞0.05)，并不影响患者预后。 结论 PBC患者常合并肝外自身免疫疾病，以甲状腺疾病最为多见，尤其是自身免疫性甲状腺炎，PBC合并HT的患者常伴更多的并发症和临床症状。PBC进展、甲状腺相关抗体TgAb、TPOAb升高是HT发生的独立危险因素，但合并HT并不影响PBC患者的预后。 -
关键词:
- 原发性胆汁性胆管炎 /
- 甲状腺炎, 自身免疫性 /
- 危险因素 /
- 预后
Abstract:Objective To investigate the clinical features, related factors, and prognosis of Hashimoto's thyroiditis (HT) in patients with primary biliary cholangitis (PBC). Methods A retrospective analysis was performed for the patients who were diagnosed with PBC in The Second Affiliated Hospital of Kunming Medical University from January 2018 to December 2020, among whom 301 patients underwent thyroid function tests and had complete clinical data. According to the involvement of thyroid disease, they were divided into HT group with 83 patients and non-HT group with 88 patients. The two groups were compared in terms of general data, clinical features, and laboratory examination, and the factors and prognostic features of HT in patients with PBC were analyzed. The independent samples t-test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test and the Bonferroni correction test were used for comparison of categorical data between two group; a Spearman correlation analysis was used to investigate correlation, and a binary logistic regression analysis or multiple linear regression analysis was used for multivariate analysis. Results The patients with PBC often had extrahepatic autoimmune diseases, and the prevalence rate of HT was 27.6%. Compared with the non-HT group, the HT group had significantly higher number of female patients (χ2=9.547, P < 0.05), Child-Pugh score (Z=-3.100, P < 0.05), and levels of IgA (Z=-1.992, P < 0.05), interleukin-6 (IL-6) (Z=-1.969, P < 0.05), thyroglobulin antibody (TgAb) (Z=-9.612, P < 0.05), and thyroid peroxidase antibody (TPOAb) (Z=-9.739, P < 0.05), significantly higher incidence rates of liver cirrhosis (χ2=8.807, P < 0.05), weakness (χ2=4.951, P < 0.05), poor appetite (χ2=6.636, P < 0.05), and abdominal distension (χ2=7.977, P < 0.05), and significantly lower levels of total cholesterol (Z=-2.743, P < 0.05), total triglyceride (Z=-2.332, P < 0.05), low-density lipoprotein(Z=-2.604, P < 0.05), and C3 (t=5.063, P < 0.05). Increases in Child-Pugh score (odds ratio [OR]=1.486, 95% confidence interval [CI]: 1.06-2.083, P < 0.05), TgAb (OR=1.032, 95%CI: 1.012-1.052, P < 0.05), and TPOAb (OR=1.007, 95%CI: 1.002-1.012, P < 0.05) were independent risk factors for the development of HT in PBC patients. Old age (t=9.147, P < 0.05), no response to UDCA treatment (t=-2.727, P < 0.05), increases in AST, ALP, total bilirubin, IgA, and IL-6 (t=2.121, 2.446, 10.114, 4.162, and 2.033, P < 0.05), reductions in total protein, high-density lipoprotein, C3, and C4 (t=-3.384, -3.887, -2.440, and -2.422, P < 0.05), comorbidities hepatic encephalopathy and ascites (t=3.685 and 6.744, P < 0.05), and positive gp210 antibodies (t=3.125, P < 0.05) were independent risk factors for the increase in Mayo risk score, which suggested a poor prognosis. PBC with HT (t=-0.077, P > 0.05) was not an independent risk factor for the increase in Mayo risk score and did not affect the prognosis of patients. Conclusion Patients with PBC often have extrahepatic autoimmune diseases, among which thyroid diseases are the most common disease, especially autoimmune thyroiditis, and the patients with PBC and HT have more complications and clinical symptoms. Progression of liver disease and increases in the thyroid-associated antibodies TgAb and TPOAb are independent risk factors for the development of HT, but comorbidity of HT does not affect the prognosis of patients with PBC. -
Key words:
- Primary Biliary Cholangitis /
- Thyroiditis, Autoimmune /
- Risk Factors /
- Prognosis
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表 1 PBC患者中非HT组与HT组一般临床资料比较
Table 1. Comparison of general clinical data between PBC without HT group and PBC with HT group
项目 非HT组(n=88) HT组(n=83) 统计值 P值 年龄(岁) 53.66±11.57 55.28±10.86 t=-0.979 0.329 性别[例(%)] χ2=9.547 0.002 男 20(22.7) 5(6.0) 女 68(77.3) 78(94.0) 吸烟[例(%)] χ2=2.112 0.146 是 11(12.5) 5(6.0) 否 77(87.5) 78(94.0) 饮酒[例(%)] χ2=1.778 0.182 是 9(10.2) 4(4.8) 否 79(89.8) 79(95.2) 高血压[例(%)] χ2=0.192 0.661 是 16(18.2) 13(15.7) 否 72(81.8) 70(84.3) 糖尿病[例(%)] χ2=0.019 0.889 是 10(11.4) 10(12.0) 否 78(88.6) 73(88.0) 合并其他自身免疫性疾病[例(%)] χ2=0.335 0.563 是 14(15.9) 16(19.3) 否 74(84.1) 67(80.7) PBC病程(年) 1.00(0.25~4.00) 2.00(0.25~6.00) Z=-1.653 0.098 UDCA应答情况[例(%)] χ2=1.971 0.160 应答 58(65.9) 46(55.4) 不应答 30(34.1) 37(44.6) 使用激素[例(%)] χ2=0.010 0.919 是 25(28.4) 23(27.7) 否 63(71.5) 60(72.3) 肝硬化[例(%)] χ2=8.807 0.003 是 32(36.4) 49(59.0) 否 56(63.6) 34(41.0) Child-Pugh评分 5(5~7) 6(5~9) Z=-3.100 0.002 BMI(kg/m2) 22.25(19.51~24.16) 21.14(19.12~24.23) Z=-1.213 0.225 
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表 2 PBC患者中非HT与HT组实验室指标比较
Table 2. Comparison of laboratory indexes between PBC without HT group and PBC with HT group
项目 非HT组(n=88) HT组(n=83) 统计值 P值 ALT(U/L) 51.50(22.25~104.00) 53.00(26.00~113.00) Z=-0.464 0.643 AST(U/L) 62.50(33.00~97.50) 68.00(36.00~115.00) Z=-0.941 0.347 ALP(U/L) 186.50(125.50~341.75) 208.00(127.00~293.00) Z=-0.346 0.729 GGT(U/L) 154.00(42.35~466.25) 134.00(55.00~329.00) Z=-0.402 0.688 TP(g/L) 75.75(67.13~82.05) 72.10(66.70~77.40) Z=-1.773 0.076 TB(μmol/L) 20.85(12.58~35.40) 22.50(15.20~60.80) Z=-1.297 0.195 TC(mmol/L) 5.09(4.01~6.65) 4.35(3.78~5.13) Z=-2.743 0.006 TG(mmol/L) 1.51(1.15~2.14) 1.23(1.03~1.70) Z=-2.332 0.020 HDL(mmol/L) 1.34(1.09~1.81) 1.24(0.78~1.70) Z=-1.919 0.055 LDL(mmol/L) 2.97(2.24~4.19) 2.58(2.01~3.26) Z=-2.604 0.009 IgA(g/L) 2.47(1.68~3.36) 2.92(1.95~4.68) Z=-1.992 0.046 IgG(g/L) 15.60(12.40~19.84) 16.80(13.50~22.30) Z=-1.402 0.161 IgM(g/L) 2.57(1.35~3.93) 2.51(1.65~3.79) Z=-0.471 0.637 C3(g/L) 0.97±0.30 0.87±0.26 t=5.063 0.026 C4(g/L) 0.17(0.14~0.23) 0.17(0.12~0.22) Z=-1.599 0.110 IL-6(pg/mL) 4.94(2.20~9.29) 7.75(2.95~14.95) Z=-1.969 0.049 AMA-M2[例(%)] χ2=1.801 0.180 阴性 34(38.6) 24(28.9) 阳性 54(61.4) 59(71.1) SSA[例(%)] χ2=0.582 0.446 阴性 72(81.8) 64(77.1) 阳性 16(18.2) 19(22.9) SSB[例(%)] χ2=2.128 0.145 阴性 80(90.9) 80(96.4) 阳性 8(9.1) 3(3.6) ANA[例(%)] χ2=0.012 0.914 阴性 29(33.0) 28(33.7) 阳性 59(67.0) 55(66.3) gp210[例(%)] χ2=0.192 0.661 阴性 59(67.0) 53(63.9) 阳性 29(33.0) 30(36.1) sp100[例(%)] χ2=0.017 0.898 阴性 79(89.8) 75(90.4) 阳性 9(10.2) 8(9.6) TgAb(IU/mL) 10.21(3.34~16.08) 217.42(53.88~569.19) Z=-9.612 ＜0.001 TPOAb(IU/mL) 11.39(2.15~18.37) 191.8(57.43~504.30) Z=-9.739 ＜0.001
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表 3 PBC肝硬化患者中非HT组与HT组失代偿症状比较
Table 3. Comparison of decompensation symptoms between non-HT group and HT group in patients with PBC cirrhosis
项目 非HT组(n=32) HT组(n=49) χ2值 P值 脾肿大[例(%)] 0.080 0.778 是 26(81.2) 41(83.7) 否 6(18.8) 8(16.3) 食管胃底静脉曲张[例(%)] 0.642 0.423 是 23(71.9) 39(79.6) 否 9(28.1) 10(20.4) 腹水[例(%)] 2.671 0.102 是 13(40.6) 29(59.2) 否 19(59.4) 20(40.8) 消化道出血[例(%)] 0.007 0.933 是 5(15.6) 8(16.3) 否 27(84.4) 41(83.7) 肝性脑病[例(%)] 2.867 0.090 是 1(3.1) 9(18.4) 否 31(96.9) 40(81.6)
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表 4 PBC患者中非HT与HT组临床症状比较
Table 4. Comparison of clinical symptoms between PBC cirrhosis without HT group and PBC cirrhosis with HT group
项目 非HT组(n=88) HT组(n=83) χ2值 P值 乏力[例(%)] 4.951 0.026 是 54(61.4) 64(77.1) 否 34(38.6) 19(22.9) 纳差[例(%)] 6.636 0.010 是 48(54.5) 61(73.5) 否 40(45.5) 22(26.5) 腹胀[例(%)] 7.977 0.005 是 34(38.6) 50(60.2) 否 54(61.4) 33(39.8) 黄疸[例(%)] 1.575 0.209 是 22(25) 28(33.7) 否 66(75) 55(66.3) 瘙痒[例(%)] 1.475 0.224 是 11(12.5) 16(19.3) 否 77(87.5) 67(80.7) 水肿[例(%)] 6.118 0.013 是 8(9.1) 19(22.9) 否 80(90.9) 64(77.1)
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表 5 PBC患者发生HT的多因素分析
Table 5. Binary logistic regression of risk factors for concurrent HT in patients with PBC
因素 B值 SE Wald P值 OR 95%CI 性别 -1.026 1.075 0.910 0.340 0.359 0.044~2.949 TC 0.331 0.461 0.517 0.472 1.393 0.564~3.438 TG -0.157 0.453 0.121 0.728 0.854 0.351~2.077 LDL -0.601 0.672 0.800 0.371 0.548 0.147~2.046 IgA 0.025 0.167 0.023 0.880 1.026 0.740~1.421 C3 -0.083 1.281 0.004 0.948 0.920 0.075~11.322 IL-6 0.020 0.017 1.311 0.252 1.020 0.986~1.056 肝硬化 -0.233 0.744 0.098 0.754 0.792 0.184~3.403 Child-Pugh评分 0.396 0.172 5.287 0.021 1.486 1.060~2.083 TPOAb 0.007 0.002 8.317 0.004 1.007 1.002~1.012 TgAb 0.031 0.010 9.991 0.002 1.032 1.012~1.052
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表 6 各影响因素与Mayo风险评分的相关性分析
Table 6. Correlation analysis of THE influencing factors with Mayo risk score
影响因素 r值 P值 影响因素 r值 P值 年龄 0.412 ＜0.001 IgA 0.349 ＜0.001 性别 -0.018 0.818 C3 -0.274 ＜0.001 PBC病程 0.046 0.547 C4 -0.214 0.005 高血压 0.031 0.688 IL-6 0.483 ＜0.001 糖尿病 0.119 0.122 脾肿大 0.555 ＜0.001 其他自身免疫性疾病 -0.033 0.666 食管胃底静脉曲张 0.569 ＜0.001 激素使用史 -0.035 0.654 腹水 0.639 ＜0.001 吸烟 0.052 0.502 消化道出血 0.285 ＜0.001 饮酒 0.081 0.293 肝性脑病 0.354 ＜0.001 UDCA应答情况 -0.440 ＜0.001 肝硬化 0.530 ＜0.001 ALT -0.025 0.750 TIPS治疗 0.224 0.003 AST 0.176 0.021 合并HT 0.243 0.001 ALP 0.156 0.042 BMI -0.167 0.029 GGT -0.041 0.592 AMA-M2 0.088 0.252 TP -0.377 ＜0.001 SSA -0.042 0.583 TBil 0.639 ＜0.001 SSB -0.053 0.490 TC -0.266 ＜0.001 ANA -0.063 0.414 TG -0.085 0.272 gp210 0.346 ＜0.001 HDL -0.460 ＜0.001 sp100 0.062 0.424 LDL -0.217 0.004 TgAb 0.040 0.604 IgG 0.147 0.056 TPOAb 0.098 0.200 IgM 0.043 0.574
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表 7 PBC患者Mayo风险评分相关危险因素的多元线性回归分析
Table 7. Multiple linear regression analysis of risk factors associated with Mayo risk score in patients with PBC
影响因素 B值 SE t值 P值 VIF 年龄 0.041 0.004 9.147 ＜0.001 1.346 UDCA应答情况 -0.291 0.107 -2.727 ＜0.001 1.517 AST 0.001 ＜0.001 2.121 0.036 1.403 ALP 0.001 ＜0.001 2.466 0.015 1.894 TP -0.015 0.005 -3.384 0.001 1.404 TBil 0.009 0.001 10.114 ＜0.001 1.691 TC -0.016 0.039 -0.403 0.688 6.630 HDL -0.333 0.086 -3.887 ＜0.001 1.689 LDL 0.005 0.055 0.098 0.922 5.625 IgA 0.105 0.025 4.162 ＜0.001 1.437 C3 -0.466 0.191 -2.440 0.016 1.629 C4 -1.090 0.450 -2.422 0.017 1.365 IL-6 0.005 0.003 2.033 0.044 1.289 脾肿大 0.086 0.148 0.584 0.560 3.018 食管胃底静脉曲张 0.107 0.186 0.571 0.569 4.491 腹水 0.936 0.139 6.744 ＜0.001 2.065 消化道出血 0.014 0.214 0.065 0.948 1.815 肝性脑病 0.909 0.247 3.685 ＜0.001 1.883 肝硬化 0.070 0.153 0.456 0.649 3.241 TIPS治疗 -0.334 0.313 -1.065 0.289 2.170 合并HT -0.007 0.093 -0.077 0.939 1.213 BMI ＜0.001 0.004 -0.034 0.973 1.124 gp210 0.319 0.102 3.125 0.002 1.317 注：VIF，方差膨胀因子。
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