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Last updated Aug 2019
Bottom line: Familial hypercholesterolemia is a common (~1/250) autosomal dominant disorder 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 familial hypercholesterolemia 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 familial hypercholesterolemia is typically based on an individual’s clinical presentation correlating with one of three familial hypercholesterolemia definitions. Genetic testing is not generally available, and a clinical diagnosis guides treatment and screening of family members. Once a person is diagnosed with familial hypercholesterolemia, cascade screening of family members using measurement of LDL-C levels is recommended. This enables early identification and treatment of at-risk individuals, with statins as first-line treatment.
Familial hypercholesterolemia 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. Familial hypercholesterolemia is the most common genetic disorder causing premature cardiovascular disease (CVD) and death in both men and women. Familial hypercholesterolemia is both underdiagnosed and undertreated worldwide despite the knowledge that early diagnosis and treatment can normalize life expectancy.1-3 It is estimated that roughly 1 in 250 Canadians has familial hypercholesterolemia, most of whom are undiagnosed.1,4
What do I need to know about the genetics of familial hypercholesterolemia?
Most cases (80-90%) of familial hypercholesterolemia are caused by mutations in the LDL receptor gene LDLR, in which over 1700 different mutations have been identified.2,5,6 The LDLR protein binds LDL, which is the major cholesterol-carrying lipoprotein of plasma, and transports LDL into cells by endocytosis. Mutations in the LDLR gene can reduce the number of LDL receptors produced within cells or disrupt the ability of the receptor to bind LDL-C.2 Mutations in APOB disrupt binding of LDL particles to the receptor, while mutations in PCSK9 cause increased degradation of the receptor. These mechanisms lead to elevated LDL levels and premature development of atherosclerotic plaque.
Pattern of inheritance
Familial hypercholesterolemia is typically inherited in an autosomal dominant manner, and can be present in a heterozygous form (HeFH), where only one copy of a familial hypercholesterolemia-causing gene is mutated. Familial hypercholesteremia can also be present in a homozygous form (HoFH) where an individual has a mutation in both copies of one familial hypercholesterolemia-causing gene. The two mutations can be identical or different. Rarely there is a mutation in one copy of two different familial hypercholesterolemia genes. All individuals with HoFH have an extremely high risk of early onset cardiovascular disease.1,3 If both parents have HeFH, their child has a 25% chance to have HoFH, which is associated with an extremely high CVD risk.
Table 1. Clinical features of familial hypercholesterolemia in heterozygotes (HeFH) and homozygotes (HoFH).
How common is familial hypercholesterolemia?
About 1 in 250 Canadians is thought to have HeFH, however familial hypercholesterolemia is significantly under-recognized in Canada.1 HoFH is much rarer and expected to affect between 1 in 250,000 and 1 in 1,000,000 Canadians.8 Familial hypercholesterolemia 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.2,8,11,12
The Canadian Cardiovascular Society (CCS) recommends the use of the Canadian diagnostic criteria for familial hypercholesterolemia proposed by the Familial Hypercholesterolemia Canada (FHCanada) network (Figure 1).13 While these criteria are relatively new, they are less complicated than those published by the Dutch Lipid Clinic Network (DLCNC) (Table 2) or the Simon Broome Registry (Table 3) and have been validated against each of these criteria, which are internationally accepted for the diagnosis of HeFH.8,13 The Simon Broome Registry criteria include lower thresholds for children with suspected familial hypercholesterolemia.9 Neither the DLCNC nor Simon Broome Registry is designed to diagnose HoFH, for which other criteria have been suggested.7 Genetic testing is not necessary for diagnosis, and is not routinely available in most of Canada. In Quebec, health care providers can order testing from CHU Sainte Justine Molecular Laboratory (Requisition here) focused on the most common gene mutations found in French Canadians with familial hypercholesterolemia. This test is of limited utility in other ethnic groups as it does not rule out the hundreds of gene mutations seen in other ethnicities residing in Canada.1 If available, genetic testing should be offered to individuals with either a probable or definite diagnosis of familial hypercholesterolemia.1 The CCS does not recommend the use of conventional cardiovascular risk calculators, e.g. Framingham Risk Score, in individuals with familial hypercholesterolemia as these greatly underestimate lifetime CVD risk.1,2
Figure 1: Canadian criteria for the clinical diagnosis of familial hypercholesterolemia (FH). From Ruel I et al, 201813. Reprinted with permission under the CC BY-NC-ND license https://creativecommons.org/licenses/by-nc-nd/4.0/. DOI: 10.1016/j.cjca.2018.05.015
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) ** Causal DNA mutation refers to the presence of a known FH-causing variant in the LDLR, APOB, or PCSK9 gene in the individual or a first-degree relative. FH diagnosis in a patient with a DNA mutation but normal LDL-C levels is unclear. Yearly follow-up of the individual is suggested and cascade screening of family members should be initiated.
Table 2. Dutch Lipid Clinic Network.3,8
Table 3. Simon Broome Registry 9,14
Cascade Screening For Family Members
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.4,9,15 Data from the UK have shown that cascade screening reduces the average age at which an individual is diagnosed and results in an increased number of individuals who are treated with statins and have subsequent lowered lipid levels.16
The Canadian Cardiovascular Society (CCS) recommends screening of first-degree relatives of the index case.1 Screening can include lipid profiles of relatives and/or genetic testing for a known familial mutation when available. Each newly diagnosed individual becomes a new index case and cascade screening of relatives continues.
Statins are the drug class of choice for individuals with HeFH. Observational studies have shown a dramatic decrease in cardiac events in statin-treated individuals with familial hypercholesterolemia.1 LDL-C should be lowered as fast and as far as possible.3 The CCS recommends a >50% reduction of LDL-C from baseline beginning at age 18 as primary prevention and that an ideal goal of LDL-C <2.0mmol/L is recommended for secondary prevention.17 The use of high-dose statins alone is usually sufficient to achieve LDL-C reduction; however, some individuals with familial hypercholesterolemia will require combination and/or emerging therapy to obtain optimal LDL-C. Specialist referral is recommended.1-3,18 Statins should not be used during pregnancy.1 For the most recent recommendations on management and treatment of individuals with HoFH please see Cuchel et al. 2014.7
Families with familial hypercholesterolemia should be counselled about the importance of lifestyle modification such as1-3,18:
- Smoking cessation and avoidance of passive smoking
- High in fibre (soluble), plant sterols/stanols and unsaturated fatty acids
- Low in trans and saturated fatty acids, refined sugars
- Moderate alcohol use only
- Daily activity beginning early in life
- Maintenance of ideal body weight
- Stress reduction
For general population guidelines on management of dyslipidemia in adults please see Anderson et al., 2016 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult http://www.onlinecjc.ca/article/S0828-282X(16)30732-2/pdf.
Lifestyle modifications discussed above remain the cornerstone of CVD prevention in both children and adolescents with familial hypercholesterolemia and referral to a specialist for treatment decisions is recommended.1 The CCS recommends that children with HoFH are referred to a lipid specialist centre for cholesterol-lowering therapies when >15kg in weight. Some experts recommend referral for specialist consultation beginning at age 2 years.
 Brunham LR, Ruel I, Aljenedil S, Rivière J, Baass A, Tu JV, et al. Canadian Cardiovascular Society position statement on familial hypercholesterolemia:Update 2018. Can J Cardiol. 2018. 34(12):1553-1563.
 Bouhairie VE, Goldberg AC. Familial Hypercholesterolemia. Cardiol Clin. 2015. 33(2): 169-179.
 Vogt A. The genetics of familial hypercholesterolemia and emerging therapies. Appl Clin Genet. 2015. 8: 27-36.
 Akioyamen LE, Genest J, Shan SD, Reel RL, Albaum JM, Chu A, Tu JV1. Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis. BMJ Open 2017;7(9)e016461.
 Norgestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013. 34(45): 3478-3490a.
 Hartgers ML, Ray KK, Hovingh GK. New approaches in detection and treatment of familial hypercholesterolemia. Curr Cardio Rep. 2015. 17: 109.
 Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014. 35(32):2146-57.
 Genest J, Hegele RA, Bergeron J, Brophy J, Carpentier A, Couture P, et al. Canadian Cardiovascular Society position statement on familial hypercholesterolemia. Can J Cardiol 2014. 30(12): 1471-1481.
 Turgeon RD, Barry AR, Pearson GJ. Familial hypercholesterolemia: Review of diagnosis, screening, and treatment. Can Fam Physician. 2016. 62(1): 32-37.
 Iyen B, Qureshi N, Kai J, Akyea RK, Leonardi-Bee J, Roderick P, Humphries SE, Weng S. Risk of cardiovascular disease outcomes in primary care subjects with familial hypercholesterolaemia: A cohort study. Atherosclerosis 2019. 287:8-15.
 Brunham L, Ruel I, Khoury E, Hegele RA, Couture P, Bergeron J, et al. Familial hypercholesterolemia in Canada: Initial results from the FH Canada National Registry. Atherosclerosis. 2018. 277: 419-424.
 Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol. 2004.160(5): 407-420.
 Ruel I, Brisson D, Aljenedil S, Awan Z, Baass A, Bélanger A, et al. Simplified Canadian definition for familial hypercholesterolemia. Can J Cardiol. 2018. 34: 1210-1214.
 Watts GF, Sullivan DR, Poplawski N, van Bockxmeer F, Hamilton-Craig I, Clifton PM, et al. Familial hypercholesterolaemia: a model of care for Australasia. Atheroscler Suppl. 2011. 12(2): 221-263.
 Knowles JW, Rader DJ, Khoury MJ. Cascade screening for familial hypercholesterolemia and the use of genetic testing. JAMA. 318(4): 381-382.
 Ned RM, Sijbrands EJ. Cascade Screening for Familial Hypercholesterolemia (FH). PLoS Curr. 2011. 3: RRN1238.
 Anderson TJ, Grégoire J, Pearson GJ, Barry AR, Couture P, Dawes M, et al. Canadian Cardiovascular Society Guidelines for the management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. Can J Cardiol. 2016. 32(11): 1263-1282.
 Feldman DI, Blaha MJ, Santos RD, Blumenthal RS, Toth PP, Sperling LS, et al. Recommendations for the management of patients with familial hypercholesterolemia. Curr Atheroscler Rep. 2015. 17(1): 473.
Authors: S Morrison MS CGC, JE Allanson MD FRCPC, RA Hegele MD FRCPC, S Hadjiyannakis MD FRCPC and JC Carroll MD CCFP
Updated by the GEC-KO team: S Yusuf MS CGC, S Morrison MS CGC, JE Allanson MD FRCPC and JC Carroll MD CCFP
GEC-KO Messenger is for educational purposes only and should not be used as a substitute for clinical judgement. GEC-KO 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 judgement in addition to published articles and the information presented herein. GEC-KO assumes no responsibility or liability resulting from the use of information contained herein.