Familia Hypercholesterolaemia (HF) Flashcards
what is HF
a monogenic disorder of lipid metabolism, causing gross elevation of LDL and lipid deposition in multiple body sites such as tendons, cornea and pulmonary arteries.
Untreated what can HF cause
obstructive coronary artery disease pre maturely (about 50 for men and 60 for women)
Describe the genetic mechanism of HF
caused by a genetic defect in LDL-receptor mediated clearance of LDL.
What does the lab do in cases of HF
lipid measurement and genetic diagnosis
Describe normal LDL clearance
VLDL is made in the liver, it is metabolised in the circulation to smaller intermediate density lipo proteins IDL via lipoprotein lipase.
some IDL can be taken up by cells, but most is metabolised to LDL by hepatic lipase.
VLDL has many proteins –> apolipoproteins
-Apo B-100: needed for VDLD synthesis, and stays on the particle through metabolism, it mediates the binding of LDL to LDL receptors
-APo e: plays a role in uptake of IDL by the LDL receptor
-Apo CII: activates lipoprotein lipase on endothelial cells.
what is the inheritance pattern of FH.
Autosomal dominant
it has co-dominance / incomplete dominance
both heterozygotes and homozygotes are affected, by it is far more serious in those who are homozygous.
where the the mutation which is most likely to cause FH
In the LDL receptor (LDLR).
Describe the phenotype of FH
increased plasma/blood LDL and cholesterol
lipid accumulation in numerous sites (inc the vascular walls)
premature OCAD
these are more prominent in homozygotes.
FH has shown the founder effect in which populations
Afrikaner population
Christain lebanese
French Canadians.
describe some clinical features of FH
(Xanthoma : nodule on the skin caused by lipid deposition)
Tendon Xanthoma
Lipid-laden xanthoma
arcus senilis (lipid deposition in the cornea)
Describe the underlying mechanisms of FH
FH is associated with defects in LDLR, there can be a number of causative mutations.
e.g defect in apo b 100
Describe the distribution of FH mutations
FH1: LDLR gene (ch 19p13) that increases plasma LDL (67%)
FH2: APO B gene (chr 2p23-24) increases LDL (14%)
FH3: PCSK9 (1p32) increases LDL (2.3%) it affects the LDLR endolytic pathway
True or false: patients with the same mutation will have the same phenotype
False: those with the same mutation will not always have the same phenotype or clinical manifestations, there is a wide variety and different degrees of hypercholesterolaemia. Some will have increased risk of CAD but not all cases wii.
Does lack of premature CAD and tendon xanthoma rule out HF
no, in fact some cases the plasma can be close to normal LDL levels.
