性别差异对自身免疫性肝炎患者临床特征及预后的影响

伍慧丽; 时红波; 刘燕敏; 丁美; 马正来; 刘霜; 陈煜; 段钟平

doi:10.3969/j.issn.1001-5256.2021.07.031

性别差异对自身免疫性肝炎患者临床特征及预后的影响

DOI: 10.3969/j.issn.1001-5256.2021.07.031

伍慧丽^a,
时红波^b,
刘燕敏^c,
丁美^d,
马正来^d,
刘霜^d,
陈煜^a,
段钟平^{a, d, ,}

a.
首都医科大学附属北京佑安医院疑难肝病及人工肝中心，北京 100069
b.
首都医科大学附属北京佑安医院肝病研究所，北京 100069
c.
首都医科大学附属北京佑安医院肝病免疫科，北京 100069
d.
首都医科大学附属北京佑安医院肝衰竭与人工肝治疗研究北京市重点实验室，北京 100069

基金项目:

国家重点研发计划资助 (2017YFA0103000);

国家科技重大专项“艾滋病和病毒性肝炎等重大传染病防治” (2012ZX10002004-006);

国家科技重大专项“艾滋病和病毒性肝炎等重大传染病防治” (2017ZX10203201-005);

国家科技重大专项“艾滋病和病毒性肝炎等重大传染病防治” (2017ZX10201201-001-001);

国家科技重大专项“艾滋病和病毒性肝炎等重大传染病防治” (2017ZX10201201-002-002);

国家科技重大专项“艾滋病和病毒性肝炎等重大传染病防治” (2017ZX10201201-004-002);

国家科技重大专项“艾滋病和病毒性肝炎等重大传染病防治” (2017ZX10202203-006-001);

国家科技重大专项“艾滋病和病毒性肝炎等重大传染病防治” (2017ZX10302201-004-002);

北京市医院管理局“登峰”人才培养计划基金资助项目 (DFL20151601);

北京市医院管理局临床医学发展专项经费资助 (ZYLX201806);

科技创新服务能力建设-高精尖学科建设项目(市级) (11920703);

首都医科大学重点实验室开放研究课题 (BJYAHKF2017008)

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：伍慧丽负责课题设计，资料分析，撰写论文；丁美、马正来、刘霜参与收集数据；时红波、刘燕敏参与修改论文；段钟平、陈煜负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
段钟平，duan@ccmu.edu.cn

中图分类号: R575
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出版历程
- 收稿日期: 2020-12-27
- 录用日期: 2021-01-20
- 出版日期: 2021-07-20

Clinical features and prognosis of autoimmune hepatitis patients with different sexes

a.
Intractable Hepatic Diseases and Artificial Liver Treatment & Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
b.
Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
c.
Department of Immunopathy and Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
d.
Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China

Research funding:

National Key R & D Program of China (2017YFA0103000);

National Science and Technology Key Project on "Major Infectious Diseases such as HIV/AIDS, Viral Hepatitis Preventon and Treatment" (2012ZX10002004-006);

National Science and Technology Key Project on "Major Infectious Diseases such as HIV/AIDS, Viral Hepatitis Preventon and Treatment" (2017ZX10203201-005);

National Science and Technology Key Project on "Major Infectious Diseases such as HIV/AIDS, Viral Hepatitis Preventon and Treatment" (2017ZX10201201-001-001);

National Science and Technology Key Project on "Major Infectious Diseases such as HIV/AIDS, Viral Hepatitis Preventon and Treatment" (2017ZX10201201-002-002);

National Science and Technology Key Project on "Major Infectious Diseases such as HIV/AIDS, Viral Hepatitis Preventon and Treatment" (2017ZX10201201-004-002);

National Science and Technology Key Project on "Major Infectious Diseases such as HIV/AIDS, Viral Hepatitis Preventon and Treatment" (2017ZX10202203-006-001);

National Science and Technology Key Project on "Major Infectious Diseases such as HIV/AIDS, Viral Hepatitis Preventon and Treatment" (2017ZX10302201-004-002);

"Beijing Muncipal Administration of Hospitals" Ascent Plan (DFL20151601);

Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX201806);

Science and Technology Innovation Service Capacity Building-high-precision Discipline Construction Project (11920703);

Open Research Project of Key Laboratory of Capital Medical University (BJYAHKF2017008)

摘要

摘要: 目的自身免疫性肝炎(AIH)主要发生在女性，目前对男性AIH患者的研究甚少，本研究比较不同性别AIH之间的临床差异。方法收集2009年10月—2019年10月在北京佑安医院住院并确诊为AIH的患者398例进行回顾性研究，分为男(n=48)、女(n=350)两组，对一般情况、临床特点及预后等影响因素进行分析。主要研究终点为死亡或肝移植治疗。正态分布的计量资料2组间比较采用t检验，非正态分布计量资料2组间比较采用Mann-Whitney U检验。计数资料2组间比较采用χ²检验或Fisher精确概率法。采用Cox比例风险模型进行单变量和多变量分析。结果年龄方面，51~60岁是两组的发病高峰，但是男性在21~30岁时段确诊率明显高于女性(8/48 vs 24/334，χ²=4.915，P=0.027)，而在41~50岁时段则低于女性(7/48 vs 97/334，χ²=4.428，P=0.035)。AIH分类方面，男性特发性AIH占比更高(31/48 vs 170/350，χ²=4.329，P=0.037)，但男性合并其他自身免疫性疾病尤其是甲状腺功能亢进比例低于女性(0/48 vs 39/348，P=0.008)。实验室检查方面，男性ANA≥1∶ 100(42/48 vs 325/340，χ²=5.375，P=0.020) 和SSA/SSB(2/48 vs 76/340，χ²=7.566，P=0.006)阳性率显著低于女性患者；男性ANA ≥1∶ 1000的比率显著低于女性(P＜0.000 1)。预后方面，男性出现死亡或接受肝移植的年龄要远小于女性[(31.5±15.9)岁vs (53.9±12.6)岁，t=3.798，P=0.001]，男性失代偿期肝硬化及肝细胞癌发生更多见(P值均＜0.05)。与生存期下降有关的高危因素，男性: 糖尿病、肝硬化以及血Alb＜31.4 g/L，女性: 肝衰竭、肝硬化、ANA≥1∶ 1000、DBil＞42 μmol/L、淋巴细胞计数＜1.2×10⁹/L以及补体C3＜0.588 g/L(P值均＜0.05)。结论性别差异对AIH患者临床表现和预后有一定影响，主要表现在男性患者更年轻、预后更差。
- 肝炎，自身免疫性 /
- 性别 /
- 体征和症状 /
- 预后
Abstract: Objective To investigate the differences between autoimmune hepatitis (AIH) patients with different sexes, since AIH is more common in female individuals and there are few studies on male AIH patients. Methods A retrospective analysis was performed for 398 patients who were hospitalized in Beijing YouAn Hospital from October 2009 to October 2019 and were diagnosed with AIH, and the patients were divided into female group and male group according to sex. General status, clinical features, and prognosis were analyzed. The primary outcome measure was death or liver transplantation. The t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test or the Fisher's exact test was used for comparison of categorical data between two groups. The Cox proportional hazards model was used to perform univariate and multivariate analyses. Results As for age, the peak of disease onset was observed in patients aged 51-60 years in both male and female groups, and compared with the female group, the male group had a significantly higher rate of confirmed diagnosis at the age of 21-30 years (8/48 vs 24/334, χ²=4.915, P=0.027) and a significantly lower rate of confirmed diagnosis at the age of 41-50 years (7/48 vs 97/334, χ²=4.428, P=0.035). As for AIH, compared with the female group, the male group had a significantly higher proportion of patients with idiopathic AIH (31/48 vs 170/350, χ²=4.329, P=0.037) and a significantly lower proportion of patients with other autoimmune diseases, especially hyperthyroidism (0/48 vs 39/348, P=0.008). As for laboratory examination, compared with the female group, the male group had significantly lower positive rates of anti-nuclear antibody (ANA)≥1∶ 100(42/48 vs 325/340, χ²=5.375, P=0.020) and SSA/SSB (2/48 vs 76/340, χ²=7.566, P=0.006), as well as a significantly lower proportion of patients with ANA ≥1∶ 1000 (P < 0.000 1). As for prognosis, compared with the female group, the male group had a significantly younger age at the time of death or liver transplantation (31.5±15.9 years vs 53.9±12.6 years, t=3.798, P=0.001) and a significantly higher proportion of patients with decompensated liver cirrhosis or hepatocellular carcinoma (both P < 0.05). Diabetes, liver cirrhosis, and blood albumin < 31.4 g/L were high-risk factors for reduced survival time in male patients, and liver failure, liver cirrhosis, ANA ≥1∶ 1000, direct bilirubin > 42 μmol/L, lymphocyte count < 1.2×10⁹/L, and C3 < 0.588 g/L were high-risk factors for reduced survival time in female patients. Conclusion Sex difference has certain influence on the clinical manifestations and prognosis of AIH patients, and male patients tend to have a younger age and a poorer prognosis.
- Hepatitis, Autoimmune /
- Gender /
- Signs and Symptoms /
- Prognosis

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图 1 不同性别的AIH患者按发病年龄段进行分组比较结果

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表 1 不同性别患者一般资料比较

指标	例数	男性	女性	统计值	P值
随访时间(月)	367	60.3±46.4	74.2±54.0	t=1.658	0.098
发病年龄(岁)	392	46.8(6.0~79.0)	50.1(3.0~85.0)	Z=1.195	0.115
发病年龄段[例(%)]
0~10岁	4	1/48(2.1)	3/334(0.9)	χ²=0.000	1.000
11~20岁	8	2/48(4.2)	6/334(1.8)	χ²=0.284	0.594
21~30岁	32	8/48(16.7)	24/334(7.2)	χ²=4.915	0.027
31~40岁	40	6/48(12.5)	34/334(10.2)	χ²=0.241	0.623
41~50岁	104	7/48(14.6)	97/334(29.0)	χ²=4.428	0.035
51~60岁	105	14/48(29.2)	91/334(27.2)	χ²=0.078	0.780
61~70岁	71	9/48(18.8)	62/334(18.6)	χ²=0.001	0.975
＞70岁	18	1/48(2.1)	17/334(5.1)	χ²=0.308	0.579
诊断年龄(岁)	392	48.0(6.0~79.0)	51.0(3.0~85.0)	Z=-0.491	0.623
诊断用时(月)	374	9.0(0~126.0)	13.9(0~241.0)	Z=-1.940	0.052
无症状体检发现[例(%)]	83	4/45(8.9)	79/334(30.0)	χ²=3.897	0.048
AIH分类[例(%)]
I-AIH	201	31/48(64.6)	170/350(48.6)	χ²=4.329	0.037
DI-AIH	115	9/48(18.8)	106/350(30.3)	χ²=2.734	0.098
OS	77	8/48(16.7)	69/350(27.6)	χ²=0.251	0.616
DI-AIH合并OS	5	0/48(0)	5/350(1.4)		1.000
肝硬化[例(%)]	168	20/47(42.6)	148/339(43.7)	χ²=0.020	0.886
失代偿	78	14/20(70.0)	64/148(43.2)	χ²=5.071	0.024
糖尿病[例(%)]	55	6/45(13.3)	49/316(15.5)	χ²=0.144	0.704
肝衰竭[例(%)]	57	6/48(12.5)	51/350(14.6)	χ²=0.148	0.701
合并其他免疫病[例(%)]	169	14/48(29.2)	155/348(44.5)	χ²=4.075	0.044
自身免疫性甲状腺疾病	45	1/48(2.2)	44/348(12.6)	χ²=3.681	0.055
甲状腺功能亢进	39	0/48(0)	39/348(11.2)		0.008
甲状腺功能减弱	6	1/48(2.1)	5/348(1.4)	χ²=0.000	1.000
PBC	70	6/48(13.3)	64/348(18.4)	χ²=1.006	0.316
PSC	3	1/48(2.2)	2/348(0.6)	χ²=0.059	0.809
SLE	10	1/48(2.2)	9/348(2.6)	χ²=0.000	1.000
干燥综合征	36	2/48(4.2)	34/348(9.8)	χ²=0.996	0.318

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表 2 男性和女性AIH患者实验室检查结果

指标	例数	男性	女性	统计值	P值
ALT(U/L)	390	514(12~2255)	372(4~2270)	Z=-1.058	0.290
AST(U/L)	389	342(21~1725)	380(16~2094)	Z=-0.568	0.570
TBil(μmol/L)	385	88.1(8.3~535.1)	100.2(5.8~765.7)	Z=-0.696	0.486
DBil(μmol/L)	378	61.8(1.9~383.0)	65.4(0.9~603.0)	Z=-0.191	0.849
GGT(U/L)	375	209(24~951)	174(11~1357)	Z=-1.034	0.306
ALP(U/L)	373	176(64~966)	182(27~1189)	Z=-0.555	0.579
TBA(μmol/L)	365	82.7(2.7~368.8)	80.0(1.3~319.0)	Z=-0.417	0.676
Alb(g/L)	379	35.30±8.31	35.10±6.28	t=-0.124	0.902
GLOB(g/L)	375	40.6±13.2	38.8±9.2	t=-0.838	0.407
ChE(U/L)	364	4642±2382	4785±2073	t=0.395	0.693
WBC(×10⁹)	374	5.7(2.2~12.5)	4.8(1.4~12.0)	Z=-2.476	0.013
NE(×10⁹)	363	2.70(2.07~3.85)	2.35(1.68±3.18)	Z=-2.500	0.012
LY(×10⁹)	360	1.80±0.77	1.60±0.66	t=-1.460	0.151
Hb(g/L)	371	131.0±24.6	118.0±17.0	t=-3.427	0.001
PLT(×10⁹)	370	163±75	161±77	t=-0.193	0.847
IgG(g/L)	377	25.6±11.5	24.6±8.9	t=-0.634	0.527
IgM(g/L)	371	1.39(0.89~2.53)	1.72(1.19~2.63)	Z=-1.609	0.108
C3(g/L)	365	0.96±0.34	0.94±0.38	t=-0.417	0.677
C4(g/L)	365	0.16(0.10~0.25)	0.15(0.10~0.21)	Z =-0.815	0.415
注：TBA，总胆汁酸；GLOB，球蛋白；ChE，胆碱酯酶；LY，淋巴细胞。

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表 3 男性和女性AIH患者血清自身抗体及核型

指标	例数	男性	女性	χ²值	P值
自身抗体阳性[例(%)]	388	48/48(100)	340/350(97.1)		0.617
ANA≥1∶100	367	42/48(87.5)	325/340(95.6)	5.375	0.020
ANA≥1∶1000	217	11/48(22.9)	206/340(60.6)	24.217	＜0.001
SMA≥1∶100	54	5/48(10.4)	49/340(14.4)	0.560	0.454
SMA≥1∶1000	8	1/48(2.1)	7/340(2.1)	0.000	1.000
AMA≥1∶320	84	7/48(14.6)	77/340(22.6)	1.612	0.204
LKM-1	12	3/48(6.3)	9/340(2.6)	0.818	0.366
SLA/LP	24	1/48(2.1)	23/340(6.8)	0.884	0.347
SSA/SSB	78	2/48(4.2)	76/340(22.4)	7.566	0.006
GP210	23	3/48(6.3)	20/340(5.9)	0.000	1.000
Sp100	15	1/48(2.1)	14/340(4.1)	0.081	0.776
ANA核型[例(%)]
核颗粒型	109	9/13(69.2)	100/154(64.9)	0.098	0.775
胞浆颗粒型	65	5/13(38.5)	60/154(39.0)	0.001	0.972
核均质型	59	4/13(30.8)	55/154(35.7)	0.003	0.955
核膜型	12	1/13(7.7)	11/154(7.1)	0.000	1.000
着丝点型	5	1/13(7.7)	4/154(2.6)	0.035	0.851
核仁型	9	0/13(0)	9/154(5.8)	0.000	1.000

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表 4 男性和女性AIH嗜肝病毒感染情况

指标	例数	男性	女性	χ²值	P值
HAV-IgG[例(%)]	333	35/35(100.0)	297/298(99.7)		1.000
抗-HBc阳性且HBsAg阴性[例(%)]	155	21/31(67.7)	134/291(46.0)	5.281	0.022
肝硬化	80	10/21(47.6)	70/134(52.2)	0.155	0.694
死亡或肝移植	18	4/21(19.0)	14/70(20.0)	0.000	1.000
HCV-IgG[例(%)]	6	0/35(0)	6/264(2.3)		1.000
HEV-IgG[例(%)]	55	3/16(18.8)	52/221(23.5)	0.017	0.896
EBV-IgG[例(%)]	30	0/17(0)	30/211(14.2)		0.138
CMV-IgG[例(%)]	115	13/19(68.4)	102/209(48.8)	2.681	0.102
PVB19-IgG[例(%)]	47	3/15(20.0)	44/126(34.9)	0.755	0.385

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表 5 男性和女性AIH治疗及预后情况

指标	例数	男性	女性	统计值	P值
治疗[例(%)]	224	28/48(56.3)	196/350(56.0)	χ²=0.093	0.974
单用皮质醇激素	156	15/28(55.6)	141/196(71.9)	χ²=3.910	0.048
单用硫唑嘌呤	5	1/28(3.7)	4/196(2.0)	χ²=0.000	1.000
皮质醇激素和硫唑嘌呤	62	11/28(40.7)	51/196(26.0)	χ²=2.154	0.142
二线药物	6	2/28(7.4)	4/196(2.0)	χ²=0.881	0.348
治疗有效[例(%)]	214	28/28(82.4)	186/196(92.1)		0.618
停药或减量后反弹	84	13/28(38.2)	71/196(36.2)	χ²=1.088	0.297
依从性好	214	27/28(92.9)	187/196(94.9)	χ²=0.000	1.000
药物不良反应[例(%)]	111	15/28(53.6)	96/196(49.0)	χ²=0.207	0.649
感染	68	10/28(35.7)	58/196(29.6)	χ²=0.434	0.510
骨质疏松	13	4/28(14.3)	9/196(4.6)	χ²=2.625	0.105
其他	35	6/28(21.4)	29/196(14.7)	χ²=0.818	0.366
结局[例(%)]
HCC	10	4/48(8.3)	6/350(1.7)	χ²=5.090	0.024
肝移植	17	2/48(4.2)	15/350(4.3)	χ²=0.052	0.820
肝病相关死亡	36	7/48(14.6)	29/350(8.3)	χ²=2.035	0.154
死亡或接受肝移植年龄(岁)	36	31.5±15.9	53.9±12.6	t=3.798	0.001
死亡或肝移植患者总生存期(月)	36	41.8±37.2	44.9±53.9	t=0.137	0.891

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表 6 影响AIH患者预后的高危因素

因素	HR	95%CI	P值
男性
肝硬化	3.250	1.356~7.793	0.008
糖尿病	17.532	1.638~18.611	0.018
Alb＜31.4 g/L	32.518	2.264~46.109	0.010
女性
肝硬化	2.923	1.251~6.828	0.013
肝衰竭	3.355	1.340~8.397	0.010
ANA≥1∶1000	0.045	0.003~0.625	0.021
DBil＞42 μmol/L	0.344	0.128~0.926	0.035
LY＜1.2×10⁹/L	5.408	1.776~16.464	0.003
C3＜0.588 g/L	4.043	1.559~10.480	0.004

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