Introduction
Homocysteine (Hcy) levels are elevated in a variety of conditions, including cardiovascular diseases (CVD), diabetes, hyperinsulinemia, and metabolic-associated steatotic liver disease (MASLD). Although the relationship between MASLD and cardiovascular diseases (CVD) is epidemiologically well established (1), the pathogenetic process linking such conditions has not been completely clarified.
Aims & Methods
In this cross-sectional study, we analyzed Hcy levels in a population of 901 control and metabolic outpatients, considering the presence of MASLD and other dysmetabolic conditions, aiming to detect and deepen the putative role of Hcy in the relationship between liver steatosis and CVD. Hyperhomocysteinemia (HHcy) was defined for Hcy levels ≥15 μmol/l. Abdominal and carotid ultrasounds and comparison of Hcy levels were performed in all subjects.
Results
HHcy was identified in 140 subjects. Comparisons between subjects with Hcy<15 and Hcy>15 showed that the latter had significantly increased waist circumference (WC) (p=0.00001). HDL-c (p=0.00071) and 25-OH-Vitamin D (p=0.00002) levels were significantly lower, and triglycerides were significantly raised (p=0.04979) in subjects with HHcy compared to patients with Hcy<15.
We evaluated Hcy levels in subjects with and without such conditions, finding that Hcy did not differ between patients with and without carotid plaques (p=0.2182), but was different in presence of liver steatosis (p=0.00192) (Table 1).
Subjects with HHcy had a strong association with liver steatosis (chi-square p=0.00001), whereas we did not find the same association in presence of atherosclerotic plaques (chi-square p=0.08388). ORs analysis showed that subjects with HHcy subjects displayed an increased risk of fatty liver, with an OR of 2.1 (95% CI 1.3-3.2, p=0.00001), whilst the risk of being diagnosed with atherosclerotic plaques, though slightly increased (OR 1.2, 95% CI 0.8-1.7), was not significant (p=0.09938).
We calculated chi-square and ORs for HHcy association with increased BMI and each criterion of the IDF definition of MetS. In the overall population, regardless of the liver steatosis diagnosis, the cardiometabolic risk conditions significantly associated with HHcy were impaired fasting glycemia (FPG) (OR 2.1, 95% CI 1.4-3.1, p=0.00001), hypertriglyceridemia (OR 1.8, 95% CI 1.2-2.6, p=0.00028) and arterial hypertension (AH) (OR 1.7, 95% CI 1.4-3.1, p=0.00088).
In subjects with MASLD, the same analysis highlighted higher ORs, with hypertriglyceridemia showing the highest OR (3.3, 95% CI 2.6-3.8, p=0.00001), followed by AH (OR 2.6, 95% CI 1.9-2.9, p=0.00011), FPG (OR 2.5, 95% CI 2.1-2.8, p=0.00083) and WC (OR 2.4, 95% CI 1.6-2.8, p=0.00099), whilst the BMI criterion was not associated with HHcy.
Table 1. Comparison of homocysteine (Hcy) levels in patients with and without atherosclerotic plaque and liver steatosis.
| NO Plaque
N=313 (128M:185F)
| Plaque
N=343 (199M:144F)
| p-value |
| Hcy | 11.6±6.3
| 12.1±8.2
| 0.2182
|
|
|
|
|
| NO Steatosis
N=321 (147M:174F)
| Steatosis
N=510 (282M:228F)
| p-value |
| Hcy | 12.6±8.3
| 18.3±9.2
| 0.00192**
|
Conclusion
Our data suggest an intriguing scenario where the reciprocal correlation between liver steatosis and HHcy may worsen underlying metabolic dysfunctions leading to CVD, and further exacerbate the key pathological features of MASLD. Addressing these interconnected risk factors could represent a crucial strategy for mitigating CVD burden in the increasingly prevalent population of patients with liver steatosis.
References
- (1). Targher G, Byrne CD, Tilg H. MASLD: a systemic metabolic disorder with cardiovascular and malignant complications. Gut 2024;73:691-702.