Familial Hypercholesterolaemia Flashcards
What type of facing molecule is cholesterol?
Janus faced
What is the property of cholesterol that makes it useful in cell membranes but also makes it lethal?
Absolute Insolubility in water
When can cholesterol not be readily mobilised?
When it accumulates in the wrong place within the wall of an artery
The presence of accumulated cholesterol in the wrong place within wall of an artery eventually leads to what?
Development of an atherosclerotic plaque
What are the 6 main sequences events in progression of atherosclerosis?
- Initial lesion
- Fatty streak
- Intermediate lesion
- Atheroma
- Fibroatheroma
- Complicated lesion
What are the differences in main growth mechanisms of the sequences involved in progression of atherosclerosis?
- Initial lesion, fatty streak, intermediate lesion and atheroma = growth mainly by lipid addition
- Fibroatheroma = increased smooth muscle and collagen increase
- Complicated lesion = thrombosis and/or hematoma
What are the differences in classification of lipoproteins?
- Good = HDL (high density lipoprotein) = 10nm
- Bad = Non-HDL = 20-1000nm
What are the subcategories of bad/non-HDL lipoproteins?
- LDL: low density lipoprotein (20nm)
- IDL: intermediate density lipoprotein (40nm)
- VLDL: very low density lipoprotein (70nm)
- Chylomicron and chylomicron remnant (1000nm)
Provide an overview of the life cycle of cholesterol carrying lipoproteins
- Liver produces lipoproteins (=VLDL)
- Fat cells store triglyceride, resulting in IDLs
- Muscle cells burn triglycerides, resulting in LDLs
Familial hypercholesterolaemia is the commonest inherited disorder of what?
Lipid metabolism
What is the mode of inheritance for familial hypercholesterolaemia?
Autosomal dominant
What is the incidence of familial hypercholesterolaemia?
1 in 500
What does familial hypercholesterolaemia cause?
High levels of low density lipoprotein cholesterol (LDL-C) which frequently lead to early coronary heart disease
If untreated, what will roughly half of men with familial hypercholesterolaemia have developed by the age of 55?
Clinical evident coronary heart disease
FH is caused by what three genetic defects?
- decreased number of LDL receptors
- poor binding to apoB (5%)
- increased degradation in recycling of LDL receptor to surface of liver (2%)
Testing for genetic mutations in familial hypercholesterolaemia involves what?
- LDL receptor: 1000 known mutations
- PCSK9: one mutation
- apoB: one mutation
What are the genetic testing methods used in familial hypercholesterolaemia?
- Exon by exon sequence analysis (EBESA)
- MLPA
- Currently 48 common mutations tested which picks up 66% of FH cases at a cost of £250
What are the diagnostic criteria used for Familial hypercholesterolaemia in adults?
Simone and Broome criteria
What are required for a definite diagnosis of familial hypercholesterolaemia using the Simone and Broome diagnostic criteria?
1A: Total cholesterol greater than 7.5 or LDL greater than 4.9 mmol/L
AND
1B: Tendon xanthomas (patient or relatives)
OR
- DNA evidence of mutation in LDL receptor, apoB or PCSK9
What are required for a POSSIBLE diagnosis of familial hypercholesterolaemia using the Simone and Broome diagnostic criteria?
- Total cholesterol greater than 7.5 or LDL greater than 4.9 mmol/L
AND
- Family history of raised total cholesterol/LDL
OR - MI under 60 yrs in first degree relative/under 50 yrs in second degree relative
How does familial hypercholesterolaemia map to the 1st criterion of screening (should be an important health problem)?
- incidence is 1 in 500
- approx 100,000 cases in U.K, of which 85% are undiagnosed
- Risk of coronary heart disease
How does familial hypercholesterolaemia map to the 2nd and 3rd criteria of screening?
2nd: natural history of condition should be well understood
3rd: there should be a detectable early stage
- the sequence of progression of atherosclerosis is well understood
- the earliest onset of the first parts of the sequence is in the first decade
How does familial hypercholesterolaemia map to the 4th criterion of screening (treatment at early stage should be of more benefit than at a later stage)?
- Statins reduce death rate in FH patients (20-59 yr olds)
- Reduction in standardised mortality ratio is more than 2 fold: with early identification and new more powerful statins, life expectancy for FH patients may not be significantly reduced at all
How does familial hypercholesterolaemia map to the 5th criterion of screening (suitable test should be devised for the early stage)?
- Using Simon Broome criteria with blood LDL-C, 20% of children of an FH index case will be misdiagnosed (15% false neg and 5% false pos) and 58% of the brothers and sisters will be misdiagnosed (42% false neg and 16% false pos)
- Detection rate using LDL cut offs results in high acceptance rate but low pick up of new FH due to out of catchment loss and low sensitivity of LDL-C cutoffs
How does familial hypercholesterolaemia map to the 6th and 7th criteria of screening?
6th: test should be acceptable
7th: the risks, both physical and psychological, should be less than the benefits
- No clinically relevant adverse psychological effects have been observed
- No evidence found to support any negative psychological effects of genetic screening in other diseases
- Large proportion of relatives are already aware of a cardiovascular problem in family and knowledge of its genetic and biochemical nature, as well as existence of effective therapeutic measures, may even improve their wellbeing
How does familial hypercholesterolaemia map to the 8th criterion of screening (Adequate health service provision should be made for extra clinical workload resulting from screening)?
- Provision of specialised FH nurse
- Increased workload requires specialised software (pedigree drawing, work files, letters to GPs, remote access, data encryption)
How does familial hypercholesterolaemia map to the 9th criterion of screening (costs should be balanced against the benefits)?
- Involves QALY (quality adjusted life years) measurement
- NICE modelled the cascade testing and found that including DNA testing alongside LDL-C gave a cost effectiveness ratio of approx £2700 per QALY (very good value considering NICE threshold is £20,000)
What are the differences in testing results for definite familial hypercholesterolaemia (DFH) versus possible familial hypercholesterolaemia (PFH)?
- Prevalence of PFH is twice that of DFH
- Significantly higher detection rate in DFH vs PFH
- Sizeable proportion of unclassifiable FH have a mutation
How does the Familial hypercholesterolaemia cascade screening programme work?
- Clinical diagnosis of FH is confirmed and a DNA test offered
- Index case invited to discuss family tracing with FH nurse
- Family pedigree drawn and used to identify first degree relatives who should be offered testing
- Relatives contacted directly by nurse or via index case and offered POCT at clinic/home
- All relatives offered DNA AND lipid test
- When FH suspected the GP is asked to refer the patient to the lipid clinic
Blood testing using LDL-C levels can result in misclassification in relatives of the index case. How does genetic testing improve this? What is the issue with genetic testing?
- Once underlying Mut in LDL receptor gene has been identified in index case the genetic screening of first degree relatives has a sensitivity and specificity close to 1 meaning misclassification is rare
- Issue = cost of genetic testing
