Liver resection remains a mainstay treatment for patients with primary or secondary liver cancer (for instance, hepatocellular carcinoma or colorectal liver metastases) with curative intent (1). However, many patients have been at an advanced stage at first diagnosis, and only 15-25% of patients are indicative of liver resection (2). For those patients who are not eligible for surgery, a majority of them are due to the limited future liver remnant (FLR), which is the remaining part of the liver after liver resection, and it serves as a key determinant for extended liver resection (3). FLR has to be sufficient to maintain normal physiologic function after liver resection, otherwise a lethal complication, post-hepatectomy liver failure will occur (4). To prevent the occurrence of liver failure after liver resection, the FLR volume limit should be > 20% of the total liver in a normal liver, > 30% in the abnormal liver (such as steatosis or post-chemotherapy), and at least 40% in the cirrhotic liver (5).

In clinical practice, many strategies have been proposed to increase the size of the FLR volume before extended liver resection. Portal vein embolization (PVE) is the commonly used technique and was first introduced by Masatoshi Makuuchi in the 1980s (6). At PVE, the branch of the portal vein leading the blood to the diseased lobes of the liver is occluded interventionally by using sponges or metal coils. By this interruption of the blood flow, the un-embolized lobes (i.e. the FLR) will be exposed to all the portal venous blood flow. This increase in flow, including exposure to nutrients, toxins, and oxygen triggers liver growth (7). Most often, after waiting for several weeks, a sufficient growth of the FLR volume has occurred and a radical liver resection can be performed safely. PVE is still the standard procedure before extended liver resection when the FLR volume is estimated to be insufficient (8). Typically, an FLR growth of 12-38% can be observed within 4-8 weeks after PVE (9). However, during the waiting period, approximately 20-40% of patients cannot proceed to hepatic resection due to insufficient liver growth or tumor progression (9, 10). Furthermore, patients with poor liver growth after PVE also have an increased risk of post-intervention complications (11).

Hepatobiliary surgeons have been committed to developing an improved method to overcome the above-mentioned limitations of PVE. In recent years, a novel strategy, called associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been proposed (12, 13). It contains two steps: in the first step, after the branch of the portal vein to the diseased lobes has been ligated (PVL, rather similar to the PVE procedure), the liver parenchyma is transected between the ligated part and the unligated part (i.e. the FLR). Once the FLR volume has increased sufficiently, liver resection can be performed to remove the liver tumor in the second step (12, 14). Interestingly, ALPPS can trigger an accelerated FLR growth in a shorter time than PVE, with a 40-80% FLR increase in only 6-9 days (12–15). However, ALPPS has high perioperative morbidity and mortality due to major surgical trauma, and the FLR growth varies among patients after ALPPS stage-1 (14). Despite surgically successful ALPPS stage-1, not all patients can complete the liver resection (14).

It is therefore of clinical importance to identify pretreatment factors that indicate a risk for insufficient FLR growth, which might allow optimizing treatment management of patients with liver cancer. Many clinical variables have been identified to be predictive for insufficient liver growth after PVE/ALPPS stage-1, for example, age, body mass index, and the diseased liver parenchyma (16). Among those, body composition is drawing increasing attention and has been assumed to be a treatable, prognostic factor in several hepatopancreatobiliary cancers after surgery (17–19). Sarcopenia is characterized by a progressive, generalized loss of skeletal muscle mass and function with aging (20). Previous studies have demonstrated sarcopenia to be associated with poor overall survival, early tumor recurrence, prolonged intensive care unit, and hospital stay after liver resection (21, 22). In recent years the influence of sarcopenia on the FLR growth after PVE/ALPPS stage-1 has been studied. However, no research systematically summarizes the results of these studies to date. This study aimed to provide such a systematic review.

The research protocol was prospectively registered at the public platform International Platform of Registered Systematic Review and Meta-analysis Protocols (https://inplasy.com/) with registration number INPLASY202280038. This study was carried out in accordance with the guidance of the Preferred Reporting Items for a Systematic Review and Meta-analysis (PRISMA) (23). The PRISMA checklist can be found in Supplementary Table S1 .

The present study systematically reviews the association between skeletal muscle loss and FLR growth after PVE/ALPPS stage-1. A high incidence of sarcopenia among patients undergoing PVE was observed, and sarcopenia was associated with impaired FLR growth after PVE/ALPPS stage-1. However, its relationship with post-treatment complication rate, post-hepatectomy liver failure as well as surgical resection rate remains unclear.

The median incidence of sarcopenia among patients undergoing PVE in the included studies was 63%, which was higher than the reported incidence in patients with colorectal liver metastases (17-26%) (18, 31) or hepatocellular carcinoma (30-54%) (18), the two most common indications for PVE/ALPPS. Generally, the incidence of sarcopenia in patients with cancer has a wide variation due to different tumor types, tumor stages, measuring methods, and indices and criteria used (32). In the case of PVE/ALPPS, the indications usually vary among centers, which may also contribute to a varying and higher incidence of sarcopenia. Another explanation for the high observed incidence of sarcopenia is that the patients requiring PVE/ALPPS often have a chronically diseased liver such as liver cirrhosis (33) or have experienced several cycles of chemotherapy (e.g. neoadjuvant chemotherapy in patients with colorectal liver metastases) (31, 34). Considering that patients undergoing PVE/ALPPS experience two major interventions in a relatively short time, the patients may be at a high risk of malnutrition if additional calories and protein cannot be supplemented in time. These additional clinical conditions may further impair patients’ nutritional status. The higher incidence of sarcopenia also implies that the evaluation of body composition in these patients should be paid more attention to the perioperative assessment.

All included studies applied CT-based measurement for muscle mass assessment. This is reasonable given that CT is a commonly used imaging modality for the diagnosis and staging of patients with liver cancer. Furthermore, in the setting of PVE/ALPPS, CT is also widely applied for liver volumetry in pretreatment evaluation and to evaluate liver volume change after intervention. That is to say, the evaluation of body composition does not pose an extra burden for these patients. Dual-energy X-ray absorptiometry and bioelectrical impedance analysis are the other two commonly used methods for body composition measurement (35), but, to the best of our knowledge, they have not been employed in predicting liver remnant growth after surgery.

However, when analyzing the body composition, only limited details on CT imaging were provided in the included studies. Only two studies reported the imaging phase and just three studies described the slice thickness. It has been shown that these factors exert a considerable impact on the results of body composition analysis (36). In a study by Morsbach et al, the influence of contrast media and slice thickness on CT body composition segmentation was evaluated (37). They found that the skeletal muscle mass area, adipose tissue area, and muscle and fat attenuation (expressed in Hounsfield Units) showed a significant change after contrast media administration. There also was a significant effect on the area measurements (skeletal muscle mass area and adipose tissue area) when the slice thicknesses were adjusted. A systematic review summarized a group of CT-related factors which may affect the sarcopenia assessment (38). The CT parameters that according to the review can potentially affect the assessment included the use of contrast media, kilovoltage, CT manufacture and model, patient position, and slice thickness (38). Considering such many potential confounders, researchers need to bear them in mind when measuring body composition before transferring their results into clinical implementation. Besides, to make the findings reproducible and to increase the comparability among different studies, it also seems necessary to provide such information when reporting the body composition results.

Recent research has identified muscle quality, which can be determined by the infiltration of fat into muscle, as an independent prognostic factor in several types of cancer (39–41). In the present review, only one study adopted a composite index that combined skeletal muscle quantity and quality (named “muscularity”) (28), while the others only assessed skeletal muscle quantity. Theoretically, muscularity should have a better performance in the prediction of the clinical outcomes, including the FLR growth after PVE/ALPPS stage-1, but this needs to be confirmed by further research. Besides, as highlighted by the European Working Group on Sarcopenia in Older People 2 evaluation of muscle strength and physical performance is equivalent to the evaluation of muscle quantity and quality in the diagnosis of sarcopenia (20). Future research assessing the impact of sarcopenia on liver growth and the clinical outcomes in patients with cancer can also consider taking these components into account.

Even though an obvious heterogeneity was displayed in the included studies, all of them drew a similar conclusion that sarcopenia had a negative influence on liver growth after PVE/ALPPS stage-1. Furthermore, sarcopenia seemed to have an association with a higher risk of post-hepatectomy liver failure and lower surgical resection rate in the patient who underwent PVE/ALPPS, although the results were inconsistent in this review. Sarcopenia is also a risk factor for poor overall survival in patients with liver cancer (21). But the impact of sarcopenia on the overall survival of patients who undergo PVE/ALPPS remains unknown.

Tumor progression is another common reason for patients not being able to reach curative surgery after PVE. Its incidence is even greater than that of insufficient liver growth contributing to a “failed” PVE, 19% vs 11%, as reported in the international DRAGON trial (42). This may be partly due to the slow growth after PVE, approximately 4-8 weeks to induce an FLR growth of 12-38% (9, 43). During this long waiting interval, the tumor is likely to progress, leaving the patient not eligible for surgery anymore. Until now, only one study explored the influence of sarcopenia on the resectability in patients undergoing PVE. It showed that sarcopenia (defined as psoas muscle index < 500 mm²/m²) was a risk factor for unresectability (44). However, the sample size of that research was limited (only 88 patients). On the other hand, a meta-analysis that included 13 studies revealed that sarcopenia was also significantly associated with tumor recurrence (adjusted hazard ratio: 1.76) (21). Whether sarcopenia results in both impaired liver growth and increased tumor progression after PVE, and whether improvement of patient sarcopenia status can increase resectability and long-term prognosis are still unclear.

Even though all studies claimed that sarcopenia impaired liver growth, it is of note to point out that sarcopenia should only be considered as a cofactor that undermines FLR growth after PVE/ALPPS stage-1. To put it another way, other vital clinical variables also determine liver growth after PVE/ALPPS stage-1. Three of the included studies also detected initial FLR volume, total bilirubin level, and body mass index as independent risk factors for insufficient liver growth (28–30). As a prognostic factor, the initial FLR volume was also reported in previous studies (45–47). Other reported indicators include age (45, 48), embolic agent (49–51), segment IV embolization (52, 53), chemotherapy (45), and portal collaterals (54, 55). It is assumed that a combination of these risk factors may improve the predictive accuracy for the FLR growth after PVE/ALPPS stage-1.

There are some limitations in this study. This review was first limited by the small number of included studies, all with a limited sample size (median: 90). Also, there were no prospective studies and only one multicenter study. The lack of large prospective multicenter studies may undermine a convincing conclusion drawn from this systematic review. Second, due to the limited study number and methodological heterogeneity, it was not possible to perform a meta-analysis and synthesize the results to provide a pooled relative risk value of sarcopenia for poor FLR growth. Third, the limited number of studies and the research heterogeneity also made it difficult to identify the most accurate and reliable parameter for sarcopenia assessment, given that a variety of indices were used for muscle mass evaluation. As summarized in a review, as many as 14 methods are currently available for sarcopenia assessment (32). Nevertheless, an index combining skeletal muscle quantity and quality evaluation (for example, muscularity) seems more rational and effective. Future studies can be designed to compare these indices. Lastly, there seems to be a need to improve the research and reporting quality of studies on sarcopenia. For example, detailed information on CT imaging during body composition measurement is required to ensure a reproducible and reliable study.

Research on the impact of sarcopenia on liver growth after PVE/ALPPS stage-1 is still in its initial stage. Based on currently available evidence, sarcopenia seems to have a high incidence in patients undergoing PVE/ALPPS and it may impair FLR growth. Its relationship with post-treatment complications, post-hepatectomy liver failure, and resection rate requires further comprehensive research.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author/s.

Conceptualization, QW, and ZL. Methodology, QW and AW. Validation, AW, ZL, and TB. Formal analysis, QW, AW and ZL. Investigation, ZL. Data curation, AW, and ES; writing—original draft preparation, QW, and AW. Writing—review and editing, ES and TB. Visualization, QW. Supervision, ZL, and TB. Project administration, QW. Funding acquisition, QW.

This research was funded by Medical Diagnostics Karolinska (grant number: 929646).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.