Factors influencing anxiety and depression in advanced hepatocellular carcinoma patients and their impact on quality of life

Abstract

BACKGROUND

Patients with middle and advanced hepatocellular carcinoma (HCC) frequently experience significant anxiety and depression, severely affecting their quality of life.

AIM

To examine the anxiety and depression status of patients with middle and advanced HCC, the influencing factors, and the correlation between these psychological factors and quality of life.

METHODS

We collected baseline data from 100 patients with HCC, assessing anxiety and depression levels using the Hamilton Anxiety Rating Scale (HAMA) and Hamilton Depression Rating Scale (HAMD). Quality of life was evaluated with the Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire. Multivariate logistic regression analyzed clinical and psychosocial factors affecting anxiety and depression, while Pearson correlation assessed relationships among HAMA, HAMD, and Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire scores.

RESULTS

Results indicated that 64% of patients exhibited anxiety and 65% showed depression symptoms. Key influencing factors included Barcelona Clinic Liver Cancer C stage, multiple tumors, social support, prior treatments (such as liver resection and transcatheter arterial chemoembolization/hepatic artery infusion chemotherapy), as well as HAMA and HAMD scores. Anxiety and depression correlated negatively with quality of life, with coefficients of -0.671 and -0.575 for HAMA and HAMD, respectively.

CONCLUSION

Anxiety and depression are prevalent among patients with middle and advanced HCC, impacting quality of life. This underscores the need for psychological health considerations in liver cancer treatment and establishing psychological interventions is essential.

Key Words: Advanced hepatocellular carcinoma; Anxiety; Depression; Quality of life; Influencing factors

Core Tip: Patients middle and advanced hepatocellular carcinoma (HCC) often experience significant anxiety and depression, which may severely affect their quality of life. This study assessed the anxiety and depression status of patients middle and advanced HCC and their influencing factors, analyzing the correlation between these psychological factors and quality of life. According to the results, a large number of advanced HCC patients suffer from depression and anxiety, which are negatively associated with social support and a high quality of life. Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale scores, prior liver resection, Barcelona Clinic Liver Cancer C stage, and multiple tumors are risk factors for depression in advanced HCC patients. Meanwhile, Karnofsky performance scores are negatively correlated with anxiety, and independent risk factors for anxiety include age over 60, a history of alcohol consumption, Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale scores, prior liver resection, Barcelona Clinic Liver Cancer C stage, and multiple tumors. Anxiety and depression scores in liver cancer patients are negatively correlated with quality of life.

INTRODUCTION

Hepatocellular carcinoma (HCC) is a prevalent malignant tumor, ranking sixth globally and fifth in China for incidence[1]. It is among the top three causes of cancer mortality and poses a significant global health challenge. HCC represents 75% to 80% of liver cancer cases, with incidence and death rates differing greatly by region due to risk factors like alcoholic and non-alcoholic cirrhosis, viral hepatitis (especially hepatitis B and C), and fatty liver[2]. Therapeutic approaches consist of surgical removal, Transcatheter arterial chemoembolization (TACE), percutaneous ethanol injection, chemotherapy, ablative therapy, and liver transplantation. Surgery can fully cure early-stage HCC, but about 70% of patients are diagnosed at intermediate or advanced stages, where surgery is not an option[3]. HCC ranks as the fifth most common cancer in men and the seventh in women. Furthermore, men are three times more likely to develop HCC than women, regardless of race or geographic location. This disease is often associated with high mortality rates and poor prognosis in its advanced stages, presenting significant psychological challenges for patients during their diagnosis and treatment. Patients middle and advanced HCC not only endure physical suffering from the disease but also frequently face anxiety and depression, severely impacting their quality of life[4].

The definitive diagnosis of HCC requires multimodal approaches including diagnostic imaging modalities (computed tomography and magnetic resonance imaging), serological biomarkers such as alpha-fetoprotein assessment, and histopathological confirmation through percutaneous tissue sampling. Among these diagnostic methods, histopathological examination of biopsy specimens obtained via needle puncture continues to represent the most authoritative diagnostic criterion in clinical practice[5]. Staging considers tumor size, number, vascular invasion, liver function, and symptoms, with the Barcelona Clinic Liver Cancer (BCLC) system being the most effective for treatment guidance[1,6]. Early-stage HCC is classified as stages 0 and A, while stages B, C, and D represent intermediate to late stages. Therapy is customized based on the tumor’s features, liver performance, and overall health. Current studies are investigating improved ultrasound, deoxycholine, and circulating tumor DNA tests for diagnostic purposes[7].

Anxiety and depression are common psychological issues among cancer patients. Studies have shown that the prevalence of anxiety and depression in liver cancer patients is higher than in the general population. A study by Klankaew et al[8] found that approximately 80% of patients with advanced liver cancer exhibited varying degrees of anxiety and depression symptoms[8]. Moreover, anxiety and depression not only affect patients’ mental health but are also closely related to physical symptoms, treatment adherence, and prognosis[9]. Patients often experience profound anxiety and depression when confronting the uncertainties of their illness, pain, treatment side effects, and declining quality of life. Therefore, understanding the influencing factors of these psychological states is crucial for improving the overall health and quality of life of liver cancer patients[10].

Liver cancer’s development is complex, involving various biological pathways and is linked to chronic hepatitis, cirrhosis, and metabolic diseases[11]. Hepatitis B and C infections significantly increase liver cancer risk by causing inflammation and fibrosis, leading to mutations[12]. The growing prevalence of non-alcoholic fatty liver disease and metabolic syndrome also contributes to the rising incidence of liver cancer[13,14]. Liver cancer is linked to abnormal activation of signaling pathways like Wnt/β-catenin, phosphatidylinositol 3-kinase/protein kinase B, mitogen-activated protein kinase, and p53, leading to unchecked cell growth and increased angiogenesis[15]. Genetic polymorphisms, particularly in the DPYD gene, also play a crucial role. Variants like DPYD*2A and DPYD*2B can reduce DPD enzyme activity, affecting drug metabolism and potentially increasing toxicity and liver dysfunction[16].

Research has indicated that multiple factors may influence the psychological health status of liver cancer patients. First, the social support system of patients has been shown to play a crucial role in psychological adjustment. Zhao et al[17] noted that good social support can effectively alleviate psychological stress and enhance patients’ coping abilities. Additionally, psychological interventions (such as counseling and cognitive behavioral therapy) have demonstrated positive effects in improving patients’ emotional states[18]. The disease context and progression that patients face may also exacerbate anxiety and depression. For example, the severity of the disease, the presence of comorbidities, and the choice of treatment options can significantly impact psychological well-being.

Lifestyle habits are also important factors to consider. According to research by Liu et al[19], long-term unhealthy lifestyle habits (such as smoking, excessive drinking, and lack of exercise). Improving lifestyle not only enhances the physical health of patients but may also have a positive impact on their psychological state. Lately, more research has concentrated on the connection between mental health and quality of life. According to research by Balikji et al[20], depression and anxiety detrimentally affect quality of life, particularly in the context of chronic disease development. The psychological state of patients directly affects their engagement in daily life and their satisfaction with life, thus it is essential to emphasize a comprehensive assessment of multiple factors, including mental health, in order to improve patient prognosis and quality of life.

Hamilton Anxiety Rating Scale (HAMA) can effectively reflect the severity of anxiety states and shows a good correlation with scores from other anxiety symptom assessment tools[21]. Hamilton Depression Rating Scale (HAMD) is the most commonly used scale for assessing depression in clinical settings, primarily used to evaluate the severity of depressive symptoms in patients with depressive disorders, making it one of the most widely used symptom assessment tools in the world[22]. Additionally, we use the Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire (FACT-Hep) scale to assess the quality of life of patients; this questionnaire has been widely applied in studies involving liver cancer patients and can comprehensively reflect patients’ physical, social/family, psychological, functional, and liver-related tumor-specific conditions[23].

In summary, the purpose of this study is to analyze the anxiety and depression status of patients with advanced liver cancer and their influencing factors, as well as to explore the correlation between these psychological factors and quality of life. The aim is to provide a theoretical basis for clinical treatment and psychological intervention to help improve the quality of life of patients with advanced liver cancer.

MATERIALS AND METHODS

Study design and participants

This study involved 105 patients diagnosed with advanced HCC at our hospital from November 2023 to November 2024.

Data collection methods

All investigators underwent standardized training. Surveys were conducted using a combination of paper and electronic questionnaires. During the survey process, principles of informed consent were strictly followed. Researchers performed logical checks on the returned questionnaires and completed quality assessments. Questionnaires that did not meet quality standards (e.g., errors, non-standard responses, or multiple missing items) were re-evaluated and verified to ensure data quality. Questionnaires with multiple unanswered questions or irreparable issues were treated as invalid. The estimated time for questionnaire completion was 10 to 15 minutes. The research team provided guidance while patients filled out the questionnaires. Data were collected via paper questionnaires and subsequently entered into a computer system by designated personnel. To ensure data accuracy, all collected data underwent double entry. A total of 105 questionnaires were distributed, and 100 valid questionnaires were returned, resulting in a response rate of 95.23%. All questionnaires were completed in one sitting.

Inclusion and exclusion criteria

Inclusion criteria: (1) Diagnosis of liver cancer conforms to the standards outlined in the “Guidelines for the Diagnosis and Treatment of Primary Liver Cancer” (2019 edition); (2) Cognitively normal, having read the questionnaire instructions and informed consent form prior to participation, understanding the study content and purpose, and voluntarily agreeing to complete the questionnaire; (3) BCLC classified as intermediate to advanced stage (B/C stage); (4) Age between 18 and 75 years; (5) Eastern Cooperative Oncology Group Performance Status of 0 to 1; (6) Child-Pugh liver function score ≤ 7; (7) Karnofsky performance score (KPS) > 60; (8) Estimated survival time ≥ 6 months; and (9) No family history of mental illness, no previous history of mental disorders, no consciousness disturbances, and normal thought processes.

Exclusion criteria: (1) Presence of other malignant tumors; (2) Consciousness disturbances preventing questionnaire completion; (3) Individuals unwilling to cooperate in completing the questionnaire for personal reasons; (4) Functional impairment of vital organs such as the heart, brain, liver, or kidneys; and (5) Women who are pregnant or nursing.

Ethical approval

The ethics committee reviewed and approved this study. All participants signed an informed consent form, ensuring they were aware of the study’s purpose, procedures, and privacy protection measures.

Data collection content

Demographic and clinical data collection: A retrospective analysis was conducted to gather participant information, including demographic data such as age, gender, and alcohol consumption, as well as disease-related data including BCLC stage, number of tumors, history of liver resection, TACE, and hepatic artery infusion chemotherapy (HAIC).

Anxiety and depression[24]: HAMA was used to assess the severity of anxiety symptoms, consisting of 14 items scored on a 0-4 scale: < 14 indicates possibly anxiety; 14-21 indicates mild anxiety; 22-28 indicates moderate anxiety; ≥ 29 indicates severe anxiety. HAMA meets psychometric standards, with a Cronbach’s alpha of 0.93. The HAMD is the most commonly used scale for assessing depressive states, comprising 24 items, most scored on a 0-4 scale, with a few on a 0-2 scale: ≤ 8 indicates possibly depression; 9-20 indicates mild depression; 21-35 indicates moderate depression; > 35 indicates severe depression. HAMD meets psychometric standards, with a Cronbach’s alpha of 0.87.

Quality of life assessment: FACT-Hep questionnaire was developed by the Outcomes Research and Education Center in the United States to assess the quality of life in liver cancer patients. It covers five dimensions: Physical, social/family, psychological, functional, and liver-related tumor-specific conditions, consisting of 45 items with a total score of 180. A higher score indicates better quality of life[23]. A FACT-Hep score < 120 is considered indicative of poor quality of life. The Chinese version of the FACT-Hep questionnaire has shown good test-retest reliability, with all module and total scale scores exceeding 0.7. The overall Cronbach’s alpha was 0.863, indicating good reliability and validity[25].

Social support level[26]: The Social Support Rating Scale (SSRS) was employed to assess social support levels among patients with HCC. This scale includes 10 items that are grouped into three categories: Subjective support (items 1, 3, 4, 5), objective support (items 2, 6, 7), and the use of support (items 8, 9, 10). The scores for items 6 and 7 depend on how many support sources the participant chooses, with ‘none’ earning 0 points; points are awarded for each additional source chosen. The other items are scored individually. Total scores can range from 0 to 66, with scores of ≤ 22 indicating low support, 23-44 indicating moderate support, and 45-66 indicating high support. In this study, the overall Cronbach’s alpha coefficient for the scale was 0.730, indicating satisfactory internal consistency.

Statistical analysis

The statistical analysis utilized SPSS Statistics version 26.0. Means and standard deviations were used to summarize continuous variables, while counts and percentages were used for categorical variables. Multivariate logistic regression identified independent risk factors for anxiety and depression in liver cancer patients, reporting odds ratios (ORs) with 95% confidence intervals (CIs). The regression model employed two-sided tests with a significance level set at P < 0.05. Moreover, Pearson correlation analysis was performed to examine the relationships between HAMA scores, HAMD scores, and FACT-Hep scores in patients with liver cancer.

RESULTS

Patient baseline data

A total of 100 patients with intermediate to advanced liver cancer were included in the study, of which 91 were male (91%). Among them, 82 patients (82%) were classified as BCLC stage C, 86 patients (86%) had multiple tumors, 38 patients (38%) had a history of liver resection, and 87 patients (87%) underwent TACE/HAIC.

HAMA scores, HAMD scores, SSRS scores, and FACT-Hep scores

In this study, 105 questionnaires were distributed, and 100 valid questionnaires were returned, resulting in a response rate of 95.23%. The average total HAMA score was 19.53 ± 3.27, the average total HAMD score was 20.89 ± 3.85, the average total SSRS score was 33.29 ± 6.98, and the average total FACT-Hep score was 136.76 ± 7.62, as shown in Figure 1.

Figure 1 Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, Social Support Rating Scale and Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire scores in patients with advanced hepatocellular carcinoma. HAMA: Hamilton Anxiety Rating Scale; HAMD: Hamilton Depression Rating Scale; FACT-Hep: Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire; SSRS: Social Support Rating Scale.

Incidence of anxiety and depression

Among the 100 patients with advanced liver cancer, 64 experienced anxiety, resulting in an incidence rate of 64.0% (64/100), with FACT-Hep scores of 119.65 ± 10.73. A total of 65 patients experienced depression, resulting in an incidence rate of 65.0% (65/100), with FACT-Hep scores of 114.62 ± 10.85. The incidence of anxiety (64.0%) and depression (65.0%) is shown in Figure 2.

Figure 2 The incidence of anxiety and depression in patients with advanced liver cancer.

Depression study using univariate methods

The results of the univariate analysis for each depression-related factor are displayed in Table 1. The univariate analysis revealed notable differences in education level, living alone, KPS scores, HAMA scores, HAMD scores, history of liver resection and TACE/HAIC, BCLC stage C, number of tumors, social support level, and FACT-Hep scores between depressed and non-depressed patients (P < 0.05).

Table 1 Univariate analysis of depression, n (%).

Variable	Without depression (n = 35)	Depression (n = 65)	P value
Age (years)			0.617
< 60	15 (42.9)	29 (44.6)
≥ 60	20 (57.1)	36 (55.4)
Sex			0.253
Male	32 (91.4)	59 (90.8)
Female	3 (8.6)	6 (9.2)
Education			< 0.001
Primary	18 (51.5)	50 (76.9)
Secondary	9 (25.7)	7 (10.8)
Senior high school	6 (17.1)	5 (7.7)
College or above	2 (5.7)	3 (4.6)
Live alone			< 0.001
Yes	17 (48.6)	51 (78.5)
No	18 (51.4)	14 (21.5)
KPS score			< 0.001
60-80	19 (54.3)	48 (73.8)
> 80	16 (45.7)	17 (26.2)
HAMA score			< 0.001
< 14	17 (48.5)	19 (29.2)
14-21	11 (31.4)	12 (18.5)
≥ 22	7 (20.1)	34 (52.3)
HAMD score			< 0.001
≤ 8	15 (42.8)	20 (30.8)
9-20	8 (22.8)	8 (12.3)
≥ 21	12 (34.3)	37 (56.9)
Previous liver resection			< 0.001
Yes	8 (22.9)	30 (46.2)
No	27 (77.1)	35 (53.8)
TACE/HAIC			< 0.001
Yes	25 (71.4)	62 (95.4)
No	10 (28.6)	3 (4.6)
BCLC stage			< 0.001
B	12 (34.3)	6 (9.2)
C	23 (65.7)	59 (90.8)
Number of tumors			0.028
Single	9 (25.7)	5 (7.7)
Multiple	26 (74.3)	60 (92.3)
FACT-Hep scores			< 0.001
Good	12 (34.3)	6 (9.2)
Poor	23 (65.7)	59 (90.8)
FACT-Hep scores, mean ± SD	136.5 ± 11.36	114.62 ± 10.85	0.039
Social support			0.017
Low support	15 (42.9)	35 (53.8)
Moderate support	9 (25.7)	19 (29.2)
High support	11 (31.4)	11 (17.0)
History of smoking			0.215
Yes	16 (45.7)	35 (53.8)
No	19 (54.3)	30 (46.2)
History of drinking			0.743
Yes	20 (57.1)	40 (61.5)
No	15 (42.9)	25 (38.5)

KPS: Karnofsky performance score; HAMA: Hamilton Anxiety Rating Scale; HAMD: Hamilton Depression Rating Scale; TACE: Transcatheter arterial chemoembolization; HAIC: Hepatic artery infusion chemotherapy; BCLC: Barcelona Clinic Liver Cancer; FACT-Hep: Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire.

Anxiety study using univariate methods

The results of the univariate analysis for each factor linked to anxiety levels are displayed in Table 2. Significant differences were found between anxious and non-anxious patients concerning age, gender, education level, living alone, KPS scores, HAMA scores, HAMD scores, history of liver resection and TACE/HAIC, BCLC stage C, number of tumors, social support level, FACT-Hep scores, and alcohol consumption (P < 0.05).

Table 2 Univariate analysis of anxiety, n (%).

Variable	Without anxiety (n = 36)	Anxiety (n = 64)	P value
Age (years)			0.041
< 60	15 (41.7)	21 (32.8)
≥ 60	21 (58.3)	43 (67.2)
Sex			0.013
Male	29 (80.6)	62 (96.9)
Female	7 (19.4)	2 (3.1)
Education			< 0.001
Primary	17 (47.2)	49 (76.6)
Secondary	9 (25.1)	8 (12.5)
Senior high school	7 (19.4)	5 (7.8)
College or above	3 (8.3)	2 (3.1)
Live alone			< 0.001
Yes	19 (52.8)	50 (78.1)
No	17 (47.2)	14 (21.9)
KPS score			< 0.001
60-80	20 (55.6)	47 (73.4)
> 80	16 (44.4)	17 (26.6)
HAMA score			< 0.001
< 14	17 (47.2)	19 (29.7)
14-21	11 (30.6)	12 (18.7)
≥ 22	8 (22.2)	33 (51.6)
HAMD score			< 0.001
≤ 8	15 (41.7)	15 (23.4)
9-20	8 (22.2)	8 (12.5)
≥ 21	13 (36.1)	41 (64.1)
Previous liver resection			< 0.001
Yes	8 (22.2)	30 (46.9)
No	28 (77.8)	34 (53.1)
TACE/HAIC			< 0.001
Yes	25 (69.4)	62 (96.9)
No	11 (30.6)	2 (3.1)
BCLC stage			< 0.001
B	13 (36.1)	5 (7.8)
C	23 (63.9)	59 (92.2)
Number of tumors			< 0.001
Single	10 (27.8)	4 (6.3)
Multiple	26 (72.2)	60 (93.7)
FACT-Hep scores			< 0.001
Good	13 (36.1)	5 (7.8)
Poor	23 (63.9)	59 (92.2)
FACT-Hep scores, mean ± SD	138.7 ± 11.42	119.65 ± 10.73	0.015
Social support			< 0.001
Low support	14 (38.9)	33 (51.6)
Moderate support	8 (22.2)	20 (31.2)
High support	14 (38.9)	11 (17.2)
History of smoking			0.571
Yes	19 (52.8)	33 (51.6)
No	17 (47.2)	31 (48.4)
History of drinking			0.039
Yes	17 (47.2)	36 (56.3)
No	19 (52.8)	28 (43.7)

KPS: Karnofsky performance score; HAMA: Hamilton Anxiety Rating Scale; HAMD: Hamilton Depression Rating Scale; TACE: Transcatheter arterial chemoembolization; HAIC: Hepatic artery infusion chemotherapy; BCLC: Barcelona Clinic Liver Cancer; FACT-Hep: Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire.

Study of depression using logistic regression techniques

Depression was treated as the dependent variable (no depression = 0, depression = 1), and variables listed in Table 1 were employed as independent variables. A multivariate logistic regression analysis was executed to pinpoint independent factors affecting depression in patients with HCC. The results indicated that higher FACT-Hep scores were associated with a lower risk of depression (OR = 0.643, 95%CI: 0.458-0.985), and patients with high levels of social support had a lower likelihood of depression compared to those with low support (OR = 0.722, 95%CI: 0.603-0.987). Higher HAMA and HAMD scores were associated with an increased risk of depression (OR = 2.003, 95%CI: 1.539-2.651) and (OR = 1.826, 95%CI: 1.324-2.318). A history of liver resection (OR = 1.267, 95%CI: 1.152-1.634) and TACE/HAIC (OR = 1.318, 95%CI: 1.167-1.826) were identified as independent risk factors for depression; BCLC stage C (OR = 1.423, 95%CI: 1.175-1.953) and multiple tumors (OR = 2.528, 95%CI: 1.582-3.256) were also independent risk factors for depression, as shown in Table 3 and Figure 3A.

Figure 3 Binary logistic regression forest plot of independent influencing factors of depression and anxiety. A: Binary logistic regression forest plot of independent influencing factors of depression; B: Binary logistic regression forest plot of independent influencing factors of anxiety. OR: Odds ratio; FACT-Hep: Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire; BCLC: Barcelona Clinic Liver Cancer; TACE: Transcatheter arterial chemoembolization; HAIC: Hepatic artery infusion chemotherapy; HAMA: Hamilton Anxiety Rating Scale; HAMD: Hamilton Depression Rating Scale; KPS: Karnofsky performance score.

Table 3 Binary logistic regression analysis of hepatocellular carcinoma combined with depression.

Variable	OR	95%CI	P value
Education (primary & secondary vs senior high school)	1.693	1.124-2.538	0.028
Live alone (yes vs no)	1.163	0.718-1.544	0.951
KPS score (> 80 vs 60-80)	0.856	0.573-0.969	0.012
HAMA score (≥ 14 vs < 14)	2.003	1.539-2.651	< 0.001
HAMD score (> 8 vs ≤ 8)	1.826	1.324-2.318	< 0.001
Previous liver resection (yes vs no)	1.267	1.152-1.634	0.017
TACE/HAIC (yes vs no)	1.318	1.167-1.826	< 0.001
BCLC stage (C vs B)	1.423	1.175-1.953	< 0.001
Number of tumors (multiple vs single)	2.528	1.582-3.256	0.034
FACT-Hep scores (good vs poor)	0.643	0.458-0.985	< 0.001
Social support (high vs low & moderate)	0.722	0.603-0.987	< 0.001

OR: Odds ratio; CI: Confidence interval; KPS: Karnofsky performance score; HAMA: Hamilton Anxiety Rating Scale; HAMD: Hamilton Depression Rating Scale; TACE: Transcatheter arterial chemoembolization; HAIC: Hepatic artery infusion chemotherapy; BCLC: Barcelona Clinic Liver Cancer; FACT-Hep: Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire.

Study of anxiety using logistic regression techniques

In this study, anxiety was designated as the dependent variable (coded as 0 for no and 1 for yes) based on the outcomes of the univariate analysis presented in Table 2. Statistically significant variables from this analysis were employed as independent variables. A multivariate logistic regression analysis was conducted to ascertain the independent factors influencing anxiety among patients with HCC. The findings revealed that elevated FACT-Hep scores were significantly associated with a reduced risk of anxiety (OR = 0.678, 95%CI: 0.473-0.978). Additionally, KPS scores exceeding 80 were identified as a protective factor against anxiety (OR = 0.888, 95%CI: 0.584-0.957). Furthermore, patients with higher levels of social support demonstrated a lower likelihood of experiencing anxiety compared to those with lower levels of support (OR = 0.752, 95%CI: 0.615-0.977).

Conversely, factors such as age over 60 years (OR = 1.228, 95%CI: 1.114-1.514) and a history of alcohol consumption (OR = 2.007, 95%CI: 1.483-2.684) were identified as independent risk factors for anxiety. Additionally, higher HAMA and HAMD scores increased the risk of anxiety (OR = 2.038, 95%CI: 1.554-2.636 and OR = 1.856, 95%CI: 1.336-2.308, respectively). A history of liver resection (OR = 1.299, 95%CI: 1.163-1.622), lower education level (OR = 1.728, 95%CI: 1.139-2.523), and undergoing TACE/HAIC (OR = 1.353, 95%CI: 1.182-1.811) were also identified as independent risk factors for anxiety. Furthermore, BCLC stage C (OR = 1.455, 95%CI: 1.187-1.943) and multiple tumors (OR = 2.567, 95%CI: 1.893-3.244) were significant independent risk factors for anxiety, as shown in Table 4 and Figure 3B.

Table 4 Binary logistic regression analysis of hepatocellular carcinoma combined with anxiety.

Variable	OR	95%CI	P value
Age (≥ 60 vs < 60)	1.228	1.114-1.514	< 0.001
Sex (male vs female)	1.104	0.925-1.353	0.773
Education (primary & secondary vs senior high school)	1.728	1.139-2.523	0.028
Live alone (yes vs no)	1.193	0.736-1.534	0.951
KPS score (> 80 vs 60-80)	0.888	0.584-0.957	0.012
HAMA score (> 14 vs ≤ 14)	2.038	1.554-2.636	< 0.001
HAMD score (> 8 vs ≤ 8)	1.856	1.336-2.308	< 0.001
Previous liver resection (yes vs no)	1.299	1.163-1.622	0.017
TACE/HAIC (yes vs no)	1.353	1.182-1.811	< 0.001
BCLC stage (C vs B)	1.455	1.187-1.943	< 0.001
Number of tumors (multiple vs single)	2.567	1.893-3.244	0.034
FACT-Hep scores (good vs poor)	0.678	0.473-0.978	< 0.001
Social support (high vs low & moderate)	0.752	0.615-0.977	< 0.001
History of drinking (yes vs no)	2.007	1.483-2.684	< 0.001

OR: Odds ratio; CI: Confidence interval; KPS: Karnofsky performance score; HAMA: Hamilton Anxiety Rating Scale; HAMD: Hamilton Depression Rating Scale; TACE: Transcatheter arterial chemoembolization; HAIC: Hepatic artery infusion chemotherapy; BCLC: Barcelona Clinic Liver Cancer; FACT-Hep: Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire.

Correlation analysis of anxiety and depression scores with quality of life

Pearson correlation analysis revealed a negative correlation between HAMA and HAMD scores and FACT-Hep scores in liver cancer patients. The correlation coefficient between HAMA scores and FACT-Hep scores was r = -0.671, while the correlation coefficient between HAMD scores and FACT-Hep scores was r = -0.575, as shown in Table 5 and Supplementary Figure 1. This indicates that higher levels of anxiety and depression are associated with lower quality of life in patients with liver cancer.

Table 5 Correlation analysis between anxiety and depression scores and quality of life in patients with hepatocellular carcinoma.

Variable	FACT-Hep scores
	r	P value
HAMA score	-0.671	< 0.001
HAMD score	-0.575	< 0.001

FACT-Hep: Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire; HAMA: Hamilton Anxiety Rating Scale; HAMD: Hamilton Depression Rating Scale.

DISCUSSION

Most liver cancer patients are already in the intermediate to advanced stage when they seek medical attention. Although there are various treatment options available, the effectiveness of these treatments is uncertain, and the cure rate is low[27]. Evaluating treatment outcomes solely based on cure rates and survival rates has certain limitations; therefore, quality of life has become an important indicator for assessing the effectiveness of clinical treatments for liver cancer. At the intermediate to advanced stage, liver cancer may be accompanied by symptoms such as hypercalcemia and spontaneous hypoglycemia, severely affecting the patient’s physical function[28]. Additionally, the side effects of chemotherapy are significant, and adverse reactions such as gastrointestinal symptoms and bone marrow suppression can greatly increase the suffering of patients, leading to a decline in their quality of life[29]. Although these physical symptoms can be alleviated through targeted medical interventions or nursing care to improve comfort, significant improvements in quality of life cannot be achieved. In recent years, research on the psychological health and quality of life of cancer and chronic disease patients has become an international research hotspot[30]. In China, although several studies have explored the factors influencing negative emotions and quality of life among liver cancer patients, the research is still not comprehensive enough.

This study found that the overall psychological health status of patients with intermediate to advanced HCC is poor. Among the 100 patients, 64 (64.0%) exhibited symptoms of anxiety, and 65 (65.0%) showed symptoms of depression, with these prevalence rates significantly higher than those in the general population. According to the literature, depression and anxiety contribute to less favorable outcomes in individuals with HCC[31]. A meta-analysis found that the prevalence of depression and anxiety in HCC patients was 24.04% and 22.20%, respectively. Depression rates were lowest when assessed with clinician-administered scales (16.07%) and highest with self-reported scales (30.03%). Geographically, the lowest depression rate was in the Americas (16.44%) and the highest in South-East Asia (66.67%)[31]. Our research results further emphasize the seriousness of this issue, suggesting that continuous monitoring and intervention for the psychological health of patients with intermediate to advanced HCC is necessary.

Our findings indicate that depression and anxiety are negatively correlated with social support and quality of life. The decrease in FACT-Hep scores is closely related to an increase in anxiety and depression, indicating that good quality of life helps alleviate psychological health issues. Consistent with other studies, social support is regarded as a crucial element for enhancing an individual’s mental well-being[32]. Furthermore, our multivariate logistic regression analysis shows that higher HAMA and HAMD scores are associated with a higher risk of depression and anxiety, while high social support and high KPS scores are protective factors. This aligns with the findings of Chu et al[33], who found that lower anxiety and depression levels were linked to higher resilience and social support.

Regarding the mechanisms and molecular genetics of liver cancer, the occurrence of liver cancer is closely related to factors such as chronic liver disease, hepatitis virus infection, and metabolic syndrome. Another study indicated that gallic acid significantly inhibited the proliferation of SMMC-7721 liver cancer cells and stimulated the apoptotic process. Although the individual effect of exosomes derived from human umbilical cord mesenchymal stem cells was not significant, the effect was markedly enhanced after their combined application. Meanwhile, the expression levels of key enzymes such as hexokinase, phosphofructokinase, pyruvate kinase, lactate dehydrogenase, tumor necrosis factor-alpha, interleukin-1beta, catalase, superoxide dismutase, and glutathione peroxidase were significantly reduced in malignant liver cells, while the expression of interleukin 6 and malondialdehyde was elevated. Pathway enrichment analysis emphasized that the metabolism of selenium compounds and the metabolism of cysteine and methionine are key pathways[34]. These pathophysiological changes not only affect the physiological health of patients but may also exacerbate their psychological burden by influencing the neuroendocrine system and immune response[35]. For example, chronic inflammation may lead to psychological health issues, which in turn can affect the physiological state of patients, creating a vicious cycle[36] (Supplementary Figure 2).

In summary, this study highlights the importance of psychological health for patients with intermediate to advanced HCC, especially against the backdrop of high rates of anxiety and depression. Future research should focus on how to reduce anxiety and depression levels in HCC patients through improving social support, enhancing quality of life, and providing psychological interventions. Additionally, further exploration of the relationship between liver cancer-related biomarkers and psychological health may provide new insights into understanding the psychological well-being of liver cancer patients.

Limitations

This study is subject to several limitations. Initially, using self-reported questionnaires for evaluating patients might result in recall bias and fail to encompass all elements of psychological health. Secondly, employing a cross-sectional design restricts the ability to analyze causal links between variables. Future studies should work to overcome these limitations. Further research is needed to explore the potential confounding connection between anxiety symptoms and a family history of HCC. In addition, in our study, male patients accounted for 91% of the sample proportion, which is significantly higher than the existing literature reported that the prevalence of male HCC is about male:female = 3:1. This discrepancy may be due to sample selection bias: Our single-center study reflects only the demographic characteristics of patients with liver cancer in our hospital, and the sample size of our study was relatively small, with only 100 patients. The incidence of liver cancer is associated with some confounding factors such as hepatitis virus infection and alcohol abuse, and the prevalence of alcohol abuse is significantly higher in men than in women, the risk of chronic hepatitis virus infection is higher, and the risk of occupational exposure (such as exposure to harmful chemicals) may affect the accuracy of the results. Finally, the fact that this study was carried out at a single center in China restricts the applicability of the findings to HCC patients in China. Future research should include more objective assessments and undertake large-scale, prospective studies, as well as randomized controlled trials, to evaluate the efficacy of specific interventions designed to alleviate anxiety and depression in patients with HCC.

CONCLUSION

The findings suggest that a significant portion of patients with intermediate to advanced HCC have symptoms of depression and anxiety. Higher levels of social support and quality of life are associated with lower levels of depression and anxiety. Higher HAMA and HAMD scores, a history of liver resection, BCLC stage C, and multiple tumors are risk factors for depression in patients with intermediate to advanced HCC. Meanwhile, KPS scores are negatively correlated with anxiety. Independent risk factors for anxiety include being over 60 years old, a history of alcohol consumption, higher HAMA and HAMD scores, a history of liver resection, BCLC stage C, and multiple tumors. The anxiety and depression scores of liver cancer patients are negatively correlated with quality of life. Therefore, encouraging patients to engage in active self-care, enhancing psychological counseling, and providing psychological therapy and behavioral interventions for those with anxiety and depression can help improve their recovery, psychological comfort, and quality of life.