Meta-analysis of factors associated with the incidence of comorbid depression and anxiety in patients with chronic hepatitis B

Abstract

BACKGROUND

Chronic hepatitis B (CHB) affects millions worldwide, and many patients develop depression and anxiety. The disease’s long-term nature, potential complications, and social stigma contribute to these mental-health issues. However, previous studies on this link differed in their methods and results, making it hard to draw clear conclusions. This study aimed to analyze factors associated with CHB through meta-analysis of previous studies to help improve patients’ mental health.

AIM

To systematically search, screen, and comprehensively analyze existing relevant research through meta-analysis of previous studies to assess the correlation of the previously identified factors found to be associated with comorbid depression and anxiety in patients with CHB, with the goal of improving the patients' mental-health status.

METHODS

This study strictly adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Relevant literature from the inception of the PubMed, EMBASE, Cochrane Library, and Web of Science databases up to January 2025 was comprehensively searched. The search used medical subject headings combined with free-text terms, supplemented by literature tracing. The search terms covered vocabulary related to CHB, such as depression, anxiety, and risk factors. The literature was selected according to strict inclusion and exclusion criteria. Two researchers independently and blindly screened the literature and extracted key information. STATA12.0 and RevMan 5.3 software were used to perform meta-analysis of the extracted data, and an appropriate model based on the heterogeneity of the studies was selected.

RESULTS

The study included 14 articles from five countries (China, United States, Turkey, Australia, and Vietnam), involving 4494 patients with CHB. The analysis revealed that the incidence of comorbid depression in patients with CHB was 30.1% [95% confidence interval (95%CI): 0.182-0.420], the incidence of comorbid anxiety was 40.2% (95%CI: 0.126-0.678), and the overall incidence of negative emotions was 33.7% (95%CI: 0.182-0.420). Further research identified eight factors significantly associated with depression and anxiety. Among them, high educational level was a protective factor against comorbid anxiety and depression in patients with CHB [odds ratio (OR) = 0.43, 95%CI: 0.20-0.93, P < 0.05]. The risk of comorbid depression and anxiety was higher for older patients (OR = 3.05, 95%CI: 1.90-4.90, P < 0.05), longer treatment duration (OR = 3.11, 95%CI: 1.72-5.62, P > 0.05), presence of comorbidities (OR = 2.65, 95%CI: 1.21-5.77, P < 0.05), poor sleep quality (Fisher’s Z = 0.48, 95%CI: 0.41-0.55, Summary r = 0.447, P < 0.05), emotional instability (Fisher’s Z = 0.42, 95%CI: 0.29-0.55, summary r = 0.393, P < 0.05), a high number of hepatitis relapses (OR = 4.07, 95%CI: 2.81-5.89, P < 0.05), and a high degree of hepatitis (OR = 4.28, 95%CI: 1.76-10.41, P < 0.05).

CONCLUSION

Multiple factors were significantly associated with comorbid depression and anxiety in patients with CHB. Clinically, it is essential to identify high-risk patients at the earliest opportunity and implement effective intervention to enhance patients’ mental health and optimize CHB disease management and treatment.

Key Words: Chronic hepatitis B; Depression; Anxiety; Correlative factors; Meta-analysis

Core Tip: Patients with chronic hepatitis B may experience a significant burden of mental-health issues, with 30.1% experiencing depression, 40.2% anxiety, and 33.7% overall negative emotions. Higher educational level was a protective factor (odds ratio = 0.43) by enhancing self-management and disease understanding, whereas older age, longer treatment duration, comorbidities, poor sleep quality, emotional instability, frequent hepatitis relapses, and severe hepatitis status all elevated the risk of comorbid depression and anxiety. Clinically, early identification of high-risk groups and targeted interventions, such as education-based counseling and sleep management, are crucial for improving mental-health outcomes, although current research heterogeneity from diverse assessment tools and regional sampling indicates the need for standardized broader population studies in the future.

INTRODUCTION

Chronic hepatitis B (CHB) is prevalent globally. According to the “Global Hepatitis Report 2024” released by the World Health Organization, approximately 254 million people worldwide were chronically infected with the hepatitis B virus (HBV) in 2022. Severe complications, such as liver failure, liver cirrhosis, and liver cancer caused by HBV, lead to approximately 1.1 million deaths each year, imposing a heavy burden on the public-health field[1,2]. Due to its long-term course, numerous complications, potential infectivity, and risk of carcinogenesis along with the current lack of effective radical treatment methods, patients with CHB potentially experience both damage to their physical functions caused by the disease itself and non-negligible negative emotions and psychological stress[3,4].

Although many studies have investigated the psychological problems of patients with CHB, a study in four provinces in China showed that approximately 75% of patients with CHB experienced discrimination due to HBV infection, causing intense negative emotions and mental stress[5]. Among these, depressive and anxious emotions were particularly prominent. Considering that chronic stress in patients with CHB may elevate cortisol levels and suppress immune function, anxiety and depressive moods might reduce patients’ medication adherence, increasing the likelihood of treatment failure and disease relapse. Furthermore, such psychological states can exacerbate physical symptoms, such as fatigue and pain, causing a vicious cycle of deteriorating quality of life.

However, the studies aimed at identifying factors correlating depression/anxiety with CHB have shown significant heterogeneity. Moreover, different studies had obvious differences in the patient samples with different ages, regions, and disease stages. Research methods have included various means, such as questionnaires, clinical interviews, and laboratory tests, making it difficult to comprehensively analyze and effectively compare different studies. Most studies also have been from single centers, so no multi-center, large-sample comprehensive studies have been conducted. These gaps hinder the translation of evidence into clinical practice, necessitating a systematic synthesis to identify robust risk factors.

The aim of this meta-analysis was to systematically evaluate the associations of demographic, clinical, and psychosocial factors with comorbid depression/anxiety in patients with CHB. Using a PICOS framework, the review focused on adults with confirmed CHB (excluding special populations), compared risk/protective factor presence, and synthesized data from cohort/case-control/cross-sectional studies.

This meta-analysis systematically evaluated the associations of demographic, clinical, and psychosocial factors with comorbid depression/anxiety in adult patients with CHB. The overall goal was to provide strong evidence useful for clinically identifying high-risk patients with comorbid depression and anxiety and for formulating targeted intervention measures, with the expectation of improving the mental health of patients with CHB, enhancing the quality of life, and optimizing the overall disease management and treatment outcomes of patients with CHB.

MATERIALS AND METHODS

Data sources

This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Relevant studies on CHB complicated with depression and anxiety were retrieved from English databases, including those of PubMed, EMBASE, MEDLINE, Web of Science, and the Cochrane Library. The retrieval period for each database was from its inception to January 2025.

Literature retrieval strategy

The retrieval method combined medical subject headings with free terms, supplemented by literature tracing. The search terms were: “Hepatitis B”, “Chronic”, “Hepatitis B Virus Infection”, “Chronic”, “Chronic Hepatitis B Virus Infection”, “Chronic Hepatitis B”, “Anxiety”, “Angst”, “Nervousness”, “Hypervigilance”, “Social Anxiety”, “Anxieties”, “Social”, “Anxiety”, “Social”, “Social Anxieties”, “Anxiousness”, “Depression”, “Depressive Symptoms”, “Depressive Symptom”, “Symptom”, “Depressive”, “Emotional Depression”, “Depression”, “Emotional”, “Risk Factors”, “Factor”, “Risk”, “Risk Factor”, “Population at Risk”, “Populations at Risk”, “Risk Scores”, “Risk Score”, “Score”, “Risk”, “Risk Factor Scores”, “Risk Factor Score”, “Score”, “Risk Factor”, “Health Correlates”, “Correlates”, “Health”, “Social Risk Factors”, “Factor”, “Social Risk”, “Factors”, “Social Risk”, “Risk Factor”, “Social”, “Risk Factors”, “Social”, and “Social Risk Factor”. The detailed retrieval strategies for each database are shown in Table 1.

Table 1 Database literature retrieval strategies.

Database	Retrieval formula
PubMed	((((((((("Emotions"[Mesh]) OR (Emotion[Title/Abstract])) OR (Feelings[Title/Abstract])) OR (Feeling[Title/Abstract])) OR (Regret[Title/Abstract])) OR (Regrets[Title/Abstract])) OR ((((((((((((((("Psychology"[Mesh]) OR (Psychological Factors[Title/Abstract])) OR (Factor, Psychological[Title/Abstract])) OR (Psychological Factor[Title/Abstract])) OR (Factors, Psychological[Title/Abstract])) OR (Side Effects, Psychological[Title/Abstract])) OR (Psychological Side Effect[Title/Abstract])) OR (Side Effect, Psychological[Title/Abstract])) OR (Psychological Side Effects[Title/Abstract])) OR (Psychologists[Title/Abstract])) OR (Psychologist[Title/Abstract])) OR (Psychosocial Factors[Title/Abstract])) OR (Factor, Psychosocial[Title/Abstract])) OR (Factors, Psychosocial[Title/Abstract])) OR (Psychosocial Factor[Title/Abstract]))) OR (((((("Depression"[Mesh]) OR (Depressive Symptoms[Title/Abstract])) OR (Depressive Symptom[Title/Abstract])) OR (Symptom, Depressive[Title/Abstract])) OR (Emotional Depression[Title/Abstract])) OR (Depression, Emotional[Title/Abstract]))) OR (((((((((("Anxiety"[Mesh]) ) OR (Angst[Title/Abstract])) OR (Nervousness[Title/Abstract])) OR (Hypervigilance[Title/Abstract])) OR (Social Anxiety[Title/Abstract])) OR (Anxieties, Social[Title/Abstract])) OR (Anxiety, Social[Title/Abstract])) OR (Social Anxieties[Title/Abstract])) OR (Anxiousness[Title/Abstract]))) AND (((("Hepatitis B, Chronic"[Mesh]) OR (Hepatitis B Virus Infection, Chronic[Title/Abstract])) OR (Chronic Hepatitis B Virus Infection[Title/Abstract])) OR (Chronic Hepatitis B[Title/Abstract]))
Web of science	(TS=(Psychology OR Psychological Factors OR Factor Psychological OR Psychological Factor OR Factors Psychological OR Side Effects Psychological OR Psychological Side Effect OR Side Effect Psychological OR Psychological Side Effects OR Psychologists OR Psychologist OR Psychosocial Factors OR Factor Psychosocial OR Factors Psychosocial OR Psychosocial Factor) And TS=(Depression OR Depressive Symptoms OR Depressive Symptom OR Symptom Depressive OR Emotional Depression OR Depression Emotional) And TS=(Anxiety OR Angst OR Nervousness OR Hypervigilance OR Social Anxiety OR Anxieties Social OR Anxiety Social OR Social Anxieties OR Anxiousness OR Emotions OR Emotion OR Feelings OR Feeling OR Regret OR Regrets) And TS=(Risk Factors OR Factor Risk OR Risk Factor OR Population at Risk OR Populations at Risk OR Risk Scores OR Risk Score OR Score Risk OR Risk Factor Scores OR Risk Factor Score OR Score Risk Factor OR Health Correlates OR Correlates Health OR Social Risk Factors OR Factor Social Risk OR Factors Social Risk OR Risk Factor Social OR Risk Factors Social OR Social Risk Factor) And TS=(Hepatitis B Chronic OR Hepatitis B Virus Infection Chronic OR Chronic Hepatitis B Virus Infection OR Chronic Hepatitis B)) (TS=(Depression OR Depressive Symptoms OR Depressive Symptom OR Symptom Depressive OR Emotional Depression OR Depression Emotional OR Anxiety OR Angst OR Nervousness OR Hypervigilance OR Social Anxiety OR Anxieties Social OR Anxiety Social OR Social Anxieties OR Anxiousness OR Emotions OR Emotion OR Feelings OR Feeling OR Regret OR Regrets) And TS=(Hepatitis B Chronic OR Hepatitis B Virus Infection Chronic OR Chronic Hepatitis B Virus Infection OR Chronic Hepatitis B))
Cochrane library	Emotions ('Emotion' OR 'Feelings' OR 'Feeling' OR 'Regret' OR 'Regrets'):ti,kw,ab OR Psychology ('Psychological Factors' OR 'Factor, Psychological' OR 'Psychological Factor' OR 'Factors, Psychological' OR 'Side Effects, Psychological' OR 'Psychological Side Effect' OR 'Side Effect, Psychological' OR 'Psychological Side Effects' OR 'Psychologists' OR 'Psychologist' OR 'Psychosocial Factors' OR 'Factor, Psychosocial' OR 'Factors, Psychosocial' OR 'Psychosocial Factor'):ti,kw,ab OR Depression ('Depressive Symptoms' OR 'Depressive Symptom' OR 'Symptom, Depressive' OR 'Emotional Depression' OR 'Depression, Emotional') OR Anxiety ('Angst' OR 'Nervousness' OR 'Hypervigilance' OR 'Social Anxiety' OR 'Anxieties, Social' OR 'Anxiety, Social' OR 'Social Anxieties' OR 'Anxiousness') AND Hepatitis B, Chronic ('Hepatitis B Virus Infection, Chronic' OR 'Chronic Hepatitis B Virus Infection' OR 'Chronic Hepatitis B'):ti,kw,ab
Database	EMBASE
Retrieval formula	Emotions: 'Emotion':ab,kw,ti OR 'Feelings':ab,kw,ti OR 'Feeling':ab,kw,ti OR 'Regret':ab,kw,ti OR 'Regrets':ab,kw,ti; Psychology: 'Psychological Factors':ab,kw,ti OR 'Factor, Psychological':ab,kw,ti OR 'Psychological Factor':ab,kw,ti OR 'Factors, Psychological':ab,kw,ti OR 'Side Effects, Psychological':ab,kw,ti OR 'Psychological Side Effect':ab,kw,ti OR 'Side Effect, Psychological':ab,kw,ti OR 'Psychological Side Effects':ab,kw,ti OR 'Psychologists':ab,kw,ti OR 'Psychologist':ab,kw,ti OR 'Psychosocial Factors':ab,kw,ti OR 'Factor, Psychosocial':ab,kw,ti OR 'Factors, Psychosocial':ab,kw,ti OR 'Psychosocial Factor':ab,kw,ti; Depression: 'Depressive Symptoms':ab,kw,ti OR 'Depressive Symptom':ab,kw,ti OR 'Symptom, Depressive':ab,kw,ti OR 'Emotional Depression':ab,kw,ti OR 'Depression, Emotional':ab,kw,ti; Anxiety: 'Angst':ab,kw,ti OR 'Nervousness':ab,kw,ti OR 'Hypervigilance':ab,kw,ti OR 'Social Anxiety':ab,kw,ti OR 'Anxieties, Social':ab,kw,ti OR 'Anxiety, Social':ab,kw,ti OR 'Social Anxieties':ab,kw,ti OR 'Anxiousness':ab,kw,ti; Hepatitis B, Chronic: 'Hepatitis B Virus Infection, Chronic':ab,kw,ti OR 'Chronic Hepatitis B Virus Infection':ab,kw,ti OR 'Chronic Hepatitis B'

Inclusion and exclusion criteria for literature

Inclusion criteria: (1) Participants: The research subjects were all patients with CHB, excluding newly diagnosed patients and special groups, such as pregnant women, adolescents, students, and children. All subjects were aware of their own medical conditions; (2) Interventions: None (observational studies); (3) Comparisons: Case group: Patients with CHB with comorbid depression and/or anxiety. Control group: Patients with CHB without depression or anxiety; and (4) Outcome: The study should include relevant factors or factors influencing depression or anxiety in patients with CHB. The data of relevant or influencing factors, including the r value, odds ratio (OR), and the 95% confidence interval (95%CI), should be clearly presented or can be calculated.

Study design: Cohort studies, case-control studies, and cross-sectional studies. The data analysis of the reviewed study had to have performed Spearman or Pearson correlation analysis or multifactor logistic regression analysis. For patients who had received psychological intervention treatment, the data before treatment should have been used.

Exclusion criteria: (1) Duplicate publications; (2) Non-English literature; (3) Literature with incomplete basic data, a large number of lost-to-follow-up patients, or obviously erroneous data; (4) Low-quality literature with a literature quality evaluation standard of grade C. The reference criteria are shown in the literature inclusion screening and quality evaluation below; and (5) Reviews, conference abstracts, case reports, letters, etc.

Screening and quality assessment of the included literature

A double-blind method was used for the literature screening process. Two researchers independently screened the retrieved literature according to the inclusion and exclusion criteria. This step ensured the objectivity and accuracy of the screening process. For the literature that met the inclusion criteria, detailed data extraction was performed, including key information, such as the first author, publication year, research design, sample size, patient age, and relevant factor indicators. During the extraction process, the pre-determined data extraction form was strictly followed to ensure the accuracy and integrity of the data. In case of any disagreement during the screening process, a third researcher would be consulted. Missing data were requested from authors via email.

Regarding the quality assessment of the included literature, the cross-sectional quality assessment criteria of the Joanna Briggs Institute Evidence-Based Health Care Research Center in Australia were adopted. These criteria covered various aspects, such as scientific research design, reasonable data collection strategies, reporting of sample response rates, samples that represented the population well, reasonable research objectives and methods, reporting of test power, and reasonable statistical methods. By evaluating these indicators, high reliability and consistency of the quality of the included literature was ensured. During the evaluation process, scoring was conducted strictly in accordance with the evaluation criteria, and a comprehensive quality assessment was made for each piece of literature. For item assessment, 1 point was awarded for low risk, 0.5 points for uncertainty, and 0 points for high-risk. Studies were graded as high (6-7 points), medium (4-5 points), or low (≤ 3 points); low-quality studies (grade C) were excluded. Risk of bias information was used to weight study contributions in the meta-analysis.

Statistical analysis

STATA12.0 and RevMan 5.3 software were used to perform a meta-analysis of the extracted data. If ≥ 2 articles involved the same correlative factor, the factor was extracted. For dichotomous variable data, the OR and its 95%CI were selected as the effect indicators to evaluate the degree of association between the risk factors of anxiety and depression and the risk of occurrence. The reliability was estimated through the 95%CI, and values of P < 0.05 indicated a statistically significant difference.

For studies using Pearson correlation analysis, when combining the effect sizes, the correlation coefficient needed to be transformed into Fisher’s Z, as shown in formula (1). For the 95%CI, the lower and upper limits of the value were Zlower and Zupper, respectively, and the 2-sided critical value = 1.96, as shown in formula (2).

Heterogeneity reflects the degree of inconsistency in the results among different studies. The Q-test and I² were used to evaluate the heterogeneity of the included literature, and the test level was set at α = 0.1. The magnitude of heterogeneity was quantitatively judged by combining it with the I² statistic. I² < 50% or P > 0.1 indicated low heterogeneity warranting a fixed-effects model.

I² ≥ 50% and P ≤ 0.1 indicated substantial heterogeneity requiring a random-effects model. Subgroup analyses by region were performed to explore geographic variation. Sensitivity analyses by sequentially excluding each study were performed to test result robustness. Publication bias was assessed by performing Egger’s test for risk factors with ≥ 10 studies.

RESULTS

Literature screening

The literature was screened as follows: First, 724 articles were retrieved through database searches in PubMed (n = 78), Web of Science (n = 260), Cochrane Library (n = 220), and EMBASE (n = 166). Subsequently, 109 duplicate articles were removed, leaving 615 articles for screening based on titles, abstracts, and keywords. Consistent with the study’s inclusion criteria, the following article types were excluded: Reviews (n = 57); meta-analyses (n = 5), involved animal experiments (n = 11); not in English (n = 29); conference papers, letters, and case reports (n = 145); were on disease types inconsistent with the requirements (n = 170); had irrelevant outcomes or without specific results data (n = 77); and did not perform multifactor logistic regression analysis or correlation analysis (n = 75). After this initial screening, 46 potentially eligible articles were identified and advanced to the full-text re-screening stage. Finally, a thorough full-text review and re-screening of these 46 articles was performed, and 14 articles were ultimately included for subsequent analysis[6-19]. The results and process of literature screening are summarized in Figure 1. The 14 included articles originated from five countries, China, the United States, Turkey, Australia, and Vietnam, and involved 4494 patients. Among them, 11 articles[2,8-12,14,16-19] reported in detail the incidence of anxiety or depression in patients with CHB. One article only reported the combined incidence of depression and anxiety[6]. Three articles presented the incidence of anxiety and depression in patients with CHB respectively[14,16,17]. Two articles reported the scores of anxiety or depression without providing the specific incidence (Table 2)[13,15].

Figure 1  Flowchart of literature inclusion screening.

Table 2 Characteristics of the included studies.

Ref.	Country	Study type	Age [(mean ± SD), (min-max), mean (min-max)]	Total sample size	Anxiety incidence (%)	Incidence of depression (%)	Period	Correlation factor
Qin et al[6], 2021	China	Descriptive research	30-71	320	-	75	January 2018 to January 2020	Education level, duration of treatment, number of relapses, complications, nursing satisfaction
Liu et al[7], 2017	China	Cohort study	51.5 (37-79)	501158	-	1.09	2004-2008	Male, age, place of residence, household income, occupation
Huang et al[8], 2019	China	Cohort study	16-70	209	-	29.20	June 2017 to May 2018	Low FT3, total bilirubin
Shi et al[9], 2010	China	Cross-sectional study	16-68	132	-	57.60	1 June 2007 to 31 December 2007	Number of relapses, total score of social support, concern about infection, emotional stability, presence or absence of antiviral therapy, hepatitis score
Kunkel et al[10], 2000	America	Cross-sectional study	24-69	50	-	46	September 1998 to December 1998	Fatigue, serum alanine aminotransferase, serum glutamic oxalacetic aminotransferase
Weinstein et al[11], 2011	America	Retrospective study	43.6 ± 13.2	190	-	3.70	January 2001 to April 2010	Excessive drinking
Hajarizadeh et al[12], 2016	Australia	Cross-sectional study	45 (22-77)	93	76	-	April 2013 to September 2013	Low level of education, life-changing possibilities
Wu et al[13], 2023	China	Case-control study	-	747	-	-	July 2016 to October 2016	Sleep disorder
Ekmen et al[14], 2021	Türkiye	Cross-sectional study	40.58 ± 9.12	182	33.52	55.22	-	Degree of illness, emotional focus
Duan et al[15], 2012	China	Case-control study	52.40 ± 14.23	120	-	-	July 2009 to July 2010	Education, mood, hepatitis grading, sleep quality
Kong et al[16], 2021	China	Cross-sectional study	35.82 (18-66)	188	38.30	33.00	March 2018 to October 2018	Age, female, education level, duration of treatment
Keskin et al[17], 2013	Türkiye	Cross-sectional study	47.53 ± 13.79	96	2.10	40.60	April 2008 to September 2008	Age, physical function, environment, culture
Liu et al[18], 2011	China	Descriptive research	37.5 ± 9.3	120	52.50	-	September 2008 to March 2010	CD4+ T cell level, CD4/CD8 ratio
Vu et al[19], 2019	Vietnam	Cross-sectional study	49.2 ± 16.0	298	31.40	37.50	October 2018	CD4+ T cell level, CD4/CD8 ratio

Literature quality assessment

Among the included articles, 3 articles[6-8] were of high quality, and 11 articles[9-19] were of medium quality (Figure 2A). The specific literature quality evaluation is presented in Figure 2B.

Figure 2 Results and evaluation table of literature quality assessment. A: Situation of literature quality assessment; B: Literature quality evaluation table. Green indicates low risk, yellow indicates uncertainty, and orange indicates high risk. Green is marked as 1 point, indicating "yes"; orange is marked as 0 points, indicating "no"; yellow is marked as 0.5 points, indicating "not clear". This scale is highly flexible, and users can adjust it according to the actual research situation. The total score of this scale is 7.0 points. Literature with a quality score of 6.0-7.0 points is of grade A (high-quality literature), literature with a score of 4.0-5.5 points is of grade B (medium-quality literature), and literature with a score of less than 4.0 points is of grade C (low-quality literature).

Incidence of depression and anxiety

The incidence of comorbid negative emotions (depression or anxiety) in patients with CHB was 33.7% (95%CI: 0.182-0.420; Figure 3A). To investigate the effect of different organ transplants and potential regions on the incidence, this study conducted subgroup analyses according to depression and anxiety, respectively. The results showed that the incidence of comorbid depression in CHB patients was 30.1% (95%CI: 0.182-0.420), and the incidence of comorbid anxiety was 40.2% (95%CI: 0.126-0.678; Figure 3).

Figure 3 Incidence of comorbid negative emotions in chronic hepatitis B patients. A: Incidence of comorbid depression; B: Incidence of comorbid anxiety. 95%CI: 95% confidence interval.

For the subgroup analysis of the incidence of comorbid depression in patients with CHB, among the included studies, the incidences of depression were 30.0%, 5.2%, 31.0%, and 37.2% in Chinese patients with CHB, Australian, Turkish, and Vietnamese, respectively, patients with CHB (Figure 4A). For the sensitivity analysis of the literature on the incidence of comorbid anxiety in patients with CHB, after each article was sequentially excluded, the combined results of the remaining studies all became statistically significant. The meta-analysis results were not prone to significant changes due to the variation in the number of studies, indicating robustness (Figure 4B).

Figure 4 Regional subgroup analysis and sensitivity analysis of depression incidence in patients with chronic hepatitis B. A: Regional subgroup analysis of the incidence of depression in chronic hepatitis B patients (Group 1: China; Group 2: The United States; Group 3: Turkey; and Group 4: Vietnam); B: Sensitivity analysis of the incidence of depression in chronic hepatitis B patients. 95%CI: 95% confidence interval.

For the subgroup analysis of the incidence of comorbid anxiety in patients with CHB, among the included studies, the incidence of comorbid anxiety was 76.3%, 42.9%, and 6.7% in the Australian, Chinese, and Turkish patients with CHB, respectively (Figure 5A). For the sensitivity analysis of the literature on the incidence of comorbid anxiety in patients with CHB, after each article was sequentially excluded, the combined results of the remaining studies were all statistically significant. The analysis results were robust and not easily affected by the change in the number of studies (Figure 5B).

Figure 5 Regional subgroup analysis and sensitivity analysis of anxiety incidence in patients with chronic hepatitis B. A: Regional subgroup analysis of the incidence of anxiety in chronic hepatitis B patients (Group 1: China; Group 3: Turkey; Group 5: Australia); B: Sensitivity analysis of the incidence of anxiety in chronic hepatitis B patients. 95%CI: 95% confidence interval.

Correlative factors of comorbid depression and anxiety in CHB patients

Through data extraction, the analysis of correlative factors and multivariate analysis of > 2 studies reported eight different risk factors: Educational level, treatment duration, comorbidities, age, sleep quality, emotional stability, number of hepatitis relapses, and degree of hepatitis. Heterogeneity tests were performed on the literature related to these 8 factors, and the combined effect sizes were calculated.

Educational level

A total of four studies[6,12,15,16] concluded that education level was correlated with anxiety and depression in patients with CHB. The literature[6,15,16] mentioned high educational level as a protective factor, whereas one study[12] mentioned low educational level as a risk factor. In the combined literature[6,15,16], due to the significant heterogeneity observed between studies (I² = 98.3%, P < 0.1), a random-effects model showed that high educational level was a protective factor for anxiety and depression in patients with CHB (OR = 0.43, 95%CI: 0.20-0.93, P < 0.05; Figure 6A). Sensitivity analysis using the random-effects model of educational level showed that the results were robust and not easily changed significantly due to changes in the number of studies (Figure 6B). The Egger’s test result was t = 1.95, P = 0.302 (> 0.05), and there was no risk of publication bias.

Figure 6 Forest plot and sensitivity analysis of the association between educational level and comorbid depression/anxiety in patients with chronic hepatitis B. A: Forest map for education level analysis; B: Sensitivity analysis of educational level analysis. 95%CI: 95% confidence interval.

Treatment duration

Two studies[6,16] evaluated the effect of treatment duration on negative emotions in patients with CHB. Since no significant heterogeneity was observed among the studies (I² = 0.00%, P > 0.1), a fixed-effects model was used for analysis. The results showed that patients with a longer treatment duration had a higher risk of developing depression and anxiety (OR = 3.11, 95%CI: 1.72-5.62, P > 0.05; Figure 7A).

Figure 7 Forest plots of associations between key factors and comorbid depression/anxiety in patients with chronic hepatitis B. A-G: Forest plot of treatment duration (A), comorbidities (B), age (C), sleep quality (D), emotional stability (E), the number of relapses (F), and hepatitis degree (G) analysis. 95%CI: 95% confidence interval.

Comorbidities

Two studies[6,19] evaluated the effect of comorbidities on depression and anxiety in patients with CHB. Due to the significant heterogeneity observed among the studies (I² = 74.4%, P < 0.1), a random-effects model was used for analysis. The results showed that the risk of comorbid depression and anxiety was higher in patients with comorbidities than in patients without (OR = 2.65, 95%CI: 1.21-5.77, P < 0.05; Figure 7B).

Age

Four studies[7,16,17,19] evaluated the effect of the age of patients with CHB on depression and anxiety. One of the studies[17] used Pearson correlation analysis (r = 0.610, P = 0.014), and three studies[7,16,19] used logistic regression analysis. These three studies[7,16,19] were combined. Since no significant heterogeneity was observed among the studies (I² = 0.00%, P > 0.1), a fixed-effects model was used for analysis. The results showed that the risk of comorbid depression and anxiety was higher with increasing patient age, (OR = 3.05, 95%CI: 1.90-4.90, P < 0.05; Figure 7C).

Sleep quality

Three studies[10,13,15] evaluated the effect of sleep quality on depression and anxiety in the patients with CHB. One of the studies[15] used logistic regression analysis (OR = 2.99, 95%CI: 1.04-8.56), and two studies[10,13] used Pearson correlation analysis. The data of these 2 studies were combined after transformation using formulas (1) and (2). Since no significant heterogeneity was observed among the studies (I² = 42.8%, P > 0.1), a fixed-effects model was used for analysis. The results showed that the risk of comorbid depression and anxiety was higher in patients with poor sleep quality than in those with good sleep quality (Fisher’ Z = 0.48, 95%CI: 0.41-0.55, Summary r = 0.447, P < 0.05; Figure 7D).

Emotional stability

Three studies[9,14,15] evaluated the effect of patients’ emotions on depression and anxiety in the patients with CHB. One of the studies[15] used logistic regression analysis (OR = 1.11, 95%CI: 1.03-1.19), and two studies[9,14] used Pearson correlation analysis. The data of these two studies were combined after transformation using formulas (1) and (2). Since significant heterogeneity was observed among the studies (I² = 83.3%, P < 0.1), a random-effects model was used for analysis. The results showed that the risk of comorbid depression and anxiety was higher in the patients with emotional instability than in those without (Fisher’s Z = 0.42, 95%CI: 0.29-0.55, Summary r = 0.393, P < 0.05; Figure 7E).

Number of relapses

Two studies[6,9] evaluated the impact of the number of relapses in patients with CHB on depression and anxiety. Since no significant heterogeneity was observed among the studies (I² = 0.00%, P > 0.1), a fixed-effects model was used for analysis. The results showed that the risk of comorbid depression and anxiety was higher in the patients with a higher number of relapses of hepatitis B than in those with a lower number (OR = 4.07, 95%CI: 2.81-5.89, P < 0.05; Figure 7F).

Degree of hepatitis

Two studies[9,15] evaluated the effect of the degree of hepatitis in patients on depression and anxiety in the patients with CHB. Since no significant heterogeneity was observed among the studies (I² = 23.4%, P > 0.1), a fixed-effects model was used for analysis. The results indicated that the risk of comorbid depression and anxiety was higher in the patients with a higher degree of hepatitis than in those with a lower degree (OR = 4.28, 95%CI: 1.76-10.41, P < 0.05; Figure 7G).

DISCUSSION

After combining the data in this meta-analysis, the results showed that the probabilities of comorbid depression and anxiety in the patients with CHB were relatively high (30.1% and 40.2%). The pooled prevalence of comorbid depression was 30.1% (95%CI: 0.182-0.420, 11 studies) and of anxiety was 40.2% (95%CI: 0.126-0.678, 7 studies) in the patients with CHB, with overall negative emotions at 33.7%. The evidence strength was moderate, limited by significant heterogeneity (I² > 98%), reflecting disparities in the diagnostic criteria across regions.

Evaluating the correlative factors of comorbid depression and anxiety in patients with CHB remains a significant challenge. Calculation of the combined effect sizes identified eight factors significantly associated with depression and anxiety.

Patients with CHB with depression and anxiety related factors

Higher education acts as a protective factor (OR = 0.43) by enhancing health literacy and access to evidence-based information. Patients with CHB and a lower educational level generally have relatively weaker self-management abilities in various aspects, such as medication compliance, symptom monitoring, dietary adjustment, and social coping. These patients have insufficient awareness of the importance of disease management, are more likely to be afraid of hepatitis B, are reluctant to talk about their condition with others, and lack the relevant knowledge and skills to effectively implement self-management measures. Consequently, these patients are more prone to negative emotions, such as fear, anxiety, and depression. In contrast, patients with a higher educational level know how to obtain hepatitis B-related knowledge and coping methods through multiple channels.

Older age (≥ 40 years) and longer treatment duration were found to be robust risk factors (OR = 3.05, 95%CI: 1.90-4.90 and OR = 3.11, 95%CI: 1.72-5.62, respectively) in this study. Currently, no treatment method can completely eliminate HBV from the patient’s body[20]. Over time, patients often become frustrated about the incurable nature of the disease and frequently worry excessively about their prognosis. Besides the financial pressure of long-term treatment, patients are also concerned about disease progression and infectivity. This disease is protracted and recurrent, increasing the probability of hepatitis B-related complications. With the gradual aggravation of clinical symptoms and the decline in quality of life, most patients are under great psychological pressure and remain in a state of emotional instability[21-23].

Our study showed that poor sleep quality was significantly correlated with comorbid mental health issues (Fisher’s Z = 0.48, r = 0.447, P < 0.05), forming a bidirectional cycle with depression. A survey by Zheng et al[24] reported that patients with CHB often have problems with poor sleep quality, mainly caused by increased toxin levels in the body due to the disease, hormonal imbalance, and increased psychological burden. Huang et al[8] found that the prevalence of depression in patients with CHB was 29.2%, and the prevalence of insomnia was 46.4%. Insomnia was almost universal among depressed patients. Insomnia may be a manifestation of depression, and the two affect each other. The study also found that liver function impairment affects thyroid hormone metabolism, reducing the FT3 Level, which in turn aggravates depression and insomnia symptoms. Severe sleep disorders affect patient quality of life, disrupt normal rest and recovery, and affect patient emotions.

The analysis of this study revealed that the emotional stability of patients with CHB was also a key factor affecting their mental health. In this study, patients with CHB who were emotionally unstable had a higher risk of combined depression and anxiety (Fisher’s Z = 0.42, Summary r = 0.393, P < 0.05). Misunderstandings about the infectivity of HBV and social discrimination also increase the psychological pressure on patients with CHB, thus promoting the development of mental disorders or depression. A study by Li et al[25] in the Dalian area of China reported that approximately 85% of the participants expressed sympathy for HBV-infected individuals. However, a study in Vietnam reported that 4.8% of patients with CHB had experienced blame, 10.2% felt ashamed, and 48.5% felt discriminated against in medical institutions. Due to external influences, patients often experience uncontrolled emotions, which also reduces their immunity and aggravates the condition. Therefore, it is very important to eliminate the psychological barriers of patients with CHB.

Our study showed that repeated illness relapses and a high degree of hepatitis were key risk factors influencing depression and anxiety in patients with CHB. Frequent relapses (≥ 3 times/year) and severe hepatitis (Child-Pugh class C) showed the highest risk (OR = 4.07, 95%CI: 2.81-5.89 and OR = 4.28, 95%CI: 1.76-10.41, respectively). As patients become older and the duration of virus carriage lengthens, depressive feelings are more likely to occur. Experiencing multiple disease relapses increases patients’ anxiety, significantly elevates stress-related hormones, and decreases the body’s immune capacity. In turn, decreased immunity exacerbates the changes in the disease, creating a vicious cycle that worsens depressive emotions[26,27]. Considering the characteristics of hepatitis B itself, the severity of the disease is closely linked to the occurrence of depression and anxiety. Our meta-analysis results showed a 4.28-fold increase in the risk of comorbid depression and anxiety in patients with a high degree of hepatitis. A study by Zhu et al[28] found that patients with Child-Pugh class C had a higher risk of depression. In addition, a study by Mirabdolhagh et al[29] found that patients with CHB had more severe depressive symptoms than inactive HBV carriers. Since patients with a higher degree of hepatitis usually experience symptoms, such as ascites, jaundice, and hepatic encephalopathy, and are also uncertain about the disease and their future lives, all of which can trigger or exacerbate depressive and anxious emotions.

It also should be noted that two of the included studies in this review suggested that income level had a significant effect on depression and anxiety in patients with CHB. However, the evaluation results of a study[7] indicated that a low-income level was a risk factor (OR = 2.38, 95%CI: 1.34-4.25), whereas the evaluation result of literature[19] showed that a high-income level was a protective factor (OR = 0.32, 95%CI: 0.13-0.76), making it impossible to calculate the combined effect size. A study by Tu et al[30] concluded that patients with CHB may have difficulty paying the out-of-pocket expenses related to blood tests and imaging examinations required for disease-staging assessments. The continuous management of CHB and physical symptoms also may lead to income loss and exacerbate financial difficulties. Moreover, the healthcare of the affected individuals is not the only cost associated with a HBV diagnosis. Family members of patients with CHB undergoing testing, vaccination, or treatment can incur a greater financial burden. A study on the annual economic burden of HBV-related diseases in 12 cities in China found that the average annual intangible cost was 6611.10 USD, imposing a heavy financial burden and thus causing negative emotions in patients[31].

Preventive measures

Therefore, in clinical practice, psychological support should be provided to early stage HBV-carrying patients. For patients with CHB with severe conditions, psychological state assessment and intervention are necessary. Timely counseling should be given to help patients cope with the psychological effect of the disease. In terms of health education, medical staff should provide targeted explanations of hepatitis B disease knowledge based on the educational level and comprehension ability of patients with CHB. This should cover aspects, such as the treatment process, transmission modes, and disease prognosis. Diverse forms, such as brochures, video demonstrations, and online communication platforms, can be used to enhance patients’ sense of cognitive control over the disease and treatment compliance, alleviating the fear and anxiety caused by a lack of knowledge. It is recommended that patients be guided to face the disease with a positive attitude, and when necessary, to adopt appropriate psychological therapies to deal with the psychological effect of the disease and regulate patients’ emotions. Patients’ family members should be encouraged to actively participate in the patients’ daily care and psychological support. Simultaneously, medical institutions can organize mutual-aid groups for patients with CHB to promote experience sharing and emotional communication among patients, reducing the sense of loneliness and helplessness caused by the disease and improving the patients’ psychological environment.

Deficiencies and prospects of the research

Several limitations at the study, outcome, and review levels merit discussion. At the study level, potential biases persisted despite the application of meta-analytic methods, including selection bias from cross-sectional designs in 11 of the 14 studies, which introduced recall bias in retrospective data collection, and performance bias due to only three studies (21%) using blinded mental-health assessments. Incomplete covariate adjustment for factors, such as antiviral therapy or comorbidities, further complicated interpretation of the results. At the outcome level, significant heterogeneity (I² > 50% for key outcomes) arose from diverse diagnostic tools and regional sample variations (anxiety prevalence ranged from 2.1% in Turkey to 76.3% in Australia), compromising the stability of pooled-effect sizes. For example, treatment duration showed an OR of 3.11 (95%CI: 1.72-5.62, P < 0.05) in only two studies, limiting the statistical power. At the review level, publication bias probably occurred due to exclusion of non-English studies and gray literature, and reporting bias was evident in the inconsistent outcome reporting. The absence of a unified assessment tool for depression and anxiety in patients with CHB exacerbated heterogeneity, affecting the reliability of the results.

Future research should prioritize rigorously designed, multi-center, large-sample studies using standardized tools (e.g., PHQ-9/GAD-7) to reduce heterogeneity. Exploring unstudied factors, such as social-support networks and coping styles, and analyzing interactions between biological markers and psychosocial stressors, will deepen our understanding of comorbid mechanisms. Inclusive literature searches and advanced meta-analytical techniques can also mitigate biases and strengthen synthesis of evidence.

CONCLUSION

This meta-analysis identified eight factors associated with comorbid depression and anxiety in patients with CHB, including high educational attainment as a protective factor (OR = 0.43), older age (OR = 3.05), longer treatment duration (OR = 3.11), and severe hepatitis (OR = 4.28) as key risk factors. These findings are consistent with those of previous research, highlighting that patients with CHB have elevated economic and mental-health burdens due to disease chronicity and social stigma. The results provide a clinical foundation for prioritizing mental-health screening and tailored interventions for older patients with CHB and lower educational and income levels. Future studies should address methodological limitations to inform evidence-based guidelines, ultimately enhancing the mental health of patients with CHB and optimizing disease management.