We read with great interest the retrospective study by Ko et al., published in the Journal of Gastroenterology and Hepatology 1. Considering the growing interest in exploring the albumin–bilirubin (ALBI) grade as an objective biomarker of hepatic reserve in hepatocellular carcinoma (HCC) patients, the authors' initiative to examine its long-term prognostication after TACE is both commendable. Although the study presents promising implications of ALBI in HCC prognosis and management, we found some methodological flaws that may compromise both the study's external and internal validity. While the authors did recognize some limitations, we believe that some are unaddressed. Firstly, assessment of ALBI grades only once, at baseline, before the first TACE is a major limitation as the study seems to presume that the ALBI, and hence, liver function remains constant throughout years of follow-up, ignoring any deterioration or improvement in liver function. Despite being unrealistic from a biological aspect, this assumption also overlooks the findings of previous studies that liver function is highly dynamic after TACE as TACE temporarily reduces hepatic blood flow, impairing hepatic reserves 2, 3. Therefore, serial ALBI assessment after each TACE session or at defined follow-up intervals could have provided a greater prognostic value. For instance, an ALBI transition from Grades 1 to 2 during follow-up could help clinicians to timely detect declining liver function, before the development of serious symptoms or irreversible failure 2. Thus, the lack of such a dynamic evaluation in this study design undermines its clinical relevance. Secondly, the study comprising exclusively of Child–Pugh A patients with a MELD score lower than 10, most of whom had chronic hepatitis B–related HCC, was all treated from a single tertiary hospital in South Korea. We are concerned that such a stringent inclusion criterion limits the study's clinical significance and generalizability as it leaves a small, homogeneous cohort, which is not representative of the broader real-world HCC population. Thus, it is unclear how broadly these findings and the study design are applicable to other demographic and clinical populations. For instance, in Western populations, the leading causes of HCC are hepatitis C, alcohol, and metabolic-associated fatty liver disease (MAFLD), which present with different baseline ALBI profiles and disease progression patterns, making these findings less applicable for them 4. Not to mention that including only Child–Pugh A patients also introduces a ceiling effect, where all the participants had preserved liver function, thus making it difficult to differentiate clinical value. Moreover, excluding patients with Child–Pugh B or C liver function removes a considerable proportion of the real-world TACE candidates for whom ALBI grading may be of even greater clinical relevance, as supported by recent studies, because conventional scoring systems often fail, and treatment options are uncertain for these patients 3. Lastly, the single-center approach could be a source of procedural bias due to local expertise, TACE techniques, and follow-up intensity. Therefore, we propose that a prospective, multicenter study across diverse populations is essential to validate the results. Thirdly, recent research indicates that the neutrophil/lymphocyte ratio (NLR) and ALBI score together provide a better prognostic value than either NLR or ALBI grade alone. This suggests that combining multiple risk factors for postoperative prognosis assessment is both feasible and effective 5. The failure to incorporate NLR thereby limits the predictive refinement. Finally, the study was conducted between 2004 and 2014, prior to the new cancer treatment becoming popular. A recent meta-analysis pointed out that the triple therapy of TACE, tyrosine kinase inhibitors (TKI), and immune checkpoint inhibitors (ICI) provides the highest disease control rate (DCR) and improves tumor response and survival outcomes for patients with advanced HCC 6. Hence, the combination of TACE, ICI, and TKI is now standard treatment, and as these treatments now improve tumor control and alter liver function differently, it is uncertain whether the prognosis through ALBI still holds the same value as described by these data. Therefore, it is now essential to reassess whether ALBI grade is still a reliable indicator of results for these combination treatments. In conclusion, while Ko et al.'s contribution is valuable, we recommend that future research validate these findings through dynamic, multicenter analyses across diverse populations and evolving therapeutic options. The authors have nothing to report. The authors declare no conflicts of interest. No new data were generated or analyzed in this study.
Ahmed et al. (Wed,) studied this question.