Copyright
©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Risk prediction of acute variceal bleeding in hepatocellular carcinoma patients undergoing systemic therapy based on immune checkpoint inhibitors
Xu Zhang, Li-Meng Song, Yu-Piao Zheng, Bao-Xin Qian, Jing Liang, Feng-Mei Wang
Xu Zhang, Feng-Mei Wang, Department of Gastroenterology and Hepatology, The First Central Hospital of Tianjin Medical University, Tianjin 300170, China
Xu Zhang, Bao-Xin Qian, Jing Liang, Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin 300170, China
Li-Meng Song, The Third Central Clinical College, Tianjin Medical University, Tianjin 300170, China
Yu-Piao Zheng, Feng-Mei Wang, Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin Key Laboratory for Organ Transplantation, Department of Gastroenterology and Hepatology, Tianjin First Central Hospital, Tianjin 300380, China
Yu-Piao Zheng, School of Medicine, Nankai University, Tianjin 300000, China
Co-first authors: Xu Zhang and Li-Meng Song.
Co-corresponding authors: Feng-Mei Wang and Jing Liang.
Author contributions: Zhang X and Song LM analyzed the data and wrote the manuscript; Qian BX and Zheng YP collected the data and performed the research; Wang FM and Liang J designed the research study; Zhang X and Song LM contribute equally to this article as co-first authors; Wang FM and Liang J are co-corresponding authors because they jointly supervised this work; all authors have read and approved the final manuscript.
Supported by Tianjin Key Medical Discipline (Specialty) Construction Project, No. TJYXZDXK-034A; and Hebei Province 2025 Traditional Chinese Medicine Scientific Research Project Plan, No. T2025008.
Institutional review board statement: The study protocol was approved by the Ethics Committee of the Third Central Hospital of Tianjin in December 2019 under the approval number: IRB2019-040-01.
Informed consent statement: Written informed consent was obtained from all patients.
Conflict-of-interest statement: This study is free of conflict of interest for the researcher, members of the ethics committee, guardians of the subjects and in relation to the disclosure of the research results.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Data sharing statement: The datasets generated are available upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Feng-Mei Wang, PhD, Professor, Department of Gastroenterology and Hepatology, The First Central Hospital of Tianjin Medical University, No. 2 Baoshan West Road, Xiyingmen Street, Xiqing District, Tianjin 300380, China.
wangfengmeitj@126.com
Received: April 28, 2025
Revised: May 27, 2025
Accepted: July 1, 2025
Published online: August 15, 2025
Processing time: 108 Days and 21.9 Hours
BACKGROUND
Acute variceal bleeding (AVB) represents a life-threatening complication in hepatocellular carcinoma (HCC) patients undergoing systemic therapy, mainly including immune checkpoint inhibitors (ICIs) and antivascular drugs used alone or in combination. The pathogenesis of AVB in this population may involve tumor-related factors, treatment-induced effects, or progression of underlying portal hypertension. Identifying high-risk factors for AVB is crucial for the management of this patient population.
AIM
To develop and validate a risk prediction model for AVB occurrence in cirrhotic HCC patients receiving ICI-based systemic therapy.
METHODS
This retrospective study analyzed 286 HCC patients (2021-2022) receiving ICIs (mono-/combination therapy), randomly split into training (n = 184) and validation (n = 102) cohorts. In the training cohort, bleeding vs non-bleeding groups were compared for general information, etiological data, laboratory indicators, tumor staging, systemic treatment drugs, variceal bleeding history, and endoscopic treatment history. Risk factors for AVB were identified and used to establish a logistic regression model for predicting bleeding, which was further validated in the validation cohort.
RESULTS
The bleeding group had significantly higher proportions of patients with platelet count ≥ 100 × 109/L, alpha-fetoprotein ≥ 400 ng/mL, tumor diameter ≥ 5 cm, portal vein tumor thrombosis, ascites, bleeding history, prior endoscopic treatment, albumin-bilirubin grade level 2-3, fibrosis-4 index (FIB-4) ≥ 4.57, and prognostic nutritional index < 45 compared to the non-bleeding group. Multivariate analysis identified tumor diameter ≥ 5 cm, portal vein thrombosis, bleeding history, and elevated FIB-4 as independent risk factors for bleeding (P < 0.05). A predictive model based on these factors showed good discrimination, with area under the receiver operating characteristic curve values of 0.861 (training) and 0.816 (validation).
CONCLUSION
A history of pre-ICI bleeding significantly increases recurrent bleeding risk, necessitating close monitoring. The FIB-4 fibrosis model, combined with tumor features, can also serve as a predictive factor for bleeding.
Core Tip: Hepatocellular carcinoma patients with a history of variceal bleeding, tumor diameter ≥ 5 cm, portal vein tumor thrombosis, or elevated fibrosis-4 index (≥ 4.57) are at significantly increase the risk of recurrent variceal bleeding during immune checkpoint inhibitor (ICI)-based systemic therapy. Closely monitor these individuals for early signs of bleeding. Prior to initiating ICIs, consider endoscopic screening in high-risk patients.
