Remnant Lipoprotein Cholesterol and Cardiovascular and Cerebrovascular Events in Patients with Non-Alcoholic Fatty Liver Disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by an atherogenic dyslipidaemia and an increased cardiovascular risk. Remnant lipoprotein cholesterol (RLP-C) is emerging as a novel cardiovascular risk factor, but its predictive value in patients with NAFLD is unknown. We investigated factors affecting RLP-C levels, and the association with major adverse cardiovascular and cerebrovascular events (MACCE) in NAFLD. A prospective observational cohort study was carried out including 798 unselected patients with cardio-metabolic diseases screened by ultrasound for the presence of NAFLD. Fasting RLP-C (mg/dL) was calculated as total cholesterol—(HDL (high-density lipoprotein) + LDL (low-density-lipoprotein)). Primary endpoint of the follow-up study was a combined endpoint of MACCE. Patients with NAFLD (79.2%) had higher median fasting RLP-C in comparison to those without (27.0 vs. 20.0 mg/dL, respectively p < 0.001). Metabolic syndrome, NAFLD, age above median, and female sex were independently associated to fasting RLP-C above the median. In patients with NAFLD, values of RLP-C were associated with liver disease severity, as shown by the increasing value of RLP-C across tertiles of aspartate aminotransferase (AST) (p = 0.002) and gamma-glutamyl transpeptidase (GGT) (p < 0.001). Furthermore, levels of RLP-C and Hamaguchi score, were significantly correlated (r = 0.193, p < 0.001). During a median follow-up of 32 months (interquartile range: 14.2–51.7, 1700 person-years), 41 MACCE (2.41%/year) were registered in 596 NAFLD patients. The rate of events was higher in NAFLD patients with RLP-C above the median compared to those below (log-rank test p = 0.040). Age (hazard ratio (HR) 1.039, 95% confidence interval (CI), 1.005–1.074, p = 0.024), previous cardiovascular events (HR 2.210, 95% CI, 1.052–4.643, p = 0.036), female sex (HR 0.454, 95% CI, 0.208–0.989, p = 0.047) and RLP-C above the median (HR 2.202, 95% CI, 1.132–4.285, p = 0.020) were associated with MACCE. In conclusion, we found that NAFLD was independently associated with higher circulating RLP-C, and that high RLP-C levels were predictive of MACCE in patients with NAFLD.

<p>Novel Application of the Traditional Lipid Ratios as Strong Risk Predictors of NASH</p>

“…20 Reduced concentration of HDL cholesterol could be correlated with numerous risk factors, including the components of the metabolic syndrome. 10 In the current study, there were positive correlations between TGs/HDL ratio and hepatic steatosis, inflammation, ballooning and NAS, and between serum TGs and hepatic inflammation, ballooning and NAS. In the initial "two-hit" model of the pathogenesis of NASH, excess TG accumulation resulting in hepatic steatosis was considered the primary harmful step for NASH development.…”

“…In light of the potential associated major adverse cardiovascular risks with fatty liver disease, the importance of early diagnosis and treatment may be protective. 10 The goal of the current study is to elucidate the predictive role of lipid profile ratios in diagnosing NAFLD concerning cardiovascular impact.…”

“…Triglycerides/ HDL, Total cholesterol/HDL, and LDL/HDL ratios can provide information on risk factors that are difficult to quantify by routine analyses and could be a better mirror of the metabolic and clinical interactions between lipid fractions. 10 Liver biopsy is the gold standard method for the diagnosis of NASH. However, liver biopsy is an invasive procedure that is associated with some pain or discomfort 11 with rare, but potentially life-threatening complications like bleeding 12 and is prone to sampling errors.…”

Lysosomal acid lipase activity and liver fibrosis in the clinical continuum of non‐alcoholic fatty liver disease

“…In a Phase 3 interventional clinical trial, performed in LAL‐D patients, sebelipase supplementation reduced the hepatic fat content compared with baseline (–32%, P = .001 vs placebo), and also caused a normalization of ALT and AST values, suggesting therefore a potential effect on reducing the risk of fibrosis . Furthermore, sebelipase alfa supplementation seems to have a positive impact on surrogate markers of atherosclerosis, a beneficial ‘pleiotropic’ effect which may turn useful in patients with NAFLD who experience a high rate of cardiovascular complications . Moreover, in experimental models, supplementation of LAL resulted in the regression of coronary and aortic atheromatous lesions .…”

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

“…Ultrasound-diagnosed NAFLD patients displayed higher fasting remnant cholesterol concentrations, indicating impaired clearance of remnant particles. Moreover, NAFLD patients with above-median concentrations of remnant cholesterol display higher CV event rates than NAFLD patients with below-median concentrations of remnant particles [ 99 ]. Indeed, similar to LDL, remnant particles can cross the arterial wall [ 100 ].…”