Background
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a key risk factor for cardiovascular disease (CVD), potentially driven by shared metabolic mechanisms. However, the metabolic perturbations linking MASLD and CVD remains unexplored in people living with HIV (PLHIV).
Methods
We investigated subjects from the longitudinal multicenter 2000HIV study (NCT03994835), which included 1895 virally suppressed PLHIV on antiretroviral treatment. Of these, 970 participants had liver measurements. Liver steatosis (CAP > 263 dB/m) and fibrosis (LSM ≥ 7.0) were assessed using transient elastography with the controlled attenuation parameter (CAP). CVD history and new incidents within a two-year follow-up, including myocardial infarction, stroke, peripheral arterial disease, and angina, were extracted from medical records, while carotid artery plaques were assessed via ultrasonography. Mass spectrometry-based untargeted metabolomics (n=500 metabolites) and nuclear magnetic resonance spectroscopy for targeted lipoproteomics (n=246 metabolites) were used to analyze metabolic perturbations linked to MASLD and CVD.
Results
PLHIV with liver steatosis were more likely to have arterial plaques (47% vs. 36%; P-value = 0.003) and CVD history (11% vs. 6.8%; P-value = 0.021) than PLHIV without liver steatosis. These associations were more pronounced in lean PLHIV compared to those with BMI ≥ 25 kg/m2. Metabolic pathways associated with liver steatosis and fibrosis primarily involved lipid and amino acid metabolism (Figure 1); a finding validated by targeted lipoproteomic measurements. Notably, metabolomic pathways and lipoproteomic signatures associated with MASLD were mostly distinct from those associated with CVD parameters. However, several pathways were shared, especially in lean PLHIV (Figure 1), including arachidonic acid metabolism and formation of prostaglandin, purine metabolism, cholecalciferol metabolism, and glycine, serine, alanine- and threonine metabolism.
Conclusions
Metabolic disturbances linked to liver steatosis and CVD differ across BMI categories in PLHIV. Lean PLHIV with liver steatosis, unlike their overweight/obese counterparts, show common metabolic perturbation with future CVD events. This suggests a heightened CVD risk in lean PLHIV with liver steatosis, potentially opening avenues for interventions targeting the arachidonic acid metabolism, such as aspirin therapy, to mitigate this risk.