Familial Cholesterol

Overview

The clinical syndrome involves

• Extremely high levels of Low-Density Lipoprotein Cholesterol (LDL-C)

• Early onset atherosclerotic cardiovascular disease (ASCVD)

Diagnosis

Using diagnostic criteria such as the Dutch Lipid Clinic Network Criteria (DLCNC)

Genetics

FH commonly involves a mutation in one of three genes

• Low-Density Lipoprotein Receptor (LDLR) = 85 to 90%

• Proprotein Convertase Subtilisin Kexin 9 (PCSK9) = 2 to 4%

• Apolipoprotein B (APOB) = 1 to 12%

Forms

• Familial Hypercholesterolemia Request Form - Sonic Genetics

Prevalence

1 in 300 people are heterozygous for FH (one chromosome has a genetic mutation, and the other is normal)

1 in 300,000 people are homozygous for FH (both chromosomes have a genetic mutation)

Clinical Presentation

• People with undiagnosed homozygous FH ( develop severe, premature, ASCVD and die before the age of 20.

• People with undiagnosed heterozygous FH present with symptoms or signs of ASCVD in early middle age.

• Many patients will have an LDL-C > 90 percentile for age and sex during a routine blood test screening.

• Coronary artery calcification can be identified at 11 to 23 years of age in heterozygotes.

• Patients may also have xanthomata and xanthelasma (cholesterol deposits in tendons and in the skin near the eyes).

Clinical Suspicion

• Elevated LDL-C > 10mmol/L

• Family member with known FH

• Xanthelasma

• Premature ASCVD in the patient or family members

• Sudden premature cardiac death in a family member

Evaluation

In patients with a clinical suspicion evaluate:

• Personal history for symptoms of ASCVD such as angina, TIA, stroke, claudication

• Family history of high cholesterol, premature cardiovascular disease or death

• Physical examination for xanthoma, pulses for vascular obstruction, signs of aortic stenosis

• Fasting lipid profile

• Genetic testing - testing for mutations in LDLR, APOB and PCSK9 can be performed if suspected homozygous however in most cases it does not alter the clinical approach

• Testing for lipoprotein(a)

Referral

Suggest for patients with homozygous FH or heterozygous FH with LDL-C above target despite the maximum dose of a statin.

Prognosis

Prior to statin therapy, the risk of premature coronary heart disease was very high estimated to be around 50% in men aged 60 and 32% in women aged 60. This decreases dramatically with treatment.

Screening

Once a diagnosis of FH has been made, it is recommended to screen all first-degree relatives

Treatment

• General lifestyle preventive measures to lower LDL-C

• Homozygous FH

  • The goal of therapy is to lower LDL-C as much as is practical

  • Usually involves a high-dose statin

  • May include Ezetimibe, a PCSK9 inhibitor, LDL apheresis or lomiapide

• Heterozygous FH

  • Set LDL-C goal based on individual risk

  • Consider aspirin

  • Start high-dose statin

  • If not to target add Ezetimibe

  • If not to target consider PCSK9

References

• Familial hypercholesterolemia in adults: Overview - Up To Date

• Familial hypercholesterolemia in adults: Treatment - Up To Date

• Hyperlipidaemia - HNE Pathways (Needs Log in)