Impact of Preoperative Frailty on Postoperative Complications and Cognitive Impairment in Liver Cancer Patients: An Observational Cohort Study

Introduction

Frailty is a common clinical syndrome characterized by a decline in multisystem physiological reserves and resilience,¹ which may manifest as unintentional weight loss, fatigue, reduced physical activity, and impairments in cognition and emotional regulation.² Frailty has increasingly been recognized as a key determinant of postoperative recovery. Previous hepatobiliary oncology studies have assessed frailty using a range of instruments, including the Kihon Checklist, a phenotypic frailty index,³ Geriatric Assessment (GA),⁴ and the Fried frailty phenotype.⁵ Although these approaches provide important evidence, the Fried frailty phenotype places greater emphasis on physical performance and is commonly applied in older patients with cancer.⁶ Importantly, it can independently predict all-cause mortality, supporting its clinical utility in oncologic settings. The progressive development of frailty imposes a substantial social, health, and economic burden, particularly among patients with liver cancer. Liver cancer has become the sixth most frequently diagnosed cancer worldwide and the third leading cause of cancer-related death.⁷ Owing to advances in disease diagnosis and treatment, the prevalence of frailty among patients with liver cancer has gradually increased. Recent data indicated that approximately 34% of liver cancer patients experienced frailty, which significantly increased the risk of adverse outcomes and reduced both quality of life and overall survival.⁸ Recent studies have demonstrated that the frailty index is an independent predictor of overall survival in patients with liver cancer.⁹

As is well known, the primary treatment modalities for liver cancer are hepatic resection and transcatheter arterial chemoembolization (TACE). Although these interventions can effectively prolong patient survival, the postoperative recurrence rate and incidence of complications remain high, reaching as much as 30%–50%.^10,11 Notably, postoperative complications following liver cancer surgery are often complex and may present as physical or cognitive manifestations. Some patients may experience multiple types of complications, which can severely impair prognosis and increase the economic burden¹² Accumulating evidences have shown that factors influencing patient prognosis may include sociodemographic characteristics, such as age and BMI;¹³ comorbid chronic diseases;¹⁴ surgical factors, such as operative time and intraoperative blood loss;¹³ and physical conditions, including sarcopenia and frailty.¹⁵ Among them, frailty has been recognized as an important determinant of postoperative complications. Several evidences have indicated that physical frailty was strongly associated with adverse clinical outcomes and cognitive impairment in older adults.^16,17 Cognitive dysfunction is characterized by a clinically meaningful decline in performance across one or more cognitive domains, including memory, language, executive functioning, attention, and related higher-order processes.¹⁸ It has been reported that the incidence of cognitive impairment during cancer treatment is high, reaching up to 75%, and that approximately 35% of patients may experience long-term cognitive impairment.¹⁹ Given its ability to detect subtle deficits, the Montreal Cognitive Assessment (MoCA)—a brief, multidomain screening instrument—has demonstrated superior discriminative performance for mild cognitive impairment compared with the Mini-Mental State Examination (MMSE). This is evidenced by its higher area under the receiver operating characteristic curve (AUC), and it can be easily administered during hospitalization.²⁰ To date, limited research has investigated the association between preoperative frailty assessment based on frailty phenotypes and postoperative complications and cognitive impairment among patients undergoing liver cancer surgery. Understanding and addressing preoperative frailty in patients with hepatocellular carcinoma requires robust health system governance, adequate financing, and efficient service delivery—challenges that are also particularly pronounced in Somalia’s health system.

Taken together, these findings suggest a potential association between preoperative frailty status and postoperative physical outcomes as well as cognitive function in patients with liver cancer. We hypothesized a priori that preoperative frailty would be associated with a higher risk of in-hospital postoperative complications and with lower MoCA scores on postoperative day 3 and frailty scores may predict the occurrence of postoperative complications. This study aimed to examine the effects of preoperative frailty and its individual components, as assessed by Frailty Phenotype questionnaire, on postoperative complications and cognitive impairment among patients undergoing liver cancer surgery.

Materials and Methods

Participants and Study Design

A total of 115 patients with pathologically confirmed liver cancer were recruited based on the following inclusion criteria: (1) pathologically confirmed liver cancer; (2) age ≥ 18 years; (3) scheduled for elective hepatic surgery; and (4) provided written informed consent and voluntarily participated in the study. Patients were excluded if they met any of the following criteria: (1) presence of other malignancies; (2) current or past psychiatric disorders; (3) impaired consciousness or inability to communicate effectively; or (4) concurrent participation in other clinical trials.

Sample Size Calculation

Based on previously published data, the reported incidence of postoperative complications following liver cancer surgery was 46.61%. The sample size was calculated according to the following formula: , with a significance level of α = 0.05 and an δ of 0.2p = 0.09322, resulting in a minimum required sample size of 110.

Frailty Assessment

Preoperative frailty was evaluated using the Fried Phenotype criteria proposed by Fried²¹ et al, which comprises five components: (1) unintentional weight loss of ≥4.5 kg or ≥5% of body weight within the previous year; (2) self-reported exhaustion for ≥3 days during the past week; (3) reduced grip strength was assessed using a dynamometer to measure grip strength in the patient’s dominant hand and was classified according to sex- and BMI-adjusted cut-off values; (4) slow walking speed was assessed by recording the time required to walk 4.57 m and was classified using sex- and height-adjusted cut-off values and (5) low physical activity, defined as <600 MET-min/week according to the International Physical Activity Questionnaire (IPAQ),²² total METs were calculated as the MET value × duration of daily physical activity (minutes) × number of days per week. Physical activity levels were categorized into three groups based on total weekly energy expenditure (MET-minutes/week): low (<600 MET-min/week), moderate (≥600 and <3000 MET-min/week), and high (≥3000 MET-min/week).

Postoperative Complication

In this study, postoperative complications were assessed during the in-hospital postoperative period. Complications included incision infection, intra-abdominal effusion, bile leakage, hypoproteinemia, lower limb venous thrombosis, and liver function impairment. Incision infection was defined as purulent discharge from the incision site or a positive bacterial culture. Intra-abdominal effusion was diagnosed based on postoperative imaging findings. Bile leakage was defined as the presence of bile-containing fluid in the abdominal drainage or imaging evidence of biliary leakage within one week after surgery. Hypoproteinemia was defined as a postoperative serum albumin level <35 g/L. Lower limb venous thrombosis was confirmed by Doppler ultrasonography. Impaired liver function was defined as postoperative elevation of liver enzymes or bilirubin above the normal reference range.

Cognitive Impairment

Postoperative cognitive impairment was assessed on postoperative day 3 using the Montreal Cognitive Assessment (MoCA), developed by Nasreddine et al,²³ which is primarily used to screen for mild cognitive impairment and has been widely applied in clinical practice to assess cognitive function The MoCA evaluates 7 core cognitive domains, namely: visuospatial and executive function, naming, attention, language, abstraction, delayed recall, and orientation. For patients with ≤12 years of education, a one-point correction was applied (1 point was added to the total score). The total MoCA score ranges from 0 to 30, with scores <26 indicating cognitive impairment. Higher scores reflect better cognitive function.

Statistical Analysis

Statistical analyses were performed using SPSS version 27.0. Continuous variables are presented as median (25th, 75th percentile) or mean ± SD, and categorical variables as counts and percentages. The Kolmogorov–Smirnov test was used to assess the normality of continuous variables. Between-group comparisons were conducted using the independent-samples t test for normally distributed data and the Mann–Whitney U-test for non-normally distributed data. Categorical variables were compared using the χ²-test or Fisher’s exact test. Multivariable logistic regression model was used to test the hypothesis that preoperative frailty is associated with postoperative complications and postoperative cognitive function outcomes. Variables with p < 0.05 in univariable analyses were entered into the subsequent multivariable logistic regression models. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the predictive ability of preoperative frailty for postoperative complications, and the AUC was calculated. A two-tailed p-value < 0.05 was considered statistically significant.

Ethical Approval

This study is an observational cohort study designed to examine preoperative frailty and its association with postoperative outcomes in patients with liver cancer. Data were prospectively collected from the Affiliated Hospital of Jiangnan University from February 2025 to June 2025, in accordance with the Declaration of Helsinki, and was approved by the Ethics Committee of the Affiliated Hospital of Jiangnan University (Approval No. LS2025059). Written informed consent was obtained from all participants prior to enrollment, and participation was voluntary.

Results

Patient Population

Among the 115 patients, 43 (37.4%) were assigned to the complication group and 72 to the non-complication group based on the presence or absence of postoperative complications. Table 1 summarizes the demographic and clinical characteristics of the two groups. Significant differences were observed between the groups in age (p = 0.008), sleep time (p = 0.044), preoperative frailty status and score (p<0.001), exhaustion (p<0.001), grip strength (p < 0.001), and low physical activity (p = 0.004).

Table 1 Comparison of General Data and Clinical Features

Meanwhile, 80 patients who had a MoCA score < 26 were assigned to the cognitive impairment group, and the remaining 35 patients were assigned to the non-cognitive impairment group. The baseline characteristics of the two groups are presented in Table S1. Significant differences were observed between the two groups in age (p = 0.015), education level (p < 0.001), family monthly income (RMB) (p = 0.004), sleep time (p = 0.008), and grip strength (p = 0.044).

Association Between Preoperative Frailty and Postoperative Complications

Table 2 shows the associations between preoperative frailty and its components with postoperative complications. After adjusting for demographic variables (such as age and sleep time) and perioperative factors (including preoperative bilirubin levels, duration of surgery, and postoperative WBC) between the two groups, preoperative frailty status (OR = 12.857, 95% CI = 4.525 ~ 36.532, p < 0.001), exhaustion (OR = 6.826, 95% CI = 2.285 ~ 20.393, p < 0.001), grip strength (OR = 8.543, 95% CI = 3.260 ~ 22.385, p < 0.001), and low physical activity (OR = 5.715, 95% CI = 1.965 ~ 16.623, p = 0.001) were significantly positively associated with postoperative complications.

Table 2 Association Between the Frailty and Its Components with Postoperative Complications (n = 115)

Association Between Preoperative Frailty and Postoperative Cognitive Impairment

As shown in Table 3, after adjusting for the variables, no significant association was found between preoperative frailty status and postoperative cognitive impairment in patients with liver cancer (p > 0.05).

Table 3 Association Between the Frailty and Its Components with Cognitive Impairment (n = 115)

Postoperative Complications and Cognitive Impairment Stratified by Frailty Indicators

As shown in Table 4, liver cancer patients who were frail preoperatively had significantly higher incidences of postoperative complications such as hypoproteinemia (p < 0.001) and impaired liver function compared (p = 0.011) with non-frail patients. Meanwhile, when cognitive function was analyzed as a continuous variable, frail patients had significantly lower total MoCA scores than non-frail patients (p = 0.044), indicating poorer cognitive performance. However, when cognitive impairment was defined using the MoCA cut-off score (<26), no statistically significant difference in its prevalence was observed between the two groups.

Table 4 Subgroup Analysis of the Relationship Between Different Levels of Frailty and Different Types of Postoperative Complications (n = 115)

Predictive Value of Preoperative Frailty for Postoperative Complications

The predictive model showed that the area under the ROC curve (AUC) of the preoperative frailty score for predicting postoperative complications in patients with liver cancer was 0.747 (95% CI: 0.659 ~ 0.836), p <0.001. Figure 1.

Figure 1 ROC curve of the frailty score for predicting postoperative complications in patients with liver cancer.

Discussion

In this study, the prevalence of preoperative frailty among patients with liver cancer was 31.3%, and the prevalences of postoperative complications and cognitive impairment were 37.4% and 69.6%, respectively. After adjusting for confounding factors, preoperative frailty and its components—including exhaustion, handgrip strength, and low physical activity were significantly associated with postoperative complications in patients with liver cancer. Compared with the non-frail group, frail patients had significantly higher prevalences of postoperative hypoalbuminemia and impaired liver function, and significantly lower MoCA scores, indicating poorer cognitive performance. ROC curve analysis further demonstrated that the frailty score could serve as a reliable predictor of postoperative complications.

In recent years, the impact of frailty on postoperative outcomes among patients with cancer has garnered considerable attention. A prospective study demonstrated that preoperative frailty in patients with hepatocellular carcinoma is strongly associated with adverse postoperative outcomes and serves as an independent prognostic factor for postoperative survival.³ Moreover, our study demonstrated that the components of frailty—including exhaustion, handgrip strength, and low physical activity were positively associated with postoperative complications. As one of the hallmark manifestations of frailty, exhaustion has been demonstrated to substantially influence the interplay between sarcopenia and cachexia among patients with cancer.²⁴ Handgrip strength is a commonly used non-invasive measure of muscle function and nutritional status that reliably reflects overall physiological status.^25,26 In a cohort study of 298 patients undergoing hepatectomy for hepatocellular carcinoma, preoperative handgrip strength served as an independent predictor of postoperative complications and an indicator of unfavorable prognosis.²⁷ Physical activity exerts a beneficial influence on postoperative recovery, which may be partly attributed to the presence of chronic conditions—such as hypertension and diabetes—that are strongly associated with lifestyle factors.²⁸ Findings from an observational cohort study indicated that colorectal cancer patients who engaged in regular physical activity exhibited reduced risks of postoperative complications and shorter lengths of hospital stay.²⁹ Therefore, the timely identification of frailty and its constituent components may play a pivotal role in improving postoperative prognostic assessment.

Liver cancer patients may experience a decline in physiological reserve as a result of tumor invasion and neoadjuvant therapies, subsequently leading to the development of frailty. Frail patients are at increased risk of adverse postoperative outcomes, including complications of any etiology. Our study demonstrated that patients who presented with preoperative frailty exhibited markedly higher prevalences of postoperative hypoproteinemia and impaired liver function. Frail patients commonly present with malnutrition, chronic low-grade inflammation, and diminished hepatic synthetic function.³⁰ In the context of surgical stress, these individuals exhibit an exaggerated inflammatory response, accompanied by suppressed mRNA expression, which further diminishes albumin synthesis and ultimately contributes to the development of postoperative hypoproteinemia.³¹ A prospective cohort study involving 253 older adults scheduled for elective surgery demonstrated that preoperative physical and cognitive frailty were significantly associated with an increased risk of postoperative hypoproteinemia.³² Sarcopenia represents the pathological core of frailty. Loss of skeletal muscle mass diminishes ammonia-clearing capacity, thereby predisposing individuals to hyperammonemia,³³ and is further characterized by mitochondrial dysfunction and insulin resistance, both of which may exacerbate hepatic fibrosis and impair liver function.³⁴ A systematic review and meta-analysis also confirmed that frail patients have a significantly increased risk of postoperative liver failure.³⁵ Meanwhile, postoperative hypoalbuminemia and impaired liver function are multifactorial outcomes and may be influenced by baseline disease severity, surgical complexity, and early postoperative inflammation or metabolic derangements. Nevertheless, preoperative frailty reflects diminished physiological reserve across nutritional, inflammatory, and functional domains, and may therefore serve as a reliable indicator for identifying increased risk of short-term postoperative complications.

Importantly, MoCA was administered on postoperative day 3 to capture early postoperative cognitive performance, and we found that patients with preoperative frailty had significantly lower MoCA scores than those without frailty. A cross-sectional study involving 1,565 older adults found that lower total MoCA scores and poorer performance in specific cognitive domains may be associated with physical frailty.³⁶ However, in the present study, preoperative frailty status was not significantly associated with the prevalence of postoperative cognitive impairment. This finding may, in part, reflect the influence of acute postoperative factors—such as pain intensity, sleep disturbances, and residual anesthetic effects—which can transiently reduce cognitive test performance. Frailty and cognitive impairment interact bidirectionally, creating a vicious cycle. A reduction in muscle mass contributes to decreased physical activity, which in turn reduces levels of brain-derived neurotrophic factor (BDNF), thereby further impairing cognitive function.³⁷ Evidence has demonstrated that U.S. nursing home residents with more severe cognitive impairment were frequently classified into the “moderate physical frailty” and “severe physical frailty” subgroups.³⁸ Similarly, a cross-sectional study involving older adults reported that those with physical frailty were at increased risk of cognitive impairment.³⁹ Preoperative frailty assessment is crucial for predicting postoperative outcomes in patients with hepatocellular carcinoma. Its effective implementation may also be influenced by broader health policies, governance, and resource availability—factors that are particularly relevant in contexts such as Somalia. In clinical practice, preoperative frailty screening should be considered an integral component of preoperative risk assessment in patients with liver cancer. Early identification of frailty may facilitate timely interventions, such as nutritional optimization and tailored activity enhancement (prehabilitation), with the potential to improve postoperative outcomes.

This study is the first to investigate the relationship between preoperative frailty assessed using the Fried Phenotype criteria and postoperative complications and cognitive impairment in liver cancer patients. Despite its strengths, this study has some limitations. First, this study employed a cross-sectional design, which precludes the examination of causal relationships between preoperative frailty and postoperative complications or cognitive impairment. Second, although we adjusted for several confounders, residual confounding from unmeasured perioperative variables may still be present. Finally, the sample was obtained from a single tertiary hospital in Jiangsu Province, which may limit the generalizability of the findings to other populations or settings.

Conclusion

Our study found that, compared with patients without preoperative frailty, frail patients exhibited higher prevalences of postoperative complications including hypoproteinemia, impaired liver function and demonstrated and lower MoCA scores on postoperative day 3, reflecting poorer early postoperative cognitive performance. Frailty and its constituent components including fatigue, handgrip strength, and low physical activity were associated with postoperative complications, and the frailty score served as an effective predictor of postoperative complications. Therefore, healthcare professionals should prioritize the early identification of preoperative frailty to facilitate frailty prevention and thereby reduce the risk of postoperative complications and cognitive impairment. These measures can not only inform clinical decision-making and optimize perioperative care for patients with liver cancer, but are also applicable in resource-limited healthcare settings, thereby promoting sustainable healthcare development.