慢性乙型肝炎合并代谢相关性脂肪性肝病的临床特征及预后影响因素分析

刘伟鸿; 刘晖; 丁惠国; 李磊

doi:10.3969/j.issn.1001-5256.2022.10.007

慢性乙型肝炎合并代谢相关性脂肪性肝病的临床特征及预后影响因素分析

DOI: 10.3969/j.issn.1001-5256.2022.10.007

首都医科大学附属北京佑安医院肝病消化中心，北京 100069

基金项目:

北京市医院管理局消化内科学科协同发展中心 (XXZ0303)

伦理学声明：本研究方案于2019年4月15日经由首都医科大学附属北京佑安医院伦理委员会审批，批号：京佑科伦字[2019]054号。

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：刘伟鸿负责收集数据，资料分析，撰写论文；刘晖负责病理评估，修改论文；李磊、丁惠国负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
李磊，m13699119545@163.com

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出版历程
- 收稿日期: 2022-03-17
- 录用日期: 2022-04-20
- 出版日期: 2022-10-20

Clinical characteristics and prognosis of patients with chronic hepatitis B combined with metabolic associated fatty liver disease

Center of Hepatic and Digestive Diseases, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China

Research funding:

Digestive Medical Coordinated Development Center of Beijing Municipal Administration of Hospitals (XXZ0303)

More Information

Corresponding author: LI Lei, m13699119545@163.com(ORCID: 0000-0002-0295-9480)

摘要

摘要: 目的分析慢性乙型肝炎(CHB)合并代谢相关性脂肪性肝病(MAFLD)患者的临床特征，并探讨影响此类患者预后的危险因素。方法选取2005年—2018年于首都医科大学附属北京佑安医院行经皮肝穿刺活检的CHB合并MAFLD患者101例，并以114例单纯CHB患者为对照组，以肝脏穿刺时间为基线，失代偿期肝硬化、肝癌、肝移植及肝脏疾病相关的死亡为临床终点事件，建立长期研究队列。对患者肝穿组织切片进行病毒性肝炎炎症活动度(G)及纤维化分期(S)计分，对合并MAFLD者进行NAS评分。根据纤维化分期分别将两组患者分为无显著纤维化组(S0~1)及显著纤维化组(S2~4)，比较纤维化同期两组患者的临床特征及预后；将CHB合并MAFLD组患者根据NAS评分分为NAS＜4分组及NAS≥4分组，分析NAS评分对合并患者临床及预后的影响。计量资料组间比较采用t检验/Wilcoxon秩和检验；计数资料采用χ²检验/Fisher检验。生存预后分析采用Log-rank检验、Kaplan-Meier生存分析及Cox多因素分析。结果各纤维化分期中CHB合并MAFLD组的BMI、血糖、TC均明显高于单纯CHB组(P值均＜0.05)；在无显著纤维化时，合并组的ALT(Z=-2.249，P=0.025)、AST(Z=-2.512，P=0.012)及GGT(Z=-5.261，P＜0.001)均高于单纯CHB组。整个队列中位随访时间为8.0年，Kaplan-Meier生存分析显示，合并MAFLD显著增加CHB患者肝脏相关不良结局风险(χ²=7.607，P=0.006)；Cox多因素分析发现，合并MAFLD[HR=5.76(95%CI：1.54~21.48)，P=0.009]是CHB患者发生肝相关结局的独立危险因素。在合并组中，NAS≥4分的患者ALT(Z=-3.139, P=0.002)、AST(Z=-2.898，P=0.004)、GGT(Z=-2.260，P=0.024)均高于NAS＜4分的患者；对其预后进行分析，发现显著纤维化[HR=4.83(95%CI：1.23~18.91)，P=0.024]与CHB合并MAFLD患者的不良预后独立相关。结论 CHB合并MAFLD患者在疾病早期时更易发生肝功能受损，加快疾病进展；合并MAFLD的CHB患者肝相关不良结局发生的风险增加，另外，显著纤维化是CHB合并MAFLD患者发生不良预后的独立危险因素。
- 乙型肝炎, 慢性 /
- 代谢相关性脂肪性肝病 /
- 预后
Abstract: Objective To analyze the clinical characteristics and prognostic factors of chronic hepatitis B (CHB) patients complicated with metabolic associated fatty liver disease (MAFLD). Methods A total of 114 CHB patients and 101 CHB patients complicated with MAFLD who underwent liver biopsy between 2005 and 2018 were included. A long-term cohort was established with the time of liver puncture as the baseline, and decompensated cirrhosis, liver cancer, liver transplantation and death related to liver disease as the clinical endpoints. The patient's NAS score, hepatitis inflammation activity (G) and fibrosis stage (S) were scored for the liver biopsy. According to fibrosis stage, patients were divided into no significant fibrosis (S0-1) and significant fibrosis (S2-4) groups. The clinical characteristics and prognosis of the CHB patients with or without MAFLD at the same fibrosis stage were compared. CHB patients with MAFLD were divided into NAS < 4 and NAS≥4 groups according to NAS score, and the influence of NAS score on clinical outcomes of patients was analyzed. The independent samples t-test / Wilcoxin test was performed for comparison of continuous data and the chi-square test was used for comparison of categorical data between groups. Survival analysis was performed using Kaplan-Meier survival cure and compared using log-rank test. Cox multivariate regression analysis was used to identify prognostic factors. Results The BMI, blood glucose and TC in CHB patients with MAFLD group were significantly higher than those in CHB alone in each fibrosis stage (P < 0.05). In patients without significant fibrosis, the levels of ALT (Z=-2.249, P=0.025), AST (Z=-2.512, P=0.012) and GGT (Z=-5.261, P < 0.001) in the complicated group were higher than those in the CHB group. With a median follow-up time of 8.0 years, the Kaplan-Meier survival analysis revealed that the complicated MAFLD significantly reduced the liver event-free survival rate of CHB patients (χ²=7.607, P=0.006). Cox multivariable analysis revealed MAFLD (HR=5.76, 95% CI: 1.54 - 21.48, P=0.009) was an independent risk factor for liver-related outcomes. In CHB patients with MAFLD, the ALT (Z=-3.139, P=0.002), AST (Z=-2.898, P=0.004), and GGT (Z=-2.260, P=0.024) of patients with NAS≥4 were higher than those of patients with NAS < 4. We found that significant fibrosis (HR=4.83, 95% CI: 1.23 - 18.91, P=0.024) was associated with the poor prognosis of CHB patients with MAFLD. Conclusions CHB patients with MAFLD are more likely to have impaired liver function in the early stage and the disease progresses more rapidly. Complicated MAFLD will increase the risk of liver-related events in patients with CHB, and significant fibrosis is an independent risk factor for adverse outcomes in CHB patients with MAFLD.
- Hepatitis B, Chronic /
- Metabolic Associated Fatty Liver Disease /
- Prognosis

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图 1 两组患者总体和分层生存分析

注：a. CHB合并MAFLD组与单纯CHB组生存分析；b. S0~1分层的CHB合并MAFLD组与单纯CHB组生存分析；c. S2~4分层的CHB合并MAFLD组与单纯CHB组生存分析。

Figure 1. Association of MAFLD for event-free survival in overall patients

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表 1 两组患者(S0~1)一般资料比较

Table 1. Comparison of baseline clinical characteristics between combined group and CHB group(S0~1)

指标	单纯CHB组(n=58)	CHB合并MAFLD组(n=61)	统计值	P值
年龄(岁)	31±8	36±10	t=-2.786	0.006
男[例(%)]	33(56.9)	50(82.0)	χ²=8.856	0.005
BMI(kg/m²)	22.2(19.5~24.1)	25.0(24.0~27.0)	Z=-5.882	＜0.001
2型糖尿病[例(%)]	0	8(13.1)	χ²=8.155	0.006
高血压[例(%)]	0	4(6.6)	χ²=3.936	0.119
高脂血症[例(%)]	12(20.7)	40(65.6)	χ²=24.345	＜0.001
HBeAg阳性[例(%)]	41(70.7)	36(59.0)	χ²=1.774	0.250
HBV DNA(log IU/mL)	6.86(3.96~7.65)	5.00(2.70~7.75)	Z=-1.540	0.124
ALT(U/L)	47.0(25.0~81.0)	62.5(42.1~105.0)	Z=-2.249	0.025
AST(U/L)	28.5(24.0~49.3)	41.0(29.0~54.0)	Z=-2.512	0.012
GGT(U/L)	20.6(12.0~35.9)	44.5(29.8~67.0)	Z=-5.261	＜0.001
血糖(mmol/L)	4.90(4.43~5.36)	5.17(4.62~5.88)	Z=-2.501	0.012
TC(mmol/L)	4.06±0.72	4.94±1.07	t=-5.194	＜0.001
PT(s)	11.5±1.0	11.3±0.8	t=1.505	0.135
PTA(%)	103.3±11.3	106.1±12.1	t=-1.284	0.202
炎症活动度≥G2[例(%)]	11(19.0)	16(26.2)	χ²=0.894	0.387

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表 2 两组患者(S2~4)一般资料比较

Table 2. Comparison of baseline clinical characteristics between combined group and CHB group(S2-4)

指标	单纯CHB组(n=56)	CHB合并MAFLD组(n=40)	统计值	P值
年龄(岁)	34(29~43)	38(30~44)	Z=-1.521	0.128
男[例(%)]	43(76.8)	29(72.5)	χ²=0.229	0.811
BMI(kg/m²)	22.7(21.3~24.3)	25.2(23.7~27.7)	Z=-5.315	＜0.001
2型糖尿病[例(%)]	6(10.7)	8(20.0)	χ²=1.615	0.247
高血压[例(%)]	3(5.4)	4(10.0)	χ²=0.744	0.446
高脂血症[例(%)]	13(23.2)	16(40.0)	χ²=3.118	0.114
HBeAg阳性[例(%)]	48(85.7)	27(67.5)	χ²=4.530	0.045
HBV DNA(log IU/mL)	6.76(5.36~7.65)	5.90(4.84~7.59)	Z=-1.071	0.284
ALT(U/L)	144.6(72.2~205.8)	109.6(66.5~229.1)	Z=-0.126	0.899
AST(U/L)	78.8(51.5~119.2)	68.7(45.9~124.0)	Z=-0.123	0.902
GGT(U/L)	69.8(34.5~113.9)	49.6(37.7~77.2)	Z=-1.185	0.236
血糖(mmol/L)	4.72(4.39~5.30)	5.32(4.95~6.06)	Z=-3.705	＜0.001
TC(mmol/L)	4.05±0.92	4.71±0.91	t=-3.450	0.001
PT(s)	11.5(10.8~12.8)	11.6(10.9~12.5)	Z=-0.439	0.661
PTA(%)	96.1(89.6~104.5)	100.0(94.5~110.6)	Z=-1.583	0.113
炎症活动度≥G2[例(%)]	52(92.9)	33(82.5)	χ²=1.552	0.213

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表 3 两组患者随访期间肝脏相关不良结局发生率比较

Table 3. Comparison of incidence of liver-related adverse outcomes between combined group and CHB group

变量	单纯CHB组(n=114)	CHB合并MAFLD组(n=101)
≥1种事件[例(%)]	3(2.6)	12(11.9)
失代偿期肝硬化[例(%)]	2(1.8)	11(10.9)
肝癌[例(%)]	2(1.8)	3(3.0)
肝移植[例(%)]	1(0.9)	0
肝脏相关的死亡[例(%)]	1(0.9)	0

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表 4 两组患者发生终点事件的单因素及多因素分析

Table 4. Unadjusted and Adjusted HRs for any Clinical Event

变量	单因素分析		多因素分析
变量	HR(95%CI)	P值	HR(95%CI)	P值
MAFLD	4.98(1.40~17.70)	0.013	5.76(1.54~21.48)	0.009
年龄	1.03(0.98~1.08)	0.281	1.03(0.97~1.10)	0.331
性别	0.17(0.02~1.29)	0.086	0.16(0.02~1.32)	0.088
乙型肝炎家族史	1.35(0.49~3.73)	0.563	1.61(0.56~4.68)	0.380
肝癌家族史	1.40(0.18~10.65)	0.745	1.23(0.14~10.83)	0.852
BMI	1.13(0.99~1.28)	0.064
2型糖尿病	3.52(1.12~11.07)	0.032
高血压	3.31(0.75~14.69)	0.116
高脂血症	5.98(1.87~19.06)	0.003
HBeAg	0.91(0.29~2.88)	0.878	0.52(0.14~1.93)	0.325
HBV DNA	0.90(0.71~1.13)	0.366
抗病毒治疗¹⁾	0.36(0.10~1.28)	0.115	0.20(0.04~0.90)	0.037
显著纤维化分期(S2~4)	3.20(1.02~10.06)	0.046	4.60(1.33~15.92)	0.016
注：1)本研究患者在基线/随访期间均满足《慢性乙型肝炎防治指南(2019年版)》^[4]，抗病毒治疗适应证共192例患者接受抗病毒治疗，其中160例在基线时即接受治疗。

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表 5 CHB合并MAFLD组不同NAS评分患者的临床特征

Table 5. Characteristics of patients with concurrent MAFLD and CHB according to NAS score

指标	NAS＜4组(n=59)	NAS≥4组(n=42)	统计值	P值
年龄(岁)	35(29~43)	35(30~42)	Z=-0.304	0.761
男[例(%)]	48(81.4)	31(73.8)	χ²=0.820	0.464
超重[例(%)]	53(89.8)	41(97.6)	χ²=2.307	0.234
糖尿病[例(%)]	8(13.6)	8(19.0)	χ²=0.554	0.582
高脂血症[例(%)]	29(49.2)	27(64.3)	χ²=2.274	0.158
HBeAg阳性[例(%)]	37(62.7)	26(61.9)	χ²=0.007	1.000
HBV DNA (log IU/mL)	5.00(2.88~7.52)	5.63(2.78~7.84)	Z=-0.852	0.394
ALT (U/L)	62.0(42.3~107.0)	110.7(71.8~201.0)	Z=-3.139	0.002
AST(U/L)	43.7(28.5~59.7)	64.0(41.0~82.0)	Z=-2.898	0.004
GGT(U/L)	43.0(26.6~63.0)	55.9(40.9~80.7)	Z=-2.260	0.024
血糖(mmol/L)	5.14(4.62~5.65)	5.47(4.95~6.20)	Z=-2.360	0.018
TC(mmol/L)	4.66±0.94	5.10±1.07	t=-2.167	0.033
PT(s)	11.6±0.9	11.3±1.0	t=1.442	0.152
PTA(%)	104.7±13.9	104.3±14.6	t=0.159	0.874
炎症活动度≥G2[例(%)]	25(42.4)	24(57.1)	χ²=2.143	0.162
纤维化≥S2[例(%)]	22(37.3)	19(45.2)	χ²=0.643	0.538

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表 6 CHB合并MAFLD组患者发生终点事件的多因素分析

Table 6. Adjusted HRs for any clinical event in patients with concurrent MAFLD and CHB

变量	HR(95%CI)	P值
NAS≥4	0.49(0.11~2.13)	0.338
BMI	1.05(0.85~1.31)	0.638
2型糖尿病	1.30(0.33~5.18)	0.713
高脂血症	3.06(0.71~13.24)	0.135
高血压	1.74(0.27~11.38)	0.561
年龄	1.05(0.96~1.15)	0.248
性别	0.24(0.02~2.62)	0.240
乙型肝炎家族史	1.82(0.53~6.21)	0.342
抗病毒治疗	0.66(0.12~3.71)	0.633
显著纤维化(S2~4)	4.83(1.23~18.91)	0.024

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