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Population Screening > Familial Hypercholesterolaemia > Flashcards

Familial Hypercholesterolaemia Flashcards

1
Q

What type of facing molecule is cholesterol?

A

Janus faced

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2
Q

What is the property of cholesterol that makes it useful in cell membranes but also makes it lethal?

A

Absolute Insolubility in water

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3
Q

When can cholesterol not be readily mobilised?

A

When it accumulates in the wrong place within the wall of an artery

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4
Q

The presence of accumulated cholesterol in the wrong place within wall of an artery eventually leads to what?

A

Development of an atherosclerotic plaque

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5
Q

What are the 6 main sequences events in progression of atherosclerosis?

A
  1. Initial lesion
  2. Fatty streak
  3. Intermediate lesion
  4. Atheroma
  5. Fibroatheroma
  6. Complicated lesion
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6
Q

What are the differences in main growth mechanisms of the sequences involved in progression of atherosclerosis?

A
  • 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
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7
Q

What are the differences in classification of lipoproteins?

A
  • Good = HDL (high density lipoprotein) = 10nm

- Bad = Non-HDL = 20-1000nm

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8
Q

What are the subcategories of bad/non-HDL lipoproteins?

A
  • LDL: low density lipoprotein (20nm)
  • IDL: intermediate density lipoprotein (40nm)
  • VLDL: very low density lipoprotein (70nm)
  • Chylomicron and chylomicron remnant (1000nm)
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9
Q

Provide an overview of the life cycle of cholesterol carrying lipoproteins

A
  1. Liver produces lipoproteins (=VLDL)
  2. Fat cells store triglyceride, resulting in IDLs
  3. Muscle cells burn triglycerides, resulting in LDLs
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10
Q

Familial hypercholesterolaemia is the commonest inherited disorder of what?

A

Lipid metabolism

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11
Q

What is the mode of inheritance for familial hypercholesterolaemia?

A

Autosomal dominant

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12
Q

What is the incidence of familial hypercholesterolaemia?

A

1 in 500

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13
Q

What does familial hypercholesterolaemia cause?

A

High levels of low density lipoprotein cholesterol (LDL-C) which frequently lead to early coronary heart disease

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14
Q

If untreated, what will roughly half of men with familial hypercholesterolaemia have developed by the age of 55?

A

Clinical evident coronary heart disease

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15
Q

FH is caused by what three genetic defects?

A
  • decreased number of LDL receptors
  • poor binding to apoB (5%)
  • increased degradation in recycling of LDL receptor to surface of liver (2%)
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16
Q

Testing for genetic mutations in familial hypercholesterolaemia involves what?

A
  • LDL receptor: 1000 known mutations
  • PCSK9: one mutation
  • apoB: one mutation
17
Q

What are the genetic testing methods used in familial hypercholesterolaemia?

A
  • Exon by exon sequence analysis (EBESA)
  • MLPA
  • Currently 48 common mutations tested which picks up 66% of FH cases at a cost of £250
18
Q

What are the diagnostic criteria used for Familial hypercholesterolaemia in adults?

A

Simone and Broome criteria

19
Q

What are required for a definite diagnosis of familial hypercholesterolaemia using the Simone and Broome diagnostic criteria?

A

1A: Total cholesterol greater than 7.5 or LDL greater than 4.9 mmol/L
AND
1B: Tendon xanthomas (patient or relatives)

OR

  1. DNA evidence of mutation in LDL receptor, apoB or PCSK9
20
Q

What are required for a POSSIBLE diagnosis of familial hypercholesterolaemia using the Simone and Broome diagnostic criteria?

A
  • 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
21
Q

How does familial hypercholesterolaemia map to the 1st criterion of screening (should be an important health problem)?

A
  • incidence is 1 in 500
  • approx 100,000 cases in U.K, of which 85% are undiagnosed
  • Risk of coronary heart disease
22
Q

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

A
  • the sequence of progression of atherosclerosis is well understood
  • the earliest onset of the first parts of the sequence is in the first decade
23
Q

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)?

A
  • 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
24
Q

How does familial hypercholesterolaemia map to the 5th criterion of screening (suitable test should be devised for the early stage)?

A
  • 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
25
Q

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

A
  • 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
26
Q

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)?

A
  • Provision of specialised FH nurse
  • Increased workload requires specialised software (pedigree drawing, work files, letters to GPs, remote access, data encryption)
27
Q

How does familial hypercholesterolaemia map to the 9th criterion of screening (costs should be balanced against the benefits)?

A
  • 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)
28
Q

What are the differences in testing results for definite familial hypercholesterolaemia (DFH) versus possible familial hypercholesterolaemia (PFH)?

A
  • Prevalence of PFH is twice that of DFH
  • Significantly higher detection rate in DFH vs PFH
  • Sizeable proportion of unclassifiable FH have a mutation
29
Q

How does the Familial hypercholesterolaemia cascade screening programme work?

A
  • 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
30
Q

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?

A
  • 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

Population Screening (9 decks)

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