Parabolic relationship between plasma triacylglycerols and LDL-cholesterol in familial combined hyperlipidaemia: the multiple-type hyperlipidaemia explained?

FCHL (familial combined hyperlipidaemia) is a highly prevalent genetic lipid disorder that accounts for a substantial number of premature cardiovascular events. To date, FCHL has been complicated by the different lipid phenotypes that are present within one family and one individual patient over time. In the present study, we hypothesized that a parabolic relationship between plasma triacylglycerols (triglycerides) and LDL (low-density lipoprotein)-cholesterol can explain this so-called 'multiple-type hyperlipidaemia' in FCHL. Our hypothesis was tested in two well-documented FCHL cohorts [Maastricht (n=145) and Nijmegen (n=299)] that were followed over a 5-year interval. Three groups were constructed depending on plasma triacylglycerols: group A (individuals with both measurements below 1.5 mmol/l), group B (one measurement below and one measurement above 1.5 mmol/l) and group C (both measurement above 1.5 mmol/l). In both male, but not female, cohorts, a significant positive relationship between plasma triacylglycerols and LDL-cholesterol was observed in group A (P=0.02 for Maastricht cohort and P=0.001 for the Nijmegen cohort), a significant negative relationship in group C (P=0.01 for Maastricht cohort and P=0.02 for the Nijmegen cohort), and a relationship intermediate to group A and C in group B. In contrast, both apoB (apolipoprotein B) levels and the prevalence of cardiovascular disease were related with plasma triacylglycerols in a more linear fashion. In conclusion, a parabolic relationship between plasma triacylglycerols and LDL-cholesterol explains the 'multiple-type hyperlipidaemia' in FCHL. In addition, the linear relationship between triacylglycerols and both apoB levels and the prevalence of cardiovascular disease substantiate the use of apoB instead of LDL-cholesterol in the diagnosis of FCHL and the prediction of cardiovascular disease.

Fatty liver is an integral feature of familial combined hyperlipidaemia: relationship with fat distribution and plasma lipids.

Overproduction of VLDL (very-low-density lipoprotein) particles is an important cause of FCHL (familial combined hyperlipidaemia). It has been shown recently that VLDL production is driven by the amount of hepatic fat. The present study was conducted to determine the prevalence of fatty liver in relation to the different fat compartments and lipid parameters in FCHL. A total of 68 FCHL patients, 110 normolipidaemic relatives and 66 spouses underwent ultrasound of the abdominal region to estimate the amount of subcutaneous, visceral and hepatic fat. Skinfold callipers were used to measure subcutaneous fat of the biceps, triceps, subscapular and supra-iliacal regions. Fatty liver was observed in 18% of the spouses, 25% of the normolipidaemic relatives and 49% of the FCHL patients. After adjustment for age, gender and body mass index, the prevalence of fatty liver was significantly higher in FCHL patients compared with spouses [OR (odds ratio), 3.1; P=0.03], and also in the normolipidaemic relatives compared with spouses (OR, 4.0; P=0.02), whereas no differences were observed between FCHL patients and normolipidaemic relatives (OR, 0.8; P=0.58). In the normolipidaemic relatives and FCHL patients combined, both visceral fat mass and subcutaneous abdominal fat were independent predictors of fatty liver (P<0.001 for both fat compartments; FCHL status corrected). Of interest, fatty liver stages were correlated with both VLDL-apoB (apolipoprotein B) and VLDL-triacylglycerols (triglycerides) in a representative subset (n=69) of patients and relatives (r(2)=0.12, P=0.006; and r(2)=0.18, P=0.001 respectively). These results show that fatty liver is a central aspect of FCHL, i.e. patients and normolipidaemic relatives. Both visceral and subcutaneous adiposity contribute to its 3-4-fold higher risk in FCHL.

Prothrombotic markers in familial combined hyperlipidemia: evidence of endothelial cell activation and relation to metabolic syndrome.

BACKGROUND: Familial combined hyperlipidemia (FCHL) is characterized by a varied expression of hypertriglyceridemia and hypercholesterolemia within a family, and a high risk of premature coronary artery disease. The present study evaluated a number of potential prothrombotic markers in familial combined hyperlipidemia, and studied their relationship to the hypercholesterolemic (Fredrickson type IIa) and hypertriglyceridemic (IIb and IV) phenotypes. METHODS AND RESULTS: Selected prothrombotic markers were studied in 68 subjects: 34 hyperlipidemic subjects with familial combined hyperlipidemia and 34 controls. FCHL patients exhibited significantly higher Thrombin-Antithrombin complex (TAT), activated coagulation factor XII (F XIIa), von Willebrand Factor (vWF), Plasminogen Activator Inhibitor-1 (PAI-1) and tissue derived Plasminogen Activator (t-PA) values in comparison to controls. Within the subgroup of familial combined hyperlipidemia subjects, elevated PAI-1 activity and soluble Thrombomodulin levels were particularly associated with features of the metabolic syndrome, including hyperinsulinemia, hypertriglyceridemia and predominance of small dense low density lipoprotein (LDL). CONCLUSIONS: A general pattern of activated blood coagulation and endothelial activation is present in all hyperlipidemic subjects studied, independent of metabolic phenotype. In those familial combined hyperlipidemia subjects with features of the metabolic syndrome, impaired fibrinolysis can provide an additional cardiovascular risk factor.