非肝硬化背景的HBV相关慢加急性肝衰竭预后评分和相关临床指标的动态变化及其与临床结局的关系

王文玲; 徐曼曼; 武羽; 张家腾; 邹怀宾; 陈煜

doi:10.12449/JCH250911

非肝硬化背景的HBV相关慢加急性肝衰竭预后评分和相关临床指标的动态变化及其与临床结局的关系

DOI: 10.12449/JCH250911

王文玲^{1, 2},
徐曼曼^{1, 2},
武羽^{1, 2},
张家腾^{1, 2},
邹怀宾^{1, 2},
陈煜^{1, 2, , ,}

1.
首都医科大学附属北京佑安医院肝病中心四科，北京 100069
2.
肝再生与人工肝转化研究北京市重点实验室，北京 100069

基金项目:

首都卫生发展科研专项项目 (CFH2024-1-2181);

高层次公共卫生技术人才建设项目资助 (Discipline leader-01-12);

北京市医院管理中心“登峰”计划专项经费资助 (DFL20221501);

国家重点研发计划项目 (2022YFC2304402)

伦理学声明：本研究方案于2020年12月4日经由首都医科大学附属北京佑安医院伦理委员会批准，批号为LL-2020-178-K，入组患者均签署知情同意书。

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：王文玲、徐曼曼负责采集数据，分析数据，撰写文章；武羽、张家腾、邹怀宾参与论文修改；陈煜负责拟定写作思路，指导撰写文章并最终定稿。王文玲、徐曼曼对本文贡献等同，为共同第一作者。

详细信息

通信作者:
陈煜， chybeyond1071@ccmu.edu.cn （ORCID： 0000-0003-1906-7486）

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出版历程
- 收稿日期: 2025-03-10
- 录用日期: 2025-05-15
- 出版日期: 2025-09-25

Dynamic changes of prognostic scores and related clinical indicators in hepatitis B virus-related acute-on-chronic liver failure patients without underlying liver cirrhosis and their relationship with clinical outcomes

Wenling WANG^{1, 2},
Manman XU^{1, 2},
Yu WU^{1, 2},
Jiateng ZHANG^{1, 2},
Huaibin ZOU^{1, 2},
Yu CHEN^{1, 2
, ,
,}

1.
Fourth Department of Liver Disease Center，Beijing YouAn Hospital，Capital Medical University，Beijing 100069，China
2.
Beijing Key Laboratory of Liver Regeneration and Artificial Liver Transformation Research，Beijing 100069，China

Research funding:

Capital’s Funds for Health Improvement and Research (CFH2024-1-2181);

Construction Project of High-level Technology Talents in Public Health (Discipline leader-01-12);

Beijing Hospitals Authority’s Ascent Plan (DFL20221501);

National Key Research and Development Program of China (2022YFC2304402)

More Information

Corresponding author: CHEN Yu， chybeyond1071@ccmu.edu.cn （ORCID： 0000-0003-1906-7486）

摘要

摘要: 目的分析非肝硬化背景的HBV相关慢加急性肝衰竭（HBV-ACLF）患者的预后评分及关键临床指标的动态轨迹，阐明其与结局的关联性，为个体化预后评估提供新依据。方法前瞻性收集2016年1月—2023年12月就诊于首都医科大学附属北京佑安医院的154例非肝硬化背景的HBV-ACLF患者病程第1、3、7、14、21、28天的预后评分及关键生化指标，依据患者1年结局分为死亡或肝移植组（n=43）、肝硬化组（n=23）和非肝硬化组（n=88），分析不同结局患者相关指标的动态变化。符合正态分布的计量资料3组间比较采用单因素方差分析；非正态分布计量资料多组间比较采用Kruskal-Wallis H检验，两组间比较采用Wilcoxon秩和检验。计数资料组间比较采用χ²检验。计算各时间点指标的均值及其95%CI；通过线性插值法连接相邻时间点均值，构建组别特异的纵向趋势曲线；使用半透明带状区域可视化95%CI，透明度参数（α=0.2）用于优化多组重叠区间的视觉辨识度。为比较不同结局之间各项指标的纵向变化趋势差异，采用线性混合效应模型，通过似然比检验评估时间与组间的交互效应显著性，若交互作用显著，进一步使用基于估计边际均值的斜率对比进行组间两两比较。结果 3组间比较，基线时腹水和Ⅲ～Ⅳ期肝性脑病发生率，MELD、MELD-Na、CLIF-C ACLF和COSSH-ACLF Ⅱ评分，以及TBil、INR、AFP、血钠、ALT、PCT水平均有显著差异（P值均<0.05）。动态轨迹分析表明，死亡或肝移植组的预后评分及总胆红素（TBil）、国际标准化比值（INR）处于高水平（TBil>400 μmol/L，INR>2.5），血小板（PLT）处于低水平（<100×10⁹/L）；非肝硬化组指标呈快速改善趋势，28天恢复到TBil<200 μmol/L、INR<1.5、PLT>100×10⁹/L；肝硬化组尽管有恢复趋势，但28天时TBil>200 μmol/L、INR>2.0、PLT<100×10⁹/L，3组间上述指标时间趋势异质性显著（P值均<0.01）。结论动态监测预后评分和关键指标可显著区分非肝硬化HBV-ACLF患者的1年预后分层，预后差的患者多表现为INR>2.5、TBil>400 μmol/L；对于生存时间超过1年的患者，若进展为肝硬化，则常表现为在28天时INR>1.5、TBil>200 μmol/L且PLT<100×10⁹/L的特征。
- 乙型肝炎病毒 /
- 慢加急性肝功能衰竭 /
- 肝硬化 /
- 预后
Abstract: Objective To investigate the dynamic trajectories of prognostic scores and key clinical indicators in hepatitis B virus-related acute-on-chronic liver failure （HBV-ACLF） patients without liver cirrhosis， to clarify their association with outcomes， and to provide new evidence for individualized prognostic assessment. Methods A prospective study was conducted for the data of 154 non-cirrhotic HBV-ACLF patients who attended Beijing YouAn Hospital of Capital Medical University from January 2016 to December 2023， including prognostic scores and key biochemical indicators on Days 3， 7， 14， 21， and 28 of the disease course. According to the outcome of patients at 1 year， they were divided into death/liver transplantation group with 43 patients， liver cirrhosis group with 23 patients， and non-liver cirrhosis group with 88 patients， and the trajectory heterogeneity of different outcome subgroups was analyzed. A one-way analysis of variance was used for comparison of normally distributed continuous data among the three groups； the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data among the three groups； the Wilcoxon test was used between two groups. the chi-square test was used for comparison of categorical data between groups. The mean and its 95% confidence interval （CI） were calculated for each indicator at difference time points； the linear interpolation method was used to connect the means at adjacent time points and construct the group-specific longitudinal trend curve； the 95%CI was visualized using the semi-transparent ribbon area， with the transparency parameter （α=0.2） optimized to enhance the visual discrimination of overlapping intervals across multiple groups. A linear mixed-effects model was used to compare the longitudinal changing trend of each indicator between the patients with different outcomes； likelihood ratio was used to evaluate the significance of the interaction effect between time and group， and in case of the significant interaction effect， the slope based on the estimated marginal mean was used for comparison between two groups. Results There were significant differences between the three groups in the incidence rates of ascites and grade Ⅲ — Ⅳ hepatic encephalopathy， MELD score， MELD-Na score， CLIF-C ACLF score， COSSH-ACLF Ⅱ score， total bilirubin （TBil）， international normalized ratio （INR）， alpha-fetoprotein， blood sodium， alanine aminotransferase， and procalcitonin at the baseline（all P<0.05）. The analysis of dynamic trajectories showed that the death/liver transplantation group had high levels of prognostic scores and the biochemical parameters of TBil and INR （TBil>400 μmol/L， INR>2.5）， as well as a low level of platelet count （PLT）（<100×10⁹/L）. The non-liver cirrhosis group had rapid improvements in indicators， with TBil<200 μmol/L， INR<1.5， and PLT>100×10⁹/L by day 28， while the liver cirrhosis group showed a trend of recovery， with TBil>200 μmol/L， INR>2.0， and PLT <100×10⁹/L on day 28， with significant global heterogeneity in the temporal trends of the above indicators across the three groups （all P<0.01）. Conclusion Dynamic monitoring of prognostic scores and key clinical indicators can effectively stratify the 1-year outcomes of non-cirrhotic patients with HBV-ACLF. Patients with poor prognosis were typically characterized by INR >2.5 and TBil >400 μmol/L. Among those who survived beyond 1 year， individuals who subsequently progressed to cirrhosis were frequently identified by the presence of INR >1.5， TBil >200 μmol/L， and PLT <100×10⁹/L at day 28.
- Hepatitis B Virus /
- Acute-On-Chronic Liver Failure /
- Liver Cirrhosis /
- Prognosis

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图 1 28天内预后评分在不同结局患者中的纵向变化趋势

Figure 1. Longitudinal trajectories of prognostic scores across outcome subgroups during the 28-day follow-up period

下载: 全尺寸图片幻灯片

图 2 28天内各指标在不同结局患者中的纵向变化趋势

Figure 2. Longitudinal trajectories of indicators across outcome subgroups during the 28-day follow-up period

下载: 全尺寸图片幻灯片

表 1 非肝硬化背景的HBV-ACLF患者人口学特征和基线临床特征

Table 1. Demographic and baseline clinical characteristics of non-cirrhotic HBV-ACLF patients

项目	非肝硬化组（n=88）	肝硬化组（n=23）	死亡或肝移植组（n=43）	统计值	P值
男性［例（%）］	74（84.1）	22（95.7）	34（79.1）	χ ²=3.149	0.209
年龄（岁）	42.8±10.9	41.6±8.9	47.6±11.2	F=3.615	0.029
诱因［例（%）］				χ ²=6.222	0.277
乙型肝炎再激活	18（20.5）	7（30.4）	14（32.6）
自发激活	44（50.0）	10（43.5）	14（32.6）
肝毒性药物	6（6.8）	1（4.4）	5（11.6）
其他^1）	8（9.1）	3（13.0）	8（18.6）
不详	12（13.6）	2（8.7）	2（4.7）
并发症［例（%）］
腹水	48（54.5）	15（65.2）	36（83.7）	χ ²=10.719	0.005
肝性脑病				χ ²=21.090	0.001
Ⅰ～Ⅱ期	11（12.5）	2（8.7）	12（27.9）
Ⅲ～Ⅳ期	0（0.0）	0（0.0）	5（11.6）
细菌感染	61（69.3）	16（69.6）	37（86.0）	χ ²=4.484	0.106
上消化道出血	2（2.3）	1（4.4）	4（9.3）	χ ²=3.292	0.171
急性肾损伤	9（10.2）	1（4.4）	2（4.7）	χ ²=2.400	0.814
预后评分（分）
MELD	20.9（18.7～23.7）	23.2（21.2～24.6）	26.5（21.5～30.4）	H=25.005	<0.001
MELD-Na	21.5（19.2～24.0）	23.2（21.5～24.6）	28.2（22.3～32.8）	H=24.483	<0.001
CLIF-C ACLF	37.0±5.7	37.0±7.1	44.7±6.8	F=33.997	<0.001
COSSH-ACLF Ⅱ	6.70（6.20～7.20）	6.75（6.17～7.42）	7.80（7.35～8.30）	H=48.675	<0.001
既往抗病毒治疗［例（%）］	16（18.2）	7（30.4）	12（27.9）	χ ²=2.470	0.291
诊断ACLF后抗病毒用药情况［例（%）］				χ ²=1.803	0.406
ETV	38（48.1）	12（60.0）	18（41.9）
TAF	41（51.9）	8（40.0）	25（58.1）
ALT（U/L）	543（178～1 160）	180（137～365）	201（92～641）	H=9.182	0.010
AST（U/L）	289（131～519）	149（105～323）	176（106～486）	H=4.265	0.119
Alb（g/L）	32.3±4.8	29.7±4.6	31.1±5.2	F=2.749	0.067
TBil（μmol/L）	285（189～377）	338（200～408）	376（281～534）	H=12.630	0.002
胆碱酯酶（U/L）	3 110（2 304～4 127）	2 795（1 783～3 276）	3 038（1 758～3 891）	H=1.470	0.479
INR	1.96（1.67～2.26）	2.27（1.98～2.77）	2.87（2.30～3.62）	H=36.524	<0.001
肌酐（μmol/L）	61.0（52.8～70.0）	61.0（53.0～70.0）	56.0（46.5～74.5）	H=0.744	0.689
血钠（mmol/L）	138（136～140）	137（136～139）	136（133～138）	H=11.861	0.003
WBC（×109/L）	7.20（5.29～8.65）	5.61（4.38～8.90）	7.88（5.80～11.00）	H=5.451	0.066
PLT（×109/L）	127（103～176）	93（60～110）	109（70～146）	H=16.122	<0.001
AFP（ng/mL）	138.0（56.3～373.0）	74.3（27.8～178.0）	45.0（9.0～93.4）	H=17.906	<0.001
HBeAg阳性［例（%）］	42（53.2）	10（43.5）	0（0.0）		0.561
HBV DNA（log₁₀ IU/mL）	5.25（3.68～6.60）	4.20（3.15～5.25）	4.80（3.80～5.80）	H=4.553	0.195
PCT（ng/mL）	0.66（0.45～0.99）	0.48（0.32～0.64）	0.84（0.59～1.31）	H=13.158	0.001
LSM（kPa）^2）	9.2（7.0～11.9）	17.6（16.6～20.4）		Z=-35.702	<0.001
FIB-4指数^2）	1.58（1.18～2.41）	3.41（2.96～6.86）		Z=-34.243	<0.001
注：MELD-Na，终末期肝病模型-钠评分；CLIF-C ACLF，慢性肝衰竭研究组慢加急性肝衰竭评分；COSSH-ACLFⅡ，中国重型乙型肝炎研究组慢加急性肝衰竭Ⅱ评分；ETV，恩替卡韦；TAF，富马酸丙酚替诺福韦；PCT，降钙素原；LSM，肝硬度值；FIB-4指数，用于评估慢性肝病患者肝纤维化程度。1）其他包括感染和劳累等；2）患病1年时检测。

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