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  4. Familial Hypercholesterolemia (FH)

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

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.

Suspect FH in adults with ANY of the following:
  • Total cholesterol >7.5 mmol/L
  • Personal or family Hx of premature coronary artery disease (in <60 y/o)

 

Homozygous FH causes much higher cholesterol levels, with onset typically in childhood or early adulthood, and has severe rapid disease progression​​​​​​.

NICE recommends suspecting homozygous FH if:

  • LDL cholesterol >13 mmol/L in adults
  • LDL cholesterol >11 mmol/L in children / young people

Perform the following in primary care if FH is suspected:
If Simon Broome criteria yield a possible or definitive OR DLCN score >5 → refer to specialist for DNA testing

Confirmatory test: DNA testing
  • Note that 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.

Approach:
  • ALL patients should receive
    • Lifestyle advice, and
    • Lipid-lowering therapy, and
    • Screening family members and offspring
 
  • Add-on specialist intervention:
    • Further lipid-lowering therapy
    • 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 monounsaturated fats and polyunsaturated fats 
  • Encourage physical activity 
  • Weight management
  • Smoking cessation
  • Advice on alcohol consumption

Young people and children → always refer to specialist

Adult → target ≥50% reduction in LDL-CLow-density lipoprotein concentration from baseline
  • Step 1: high-intensity statin for life-long
  • Step 2: add  ezetimibe
  • Step 3: refer to specialist to consider 3rd line options:
    • PCSK9 inhibitors (alirocumab, eculizumab)
    • Bile acid sequestrant (resin) (e.g. cholestyramine)
    • Fibrate
Alternative to statin: ezetimibe monotherapy

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

Screening of offspring
  • 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