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)