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不同抗体状态的自身免疫性肝炎肝脏组织病理学与临床特征的比较
DOI: 10.3969/j.issn.1001-5256.2022.12.012
伦理学声明：本研究方案于2018年3月22日经由首都医科大学北京地坛医院伦理委员会审批，批号：201801302。所有患者均签署知情同意书。
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：谢尧、李明慧对研究思路和研究设计有关键贡献；毕潇月、邓雯、蒋婷婷、孙芳芳、路遥、张璐收集和分析数据；林妍洁、杨柳参与统计学方法的选择和文章的修改；高媛娇负责撰写成文。
Liver histopathology and clinical features of autoimmune hepatitis with different antibody statuses
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摘要:
目的 比较自身抗体阳性和阴性的自身免疫性肝炎(AIH)患者的临床与病理特征，总结诊断经验。 方法 回顾性入组2010年1月—2021年8月就诊于北京地坛医院经肝脏组织病理学诊断为AIH的患者为研究对象，根据有无自身抗体分为自身抗体阳性组和自身抗体阴性组，对比两组患者的生化、免疫、组织病理、疾病分期及临床症状体征等特征。计量资料组间比较采用t检验或Mann－Whitney U检验；计数资料组间比较采用χ2检验或Fisher确切概率法。 结果 共入组110例患者，自身抗体阳性患者78例(71%)，自身抗体阴性患者32例(29%)，检测的主要抗体为抗核抗体(ANA)、抗线粒体抗体(AMA)、抗平滑肌抗体(ASMA)，其中ANA阳性74例(67.27%)，AMA阳性1例(0.91%)，ASMA阳性5例(4.55%)，抗Ro-52抗体阳性14例(12.73%)。临床、免疫方面，自身抗体阴性组皮肤巩膜黄染(21.90% vs 50.00%，χ2=7.377, P=0.007)、纳差(18.80% vs 41.00 %，χ2=4.979，P=0.026)发生率、DBil[7.30(4.05~12.10)μmol/L vs 16.80(6.48~69.75)μmol/L，Z=-2.304，P=0.021]、IgG[16.40(13.15~18.05)g/L vs 20.30 (16.00~27.15)g/L, Z=-2.715，P=0.007]、Glo[30.60(26.00~34.90)g/L vs 37.30(30.50~42.50)g/L，Z=-3.356，P=0.001]中位数水平均低于自身抗体阳性组。肝组织病理方面，自身抗体阳性患者淋巴细胞浸润(91.03% vs 68.75%，χ2=6.997，P=0.008)及浆细胞浸润(82.05% vs 50.00 %，χ2=11.572，P=0.001)的比例显著高于自身抗体阴性患者；ANA阳性患者平均炎症水平(G1~G4)及纤维化水平(S1~S4)均显著高于ANA阴性患者(9.46% vs 5.56%，16.22% vs 27.78%，44.59% vs 63.89%，29.73% vs 2.78%；Z=-2.179, P=0.029)；(37.84% vs 13.89%，25.68% vs 41.67%，32.43% vs 30.56%，4.05% vs 13.89%；Z=-0.082, P=0.037)。 结论 与自身抗体阳性AIH患者相比，自身抗体阴性的AIH患者病情多处于疾病初期，IgG不高，临床易漏诊，早期的、积极的肝穿刺病理活检尤为重要。 Abstract:Objective To compare clinical and pathological features between autoimmune hepatitis (AIH) patients with positive and negative autoantibodies, and to summarize the experience in diagnosis. Methods A retrospective analysis was performed for the patients who attended Beijing Ditan Hospital from January 2010 to August 2021 and were diagnosed with AIH by liver histopathology, and according to the presence or absence of autoantibodies, they were divided into positive autoantibody group and negative autoantibody group. The two groups were compared in terms of biochemical parameters, immunological features, histopathological features, disease stage, and clinical symptoms and signs. The t-test or the Mann-Whitney U test was used for comparison of continuous data between groups, and the chi-square test or the Fisher's exact test was used for comparison of categorical data. Results A total of 110 patients were enrolled, among whom 78 (71%) had positive autoantibodies and 32 (29%) had negative autoantibodies. Anti-nuclear antibody (ANA), anti-mitochondrial antibody (AMA), and anti-smooth muscle antibody (ASMA) were the main autoantibodies detected, and of all 110 patients, 74 (67.27%) had positive ANA, 1 (0.91%) had positive AMA, 5 (4.55%) had positive ASMA, and 14 (12.73%) had positive anti-Ro-52 antibody. As for clinical and immunological features, compared with the positive autoantibody group, the negative autoantibody group had significantly lower incidence rates of jaundice of the skin and sclera (21.90% vs 50.00%, χ2=7.377, P=0.007) and poor appetite (18.80% vs 41.00%, χ2=4.979, P=0.026) and significantly lower median levels of direct bilirubin [7.30(4.05~12.10) μmol/L vs 16.80(6.48~69.75) μmol/L, Z=-2.304, P=0.021], IgG [16.40(13.15~18.05) g/L vs 20.30(16.00~27.15) g/L, Z=-2.715, P=0.007], and GLo [30.60(26.00~34.90) g/L vs 37.30(30.50~42.50) g/L, Z=-3.356, P=0.001]. In terms of liver histopathology, compared with the negative autoantibody group, the positive autoantibody group had a significantly higher proportion of patients with lymphocyte infiltration (91.03% vs 68.75%, χ2=6.997, P=0.008) and plasma cell infiltration (82.05% vs 50.00%, χ2=11.572, P=0.001); compared with the ANA-negative patients, the ANA-positive patients had significantly higher inflammation grade (G1-G4) (9.46%/16.22%/44.59%/29.73% vs 5.56%/27.78%/63.89%/2.78%, Z=-2.179, P=0.029) and fibrosis degree (S1-S4) (37.84%/25.68%/32.43%/4.05% vs 13.89%/41.67%/30.56%/13.89%, Z=-0.082, P=0.037). Conclusion Compared with AIH patients with positive autoantibodies, AIH patients with negative autoantibodies are mostly in the early stage of the disease and tend to have a low level of IgG, with a relatively high rate of missed diagnosis in clinical practice. Early and active liver biopsy is of particular importance. -
Key words:
- Hepatitis, Autoimmune /
- Pathology, Clinical /
- Autoantibodies
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表 1 AIH患者生化及免疫特征
Table 1. Biochemical and immune characteristics of AIH patients
指标 数值 ALT(U/L) 74.15(31.53~232.85) AST(U/L) 76.20(37.40~208.43) TBil(μmol/L) 22.45(13.90~47.90) DBil(μmol/L) 11.85(4.80~34.05) ALP(U/L) 108.60(81.50~146.70) GGT(U/L) 101.90(47.70~216.80) TBA(μmol/L) 34.70(11.60~77.10) Alb(g/L) 37.19±6.07 Glo(g/L) 35.30(29.60~40.80) IgG(g/L) 18.65(15.20~24.93) IgM(g/L) 1.48(0.97~2.13) IgA(g/L) 2.94(1.94~4.18) 
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表 2 自身抗体阳性与阴性患者生化特征比较
Table 2. Comparison of biochemical characteristics between patients with positive and negative autoantibodies
指标 自身抗体阴性(n=32) 自身抗体阳性(n=78) 统计值 P值 发病年龄(岁) 51.00(36.50~59.00) 49.50(40.75~57.00) Z=-0.843 0.399 生化指标 ALT(U/L) 57.50(33.45~107.15) 79.05(28.73~244.40) Z=-0.529 0.597 AST(U/L) 44.80(33.10~177.90) 89.15(39.05~282.43) Z=-1.361 0.174 TBil(μmol/L) 19.20(11.40~24.25) 25.70(14.98~83.95) Z=-1.937 0.053 DBil(μmol/L) 7.30(4.05~12.10) 16.80(6.48~69.75) Z=-2.304 0.021 ALP(U/L) 95.90(81.50~122.30) 111.25(79.85~173.03) Z=-1.139 0.255 GGT(U/L) 56.60(39.55~174.00) 112.20(56.20~272.38) Z=-1.367 0.172 TBA(μmol/L) 36.20(10.45~62.55) 36.75(14.15~92.83) Z=-1.01 0.312 Alb(g/L) 38.77±4.49 36.72±6.42 t=1.723 0.091 Glo(g/L) 30.60(26.00~34.90) 37.30(30.50~42.50) Z=-3.356 0.001 特种蛋白 IgG(g/L) 16.40(13.15~18.05) 20.30(16.00~27.15) Z=-2.715 0.007 IgM(g/L) 1.11(0.88~2.40) 1.48(1.05~2.09) Z=-0.527 0.598 IgA(g/L) 2.75±1.35 3.33±1.73 t=-1.327 0.188
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表 3 自身抗体阳性与阴性患者组织病理、临床症状及体征比较
Table 3. Comparison of histopathology, clinical symptoms and signs between patients with positive and negative autoantibodies
指标 自身抗体阴性(n=32) 自身抗体阳性(n=78) χ2值 P值 组织病理[例(%)] 界面性肝炎 24(75.00) 61(78.20) 0.133 0.716 肉芽肿形成 2(6.25) 2(2.56) 0.142 0.706 点灶状坏死 30(93.75) 66(84.62) 0.981 0.322 桥接坏死 12(37.50) 42(53.85) 2.426 0.119 玫瑰花环样表现 6(18.75) 11(14.10) 0.104 0.747 淋巴细胞浸润 22(68.75) 71(91.03) 6.997 0.008 浆细胞浸润 16(50.00) 64(82.05) 11.752 0.001 中性粒细胞浸润 3(9.38) 9(11.54) 0 ＞0.999 胆管损伤或消失 5(15.63) 16(20.51) 0.386 0.534 凋亡小体形成 11(34.38) 22(28.21) 0.411 0.521 假小叶形成 5(15.63) 7(8.97) 0.462 0.497 淋巴细胞穿入现象 2(6.25) 2(2.56) 0.142 0.706 临床症状及体征[例(%)] 女性 22(68.75) 66(84.62) 3.57 0.059 乏力 19(59.38) 38(48.72) 1.032 0.31 纳差 6(18.75) 32(41.03) 4.979 0.026 尿黄 4(12.50) 15(19.23) 0.719 0.396 皮肤巩膜黄染 7(21.88) 39(50.00) 7.377 0.007 腹胀肝区不适 2(6.25) 11(14.10) 0.695 0.405 皮肤瘙痒 1(3.13) 4(5.13) 0 ＞0.999 发热 0 3(3.85) 0.555 口干 0 1(1.28) ＞0.999 肝掌 5(15.63) 9(11.54) 0.072 0.788
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表 4 不同抗体状态的炎症分级和纤维化分级比较
Table 4. Comparison of inflammation grades in different antibody states
分级 例数 ANA阳性 AMA阳性 ASMA阳性 Ro52阳性 SSA/SSB阳性 炎症分级[例(%)] G1 9 7(77.80) 0 0 1(11.10) 0 G2 22 12(54.50) 1(4.50) 1(4.50) 1(4.50) 1(4.50) G3 56 33(58.90) 0 2(3.60) 8(14.30) 6(10.70) G4 23 22(95.70) 0 2(8.70) 4(17.40) 4(17.40) Z值 -2.179 -1.195 -0.934 -1.172 -1.761 P值 0.029 0.232 0.350 0.241 0.078 纤维化分级[例(%)] S1 33 28(84.80) 1(3.00) 1(3.00) 7(21.20) 5(15.20) S2 34 19(55.90) 0 2(5.90) 2(5.90) 3(8.80) S3 35 24(68.60) 0 2(5.70) 5(14.30) 3(8.60) S4 8 3(37.50) 0 0 0 0 Z值 -2.082 -1.270 -0.158 -1.240 1.242 P值 0.037 0.204 0.875 0.215 0.214
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表 5 ANA阳性和阴性患者在不同炎症及纤维化分级中占比
Table 5. Proportion of ANA-positive and ANA-negative patients in different grades of inflammation and fibrosis
分级 ANA阳性(n=74) ANA阴性(n=36) 炎症分级[例(%)] G1 7(9.46) 2(5.56) G2 12(16.22) 10(27.78) G3 33(44.59) 23(63.89) G4 22(29.73) 1(2.78) 纤维化分级[例(%)] S1 28(37.84) 5(13.89) S2 19(25.68) 15(41.67) S3 24(32.43) 11(30.56) S4 3(4.05) 5(13.89)
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[1] Chinese Society of Hepatology, Chinese Medical Association. Guidelines on the diagnosis and management of autoimmune hepatitis (2021)[J]. J Clin Hepatol, 2022, 38(1): 42-49. DOI: 10.3969/j.issn.1001-5256.2022.01.008.中华医学会肝病学分会. 自身免疫性肝炎诊断和治疗指南(2021)[J]. 临床肝胆病杂志, 2022, 38(1): 42-49. DOI: 10.3969/j.issn.1001-5256.2022.01.008. [2] CZAJA AJ. Diagnosis and management of autoimmune hepatitis: Current status and future directions[J]. Gut Liver, 2016, 10(2): 177-203. DOI: 10.5009/gnl15352. [3] CZAJA AJ. Global disparities and their implications in the occurrence and outcome of autoimmune hepatitis[J]. Dig Dis Sci, 2017, 62(9): 2277-2292. DOI: 10.1007/s10620-017-4675-y. [4] BISCHOFF S, YESMEMBETOV K, ANTONI C, et al. Autoimmune hepatitis: a review of established and evolving treatments[J]. J Gastrointestin Liver Dis, 2020, 29(3): 429-443. DOI: 10.15403/jgld-2667. [5] TAKAHASHI A, ARINAGA-HINO T, OHIRA H, et al. Autoimmune hepatitis in Japan: trends in a nationwide survey[J]. J Gastroenterol, 2017, 52(5): 631-640. DOI: 10.1007/s00535-016-1267-0. [6] KIM BH, CHOI HY, KI M, et al. Population-based prevalence, incidence, and disease burden of autoimmune hepatitis in South Korea[J]. PLoS One, 2017, 12(8): e0182391. DOI: 10.1371/journal.pone.0182391. [7] LV T, LI M, ZENG N, et al. Systematic review and meta-analysis on the incidence and prevalence of autoimmune hepatitis in Asian, European, and American population[J]. J Gastroenterol Hepatol, 2019, 34(10): 1676-1684. DOI: 10.1111/jgh.14746. [8] SCHEUER PJ. Classification of chronic viral hepatitis: a need for reassessment[J]. J Hepatol, 1991, 13(3): 372-374. DOI: 10.1016/0168-8278(91)90084-O. [9] OKA S, HIGUCHI T, FURUKAWA H, et al. Association of a single nucleotide polymorphism in TNIP1 with type-1 autoimmune hepatitis in the Japanese population[J]. J Hum Genet, 2018, 63(6): 739-744. DOI: 10.1038/s10038-018-0440-0. [10] SUCHER E, SUCHER R, GRADISTANAC T, et al. Autoimmune hepatitis-immunologically triggered liver pathogenesis-diagnostic and therapeutic strategies[J]. J Immunol Res, 2019, 2019: 9437043. DOI: 10.1155/2019/9437043. [11] PRASIDTHRATHSINT K, STAPLETON JT. Laboratory diagnosis and monitoring of viral hepatitis[J]. Gastroenterol Clin North Am, 2019, 48(2): 259-279. DOI: 10.1016/j.gtc.2019.02.007. [12] HAN LL, LU Y, ZHANG YL, et al. Significance of autoantibodies and biochemical indicators in diagnosis of autoimmune liver diseases[J/CD]. Chin J Clinicians(Electronic Edition), 2012, 6(20): 49-53. DOI: 10.3877/cma.j.issn.1674-0785.2012.20.020.韩丽利, 路遥, 张艳丽, 等. 自身抗体及生化学指标对自身免疫性肝病筛查及诊断的意义[J/CD]. 中华临床医师杂志(电子版), 2012, 6(20): 49-53. DOI: 10.3877/cma.j.issn.1674-0785.2012.20.020. [13] MIYAKE Y, IWASAKI Y, KOBASHI H, et al. Clinical features of antinuclear antibodies-negative type 1 autoimmune hepatitis[J]. Hepatol Res, 2009, 39(3): 241-246. DOI: 10.1111/j.1872-034X.2008.00454.x. [14] WANG QX, JIANG WJ, MIAO Q, et al. Clinical and histological features of autoantibody-negative autoimmune hepatitis in Chinese patients: A Single Center Experience[J]. Chin J Gastroenterol, 2014, 19(3): 129-133. DOI: 10.3969/j.issn.1008-7125.2014.03.001.王绮夏, 江伟骏, 苗琪, 等. 自身抗体阴性自身免疫性肝炎患者临床病理学特点[J]. 胃肠病学, 2014, 19(3): 129-133. DOI: 10.3969/j.issn.1008-7125.2014.03.001. [15] CZAJA AJ. Autoantibody-negative autoimmune hepatitis[J]. Dig Dis Sci, 2012, 57(3): 610-624. DOI: 10.1007/s10620-011-2017-z. [16] YASUI S, FUJIWARA K, YONEMITSU Y, et al. Clinicopathological features of severe and fulminant forms of autoimmune hepatitis[J]. J Gastroenterol, 2011, 46(3): 378-390. DOI: 10.1007/s00535-010-0316-3. [17] FUJIWARA K, NAKANO M, YASUI S, et al. Advanced histology and impaired liver regeneration are associated with disease severity in acute-onset autoimmune hepatitis[J]. Histopathology, 2011, 58(5): 693-704. DOI: 10.1111/j.1365-2559.2011.03790.x. [18] KRAWITT EL. Autoimmune hepatitis[J]. N Engl J Med, 2006, 354(1): 54-66. DOI: 10.1056/NEJMra050408. [19] MANNS MP, CZAJA AJ, GORHAM JD, et al. Diagnosis and management of autoimmune hepatitis[J]. Hepatology, 2010, 51(6): 2193-2213. DOI: 10.1002/hep.23584. -
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