Abstract
The term “metabolic dysfunction-associated steatotic liver disease” (MASLD) was introduced to replace the term “nonalcoholic fatty liver disease”. The prevalence of MASLD is increasing worldwide. The prevalence of concomitant MASLD and hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is also increasing. This study explored the effect of the coexistence of MASLD and HBV on clinicopathological features and long-term clinical prognoses in patients with MASLD-related and/or HBV-related HCC after curative hepatectomy. The study retrospectively collected the data of 653 patients with HCC who had undergone curative hepatectomy between 2011 and 2022. We assessed the association of histologically confirmed MASLD with HCC recurrence and mortality. Of 653 patients, 320 (49.0%), 103 (15.8%), and 230 (35.2%) had concomitant MASLD and HBV, MASLD only, and HBV only, respectively. The median follow-up period was 5.1 years. Patients with concomitant MASLD and HBV were at a significantly increased risk of HCC recurrence (P = 0.013 and P = 0.041) and mortality (P = 0.044 and P = 0.026) than those with MASLD or HBV alone. In multivariable analyses, concomitant MASLD and HBV, male sex, body mass index < 23, absence of antiviral therapy, and tumor size ≥ 5 cm were significantly associated with increased HCC recurrence. Concomitant MASLD and HBV, male sex, type 2 diabetes mellitus, serum aspartate aminotransferase ≥ 40 U/L, tumor size ≥ 5 cm, tumor cell differentiation II-III, microvascular invasion, lymph node invasion, and tumor recurrence were significantly associated with increased mortality. In conclusion, patients with concomitant MASLD and HBV are at a significantly greater risk of HCC recurrence and mortality after curative hepatectomy than those with MASLD or HBV alone.
Keywords: Metabolic dysfunction-associated steatotic liver disease, hepatitis B virus, hepatocellular carcinoma, recurrence, mortality
Introduction
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second most common cause of cancer-related death worldwide [1-3]. In Taiwan, HCC is often caused by viral or alcohol-related diseases [4,5]. Recent advances in treatments for chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections have reduced the proportion of HCC cases caused by these viruses [6]. Despite advancements in diagnosis and treatment approaches, the risk of HCC recurrence and mortality after resection remains high, with recurrence and mortality rates exceeding 50% within 5 years [7,8]. Key prognostic factors for HCC recurrence after resection include tumor number and size, microvascular invasion, metabolic syndrome, cirrhosis, and Barcelona Clinic Liver Cancer (BCLC) stage [7,9,10].
The global incidence of nonalcoholic fatty liver disease (NAFLD) is increasing because of the increasing rates of metabolic disorders, such as insulin resistance, type 2 diabetes mellitus, dyslipidemia, obesity, and hypertension [11,12]. In the Asia-Pacific region, the coexistence of NAFLD and HBV infection is an emerging clinical concern. The interaction between NAFLD and HBV has been shown to accelerate HCC development [13].
In Taiwan, where HBV is endemic, the prevalence of concurrent metabolic dysfunction-associated fatty liver disease (MAFLD) in HBV-related HCC is expected to increase. However, in previous international guidelines, NAFLD was defined by excluding secondary causes of hepatic steatosis, such as substantial alcohol consumption, HBV infection, and other factors; consequently, MAFLD and chronic hepatitis B (CHB) were not considered to coexist [14,15]. Accordingly, data on the effect of MAFLD on HBV-related HCC, particularly in HBV-endemic regions with a high HCC prevalence, remain limited. Specifically, few studies have reported the influence of MAFLD on the pathological characteristics and outcomes of HBV-related HCC after curative resection [10,16]. In 2020, the term “metabolic dysfunction-associated fatty liver disease” was introduced to replace NAFLD, reflecting the disease’s association with metabolic dysfunction [17,18]. MAFLD is currently recognized as the most prevalent chronic liver disease worldwide, driven by the increased prevalence of metabolic syndrome features [19,20]. Additionally, the prevalence of MAFLD-related cirrhosis and HCC is increasing [21-26].
In 2023, a multisociety Delphi consensus redefined the classification of liver diseases, introducing the term “metabolic dysfunction-associated steatotic liver disease” (MASLD) to replace NAFLD and MAFLD [27]. MASLD is diagnosed by identifying hepatic steatosis and at least one cardiometabolic risk factor [27]. This updated definition allows for the coexistence of MASLD and HBV, which is particularly relevant in regions such as Taiwan, where HBV is endemic. Consequently, the incidence of concurrent MASLD and HBV-related HCC is expected to increase due to the increasing prevalence of MASLD and its broader diagnostic criteria.
Only one study has explored the effect of MASLD on the clinical prognosis of HBV-related HCC after curative hepatectomy [28]. The new definitions emphasize MASLD as a critical condition that can coexist with HBV, highlighting the need for further research in this area. Accordingly, the present study investigated the effect of MASLD and HBV coexistence on the clinicopathological features and long-term clinical outcomes of MASLD and/or HBV-related HCC after curative hepatectomy. The study focused on HBV-endemic countries with a high prevalence of HCC.
Materials and methods
Study design and ethics
This multicenter, retrospective, cross-sectional cohort study was conducted in Taiwan. The research was approved by the Institutional Review Board of E-DA Hospital. The requirement for informed consent was waived because of the minimal risk to participants and the study’s retrospective design. Moreover, the study was conducted in accordance with the Declaration of Helsinki and the guidelines of the International Conference on Harmonization for Good Clinical Practice.
Study population
Data for this study were sourced from E-Da Hospital, E-Da Cancer Hospital, and E-Da Dachang Hospital. The data of patients with HCC treated between October 2011 and December 2022 were collected. The last follow-up time was October 31, 2023. Patients were included if they were diagnosed as having HBV infection, were diagnosed as having MASLD, underwent curative hepatectomy between 2011 and 2022, and had a pathology report of liver steatosis. Patients were excluded if they lacked a report of liver steatosis, were diagnosed as having HCV infection, consumed a substantial amount of alcohol (> 210 g/week for men, > 140 g/week for women), or had less than 6 months of follow-up data. A flowchart of the patient enrollment process is illustrated in Figure 1. In total, 910 patients with HBV and/or MASLD underwent surgical resection for HCC. Of these patients, 67 were excluded owing to the lack of a report of liver steatosis, 81 were excluded owing to having HCV, 87 were excluded owing to substantial alcohol consumption, and 22 were excluded owing to the lack of at least 6 months of follow-up data. Consequently, 653 patients with complete liver steatosis data were eligible for analysis (Figure 1).
Figure 1.
Flow chart of patient’s selection.
Data collection
Patient data were retrospectively collected from medical records at the time of surgery. Data were collected on sex, age, body mass index (BMI), type 2 diabetes mellitus status, hypertension, dyslipidemia, alcohol intake, smoking history, serum biochemistry, tumor markers, hepatitis B markers, and HBV DNA level. Data on the pathological features of resected tumors were also collected (i.e., tumor number, tumor size, macrovascular invasion, microvascular invasion, lymph node invasion, tumor cell differentiation, histological grade, and cirrhosis).
Study outcomes
The primary and secondary endpoints were HCC recurrence and overall mortality after surgery, respectively. The follow-up time was defined as the time from the date of inclusion to the date of death, the last follow-up, or the end of the study (October 31, 2023), whichever was earliest. The recurrence time was defined as the time from the date of inclusion to the date of HCC operation, the date of death, the last follow-up, or the end of the study (October 31, 2023), whichever was earliest. HCC recurrence was established on the basis of histology or at least two typical HCC imaging methods, as outlined by the HCC guidelines of the American Association for the Study of Liver Disease [3].
Definition
MASLD diagnosis requires evidence of hepatic steatosis (> 5%) and at least one of the following five cardiometabolic risk factors: (1) a BMI of ≥ 23 kg/m2 for Asian populations or a waist circumference of > 94 cm for men or > 80 cm for women; (2) a diagnosis or treatment of type 2 diabetes mellitus, fasting serum glucose level of ≥ 5.6 mmol/L (100 mg/dL), 2-hour postload glucose level of ≥ 7.8 mmol/L (140 mg/dL), or HbA1c level of ≥ 5.7% (39 mmol/mol); (3) a blood pressure level of ≥ 130/85 mmHg or treatment with specific antihypertensive drugs; (4) a plasma triglyceride level of ≥ 1.70 mmol/L (150 mg/dL) or treatment with lipid-lowering medications; or (5) a plasma HDL cholesterol level of < 1.0 mmol/L (40 mg/dL) for men or < 1.3 mmol/L (50 mg/dL) for women, treatment with lipid-lowering medications, or exclusion of other causes of steatosis, including exclusion of excessive alcohol consumption (> 210 g/week for men, > 140 g/week for women) [27].
HCC staging was conducted in accordance with BCLC guidelines [29]. Tumor differentiation was graded histologically using the modified nuclear grading scheme developed by Edmondson and Steiner [3]. Liver cirrhosis was diagnosed on the basis of an Ishak fibrosis score of 5-6 in nontumor tissues [30]. Type 2 diabetes mellitus was diagnosed in accordance with criteria set by the American Diabetes Association [31].
Statistical analysis
Continuous data are expressed as means and standard deviations (SDs), and categorical data are expressed as numbers and percentages. Normally distributed continuous variables were compared using Student’s t test, and the Wilcoxon rank-sum test was applied for comparisons of two groups when continuous variables were not normally distributed. A chi-square test was used to compare categorical variables. Cumulative HCC recurrence and mortality rates were evaluated using the Kaplan-Meier method. Because patients who have died are no longer at risk for HCC recurrence, competing risk analyses were conducted to evaluate cumulative HCC recurrence while accounting for mortality. Both univariable and multivariable analyses were used to identify risk factors for HCC recurrence and mortality. Multivariable analyses were conducted using Cox proportional regression models for HCC. P < 0.05 indicated statistical significance. All analyses were performed using Statistical Package for Social Sciences (version 23.0; Chicago, IL, USA).
Results
Patient characteristics
Of 653 eligible patients, 320 (49.0%) had HCC with concomitant MASLD and HBV, 103 (15.8%) had HCC with MASLD only, and 230 (35.2%) had HCC with HBV only. The demographic and clinicopathological characteristics of the study patients are presented in Table 1. Notably, 555 (85%) patients were men. The mean (SD) age was 60 (10) years. HCC recurrence occurred in 287 (44.0%) patients, and mortality occurred in 277 (42.4%) patients. Additionally, 26.9% of the patients received a diagnosis of type 2 diabetes mellitus, and 27.9% of the patients had dyslipidemia. One-fourth of the patients had liver cirrhosis. Regarding tumor stage, 85.5% and 79.5% of the patients’ tumors were classified as BCLC stage 0-A and tumor-node-metastasis (TNM) stage I-II, respectively.
Table 1.
Demographic data of all patients
| Characteristics | Total cohort (n = 653) | MASLD+HBV (n = 320) | MASLD (n = 103) | HBV (n = 230) | P-value* |
|---|---|---|---|---|---|
| Gender (male) | 555 (85.0) | 285 (89.1) | 85 (82.5) | 185 (80.4) | 0.015 |
| Age (years) | 60 (10) | 60 (10)a | 67 (8)c | 55 (11)b | < 0.001 |
| BMI (kg/m2) | 24.8 (3.8) | 26.1 (3.2) | 26.0 (3.5)c | 22.4 (3.6)b | 0.018 |
| Hypertension, present | 339 (47.9) | 191 (59.7) | 56 (54.4)c | 66 (28.7)b | < 0.001 |
| Diabetes, present | 147 (26.9) | 102 (31.9)a | 45 (43.7)c | 29 (12.6)b | < 0.001 |
| Dyslipidemia, present | 182 (27.9) | 96 (30.0)a | 48 (46.6)c | 38 (16.5)b | < 0.001 |
| Alcohol, present | 86 (13.2) | 48 (15.0)a | 5 (4.8)c | 38 (16.5) | < 0.001 |
| Smoking, present | 110 (16.8) | 66 (20.6)a | 8 (7.8)c | 36 (15.7) | 0.008 |
| AST (IU/L) | 49 (39) | 43 (24) | 49 (36)c | 57 (53)b | 0.002 |
| ALT (IU/L) | 49 (44) | 47 (41) | 44 (36) | 53 (50) | 0.713 |
| Total bilirubin (mg/dL) | 0.8 (0.5) | 0.8 (0.5) | 0.8 (0.5) | 0.8 (0.5) | 0.928 |
| Albumin (g/dL) | 4.2 (0.3) | 4.3 (0.3) | 4.2 (0.3) | 4.2 (0.4)b | 0.598 |
| Platelet count (×103/mL) | 190 (74) | 192 (70) | 200 (71)c | 182 (81)b | 0.012 |
| INR | 1.0 (0.1) | 1.0 (0.1) | 1.0 (0.1) | 1.0 (0.1) | 0.934 |
| α-fetoprotein (ng/mL) | 8399 (50988) | 4454 (27750) | 7031 (34958) | 14500 (75663)b | 0.048 |
| ALBI grade (I) | 552 (84.5) | 282 (88.1) | 86 (83.5) | 184 (80.0)b | 0.032 |
| ICG (%) | 11.4 (6.7) | 11.6 (6.9) | 11.5 (5.9) | 11.0 (6.6) | 0.835 |
| HBsAg-positive | 550 (84.2) | 320 (100)a | 0 (0)c | 230 (100) | < 0.001 |
| HBeAg-positive | 100 (15.3) | 57 (17.8)a | 0 (0)c | 43 (18.7) | < 0.001 |
| Baseline HBV DNA (log10 IU/mL) | 6.8 (7.5) | 5.7 (7.2)a | 0 (0)c | 7.1 (7.8) | < 0.001 |
| Baseline HBV DNA, detectable | 304 (46.6) | 174 (54.4)a | 0 (0)c | 130 (56.5) | < 0.001 |
| Antiviral therapy-positive | 430 (65.8) | 256 (80.0)a | 0 (0)c | 174 (75.7) | < 0.001 |
| Ishak score | 2.9 (2.0) | 2.8 (2.0)a | 2.3 (1.9)c | 3.1 (2.0) | 0.002 |
| Liver cirrhosis, present | 161 (24.7) | 77 (24.1) | 15 (14.6) | 69 (30.0) | 0.010 |
| Child-Pugh class A | 644 (98.6) | 315 (98.4) | 102 (90.0) | 227 (98.7) | 0.896 |
| Operative margin (> 1 cm) | 457 (70.0) | 232 (72.5) | 71 (68.9) | 154 (67.0) | 0.364 |
| Tumor cell differentiation, I | 61 (9.3) | 30 (9.4) | 11 (10.7) | 20 (8.7) | 0.847 |
| Macrovascular invasion, present | 73 (11.2) | 32 (10.0) | 13 (12.6) | 28 (12.2) | 0.640 |
| Microvascular invasion, present | 199 (30.5) | 104 (32.5) | 27 (26.2) | 68 (29.6) | 0.451 |
| Lymph node invasion, present | 22 (3.4) | 13 (4.1) | 2 (1.9) | 7 (3.0) | 0.551 |
| Tumor number, single | 591 (90.5) | 293 (91.6) | 95 (92.2) | 203 (88.3) | 0.346 |
| Tumor size (cm) | 5.2 (3.4) | 5.0 (3.1)a | 6.0 (3.6)c | 5.1 (3.7) | 0.036 |
| Tumor size, < 5 cm | 384 (58.8) | 190 (59.4)a | 50 (48.5)c | 144 (62.2) | 0.053 |
| TNM stage I-II | 519 (79.5) | 249 (77.8) | 85 (82.5) | 185 (80.4) | 0.553 |
| BCLC stage 0-A | 560 (85.5) | 282 (88.1) | 88 (85.4) | 190 (82.6) | 0.188 |
| Recurrence | 287 (44.0) | 167 (52.2)a | 32 (31.1) | 88 (38.3)b | < 0.001 |
| Recurrence time | 4.3 (3.2) | 4.5 (3.2) | 4.2 (3.1) | 4.2 (3.4) | 0.687 |
| Mortality | 277 (42.4) | 159 (49.7)a | 36 (35.0) | 82 (35.7)b | 0.001 |
| Follow up time | 5.1 (3.3) | 5.1 (3.3) | 5.2 (3.2)c | 5.0 (3.5) | 0.523 |
Data shown as mean (standard deviation) or number (%); MASLD: Metabolic dysfunction-associated steatotic liver disease; BMI: Body mass index; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; INR: international normalized ratio; ALBI grade: Albumin-bilirubin grade; HBsAg: Hepatitis B Surface Antigen; HBeAg: Hepatitis B e Antigen; HBV: Hepatitis B Virus; BCLC stage: Barcelona clinic liver cancer;
P-value < 0.05, HBV+MASLD vs. MAFLD;
P-value < 0.05, HBV+MASLD vs. HBV;
P-value < 0.05, MASLD vs. HBV;
P-value is used by Student’s t tests, Wilcoxon rank-sum statistics or Chi-squared tests.
P-value is used by one-way ANOVA test among three groups.
Effect of concomitant MASLD and HBV on clinical prognosis of HCC after surgical resection
After a mean follow-up period of 5.1 years, 167 (52.2%), 32 (31.1%), and 88 (38.3%) patients with concomitant MASLD and HBV, MASLD only, and HBV only, respectively, experienced HCC recurrence (Table 1). The cumulative incidence of HCC recurrence was significantly higher among patients with concomitant MASLD and HBV than among those with MASLD only (P = 0.013) or HBV only (P = 0.041; Figure 2A). HCC recurrence did not differ significantly between the patients with MASLD only and those with HBV only (P = 0.312; Figure 2A). Moreover, 159 (49.7%), 36 (35%), and 82 (35.7%) patients with concomitant MASLD and HBV, MASLD only, and HBV only, respectively, experienced mortality (Table 1). The cumulative incidence of mortality was significantly higher among patients with concomitant MASLD and HBV than among those with MASLD only (P = 0.044) or HBV only (P = 0.026; Figure 2B). Mortality did not differ significantly between the patients with MASLD only and those with HBV only (P = 0.733; Figure 2B). These results indicate that patients with concomitant MASLD and HBV are at significantly increased risk of HCC recurrence and mortality when compared with those with MASLD or HBV alone.
Figure 2.
The cumulative incidences of hepatocellular carcinoma recurrence and mortality after surgical resection. The cumulative incidences of HCC recurrence according to different etiologies (A). Patients with concomitant MASLD and HBV significantly increased the incidence of HCC recurrence compared to those with MASLD or HBV alone. The cumulative incidences of mortality according to different etiologies (B). Patients with concomitant MASLD and HBV significantly increased the incidence of mortality compared to those with MASLD or HBV alone.
HCC recurrence risk factors in patients who had undergone hepatectomy
A Cox proportional hazards model was used to summarize the prognostic factors for HCC recurrence (Table 2). Univariate analysis results revealed that sex, BMI, type 2 diabetes mellitus status, dyslipidemia, surface antigen of HBV, HBV DNA level, antiviral therapy, tumor size, microvascular invasion, lymph node invasion, TNM stage, BCLC stage, and etiology were significant risk factors for HCC recurrence (Table 2). Multivariable analysis results indicated that male sex (hazard ratio [HR]: 1.66; 95% confidence interval [CI]: 1.15-2.42, P = 0.008), tumor size ≥ 5 cm (HR: 1.35; 95% CI, 1.06-1.72, P = 0.022), and concomitant MASLD and HBV (HR: 1.62; 95% CI, 1.13-2.33, P = 0.007) were also significant risk factors for HCC recurrence. However, BMI ≥ 23 (HR: 0.56; 95% CI, 0.41-0.76, P < 0.001) and antiviral therapy (HR: 0.74; 95% CI, 0.56-0.95, P = 0.021) were significantly associated with lower HCC recurrence rates.
Table 2.
Univariate and multivariate Cox regression analyses predicting hepatocellular carcinoma recurrence in the all hepatocellular carcinoma patients after surgical resection
| Characteristics | HCC recurrence | |||
|---|---|---|---|---|
|
| ||||
| Univariate analyses | Multivariate analyses | |||
|
|
|
|||
| HR (95% CI) | P-value | HR (95% CI) | P-value | |
| Gender, Female vs. Male | 1.53 (1.07-2.18) | 0.019 | 1.66 (1.15-2.42) | 0.008 |
| Age (years), < 60 vs. ≥ 60 | 0.94 (0.75-1.19) | 0.620 | ||
| BMI (kg/m2), < 23 vs. ≥ 23 | 0.78 (0.61-0.99) | 0.045 | 0.56 (0.41-0.76) | < .001 |
| Diabetes Mellitus, No vs. Yes | 1.32 (1.01-1.72) | 0.039 | 1.21 (0.88-1.63) | 0.233 |
| Hypertension, No vs. Yes | 1.23 (0.98-1.56) | 0.079 | ||
| Hyperlipidemia, No vs. Yes | 1.28 (0.97-1.65) | 0.042 | 1.16 (0.79-1.57) | 0.429 |
| Alcohol, No vs. Yes | 1.27 (0.96-1.62) | 0.059 | ||
| Smoking, No vs. Yes | 0.98 (0.73-1.32) | 0.898 | ||
| AST (IU/L), < 40 vs. ≥ 40 | 1.25 (0.95-1.61) | 0.055 | ||
| ALT (IU/L), < 40 vs. ≥ 40 | 1.16 (0.91-1.46) | 0.224 | ||
| Total Bilirubin (mg/dl), < 1.2 vs. ≥ 1.2 | 1.09 (0.95-1.35) | 0.398 | ||
| Albumin (g/dl), < 3.5 vs. ≥ 3.5 | 0.95 (0.53-1.70) | 0.871 | ||
| Platelet count (×103/ml), < 150K vs. ≥ 150K | 0.99 (0.78-1.27) | 0.953 | ||
| INR, < 1.0 vs. ≥ 1.0 | 0.95 (0.73-1.33) | 0.899 | ||
| AFP (ng/dl), < 200 vs. ≥ 200 | 1.17 (0.90-1.53) | 0.252 | ||
| ALBI grade I vs. II-III | 0.97 (0.70-1.32) | 0.823 | ||
| HBsAg, Positive vs. Negative | 1.46 (1.01-2.11) | 0.044 | 1.15 (0.71-1.86) | 0.571 |
| HBeAg, Positive vs. Negative | 0.84 (0.60-1.17) | 0.838 | ||
| Serum HBV DNA, detectable vs. undetectable | 1.27 (1.01-1.60) | 0.045 | 1.08 (0.83-1.41) | 0.591 |
| Antiviral therapy, No vs. Yes | 0.68 (0.53-0.88) | 0.004 | 0.74 (0.56-0.95) | 0.021 |
| Ishak score, 0-4 vs. 5-6 | 1.13 (0.95-1.38) | 0.379 | ||
| Liver cirrhosis, No vs. Yes | 1.47 (1.13-1.92) | 0.004 | ||
| Child-Pugh class, A vs. B | 1.74 (0.77-3.9) | 0.182 | ||
| Operative margin (cm), < 1.0 vs. ≥ 1.0 | 1.08 (0.83-1.38) | 0.578 | ||
| Tumor number, Single vs. Multiple | 1.42 (0.97-2.04) | 0.076 | ||
| Tumor size (cm), < 5 vs. ≥ 5 | 1.54 (1.22-1.94) | < .001 | 1.35 (1.06-1.72) | 0.022 |
| Tumor cell differentiation I vs. II-III | 1.21 (0.79-1.85) | 0.388 | ||
| Macrovascular invasion, No vs. Yes | 1.14 (0.79-1.62) | 0.496 | ||
| Microvascular invasion, No vs. Yes | 1.36 (1.05-1.76) | 0.017 | 1.18 (0.89-1.55) | 0.249 |
| Lymph node invasion, No vs. Yes | 3.07 (1.71-5.51) | < .001 | 1.89 (0.99-3.56) | 0.051 |
| TNM stage, I-II vs. III-IV | 1.55 (1.18-2.04) | 0.002 | 1.29 (0.93-1.81) | 0.122 |
| BCLC stage, 0-A vs. B-C | 1.43 (1.03-2.01) | 0.035 | 1.04 (0.72-1.51) | 0.848 |
| Etiology, MASLD+HBV vs. HBV | 1.61 (1.11-2.36) | 0.013 | 1.62 (1.13-2.33) | 0.007 |
| Etiology, MASLD+HBV vs. MASLD | 1.23 (0.82-1.85) | 0.312 | 1.19 (0.82-1.58) | 0.556 |
BMI: Body mass index; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; INR: international normalized ratio; ALBI grade: Albumin-bilirubin grade; HBsAg: Hepatitis B Surface Antigen; HBeAg: Hepatitis B e Antigen; HBV: Hepatitis B Virus; BCLC stage: Barcelona clinic liver cancer; MAFLD: Metabolic associated fatty liver disease.
Kaplan-Meier analysis results revealed that patients with concomitant MASLD and HBV had a significantly higher risk of HCC recurrence than did those with MASLD only (P = 0.013) or HBV only (P = 0.041; Figure 2A). For patients with concomitant MASLD and HBV, the 1-, 5-, and 10-year cumulative HCC recurrence rates were 11.2%, 42.8%, and 68.2%, respectively. By contrast, those with MASLD only had 1-, 5-, and 10-year cumulative HCC recurrence rates of 2.9%, 36.0%, and 42.9%, respectively, and those with HBV only had 1-, 5-, and 10-year cumulative HCC recurrence rates of 8.4%, 38.4%, and 43.2%, respectively (Figure 2A).
In the competing risk analysis, patients with concomitant MASLD and HBV still had a significantly higher risk of HCC recurrence than did those with MASLD only (P = 0.019) or HBV only (P = 0.031; Figure 3). For patients with concomitant MASLD and HBV, the 1-, 5-, and 10-year cumulative HCC recurrence rates were 3.1%, 26.4%, and 54.9%, respectively, whereas these rates were 1.5%, 20.4%, and 23.5%, respectively, for those with MASLD only and 4.2%, 21.7%, and 29%, respectively, for those with HBV only (Figure 3).
Figure 3.
The cumulative incidences of hepatocellular carcinoma recurrence after surgical resection after competing risk analysis. Patients with concomitant MASLD and HBV significantly increased the incidence of HCC recurrence compared to those with MASLD or HBV alone after competing risk analysis.
Mortality risk factors in patients who had undergone hepatectomy
A Cox proportional hazards model was used to summarize the prognostic factors for mortality (Table 3). Univariate analysis results demonstrated that sex, BMI, type 2 diabetes mellitus, hypertension, dyslipidemia, serum aspartate aminotransferase, alpha-fetoprotein, Hepatitis B e Antigen, Ishak score, tumor number, tumor size, tumor cell differentiation, macrovascular invasion, microvascular invasion, lymph node invasion, TNM stage, BCLC stage, recurrence, and etiology were significant risk factors for mortality (Table 3). Multivariable analysis results revealed that male sex (HR: 1.66; 95% CI: 1.09-2.52, P = 0.019), type 2 diabetes mellitus (HR: 1.54; 95% CI, 1.13-2.09, P = 0.006), serum aspartate aminotransferase ≥ 40 U/L (HR: 1.34; 95% CI, 1.02-1.76, P = 0.033), tumor size ≥ 5 cm (HR: 1.56; 95% CI, 1.19-2.05, P < 0.001), tumor cell differentiation II-III (HR: 3.63; 95% CI, 1.89-6.95, P < 0.001), microvascular invasion (HR: 1.51; 95% CI, 1.21-2.05, P = 0.007), lymph node invasion (HR: 2.29; 95% CI, 1.28-4.09, P = 0.005), tumor recurrence (HR: 2.79; 95% CI, 2.14-3.66, P < 0.001), and concomitant MASLD and HBV (HR: 1.45; 95% CI, 1.01-2.08, P = 0.046) were significant risk factors for mortality.
Table 3.
Univariate and multivariate Cox regression analyses predicting mortality in the hepatocellular carcinoma patients after surgical resection
| Characteristics | Mortality | |||
|---|---|---|---|---|
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| ||||
| Univariate analyses | Multivariate analyses | |||
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| HR (95% CI) | P-value | HR (95% CI) | P-value | |
| Gender, Female vs. Male | 1.77 (1.21-2.62) | 0.004 | 1.66 (1.09-2.52) | 0.019 |
| Age (years), < 60 vs. ≥ 60 | 0.78 (0.77-1.24) | 0.841 | ||
| BMI (kg/m2), < 23 vs. ≥ 23 | 0.73 (0.57-0.93) | 0.011 | 0.78 (0.56-1.08) | 0.144 |
| Diabetes Mellitus, No vs. Yes | 1.63 (1.26-2.11) | < .001 | 1.54 (1.13-2.09) | 0.006 |
| Hypertension, No vs. Yes | 1.42 (1.12-1.79) | 0.004 | 1.32 (0.97-1.78) | 0.075 |
| Hyperlipidemia, No vs. Yes | 1.35 (1.09-1.62) | 0.039 | 1.24 (0.98-1.71) | 0.068 |
| Alcohol, No vs. Yes | 1.31 (0.95-1.81) | 0.096 | ||
| Smoking, No vs. Yes | 1.11 (0.83-1.49) | 0.488 | ||
| AST (IU/L), < 40 vs. ≥ 40 | 1.81 (1.42-2.31) | < .001 | 1.34 (1.02-1.76) | 0.033 |
| ALT (IU/L), < 40 vs. ≥ 40 | 1.21 (0.96-1.53) | 0.115 | ||
| Total Bilirubin (mg/dl), < 1.2 vs. ≥ 1.2 | 1.16 (0.97-1.48) | 0.298 | ||
| Albumin (g/dl), < 3.5 vs. ≥ 3.5 | 0.79 (0.45-1.39) | 0.416 | ||
| Platelet count (×103/ml), < 150K vs. ≥ 150K | 0.88 (0.69-1.12) | 0.291 | ||
| INR, < 1.0 vs. ≥ 1.0 | 0.92 (0.78-1.07) | 0.469 | ||
| AFP (ng/dl), < 200 vs. ≥ 200 | 1.55 (1.21-2.01) | 0.001 | 1.24 (0.91-1.69) | 0.181 |
| ALBI grade I vs. II-III | 0.98 (0.97-1.34) | 0.993 | ||
| HBsAg, Positive vs. Negative | 1.29 (0.91-1.84) | 0.149 | ||
| HBeAg, Positive vs. Negative | 1.31 (1.01-1.69) | 0.048 | 1.34 (0.95-1.89) | 0.103 |
| Serum HBV DNA, detectable vs. undetectable | 1.08 (0.85-1.37) | 0.515 | ||
| Antiviral therapy, Yes vs. No | 1.29 (0.95-1.83) | 0.227 | ||
| Ishak score, 0-4 vs. 5-6 | 1.38 (1.03-1.86) | 0.032 | 1.35 (0.98-1.83) | 0.061 |
| Liver cirrhosis, No vs. Yes | 1.16 (0.88-1.53) | 0.304 | ||
| Child-Pugh class, A vs. B | 2.06 (0.92-4.63) | 0.081 | ||
| Operative margin (cm), < 1.0 vs. ≥ 1.0 | 1.01 (0.78-1.31) | 0.953 | ||
| Tumor number, Single vs. Multiple | 1.59 (1.13-2.25) | 0.009 | 1.31 (0.86-1.99) | 0.311 |
| Tumor size (cm), < 5 vs. ≥ 5 | 2.16 (1.71-2.74) | < .001 | 1.56 (1.19-2.05) | 0.001 |
| Tumor cell differentiation I vs. II-III | 3.28 (1.75-6.17) | < .001 | 3.63 (1.89-6.95) | < .001 |
| Macrovascular invasion, No vs. Yes | 1.86 (1.36-2.54) | < .001 | 0.98 (0.63-1.46) | 0.842 |
| Microvascular invasion, No vs. Yes | 1.85 (1.44-2.38) | < .001 | 1.51 (1.21-2.04) | 0.007 |
| Lymph node invasion, No vs. Yes | 5.14 (3.16-8.34) | < .001 | 2.29 (1.28-4.09) | 0.005 |
| TNM stage, I-II vs. III-IV | 1.92 (1.47-2.51) | < .001 | 1.37 (0.98-1.93) | 0.065 |
| BCLC stage, 0-A vs. B-C | 2.22 (1.65-2.98) | < .001 | 1.45 (0.99-2.11) | 0.052 |
| Recurrence, Yes vs. No | 3.06 (2.37-3.94) | < .001 | 2.79 (2.14-3.66) | < .001 |
| Etiology, MASLD+HBV vs. HBV | 1.62 (1.09-2.35) | 0.025 | 1.45 (1.01-2.08) | 0.046 |
| Etiology, MASLD+HBV vs. MASLD | 1.07 (0.72-1.58) | 0.733 | 1.03 (0.61-1.55) | 0.885 |
BMI: Body mass index; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; INR: international normalized ratio; ALBI grade: Albumin-bilirubin grade; HBsAg: Hepatitis B Surface Antigen; HBeAg: Hepatitis B e Antigen; HBV: Hepatitis B Virus; BCLC stage: Barcelona clinic liver cancer; MAFLD: Metabolic associated fatty liver disease.
The Kaplan-Meier analysis revealed that patients with concomitant MASLD and HBV had a significantly higher risk of mortality than did those with MASLD only (P = 0.044) or HBV only (P = 0.026; Figure 2B). For patients with concomitant MASLD and HBV, the 1-, 5-, and 10-year cumulative mortality rates were 7.6%, 38.7%, and 60.2%, respectively, whereas these rates were 0%, 31.8%, and 53.0%, respectively, for those with MASLD only and 5.8%, 33.5%, and 46.7%, respectively, for those with HBV only (Figure 2B).
Discussion
This study analyzed the data of 653 patients with MASLD and/or HBV who had undergone curative resection for HCC. The median follow-up period was 5.1 years. The study explored the effect of concurrent MASLD and HBV on long-term clinical prognoses after curative hepatectomy for HCC. Notably, patients with concomitant MASLD and HBV were significantly more likely to experience HCC recurrence and mortality when compared with those with MASLD only or HBV only, even after relevant demographic and clinical characteristics were accounted for. According to our review of the literature, this study is the first to demonstrate that among patients with HCC, those with concurrent MASLD (as per the newly defined criteria) and HBV have significantly worse clinical outcomes following hepatectomy than do those with MASLD or HBV alone.
MASLD has been significantly associated with increased overall survival but not recurrence-free survival in patients who underwent curative resection for HBV-related early-stage HCC (BCLC stage 0 or A) [28]. The present study revealed that patients with concurrent MASLD and HBV were at a significantly higher risk of HCC recurrence and mortality when compared with those with MASLD or HBV alone. Our study showed that patients with concurrent MASLD and HBV were at a significantly greater risk of HCC recurrence than those with HBV only. Our study also showed that patients with concurrent MASLD and HBV were at a significantly greater risk of HCC recurrence than those with MASLD only. Our study examined clinical prognoses across a broader range of disease stages than did other studies.
Several studies have examined the effects of metabolic dysfunction and fatty liver disease on clinical outcomes in patients with HBV-related HCC after surgery. Some studies have suggested that MAFLD is a risk factor for HCC recurrence, especially among patients with HBV-related HCC who have undergone hepatectomy. Our study findings are consistent with those of other relevant studies, suggesting that MAFLD increases the risk of HCC recurrence among patients with HBV-related HCC [16,32-35]. A meta-analysis reported that patients (especially Asian patients) with NAFLD-related HCC have shorter survival after cancer recurrence [36]. Another study demonstrated that MAFLD is not associated with HCC recurrence [37]. Our study findings are consistent with those of several studies reporting that MASLD is a significant risk factor for HCC recurrence in patients with HBV-related HCC after curative hepatectomy. Some studies have suggested that MAFLD has a protective effect on the clinical prognosis of patients with overall survival, especially in the context of HBV-related HCC after hepatectomy. Some studies have shown that among patients who underwent hepatectomy for HCC, those with both MAFLD and HBV lived longer than did those with only HBV. Our study is different from other studies suggesting MAFLD improves overall survival outcomes among patients with HBV-related HCC [36,38]. The negative effects of fatty liver disease on overall survival differ by study population. Our study revealed that patients with both MASLD and HBV had lower overall survival rates than did those with HBV only, similar to the findings of other studies [34,35,39]. Xue et al. observed that concurrent MAFLD was correlated with a lower rate of overall survival in patients with HBV-related HCC [40]. Yun et al. reported that MAFLD was significantly associated with poorer survival outcomes [16]. These findings highlight the complexity of the association among metabolic dysfunction, fatty liver disease, HBV, and HCC, suggesting that factors such as population demographics and study design influence study results. Huang et al. indicated that concurrent MASLD was associated with higher rates of HBsAg seroclearance and seroconversion in patients with HBV infection [41]. This suggests that hepatic steatosis may facilitate favorable outcomes in HBV. A negative association between MASLD and clinical outcomes was observed in the context of HCC. Comorbidities such as obesity, type 2 diabetes mellitus, dyslipidemia, and liver steatosis increase the risk of an adverse clinical prognosis, adding to the complexity of these associations. Possible explanations include MASLD creating a different immune environment in the liver, affecting tumor progression, and metabolic alterations like lipid acumination, insulin resistance and changes in adipokines impacting tumor growth. I Additionally, metabolic dysfunctions characteristic of MASLD along with a cellular inflammatory environment marked by oxidative stress, endoplasmic reticulum stress, and cytokine imbalance are likely to exacerbate the hepatocarcinogenic potential of HBV. Furthermore, several signaling pathways have been reported to be deregulated in HCC. These are the subject of considerable interest as a means to identify therapeutic targets, particularly those involving cell proliferation, apoptosis and metabolism. Further research is required to elucidate the mechanisms underlying these observations [42]. Our study, along with others, indicates that fatty liver disease negatively affects clinical outcomes in patients with HCC.
Our study has several limitations. First, selection bias may be present. Second, we were not able to establish any causal associations. Third, we excluded patients with HCV; therefore, whether MASLD interacts with HCV in the same way it interacts with HBV is unknown. Our study findings should be validated in other cohorts. Future largely prospective studies are warranted to address this study’s limitations and to provide a more comprehensive assessment of MASLD’s role in HCC.
Conclusion
Among patients with HCC who had undergone hepatectomy, those with concomitant MASLD and HBV were at a significantly increased risk of HCC recurrence and mortality than those with MASLD or HBV alone. Accordingly, MASLD should be considered in the clinical management and prognostic assessment of HBV-related HCC. Further research is necessary to confirm these findings and investigate the mechanisms underlying the adverse or protective effects of MASLD.
Disclosure of conflict of interest
None.
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