Familial Hypercholesterolaemia

Question 1

Describe cholesterol and atherosclerosis.

Answer 1

• Cholesterol is a Janus faced molecule.
• The very property that makes it useful in cell membranes, namely its absolute insolubility in water, also makes it lethal.
• When cholesterol accumulates in the wrong place within the wall of an artery, it cannot be readily mobilised.
• Its presence eventually leads to the development of an atherosclerotic plaque.
• The whole process starts quite early on in life. Autopsies of children have shown a fatty streak.

Question 2

Describe the sequence in progression of atherosclerosis.

Answer 2

FROM FIRST DECADE:

1) . Initial lesion - histologically normal. Macrophage infiltration. Isolated foam cell.
2) . Fatty streak - mainly intracellular lipid accumulation.

FROM THIRD DECADE:

3) . Intermediate lesion - intracellular lipid accumulation. Small extracellular lipid pools.
4) . Atheroma - Intracellular lipid accumulation. Core of extracellular lipid.

FROM FOURTH DECADE:

5) . Fibroatheroma - single or multiple lipid cores. Fibrotic/calcific layers.
6) . Complicated lesion - surface defect, haematoma-haemorrhage, thombosis.

Silent condition for most of life until an event occurs.

Question 3

What are the fat molecules involved in the lipid accumulation in atherosclerosis?

Answer 3

• There are various kinds of fat in the body. There is ‘good fat’ and ‘bad fat’.
• The good fat is High Density Lipoprotein (HDL).
• The bad fat is Non-HDL including the Chylomicron and Chylomicron remnant, Very Low Density Lipoprotein (VLDL), Intermediate Density Lipoprotein (IDL), and Low Density Lipoprotein (LDL).
• There is a lot of variation between the sizes of these fat molecules. The Chylomicron and Chylomicron remnant are the largest, followed by VLDL, IDL, LDL and HDL.

Question 4

What are the functions of the different types of lipids? Outline the circulation of fats in the body.

Answer 4

• When you take somebody’s blood you can measure LDL and also HDL. However, it is a dynamic process.
• The liver produces VLDL which is essentially a way to transport triglycerides to cells which is a form of energy or for storage in fat cells.
• The triglycerides are then taken up by cells. Muscle cells burn triglyceride. You have an intermediate product IDL.
• LDL is the bad cholesterol which is then taken up by the liver.

Question 5

What is Familial Hypercholesterolaemia (FH)?

Answer 5

• It is the commonest inherited disorder of lipid metabolism.
• Its inheritance is autosomal dominant.
• Incidence is 1 in 5,000 and there are 100,000 predicted cases in the UK.
• It causes high levels of Low-Density-Lipoprotein Cholesterol (LDL-C) which frequently lead to early coronary heart disease (CHD).
• Roughly half of men with FH, if untreated, will have developed clinically evident CHD by the age of 55 years.

Question 6

What inheritance pattern does FH follow?

Answer 6

AD.

Question 7

What is the incidence of FH?

Answer 7

Incidence is 1 in 5,000 and there are 100,000 predicted cases in the UK.

Question 8

What happens in Familial Hypercholesterolaemia (FH)?

Answer 8

1). LDL binds to its receptor on the liver and the receptor is then internalised with the LDL molecule.

2) . FH can be caused by either:
- A decrease in the number of LDL receptors (most common reason with about 50% fewer receptors)
- Poor binding to apoB (5%)
- Increased degradation in recycling of the receptor (2%)

Question 9

What is the most common cause of FH pathology?

Answer 9

A decreased number of LDL receptors on the liver.

Question 10

What mutations are seen in FH? How is FH tested for genetically?

Answer 10

MUTATIONS IN FH:

• There are lots of mutations in FH.
• LDL receptor: 1000 known mutations.
• PCSK9: 1 mutation.
• ApoB: 1 mutation.

GENETIC TESTING IN FH:

• Exon by exon sequence analysis (EBESA) - may not pick up large deletions.
• Multiplex ligation dependent probe amplification (MLPA).
• Currently: 48 common mutations tested and picks up 66% of cases of FH at a cost of £250.

Question 11

Describe the clinical presentation of FH.

Answer 11

CASE STUDY:

• 28 yr old. Offered a new job and had routine pre-employment check up.
• Total Cholesterol = 8.1mmol/L
• Triglycerides = 1.7mmol/L
• HDL cholesterol = 1.2mmol/L
• LDL cholesterol = 6.8mmol/L
• Normal TFTs, HbA1C
• Non-Hypertensive, non-smoker, no history of excess alcohol intake.
• Referred by GP.
• Normally would expect LDL to be around 2-3mmol/L.
• On examination may see lipid deposits around eyes called Xanthelesma and may see tendon xanthoma.
• Has a sibling with a total cholesterol value of 9mmol/L who had a MI at the age of 30. Also a family history of his mother dying of a heart attack quite early with high total cholesterol.
• The question is how do we define familial hypercholestoraemia? This is done using the the Simone and Broome diagnostic criteria (adults).

Question 12

Outline the Simone and Broome diagnostic criteria for defining Familial Hypercholesterolaemia in adults.

Answer 12

DEFINITE:

1.A. TC > 7.5 or LDL > 4.9 mmol/L

and

1.B. Tendon xanthomas (pt or relatives)

or

2. DNA evidence of mutation in LDL receptor, ApoB or PCSK9.

POSSIBLE:

1.A. TC > 7.5 or LDL > 4.9 mmol/L

and

1.B. Family history of: Raised TC/LDL

or

2. MI < 60 yrs in first degree relative / MI < 50 yrs in second degree relative.
   - Classifies patients as having definite or possible FH based on the lipid levels and presence of clinical features or DNA evidence.
   - Definite is a few of the definite criteria plus DNA evidence or clinical features. Possible is when you have the lipid levels and you have a family history of early hear attacks.
   - This is a way you can pick these patients up on the basis of clinical features, family history +/- genetic testing.

Question 13

What is screening?

Answer 13

“The presumptive identification of unrecognised disease or defect by the application of tests, examinations or other procedures which can be applied rapidly”

Question 14

Outline the different kinds of screening.

Answer 14

1) . Universal / mass population screening:
e. g. newborn screening for hypothyroidism, PKU, cystic fibrosis, MCAD.
2) . Targeted / high risk population screening:

Testing can be opportunistic or systematic. Cascade screening - testing family members of the index case.

Question 15

Outline the WHO screening criteria.

Answer 15

1) . The condition being screened for should be an important health problem.
2) . The natural history of the condition should be well understood.
3) . There should be a detectable early stage.
4) . Treatment at an early stage should be of more benefit than at a later stage.
5) . A suitable test should be devised for the early stage.
6) . This test should be acceptable.
7) . The risk, both physical and psychological, should be less than the benefits.
8) . Adequate health service provision should be made for the extra workload resulting from screening.
9) . The costs should be balanced against the benefits.

Question 16

What criteria may constitute an important health problem for screening? Does FH meet these criteria?

Answer 16

• Incidence is high (1 in 5,000)
• There are lots of cases (100,000 in UK)
• 85% are undiagnosed

Question 17

Is the natural history of FH well understood?

Answer 17

• The natural history of FH is well understood and therefore it can be detected at an early stage.

Question 18

Are there treatments that are of benefit for FH and is treatment at an early stage of more benefit than at a later stage?

Answer 18

• Stating became available widely after 1992. The Simone and Broome register had patients that were not on treatment and then after treatment they followed them up.
• On treatment the mortality ratio reduced from 8 times to 3 times.
• Statins are the key treatment that lower the lipids.
• Statins reduce death rate in FH patients (20-59 years old).
• Reduction in Standardised Mortality Ratio (SMR) is more than 2 fold. With early identification and new more powerful statin drugs, life expectancy for FH patients may not be significantly reduced at all.

Question 19

Is there a suitable test devised for the early stage of FH? What are the benefits of genetic testing for FH compared to blood tests?

Answer 19

Here there is some controversy.

Using the Simon and Broome criteria with blood LDL-C:

• There is a significant overlap in LDL levels in normal cases and FH cases - this gets worse as you get older.
• 20% of the children of an FH index case will be misdiagnosed (15% false negatives and 5% false positives).
• 58% of the brothers and sisters will be misdiagnosed (42% false negatives and 15% false positives).
• To address the issue of overlap and changing LDL levels relating to age there is a specific table available which gives age-related LDL levels. Based on age and LDL levels it will show you those that are likely FH, Uncertain, or unlikely FH.
• Many doctors are not aware of these changing cut off levels.
• There is a considerable grey area of around 16% in adults and 10% in children of uncertainty even if you use the charts.
• High acceptance rate for rest, but low pick up of new FH due to out of catchment loss and low sensitivity of LDL-C cut offs. A national integrated service is required.
• If we do genetic testing on top of the blood test for lipids you see that in patients with possible FH you will detect a significant proportion of patients with a mutation and half of the definite cases will have a mutation but half won’t. Nearly 1/4 of the probably cases will have a mutation detected.
• The prevalence of probable FH is approximately twice that of definite FH. Significantly higher detection rate in DFH vs PFH as expected from published data. Sizeable proportion of UFH have mutation.
• If you look at overall comparisons, for every 1 index case 1 relative was tested and around half of those tested were found to have the condition on the basis of using only lipid testing.
• If you use DNA testing then your pickup rate is around 50-60%.
• The acceptability and the pickup rate is higher using DNA mutation testing as compared to using LDL blood testing.
• Supports acceptance and utility of DNA based cascade testing.
• Once the underlying mutation in the LDL receptor gene has been identified in an index patient, molecular genetic screening of first degree relatives has a sensitivity and specificity close to 1.0, which makes misclassification a rarity.
• However, the problem is we cannot pickup about 30% of the mutations so we may not be able to detect underlying mutation in the LDL receptor. May still have to treat them based in clinical instincts.
• The issue is cost of genetic testing is also a concern.

Question 20

Outline the 3 layer screening process for FH.

Answer 20

1) . Look for 48 common mutations in LDL receptor gene.
2) . If neg do whole sequence analysis.
3) . If neg do MLPA.

Question 21

Is the screening test for FH acceptable and are the risks, both physical and psychological less than the benefits?

Answer 21

• No clinically relevant adverse psychological effects have been observed.
• No evidence has been found to support any negative psychological effects of genetic screening in other genetic diseases.
• A large proportion of the relatives are already aware of a cardiovascular problem in the family and a knowledge of its genetic and biochemical nature, as well as the existence of effective therapeutic measures that may improve their well being.

Question 22

Summarise the experience of FH screening in the Netherlands.

Answer 22

• FH screening programme has been established for over 10 years.
• In the Netherlands only 2% of the relatives regretted that they had undergone genetic screening.
• A population-based survey has shown that 77% of the respondents would enter a cascade genetic screening programme for FH if they had a family member with FH.
• 72-90% of first-degree relatives who are being offered cascade genetic screening actually undergo genetic screening.

Question 23

What is the health provision required for the extra clinical workload generated as a result of FH screening?

Answer 23

• Provision of a specialised FH nurse.
• The increased workload requires a specialised software.
• The PASS clinical software used in the Netherlands screening programme has been piloted in Wales and found suitable. Used for pedigree drawing, work files, letters to GP/patients, remote access, data encryption.

Question 24

How do the costs balance against benefits for FH screening? What is QALY and how is it calculated?

Answer 24

• QALY = the quality-adjusted life years measurement.
• Say a patient continues receiving standard treatment and he will live for 1 year and his quality of life will be 0.4 (0 or below = worst possible health, 1 = best possible health).
• If he receives the new drug he will live for 1.25 years, with a quality of life of 0.6.
• The new treatment is compared with standard care in terms of the QALY’s gained.
• Standard treatment: 1 extra year of life x 0.4 = 0.4 QALY.
• New treatment: 1.25 extra year of life x 0.6 = 0.75 QALY.
• Therefore, the new treatment leads to 0.35 additional QALYs.
• The cost of the new drug is assumed to be £10,000, standard treatment cost is £3,000.
• The difference in treatment costs (£7000) is divided by the QALYs gained (0.35) to calculate the cost per QALY. So the new treatment would cost £20,000 per QALY. This is the max NICE will recommend paying per QALY.
• This has been calculated for FH screening.
• For LDL-cholesterol only screening the cost/QALY is £1184.
• For DNA only (only CT from mutation +ve probands) the cost/QALY is £1463.
• For DNA where mutation plus LDL-C in DFH the cost/QALY is £1456.
• For DNA where mutation plus LDL-C in DFH + PFH the cost/QALY is £1376.
• Compared to LDL-C only, use of DNA where a mutation can be found using LDL for identification of FH relatives in definite and probable FH cases gave most QALYs.
• Incremental cost effectiveness ratio of approximately £2700/QALY.
• Compared to the NICE threshold value of £20,000 this is very good value and should be implemented.
• Universal and opportunistic GP testing all costs about the same for FH screening. Opportunistic MI testing is much cheaper and case finding screening is cheaper again per case detected.

Question 25

Does FH meet the screening criteria?

Answer 25

• FH satisfies most of the WHO criteria.
• Cascade genetic screening is recommended by international organisations such as MEDPED consortium and the European Atherosclerosis Society.
• NICE in 2008 recommended a cascade screening programme for 1st, 2nd and 3rd degree relatives.

Question 26

Outline the screening programme that is currently recommended for FH.

Answer 26

1) . Confirm a clinical diagnosis of FH and a DNA test is offered.
2) . Index case is invited to discuss family tracing with the FH nurse.
3) . Family pedigree is drawn and used to identify first degree relatives who should be offered testing.
4) . Relatives are contacted directly by nurse or via index case.
5) . Relatives are offered a point-of-care test at the clinic or at home (or are advised to visit their GP for a test).
6) . All relatives are offered a DNA lipid test.
7) . When FH is suspected the GP is asked to refer the patient to the lipid clinic.

• Three key aspects:
  1) . DNA testing
  2) . Using an FH nurse
  3) . Software tools

Question 27

What are the requirements for an effective FH cascade screening programme?

Answer 27

• National Integrate Service.
• FH clinics run by lipidologists.
• Access to paediatric input.
• Trained FH nurse to run cascade screening.
• National register - link families and avoid duplication.
• Appropriate computer software and connectivity.
• Core data set and agreed quality standards.
• Audit of service.