Familial Hypercholesterolaemia

Usually LDL receptor gene mutations (on liver, for removing lipids from blood). One Apo-B mutation (on LDL) identified.  Least common is PCSK9 mutation – higher degradation of receptor, most severe.

If normal BMI, elevated LDL, autosomal dom inheritance, normal TFTs then 95% LDL receptor defect.

If one sibling has a LDL double that of another sibling, 99.8% LDL receptor mutation.

Highly heterogeneous in UK, over a 1000 mutations.

Estimated 1/500 in most countries [but in Denmark found 1/137, Holland has found 1 in 232].  So prob only 12% of cases identified in UK, even less in young individuals!

DNA screening cf lipid testing cost effective (and enhances cascade screening).  Using LDL only, 8-15% false neg and pos, due to overlapping of ranges.  Gene scoring (using SNPs) for mutation neg clinical cases helps to find polygenic cases. But 40% less risk of disease so cascade testing less effective.

American college of med genetics have recommended that familial hypercholesterolaemia (FH) mutations detected on whole genome should be reported to patient.

Cases of sudden cardiac death in 4-6yr olds reported in homozygous.  Heterozygous cases still important – 100X coronary risk age 20-40yrs…


Diagnosis in childhood could save 50 healthy life years!!!  Dutch cascade screening since 1994 stopped last year. Only 1/3 of known paed cases came clinically, hence big gap in case finding.

Simon Broome criteria – (else use Dutch system) distinguishes Definite FH vs Possible.

  • Definite = DNA pos for known mutation, else tendon xanthomata (personal or 1st or 2nd deg relative) plus cholesterol as below.
  • Possible = cholesterol concentrations as below PLUS:
    • Family history of myocardial infarction: aged younger than 50 years in second-degree relative or aged younger than 60 years in first-degree relative.
    • Family history of raised total cholesterol: greater than 7.5 mmol/l in adult first- or second-degree relative or greater than 6.7 mmol/l in child, brother or sister aged younger than 16 years.

Cholesterol cut offs for Simon Broome

Total cholesterol LDL-C
Child/young person > 6.7 mmol/l > 4.0 mmol/l
Adults > 7.5 mmol/l > 4.9 mmol/l

Refer both definite and possible cases for DNA testing. Plus there are age/sex specific cholesterol cut offs for relative of a known case where DNA is negative.  NICE standard is that children with possible FH should be offered diagnostic tests by age 10.

Given how prevalent use of statins is now, it’s harder to get a positive family history! So history of grandparents more important! 10% have no family history

Only 4% of heterozygotes have xanthomas (can be in buttock cleft, but only look if found elsewhere!). Arcus at 6 oclock in children, all round in adults. Palpable in Achilles tendon rather than seen? Pain in achilles often reported! Resolve with treatment.


NL guidelines – 5-7yr diet etc only.  Diet with plant sterols can drop LDL by 7%

Over 10yrs, treatment (high dose, low dose, combination) depends on mutation and LDL. Most experience with pravastatin.

LDL apheresis as treatment.

Excellent safety and tolerance of statins. Significant reduction within 2 years.

Like any regular medication, compare it to toothbrushing.  Do both at the same time!

Most cardiologists don’t consider FH when high cholesterol found. Nurses? Via labs?

Check growth, puberty, healthy lifestyle. Update family pedigree, contraception.

Smoking confers massive additional risk.  Albert Wiegman has had a 5yr old admitting to smoking…

Treating from age 6.


10yr follow up submitted – mean age 24yrs. 7 already older than the age their parent had event. LDL still higher than sibs.


Boys have higher risk of cardiac death then girls, but smoking gives girls worse risk than boys.

Intima media thickness – increases year on year, so earlier treatment the better?  Even before age 8 significantly different from non FH.


In NICE audit, majority of children not on treatment, and being seen in adult lipid clinics.

No evidence that low fat diets etc are affecting growth (limited numbers so far).

Homozygous FH being recommended as rare disease, so deserving of national specialist service.