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合并肝细胞癌对肝硬化食管胃静脉曲张出血患者急诊内镜治疗预后的影响
DOI: 10.12449/JCH250213
伦理学声明：本研究方案于2024年6月25日经武汉大学人民医院伦理委员会审批，批号：WDRY2024-K142。
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：朱小琴负责拟定写作思路、数据分析，并撰写论文；韦娜参与收集数据，修改论文；肖勇负责课题设计，修改论文；余保平指导撰写文章并最后定稿。
Impact of hepatocellular carcinoma on the prognosis of patients with liver cirrhosis undergoing emergency endoscopic therapy due to esophagogastric variceal bleeding
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摘要:
目的 探究合并肝细胞癌（HCC）对肝硬化食管胃静脉曲张出血患者急诊内镜治疗预后的影响，并分析肝硬化食管胃静脉曲张出血未合并HCC患者急诊内镜治疗预后的独立影响因素。 方法 选取武汉大学人民医院2017年1月—2023年7月肝硬化食管胃静脉曲张出血经急诊内镜治疗且未合并HCC患者117例，合并HCC患者119例。收集患者年龄、性别等基本信息；是否合并高血压、糖尿病、冠心病等慢性疾病情况；入院后行急诊内镜时间，INR、Alb、肌酐、钠、TBil、ALT、AST等肝功能相关指标。正态分布的连续型变量两组间比较采用成组t检验；非正态分布连续型变量两组间比较采用Wilcoxon秩和检验。分类变量组间比较采用χ²检验。用协方差分析及多因素Logistic回归分析控制基线变量再对结局变量进行比较，并绘制两组生存时间的Kaplan-Meier曲线；对未合并HCC组生存时间进行单因素及Cox多因素回归分析，分析生存时间的独立影响因素，并进一步分组进行Kaplan-Meier曲线绘制及Log-rank检验，验证独立影响因素，并分析次要结局的独立影响因素。 结果 合并HCC组红细胞输注单位明显高于未合并HCC组［6.00（2.00～9.00） vs 4.00（1.75～7.00）， Z=-2.050， P=0.040，F=4.869，调整P=0.028］，生存时间明显低于未合并HCC组［（29.77±16.01）d vs （38.07±11.43）d，t=4.574，P<0.001，F=17.294，调整P<0.001］，5 d再出血情况明显高于未合并HCC组（22.69% vs 6.84% ，χ2=11.736，P<0.001，调整P=0.021）；Kaplan-Meier曲线显示合并HCC组42 d死亡风险是未合并HCC组的3.897倍（95%CI：2.338～6.495，P<0.001）；对未合并HCC组进行Cox多因素回归分析显示，住院总时长（HR=0.793，95%CI：0.644～0.976，P=0.029）是此类患者42 d生存情况的独立保护因素；Kaplan-Meier曲线显示住院时长>9 d，有利于患者预后（HR=4.302，95%CI：1.439～12.870，P=0.037）；血Na水平（OR=0.523，95%CI：0.289～0.945，P=0.032）及MELD-Na评分（OR=0.495，95%CI：0.257～0.954，P=0.036）是5 d再出血情况的独立保护因素，AST水平是5 d再出血情况（OR=1.023，95%CI：1.002～1.043，P=0.028）及院内死亡的独立危险因素（OR=1.036，95%CI：1.001～1.073，P=0.045）。 结论 合并HCC的肝硬化静脉曲张出血患者预后更差；AST水平越高，未合并HCC组院内病死率更高；住院总时长是未合并HCC组生存时间的独立保护因素，建议适当延长此类患者的住院时长。 Abstract:Objective To investigate the impact of hepatocellular carcinoma （HCC） on the prognosis of patients with liver cirrhosis undergoing emergency endoscopic therapy for esophagogastric variceal bleeding， as well as independent influencing factors for the prognosis of liver cirrhosis patients without HCC after emergency endoscopic therapy for esophagogastric variceal bleeding. Methods A total of 117 liver cirrhosis patients without HCC and 119 liver cirrhosis patients with HCC who underwent emergency endoscopic therapy for esophagogastric variceal bleeding in Renmin Hospital of Wuhan University from January 2017 to July 2023 were enrolled. Basic information including age and sex was collected from all patients， as well as the presence or absence of chronic diseases such as hypertension， diabetes， and coronary heart disease， the time of emergency endoscopy after admission， and liver function parameters including international normalized ratio， albumin， creatinine， sodium， total bilirubin， alanine aminotransferase， and aspartate aminotransferase （AST）. The independent-samples t test was used for comparison of normally distributed continuous variables between two groups， and the Wilcoxon rank-sum test was used for comparison of non-normally distributed continuous variables between two groups； the chi-square test was used for comparison of categorical variables between groups. The covariance analysis and the multivariate logistic regression analysis were used for comparison of outcome variables after control of baseline variables， and the Kaplan-Meier survival curve was plotted for each group. The univariate and multivariate Cox regression analyses were performed for survival time in the non-HCC group to investigate the independent influencing factors for survival time， and then the Kaplan-Meier curve analysis and the log-rank test were performed to validate such independent influencing factors and analyze the independent influencing factors for secondary outcomes. Results Compared with the non-HCC group， the HCC group had significantly higher red blood cell transfusion units （6.00［2.00～9.00］ vs 4.00［1.75～7.00］， Z=-2.050， P=0.040， F=4.869， adjusted P=0.028）， a significantly shorter survival time （29.77±16.01 days vs 38.07±11.43 days， t=4.574， P<0.001， F=17.294， adjusted P<0.001）， and a significantly higher 5-day rebleeding rate （22.69% vs 6.84%， χ2=11.736， P<0.001， adjusted P=0.021）. The Kaplan-Meier curve analysis showed that the risk of 42-day mortality in the HCC group was 3.897 （95% confidence interval ［CI］： 2.338 — 6.495， P<0.001） times that in the non-HCC group. The multivariate Cox regression analysis of the non-HCC group showed that the total length of hospital stay （hazard ratio ［HR］=0.793， 95%CI： 0.644 — 0.976， P=0.029） was an independent protective factor for 42-day survival. The Kaplan-Meier curve analysis showed that a length of hospital stay of >9 days was beneficial for the prognosis of patients （HR=4.302， 95%CI： 1.439 — 12.870， P=0.037）. Blood sodium level （odds ratio ［OR］=0.523， 95%CI： 0.289 — 0.945， P=0.032） and MELD-Na score （OR=0.495， 95%CI： 0.257 — 0.954， P=0.036） were independent protective factors against 5-day rebleeding， while AST level was an independent risk factor for 5-day rebleeding （OR=1.023， 95%CI： 1.002 — 1.043， P=0.028） and in-hospital death （OR=1.036， 95%CI： 1.001— 1.073， P=0.045）. Conclusion Liver cirrhosis patients with variceal bleeding and HCC tend to have a worse prognosis， and for the non-HCC group， in-hospital mortality rate increases with the increase in AST level. The total length of hospital stay is an independent protective factor for survival time in the non-HCC group， and it is recommended to appropriately prolong the length of hospital stay for such patients. -
Key words:
- Liver Cirrhosis /
- Esophageal and Gastric Varices /
- Carcinoma， Hepatocellular /
- Prognosis
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图 2 两组42 d死亡情况的Kaplan-Meier曲线
Figure 2. Kaplan-Meier curves of 42-day mortality between the two groups
图 3 两组住院总时长的Kaplan-Meier曲线
Figure 3. Kaplan-Meier curves of total length of hospital stay between the two groups
表 1 未合并HCC组与合并HCC组的基线资料比较
Table 1. Baseline analysis of non-hepatocellular carcinoma and hepatocellular carcinoma groups
基线变量 未合并HCC组（n=117） 合并HCC组（n=119） 统计值 P值 年龄（岁） 59.56±12.49 57.75±11.94 t=1.142 0.255 男/女（例） 77/40 101/18 χ2=11.565 0.001 生化指标 INR 1.43±0.97 1.41±0.36 t=0.254 0.800 Alb（g/L） 29.91±4.89 27.88±4.86 t=3.197 0.002 Cr（μmol/L） 67.00（52.50～84.00） 61.00（46.00～82.00） Z=-1.165 0.244 Na（mmol/L） 137.98±10.95 138.02±5.16 t=-0.040 0.968 TBil（μmol/L） 20.54（15.43～30.96） 26.22（16.64～42.16） Z=-2.272 0.023 AST（U/L） 33.00（22.00～57.50） 64.00（35.00～115.00） Z=-5.161 0.001 ALT（U/L） 24.00（16.00～38.50） 30.00（21.00～55.00） Z=-3.027 0.002 慢性疾病史［（例（%）］ 高血压 26（22.22） 29（24.37） χ2=0.152 0.696 糖尿病 28（23.93） 32（26.89） χ2=0.272 0.602 冠心病 8（6.84） 4（3.36） χ2=1.477 0.224 合并慢性疾病 45（38.46） 46（38.66） χ2=0.001 0.976 肝功能评分 MELD（分） 11.82±5.08 12.55±4.88 t=-1.123 0.262 MELD-Na（分） 10.71±11.18 13.89±6.57 t=-2.673 0.008 注：MELD=3.78×ln（TBil）+11.2×ln（INR）+9.57×ln（Cr）+6.43； MELD-Na=MELD+1.32×（137－Na）－［0.033×MELD×（137－Na）］。
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表 2 未合并HCC组与合并HCC组的结局指标分析
Table 2. Analysis of outcome indicators between non-hepatocellular carcinoma and hepatocellular carcinoma groups
结局指标 未合并HCC组
（n=117）
合并HCC组
（n=119）
统计值 P值 F值1） P值1） 红细胞输注单位（U） 4.00（1.75～7.00） 6.00（2.00～9.00） Z=-2.050 0.040 4.869 0.028 ICU住院时长（d） 3（2～4） 3（2～4） Z=-0.645 0.519 0.037 0.848 住院总时长（d） 9（6～12） 10（6～13） Z=-1.348 0.178 1.703 0.193 生存时间（d） 38.07±11.43 29.77±16.01 t=4.574 <0.001 17.294 <0.001 5 d再出血情况［（例（%）］ 8（6.84） 27（22.69） χ2=11.736 <0.001 0.021 院内死亡情况［（例（%）］ 7（5.98） 11（9.24） χ2=0.890 0.345 0.676 42 d死亡情况［（例（%）］ 13（11.11） 46（38.66） χ2=23.872 <0.001 0.250 注：1）连续型结局指标进行协方差分析调整基线差异指标，分类变量进行多因素逻辑回归分析调整基线差异指标。
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表 3 生存时间的Cox单因素及多因素回归分析
Table 3. Survival time Cox univariate and multivariate regression analysis
影响因素 单因素分析 多因素分析 HR（95%CI） P值 β值 SE Wald HR（95%CI） P值 TBil 1.008（1.004～1.012） <0.001 0.004 0.005 0.450 1.004（0.993～1.014） 0.502 MELD评分 1.101（1.031～1.177） 0.004 -0.008 0.095 0.006 0.992（0.824～1.195） 0.936 5 d再出血情况 25.369（8.141～79.055） <0.001 -2.654 0.692 14.717 0.070（0.018～0.273） <0.001 住院总时长 0.722（0.603～0.864） <0.001 -0.232 0.106 4.772 0.793（0.644～0.976） 0.029
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表 4 次要结局线性或Logistic多因素回归分析
Table 4. Linear or logistic multivariate regression analysis of secondary outcomes
结局变量 影响因素 多因素回归分析 β值 SE Wald/t值 OR/线性回归系数 95%CI P值 5 d再出血情况 Na -0.694 0.302 4.607 0.523 0.289～0.945 0.032 AST 0.022 0.010 4.824 1.023 1.002～1.043 0.028 MELD-Na评分 -0.703 0.335 4.418 0.495 0.257～0.954 0.036 ICU住院时长 AST -0.021 0.005 -4.435 -0.021 -0.031～-0.012 <0.001 ALT 0.038 0.008 4.684 0.038 0.022～0.084 <0.001 住院总时长 AST -0.035 0.008 -4.626 -0.035 -0.031～-0.020 <0.001 ALT 0.059 0.013 4.579 0.059 0.033～0.054 <0.001 院内死亡 AST 0.036 0.018 4.022 1.036 1.001～1.073 0.045
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