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GOTR FH 

Download the PDF here. Check out our FH point of care tools here and our more comprehensive overview, GECKO deep dive. Updated November 2023 (Under review).

Bottom line: Familial hypercholesterolemia (FH) is a common (~1/250) autosomal dominant condition that results in a 6 to 22-fold increase in premature cardiovascular disease (CVD) and death. Early diagnosis and treatment can normalize life expectancy. Key features of FH are elevated LDL-C ≥ 5mmol/L with additional features such as early onset CVD (<55 years in men, <65 years in women), cholesterol deposition in the tendons (xanthomata) and/or around the eyes (xanthelasma), arcus cornealis with onset <45years, and family history of early onset CVD or hyperlipidemia requiring treatment. In Canada, a diagnosis of FH is typically based on an individual’s clinical presentation and history as outlined in the Canadian Cardiovascular Society algorithm. Genetic testing is not widely clinically available in Canada with some exceptions. A clinical diagnosis guides treatment and screening of family members. Once a person is diagnosed with FH, cascade screening of family members using measurement of LDL-C levels and/or genetic testing is recommended. This enables early identification and treatment of at-risk individuals, with statins as first-line treatment.

What is Familial Hypercholesterolemia?

Familial hypercholesterolemia (FH) is an autosomal dominant genetic condition where the uptake of low-density lipoprotein cholesterol (LDL-C) into cells is either decreased or inhibited. This results in lifetime exposure to very high levels of LDL-C.  FH is the most common genetic disorder causing premature cardiovascular disease (CVD) and death in both men and women.

About 1 in 250 Canadians is thought to have the heterozygous (HeFH) form of FH. FH is more common in certain populations due to founder effects: in certain areas of Quebec, the prevalence is as high as 1 in 80; it affects approximately ~1/100 Lebanese and Afrikaners, and 1/67 South African Ashkenazi Jews.

FH is both underdiagnosed and undertreated in Canada and worldwide.  Only ~10% of affected Canadians are thought to be identified, despite the knowledge that early diagnosis and treatment can normalize life expectancy.   

Table 1.  Clinical features of familial hypercholesterolemia in heterozygotes (HeFH) and homozygotes (HoFH).

FH Table1

Clinical features

HeFH

HoFH

Genetics

pathogenic/likely pathogenic (P/LP) variants (what used to be called mutations)

P/LP variant in one copy of one FH gene

P/LP variant in two FH genes, one inherited from each parent

Untreated* LDL-C levels

≥ 5mmol/L at age 40 years or older

>4.5mmol/L at age 18-39 years

>4mmol/L  at ages younger than 18 years

with additional features shown in following boxes

>12 mmol/L

lower LDL-C levels, especially in children or in treated patients, do not exclude HoFH

Cardiovascular disease (CVD) onset

<55 years of age in men                   

<65 years of age in women

<20 years of age

can be as early as the first year of life

Other atherosclerotic disease risks

  • Stroke or transient ischaemic attack
  • Peripheral vascular disease

Physical findings

·         Cholesterol deposits in the tendons (xanthomata) and/or around the eyes (xanthelasma)

·         Arcus cornealis (white, grey, or blue opaque ring in the corneal margin) onset <45years

Family history

·         Early onset CVD

·         Hyperlipidemia, often requiring treatment

*The CardioRisk app has a validated algorithm to impute a baseline value from LDL-C levels while on lipid lowering medications, additionally it can be used for the clinical diagnosis of FH, assessing the degree of severity of FH for new patients and helps facilitate FH diagnosis.

 

How is familial hypercholesterolemia diagnosed?

The Canadian Cardiovascular Society (CCS) recommends use of the Canadian diagnostic criteria for FH proposed by the Familial Hypercholesterolemia Canada (FHCanada) network (Figure 1). These Canadian criteria are a simplified approach to the traditionally used Dutch Lipid Clinic Network (DLCNC) or the Simon Broome Registry (see the GECKO Messenger for more on these criteria). The Canadian criteria have been validated against each of these criteria, which are internationally accepted for the diagnosis of HeFH.

Genetic testing is not necessary for diagnosis and is not yet routinely available in most of Canada.

In Quebec, clinicians can order genetic testing of the three major FH genes through The Core Molecular Diagnostic Laboratory at the McGill University Health Centre when clinical criteria are met. CHU Sainte Justine Molecular Laboratory offers targeted genetic testing for only the most common P/LP variants in those French-Canadian (FC) ancestry. As a targeted test this has limited/no value in those not of FC ancestry. A negative result would not rule out an FH diagnosis

In Ontario, any physician can order genetic testing for FH through London Health Sciences Centre and Trillium Health Partners. An 8-gene panel is available for those that meet criteria.

Other provinces are looking at how to implement genetic testing and screening.

Fig 1 FH Messenger Canadian diagnosis criteria 2019

Figure 1: Canadian criteria for the clinical diagnosis of familial hypercholesterolemia (FH). From Ruel I et al., 2018 Can J Cardiol. Reprinted with permission under the CC BY-NC-ND license

ASCVD: atherosclerotic cardiovascular disease; LDL-C: low-density lipoprotein cholesterol. * Secondary causes of high LDL-C should be ruled out (severe or untreated hypothyroidism, nephrotic syndrome, hepatic disease [biliary cirrhosis], medication, especially antiretroviral agents).  

Cascade Screening

The most cost-effective approach for identification of new familial hypercholesterolemia cases is cascade screening of family members of the first individual with a confirmed diagnosis, known as the index case.

This approach is recommended by the Canadian Cardiovascular Society (CCS). Screening can include lipid profiles of relatives and/or genetic testing for a known familial P/LP gene variant, when available. Each newly diagnosed individual becomes a new index case and cascade screening of relatives continues.

Surveillance and Management

Statins are the drug class of choice for individuals with HeFH.  LDL-C should be lowered as fast and as far as possible.  The CCS recommends a >50% reduction of LDL-C from baseline beginning at age 18 as primary prevention with a goal of LDL-C <2.0mmol/L for secondary prevention.  Some individuals with FH will require combination and/or emerging therapy to obtain optimal LDL-C. Families with FH should be counselled about the importance of lifestyle modification such as smoking cessation and avoidance of passive smoking, diet, exercise, daily activity beginning early in life, maintenance of ideal body weight, and stress reduction.

Additional guidance can be found in CCS’s position statement published open-access in the Canadian Journal of Cardiology or from your local cardiologist.

Children:  Lifestyle modifications discussed above remain the cornerstone of CVD prevention in both children and teens with FH and referral to a specialist for treatment decisions is recommended.

See https://www.geneticseducation.ca/  for the comprehensive GECKO Messenger with complete reference list and more on HoFH.  For the updated Canadian definition of FH visit www.FHCanada.net to find Ruel et al., Simplified Canadian definition for familial hypercholesterolemia. Can J Cardiol 2018 34: 1210-1214.

Updated: November 2023

Authors: S Morrison MS CGC, JE Allanson MD FRCPC, RA Hegele MD FRCPC, S Hadjiyannakis MD FRCPC  and JC Carroll MD CCFP

GECKO on the run is for educational purposes only and should not be used as a substitute for clinical judgement.  GECKO aims to aid the practicing clinician by providing informed opinions regarding genetic services that have been developed in a rigorous and evidence-based manner. Physicians must use their own clinical judgment in addition to published articles and the information presented herein. GECKO assumes no responsibility or liability resulting from the use of information contained herein. 

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