Total bilirubin serves as a robust predictor of 6-week mortality in patients with liver cirrhosis and acute esophagogastric variceal bleeding

Total bilirubin serves as a robust predictor of 6-week mortality in patients with liver cirrhosis and acute esophagogastric variceal bleeding | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Total bilirubin serves as a robust predictor of 6-week mortality in patients with liver cirrhosis and acute esophagogastric variceal bleeding Qi Li, Ruifeng Liu, Shenghui Zhou, Lingna Lyu, Yanjing Wu, Chunlei Fan, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7262310/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Acute esophagogastric variceal bleeding (AEGVB) is a frequent and life-threatening complication of liver cirrhosis. This study aimed to investigate robust factors associated with 6-week mortality in cirrhotic patients with AEGVB using advanced statistical analysis. Methods We retrospectively enrolled 656 consecutive cirrhotic patients with AEGVB from April 1st, 2021 to September 30th, 2022 in Beijing You’an Hospital, Capital Medical University. A 1:4 matched analysis was performed to adjust the effect of admission time on statistical results. Cluster analysis was used to divide the whole cohort into three groups with distinct clinical characteristics. Kaplan-Meier analysis was used to estimate 6-week overall survival among the three clustered groups. Cox regression analysis were used to investigate predictors of 6-week mortality for cirrhotic patients with AEGVB. A competing risk model was used to identify robust predictors for 6-week mortality. The prognostic value of total bilirubin (TB) was assessed using restricted cubic spline (RCS) analysis. Results Cluster analysis identified the top 10 most important variables for clustering, including TB and D-dimer. After clustering with these variables, we found that cluster 0 group had the highest rates of early death, rebleeding and hemostasis failure. Kaplan-Meier analysis demonstrated that the 6-week mortality rate was significantly higher in the cluster 0 group than in the cluster 1 and 2 groups. Cox regression analysis showed that 6-week mortality was independently associated with several variables including 6-week rebleeding (HR 21.904, 95% CI 8.446 to 56.805, P < 0.001), TB (HR 1.011, 95% CI 1.007 to 1.014, P < 0.001), rebleeding within 72h (HR 16.767, 95% CI 6.309 to 44.556, P < 0.001), and rebleeding within 4–5 days (HR 10.137, 95% CI 2.338 to 43.945, P = 0.002). However, the competing risk model demonstrated that for 6-week mortality, TB was the only significant risk factor, with an HR of 1.43 and 95% CI of 1.100 to1.860 ( P = 0.008). Furthermore, RCS analysis indicated that TB level above 127.35µmol/L was associated with a significantly increased risk of 6-week mortality. Conclusion Cluster analysis allows the identification of distinct profiles of AEGVB that form clinically relevant subsets. TB can serve as a robust biomarker for assessing short-term mortality risk in cirrhotic patients with AEGVB. Acute esophagogastric variceal bleeding Liver cirrhosis 6-week mortality Total bilirubin Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Acute esophagogastric variceal bleeding (AEGVB) is a critical complication of liver cirrhosis, primarily driven by portal hypertension[ 1 ]. Current treatment approaches include endoscopic interventions and pharmacological therapies. Pharmacological therapies involve vasoactive drugs and antibiotics, which aim to stabilize patients and prevent rebleeding[ 2 ]. This condition represents a significant clinical challenge due to its potential to cause life-threatening hemorrhage, which contributes to a 15%-25% mortality within 6 weeks[ 3 – 5 ]. The economic burden of this condition on healthcare systems is substantial, necessitating extensive hospitalization and intensive management efforts[ 6 ]. Research has identified several clinical and laboratory parameters that correlate with outcomes in patients experiencing AEGVB. Among them, the Child-Pugh score and MELD score have emerged as key factors potentially linked to mortality and disease progression[ 7 ]. The median survival time was shorter in Child-Pugh B/C patients with AEGVB, and Child-Pugh grade was a predictor of survival[ 8 ]. Moreover, the 5-year survival was only 15.1% in Child-Pugh C patients who received endoscopic treatment or balloon-occluded retrograde transvenous obliteration[ 9 ]. The Child-Pugh score and MELD score had similar efficacy to predict short-term mortality in patients with AEGVB (AUROC = 0.72 vs. 0.74)[ 10 ]. General statistical analysis has shown that both scores predict 6-week mortality in cirrhotic patients with AEGVB. In this current study, we aim to identify more robust factors associated with 6-week mortality beyond the Child-Pugh score and MELD score in cirrhotic patients with AEGVB by performing advanced statistical analysis. This may contribute to developing improved management strategies and clinical protocols for patients suffering from AEGVB. Methods Study cohort This retrospective single-center study used patient information from a previous cohort. The cohort included patients over 18 years old with acute gastrointestinal bleeding (AGIB) who were admitted to the Emergency Room at Beijing You’an Hospital, Capital Medical University, from April 1st 2021 to Sep 30th 2022. For patients with multiple admissions due to AGIB during the study period, only their first admission was considered. Only patients with liver cirrhosis were included for data analysis. Patients were excluded if they met any of the following criteria: i) discharged against medical advice in the Emergency Room; ii) did not receive endoscopy within 6 months prior to admission and refused endoscopy after admission; iii) had non-variceal bleeding; iv) were lost to follow-up; v) had malignancies other than hepatocellular carcinoma (HCC); vi) had malignant portal vein thrombosis (PVT); or vii) had unidentified malignant PVT. Ultimately, 656 cirrhotic patients with AEGVB who met the inclusion/exclusion criteria were included and followed up for 6 weeks. The primary endpoint was 6-week mortality. Secondary endpoints included in-hospital mortality, mortality at 72 hours and 5 days, as well as rebleeding events within 72 hours, between 4 and 5 days and up to 6 weeks. Clinical, laboratory, and radiological parameters Liver cirrhosis was diagnosed based on the medical history, physical examination, laboratory tests, imaging studies, and liver biopsy. AEGVB was defined as clinical signs of bleeding (haematemesis, melena or hematochezia) originating from the gastrointestinal tract and confirmed by endoscopy showing esophagogastric varices within the preceding 6 months. HCC was diagnosed based on historical data, pathology or imaging studies such as computed tomography and/or magnetic resonance imaging[ 11 ]. We recorded the following clinical parameters: shock index, etiology of cirrhosis, underlying diseases, grades of ascites, stages of hepatic encephalopathy, Child-Pugh score/class. Outcomes included in-hospital mortality, 6-week mortality, 6-week rebleeding, death within 72 hours, rebleeding within 72 hours, hemostasis failure within 72 hours, death within 4–5 days, rebleeding within 4–5 days, hemostasis failure within 4–5 days, death within 5 days, rebleeding within 5 days, hemostasis failure within 5 days. Other variables included history of endoscopic therapy, history of splenectomy, active bleeding during endoscopy, time from admission to endoscopy, time from bleeding to admission, use of Sengstaken-Blakemore tube during hospitalization, transfusions of red blood cells, platelets and plasma. The following laboratory parameters were included: hemoglobin (Hb), hematocrit (Hct), platelet count (PLT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cr), total bilirubin (TB), albumin, prothrombin time (PT), blood urea nitrogen (BUN), creatinine kinase-MB (CK-MB), troponin I (TnI), myoglobin, activated partial thromboplastin time (APTT), international normalized ratio (INR), prothrombin time activity (PTA), fibrinogen (FIB), thrombin time (TT), D-dimer, fibrinogen degradation products (FDP) and antithrombin (AT). Child-Pugh classes were estimated based on the degree of hepatic encephalopathy, ascites, TB, albumin, and PT. Grade of ascites and stages of hepatic encephalopathy were diagnosed according to the criteria by Chinese Society of Hepatology, Chinese Medical Association[ 12 ]. Treatment received All enrolled patients received treatments including antibiotics, vasoactive drugs (octreotide or terlipressin) and proton pump inhibitors. For patients with AEGVB, some received treatment with a Sengstaken-Blakemore tube and/or endoscopic therapies such as endoscopic variceal ligation (EVL), gastric variceal ligation, endoscopic injection sclerotherapy (EIS) or tissue adhesive injection for gastric varices, depending on the patients’ clinical condition. Ethics This study was approved by the Clinical Research Ethics Committee of Beijing You’an Hospital, Capital Medical University, following the Declaration of Helsinki (No. LL-2023-143-K). The clinical data in this study were anonymized prior to analysis. The Clinical Research Ethics Committee waived the need for consent due to the retrospective nature of the study. Statistical analysis Quantitative variables were expressed as median and interquartile range (IQR), and differences between groups were compared using Student’s t-test. Qualitative variables were presented as frequencies and percentages, and the Chi-square test was used to compare differences. Non-parametric tests were performed when variables did not meet the normality assumption. A 1:4 matched analysis was conducted to adjust for the effect of admission time alone on our statistical results. Cluster analysis was used to identify distinct profiles of AEGVB that formed clinical subsets with similar characteristics. Kaplan-Meier survival analysis was performed to display overall survival over six weeks among the three clustered groups. Univariable and multivariable Cox regression analyses were used to investigate predictors of 6-week mortality for cirrhotic patients with AEGVB. The competing risk models were used to identify robust predictors of six-week mortality. The prognostic value of TB levels was determined by restricted cubic spline (RCS) analysis. A P value less than 0.05 was considered statistically significant. All statistical analyses were performed with R software version 4.2.1 (R Foundation for Statistical Computing, Vienna, Austria). Results Characteristics of cirrhotic patients with AEGVB who died within 6 weeks after admission compared with survivors A total of 1901 electronic records of patients with emergent acute gastrointestinal bleeding were reviewed. After excluding multiple admissions and applying inclusion/exclusion criteria, we enrolled 656 cirrhotic patients with AEGVB who were followed up for 6 weeks (Figure 1). These patients were divided into the 6-week death group and the survivor group. A total of 52 patients died within 6 weeks and were classified as the 6-week death group. Six-week mortality was 7.93%. A 1:4 matched analysis was performed to adjust for the effect of admission time on the comparison between the two groups. Therefore, 208 patients who survived beyond 6 weeks comprised the survivor group. Finally, only 260 patients were included in the data analysis. The demographic and clinical characteristics of cirrhotic patients with AEGVB were shown in Table 1. The patients who died within 6 weeks after admission were older than the survivors (60.71±11.15 vs. 56.93±11.36, P =0.032). Compared with the survivors, patients who died presented with higher levels of shock index and Child-Pugh score. The death group exhibited a significantly higher incidence of liver failure and HCC. Regarding laboratory parameters, patients who died had higher levels of TB, PT, APTT, INR, TT, D-dimer, FDP, PLT, BUN, Cr, ALT, AST, myoglobin, and TnI, and lower levels of albumin, PTA, AT%, Hb, Hct. A higher proportion of patients who died had active bleeding during endoscopy and were treated with a Sengstaken-Blakemore tube. A significantly higher proportion of patients in the 6-week death group experienced death within 72 hours, rebleeding within 72 hours, hemostasis failure within 72 hours, death within 4-5 days, rebleeding within 4-5 days, hemostasis failure within 4-5 days, death within 5 days, rebleeding within 5 days and hemostasis failure within 5 days compared to the survivor group. Furthermore, patients in 6-week death group received more red blood cell transfusions and plasma transfusions. Clinical characteristics of cirrhotic patients with AEGVB by cluster analysis To identify cirrhotic patients with AEGVB who had similar clinical characteristics, we performed cluster analysis. Figure 2 showed the top 10 important variables for clustering, which were D-dimer, plasma transfusion, AST, myoglobin, ALT, time from admission to endoscopy, TB, PLT, time from bleeding to admission and PTA. All 260 patients of cirrhotic AEGVB were divided into three clusters based on the above 10 important factors (Figure 3). Table 2 presents the clinical characteristics of cirrhotic patients with AEGVB after clustering. Among the three clustered groups, cluster 0 group had the highest rates of in-hospital death, as well as death, rebleeding and hemostasis failure within 72 hours, 4-5 days and 5 days. Furthermore, patients in cluster 0 group more frequently had a history of splenectomy and use of the Sengstaken-Blakemore tube. They also had shorter times from bleeding to admission and from admission to endoscopy, more active bleeding during endoscopy, and higher rates of red blood cell and plasma transfusions ( P <0.001). Kaplan-Meier analysis showed that the 6-week mortality rate was significantly higher in cluster 0 group than in clusters 1 and 2, while cluster 1 had the highest survival rate (long-rank test, P <0.05) (Figure 4). Univariate and stepwise multivariate Cox regression analysis of 6-week mortality in cirrhotic patients with AEGVB The results of univariate and multivariate Cox regression analysis were presented in Table 3. Independent predictors of 6-week mortality included 6-week rebleeding (HR, 21.904; 95% CI, 8.446 to56.805; P <0.001), rebleeding within 72h (HR, 16.767; 95% CI, 6.309 to 44.556; P <0.001), rebleeding within 4-5 days (HR, 10.137; 95% CI, 2.338 to 43.945; P =0.002), TB (HR, 1.011; 95% CI, 1.007 to 1.014; P <0.001), CK-MB (HR, 1.256; 95% CI, 1.115 to 1.415; P <0.001), BUN (HR, 1.103; 95% CI, 1.030 to 1.182; P= 0.005), red blood cell transfusion (HR, 0.866; 95% CI, 0.793 to 0.947; P =0.002), myoglobin (HR, 0.997; 95% CI, 0.995 to 0.999; P =0.003). Competing risk model analysis for 6-week mortality in cirrhotic patients with AEGVB In some cirrhotic patients, AEGVB may cause death. Therefore, bleeding and death compete as outcomes. Next, we performed competing risk model analysis to identify the most robust predictors independently associated with 6-week death in cirrhotic patients with AEGVB. The competing risk model demonstrated that TB was the only significant risk factor with HR=1.43 and 95% CI of 1.100 to1.860 ( P =0.008), indicating that a one-unit increase in TB (mg/dl) increased risk of death by 43% (Table 4). The cumulative incidence curves showed that 6-week rebleeding mainly occurred at an early stage, while the cumulative incidence of death increased more gradually. The pie chart demonstrated that within 6 weeks after AEGVB, the majority of the patients (63.1%) experienced no events, 31.9% died and only 5.0% rebled. The boxplot further indicated that patients in the 6-week death group had a higher and more widely distributed TB values. In contrast, patients in the no event group and the 6-week rebleeding group showed lower and more concentrated TB distributions (Figure 5). These results suggested that TB could serve as a robust predictor to assess short-term mortality risk for cirrhotic patients with AEGVB. Prognostic evaluation of TB for 6-week mortality in cirrhotic patients with AEGVB by RCS analysis Since TB was the most robust predictor for 6-week mortality in cirrhotic patients with AEGVB, we further investigated the relationship between TB and the risk of death within 6 weeks by applying RCS analysis. The overall goodness-of-fit test of the RCS model showed a P value <0.001, indicating a significant association between TB and the risk of death within 6 weeks. The P value of the nonlinear test was 0.2576, suggesting a linear relationship between TB and 6-week mortality. Using an OR of 1 as the cutoff, the threshold of TB value was determined to be 127.35μmol/L. If TB level was higher than 127.35μmol/L, the risk of death within 6 weeks was higher than the reference level. If TB was below this value, the risk of death was relatively low. The sensitivity of this cut-off value was 26.90% and specificity was 97.10%. The positive predictive value was 70.00% and the negative predictive value was 84.20%. In Figure 6, the upper graph showed a smooth curve, while the lower graph displayed a RCS curve. Both graphs reflected the trend of changes in TB levels and the risk of death within 6 weeks. The smooth curve used the probability of death within 6 weeks as the ordinate, which intuitively demonstrated the overall distribution and trend of the actual death probability at different TB levels. The RCS curve used OR as the vertical ordinate, reflecting how the risk of death within 6 weeks changed with increasing or decreasing TB levels. Discussion Understanding AEGVB in patients with liver cirrhosis is paramount because it significantly affects patient morbidity and mortality[ 13 ]. The management of AEGVB primarily involves endoscopic interventions and pharmacological therapies. However, challenges in predicting outcomes and managing complications remain, highlighting the need for continued research in this area[ 5 , 14 ]. In light of these challenges, the present study addresses the clinical and laboratory characteristics of cirrhotic patients experiencing AEGVB, with a specific focus on identifying prognostic factors associated with 6-week mortality. Cox regression analysis revealed that the 6-week mortality was independently associated with 6-week rebleeding, CK-MB, BUN, red blood cell transfusion, myoglobin and rebleeding within 4–5 days. However, the competing risk model showed that TB was the only significant risk factor for 6-week mortality. Further RCS analysis indicated that TB was a robust prognostic marker for 6-week mortality, with a cutoff value of 127.35 µmol/L, above which the risk of mortality increased substantially. Six weeks after AEGVB marks a key moment to assess patients’ prognosis. At this time point, the risk of death becomes similar to that of patients who have never experienced AEGVB[ 15 , 16 ]. Predicting short-term mortality and rebleeding is critical for guiding precision medicine in cirrhotic patients with AEGVB[ 3 ]. The 6-week mortality rate in our study, which was 7.93% and included cases of HCC, was markedly lower than 17.2% reported in recent study by Adam Buckholz et al [ 17 ]. This difference may be due to a relatively high proportion (10.71%) of patients who were lost to follow-up or discharged against medical advice from the emergency room. However, we used a 1:4 matching method to enroll patients for the final statistical analysis. This approach yielded a 6-week mortality rate of 20%, similar to previous reports, and helped reduce bias[ 5 ]. Previous studies demonstrated that the Child-Pugh score and MELD score could predict 6-week mortality rate with AUROCs of 0.72 and 0.74 respectively. However, both scores failed to predict rebleeding, with AUROCs less than 0.65. Rockall, Glasgow-Blatchford, and AIMS65 scores cannot be used to predict 6-week mortality rate and rebleeding(all AUROC < 0.7)[ 10 ]. Adam Buckholz et al found that all recalibrated MELD-based and CTP-based models had excellent discrimination in identifying patients at higher risk for 6-week mortality[ 17 ]. In addition, D-dimer/Albumin ratio (DAR) was proposed as a rapid prognostic marker for AEGVB in the emergency room. DAR > 450 was associated with a 26 fold increased risk of mortality compared to DAR ≤ 450༈95% CI: 3.054 to 225.827༉[ 18 ]. J Altamirano et al discovered a simple algorithm based on just three variables (albumin, bilirubin and in-hospital rebleeding) using Classification and Regression Tree analysis (CART analysis) to predict 6-week mortality rate in cirrhotic patients with AEGVB, which had an AUROC of 0.91[ 19 ]. In our study, we used cluster analysis to stratify patients into three groups, which was a novelty of our research. We identified 10 important variables for clustering. We found that cluster 0 group, the highest-risk group, had the highest rates of death, rebleeding and hemostasis failure within 5 days after admission. Furthermore, Kaplan-Meier analysis demonstrated that the 6-week mortality rate was significantly higher in cluster 0 group than in cluster 1 and 2 groups. Obviously, patients in cluster 0 group should receive more attention and active treatments in clinical practice. Therefore, cluster analysis is suggested for identifying high-risk AEGVB patients and implementing aggressive management strategies at an earlier time, which may help reduce mortality. A major innovation of our research lies in the identification of TB as a robust prognostic marker for short-term mortality in cirrhotic patients with AEGVB. Bilirubin is a key index of liver function, and its elevation reflects hepatocyte necrosis and metabolic dysfunction. Moreover, a high TB level specifically indicates end-stage liver cirrhosis, which strongly correlates with patient mortality and predicts poor outcomes[ 20 ]. It was reported that in Child-Pugh class C cirrhotic patients with esophageal/gastric varices, a bilirubin level ≥ 4.0 mg/dl was a risk factor for one-year mortality. This was observed after invasive treatments such as endoscopic therapy and balloon-occluded retrograde transvenous obliteration[ 9 ]. After treating gastric varices with balloon-occluded retrograde transvenous obliteration, the survival rate was significantly increased in patients who had a baseline TB level of less than 3.5mg/dl and had a one-year survival rate greater than 90%[ 21 ]. After treating AEGVB with EIS, a high TB level, as well as Child-Pugh score and albumin, were independently associated with 6-week mortality[ 22 ]. In Child-Pugh class C cirrhotic patients with AEGVB, higher bilirubin was one of the predictive parameters for 6-week survival[ 23 ]. Although the above studies have pointed out that TB level is associated with patient outcomes in cirrhotic patients with AEGVB, they did not further explore the specific contribution of TB to mortality prediction in cirrhotic patients experiencing AEGVB in real-world clinical settings. Interestingly, our findings established TB as a robust predictor. We identified a cutoff value of 127.35 µmol/L, beyond which the risk of death escalates significantly. This novel insight highlights the importance of routine TB monitoring to enable timely interventions for at-risk patients. These findings impact not only individual patient management but also clinical practice and policy formulation. Furthermore, by demonstrating that high TB levels correlate with increased mortality, this study suggests that early identification of patients with elevated TB may prompt more aggressive management strategies, including advanced therapies or earlier referrals for potential liver transplantation. Moreover, this research highlights standardized treatment protocols, such as vasoactive drugs and endoscopic interventions, which could be more widely adopted to improve patient outcomes and reduce the burden of AEGVB on healthcare systems, such as increased hospitalization rates and resource utilization. This aligns with current guidelines advocating for tailored treatment approaches based on individual risk profiles, which may ultimately lead to improved survival rates and quality of life for cirrhotic patients [ 2 ]. The limitations of this study primarily stem from its retrospective design. This design inherently introduces biases related to data collection and patient selection. Relying on electronic medical records may cause incomplete data and potential misclassification of outcomes. Additionally, without prospective external validation, the findings’ generalizability remains limited. The matched analysis helps control for confounding variables. However, it cannot entirely eliminate the risk of unmeasured confounding. Furthermore, the relatively short follow-up period of six weeks may not adequately capture significantly long-term outcomes associated with AEGVB. Future research should adopt prospective designs with larger sample sizes and longer follow-up periods. This approach will help validate the current findings and assess the long-term effects of elevated TB levels in cirrhotic patients. Additionally, exploring the mechanisms linking TB to mortality in AEGVB could provide insights for developing targeted therapies. Such therapies may reduce liver dysfunction and improve survival rates in this vulnerable population. Conclusions In conclusion, this research highlights a critical link between specific clinical and biochemical markers and short-term mortality in cirrhotic patients with AEGVB. Cluster analysis identifies distinct clinical profiles of AEGVB, which correspond to clinical subsets. These subsets can be useful for personalized clinical management and for predicting clinical outcomes. Identifying TB as a significant prognostic factor underscores its important role and potential utility in clinical decision-making. This study advances our understanding of mortality predictors and lays the groundwork for the development of targeted therapeutic interventions aimed at improving outcomes for this vulnerable patient population. Future research should validate these findings prospectively and explore the mechanisms behind the observed associations. Abbreviations AEGVB Acute esophagogastric variceal bleeding PVT Portal vein thrombosis DM Diabetes mellitus SD Standard deviation Hb Hemoglobin PLT Platelet PT Prothrombin time BUN Blood urea nitrogen TB Total bilirubin AST Aspartate transaminase ALT Alanine transferase APTT Activated partial thromboplastin time CK-MB Creatinine kinase-MB TnI Troponin I AFP Alpha-fetoprotein HCC Hepatocellular carcinoma RCS Restricted cubic spline INR International normalized ratio PTA Prothrombin time activity FIB Fibrinogen TT Thrombin time FDP Fibrinogen degradation products AT Antithrombin MELD Model for End-Stage Liver Disease CKD Chronic kidney disease Hct Hematocrit Cr Creatinine IQR Interquartile range Declarations Ethics approval and consent to participate: This study was approved by the Clinical Research Ethics Committee of Beijing You’an Hospital, Capital Medical University following the declaration of Helsinki (No. LL-2023-143-K). The clinical data used in this study were anonymous to protect patient confidentiality. The need for consent was waived by ethics committee for the retrospective nature of the study. Consent for publication: Not applicable. Availability of data and materials: The data associated with this study are available from the corresponding author upon reasonable request. Competing interests: The authors declared no potential competing interests with respect to the research, authorship, and/or publication of this article. Funding: The present study was supported by the funding from Scientific Research Project of You’an Hospital, CCMU, 2023 (grant No. BJYAYY-YN2023-07) . Authors’ contributions: Qi Li recorded patients’ information, analyzed and interpreted the patient data regarding liver cirrhosis and AEGVB, wrote the manuscript. Ruifeng Liu performed statistical design/analysis, interpreted the patient data and wrote the manuscript. Shenghui Zhou recorded patients’ information, collected patients’ follow-up. Lingna Lyu administrated this project, interpreted the data and reviewed the manuscript. Yanjing Wu collected patients’ follow-up and reviewed the manuscript. Chunlei Fan interpreted the data and reviewed the manuscript. Yuening Zhang interpreted the patient data, reviewed and edited the manuscript. Huiguo Ding conceived and supervised the project, and reviewed the manuscript. Acknowledgements: Not applicable. References Villanueva C TD, Bosch J.: Preventing the progression of cirrhosis to decompensation and death. Nat Rev Gastroenterol Hepatol 2025, 22 (4):265-280. Xu X TC, Linghu E, Ding H; Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Gastroenterology, Chinese Medical Association; Chinese Society of Digestive Endoscopy, Chinese Medical Association.: Guidelines for the Management of Esophagogastric Variceal Bleeding in Cirrhotic Portal Hypertension. J Clin Transl Hepatol 2023, 11 (7):1565-1579. Bambha K KW, Pedersen R, Bida JP, Kremers WK, Kamath PS.: Predictors of early re-bleeding and mortality after acute variceal haemorrhage in patients with cirrhosis. Gut 2008, 57 (6):814-820. Garcia-Tsao G SA, Grace ND, Carey W; Practice Guidelines Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology.: Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007, 46 (3):922-938. Garcia-Tsao G J, Berzigotti A, Bosch J.: Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology 2017, 65 (1):310-335. Jakab SS G-TG: Evaluation and Management of Esophageal and Gastric Varices in Patients with Cirrhosis. Clin Liver Dis 2020, 24 (3):335-350. Tantai XX LN, Yang LB, Wei ZC, Xiao CL, Song YH, Wang JH.: Prognostic value of risk scoring systems for cirrhotic patients with variceal bleeding. World J Gastroenterol 2019, 25 (45):6668-6680. Kawai T YY, Sugimoto T, Sato T, Kanda M, Enomoto N, Sato S, Obi S.: Emergency endoscopic variceal ligation following variceal rupture in patients with advanced hepatocellular carcinoma and portal vein tumor thrombosis: a retrospective study. World J Surg Oncol 2016, 14 :52. Yokoyama K YR, Shibata K, Fukuda H, Kunimoto H, Takata K, Tanaka T, Inomata S, Morihara D, Takeyama Y, Shakado S, Sakisaka S.: Endoscopic treatment or balloon-occluded retrograde transvenous obliteration is safe for patients with esophageal/gastric varices in Child-Pugh class C end-stage liver cirrhosis. Clin Mol Hepatol 2019, 25 (2):183-189. Carla Luiza de Souza Aluizio CGM, Glaucia Fernanda Soares Ruppert Reis, Cristiane Kibune Nagasako.: Risk stratification in acute variceal bleeding: Far from an ideal score. Clinics (Sao Paulo) 2021, 76 :e2921. Zhou J SH, Wang Z, Cong WM, Wang JH, Zeng MS, Yang JM, Bie P, Liu LX, Wen TF, Han GH, Wang MQ, Liu RB, Lu LG, Ren ZG, Chen MS, Zeng ZC, Liang P, Liang CH, Chen M, Yan FH, Wang WP, Ji Y, Cheng WW, Dai CL, Jia WD, Li YM, Li YX, Liang J, Liu TS, Lv GY, Mao YL, Ren WX, Shi HC, Wang WT, Wang XY, Xing BC, Xu JM, Yang JY, Yang YF, Ye SL, Yin ZY, Zhang BH, Zhang SJ, Zhou WP, Zhu JY, Liu R, Shi YH, Xiao YS, Dai Z, Teng GJ, Cai JQ, Wang WL, Dong JH, Li Q, Shen F, Qin SK, Fan J.: Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China (2017 Edition). Liver Cancer 2018, 7 (3):235-260. Xu XY DH, Li WG, Xu JH, Han Y, Jia JD, Wei L, Duan ZP, Ling-Hu EQ, Zhuang H.: Chinese guidelines on the management of liver cirrhosis (abbreviated version). World J Gastroenterol 2020, 26 (45):7088-7103. Fortune BE G-TG, Ciarleglio M, Deng YH, Fallon MB, Sigal S, Chalasani NP, Lim JK, Reuben A, Vargas HE, Abrams G, Lewis MD, Hassanein T, Trotter JF, Sanyal AJ, Beavers KL, Ganger D, Thuluvath PJ, Grace ND, Groszmann RJ; Vapreotide Study Group.: Child-Turcotte-Pugh Class is Best at Stratifying Risk in Variceal Hemorrhage: Analysis of a US Multicenter Prospective Study. J Clin Gastroenterol 2017, 51 (5):446-453. Raţiu I LR, Popescu A, Sporea I, Goldiş A, Dănilă M, Miuţescu B, Moga T, Barbulescu A, Şirli R.: Acute gastrointestinal bleeding: A comparison between variceal and nonvariceal gastrointestinal bleeding. Medicine (Baltimore) 2022, 101 (45):e31543. A. AM: Survival of patients with cirrhosis after acute variceal bleeding. Rev Esp Enferm Dig 2009, 101 (4):231-235. Matei D CD, Procopet B, Groza L, Furnea B, Levi C, Tantau M.: Predictive factors of failure to control bleeding and 6-week mortality after variceal hemorrhage in liver cirrhosis - a tertiary referral center experience. Arch Med Sci 2021, 18 (1):52-61. Buckholz A WR, Curry MP, Baffy G, Chak E, Rustagi T, Mohanty A, Fortune BE.: MELD, MELD 3.0, versus Child score to predict mortality after acute variceal hemorrhage: A multicenter US cohort. Hepatol Commun 2023, 7 (10):e0258. Seo JS KY, Lee YS, Chung HY, Kim TY.: Usefulness of the d-dimer to albumin ratio for risk assessment in patients with acute variceal bleeding at the emergency department: retrospective observational study. BMC Emerg Med 2022, 22 (1):135. Altamirano J ZL, Agustin S, Muntaner L, González-Angulo A, Ortiz AL, Degiau L, Garibay J, Camargo L, Genescà J.: Predicting 6-week mortality after acute variceal bleeding: role of Classification and Regression Tree analysis. Ann Hepatol 2009, 8 (4):308-315. Kim HJ LH, Cho JH.: Factor analysis of the biochemical markers related to liver cirrhosis. Pak J Med Sci 2015, 31 (5):1043-1046. Cho SK SS, Lee IH, Do YS, Choo SW, Park KB, Yoo BC.: Balloon-occluded retrograde transvenous obliteration of gastric varices: outcomes and complications in 49 patients. AJR Am J Roentgenol 2007, 189 (6):W365-372. Prindiville T MM, Trudeau W.: Prognostic indicators in acute variceal hemorrhage after treatment by schlerotherapy. Am J Gastroenterol 1987, 82 (7):655-659. Hori S TA, Okada H, Fujiwara A, Takenaka R, Makidono C, Shiratori Y.: Endoscopic therapy for bleeding esophageal varices improves the outcome of Child C cirrhotic patients. J Gastroenterol Hepatol 2006, 21 (11):1704-1709. Tables Tables 1 to 4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7262310","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":507751566,"identity":"b5729991-6206-4a8f-b41c-6d6d7d476cc9","order_by":0,"name":"Qi Li","email":"","orcid":"","institution":"Beijing You’an Hospital Affiliated with Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qi","middleName":"","lastName":"Li","suffix":""},{"id":507751567,"identity":"0a0ebe01-b46e-408b-b399-dbd6c9d1a302","order_by":1,"name":"Ruifeng Liu","email":"","orcid":"","institution":"Beijing Friendship Hospital Affiliated with Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ruifeng","middleName":"","lastName":"Liu","suffix":""},{"id":507751568,"identity":"2a25c049-4a30-4739-833b-865a02a70bed","order_by":2,"name":"Shenghui Zhou","email":"","orcid":"","institution":"Beijing You’an Hospital Affiliated with Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shenghui","middleName":"","lastName":"Zhou","suffix":""},{"id":507751569,"identity":"9aa983d7-dbef-4cb8-8a4b-d5e9ae0e28a6","order_by":3,"name":"Lingna Lyu","email":"","orcid":"","institution":"Beijing You’an Hospital Affiliated with Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lingna","middleName":"","lastName":"Lyu","suffix":""},{"id":507751570,"identity":"5404b6a6-8044-4a4b-a68e-0d3ff3f9d246","order_by":4,"name":"Yanjing Wu","email":"","orcid":"","institution":"Beijing You’an Hospital Affiliated with Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yanjing","middleName":"","lastName":"Wu","suffix":""},{"id":507751571,"identity":"5d23c58b-995f-46a4-abad-0354408cc5ad","order_by":5,"name":"Chunlei Fan","email":"","orcid":"","institution":"Beijing You’an Hospital Affiliated with Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chunlei","middleName":"","lastName":"Fan","suffix":""},{"id":507751572,"identity":"5e1d48ef-2d2e-4abf-9304-da07b797e148","order_by":6,"name":"Yuening Zhang","email":"","orcid":"","institution":"Beijing You’an Hospital Affiliated with Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuening","middleName":"","lastName":"Zhang","suffix":""},{"id":507751573,"identity":"06b9bd69-8692-4210-9720-058924d9adc3","order_by":7,"name":"Huiguo 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12:38:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7262310/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7262310/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90465613,"identity":"a2e1af73-3a58-4749-be10-c53a82e8021e","added_by":"auto","created_at":"2025-09-03 05:31:27","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":199885,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic diagram of patient selection procedure\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7262310/v1/184e285ce98b6350aee80639.jpg"},{"id":90465051,"identity":"387f67ce-df97-407e-b002-f5b8c6c23c91","added_by":"auto","created_at":"2025-09-03 05:13:21","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":64933,"visible":true,"origin":"","legend":"\u003cp\u003eTop 10 important variables for clustering\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7262310/v1/41c0f53f6d7d370334f230c3.png"},{"id":90465058,"identity":"749622c6-89d8-47c9-970e-e9b534944449","added_by":"auto","created_at":"2025-09-03 05:13:21","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":75238,"visible":true,"origin":"","legend":"\u003cp\u003eK-means clustering results (PCA reduced)\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7262310/v1/51d489e29d9b344ae0f293fd.png"},{"id":90465064,"identity":"2197c6a7-e237-49e6-81e0-400b291f661b","added_by":"auto","created_at":"2025-09-03 05:13:22","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":79426,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier survival curves by cluster\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7262310/v1/9395557f5c87660b4c946553.png"},{"id":90465578,"identity":"886ef13f-b2e9-4f56-8d0d-95f98224bcb7","added_by":"auto","created_at":"2025-09-03 05:31:27","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":48360,"visible":true,"origin":"","legend":"\u003cp\u003eCompeting Risk Model Analysis for 6-week mortality in cirrhotic patients with AEGVB\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7262310/v1/bc7a29f38e8c414a77a9d9aa.png"},{"id":90465063,"identity":"88741bdf-3576-4c4b-b037-280a835103b9","added_by":"auto","created_at":"2025-09-03 05:13:22","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":49552,"visible":true,"origin":"","legend":"\u003cp\u003eTB predicting 6-week death by RCS analysis\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7262310/v1/620e2ec95ad1ac7b334c77c5.png"},{"id":91335690,"identity":"b6ddca19-314b-4487-896d-1c1ec2f47ff0","added_by":"auto","created_at":"2025-09-15 11:54:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2304801,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7262310/v1/c841737f-5d3e-4f24-bf91-d2bc8a243b66.pdf"},{"id":90465052,"identity":"e8025739-291e-4903-b5e6-b43cd5f2a19c","added_by":"auto","created_at":"2025-09-03 05:13:21","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":41037,"visible":true,"origin":"","legend":"","description":"","filename":"tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-7262310/v1/becb03aef4ca0ca5a4bea980.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Total bilirubin serves as a robust predictor of 6-week mortality in patients with liver cirrhosis and acute esophagogastric variceal bleeding","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcute esophagogastric variceal bleeding (AEGVB) is a critical complication of liver cirrhosis, primarily driven by portal hypertension[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Current treatment approaches include endoscopic interventions and pharmacological therapies. Pharmacological therapies involve vasoactive drugs and antibiotics, which aim to stabilize patients and prevent rebleeding[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This condition represents a significant clinical challenge due to its potential to cause life-threatening hemorrhage, which contributes to a 15%-25% mortality within 6 weeks[\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e–\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The economic burden of this condition on healthcare systems is substantial, necessitating extensive hospitalization and intensive management efforts[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eResearch has identified several clinical and laboratory parameters that correlate with outcomes in patients experiencing AEGVB. Among them, the Child-Pugh score and MELD score have emerged as key factors potentially linked to mortality and disease progression[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The median survival time was shorter in Child-Pugh B/C patients with AEGVB, and Child-Pugh grade was a predictor of survival[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Moreover, the 5-year survival was only 15.1% in Child-Pugh C patients who received endoscopic treatment or balloon-occluded retrograde transvenous obliteration[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The Child-Pugh score and MELD score had similar efficacy to predict short-term mortality in patients with AEGVB (AUROC = 0.72 \u003cem\u003evs.\u003c/em\u003e 0.74)[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. General statistical analysis has shown that both scores predict 6-week mortality in cirrhotic patients with AEGVB. In this current study, we aim to identify more robust factors associated with 6-week mortality beyond the Child-Pugh score and MELD score in cirrhotic patients with AEGVB by performing advanced statistical analysis. This may contribute to developing improved management strategies and clinical protocols for patients suffering from AEGVB.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cb\u003eStudy cohort\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis retrospective single-center study used patient information from a previous cohort. The cohort included patients over 18 years old with acute gastrointestinal bleeding (AGIB) who were admitted to the Emergency Room at Beijing You’an Hospital, Capital Medical University, from April 1st 2021 to Sep 30th 2022. For patients with multiple admissions due to AGIB during the study period, only their first admission was considered. Only patients with liver cirrhosis were included for data analysis. Patients were excluded if they met any of the following criteria: i) discharged against medical advice in the Emergency Room; ii) did not receive endoscopy within 6 months prior to admission and refused endoscopy after admission; iii) had non-variceal bleeding; iv) were lost to follow-up; v) had malignancies other than hepatocellular carcinoma (HCC); vi) had malignant portal vein thrombosis (PVT); or vii) had unidentified malignant PVT. Ultimately, 656 cirrhotic patients with AEGVB who met the inclusion/exclusion criteria were included and followed up for 6 weeks. The primary endpoint was 6-week mortality. Secondary endpoints included in-hospital mortality, mortality at 72 hours and 5 days, as well as rebleeding events within 72 hours, between 4 and 5 days and up to 6 weeks.\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical, laboratory, and radiological parameters\u003c/b\u003e\u003c/p\u003e\u003cp\u003eLiver cirrhosis was diagnosed based on the medical history, physical examination, laboratory tests, imaging studies, and liver biopsy. AEGVB was defined as clinical signs of bleeding (haematemesis, melena or hematochezia) originating from the gastrointestinal tract and confirmed by endoscopy showing esophagogastric varices within the preceding 6 months. HCC was diagnosed based on historical data, pathology or imaging studies such as computed tomography and/or magnetic resonance imaging[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. We recorded the following clinical parameters: shock index, etiology of cirrhosis, underlying diseases, grades of ascites, stages of hepatic encephalopathy, Child-Pugh score/class. Outcomes included in-hospital mortality, 6-week mortality, 6-week rebleeding, death within 72 hours, rebleeding within 72 hours, hemostasis failure within 72 hours, death within 4–5 days, rebleeding within 4–5 days, hemostasis failure within 4–5 days, death within 5 days, rebleeding within 5 days, hemostasis failure within 5 days. Other variables included history of endoscopic therapy, history of splenectomy, active bleeding during endoscopy, time from admission to endoscopy, time from bleeding to admission, use of Sengstaken-Blakemore tube during hospitalization, transfusions of red blood cells, platelets and plasma. The following laboratory parameters were included: hemoglobin (Hb), hematocrit (Hct), platelet count (PLT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cr), total bilirubin (TB), albumin, prothrombin time (PT), blood urea nitrogen (BUN), creatinine kinase-MB (CK-MB), troponin I (TnI), myoglobin, activated partial thromboplastin time (APTT), international normalized ratio (INR), prothrombin time activity (PTA), fibrinogen (FIB), thrombin time (TT), D-dimer, fibrinogen degradation products (FDP) and antithrombin (AT). Child-Pugh classes were estimated based on the degree of hepatic encephalopathy, ascites, TB, albumin, and PT. Grade of ascites and stages of hepatic encephalopathy were diagnosed according to the criteria by Chinese Society of Hepatology, Chinese Medical Association[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003eTreatment received\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAll enrolled patients received treatments including antibiotics, vasoactive drugs (octreotide or terlipressin) and proton pump inhibitors. For patients with AEGVB, some received treatment with a Sengstaken-Blakemore tube and/or endoscopic therapies such as endoscopic variceal ligation (EVL), gastric variceal ligation, endoscopic injection sclerotherapy (EIS) or tissue adhesive injection for gastric varices, depending on the patients’ clinical condition.\u003c/p\u003e\u003cp\u003e\u003cb\u003eEthics\u003c/b\u003e\u003c/p\u003e\u003cp\u003e This study was approved by the Clinical Research Ethics Committee of Beijing You’an Hospital, Capital Medical University, following the Declaration of Helsinki (No. LL-2023-143-K). The clinical data in this study were anonymized prior to analysis. The Clinical Research Ethics Committee waived the need for consent due to the retrospective nature of the study.\u003c/p\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eQuantitative variables were expressed as median and interquartile range (IQR), and differences between groups were compared using Student’s t-test. Qualitative variables were presented as frequencies and percentages, and the Chi-square test was used to compare differences. Non-parametric tests were performed when variables did not meet the normality assumption. A 1:4 matched analysis was conducted to adjust for the effect of admission time alone on our statistical results. Cluster analysis was used to identify distinct profiles of AEGVB that formed clinical subsets with similar characteristics. Kaplan-Meier survival analysis was performed to display overall survival over six weeks among the three clustered groups. Univariable and multivariable Cox regression analyses were used to investigate predictors of 6-week mortality for cirrhotic patients with AEGVB. The competing risk models were used to identify robust predictors of six-week mortality. The prognostic value of TB levels was determined by restricted cubic spline (RCS) analysis. A \u003cem\u003eP\u003c/em\u003e value less than 0.05 was considered statistically significant. All statistical analyses were performed with R software version 4.2.1 (R Foundation for Statistical Computing, Vienna, Austria).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eCharacteristics of cirrhotic patients with AEGVB who died within 6 weeks after admission compared with survivors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 1901 electronic records of patients with emergent acute gastrointestinal bleeding were reviewed. After excluding multiple admissions and applying inclusion/exclusion criteria, we enrolled 656 cirrhotic patients with AEGVB who were followed up for 6 weeks (Figure 1). These patients were divided into the 6-week death group and the survivor group. A total of 52 patients died within 6 weeks and were classified as the 6-week death group. Six-week mortality was 7.93%. A 1:4 matched analysis was performed to adjust for the effect of admission time on the comparison between the two groups. Therefore, 208 patients who survived beyond 6 weeks comprised the survivor group. Finally, only 260 patients were included in the data analysis. The demographic and clinical characteristics of cirrhotic patients with AEGVB were shown in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe patients who died within 6 weeks after admission were older than the survivors (60.71\u0026plusmn;11.15 \u003cem\u003evs.\u0026nbsp;\u003c/em\u003e56.93\u0026plusmn;11.36, \u003cem\u003eP\u003c/em\u003e=0.032). Compared with the survivors, patients who died presented with higher levels of shock index and Child-Pugh score. The death group exhibited a significantly higher incidence of liver failure and HCC. Regarding laboratory parameters, patients who died had higher levels of TB, PT, APTT, INR, TT, D-dimer, FDP, PLT, BUN, Cr, ALT, AST, myoglobin, and TnI, and lower levels of albumin, PTA, AT%, Hb, Hct. A higher proportion of patients who died had active bleeding during endoscopy and were treated with a Sengstaken-Blakemore tube. A significantly higher proportion of patients in the 6-week death group experienced death within 72 hours, rebleeding within 72 hours, hemostasis failure within 72 hours, death within 4-5 days, rebleeding within 4-5 days, hemostasis failure within 4-5 days, death within 5 days, rebleeding within 5 days and hemostasis failure within 5 days compared to the survivor group. Furthermore, patients in 6-week death group received more red blood cell transfusions and plasma transfusions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical characteristics of cirrhotic patients with AEGVB by cluster analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo identify cirrhotic patients with AEGVB who had similar clinical characteristics, we performed cluster analysis. Figure 2 showed the top 10 important variables for clustering, which were D-dimer, plasma transfusion, AST, myoglobin, ALT, time from admission to endoscopy, TB, PLT, time from bleeding to admission and PTA. All 260 patients of cirrhotic AEGVB were divided into three clusters based on the above 10 important factors (Figure 3). Table 2 presents the clinical characteristics of cirrhotic patients with AEGVB after clustering.\u003c/p\u003e\n\u003cp\u003eAmong the three clustered groups, cluster 0 group had the highest rates of in-hospital death, as well as death, rebleeding and hemostasis failure within 72 hours, 4-5 days and 5 days. Furthermore, patients in cluster 0 group more frequently had a history of splenectomy and use of the Sengstaken-Blakemore tube. They also had shorter times from bleeding to admission and from admission to endoscopy, more active bleeding during endoscopy, and higher rates of red blood cell and plasma transfusions (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001). Kaplan-Meier analysis showed that the 6-week mortality rate was significantly higher in cluster 0 group than in clusters 1 and 2, while cluster 1 had the highest survival rate (long-rank test, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05) (Figure 4).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUnivariate and stepwise multivariate Cox regression analysis of 6-week mortality in cirrhotic patients with AEGVB\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results of univariate and multivariate Cox regression analysis were presented in Table 3. Independent predictors of 6-week mortality included 6-week rebleeding (HR, 21.904; 95% CI, 8.446 to56.805; \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), rebleeding within 72h (HR, 16.767; 95% CI, 6.309 to 44.556; \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), rebleeding within 4-5 days (HR, 10.137; 95% CI, 2.338 to 43.945; \u003cem\u003eP\u003c/em\u003e=0.002), TB (HR, 1.011; 95% CI, 1.007 to 1.014; \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), CK-MB (HR, 1.256; 95% CI, 1.115 to 1.415; \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), BUN (HR, 1.103; 95% CI, 1.030 to 1.182; \u003cem\u003eP=\u003c/em\u003e0.005), red blood cell transfusion (HR, 0.866; 95% CI, 0.793 to 0.947; \u003cem\u003eP\u003c/em\u003e=0.002), myoglobin (HR, 0.997; 95% CI, 0.995 to 0.999; \u003cem\u003eP\u003c/em\u003e=0.003).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting risk model analysis for 6-week mortality in cirrhotic patients with AEGVB\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn some cirrhotic patients, AEGVB may cause death. Therefore, bleeding and death compete as outcomes. Next, we performed competing risk model analysis to identify the most robust predictors independently associated with 6-week death in cirrhotic patients with AEGVB. The competing risk model demonstrated that TB was the only significant risk factor with HR=1.43 and 95% CI of 1.100 to1.860 (\u003cem\u003eP\u003c/em\u003e=0.008), indicating that a one-unit increase in TB (mg/dl) increased risk of death by 43% (Table 4). The cumulative incidence curves showed that 6-week rebleeding mainly occurred at an early stage, while the cumulative incidence of death increased more gradually. The pie chart demonstrated that within 6 weeks after AEGVB, the majority of the patients (63.1%) experienced no events, 31.9% died and only 5.0% rebled. The boxplot further indicated that patients in the 6-week death group had a higher and more widely distributed TB values. In contrast, patients in the no event group and the 6-week rebleeding group showed lower and more concentrated TB distributions (Figure 5). These results suggested that TB could serve as a robust predictor to assess short-term mortality risk for cirrhotic patients with AEGVB.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrognostic evaluation of TB for 6-week mortality in cirrhotic patients with AEGVB by RCS analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSince TB was the most robust predictor for 6-week mortality in cirrhotic patients with AEGVB, we further investigated the relationship between TB and the risk of death within 6 weeks by applying RCS analysis. The overall goodness-of-fit test of the RCS model showed a \u003cem\u003eP\u003c/em\u003e value \u0026lt;0.001, indicating a significant association between TB and the risk of death within 6 weeks. The \u003cem\u003eP\u003c/em\u003e value of the nonlinear test was 0.2576, suggesting a linear relationship between TB and 6-week mortality. Using an OR of 1 as the cutoff, the threshold of TB value was determined to be 127.35\u0026mu;mol/L. If TB level was higher than 127.35\u0026mu;mol/L, the risk of death within 6 weeks was higher than the reference level. If TB was below this value, the risk of death was relatively low. The sensitivity of this cut-off value was 26.90% and specificity was 97.10%. The positive predictive value was 70.00% and the negative predictive value was 84.20%.\u003c/p\u003e\n\u003cp\u003eIn Figure 6, the upper graph showed a smooth curve, while the lower graph displayed a RCS curve. Both graphs reflected the trend of changes in TB levels and the risk of death within 6 weeks. The smooth curve used the probability of death within 6 weeks as the ordinate, which intuitively demonstrated the overall distribution and trend of the actual death probability at different TB levels. The RCS curve used OR as the vertical ordinate, reflecting how the risk of death within 6 weeks changed with increasing or decreasing TB levels.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eUnderstanding AEGVB in patients with liver cirrhosis is paramount because it significantly affects patient morbidity and mortality[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The management of AEGVB primarily involves endoscopic interventions and pharmacological therapies. However, challenges in predicting outcomes and managing complications remain, highlighting the need for continued research in this area[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In light of these challenges, the present study addresses the clinical and laboratory characteristics of cirrhotic patients experiencing AEGVB, with a specific focus on identifying prognostic factors associated with 6-week mortality. Cox regression analysis revealed that the 6-week mortality was independently associated with 6-week rebleeding, CK-MB, BUN, red blood cell transfusion, myoglobin and rebleeding within 4\u0026ndash;5 days. However, the competing risk model showed that TB was the only significant risk factor for 6-week mortality. Further RCS analysis indicated that TB was a robust prognostic marker for 6-week mortality, with a cutoff value of 127.35 \u0026micro;mol/L, above which the risk of mortality increased substantially.\u003c/p\u003e\u003cp\u003eSix weeks after AEGVB marks a key moment to assess patients\u0026rsquo; prognosis. At this time point, the risk of death becomes similar to that of patients who have never experienced AEGVB[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Predicting short-term mortality and rebleeding is critical for guiding precision medicine in cirrhotic patients with AEGVB[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The 6-week mortality rate in our study, which was 7.93% and included cases of HCC, was markedly lower than 17.2% reported in recent study by Adam Buckholz \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This difference may be due to a relatively high proportion (10.71%) of patients who were lost to follow-up or discharged against medical advice from the emergency room. However, we used a 1:4 matching method to enroll patients for the final statistical analysis. This approach yielded a 6-week mortality rate of 20%, similar to previous reports, and helped reduce bias[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePrevious studies demonstrated that the Child-Pugh score and MELD score could predict 6-week mortality rate with AUROCs of 0.72 and 0.74 respectively. However, both scores failed to predict rebleeding, with AUROCs less than 0.65. Rockall, Glasgow-Blatchford, and AIMS65 scores cannot be used to predict 6-week mortality rate and rebleeding(all AUROC\u0026thinsp;\u0026lt;\u0026thinsp;0.7)[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Adam Buckholz \u003cem\u003eet al\u003c/em\u003e found that all recalibrated MELD-based and CTP-based models had excellent discrimination in identifying patients at higher risk for 6-week mortality[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In addition, D-dimer/Albumin ratio (DAR) was proposed as a rapid prognostic marker for AEGVB in the emergency room. DAR\u0026thinsp;\u0026gt;\u0026thinsp;450 was associated with a 26 fold increased risk of mortality compared to DAR\u0026thinsp;\u0026le;\u0026thinsp;450༈95% CI: 3.054 to 225.827༉[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. J Altamirano \u003cem\u003eet al\u003c/em\u003e discovered a simple algorithm based on just three variables (albumin, bilirubin and in-hospital rebleeding) using Classification and Regression Tree analysis (CART analysis) to predict 6-week mortality rate in cirrhotic patients with AEGVB, which had an AUROC of 0.91[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In our study, we used cluster analysis to stratify patients into three groups, which was a novelty of our research. We identified 10 important variables for clustering. We found that cluster 0 group, the highest-risk group, had the highest rates of death, rebleeding and hemostasis failure within 5 days after admission. Furthermore, Kaplan-Meier analysis demonstrated that the 6-week mortality rate was significantly higher in cluster 0 group than in cluster 1 and 2 groups. Obviously, patients in cluster 0 group should receive more attention and active treatments in clinical practice. Therefore, cluster analysis is suggested for identifying high-risk AEGVB patients and implementing aggressive management strategies at an earlier time, which may help reduce mortality.\u003c/p\u003e\u003cp\u003eA major innovation of our research lies in the identification of TB as a robust prognostic marker for short-term mortality in cirrhotic patients with AEGVB. Bilirubin is a key index of liver function, and its elevation reflects hepatocyte necrosis and metabolic dysfunction. Moreover, a high TB level specifically indicates end-stage liver cirrhosis, which strongly correlates with patient mortality and predicts poor outcomes[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. It was reported that in Child-Pugh class C cirrhotic patients with esophageal/gastric varices, a bilirubin level\u0026thinsp;\u0026ge;\u0026thinsp;4.0 mg/dl was a risk factor for one-year mortality. This was observed after invasive treatments such as endoscopic therapy and balloon-occluded retrograde transvenous obliteration[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. After treating gastric varices with balloon-occluded retrograde transvenous obliteration, the survival rate was significantly increased in patients who had a baseline TB level of less than 3.5mg/dl and had a one-year survival rate greater than 90%[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. After treating AEGVB with EIS, a high TB level, as well as Child-Pugh score and albumin, were independently associated with 6-week mortality[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In Child-Pugh class C cirrhotic patients with AEGVB, higher bilirubin was one of the predictive parameters for 6-week survival[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Although the above studies have pointed out that TB level is associated with patient outcomes in cirrhotic patients with AEGVB, they did not further explore the specific contribution of TB to mortality prediction in cirrhotic patients experiencing AEGVB in real-world clinical settings.\u003c/p\u003e\u003cp\u003eInterestingly, our findings established TB as a robust predictor. We identified a cutoff value of 127.35 \u0026micro;mol/L, beyond which the risk of death escalates significantly. This novel insight highlights the importance of routine TB monitoring to enable timely interventions for at-risk patients. These findings impact not only individual patient management but also clinical practice and policy formulation. Furthermore, by demonstrating that high TB levels correlate with increased mortality, this study suggests that early identification of patients with elevated TB may prompt more aggressive management strategies, including advanced therapies or earlier referrals for potential liver transplantation. Moreover, this research highlights standardized treatment protocols, such as vasoactive drugs and endoscopic interventions, which could be more widely adopted to improve patient outcomes and reduce the burden of AEGVB on healthcare systems, such as increased hospitalization rates and resource utilization. This aligns with current guidelines advocating for tailored treatment approaches based on individual risk profiles, which may ultimately lead to improved survival rates and quality of life for cirrhotic patients [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe limitations of this study primarily stem from its retrospective design. This design inherently introduces biases related to data collection and patient selection. Relying on electronic medical records may cause incomplete data and potential misclassification of outcomes. Additionally, without prospective external validation, the findings\u0026rsquo; generalizability remains limited. The matched analysis helps control for confounding variables. However, it cannot entirely eliminate the risk of unmeasured confounding. Furthermore, the relatively short follow-up period of six weeks may not adequately capture significantly long-term outcomes associated with AEGVB. Future research should adopt prospective designs with larger sample sizes and longer follow-up periods. This approach will help validate the current findings and assess the long-term effects of elevated TB levels in cirrhotic patients. Additionally, exploring the mechanisms linking TB to mortality in AEGVB could provide insights for developing targeted therapies. Such therapies may reduce liver dysfunction and improve survival rates in this vulnerable population.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, this research highlights a critical link between specific clinical and biochemical markers and short-term mortality in cirrhotic patients with AEGVB. Cluster analysis identifies distinct clinical profiles of AEGVB, which correspond to clinical subsets. These subsets can be useful for personalized clinical management and for predicting clinical outcomes. Identifying TB as a significant prognostic factor underscores its important role and potential utility in clinical decision-making. This study advances our understanding of mortality predictors and lays the groundwork for the development of targeted therapeutic interventions aimed at improving outcomes for this vulnerable patient population. Future research should validate these findings prospectively and explore the mechanisms behind the observed associations.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAEGVB\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAcute esophagogastric variceal bleeding\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePVT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePortal vein thrombosis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDM\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDiabetes mellitus\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eStandard deviation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHb\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHemoglobin\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePLT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePlatelet\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eProthrombin time\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBUN\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eBlood urea nitrogen\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTB\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTotal bilirubin\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAST\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAspartate transaminase\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eALT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAlanine transferase\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAPTT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eActivated partial thromboplastin time\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCK-MB\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCreatinine kinase-MB\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTnI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTroponin I\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAFP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAlpha-fetoprotein\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHCC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHepatocellular carcinoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRCS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRestricted cubic spline\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eINR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInternational normalized ratio\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePTA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eProthrombin time activity\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFIB\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eFibrinogen\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eThrombin time\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFDP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eFibrinogen degradation products\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAntithrombin\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMELD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eModel for End-Stage Liver Disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCKD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eChronic kidney disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHct\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHematocrit\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCr\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCreatinine\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInterquartile range\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e This study was approved by the Clinical Research Ethics Committee of Beijing You\u0026rsquo;an Hospital, Capital Medical University following the declaration of Helsinki (No. LL-2023-143-K). The clinical data used in this study were anonymous to protect patient confidentiality.\u0026nbsp;The need for consent was waived by ethics committee for the retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eThe data associated with this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declared no potential competing interests with respect to the research, authorship, and/or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThe present study was supported by the funding from Scientific Research Project of You\u0026rsquo;an Hospital, CCMU, 2023 (grant No. BJYAYY-YN2023-07) .\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u0026nbsp;\u003c/strong\u003eQi Li recorded patients\u0026rsquo; information, analyzed and interpreted the patient data regarding liver cirrhosis and AEGVB, wrote the manuscript. Ruifeng Liu performed statistical design/analysis, interpreted the patient data and wrote the manuscript. Shenghui Zhou recorded patients\u0026rsquo; information, collected patients\u0026rsquo; follow-up. Lingna Lyu administrated this project, interpreted the data and reviewed the manuscript. Yanjing Wu collected patients\u0026rsquo; follow-up and reviewed the manuscript. Chunlei Fan interpreted the data and reviewed the manuscript. Yuening Zhang interpreted the patient data, reviewed and edited the manuscript. Huiguo Ding conceived and supervised the project, and reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eVillanueva C TD, Bosch J.: \u003cstrong\u003ePreventing the progression of cirrhosis to decompensation and death.\u003c/strong\u003e \u003cem\u003eNat Rev Gastroenterol Hepatol \u003c/em\u003e2025, \u003cstrong\u003e22\u003c/strong\u003e(4):265-280.\u003c/li\u003e\n\u003cli\u003eXu X TC, Linghu E, Ding H; Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Gastroenterology, Chinese Medical Association; Chinese Society of Digestive Endoscopy, Chinese Medical Association.: \u003cstrong\u003eGuidelines for the Management of Esophagogastric Variceal Bleeding in Cirrhotic Portal Hypertension.\u003c/strong\u003e \u003cem\u003eJ Clin Transl Hepatol \u003c/em\u003e2023, \u003cstrong\u003e11\u003c/strong\u003e(7):1565-1579.\u003c/li\u003e\n\u003cli\u003eBambha K KW, Pedersen R, Bida JP, Kremers WK, Kamath PS.: \u003cstrong\u003ePredictors of early re-bleeding and mortality after acute variceal haemorrhage in patients with cirrhosis.\u003c/strong\u003e \u003cem\u003eGut \u003c/em\u003e2008, \u003cstrong\u003e57\u003c/strong\u003e(6):814-820.\u003c/li\u003e\n\u003cli\u003eGarcia-Tsao G SA, Grace ND, Carey W; Practice Guidelines Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology.: \u003cstrong\u003ePrevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis.\u003c/strong\u003e \u003cem\u003eHepatology \u003c/em\u003e2007, \u003cstrong\u003e46\u003c/strong\u003e(3):922-938.\u003c/li\u003e\n\u003cli\u003eGarcia-Tsao G J, Berzigotti A, Bosch J.: \u003cstrong\u003ePortal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.\u003c/strong\u003e \u003cem\u003eHepatology \u003c/em\u003e2017, \u003cstrong\u003e65\u003c/strong\u003e(1):310-335.\u003c/li\u003e\n\u003cli\u003eJakab SS G-TG: \u003cstrong\u003eEvaluation and Management of Esophageal and Gastric Varices in Patients with Cirrhosis.\u003c/strong\u003e \u003cem\u003eClin Liver Dis \u003c/em\u003e2020, \u003cstrong\u003e24\u003c/strong\u003e(3):335-350.\u003c/li\u003e\n\u003cli\u003eTantai XX LN, Yang LB, Wei ZC, Xiao CL, Song YH, Wang JH.: \u003cstrong\u003ePrognostic value of risk scoring systems for cirrhotic patients with variceal bleeding.\u003c/strong\u003e \u003cem\u003eWorld J Gastroenterol \u003c/em\u003e2019, \u003cstrong\u003e25\u003c/strong\u003e(45):6668-6680.\u003c/li\u003e\n\u003cli\u003eKawai T YY, Sugimoto T, Sato T, Kanda M, Enomoto N, Sato S, Obi S.: \u003cstrong\u003eEmergency endoscopic variceal ligation following variceal rupture in patients with advanced hepatocellular carcinoma and portal vein tumor thrombosis: a retrospective study.\u003c/strong\u003e \u003cem\u003eWorld J Surg Oncol \u003c/em\u003e2016, \u003cstrong\u003e14\u003c/strong\u003e:52.\u003c/li\u003e\n\u003cli\u003eYokoyama K YR, Shibata K, Fukuda H, Kunimoto H, Takata K, Tanaka T, Inomata S, Morihara D, Takeyama Y, Shakado S, Sakisaka S.: \u003cstrong\u003eEndoscopic treatment or balloon-occluded retrograde transvenous obliteration is safe for patients with esophageal/gastric varices in Child-Pugh class C end-stage liver cirrhosis.\u003c/strong\u003e \u003cem\u003eClin Mol Hepatol \u003c/em\u003e2019, \u003cstrong\u003e25\u003c/strong\u003e(2):183-189.\u003c/li\u003e\n\u003cli\u003eCarla Luiza de Souza Aluizio CGM, Glaucia Fernanda Soares Ruppert Reis, Cristiane Kibune Nagasako.: \u003cstrong\u003eRisk stratification in acute variceal bleeding: Far from an ideal score.\u003c/strong\u003e \u003cem\u003eClinics (Sao Paulo) \u003c/em\u003e2021, \u003cstrong\u003e76\u003c/strong\u003e:e2921.\u003c/li\u003e\n\u003cli\u003eZhou J SH, Wang Z, Cong WM, Wang JH, Zeng MS, Yang JM, Bie P, Liu LX, Wen TF, Han GH, Wang MQ, Liu RB, Lu LG, Ren ZG, Chen MS, Zeng ZC, Liang P, Liang CH, Chen M, Yan FH, Wang WP, Ji Y, Cheng WW, Dai CL, Jia WD, Li YM, Li YX, Liang J, Liu TS, Lv GY, Mao YL, Ren WX, Shi HC, Wang WT, Wang XY, Xing BC, Xu JM, Yang JY, Yang YF, Ye SL, Yin ZY, Zhang BH, Zhang SJ, Zhou WP, Zhu JY, Liu R, Shi YH, Xiao YS, Dai Z, Teng GJ, Cai JQ, Wang WL, Dong JH, Li Q, Shen F, Qin SK, Fan J.: \u003cstrong\u003eGuidelines for Diagnosis and Treatment of Primary Liver Cancer in China (2017 Edition).\u003c/strong\u003e \u003cem\u003eLiver Cancer \u003c/em\u003e2018, \u003cstrong\u003e7\u003c/strong\u003e(3):235-260.\u003c/li\u003e\n\u003cli\u003eXu XY DH, Li WG, Xu JH, Han Y, Jia JD, Wei L, Duan ZP, Ling-Hu EQ, Zhuang H.: \u003cstrong\u003eChinese guidelines on the management of liver cirrhosis (abbreviated version).\u003c/strong\u003e \u003cem\u003eWorld J Gastroenterol \u003c/em\u003e2020, \u003cstrong\u003e26\u003c/strong\u003e(45):7088-7103.\u003c/li\u003e\n\u003cli\u003eFortune BE G-TG, Ciarleglio M, Deng YH, Fallon MB, Sigal S, Chalasani NP, Lim JK, Reuben A, Vargas HE, Abrams G, Lewis MD, Hassanein T, Trotter JF, Sanyal AJ, Beavers KL, Ganger D, Thuluvath PJ, Grace ND, Groszmann RJ; Vapreotide Study Group.: \u003cstrong\u003eChild-Turcotte-Pugh Class is Best at Stratifying Risk in Variceal Hemorrhage: Analysis of a US Multicenter Prospective Study.\u003c/strong\u003e \u003cem\u003eJ Clin Gastroenterol \u003c/em\u003e2017, \u003cstrong\u003e51\u003c/strong\u003e(5):446-453.\u003c/li\u003e\n\u003cli\u003eRaţiu I LR, Popescu A, Sporea I, Goldiş A, Dănilă M, Miuţescu B, Moga T, Barbulescu A, Şirli R.: \u003cstrong\u003eAcute gastrointestinal bleeding: A comparison between variceal and nonvariceal gastrointestinal bleeding.\u003c/strong\u003e \u003cem\u003eMedicine (Baltimore) \u003c/em\u003e2022, \u003cstrong\u003e101\u003c/strong\u003e(45):e31543.\u003c/li\u003e\n\u003cli\u003eA. AM: \u003cstrong\u003eSurvival of patients with cirrhosis after acute variceal bleeding.\u003c/strong\u003e \u003cem\u003eRev Esp Enferm Dig \u003c/em\u003e2009, \u003cstrong\u003e101\u003c/strong\u003e(4):231-235.\u003c/li\u003e\n\u003cli\u003eMatei D CD, Procopet B, Groza L, Furnea B, Levi C, Tantau M.: \u003cstrong\u003ePredictive factors of failure to control bleeding and 6-week mortality after variceal hemorrhage in liver cirrhosis - a tertiary referral center experience.\u003c/strong\u003e \u003cem\u003eArch Med Sci \u003c/em\u003e2021, \u003cstrong\u003e18\u003c/strong\u003e(1):52-61.\u003c/li\u003e\n\u003cli\u003eBuckholz A WR, Curry MP, Baffy G, Chak E, Rustagi T, Mohanty A, Fortune BE.: \u003cstrong\u003eMELD, MELD 3.0, versus Child score to predict mortality after acute variceal hemorrhage: A multicenter US cohort.\u003c/strong\u003e \u003cem\u003eHepatol Commun \u003c/em\u003e2023, \u003cstrong\u003e7\u003c/strong\u003e(10):e0258.\u003c/li\u003e\n\u003cli\u003eSeo JS KY, Lee YS, Chung HY, Kim TY.: \u003cstrong\u003eUsefulness of the d-dimer to albumin ratio for risk assessment in patients with acute variceal bleeding at the emergency department: retrospective observational study.\u003c/strong\u003e \u003cem\u003eBMC Emerg Med \u003c/em\u003e2022, \u003cstrong\u003e22\u003c/strong\u003e(1):135.\u003c/li\u003e\n\u003cli\u003eAltamirano J ZL, Agustin S, Muntaner L, Gonz\u0026aacute;lez-Angulo A, Ortiz AL, Degiau L, Garibay J, Camargo L, Genesc\u0026agrave; J.: \u003cstrong\u003ePredicting 6-week mortality after acute variceal bleeding: role of Classification and Regression Tree analysis.\u003c/strong\u003e \u003cem\u003eAnn Hepatol \u003c/em\u003e2009, \u003cstrong\u003e8\u003c/strong\u003e(4):308-315.\u003c/li\u003e\n\u003cli\u003eKim HJ LH, Cho JH.: \u003cstrong\u003eFactor analysis of the biochemical markers related to liver cirrhosis.\u003c/strong\u003e \u003cem\u003ePak J Med Sci \u003c/em\u003e2015, \u003cstrong\u003e31\u003c/strong\u003e(5):1043-1046.\u003c/li\u003e\n\u003cli\u003eCho SK SS, Lee IH, Do YS, Choo SW, Park KB, Yoo BC.: \u003cstrong\u003eBalloon-occluded retrograde transvenous obliteration of gastric varices: outcomes and complications in 49 patients.\u003c/strong\u003e \u003cem\u003eAJR Am J Roentgenol \u003c/em\u003e2007, \u003cstrong\u003e189\u003c/strong\u003e(6):W365-372.\u003c/li\u003e\n\u003cli\u003ePrindiville T MM, Trudeau W.: \u003cstrong\u003ePrognostic indicators in acute variceal hemorrhage after treatment by schlerotherapy.\u003c/strong\u003e \u003cem\u003eAm J Gastroenterol \u003c/em\u003e1987, \u003cstrong\u003e82\u003c/strong\u003e(7):655-659.\u003c/li\u003e\n\u003cli\u003eHori S TA, Okada H, Fujiwara A, Takenaka R, Makidono C, Shiratori Y.: \u003cstrong\u003eEndoscopic therapy for bleeding esophageal varices improves the outcome of Child C cirrhotic patients.\u003c/strong\u003e \u003cem\u003eJ Gastroenterol Hepatol \u003c/em\u003e2006, \u003cstrong\u003e21\u003c/strong\u003e(11):1704-1709.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Acute esophagogastric variceal bleeding, Liver cirrhosis, 6-week mortality, Total bilirubin","lastPublishedDoi":"10.21203/rs.3.rs-7262310/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7262310/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eAcute esophagogastric variceal bleeding (AEGVB) is a frequent and life-threatening complication of liver cirrhosis. This study aimed to investigate robust factors associated with 6-week mortality in cirrhotic patients with AEGVB using advanced statistical analysis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe retrospectively enrolled 656 consecutive cirrhotic patients with AEGVB from April 1st, 2021 to September 30th, 2022 in Beijing You\u0026rsquo;an Hospital, Capital Medical University. A 1:4 matched analysis was performed to adjust the effect of admission time on statistical results. Cluster analysis was used to divide the whole cohort into three groups with distinct clinical characteristics. Kaplan-Meier analysis was used to estimate 6-week overall survival among the three clustered groups. Cox regression analysis were used to investigate predictors of 6-week mortality for cirrhotic patients with AEGVB. A competing risk model was used to identify robust predictors for 6-week mortality. The prognostic value of total bilirubin (TB) was assessed using restricted cubic spline (RCS) analysis.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eCluster analysis identified the top 10 most important variables for clustering, including TB and D-dimer. After clustering with these variables, we found that cluster 0 group had the highest rates of early death, rebleeding and hemostasis failure. Kaplan-Meier analysis demonstrated that the 6-week mortality rate was significantly higher in the cluster 0 group than in the cluster 1 and 2 groups. Cox regression analysis showed that 6-week mortality was independently associated with several variables including 6-week rebleeding (HR 21.904, 95% CI 8.446 to 56.805, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), TB (HR 1.011, 95% CI 1.007 to 1.014, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), rebleeding within 72h (HR 16.767, 95% CI 6.309 to 44.556, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and rebleeding within 4\u0026ndash;5 days (HR 10.137, 95% CI 2.338 to 43.945, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002). However, the competing risk model demonstrated that for 6-week mortality, TB was the only significant risk factor, with an HR of 1.43 and 95% CI of 1.100 to1.860 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008). Furthermore, RCS analysis indicated that TB level above 127.35\u0026micro;mol/L was associated with a significantly increased risk of 6-week mortality.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eCluster analysis allows the identification of distinct profiles of AEGVB that form clinically relevant subsets. TB can serve as a robust biomarker for assessing short-term mortality risk in cirrhotic patients with AEGVB.\u003c/p\u003e","manuscriptTitle":"Total bilirubin serves as a robust predictor of 6-week mortality in patients with liver cirrhosis and acute esophagogastric variceal bleeding","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-03 05:13:16","doi":"10.21203/rs.3.rs-7262310/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"aab32896-2e5c-4797-8d9f-9a8038a5bdf2","owner":[],"postedDate":"September 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-15T11:53:53+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-03 05:13:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7262310","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7262310","identity":"rs-7262310","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}