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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

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