Background Information

Definition

FH is a genetic disorder of cholesterol metabolism characterised by markedly elevated LDL cholesterol levels.
Aetiology
Inheritance pattern: autosomal dominant 

FH is typically monogenic, involved genes include: ^[ref]

• Most common: loss-of-function in the LDL receptor gene
• Loss-of-function mutation in APOB gene
• Gain-of-function mutation in PCSK9 gene

Heterozygous FH is much more common, while homozygous FH is rare.

Complications

Main complication is atherosclerosis → premature atherosclerotic cardiovascular disease ^[ref]

• Coronary artery disease – most significant
• Ischaemic stroke
• Peripheral arterial disease

Diagnosis Guidelines

The author would like to acknowledge that NICE made recommendations specific to homozygous and heterozygous FH. However, that is excessive detail for a medical student, therefore not specified in this article.

Clinical Features

Characteristic findings of FH: ^[ref]

• Tendon xanthomata – most commonly found in Achilles and extensor hand tendons)
• Xanthelasmas
• Corneal arcus

Investigation and Diagnosis

When to Suspect FH

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)

Diagnostic Pathway

Perform all the following if FH is suspected to check against the Simon Broome Criteria OR Dutch Lipid Clinic Network (DLCN) Criteria

• Obtain 2 LDL-C measurements
• 3-generation pedigree
  • Assessing for CAD age of onset, lipid levels and smoking history in these relatives
  • Also include deceased relatives

If Simon Broome criteria yield a possible or definitive OR DLCN score >5 → refer to specialist for DNA testing

• DNA testing is the confirmatory test for FH
• Note that a +ve DNA testing alone is diagnostic, even if LDL-C does not meet the diagnostic criteria

Management Guidelines

FH in young people and children → always refer to specialist immediately

Approach – patients should receive ALL the following:

1. Lifestyle advice, and
2. Lipid-lowering therapy, and
3. Screening family members and offspring

1. Lifestyle Advice

• 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

2. Lipid-Lowering Therapy

Target ≥50% reduction in LDL-C from baseline (adults)

Choice of lipid-lowering therapy:

• Step 1: high-intensity statin (e.g. atorvastatin 20-80mg, rosuvastatin 10-40mg)
• Step 2: add ezetimibe
• Step 3: refer to specialist to consider
  • PCSK9 inhibitors (alirocumab, eculizumab)
  • Bile acid sequestrant (resin) (e.g. cholestyramine)
  • Fibrate

Alternative to statin: ezetimibe monotherapy

3. Screening Family Members and Offspring

Family member screening:

• Once FH is diagnosed with DNA testing, offer cascade testing to 1^st, 2^nd, and 3^rd 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-C ASAP
  • If LDL-C >11 mmol/L → consider homozygous FH

Specialist Intervention

Possible specialist interventions include:

• Further lipid-lowering therapy
• LDL apheresis
• Liver transplant

References