Rethinking portal hypertension in hepatocellular carcinoma resection: a gradient of risk beyond black and white

The presence of portal hypertension (PHT) has long been considered a red flag in patients with resectable hepatocellular carcinoma (HCC) (1). Accordingly, evaluation of PHT is embedded in clinical guidelines for HCC and respective treatment algorithms like the one proposed by the Barcelona Clinic Liver Cancer (BCLC). In fact, the presence of PHT typically steers patients away from resection and toward transplantation or palliative treatment in a substantial proportion of cases. However, withholding potentially curative treatment and dropping out of the waiting list for transplantation do negatively impact outcome (2). Further, the presence of PHT is usually associated with reduced hepatic reserve, a parameter that is known to be a main indicator for non-recurrence related morbidity and mortality after liver resection (3,4).

The study by Aliseda et al., published in Annals of Surgery (5), signals an important shift towards a more granular view on PHT, thereby possibly making safe surgical treatment options available for patients who were previously deemed inoperable. The data further evaluate a difference between methods for PHT assessment: in particular, this comprehensive meta-analysis distinguished between invasive measurement of hepatic venous pressure gradient (HVPG) and indirect signs of PHT posed by the presence of thrombocytopenia, splenomegaly or esophageal varices. While indirect signs of PHT were not associated with a significantly increased risk for complications, hepatic decompensation, or 90-day mortality, individuals with clinically significant PHT (CSPHT), defined as a HVPG ≥10 mmHg, displayed an increased risk for liver-related morbidity after resection.

A similar observation was made by Boleslawski et al. in 2012 (6). Patients undergoing hepatic resection in the presence of CSPHT display an increased risk for postoperative mortality, while indirect signs of PHT failed to identify patients with adverse postoperative outcomes. Importantly, patients with CSPHT in the present meta-analysis achieved a 5-year overall survival (OS) rate of 55.2% after hepatic resection, which is comparable or even better than outcomes reported for non-curative treatments. This novel insight thereby underlines a potential role of liver resection even in high-risk patients when careful patient selection and individualized tailoring of surgical procedures are applied.

In this context, we recently reported on von Willebrand factor antigen (vWF-Ag) as a robust biomarker for decision making prior to liver resection, specifically in patients with HCC (7). While vWF-Ag is a known predictor for adverse postoperative outcomes, including post-hepatectomy liver failure and reduced postoperative OS, a close association with PHT evaluated via direct measurement of HVPG was previously described (8). In an observational study including a surgical evaluation and validation cohort of patients with HCC, as well as a cohort of HCC patients who did not undergo liver resection, clinically useful cut-offs for ruling in and ruling out of CSPHT were established (7). Intriguingly, the sole evaluation of vWF-Ag in plasma allowed for identification of HCC patients who are optimal candidates for liver resection (vWF-Ag ≤182%) even without evaluation of HVPG, while a high-risk group of patients who might not benefit from liver resection was characterized by high levels of vWF-Ag (>291%).

While we believe that vWF-Ag is a robust preoperative screening tool in this patient cohort, additional biomarkers are needed. In fact, approximately one-third of patients in this analysis were in an intermediate-risk cohort, where ruling in or out of CSPHT was not possible. This further illustrates the broad spectrum of risk evaluation in the context of PHT. In this subset, additional workup of patients in this grey zone is particularly challenging. In accordance with the Baveno VII consensus, liver stiffness measurement via transient elastography is most helpful for accurate estimation of PHT while also being predictive of postoperative outcome after liver resection in HCC patients (9,10). Recent findings validated liver stiffness measurement in different chronic liver diseases, which renders this method clinically relevant in the cohort of HCC patients, due to the spectrum of potential underlying etiologies (11,12). In addition, integration of biomarkers associated with divergent pathophysiological components of PHT, such as soluble cluster of differentiation 163 (CD163), angiopoietin-2 (Ang-2), and lipopolysaccharide-binding protein (LPB), as well as composite parameters like the enhanced liver fibrosis (ELF) test, fibrosis-4 (FIB-4 based on age, transaminases and platelet count) or VITRO score (vWF-Ag/platelet ratio), might further allow for increased granularity of risk assessment in these high-risk patients in the future (13-15). Ultimately, invasive evaluation of PHT via transjugular HVPG measurement needs to be considered whenever doubts remain.

The analysis by Aliseda et al. further evaluated minimally invasive liver surgery (MILS) as a relevant risk modulator. Indeed, MILS was associated with reduced postoperative complications, particularly in individuals with CSPHT, where the risk of mortality and hepatic decompensation was not altered when compared with patients undergoing MILS without CSPHT. While patient selection for MILS needs to be acknowledged as a potential bias, physiological benefits of laparoscopy, including reduced blood loss, preservation of collateral blood flow, less manipulation, and a potentially beneficial effect of tamponade due to the capnoperitoneum, deserve recognition. An additional essential factor influencing outcomes is the extent of hepatic resection. Major hepatectomies (i.e., ≥3 segments) in patients with PHT showed significantly higher rates of post-hepatectomy liver failure and decompensation, reinforcing the importance of parenchymal preservation and emphasizing future liver remnant evaluation, especially in HCC patients with underlying parenchymal disease.

So, where does this leave us now? Most importantly, the presented data render the dogma that PHT is an absolute contraindication for liver resection secondary. While an increased risk for adverse postoperative outcomes in the cohort of HCC patients with PHT was confirmed, the analysis by Aliseda et al. encourages a personalized and risk-adapted approach. Further, as clinicians in 2025, we should omit to solely rely on indirect signs of PHT like thrombocytopenia or splenomegaly for decision making in this cohort. Instead, a more sophisticated algorithm should be implemented—one that incorporates plasma biomarkers such as vWF-Ag, indirect HVPG estimation through transient elastography, and, when needed, direct HVPG measurement. Thereby, diagnostic accuracy and quantification of PHT can be improved to ultimately optimize perioperative outcomes in HCC patients.

Yet, relevant questions remain. Selection bias, variations in matching methodology, and lack of standardization in preoperative management, including use of antiviral drugs or nonselective beta-blocker therapy, pose limits to generalizability. In addition, oncological parameters must be integrated to fully evaluate this patient cohort in a holistic manner. While this study provides the highest level of evidence to date outside of randomized trials further data and validation of potential treatment and selection algorithms are highly warranted.

In summary, the future of liver surgery for HCC, particularly in cirrhotic patients, must evolve to integrate quantification of PHT, tumor biology, and personalized treatment strategies. While liver transplantation will continue to play a dominant role, particularly in individuals with limited liver function or multifocal disease, we must critically re-evaluate whether it should remain the default option in all cases of PHT. The meta-analysis by Aliseda et al. redefines the presence of PHT as a relative, not absolute, contraindication to resection. Moving forward, surgical decision-making must be guided by individualized risk stratification and executed with minimally invasive and parenchymal sparing approaches wherever feasible. This paradigm shift demands action: we must rethink, not reflexively reject, resection in the presence of PHT. By moving beyond black and white dogma toward a nuanced gradient of risk, we may unlock safer, more personalized surgical pathways for patients previously considered ineligible for resection.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-213/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-213/coif). The authors have no conflicts of interest to declare.

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