Pathophysiology of depression and anxiety in metabolic dysfunction-associated steatotic liver disease

Table 1 Key studies highlighting the increased risk of depression and anxiety in patients with metabolic-associated steatotic liver disease

Ref.	Year	Type	Population	Key findings
Weinstein et al[30]	2011	Cross-sectional study. MASLD was diagnosed through pathology and/or radiologic testing	878 patients with chronic liver disease (MASLD, HBV, HCV) seen at a tertiary liver center	MASLD patients had a significantly higher prevalence of depression (27.2%). Independent predictors of depression for MASLD patients included hypertension, current smoking, history of lung disease, female sex, and nonAfricanAmerican ethnicity
Goulart et al[33]	2023	Cross-sectional study. MASLD was diagnosed by ultrasound imaging	7241 working-age adults from a primary care center in Brazil. Comorbidities included metabolic syndrome components such as obesity, diabetes, dyslipidemia and hypertension	MASLD was positively associated with depression (OR = 1.17, 95%CI: 1.00-1.38). MASLD was inversely associated with anxiety (OR = 0.75, 95%CI: 0.63-0.90) and when stratified by sex, only men presented this association (OR = 0.73; 95%CI: 0.60-0.89)
Christian Labenz et al[34]	2020	Retrospective cohort study. MASLD diagnosed primarily by ICD codes in primary care records	19871 German adults with an initial diagnosis of MASLD/MASH without liver cirrhosis matched with 19871 controls from German primary care records between years 2010–2015. Comorbidities such as type 2 diabetes, obesity, and cardiovascular disease were accounted for using the Charlson Comorbidity Index in the analysis	MASLD patients had a higher incidence of both depression (21.2% vs 18.2%) and anxiety (7.9% vs 6.5%) compared to controls. After adjusting for confounders, MASLD remained an independent risk factor, with hazard ratios of 1.21 for depression and 1.23 for anxiety
Youssef et al[13]	2013	Cross-sectional study. MASLD diagnosed by liver biopsy	567 biopsy-proven MASLD patients enrolled in the Duke MASLD Clinical Database. Comorbidities including diabetes and obesity were reported and considered	14% of patients were noted to have clinical depression while 23% had clinical anxiety. The severity of depressive symptoms increased with the severity of hepatocellular ballooning with adjusted cumulative odds ratio of clinical depression 3.6 (95%CI: 1.4-8.8)
Brodosi et al[35]	2024	Cross-sectional study. MASLD diagnosed by ultrasound and/or clinical criteria	286 Italian adults out of which 223 met MASLD criteria. Comorbidities included obesity, diabetes, and hypertension reported among participants	MASLD was not independently associated with moderate/severe depression (OR = 0.34; 95%CI: 0.12–1.01) or severe trait anxiety (OR = 0.79; 95%CI: 0.27–2.34). This was attributed to awareness of MASLD progression by the patient
Tomeno et al[31]	2015	Prospective observational study. MASLD was diagnosed by biopsy	258 Japanese adults with biopsy confirmed MASLD, out of which 32 were diagnosed with depression	Patients comorbid with depression showed higher severity of steatosis and increased levels of serum aminotransferase, γ-glutamyl transpeptidase and ferritin
Choi et al[11]	2021	Retrospective cross-sectional study. MASLD was diagnosed by ultrasonography	25333 Korean adults among whom MASLD prevalence was 30.9%. Comorbidities including obesity, diabetes, and hypertension were reported	In women, MASLD was significantly associated with depression (adjusted OR = 1.43, 95%CI: 1.14–1.80; P = 0.002). Additionally, severe MASLD showed a significant correlation with both state anxiety (adjusted OR = 1.84, 95%CI: 1.01–3.37; P = 0.047) and trait anxiety (adjusted OR = 2.45, 95%CI: 1.08–4.85; P = 0.018)
He et al[37]	2025	Cross-sectional study. MASLD diagnosed by NHANES criteria including imaging and lab markers	3332 ethnically diverse MASLD patients drawn from NHANES dataset	Overall, central fat mediated 16.6% of the link between MASLD and depression. In women, the mediation by central fat was 17.8%, while no mediation was found in men
Roy et al[38]	2012	Systematic review	Adults with and without type 2 diabetes from multiple studies published between 2006 and 2011	Both, women with diabetes and also women without diabetes experience a higher prevalence of depression than men. The prevalence rate of depression is almost twice as high in people with type 2 diabetes (19.1%, range 65%-33% vs 10.7%, range 38-19.4%) than those without
Liang et al[40]	2024	Two-sample Mendelian randomization	807553 individuals, comprising 246363 cases and 561190 controls, derived from three GWAS conducted on individuals of European ancestry	Depression increased the risk of MASLD (OR: 1.557; 95%CI: 1.097-2.211; P = 0.016) but no inverse causal relationship was found
Zhou et al[41]	2024	Prospective cohort study followed by mendelian randomisation. MASLD diagnosed using United Kingdom Biobank clinical data	481181 United Kingdom Biobank participants after excluding participants with liver disease or alcohol/drug use disorders at baseline, without related exact date for liver disease or alcohol/drug use disorders, and new-onset severe MASLD within 5 years follow-up (median follow-up 13.5 years)	Participants with depression had a significantly higher risk of developing severe MASLD compared to those without depression (HR: 1.21, 95%CI: 1.09–1.34)
Noon et al[42]	2021	Prospective longitudinal cohort study. MASLD was diagnosed by liver biopsy	160 adolescents (ages 12–17) with MASLD followed for a mean of 3.8 years	At baseline, 8.1% had depression and 6.3% had anxiety. Over follow-up, an additional 95% developed depression (95%CI: 4.7%-14.3%) and 6.7% developed anxiety (95%CI: 2.6%-10.7%). Those who developed depression had significantly worse ALT changes in comparison to those without depression
Weinstein et al[43]	2022	Cross-sectional study	589 survey participants from a southern California community aged less than 70 years	After adjusting for various comorbidities, individuals with MASLD and higher levels of physical activity were at a decreased odds of having depressive symptoms [16.1% reduction (95%CI: -25.6 to -5.4%), P = 0.004], which was not observed in those without MASLD

MASLD: Metabolic dysfunction-associated steatotic liver disease; HBV: Hepatitis B virus; HCV: Hepatitis C virus; OR: Odds ratio.