mechanism of development of polygenic hypercholesterolaemia and familial combined hyperlipidaemia

Last reviewed 05/2023

• increased hepatic secretion of VLDL particles by the liver are associated with both polygenic hypercholesterolaemia and familial combined hyperlipidaemia
  • LDL production is increased (VLDL is the precursor of LDL) and often the LDL-receptor mechanism becomes overloaded
  • in polygenic hypercholesterolaemia, the VLDL levels (and hence triglyceride levels) do not increase because there is rapid conversion of VLDL to LDL - also it may be that the VLDL contains relatively fewer triglycerides and more cholesterol when it is secreted by the liver - thus biochemically the cholesterol level is raised but triglycerides are normal
  • in familial combined hyperlipidaemia a combined hyperlipidaemia occurs because individuals cannot rapidly convert VLDL to LDL
• hyperapobetalipoproteinaemia is present in both polygenic hypercholesterolaemia and familial combined hyperlipidaemia. This is is because each VLDL particle has one molecule of apo B and this remains with each particle as it is first converted to LDL and then catabolised

Notes:

• there is considerable variation in the level of hypercholesterolaemia necessary to produce a given rise in apo B and raised apo B levels may be present in patients with pure hypertriglyceridaemia and sometimes in patients with apparently normal levels of triglycerides and cholesterol. Also, as stated previously, each LDL particle contains one apoB molecule - however the amount of cholesterol contained in each LDL particle is variable. This can lead to the situation where a person is estimated to have a normal LDL cholesterol level but, because of increased levels of apo B (and hence LDL particles), the LDL cholesterol is made of small, dense LDL which are commonly associated with coronary heart disease. A clue to the presence of small, dense LDL is the presence of low serum HDL cholesterol, particularly if there is some degree of hypertriglyceridaemia
• there is evidence that genetic variants of PCSK9 could also affect plasma levels of LDL-C in polygenic (non-Mendelian) hypercholesterolemia (1)

Reference:

1. Chen SN et al. A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis. J Am Coll Cardiol. 2005 May 17;45(10):1611-9.