Homozygous Familial Hypercholesterolaemia: Insights to Improve
Homozygous Familial Hypercholesterolaemia: Insights to Improve
Impaired functionality of the LDL receptor underlies the hypercholesterolaemia of HoFH. While defective hepatic LDL uptake is the main and most direct consequence, other metabolic perturbations may contribute to the metabolic characteristics and accelerated atherosclerotic disease associated with HoFH. ApoB metabolism in HoFH remains incompletely defined, although in vitro and in vivo studies suggest that LDLR-negative mutations are associated with hepatic oversecretion of apoB. In addition, while levels of triglycerides are frequently within the normal range, hypertriglyceridaemia has been observed, and may be more common with an increasing prevalence of the metabolic syndrome. Decreased catabolism of triglyceride-rich lipoproteins may result from deficient LDL receptor function and account for postprandial dyslipidaemia. Familial hypercholesterolaemia is also associated with increased plasma levels of lipoprotein(a) [Lp(a)] by an undefined mechanism that may not directly involve the LDL receptor pathway. Lipoprotein(a) levels tend to be higher in HoFH than HeFH, and are independent of genetic variation in apolipoprotein(a). Finally, HoFH patients frequently have low levels of high-density lipoprotein cholesterol (HDL-C), probably due to accelerated turnover of HDL apoA-I, and defective HDL-driven cholesterol efflux. These metabolic perturbations have been extensively reviewed.
Metabolic Characteristics of Homozygous Familial Hypercholesterolaemia
Impaired functionality of the LDL receptor underlies the hypercholesterolaemia of HoFH. While defective hepatic LDL uptake is the main and most direct consequence, other metabolic perturbations may contribute to the metabolic characteristics and accelerated atherosclerotic disease associated with HoFH. ApoB metabolism in HoFH remains incompletely defined, although in vitro and in vivo studies suggest that LDLR-negative mutations are associated with hepatic oversecretion of apoB. In addition, while levels of triglycerides are frequently within the normal range, hypertriglyceridaemia has been observed, and may be more common with an increasing prevalence of the metabolic syndrome. Decreased catabolism of triglyceride-rich lipoproteins may result from deficient LDL receptor function and account for postprandial dyslipidaemia. Familial hypercholesterolaemia is also associated with increased plasma levels of lipoprotein(a) [Lp(a)] by an undefined mechanism that may not directly involve the LDL receptor pathway. Lipoprotein(a) levels tend to be higher in HoFH than HeFH, and are independent of genetic variation in apolipoprotein(a). Finally, HoFH patients frequently have low levels of high-density lipoprotein cholesterol (HDL-C), probably due to accelerated turnover of HDL apoA-I, and defective HDL-driven cholesterol efflux. These metabolic perturbations have been extensively reviewed.
Source...