Abstract
Background/Aim: In hepatocellular carcinoma (HCC), portal hypertension (PHT) during the advanced stages of cirrhosis leads to splenomegaly. Additionally, the immune environment is an important factor in HCC treatment. Splenectomy and partial splenic embolization (PSE) are expected to improve this condition; however, data on the effects of PSE on immune function are limited. Therefore, we investigated the effects of PSE on the immune environment and hepatic function in patients with PHT-related cirrhosis.
Patients and Methods: The study included 117 of 238 patients who underwent PSE for PHT at our Department between 2011 and 2024 and were followed-up for more than 12 months, excluding those who underwent additional procedures concurrent with PSE. Changes in blood cell counts, hepatic function and immunological parameters including the neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio, were examined.
Results: The mean splenic volume, mean splenic infarction volume, and splenic infarction rate were 396.64 ml, 222.8 ml, and 58.6%, respectively. The preoperative splenic volume was inversely correlated with platelet and lymphocyte counts. The platelet count increased from 7.3 to 10.4 at 1 year; the platelet-albumin-bilirubin score improved from −2.38 to −2.49 (p<0.01); the fibrosis-4 index improved from 6.02 to 4.69 (p<0.01); the albumin-bilirubin score improved from −2.10 to −2.27 (p<0.01); and the NLR improved from 2.49 to 2.25 (p=0.028). Additionally, analysis of the background liver revealed improvements in platelet count and NLR.
Conclusion: PSE not only improved platelet counts, but also increased lymphocyte counts and improved the NLR. PSE-induced improvements in the immune environment may be useful for introducing combination immunotherapy for HCC.
Introduction
The advanced stages of liver cirrhosis are characterised by portal hypertension (PHT), liver failure, and development of progressive immune abnormalities collectively known as cirrhosis-associated immune dysfunction. This condition results from changes in the gut-liver axis that increase intestinal permeability and induce dysbiosis, ultimately leading to systemic inflammation, immune deficiency (1), and impaired innate and adaptive immune responses. In the advanced stages of cirrhosis, PHT leads to the development of splenomegaly as the disease progresses.
The spleen, a crucial organ of the immune system, contains several subpopulations of immune cells that are involved in various immune response pathways and pathophysiological processes (2). Reportedly, patients with splenomegaly may present with splenic dysfunction and imbalances in the immune microenvironment (3). As an important immune organ outside the tumour microenvironment, the spleen regulates haematopoiesis and both innate and adaptive immune responses, playing a crucial role in tumour-host interactions and systemic immunity. Thus, it is an important organ in evaluating the efficacy of immunotherapy in several types of cancers.
The importance of splenic volume in predicting the prognosis of patients with cancer undergoing curative or palliative treatment has been demonstrated (4-6). Splenic volume is an important predictor of postoperative survival and liver failure in patients with HCC. Splenomegaly can also predict the survival of patients with advanced primary liver cancer treated with immune checkpoint inhibitors (ICIs) (7). Furthermore, an increased splenic volume is associated with the overall and progression-free survival in patients with metastatic renal cell carcinoma receiving ICIs (8).
From an immunological perspective, myeloid-derived suppressor cells (MDSCs) contribute to immunotherapy resistance by inhibiting T-cell activity (9). MDSCs are known to accumulate in the tumour microenvironment and bloodstream, as well as lymphoid organs such as the spleen. In animal models, the accumulation of MDSCs in the spleen contributes to the development of splenomegaly (10, 11). Furthermore, several clinical studies have shown that MDSC levels correlate with splenic volume (12). In recent years, systemic immune-related haematological parameters, such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), have garnered attention as important indicators in combination immunotherapy for HCC (13-17).
The immune status of patients with cirrhosis is generally impaired due to concomitant splenomegaly. Splenectomy has been suggested to improve the impaired immune status of patients with cirrhosis by reducing inhibitory MDSCs and enhancing effector cell populations and functions (18). However, the immunological outcomes after partial splenic embolization (PSE) remain poorly understood. Therefore, this study aimed to clarify whether PSE for PHT-associated cirrhosis influences changes in immune markers.
Patients and Methods
Among the 238 patients who underwent PSE for PHT at the Saiseikai Niigata Hospital between 2011 and 2024, 117 who received PSE monotherapy and were followed up for more than 1 year were included in the analyses. Patients who underwent PSE combined with transcatheter arterial chemoembolization or balloon-occluded retrograde transvenous obliteration/percutaneous transhepatic obliteration were excluded. Changes in platelet, neutrophil, and lymphocyte counts; changes in liver reserve function markers such as albumin-bilirubin (ALBI) (19) and platelet-albumin-bilirubin (PALBI) scores (20), and changes in NLR, PLR, and systemic immuneinflammation index (SII) were analysed (Figure 1).
Flowchart of patient eligibility. TACE: Trancatheter arterial chemoembolization; TAI: trancatheter arterial chemoinfusion; PHT: portal hypertension; BRTO: balloon-occluded retrograde transvenous obliteration.
Inflammatory markers classification. The NLR, prognostic nutritional index (PNI), PLR, and SII were calculated using the following formulae: NLR = neutrophil count/lymphocyte count; PNI=Albumin (g/l)+5×total lymphocyte count (109/l); PLR=platelet count/lymphocyte count; SII=(neutrophil count×platelet count)/lymphocyte count.
PSE procedure. PSE was performed according to the Seldinger method. Briefly, a 4Fr catheter (Seiyahook; Medikit Co., Ltd., Tokyo, Japan) was inserted via the right femoral artery until it reached near the splenic hilum. Following splenic arteriography, each branch was identified from the obtained intrasplenic artery map. Microcatheters (Ramda; Terumo Clinical Supply Co., Ltd., Tokyo, Japan) were then selectively inserted into each of the vessels, and embolization was performed using coils and gelatin sponges soaked with 20 mg of gentamicin (Gentacin; Merck & Co., Inc., Whitehouse Station, NJ, USA). Contrast-enhanced computed tomography (CT) was performed after PSE to confirm the extent of splenic infarction. The splenic embolization ratio from PSE was measured using angio-CT immediately after PSE. The patients underwent routine follow-up at one, 3, 6, and 12 months post-PSE.
Ethics approval and informed consent. The study protocols were approved by the Institutional Review Board of Saiseikai Niigata Hospital, and the study was conducted in accordance with the principles of the Declaration of Helsinki (as revised in 2013). Prior to participation in this study, written informed consent was obtained from all patients.
Statistical analysis. Categorical variables are expressed as numbers, and continuous variables are reported as median values with interquartile ranges. Differences in quantitative values were analysed using the Mann-Whitney U-test. If the repeated measurement data demonstrated a normal distribution, the repeated measures ANOVA followed by multiple comparisons tests (comparing each time point to every other) was used. Pearson correlation was used to analyse the associations between splenic volume, platelet count, and lymphocyte count. Correlations between variables were assessed using Spearman’s rho coefficient for ordinal and non-normally distributed variables. The correlation was analysed using Pearson’s correlation coefficient. All statistical analyses were performed using EZR (Saitama Medical Centre, Jichi Medical University, Shimotsuke, Japan), a graphical user interface for R version 3.2.2 (The R Foundation for Statistical Computing, Vienna, Austria) (21). A two-tailed p-value of p<0.05 was considered statistically significant.
Results
Patient characteristics. The background characteristics of the patients are summarised in Table I. The mean age of the cohort was 61.8±10.6 years; 64 patients were men and 53 were women. There were nine cases of hepatitis B, 45 of hepatitis C, 23 of non-alcoholic fatty liver disease, 34 of alcoholic liver disease, four of autoimmune hepatitis (AIH), and two of primary sclerosing cholangitis. The mean splenic volume was 396.64 ml, with a mean platelet count of 73,000, a mean albumin level of 3.45 g/dl, a mean ALBI score of −2.10, and a mean fibrosis-4 (Fib-4) index of 6.10.
Demographic and baseline characteristics of the study cohort.
PSE outcome. The mean splenic infarction volume across all 117 cases was 222.8 mL, with a splenic infarction rate of 58.6%. There were no significant differences in splenic volume or splenic infarction rate by sex (p=0.34) or age (p =0.21); however, patients with AIH had a splenic volume of 721.9 ml, an infarction volume of 309.1 ml, and a splenic infarction rate of 42.4%. Additionally, the splenic volume was inversely correlated with the platelet and lymphocyte counts (Figure 2).
Correlation between pre-treatment spleen volume and blood cell counts in patients undergoing PSE. (A) Correlation between pre-treatment spleen volume and platelet counts. (B) Correlation between pre-treatment spleen volume and lymphocytes. PSE: Partial splenic embolization.
In the longitudinal course of all cases, the platelet count improved from 7.3 to 10.4 (p<0.01); the PALBI score improved from −2.38 to −2.49 (p<0.01); the Fib-4 index improved from 6.02 to 4.69 (p<0.01); the ALBI score improved from −2.10 to −2.27 (p<0.01); and the NLR improved from 2.49 to 2.25 (p=0.028). However, the monocyte-to-lymphocyte ratio (MLR) remained at 0.31. Although the SII increased from 183.2 to 189.8 and the PLR increased from 97.1 to 109.7, the changes were not significant (Table II).
Changes over time following PSE in all patients with liver cirrhosis.
In patients with Hepatitis C virus-related cirrhosis, the platelet count improved from 6.9 to 9.4 (p<0.01); the PALBI score improved from −2.58 to −2.62 (p<0.01); the Fib-4 index improved from 8.15 to 5.84 (p<0.01); the ALBI score improved from −2.21 to −2.38 (p<0.01); the NLR improved from 1.70 to 1.51 (p=0.018); the MLR improved from 0.29 to 0.28 (p<0.01); and the PLR improved from 63.5 to 100.7 (p<0.01). The SII showed a trend toward improvement from 121.3 to 149.0 (p=0.08) (Table III).
Changes over time following PSE in patients with HCV-related cirrhosis.
In patients with Hepatitis B virus-related cirrhosis, the NLR improved from 3.55 to 2.68 (p=0.037). Additionally, the platelet count improved from 7.3 to 9.3; the PALBI score improved from −2.60 to −2.61; the Fib-4 index improved from 5.19 to 4.32; the ALBI score improved from −2.66 to −2.28; the MLR changed from 0.34 to 0.41; the SII improved from 299.0 to 219.6; and the PLR improved from 158.5 to 134.5. However, none of the changes were significant (Table IV).
Changes over time following PSE in patients with HBV-related cirrhosis.
In patients with alcoholic cirrhosis, the platelet count improved from 8.0 to 11.7 (p<0.01); the Fib-4 index improved from 5.36 to 3.57 (p<0.01); and the NLR improved from 2.33 to 1.74 (p=0.01). Additionally, the PALBI score changed from −2.25 to −2.27, and the ALBI score changed from −2.02 to −2.18. However, these changes were not significant (Table V).
Changes over time following PSE in patients with alcohol-associated cirrhosis.
In patients with metabolic dysfunction-associated steatohepatitis, the platelet count improved from 6.5 to 8.8 (p <0.01); the Fib-4 index improved from 7.85 to 5.37 (p <0.01); and the NLR improved from 3.33 to 2.24 (p =0.032). Additionally, the PALBI score changed from −2.45 to −2.49; the ALBI score changed from −2.11 to −2.12; the MLR changed from 0.28 to 0.25; the SII changed from 219.9 to 190.0; and the PLR changed from 109.8 to 109.4. However, these changes were not significant (Table VI).
Changes over time following PSE in patients with MASH-related cirrhosis.
In patients with autoimmune diseases, such as AIH and primary biliary cholangitis, the NLR improved from 3.25 to 2.29 (p<0.01). Additionally, the platelet count improved from 9.8 to 16.0; the Fib-4 index improved from 4.68 to 3.84; the PALBI score improved from −2.27 to −2.16; the ALBI score improved from −1.93 to −1.96; the MLR increased from 0.21 to 0.48; the SII increased from 256.1 to 287.0; and the PLR increased from 107.8 to 125.5. However, none of these changes were significant.
Discussion
Overall, this study investigated whether PSE for PHT and cirrhosis-induced splenomegaly could improve the immune environment and function. The results revealed that PSE not only improved the platelet count but also improved the NLR, an immune marker, in patients with PHT.
The spleen contains a rich variety of immune cell subpopulations, and changes in its volume reflect changes in the number of immune cells in the body (3, 22). A chronically enlarged spleen indicates chronic inflammation and immune dysregulation, which may be related to an increase in the presence of immunosuppressive cells, such as MDSCs and regulatory T cells, within the tumour microenvironment, inhibiting antitumor immunity (23). Splenomegaly is typically associated with the pathological state of PHT, which can lead to further deterioration of liver function, thereby affecting patient survival (24).
The NLR, a known peripheral marker of chronic inflammation (25), is associated with splenomegaly and indicates a high level of chronic inflammation in cases of persistent splenomegaly. In chronic inflammation, increased MDSC levels, owing to the influence of cytokines, inhibit the cellular activity of T and natural killer cells, promote tumour progression, contribute to ICI resistance, and create a negative spiral in splenomegaly. Furthermore, MDSCs stimulate the production of regulatory T cells, specifically inhibit the activity of CD4+ and CD8+ T cells, and increase the release of immunosuppressive cytokines such as interleukin-10, which promotes tumour growth (26). Splenomegaly is closely associated with the management of cirrhosis, and its treatment is broadly categorised into splenectomy and PSE. Splenectomy has been reported to improve platelet, white blood cell, and lymphocyte counts in several patients. In a previous study, splenectomy was conducted in 11 patients with cirrhosis and splenomegaly, and the postoperative immune status was assessed (18). A comparison of the immune status of the peripheral blood before and at 1, 3, and 6 months after splenectomy showed that lymphocytes in the peripheral circulation increased sharply at postoperative 3 and 6 months, and the NLR decreased significantly after splenectomy. The frequency of CD4+ T cells decreased after splenectomy, whereas that of CD8+ T cells increased. Moreover, the frequencies of naïve and central memory subsets of CD4+ and CD8+ T cells decreased, whereas those of effector memory subsets showed an increasing trend. Additionally, the frequencies of other immune cells, such as γδ T cells, natural killer T cells, and natural killer cells, transiently increased, while those of inhibitory cells, such as regulatory T cells and bone marrow-derived suppressor cells, significantly decreased.
T-cell responses to viral and tumour antigens have been reported to increase after splenectomy. Furthermore, splenectomy has been reported to suppress the proliferation and metastasis of HCC by reducing MDSCs. Studies have also shown that splenectomy may facilitate systemic therapy for advanced HCC with splenomegaly; however, the procedure remains highly invasive (27, 28).
In contrast, PSE is less invasive than splenectomy and may increase hepatocyte growth factors or reduce factors inhibiting liver regeneration (29, 30). Despite potential fluctuations in portal vein blood flow, PSE may increase hepatic arterial blood flow by inducing the hepatic arterial buffer response, potentially improving the reserve capacity. PSE is widely performed for thrombocytopenia in cases of oesophageal varices and HCC. Matsukiyo et al. reported a significant increase in T lymphocytes in 23 patients who underwent PSE (31). In cases of splenomegaly and PHT in patients with HCC undergoing combination immunotherapy with atezolizumab and bevacizumab, PSE has been reported to improve immune parameters and the NLR and yield favourable therapeutic effects (32). Furthermore, it has also been reported that PSE contributes to the treatment of HCC with the multi-tyrosine kinase inhibitor (33).
In this study, PSE was administered for splenomegaly caused by PHT, the terminal stage of cirrhosis. A decrease in MDSC was expected, with concomitant improvements in the immune microenvironment. Further investigations are required to determine the impact of the immune environment on the long-term survival of patients with cirrhosis and the efficacy of PSE as a pretreatment for enhancing the effectiveness of combination immunotherapy for HCC.
Study limitations. First, this was a retrospective study conducted at a single institution; therefore, validation using cohorts from other institutions is necessary. Second, various immune cells contribute to the immune deficiency observed in cirrhosis; therefore, in future studies, it is necessary to assess the relationships among the activity states of each immune cell.
In conclusion, in patients with cirrhosis complicated by PHT, PSE may have the potential to break the negative spiral of disease progression by improving the immune environment and liver reserve capacity. This suggests that PSE-based therapy could emerge as a new treatment strategy for immune dysfunction in patients with cirrhosis (34).
Acknowledgements
The Authors thank Editage (www.editage.com) for English language editing.
Footnotes
Authors’ Contributions
Conceptualization: Toru Ishikawa; Data Curation: Toru Ishikawa; Formal Analysis: Toru Ishikawa; Investigation: Toru Ishikawa, Ryo Sato, Hiroki Natsui, Takahiro Iwasawa, Masahiro Ogawa, Yuji Kobayashi, Toshifumi Sato, Junji Yokoyama and Terasu Honma; Methodology: Toru Ishikawa; Project Administration: Toru Ishikawa; Resources: Toru Ishikawa; Software: Toru Ishikawa; Visualization: Toru Ishikawa; Writing – Original Draft: Toru Ishikawa; Writing – Review & Editing: Toru Ishikawa, Ryo Sato, Hiroki Natsui, Takahiro Iwasawa, Masahiro Ogawa, Yuji Kobayashi, Toshifumi Sato, Junji Yokoyama, and Terasu Honma.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this study.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received October 24, 2025.
- Revision received November 7, 2025.
- Accepted November 12, 2025.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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