• Cholesterol is a major lipid in human plasma and makes up structural components of the cell membrane. Cholesterol and other lipids are circulated in the form of lipoprotein particles and predominantly packaged in low density lipoprotein (LDL) particles.
  • LDL cholesterol is cleared from circulation by LDL receptors (LDLr) on the surface of liver cells. The LDLr controls cholesterol levels in the blood and in the liver.
  • In FH, there is a disturbance in the LDLr pathway and this leads to a reduced clearance of LDL particles, with a consequence of an increase in the plasma concentration of LDL cholesterol.
  • The extent of elevation of plasma cholesterol in FH is hence dependent on the severity of the genetic mutation.
  • Genetic defects in the LDLr gene can affect receptor synthesis, transport, internalisation and recycling. At present, there are more than 1600 LDLr mutations reported.
  • Other genetic defects which impair the LDLr pathway are mutations in:
    • apolipoprotein B (apoB), the receptor ligand
    • proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme that degrades LDLr.
  • Mutations in the apoB and PCSK9 gene have the same functional consequences on LDL cholesterol catabolism as mutations in the LDLr gene. However, they are more rare and account for <6% of cases.
  • The inheritance of FH is autosomal dominant. Hence, if one parent has heterozygous FH, there is a 50% chance of passing on the mutation to each of their children.
  • In heterozygous FH, approximately 50% of the LDLr are functionally inactive and this typically elevates plasma LDL cholesterol concentrations from 5 to 12mmol/L.
  • In homozygous FH, the LDLr has less than 20% functional activity and this typically increases LDL cholesterol concentrations to >13mmol/L.