Beyond the composite: Differential impact of albumin and bilirubin relative to tumor burden in HCC

Background: Existing prognostic models for hepatocellular carcinoma (HCC) after hepatectomy often use the Albumin–Bilirubin (ALBI) score, which treats albumin and bilirubin as a fixed composite. This approach may overlook their differential prognostic relevance depending on tumor burden. We aimed to evaluate whether stratifying albumin and bilirubin by Tumor Burden Score (TBS) enhances overall survival (OS) prediction, as well as develop a novel ALBI–TBS score incorporating tumor burden–dependent weighting. Methods: Patients undergoing curative-intent hepatectomy for HCC (2000–2023) were identified from an international, multi-institutional database. Albumin and bilirubin were assessed separately in low- and high-TBS cohorts using spline and Cox regression analyses. A novel ALBI–TBS score was derived by weighting albumin and bilirubin coefficients proportionally to normalized TBS (0–10) and validated in training and testing cohorts. Discrimination was measured using the concordance index (C-index). Results: Among 1312 patients, prognostic relevance varied by TBS. In low-TBS patients, high albumin (≥40 g/L) was protective (HR 0.416 [0.279–0.620]; p < 0.001), while bilirubin was not. In high-TBS patients, elevated bilirubin (≥1.0 mg/dL) predicted worse OS (HR 1.743 [1.221–2.488]; p = 0.002), whereas albumin was not prognostic. The ALBI–TBS score outperformed conventional ALBI (training C-index 0.64 vs 0.57; testing 0.66 vs 0.59) and stratified patients into three distinct risk groups. Conclusion: Tumor burden modifies the prognostic contributions of albumin and bilirubin in HCC. The ALBI–TBS score improves OS prediction and provides a simple, clinically applicable tool for preoperative risk stratification after hepatectomy.