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Familial Hypercholesterolemia (FH)

NICE guideline [CG71] Familial hypercholesterolaemia: identification and management. Published: Aug 2008. Last updated: Oct 2019.

Background Information

  • Autosomal dominant 
  • Mutations
    • Most common: loss-of-function mutation in LDL receptor gene
    • Loss-of-function mutation in APOB gene
    • Gain-of-function mutation in PCSK9 gene
Homozygous FH is rare, with clinical features appearing in childhood.

  • Tendon xanthomata - highly suggestive of FH 
  • Eyelid xanthelasma
  • Corneal arcus

Guidelines

Suspect FH in adults with ANY of the following:
  • Total cholesterol >7.5 mmol/L
  • Personal or family Hx of premature coronary heart disease (<60 y/o)
Suspect homozygous FH if:
  • LDL-C >13 mmol/L in adults
  • LDL-C >11 mmol/L in children / young people


1st line Ix in primary care when FH is suspected:
If Simon Broome criteria yield possible or definitive OR DLCN score >5 → refer to specialist for DNA testing

Confirmatory test: DNA testing
  • Note a +ve DNA testing alone is diagnostic, even if LDL-C does not meet the diagnostic criteria
 

Absence of clinical signs of FH (e.g. tendon xanthomata) does NOT exclude FH.

The author would like to acknowledge that NICE made recommendations specific to homozygous and heterozygous FH, that are slightly different. However, it is deemed confusing and excessive in detail to a non-specialist level and, therefore not specified in this article.

ALL patients:
  • Lifestyle advice
  • Lipid lowering therapy (1st line statins, +/- ezetimibe)
  • Screening family members and offspring

Add-on specialist intervention:
  • 3rd line lipid lowering drugs
  • LDL apheresis
  • Liver transplant

  • Healthy eating (refer to https://www.nhs.uk/live-well/)
  • Offer individualised nutritional advice
    • Total fat intake </=30% of total energy intake
    • Saturated fat intake </=10% of total energy intake
    • Dietary cholesterol intake <300mg/day
    • Replace saturated fats with mono-unsaturated fat and polyunsaturated fats 
  • Encourage physical activity 
  • Weight management
  • Smoking cessation
  • Advise on alcohol consumption

Young people and children → always refer to specialist

Adult → target ≥50% reduction in LDL-CLow-density lipoprotein concentration from baseline
  • 1st line: high-intensity statin for life-long
  • 2nd line: add  ezetimibe
  • If target still not met → refer to specialist to consider 3rd line options:
    • Alirocumab
    • Eculizumab
    • Bile acid sequestrant (resin) (e.g. cholestyramine)
    • Fibrate
Alternative to statin: ezetimibe monotherapy

  • LDL apheresis via arteriovenous fistula
  • Consider liver transplantation

Cascade testing
  • Once FH diagnosed with DNA result, offer cascade testing to 1st, 2nd, 3rd degree biological relatives of the index individual if possible.

Screening of offsprings
  • 1 affected parent → offer DNA testing ASAP 
  • 2 affected  parents / presence of clinical signs → measure LDL-CLow-density lipoprotein concentration ASAP
    • If LDL-C >11 mmol/L → consider homozygous FH 

References

Author: Adams Lau 
Reviewer:
Last Edited: 07/01/2025