Cardiovascular Disease Risk Is Increased In Adolescents With Metabolic Dysfunction-associated Steatotic Liver Disease

PURPOSE: Metabolic dysfunction-associated steatotic liver disease (MASLD) in adults increases cardiovascular disease (CVD) risk, but less is known about those risks in adolescents. We hypothesized that MASLD raises CVD risk in adolescents beyond what could be attributed to the presence of obesity and low aerobic fitness. METHODS: We compared 4 groups of boys and girls, ages 11-20y, across a continuum of body size, fitness, and liver health: 1) the healthiest were normal weight with adequate aerobic fitness based on reported thresholds for metabolic health (NW-Fit, n = 22), followed by; 2) NW with low fitness (NW-LoFit, n = 53); 3) obese with low fitness and without MAFLD (Ob, n = 47); and 4) obese with low fitness and biopsy-confirmed MASLD (n = 60). All MASLD patients had moderate to severe liver steatosis and 87% had ≥ stage 1 liver fibrosis. RESULTS: MASLD and Ob had similar body fat (45 ± 7%), and were much higher (p < 0.01) than NW-LoFit (29 ± 7%) or NW-Fit (22 ± 7%). VO2peak was ~10% lower in MASLD (1.76 ± 0.38 l/min adjusted for lean mass) than either Ob (1.95 ± 0.33, p = 0.03) or NW-LoFit (1.94 ± 0.25, p = 0.03), which were all lower (p < 0.01) than NW-Fit (2.48 ± 0.31). MASLD had higher triglycerides (p < 0.01) than all other groups, while Ob was intermediate (64 ± 28, 80 ± 38, 107 ± 50, & 195 ± 114 mg/dl for groups 1-4, respectively). Likewise, MASLD had the lowest HDL-C, while Ob was intermediate (57 ± 14, 57 ± 14, 47 ± 13, & 39 ± 9 mg/dl for groups 1-4, respectively). Insulin resistance (iHOMA2-IR) differed among all groups (all p < 0.01), increasing from group 1 to 4. Systolic and diastolic blood pressures for MASLD were 6% higher than Ob and 9-12% higher than either of the NW groups (all p < 0.01). Carotid-femoral pulsewave velocity did not differ between NW-Fit and NW-LoFit (4.6 ± 0.6 & 4.8 ± 0.6 m/s, respectively) but was higher (p < 0.01) in Ob (5.2 ± 0.7 m/s) and higher still in MASLD (5.6 ± 0.7 m/s, p < 0.01 versus Ob). Augmentation index (adjusted for heart rate), increased from NW-Fit (-11 ± 10%) to NW-LoFit (-2 ± 10%) to Ob (7 ± 11%) to MASLD (13 ± 13%, all p < 0.01). CONCLUSION: All of these CVD risk factors progressed in severity from the NW-Fit to the MASLD groups. Similar to adults, adolescents with MASLD have added CVD risk compared to NW and Ob peers without MASLD, as shown by higher blood pressure, arterial stiffening, dyslipidemia, and insulin resistance. NIH R01DK129656; Oklahoma Shared Clinical and Translational Resource; Presbyterian Health Foundation; Harold Hamm Oklahoma Diabetes Center