LDL receptor and FH (familial hypercholesterolaemia)

• the LDL receptor is located on chromosome 19
  
  
• the usual function of the LDL receptor is to allow LDL to be taken up by cells from tissue fluid and is summarised below:
  • LDL receptors are synthesized and migrate to the surface of the cell
  • the LDL receptor binds with the LDL
  • the LDL receptor and bound LDL enters the cell as a vesicle
  • the LDL receptors are released back into the cytoplasm and then travel back to the cell membrane
  • vesicles containing LDL fuse to form larger vesicles called endosomes - the esterified cholesterol and apo B are broken down into free cholesterol and amino acids respectively and then are able to diffuse out into the cytoplasm
    
    
• Familial Hypercholesterolaemia (FH) occurs because there is a mutation in the LDL receptor which prevents efficient uptake of LDL - i.e. either does not allow proper binding to LDL, or the receptor and ligand cannot be internalised, or the LDL receptor is not released from the vesicle, or the LDL receptor cannot be transported back to the cell surface. Over 200 mutations of the LDL receptor have been found that cause the clinical syndrome of FH
  
  
• FH heterozygotes - these individuals have one of the LDL receptor genes containing a mutation; in homozygotes both LDL receptor genes have mutations
  
  
• in the UK, FH in the heterozygous form affects about 1 in 500 people

There have been more recent genetic studies suggesting a prevalence of 1 in 200 to 250 (1,2)

• however these were based on data from a mainly white Danish population and so it is unclear how direcly applicable this data is to the UK population
• the prevalence of FH based on common LDLR and APOB mutations alone was one in 650 (1)
• UK guidance states "..Most cases of FH remain undiagnosed, and only an estimated 8-15% of cases are known (based on prevalence estimates of 1:250 and 1:500)" (3)

Reference:

• Benn M, Watts GF, Tybjaerg-Hansen A, et al. Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab. 2012 Nov;97(11):3956-64.
• Sjouke B, Kusters D, Kindt I, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur Heart J. 2014 Feb 28; doi: 10.109
• Public Health England (August 2018).Familial Hypercholesterolaemia Implementing a systems approach to detection and management.