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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Insights into the GALAD score: A new optimal cut-off for hepatocellular carcinoma
Erica Villa, Rossella Donghia, Sergio Coletta, Caterina Bonfiglio, Rosina Maria Critelli, Anna Ancona, Endrit Shahini, Palma Aurelia Iacovazzi, Raffaele Cozzolongo, Francesca Pavone, Nicola Carella, Patrizia Pontisso, Andrea Martini, Sherin Al Aoua, Heike Bantel, Gianluigi Giannelli
Erica Villa, Department of Gastroenterology, University of Modena and Reggio Emilia, Modena 41124, Emilia-Romagna, Italy
Rossella Donghia, Caterina Bonfiglio, Data Science Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte 70013, Bari, Italy
Sergio Coletta, Anna Ancona, Core Facility Biobank, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte 70013, Bari, Italy
Rosina Maria Critelli, Department of Chimomo, University of Modena and Reggio Emilia, Modena 41124, Emilia-Romagna, Italy
Endrit Shahini, Raffaele Cozzolongo, Francesca Pavone, Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte 70013, Puglia, Italy
Palma Aurelia Iacovazzi, Clinical Pathology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte 70013, Bari, Italy
Nicola Carella, Clinical Research Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte 70013, Puglia, Italy
Patrizia Pontisso, Andrea Martini, Department of Medicine, Azienda Ospedaliera-Università Padova, Padova 35123, Veneto, Italy
Sherin Al Aoua, Heike Bantel, Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover 30625, Lower Saxony, Germany
Gianluigi Giannelli, Scientific Direction, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte 70013, Puglia, Italy
Co-first authors: Erica Villa and Rossella Donghia.
Author contributions: Giannelli G contributed to conceptualization; Villa E and Donghia R contributed to methodology; Villa E, Coletta S, Ancona A and Iacovazzi PA contributed to investigation; Giannelli G and Villa E contributed to resources; Donghia R and Bonfiglio C contributed to data curation; Villa E and Giannelli G contributed to writing, review and editing; Shahini E, Cozzolongo R, Pavone F, Carella N, Pontisso P, Martini A, Al Aoua S and Bantel H contributed to visualization; Shahini E, Cozzolongo R, Al Aoua S, Bantel H and Giannelli G contributed to supervision; Donghia R contributed to formal analysis; Villa E, Donghia R, Coletta S, Bonfiglio C, Critelli RM, Ancona A, Shahini E, Iacovazzi PA, Cozzolongo R, Pavone F, Carella N, Pontisso P, Martini A, Al Aoua S, Bantel H, Giannelli G were responsible for the decision to submit the manuscript for publication.
Institutional review board statement: All studies were conducted in accordance with the ethical standards of the institutional research committee [Human Studies Committee of the IRCCS Oncological Hospital-Giovanni Paolo II, Bari, Italy approval for the Great Age-Aging based on MICOL Study (No. 144, April 09, 2019)]; patients with compensated advanced CLD from the Gastroenterology Unit “IRCCS Saverio de Bellis”: Human Studies Committee of the IRCCS Oncological Hospital-Giovanni Paolo II, Bari, Italy (No. 28, January 25, 2023; ClinicalTrials.gov, No. NCT05781568); patients from Modena (No. 1389, May 20, 2008; ClinicalTrials.gov, No. NCT01657695); patients from Padua (Ethical Committee based on resolution, No. 154, February 28, 2005); patients form Hannover (No. 10129_BO_K_2021) and with the 2024 Helsinki declaration.
Informed consent statement: Written informed consent was obtained from all participants.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
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: Gianluigi Giannelli, Director, Professor, Scientific Direction, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Via Turi, 27, Castellana Grotte 70013, Puglia, Italy.
gianluigi.giannelli@irccsdebellis.it
Received: July 8, 2025
Revised: July 29, 2025
Accepted: September 23, 2025
Published online: October 28, 2025
Processing time: 111 Days and 19.8 Hours
BACKGROUND
Chronic liver disease (CLD) causes approximately two million deaths each year, and its clinical diagnosis and management remain challenging. Ultrasound is currently the most widely used technique for disease detection.
AIM
To propose a practical cut-off value for identifying patients with hepatocellular carcinoma (HCC) among those with compensated advanced CLD or healthy individuals using the GALAD score, an algorithm based on a formula that incorporates gender, age, serum alpha-fetoprotein (AFP), AFP-L3, and des-gamma-carboxy prothrombin values.
METHODS
This cross-sectional analysis was conducted using prospectively collected data from five cohorts (n = 1431) comprising healthy individuals, cirrhosis, and HCC patients. These subjects were enrolled from an Italian retrospective cohort, including patients from the IRCCS “Saverio de Bellis”, Department of Gastroenterology, the University of Modena and Reggio Emilia Gastroenterology Department, and the Padua University Hospital and the Department of Gastroenterology, Hepatology, Infectious diseases and Endocrinology, Hannover Medical School.
RESULTS
Using healthy subjects as reference, a GALAD score cut-off of -1.67 identified HCC with a sensitivity of 89.77% and specificity of 97.59%. Individuals with GALAD values > -1.67 exhibited a moderate to very high probability (over 90%) of having HCC. When cirrhotic patients were used as the reference category, a cut-off of -0.77 yielded a sensitivity of 78.17% and a specificity of 89.55%.
CONCLUSION
We strongly recommend incorporating this GALAD cut-off into clinical guidelines for the screening of patients with a compensated advanced CLD who are at high risk of developing HCC. Given the rapid global rise in metabolic-associated steatotic liver disease (MASLD)-related CLD, future research should prioritize larger MASLD cohorts to establish the most appropriate GALAD cut-off for diagnostic use, compared to healthy controls and to patients with other forms of CLD.
Core Tip: The GALAD score, combining gender, age, alpha-fetoprotein (AFP), AFP-L3, and des-gamma-carboxy prothrombin levels, is a promising tool for identifying hepatocellular carcinoma (HCC). In this multi-center study involving 1431 subjects, we propose a cut-off of -1.67 to distinguish HCC from healthy individuals, and -0.77 to differentiate HCC from cirrhotic patients, achieving high sensitivity and specificity. These thresholds can enhance early HCC detection and are recommended for integration into screening protocols. Future studies should validate these findings, particularly in metabolic-associated steatotic liver disease-related liver disease, which is becoming increasingly prevalent worldwide.
