Familial hypercholesterolemia (FH) is a dominantly inherited disorder characterized by marked elevation of plasma
low-density lipoprotein (
LDL) cholesterol concentrations and premature
coronary artery disease (CHD). In addition to impaired
LDL receptor-mediated clearance of
LDL particles, in vitro and in vivo studies suggest that hepatic oversecretion of
apolipoprotein (
apo) B may contribute to the
hypercholesterolemia in FH. This may be due to an effect of the expanded hepatic pool of
cholesterol (a consequence of increased receptor-independent uptake of
LDL) and/or a direct effect of the
LDL receptor on
apoB secretion. Hepatic oversecretion of
apoB may depend on the type and severity of the genetic mutation causing FH. FH can also increase plasma Lp(a) concentration by an undefined mechanism that may not directly involve the
LDL receptor pathway. Decreased catabolism of
triglyceride-rich
lipoproteins could also be due to deficient
LDL receptor function, accounting for postprandial
dyslipidemia in FH. The metabolism of
high-density lipoprotein (HDL) in FH is poorly understood, but preliminary data suggest abnormal HDL composition and functionality, as well as altered transport of
apoA-I. Beyond effects related to specific genetic defects in the
LDL pathway, co-existing secondary causes, particularly
obesity and
insulin resistance, and other genetic variants may also perturb
lipoprotein metabolism in individuals with FH. Furthermore, residual risk remains high in
statin-treated FH. Knowledge of an extended metabolic framework will, therefore, provide the basis for judiciously selecting new
pharmacotherapies to treat FH, including
apoB antisense oligonucleotides, microsomal transfer
protein (MTP) inhibitors and
proprotein convertase subtilisin/kexin type 9 (
PCSK9) inhibitors.