Impact of metabolic dysfunction-associated steatotic liver disease on long-term prognosis in hepatocellular carcinoma patients undergoing hepatectomy

Introduction

Hepatocellular carcinoma (HCC) is a prevalent malignancy worldwide and is ranked as the fourth most commonly diagnosed cancer (1). Globally, over half a million new diagnoses of liver cancer are made each year (2). Surgical resection, as one of the effective approaches for treating HCC, is influenced by various factors in determining the prognosis of HCC patients (3). In addition to traditional factors such as tumor burden and pathology, metabolic-related factors are receiving increasing attention (4,5). Many studies have reported that diabetes and obesity have a significant impact on the long-term prognosis of HCC patients undergoing hepatectomy (6-10). Some studies also have reported that metabolic syndrome is a risk factor for long-term prognosis in HCC patients undergoing surgical resection (11,12). The use of statin drugs was associated with a better prognosis in HCC patients after hepatic resection, which further indicates that metabolic-related factors play an important role in the prognosis of HCC patients undergoing liver resection (13).

Nonalcoholic fatty liver disease (NAFLD) is one of the causes of HCC, and its increasing incidence worldwide has resulted in a rising number of patients developing liver cancer (14,15). In recent years, metabolic dysfunction-associated fatty liver disease (MAFLD) was recommended to better identify the pathogenic role of hepatic steatosis and metabolic dysfunction than NAFLD (16). Nevertheless, a recent consensus has proposed the concept of metabolic dysfunction-associated steatotic liver disease (MASLD), receiving unanimous agreement from experts globally (17). Its diagnosis encompasses not only imaging or pathologically confirmed hepatic steatosis but also the presence of at least one of five cardiometabolic risk factors. People without abnormal metabolic parameters are considered to have cryptogenic steatotic liver disease (SLD) (18). Imaging techniques, including computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound, are the most commonly used methods for diagnosing hepatic steatosis. Compared to liver biopsy, it has the advantages of minimal trauma, simple operation, and ease of implementation (19,20). Metabolic factors play a significant role in the long-term prognosis of HCC patients after hepatectomy. MASLD, as a systemic metabolic disorder, is often accompanied by the occurrence of diabetes and obesity. Therefore, we have reason to believe that MASLD has an important impact on the long-term prognosis of HCC patients after liver resection. A previous study has already reported a highly significant correlation between MASLD and the incidence of HCC, the progression of liver disease, and the risk of liver-related mortality (21). Research has also reported that metabolic dysfunction has a beneficial impact on the treatment of hepatitis B (22). However, there have been no studies reported on the impact of MASLD on the prognosis of HCC patients after liver resection. Due to the relatively recent proposal of the MASLD definition, our current understanding of MASLD as an etiological factor influencing HCC prognosis is still limited. Therefore, the impact of MASLD on postoperative outcomes in HCC remains controversial. This study aimed to compare the long-term prognosis of liver resection among HCC patients with and without MASLD. This provides new insights into exploring the impact of metabolic diseases on the prognosis of HCC patients undergoing hepatectomy. We present this article in accordance with the STROBE reporting checklist (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-489/rc).

Methods

Study design and patients

This study was designed as a retrospective study and was reviewed by the Ethics Committee of West China Hospital of Sichuan University (No. 2022-1774). All patients signed an informed consent form. It conformed to the ethical guidelines of the Declaration of Helsinki and its subsequent amendments. The study included patients who were diagnosed with HCC and underwent hepatectomy at West China Hospital of Sichuan University between January 2011 and December 2017.

The inclusion criteria for this study were patients with a pathological histological diagnosis of HCC who underwent partial hepatectomy. The exclusion criteria were as follows: (I) preoperatively, patients underwent any intervention, including transcatheter arterial chemoembolization and neoadjuvant chemotherapy; (II) patients underwent radiofrequency ablation; (III) pathology after surgery confirmed non HCC or other pathological types of tumors; (IV) patients who underwent hepatectomy surgery did not participate in postoperative follow-up; (V) clinical data of the patients were missing; (VI) patients suffered liver transplant; and (VII) patients suffered partial tumor resection or palliative surgery.

Hepatic steatosis can be defined using various imaging modalities. In CT, both unenhanced and contrast-enhanced scans reveal steatosis when the liver’s absolute attenuation measures equal to or less than 40 Hounsfield units (HU) (23). MRI contributes to the definition by assessing the average MRI-estimated proton density fat fraction (PDFF) value, considering values equal to or greater than 5% indicative of hepatic steatosis (24). Additionally, ultrasound, specifically using the controlled attenuation parameter (CAP) with a threshold set at 283 dB/m, aids in monitoring hepatic steatosis. Values surpassing 283 dB/m are identified as indicative of the presence of hepatic steatosis (25). These criteria collectively provide insights into fatty liver characterization across CT, MRI, and ultrasound imaging methods. In this study, patients in the metabolic dysfunction-associated fatty liver disease (MASLD) group were diagnosed based on the diagnostic criteria for MASLD, which requires the presence of hepatic steatosis through preoperative imaging techniques including MRI, CT, or ultrasound and at least one of five cardiometabolic risk factors: overweight or obesity, hypertension, type 2 diabetes mellitus (T2D), plasma triglyceride (TG) levels equal to or greater than 1.7 mmol/L, and plasma high-density lipoprotein (HDL) less than or equal to 1.0 in males and less than or equal to 1.3 in females. In the subgroup analysis, patients in the overweight group were categorized as having a body mass index (BMI) of more than 23 kg/m² (26).

Data collection and study outcomes

Retrospective data collection was performed at the time of surgery, which encompassed information on age, sex, BMI, presence of T2D, hypertension, ascites, extrahepatic metastasis, and other laboratory examinations. Meanwhile, we recorded the histopathological characteristics of the tumor excised after hepatectomy, including satellite nodules, cirrhosis, microvascular invasion (MVI), tumor thrombus, lymph node metastasis, and degree of differentiation.

The follow-up period concluded on November 20th, 2022. The main outcome of the study was recurrence-free survival (RFS), which was defined as the period between the surgery and the date when the first HCC recurrence was diagnosed. The secondary endpoint was overall survival (OS), which was defined as the period between the date of surgery and death.

Statistical analysis

This study conducted statistical analyses using IBM SPSS Version 23.0 and used GraphPad Prism 8 to create graphs. Continuous variables are presented as the means with standard deviations, while categorical variables are summarized as frequencies and percentages. Kaplan-Meier survival curves were used to assess the prognosis of the two groups, and the log-rank (Mantel-Cox) test was used to compare whether there was a significant difference between the survival curves of the two groups. The Cox proportional hazards regression model was used to conduct both univariate and multivariate analyses of the hazard ratio (HR) of RFS and OS. A P value less than 0.05 was considered statistically significant (27).

The use of propensity score matching (PSM) analysis is prevalent in retrospective research analysis, as it allows for post-hoc adjustments of diverse baseline parameters, thereby mimicking the outcomes of an imaginary randomized study (28). Propensity scores were computed using the following 26 variables: age, BMI, tumor size, tumor number, total bilirubin, γ-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), HDL, low-density lipoprotein (LDL), triglycerides (TG), alpha-fetoprotein (AFP), sex, hypertension, diabetes, cirrhosis, ascites, satellite nodule, tumor thrombus, lymph node metastasis, extrahepatic metastasis, hepatitis B virus, hepatitis C virus, MVI, and high differentiation. To increase the authenticity and reliability of the results, a PSM analysis was employed with a nearest-neighbor matching scheme of 1:1 and a caliper size of 0.1 to minimize the influence of potential confounding factors and selection bias between the MASLD and non-MASLD groups.

Results

Patient characteristics

To explore the impact of MASLD on the long-term prognosis of HCC patients undergoing hepatectomy, a total of 1,525 patients from West China Hospital of Sichuan University between January 2011 and December 2017 were collected. Due to incomplete clinical data, patients lost to follow-up for various reasons after hepatectomy and postoperative pathological diagnosis, our study preliminarily excluded 179, 204, and 33 patients, respectively. In addition, to reduce the heterogeneity of collected patients and ensure the authenticity of the study, we excluded patients who underwent neoadjuvant chemotherapy, preoperative transcatheter arterial chemoembolization, and radiofrequency ablation. Eventually, our study included a total of 909 HCC patients who underwent liver resection surgery. Among them, 97 (10.7%) patients who received hepatectomy meeting the diagnostic criteria for MASLD were designated as the MASLD group, while the remaining 812 (89.3%) patients who received hepatectomy formed the non-MASLD group (Figure 1).

Figure 1 Study flow diagram. HCC, hepatocellular carcinoma; MASLD, metabolic dysfunction-associated steatotic liver disease; PSM, propensity score matching.

The characteristics of the study group at baseline are displayed in Table 1. The study population had a mean age of 54.4 years, with the majority of patients being male (n=739, 81.30%). The median tumor size was 4.00 cm, and most patients had a single tumor (n=758, 83.3%). Compared to the non-MASLD group, the individuals in the MASLD group had notably higher levels of TG (1.35 vs. 0.93 mmol/L; P<0.001), but lower levels of HDL (1.10 vs. 1.27 mmol/L; P<0.001) and levels of AFP (18.31 vs. 126.10 ng/mL; P<0.001). The MASLD group had a greater percentage of diabetes (20.62% vs. 5.67%; P<0.001) and hypertension (29.90% vs. 11.95%; P<0.001), however, the percentage of cirrhosis was lower (30.92% vs. 71.67%; P<0.001). To minimize the impact of confounding factors on the results, we conducted a PSM (1:1 matching) analysis, and each group had 83 individuals after matching. The baseline characteristics of the two groups were balanced after matching, and the standardized mean differences in all variables were less than 0.1 (Table 2).

Survival outcomes before PSM

In the entire study population, a total of 629 patients developed HCC recurrence during the follow-up period. The 1-, 3-, and 5-year RFS rates for the entire population were 62.8%, 39.9%, and 27.6%, respectively. The MASLD group had a median RFS of 23.1 months, whereas the non-MASLD group had a median RFS of 25.5 months. In the MASLD group, the 1-, 3-, and 5-year RFS rates were 52.6%, 20.62%, and 0%, respectively. These rates were lower than those of the non-MASLD group, which were 64.0%, 42.2%, and 30.9%, respectively (P=0.04).

During the follow-up period, a total of 241 patients died in the entire cohort. The 1-, 3-, and 5-year OS rates for the entire population were 73.2%, 54.5%, and 42.5%, respectively. At the same time, the non-MASLD group exhibited OS rates at 1-, 3-, and 5-year intervals, with rates of 76.2%, 59.2%, and 47.5%, respectively. These rates were higher than those observed in the MASLD group, which were 47.4%, 14.4%, and 0%, respectively (P=0.01). In summary, the patients without MASLD in our study demonstrated significantly longer recurrence-free survival and OS than those with MASLD (Figure 2).

Figure 2 RFS (A) and OS (B) after hepatectomy in HCC patients with or without MASLD before PSM. RFS, recurrence-free survival; OS, overall survival; HCC, hepatocellular carcinoma; HR, hazard ratio; CI, confidence interval; MASLD, metabolic dysfunction-associated steatotic liver disease; PSM, propensity score matching.

MASLD was observed to be a risk factor for both RFS and OS in HCC patients after univariate analysis (P=0.03 and P=0.03, respectively) (Table 2). According to multivariate analysis, cirrhosis, satellite nodule, tumor thrombus, tumor size, tumor number, AST, GGT, AFP, and MASLD were all important factors that affected the OS prognosis of patients. All factors were identified as risk factors for OS in HCC patients who underwent hepatectomy. Meanwhile, satellite nodule, tumor thrombus, tumor size, tumor number, AFP, and MASLD were risk factors that affected RFS. The multivariate analysis results from the Cox proportional hazards model indicated that MASLD could be associated with worse RFS [HR =1.23; 95% confidence interval (CI), 1.13–1.72; P=0.03] and OS (HR =2.04; 95% CI, 1.06–2.73; P=0.03) in HCC patients who underwent liver resection surgery.

Survival outcomes after PSM

Additionally, we also conducted a PSM analysis of our database (Table 3). After PSM analysis, in the MASLD group, the median RFS was 26.1 months, which was significantly lower than the 39.7 months observed in the non-MASLD group. The RFS rates in the MASLD group were lower at the 1-, 3-, and 5-year intervals, with rates of 51.8%, 18.1%, and 0%, respectively, than those in the non-MASLD group, which had rates of 71.1%, 55.4%, and 42.2%, respectively. Moreover, the 1-, 3-, and 5-year RFS rates were higher in the non-MASLD group (81.9%, 69.9%, and 59.0%, respectively) than in the MASLD group (43.4%, 10.8%, and 0%, respectively). Additionally, we found that the two groups had significant differences in both RFS and OS based on the Kaplan-Meier survival curve analysis (P=0.02 and P=0.01, respectively) (Figure 3). The results remained consistent with the results before PSM analysis. Thus, MASLD might be related to the poor prognosis of HCC patients undergoing liver resection.

Figure 3 RFS (A) and OS (B) after hepatectomy in HCC patients with or without MASLD after PSM. RFS, recurrence-free survival; OS, overall survival; HCC, hepatocellular carcinoma; HR, hazard ratio; CI, confidence interval; MASLD, metabolic dysfunction-associated steatotic liver disease; PSM, propensity score matching.

Subgroup analysis

According to the diagnostic criteria for MASLD, based on BMI values, we divided MASLD patients into two groups for subgroup analysis: the lean/normal weight group (BMI <23 kg/m²) and the overweight group (BMI ≥23 kg/m²). In the subgroup analysis, patients in the overweight group in our study had better RFS than those in the lean/normal group (P=0.03) (Figure S1). Lin et al. also found that lean status was a risk factor for HCC recurrence (29). In terms of OS, there was no statistically significant difference between the two groups, with an exact P value of 0.88. Similarly, based on the diabetes criteria in the MASLD diagnostic standard, we divided MASLD into a T2D group (T2D) and a non-T2D group (non-T2D). Analysis showed no statistically significant differences in either RFS or OS between the two groups (P=0.71 and P=0.89, respectively) (Figure S2). Thus, in HCC patients with MASLD, overweight appears to have a positive effect on tumor recurrence, yet further validation with a larger sample size is required.

Meanwhile, we conducted a subgroup analysis on patients with concurrent HBV infection. We found that the two groups had significant differences in both OS and RFS based on the Kaplan-Meier survival curve analysis (P=0.003 and P=0.04, respectively) (Figure S3). Similarly, in HCC patients without HBV infection, MASLD was also closely associated with poor RFS. Unfortunately, we did not observe the effect of MASLD on OS, but according to the survival curve, we were able to obtain that the median OS time of the MASLD group was significantly lower than that of the non-MASLD group (Figure S4). The results before and after the subgroup analysis remained consistent, further enhancing the authenticity and reliability of the study.

Discussion

The results of the Kaplan-Meier survival analysis in this study indicated that MASLD might decrease both RFS and OS. According to the results of the multivariate Cox proportional hazards model in this study, it was evident that MASLD was a strong risk factor for both OS and RFS in HCC patients who underwent liver resection. However, there is currently controversy regarding the impact of hepatic steatosis on the prognosis of HCC. Chen et al stated that the presence of several metabolic risk factors would decrease the likelihood of developing HCC in patients with NAFLD (30). Liu et al. and Lin et al. reported that HCC patients with MAFLD had better long-term survival than the chronic hepatitis B group (31,32). Differently, some studies suggest that hepatic steatosis does not have an impact on the prognosis of HCC (33,34). Similarly, some studies also illustrated that hepatic steatosis might be a risk factor. For HBV-related HCC patients, Xue et al. concluded that MAFLD was associated with a higher risk of poor prognosis (35). Patients with CHB and coexisting MAFLD had a higher likelihood of experiencing liver-related clinical events and mortality (36). All the studies were published before the definition of MASLD was proposed.

As the concept of MASLD was recently introduced, there is currently a lack of relevant studies on the association between MASLD and HCC. Therefore, in clinical practice, more studies are needed for HCC patients with MASLD.

Non-invasive imaging has become the most common method for assessing hepatic steatosis and liver fat content (37). They have the advantages of being minimally invasive and easy to operate. The technologies of CT, MRI, and ultrasound for diagnosing hepatic steatosis are highly mature, and their results show minimal differences compared to liver biopsy (38-40). All patients included in this study were assessed for the presence of hepatic steatosis through preoperative imaging examinations. Among them, 785 (86%) patients underwent two or more imaging examinations preoperatively, while 124 (14%) patients had only one imaging examination. If any of the imaging examinations suggests hepatic steatosis, the patient is classified as having hepatic steatosis. Multiple imaging examinations can significantly increase the sensitivity of detecting hepatic steatosis.

Multiple factors can affect the outcome of tumors. Multivariate analysis can incorporate many factors that affect the outcome of tumors, such as tumor size and postoperative pathological results, into the analysis, thereby avoiding possible spurious or indirect associations between independent and dependent variables (41). The univariate analysis only considers the MASLD factor, while multivariate analysis and PSM analysis consider other factors that may affect OS and RFS. According to our study findings, both multivariate analysis and PSM analysis revealed an adverse prognosis for HCC patients with MASLD. Therefore, our results based on multivariate analysis and PSM analysis are reliable. We also need to consider the potential mechanisms of hepatic steatosis on tumor survival (42,43), as well as other influencing factors that may exist. Further research, including larger sample sizes and more in-depth mechanistic studies, may be needed to validate these results (44).

While this research offers meaningful insights, certain limitations remain. Primary among these, our study being retrospective and lacking randomized selection, introduces the potential for inevitable selection bias and confounding factors. However, we attempted to surmount these limitations via the application of PSM analysis. Second, the number of HCC patients with MASLD undergoing liver resection surgery still remains moderately low. Hence, the representation of the samples was limited. Further research is encouraged, incorporating more substantial sample sizes coupled with a more comprehensive exploration of mechanistic studies, in order to validate and internalize these findings.

Conclusions

The simultaneous diagnosis of MASLD in HCC patients is closely associated with long-term adverse outcomes after hepatectomy. These findings indicate that preoperative diagnosis of MASLD in HCC patients holds crucial significance in guiding patient long-term prognosis. However, further research is still needed for confirmation.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-489/rc

Data Sharing Statement: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-489/dss

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-489/prf

Funding: This work was supported by Sichuan Provincial Science and Technology Department Project (No. 2023YFS0146), Sichuan Provincial Department of Science and Technology Central-Guided Local Science and Technology Development Program (No. 23ZYZYTS0267) and the National Natural Science Foundation of China (No. 82205119).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-489/coif). The authors report that this work was supported by Sichuan Provincial Science and Technology Department Project (No. 2023YFS0146), Sichuan Provincial Department of Science and Technology Central-Guided Local Science and Technology Development Program (No. 23ZYZYTS0267) and the National Natural Science Foundation of China (No. 82205119). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All patients signed an informed consent form. It conformed to the ethical guidelines of the Declaration of Helsinki and its subsequent amendments and was reviewed by the Ethics Committee of West China Hospital of Sichuan University (No. 2022-1774).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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