In patients with HCC undergoing systemic therapy, the management of PH-related complications is vital to effectively prevent treatment interruption secondary to PH-related complications and to maximize treatment benefits. Several studies have evaluated the impact of systemic therapy on PH-related complications [18,19,20,21]. However, to the best of our knowledge, only a few studies have identified factors that may contribute to the incidence or exacerbation of PH-related complications during systemic therapy in patients with HCC. In our report, we propose that identifying predictors of PH-related complications prior to treatment may provide an opportunity for prophylactic treatment in patients at a high risk of PH-related complications.

CECT is essential for determining the efficacy of systemic therapy and is frequently performed during treatment to evaluate tumor progression and vascular invasion. Therefore, in terms of invasiveness, and cost efficiency, the evaluation of PH-related complications with CECT would be beneficial. The gold standard for EV screening is endoscopy. However, as our previous and present reports have revealed, CECT has the potential of usefulness in variceal evaluation during systemic therapy for HCC [15]. Furthermore, the portosystemic shunt, a factor in the incidence of HE, can be identified using CECT prior to systemic therapy.

In the literature, some controversy exists regarding the effect of systemic therapy on PH. VEGF produced by hepatocytes and hepatic stellate cells induces angiogenesis in the mesenteric vascular bed and portal circulatory collateral vessels [4], which may exacerbate PH-related complications [5]. The use of anti-VEGF antibodies in rodent models has been reported to reduce portal pressure [6]. Conversely, the inhibition of VEGF affects conserved hepatic sinusoids in non-neoplastic livers, causing sinusoidal changes, and impairment of oxygen and nutrient supply to hepatocytes. This in turn can cause and exacerbate underlying liver disease and PH [8]. Several clinical studies have suggested that SOR may improve PH, while LEN has been reported to worsen PH [7]. Moreover, chronic inflammation may exacerbate PH-related complications as bacterial infection increases portal pressure [8]. In the liver, the innate immune system recognizes damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors, such as Toll-like receptors, resulting in inflammatory cytokine and reactive oxygen species production [22]. ATZ is an immune checkpoint inhibitor (anti-PD-L1 antibody) that may eliminate DAMPs and PAMPs; however, some studies have reported that the administration of immune checkpoint inhibitors causes liver injury and fibrosis progression [9]. In this study, factors contributing to the incidence and exacerbation of PH-related complications during first-line systemic therapy were explored. In our study, the most accurate and best predictive factor for EV exacerbation after 3 months of treatment was the use of ATZ/BEV. However, ATZ/BEV treatment had no significant effect on the development of HE or the exacerbation of ascites. According to previous reports [23, 24], the HVPG level at which esophageal varices develop is 10.9 mmHg or higher, and the development of ascites has been reported at HVPG levels of 12.5 mmHg or higher, suggesting that the negative effect of ATZ/BEV on PH may first appear in the worsening of esophageal varices. In addition, hepatic encephalopathy is often caused by a low residual intrahepatic venous pressure [25], which was considered less likely to be affected by the negative effect of ATZ/BEV on PH. Thus, our study implies that in patients without EV before systemic therapy, the rapid EV deterioration could be attributed to ATZ/BEV and should be carefully evaluated on CECT during systemic therapy. In our study, the cumulative EV bleeding rate during systemic therapy was 6.4% at 1 year and 11.7% at 2 years. In our previous report, the cumulative EV bleeding rate for patients with early advanced HCC was 3.4% at 1 year and 5.9% at 2 years. A cumulative bleeding rate of 32.4% in patients with EV before systemic therapy was also demonstrated in our study. In another report, the cumulative EV bleeding rate was 12.0% at 2 years in EV patients without HCC [26]. These results suggest that systemic therapy has a negative impact on EV exacerbation and bleeding. Previous reports have also reported that BEV contributes to EV bleeding owing to its effect on PH [27, 28]. Therefore, all patients should undergo endoscopy prior to systemic therapy [28,29,30,31]. Patients without PVTT and with an EIV diameter < 3.1 mm could have a relatively low risk of EV bleeding and are less likely to require screening endoscopy before systemic therapy. In this study, no significant difference was found for the EV bleeding rate by type of systemic therapy, although a higher bleeding rate has been reported with the use of ATZ/BEV [28,29,30,31]. This may be because more patients in the ATZ/BEV and LEN groups compared to those in the SOR group received prophylactic treatment during systemic therapy (SOR vs. LEN vs. ATZ/BEV 0.5% vs. 3.1% vs. 2.2%. p = 0.03).

Limited literature exists regarding the incidence of HE during systemic therapy; however, it has been reported that HE often occurs within 2 weeks upon systemic therapy initiation [32]. In our study, HE incidence within 2 weeks was 2.1%, which is comparable with other published reports (3.8% incidence of HE per 16 days of the median observation period for LEN) [33]. In addition, although PPI administration has been previously reported to be associated with the development of HE [34], this study did not reveal the risk of HE related to the use of PPI. It may be because the development of HE was assessed within 2 weeks, which may have been too short to evaluate the impact of PPI on the development of HE. It has been reported that hyperammonemia is a risk factor for HE [35]. Moreover, ammonia levels peak 2 weeks after systemic therapy [36], and HE is likely to develop a few days after the initiation of systemic therapy [32]. In a previous report from our institution, we reported that hyperammonemia and the presence of a portosystemic shunt were significant factors in the development of HE for LEN [37], which were similarly observed in this study. Therefore, prophylactic medical therapy for HE might be administered early in case of high ammonia levels. This study also demonstrated that a portosystemic shunt of 6.8 mm or greater is a high-risk factor for the development of HE. This concurs with the findings of a previous report that an 8-mm portosystemic shunt diameter is a risk factor for HE [38]. In this study, balloon-occluded retrograde transvenous obliteration (BRTO) might be considered before systemic therapy in high-risk patients. However, validation studies are warranted to determine cases in which BRTO for portosystemic shunts could improve the prognosis of patients during systemic therapy.

One of the most common complications of HCC with cirrhosis is ascites, and the occurrence of ascites is associated with prognosis [39,40,41]. In our study, the occurrence of ascites at 3 months in patients without ascites prior to systemic therapy was approximately 20.3%, which is considerably higher than that previously reported in patients with cirrhosis (5.1% at 1 year) [42], suggesting that systemic therapy poses a negative influence on the occurrence of ascites. Moreover, PVTT and PD after 3 months of systemic therapy were independent factors for the exacerbation of ascites after 3 months. Cachexia secondary to HCC progression is associated with the development of ascites, similar to other advanced cancers [43].

This study has several limitations. First, a retrospective analysis of data was conducted. Therefore, a prospective evaluation of these data is warranted. Second, this study did not directly establish the correlation between PH-related complications and systemic therapy because of the lack of comparative analysis between groups with and without systemic therapy. Additionally, the evaluation of EV is incomplete based on form factors only. This study did not examine red color signs on endoscopic findings as a bleeding factor for EV, which cannot be evaluated via CECT, and prospective validation is needed in further studies to determine whether red color signs are a significant predictive factor for EV bleeding compared to predictors evaluated by CECT.

In conclusion, systemic therapy may be involved in the exacerbation of PH-related complications during systemic therapy. Therefore, early prophylactic treatment of patients with risk factors for the incidence or exacerbation of PH-related complications should be employed. Additionally, CECT may be useful for the reduction of unnecessary endoscopy and assessment of predictors of PH-related complications.