Abstract
Background
Severe liver disease (SLD), including non-alcoholic fatty liver disease, alcoholic liver disease, viral hepatitis, and liver fibrosis/cirrhosis, is a systemic metabolic disorder that frequently coexists with diabetes. As one of the most common diabetic complications, diabetic retinopathy (DR) still has an unclear association with SLD. This study aimed to examine the relationship between hospitalization-defined SLD and subsequent hospitalization-defined DR, multimodal retinal imaging phenotypes, and shared plasma metabolic signatures that statistically accounted for part of the observed association.Methods
We analyzed UK Biobank data from 499,852 participants. Time-dependent Cox models evaluated associations of SLD and its subtypes with incident DR. Multistate models assessed observed transitions from healthy state to diabetes and then to DR. Optical coherence tomography and color fundus photography parameters were analyzed to characterize retinal structural and vascular features cross-sectionally, and plasma metabolomic profiling was used to identify potential metabolic correlates shared by SLD and subsequent DR.Results
During follow-up, 12,632 participants developed SLD. Incident SLD was associated with higher DR risk (HR, 2.38; 95% CI, 2.08-2.73). In multistate analyses, SLD was associated with increased observed rate of transition from diabetes to DR (HR, 1.18; 95% CI, 1.03-1.35). SLD was primarily associated with lower OCT-derived macular and neuroretinal thickness in the cross-sectional imaging subset. Exploratory mediation analyses identified a shared metabolic signature, predominantly characterized by apoB-containing lipoprotein composition and triglyceride-enriched remnant-related measures, that statistically accounted for part of the association between baseline SLD and subsequent DR.Conclusions
Hospitalization-defined SLD and several of its subtypes were associated with a higher subsequent risk of hospitalization-defined DR and with a higher observed rate of transition from diabetes to DR. Cross-sectional retinal imaging analyses identified retinal structural and vascular imaging phenotypes associated with SLD. Circulating lipoprotein-related measures constituted a shared metabolic signature and statistically accounted for part of the observed association. These findings identify hospitalization-defined SLD as a marker of systemic disease burden associated with DR.