Research ArticleClinical Studies
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Significance of Skeletal Muscle Loss in Liver Hypertrophy in Patients Undergoing Portal Vein Embolization Before Major Hepatectomy: Assessment With Body Composition and Nutritional Indicators

KENICHIRO ARAKI, NORIFUMI HARIMOTO, KEI SHIBUYA, AKIRA WATANABE, MARIKO TSUKAGOSHI, NORIHIRO ISHII, KEI HAGIWARA, RYO MURANUSHI, KOUKI HOSHINO, TAKAOMI SEKI and KEN SHIRABE
Anticancer Research January 2023, 43 (1) 209-216; DOI: https://doi.org/10.21873/anticanres.16151

Abstract

Background/Aim: The relationship between body composition including skeletal muscle and liver hypertrophy initiated by portal vein embolization (PVE) for major hepatectomy has not been clarified. This study aimed to investigate the effects of skeletal muscle, body adipose, and nutritional indicators on liver hypertrophy. Patients and Methods: Fifty-nine patients who underwent PVE scheduled for major right-sided hepatectomy were included. The skeletal muscle area of L3 as skeletal muscle index was calculated. The relationship between skeletal muscle loss and clinical variables was assessed. We also evaluated the relationship between >30% liver growth or >12% liver growth/week after PVE. Results: Skeletal muscle loss was observed in 39 patients (66.1%) and associated with zinc deficiency, visceral adipose index, liver growth rate, and liver growth rate/week. Multivariate analysis indicated that future liver volume and skeletal muscle index were associated with >30% liver growth, and functional future liver volume and skeletal muscle index were associated with >12% liver growth/week. Conclusion: Loss of skeletal muscle, and a small future remnant liver volume, attenuates liver hypertrophy initiated by PVE. Strength building and nutritional supplementation may have positive effects on liver hypertrophy after PVE.

Key Words:

It is essential to secure the future liver remnant volume (FRLV) to meet the safety of modern standards in major hepatectomy and prevent post-hepatectomy liver failure and mortality (1, 2). Portal vein embolization (PVE) is a conventional method to obtain sufficient FRLV before hepatectomy (3, 4). We conducted this research to ensure major hepatectomy safety by setting the criteria for hepatectomy using functional FRLV with ethoxybenzyl-magnetic resonance imaging (EOB-MRI) (5) and analyzing predictors that reach the criteria (6). However, with the advent of a super-aging society, there is a possibility that the conventional concepts of liver functional reserve and hepatectomy standards will not apply to elderly patients, and an approach using different multifaceted evaluations, including body composition and nutritional factors, is necessary (7).

Numerous studies have reported that sarcopenia is associated with poor prognosis and postoperative complications in various conditions in the surgical field of hepatic malignancies (8-10). In recent years, nutritional indicators have been closely related to the prognosis of pathological conditions and postoperative complications, and various serum markers and indices have been reported. Furthermore, a recent study reported that sarcopenia, diagnosed based on skeletal muscle mass, may attenuate liver hypertrophy after PVE (11). As mentioned above, to ensure the safety of major hepatectomy in an aging society, this study aimed to elucidate how skeletal muscle mass, body composition, and nutritional indicators affect liver hypertrophy after PVE.

Patients and Methods

Study design including patient selection and variables. We retrospectively selected patients who underwent PVE before scheduling a major hepatectomy between December 2015 and June 2022 in our hospital. To avoid bias due to liver hypertrophy, only cases scheduled for right-sided hepatectomy were included in the study. The first evaluation of computed tomography (CT) was conducted at the first visit to our hospital, and the second evaluation of CT after PVE was conducted approximately 3 weeks after PVE. Image analysis was performed using volume analyzer software to calculate FRLV, functional FRLV (fFRLV) (5), and body composition including skeletal muscle mass.

Data on patient status, liver function, and nutritional indicators, including neutrophil-to-lymphocyte ratio (NLR), serum level of zinc (Zn), branched chain amino acid (BCAA), BCAA/tyrosine molar ratio (BTR), prognostic nutritional index (PNI), and modified Glasgow prognostic score (mGPS), were collected from the medical records. Body composition values, including skeletal muscle and adipose areas, were calculated using volume analyzer software. All variables were obtained before performing PVE.

Ethical statement. The authors are accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki (revised in 2013). The study was approved by the Institutional Ethics Board (Approval no.: HS2020-127), which deemed informed consent unnecessary.

Image analysis of future remnant liver volume. In principle, a second CT scan was performed approximately 3 weeks after PVE. FRLV was calculated using volume analyzer software (SYNAPSE VINCNET, Olympus Medical Systems, Tokyo, Japan). Liver growth rate (%) after PVE was calculated using the following formula: [(FRLV after PVE/FRLV before PVE) × 100]−100. The liver growth rate/week (%) was calculated using the formula: liver growth rate/period from pre-PVECT to post-PVE CT scanning. The methodology for calculating fFRLV using EOB-MRI has been previously reported (5, 6).

Analysis of skeletal muscle and body composition. The skeletal muscle area on the underside of the 3rd lumbar vertebra (L3) was measured using CT performed within 30 days prior to PVE. Trained researchers were unaware of all anthropometric and patient characteristics and were dedicated processing systems to minimize measurement bias. A volume analyzer software (same as above) was used to identify and measure the skeletal muscle area. The visceral adipose and subcutaneous adipose areas in the umbilical region were measured similarly. These measurements were standardized to height (m2) to define skeletal muscle index (SMI), visceral adipose index (VAI), and subcutaneous adipose index (SAI).

The cutoff values for skeletal muscle loss were defined as 42 cm2/m2 for men and 38 cm2/m2 for women, according to the Japan Society of Hepatology guidelines (12).

PVE procedure. PVE was performed by interventional radiologists as described previously (6). Briefly, PVE was performed via an ipsilateral, percutaneous, transhepatic approach using coils and a gelatin sponge under local anesthesia. Access to a segmental branch of the portal vein was established under ultrasound guidance using a 21-gauge needle (PTCD injection needle; Hakko Medical, Chikuma, Japan). A 5-Fr sheath (Super Sheath; Medikit, Tokyo, Japan) was inserted into the portal branch using the Seldinger technique. Flush portography was performed using a 5-Fr balloon catheter (Selecon MP; Terumo, Tokyo, Japan) placed in the main and segmental branches. Selective embolization of the segmental branches was performed using a mixture of crushed gelatin sponge and iodine oil (Lipiodol, Guerbet, France) under balloon occlusion, followed by coil embolization. A 2.1-Fr microcatheter (Lighthouse, Piolax, Kanagawa, Japan) and microcoils were used, when necessary. Angiography of the main PV was performed to confirm the efficacy of PVE and patency of the non-target PV branches. At the end of embolization, the sheath was pulled back with tract embolization using a gelatin sponge.

Statistical analysis. Continuous data were presented as mean (SD) and median (range) for normally and non-normally distributed variables, respectively. Differences between the two cohorts were assessed using the Mann–Whitney U-test or Fisher’s exact test, as appropriate. Correlations against >30% liver growth rate or >12% liver growth rate/week were assessed by logistic regression analysis with continuous variables. These cutoff values (>30% for growth rate, >12% for growth rate/week) were derived from cutoffs determined by ROC analysis with Youden’s index for meeting our liver resection criteria of fFRLV: 615 ml/m2. In the multivariate analysis, a stepwise procedure was performed using backward stepwise selection. Confounding factors, such as FRLV and fFRLV, were assessed using different multivariate models. These models were subsequently compared using standard criteria [Akaike information criterion (AIC) values]. Correlations between SMI and growth rate and between SMI and growth rate/week were assessed using Pearson’s correlation coefficient. Receiver operating characteristic (ROC) curve analysis was performed to determine the cutoff value using the Youden index. All statistical analyses were performed using the JMP Pro software ver. 14.0 (SAS Institute Inc., Cary, NC, USA). Statistical significance was set at p<0.05.

Results

Participants for evaluation. A total of 74 patients were identified who underwent PVE. Of the 74 patients, 15 were excluded because they did not schedule right-sided major hepatectomy, such as left hemi-hepatectomy or left tri-sectionectomy. Therefore, 59 patients were retained in this study, and factor data were extracted from all 59 cases. Among these patients, 20 (33.9%) did not have skeletal muscle loss, and 39 (66.1%) met the criteria for skeletal muscle loss.

Characteristics depending on the loss of skeletal muscle. The characteristics depending on the absence or presence of skeletal muscle loss are shown in Table I. Female sex (p=0.022) and body mass index (BMI) (p=0.025) were significantly related to skeletal muscle loss. Among the nutritional indicators, Zn (p=0.004) was significantly related to skeletal muscle loss. VAI (p=0.003) was significantly associated with skeletal muscle loss. In the image analysis, growth rate (p<0.001) and growth rate/week (p<0.001) were significantly related to skeletal muscle loss. The growth rate of the fFRLV (p=0.067) tended to be related to skeletal muscle loss.

View this table:
Table I.

Characteristics depending on absence or presence of skeletal muscle loss.

Univariate and multivariable analyses for >30% growth rate after PVE. We performed logistic regression analysis to assess factors related to >30% liver growth rate after PVE (Table II). In univariate analysis, SMI [odds ratio (OR)=1.132, 95% confidence interval (CI)=1.040-1.233, p=0.004], FRLV before PVE (OR=0.985, 95%CI=0.976-0.994, p<0.001), and fFRLV before PVE (OR=0.987, 95%CI=0.980-0.994, p<0.001) were significantly related to >30% liver growth rate after PVE. In multivariate analysis, skeletal muscle loss (OR=1.163, 95%CI=1.051-1.286, p=0.006), FRLV before PVE <415 ml/m2 (OR=0.982, 95%CI=0.972-0.993, p<0.001), and fFRLV before PVE (OR=0.986, 95%CI=0.977-0.995, p=0.002) were significantly associated with >30% liver growth rate after PVE. Univariate and multivariable analyses for >12% growth rate/week after PVE. We performed logistic regression analysis to assess factors related to >12% liver growth rate after PVE (Table III). In univariate analysis, SMI (OR=1.004, 95%CI=1.037-1.232, p=0.006), FRLV before PVE (OR=0.994, 95%CI=0.988-1.000, p=0.044), and fFRLV before PVE (OR=0.993, 95%CI=0.987-0.999, p=0.016) were significantly related to >12% liver growth rate/week after PVE. In multivariate analysis, SMI (OR=1.121, 95%CI=1.031-1.220, p=0.010), FRLV before PVE (OR=0.994, 95%CI=0.987-1.000, p=0.054), and fFRLV (OR=0.993, 95%CI=0.987-0.99, p=0.030) were significantly related to >12% liver growth rate/week after PVE.

View this table:
Table II.

Univariate and multivariate analyses for >30% of liver growth rate after portal vein embolization (PVE).

View this table:
Table III.

Univariate and multivariate analyses for >12% of liver growth rate/week after portal vein embolization (PVE).

Correlation between the loss of skeletal muscle and liver growth by PVE. We evaluated the correlative relationships between SMI (cm2/m2) and liver growth rate (%), and between SMI (cm2/m2) and liver growth rate/week (%). The SMI significantly correlated with liver growth rate (R=0.475, p<0.001) (Figure 1A). The SMI and liver growth rate/week were also significantly correlated (R=0.500, p<0.001) (Figure 1B).

Figure 1.
Figure 1.

Correlation between SMI and liver growth rate after PVE. Correlation scatter plots between skeletal muscle index (SMI) and liver growth rate and between SMI and liver growth rate/week. (A) Correlation between SMI (cm2/m2) and liver growth rate (%). (B) Correlation between SMI (cm2/m2) and liver growth rate/week (%).

We also evaluated the correlation between skeletal muscle loss and insufficient liver growth using ROC analysis. The correlation of the loss of skeletal muscle after PVE for each factor was as follows: liver growth rate [area under curve (AUC)=0.793, 95%CI=1.215-3.789] (Figure 2A) and liver growth rate/week (AUC=0.791, 95%CI=1.132-3.924) (Figure 2B).

Figure 2.
Figure 2.

Receiver-operating characteristic analysis of liver growth rate after PVE. (A) A receiver-operating characteristic (ROC) analysis of liver growth rate after portal vein embolization (PVE) for the loss of skeletal muscle with area under curve (AUC) of 0.793 in the study cohort (n=59). (B) A ROC analysis of liver growth rate/week after PVE for the loss of skeletal muscle with AUC of 0.791.

Discussion

This study indicated that loss of skeletal muscle attenuated liver hypertrophy after PVE. We previously reported that in elderly patients, liver regeneration after hepatectomy may be diminished and may lead to liver failure. Based on these results, we hypothesized that liver regeneration may be attenuated in a population with low skeletal muscle mass, such as elderly patients (13). A previous study by a MD Anderson group reported that the degree of hypertrophy and kinetic growth rate, which were calculated using standardized future liver remnant (sFLR), were associated with sarcopenia defined by skeletal muscle mass (11). Other multicentric groups, named DRAGON collaborative, reported the study with the largest number, and sFLR before PVE was also associated with sarcopenia (14). “sFLR” is calculated by sFLR with body surface area (15). Since the three studies including our results, are homologous, it seems that skeletal muscle mass affects both liver hypertrophy and liver hypertrophy per week.

In our previous study, fFRLV was the most significant predictor of the resection limit for hepatectomy after PVE (6). From the results of this study, FRLV is a significant factor for liver growth rate (>30%) after PVE, and fFRLV, which includes two elements of both future liver volume and regional liver function, was a significant factor for liver growth rate/week (>12%) after PVE. However, this study also indicated that no single factor of liver function test was associated with liver hypertrophy with PVE. Based on these results, the degree of liver hypertrophy may be related to the small size of the future remnant liver, regional remnant liver function, and skeletal muscle mass, but not to total liver function.

To the best of our knowledge, this is the first study to examine liver hypertrophy after PVE, including skeletal muscle and body composition as well as various nutritional indicators. Other than skeletal muscle, body composition (VAI and SAI) and nutritional indicators, such as NLR, PNI, zinc level, amino acid status, and mGPS were not associated with liver hypertrophy. However, since visceral adipose tissue (VAI) and zinc deficiency were significantly associated with skeletal muscle loss in this study, these factors could be involved in skeletal muscle formation and may indirectly affect hepatic hypertrophy. In our previous study, zinc deficiency was significantly associated with poor liver function, more severe liver fibrosis, high incidence of postoperative complications, and worse overall survival according to multivariate analysis (16). Concerning patients with skeletal muscle loss, it is necessary to verify whether zinc supplementation directly or indirectly has a positive effect on liver hypertrophy and postoperative outcomes.

Amino acids, including BCAA, play an important role in skeletal muscle formation (17). In the current study, BCAA and BTR were not associated with liver hypertrophy. Beppu et al. conducted a randomized controlled trial and found that BCAA supplementation improved functional liver regeneration and function in patients undergoing PVE followed by major hepatic resection (18). According to this result, the serum level of BCAA was not related to liver hypertrophy, and BCAA supplementation may have stimulated metabolism and affected hypertrophy. We are currently conducting basic research on amino acid metabolism and liver regeneration caused by skeletal muscle abnormalities using a transgenic mouse model of skeletal muscle dysplasia. We believe that this study provides insight into the significance of amino acids in liver regeneration. The molecular mechanisms underlying the relationship between sarcopenia and liver regeneration remain unclear. In recent years, attention has been paid to “the liver-muscle correlation” between the liver and skeletal muscle due to crosstalk mediated by amino acids, insulin resistance, and myokine (19, 20). We considered the possible effects of association with myokines and amino acids on liver regeneration. This molecular mechanism is expected to be further elucidated in the future.

Limitations. This study had several limitations. First, this was a retrospective study conducted at a single center. The two previous studies were also retrospective. Therefore, a larger prospective study is warranted to confirm and update the conclusions of this study. Second, there was a possibility of patient selection bias. Before 2018, the indication for PVE was decided primarily by the attending physician. After 2018, we strictly decided on the indication of PVE based on the value of fFRLV using EOB-MRI. Fourth, there were several criteria for skeletal muscle loss and sarcopenia. Since this study targeted Japanese patients, the criteria proposed by the Japan Society of Hepatology guidelines for liver disease were used to ensure the reliability of these criteria.

In conclusion, loss of skeletal muscle attenuates liver hypertrophy initiated by PVE, and visceral adipose and nutritional factors may affect skeletal muscle and, eventually, liver hypertrophy. Patients with abundant skeletal muscle and sufficient nutritional status can expect sufficient liver hypertrophy owing to PVE scheduled for major hepatectomy. In elderly patients with sarcopenia, strength building, and nutritional supplementation may have a positive effect on liver hypertrophy.

Footnotes

  • Authors’ Contributions

    Conception and design: Araki K, Harimoto N, Shirabe K. Data analysis and interpretation: Araki K, Watanabe A, Tsukagoshi M, Ishii N. Manuscript writing: All Authors. Final approval of manuscript: All Authors.

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest in relation to this study.

  • Received November 3, 2022.
  • Revision received November 29, 2022.
  • Accepted November 30, 2022.

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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Significance of Skeletal Muscle Loss in Liver Hypertrophy in Patients Undergoing Portal Vein Embolization Before Major Hepatectomy: Assessment With Body Composition and Nutritional Indicators
KENICHIRO ARAKI, NORIFUMI HARIMOTO, KEI SHIBUYA, AKIRA WATANABE, MARIKO TSUKAGOSHI, NORIHIRO ISHII, KEI HAGIWARA, RYO MURANUSHI, KOUKI HOSHINO, TAKAOMI SEKI, KEN SHIRABE
Anticancer Research Jan 2023, 43 (1) 209-216; DOI: 10.21873/anticanres.16151
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