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Canadian Journal of Cardiology

Canadian Cardiovascular Society Position Statement on Familial Hypercholesterolemia

Open AccessPublished:September 30, 2014DOI:https://doi.org/10.1016/j.cjca.2014.09.028

      Abstract

      Familial hypercholesterolemia (FH) is the most common genetic disorder causing premature cardiovascular disease and death. Heterozygous FH conservatively affects approximately 1:500 Canadians, and the more serious homozygous form affects approximately 1:1,000,000 Canadians, although these numbers might be underestimated. Of approximately 83,500 Canadians estimated to have FH, most are undiagnosed, which represents a simultaneous public health deficit and opportunity, because early treatment of heterozygous FH can normalize life expectancy. Diagnostic algorithms for FH incorporate increased plasma low-density lipoprotein cholesterol, pathognomonic clinical features, and family history of early cardiovascular disease and hyperlipidemia. DNA-based detection of causative mutations in FH-related genes can help with diagnosis. Maximizing diagnosis and treatment of FH in Canada will involve a multipronged approach, including: (1) increasing awareness of FH among health care providers and patients; (2) creating a national registry for FH individuals; (3) setting standards for screening, including cascade screening in affected families; (4) ensuring availability of standard-of-care therapies, in particular optimization of plasma low-density lipoprotein cholesterol levels and timely access to future validated therapies; (5) promoting patient-based support and advocacy groups; and (6) forming alliances with international colleagues, resources, and initiatives that focus on FH. This document aims to raise awareness of FH nationally, and to mobilize knowledge translation, patient support, and availability of treatment and health care resources for this underrecognized, but important medical condition.

      Résumé

      L’hypercholestérolémie familiale (HF) qui est la maladie génétique la plus fréquente entraîne de manière précoce la maladie cardiovasculaire et la mort. Bien que ces chiffres puissent être sous-estimés, la forme hétérozygote de l'HF touche environ 1 Canadien sur 500, alors que la forme homozygote, qui s’avère être la forme la plus sérieuse, touche environ 1 Canadien sur 1 000 000. On estime que parmi les quelque 83 500 Canadiens souffrant d’HF la plupart ne sont pas diagnostiqués, ce qui représente simultanément un déficit et une opportunité pour la santé publique, puisque le traitement précoce de la forme hétérozygote de l'HF peut normaliser l’espérance de vie. Les algorithmes diagnostiques de l'HF incorporent l’augmentation de la concentration plasmatique du cholestérol à lipoprotéines de basse densité, les signes cliniques pathognomoniques et les antécédents familiaux de maladie cardiovasculaire précoce et d’hyperlipidémie. L’analyse de l’ADN pour la détection des mutations causales dans les gènes liés à l'HF peut faciliter le diagnostic. La maximisation du diagnostic et du traitement de l'HF au Canada impliquera une approche à volets multiples, y compris : 1) accroître la sensibilisation des prestataires de soins de santé et des patients à l'HF; 2) créer un registre national d’individus souffrant de l'HF; 3) fixer des normes de dépistage, y compris le dépistage en cascade auprès des familles touchées; 4) assurer la disponibilité des traitements correspondant aux normes de soins, en particulier l’optimisation des concentrations plasmatiques de cholestérol à lipoprotéines de basse densité et l’accès en temps opportun aux traitements validés futurs; 5) promouvoir les groupes de soutien et de défense des droits des patients; 6) conclure des alliances internationales avec les collègues, les ressources et les initiatives qui se concentrent sur l'HF. Ce document a pour objectif d’accroître la sensibilisation de l'HF sur le plan national et de mobiliser les connaissances, le soutien au patient et la disponibilité des traitements et des ressources en soins de santé concernant cette maladie méconnue, mais importante.
      Familial hypercholesterolemia (FH) is an autosomal codominant genetic disorder characterized by very high plasma levels of low-density lipoprotein (LDL) cholesterol (LDL-C), increased cardiovascular risk—by up to 20-fold—and early onset cardiovascular disease.
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • 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.
      • Goldberg A.C.
      • Hopkins P.N.
      • Toth P.P.
      • et al.
      Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the national lipid association expert panel on familial hypercholesterolemia.
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • Nordestgaard B.G.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
      FH is the most common monogenic disorder leading to premature coronary heart disease and cardiac death. FH is often unrecognized until the inaugural cardiovascular event. Early diagnosis and treatment of FH can normalize life expectancy. If left untreated, men with FH develop cardiovascular disease in the third to fourth decade of life and women 10 years later on average. The prevalence of heterozygous FH (HeFH) had been conservatively estimated at 1:500, based on a survey of familial lipoprotein disorders in myocardial infarction survivors.
      • Goldstein J.L.
      • Hazzard W.R.
      • Schrott H.G.
      • Bierman E.L.
      • Motulsky A.G.
      Hyperlipidemia in coronary heart disease. I. Lipid levels in 500 survivors of myocardial infarction.
      Recent molecular studies indicate that 3.4% of patients with early myocardial infarction have FH mutations.

      Do R, Stitziel NO, Won HH, et al. A rare variant association study with exome sequencing in > 9,700 early-onset myocardial infarction cases and controls. Nature, in press.

      Increased rates of FH are observed in populations in which founder effects are present.
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • 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.
      The prevalence of HeFH in French-Canadians is estimated at approximately 1:270.
      • Moorjani S.
      • Roy M.
      • Gagne C.
      • et al.
      Homozygous familial hypercholesterolemia among French Canadians in Quebec province.
      Thus, assuming that the prevalence of HeFH in the rest of Canada is 1:500, and that populations of Quebec and the rest of Canada are 8 and 27 million, respectively, the number of FH subjects in Canada is approximately 83,500, although this likely underestimates the true number, because recent population surveys using direct molecular screening in Europeans diagnosed approximately 1:250 individuals with HeFH.
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • 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.
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • Nordestgaard B.G.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.

      Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome [e-pub ahead of print]. Eur Heart J doi:10.1093/eurheartj/ehu058, accessed October 30, 2014.

      Unfortunately, most FH patients are unrecognized, because of factors including inconsistent screening practices and general unawareness regarding diagnosis. National programs that include a patient registry and targeted cascade screening for FH have proven to be cost-effective and to improve outcomes in several European countries. The aim of this Position Statement is to raise awareness and stimulate discussion toward development of national guidelines for the diagnosis and treatment of FH in Canada.

      Choice of Outcomes and Appraisal of the Evidence

      The most relevant outcomes in the diagnosis and care of patients with FH are: (1) biochemical, specifically attaining optimal LDL-C levels; (2) clinical, primarily reducing cardiovascular events; and (3) societal, including processes of care. Another potential outcome is sequential imaging of atherosclerosis burden as a surrogate marker for the treatment effectiveness (see the section on Secondary Testing and Imaging in FH). No randomized cardiovascular end point trials exist to prove that lowering of LDL-C should be the primary treatment target in FH patients, however overwhelming evidence from the general population indicates that reducing LDL-C is effective.
      • Baigent C.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists Collaborators
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      Moreover, the totality of evidence reviewed strongly suggests that early diagnosis and institution of multidimensional risk factor modification in FH patients, including lifestyle modification and appropriate use of pharmacotherapy is cost-effective and life-saving.

      Processes of Care As an Outcome

      Underestimation of FH prevalence and insufficient awareness of favourable cost-benefit of interventions, make the implementation of processes of care at the societal level a key outcome. Such primary processes include: (1) prompt recognition of patients at high risk of having FH (eg, adults with LDL-C > 5.0 mmol/L); (2) implementation of strict lifestyle changes in patients with probable or definite FH, including smoking cessation, prudent diet, weight management, avoidance of sedentary lifestyle, and control of other cardiovascular risk factors; (3) referral of probable and definite cases of FH for specialist care; (4) cascade screening of probands and relatives to identify additional cases; (5) construction of a national FH registry to collect data on FH incidence and prevalence and to disseminate educational material to health care providers, patients, and the general public; and (6) education of primary care physicians, and specialists in internal medicine, pediatrics, cardiology, endocrinology, and obstetrics and gynecology on the basics of diagnosis and treatment of FH.
      Recommendation
      • 1.
        We suggest implementation of standard processes of care for the identification and treatment of subjects with FH (Conditional Recommendation, Moderate-Quality Evidence).
      Values and Preferences. Stakeholders in health care management should support regional centres of expertise in the detection of FH, cascade screening, and molecular diagnosis.

      Diagnosis of FH

      Early diagnosis of FH enables early initiation of preventive measures to reduce cardiovascular disease risk.
      • Versmissen J.
      • Oosterveer D.M.
      • Yazdanpanah M.
      • et al.
      Efficacy of statins in familial hypercholesterolaemia: a long term cohort study.
      In Canada, most HeFH patients are diagnosed using clinical and biochemical features,
      • Yuan G.
      • Wang J.
      • Hegele R.A.
      Heterozygous familial hypercholesterolemia: an underrecognized cause of early cardiovascular disease.
      including: (1) very high LDL-C (typically > 5.0 mmol/L); (2) typical physical findings (stigmata) such as tendon xanthomata, xanthelasma, and arcus corneae (Fig. 1); (3) personal history of early cardiovascular disease; and (4) family history of early cardiovascular disease or of marked hyperlipidemia, often requiring treatment.
      Figure thumbnail gr1
      Figure 1Physical findings (stigmata) in FH. (A) Bilateral xanthelasma on eyelids. (B) Bilateral arcus corneae, which are pathognomonic when detected by the fifth decade of life, but are nonspecific to FH by the eighth decade of life. (C) Arrows indicate xanthoma with the extensor tendon of the hand. (D) Arrows indicate xanthomas within the Achilles tendons. FH, familial hypercholesterolemia.
      Secondary or nongenetic causes of increased LDL-C
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • 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.
      • Yuan G.
      • Wang J.
      • Hegele R.A.
      Heterozygous familial hypercholesterolemia: an underrecognized cause of early cardiovascular disease.
      must first be ruled out (Table 1). The most commonly used diagnostic algorithms for HeFH are the United Kingdom Simon Broome Registry
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Humphries S.E.
      A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia.
      and the Dutch Lipid Clinic Network criteria
      • Fouchier S.W.
      • Defesche J.C.
      • Umans-Eckenhausen M.W.
      • Kastelein J.P.
      The molecular basis of familial hypercholesterolemia in the Netherlands.
      (Table 2). The less widely used US MedPed criteria focuses on LDL-C levels, without regard to clinical features.
      • Williams R.R.
      • Hunt S.C.
      • Schumacher M.C.
      • et al.
      Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics.
      The Simon Broome Registry and Dutch Lipid Clinic Network criteria incorporate weighted combinations of the aforementioned factors,
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Humphries S.E.
      A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia.
      • Fouchier S.W.
      • Defesche J.C.
      • Umans-Eckenhausen M.W.
      • Kastelein J.P.
      The molecular basis of familial hypercholesterolemia in the Netherlands.
      and produce scores that lead to classification of either “definite” or “probable” FH, with a third category of “possible FH” in the Dutch Lipid Clinic Network system. Detection of a pathogenic DNA mutation in an FH-related gene essentially leads to a diagnosis of “definite FH”.
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Humphries S.E.
      A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia.
      • Fouchier S.W.
      • Defesche J.C.
      • Umans-Eckenhausen M.W.
      • Kastelein J.P.
      The molecular basis of familial hypercholesterolemia in the Netherlands.
      Head-to-head comparisons suggest that the Simon Broome Registry and Dutch Lipid Clinic Network criteria perform comparably well in diagnosing HeFH.
      • Futema M.
      • Whittall R.A.
      • Kiley A.
      • et al.
      Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic.
      DNA sequence analysis of FH-associated genes can help in specific instances (see Supplemental material sub-section “DNA testing for FH” and Fig. 2). There are several reasons to consider development of Canadian-specific diagnostic criteria for FH (see Supplemental material sub-section “Need for new Canadian-specific diagnostic criteria for HeFH”, and Fig. 3).
      Recommendation
      • 2.
        We suggest that the diagnosis of FH should rely on the Simon Broome Registry or Dutch Lipid Clinic Network criteria (Conditional Recommendation, Moderate-Quality Evidence).
      Values and Preferences. Because there is no “gold standard” to diagnose FH, further clarification of specific criteria to facilitate diagnosis is required—especially to increase diagnostic sensitivity in the primary care setting.
      Table 1Secondary causes of severe increased low-density lipoprotein cholesterol
       • Obstructive liver disease
       • Hypothyroidism
       • Nephrotic syndrome
       • Anorexia
      Table 2Criteria for FH
      Criteria required for diagnosis of: definite HeFH, A + B or C; and probable HeFH, A + D or A + E.
      A. Simon Broome Registry
      Criteria
       1. A plasma measurement of either:
      Total cholesterol > 7.5 mmol/L (adult patient) or > 6.7 mmol/L (child aged < 16 years)
      Low-density lipoprotein cholesterol > 4.9 mmol/L (adult patient) or > 4.0 mmol/L (child aged < 16 years)
       2. Tendon xanthomas in the patient or any of the patient's first- or second-degree relatives
       3. DNA-based evidence in the patient of mutation in LDLR or other FH-related gene
       4. Family history of myocardial infarction before the age of:
      50 Years, in any first- or second-degree relative
      60 Years, in any first-degree relative
       5. Family history of plasma total cholesterol > 7.5 mmol/L in any first- or second-degree relative
      B. Dutch Lipid Clinic Network
      PointsCriteriaDiagnosis
      1First-degree relative with premature cardiovascular disease or LDL-C > 95th percentile, or personal history of premature peripheral or cerebrovascular disease, or LDL-C between 4.01 and 4.89 mmol/L (155 and 189 mg/dL)Definite FH (≥ 8 points)
      2First-degree relative with tendinous xanthoma or corneal arcus, or First-degree relative child (< 18 years) with LDL-C > 95th percentile, or personal history of coronary artery diseaseProbable FH (6-7 points)
      3LDL-C between 4.91 and 6.44 mmol/L (190 and 249 mg/dL)
      4Presence of corneal arcus in patient younger than 45 years of age
      5LDL-C between 6.46 and 8.51 mmol/L (250 and 329 mg/dL)Possible FH (3-5 points)
      6Presence of a tendon xanthoma
      8LDL-C > 8.53 mmol/L (330 mg/dL), or functional mutation in the LDLR gene
      FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; LDLR, gene encoding the LDL receptor.
      Criteria required for diagnosis of: definite HeFH, A + B or C; and probable HeFH, A + D or A + E.
      Figure thumbnail gr2
      Figure 2Genetics of FH. (A) Familial inheritance of heterozygous FH (HeFH). Squares and circles represent male and female individuals, respectively. Up to 1:250 matings in Canada involve an HeFH subject and a normolipidemic individual. Clinical and biochemical features of affected individuals are discussed in “Diagnosis of FH”, , and . Genotypic inheritance of FH-causing mutations and their cosegregation with the HeFH phenotype are shown below each pedigree symbol. Fifty percent of children of such a mating will have HeFH, which is usually fully expressed early in life. Because 50%, 25%, and 12.5% of first-, second-, and third-degree relatives of an affected individual will also have HeFH, systematic biochemical cascade screening of family members is considered by many to be a cost-effective approach to finding new cases. (B) Main genes causing FH. Chromosomal location of the main genes causing dominant HeFH and their chromosomal location: LDLR encoding the LDL receptor (approximately 95% of all causative mutations), APOB encoding apolipoprotein B (approximately 3% of all mutations), PCSK9 encoding proprotein convertase subtilisin kexin 9 (approximately 1% of all mutations), and some very rare genes are not shown. APOB, gene encoding apolipoprotein B; Chr, chromosome; FH, familial hypercholesterolemia; LDL, low-density lipoprotein; LDLR, gene encoding LDL receptor; PCSK9, gene encoding pro-protein convertase subtilisin/kexin type 9.
      Figure thumbnail gr3
      Figure 3Diagnostic and treatment flow when familial hypercholesterolemia (FH) is suspected. APOB, gene encoding apolipoprotein B; C, cholesterol; LDL, low-density lipoprotein; LDLR, gene encoding LDL receptor; PCSK9, gene encoding pro-protein convertase subtilisin/kexin type 9.

      Screening for FH in Adults

      Early detection of affected individuals is the cornerstone of cardiovascular disease prevention. Furthermore, FH is among the few genetic disorders that meets all conditions for large-scale screening programs.
      Universal screening for dyslipidemia is already recommended for Canadian men 40 years of age and older, for women 50 years of age and older, or those who are postmenopausal, and for subjects at risk of cardiovascular disease; some cases of FH will be found this way.
      • Anderson T.J.
      • Gregoire J.
      • Hegele R.A.
      • et al.
      2012 Update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult.
      To maximize identification of previously undiagnosed adult FH subjects, 2 complementary strategies are proposed: (1) targeted screening to identify FH index cases (probands) among hypercholesterolemic adults with at least 1 feature such as personal or family history of clinical stigmata, personal or familial history of premature cardiovascular disease, or family history of significant hypercholesterolemia; and (2) cascade screening—or systematic family tracing—of first-, second-, and eventually third-degree relatives of probands to detect affected members; each of whom then serves as an index case.
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Humphries S.E.
      A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia.
      Identification of index cases requires a fasting lipid profile performed while the subject is free of intercurrent illnesses. Although cascade screening is largely based on LDL-C levels, screened subjects with “possible” or “probable” FH can be considered for genetic testing to confirm the diagnosis (see Supplemental material sub-section “DNA testing for FH”).
      Cascade screening, starting with LDL-C measurement, after ascertaining an index patient, can effectively identify related affected individuals who can be treated. Because HeFH shows autosomal dominant transmission, 50%, 25%, and 12.5% of first-, second-, and third-degree relatives screened, respectively, will be affected.
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Humphries S.E.
      A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia.
      We suggest that: (1) Canadian primary care providers should be sensitized to the diagnosis of FH and offered tools to effectively identify index cases; (2) national, provincial, and local protocols should be developed for screening of adults and children with FH; (3) community laboratories could alert providers about abnormal LDL-C (eg, ≥ 5.0 mmol/L); (4) opportunistic screening should be performed systematically around the time of a cardiovascular disease event; (5) Canadian-specific cascade screening should be maximally cost-effective, systematic, and centrally coordinated; (6) national, provincial, and local registries of FH subjects can support cascade screening; (7) genetic testing should be performed only in specialized, accredited laboratories; (8) counselling before and after testing should be available; and (9) local ethics boards should review the sensitive issue of contacting relatives in the course of cascade screening.
      Recommendation
      • 3.
        We recommend strategic use of targeted and cascade screening for timely recognition and treatment of new adult cases of FH (Strong Recommendation, Low-Quality Evidence).
      Values and Preferences. Cascade screening, starting with LDL-C measurement, can be considered after the identification of an index patient. DNA testing should be reserved for cases of diagnostic uncertainty, for example, when accurate family history is unavailable, when lipid levels are borderline, when screened family members have “possible” or “probable” FH, and in cases in which management will be altered by the results of such testing.

      Screening for FH in Children

      Except for individuals with rare homozygous FH (HoFH), children with FH have no physical findings or overt cardiovascular disease; hence, detection can only be accomplished using lipid screening. However, there remain important evidence gaps regarding the benefits, harms, and costs of childhood lipid screening.
      • Newman T.
      • Pletcher M.
      • Hulley S.
      Overly aggressive new guidelines for lipid and lipoprotein screening in children: evidence of a broken process.
      • McCrindle B.W.
      • Kwiterovich P.O.
      • McBride P.E.
      • Daniels S.R.
      • Kavey R.E.
      Guidelines for lipid screening in children and adolescents: bringing evidence to the debate.
      • McCrindle B.W.
      • Kwiterovich P.O.
      • McBride P.E.
      • Daniels S.R.
      • Kavey R.E.
      Author's response. Universal lipid screening: in response to ongoing debate.
      Also, appropriate management is limited by lack of resources and time within a busy clinical practice.
      • Dixon D.B.
      • Kornblum A.P.
      • Steffen L.M.
      • Zhou X.
      • Steinberger J.
      Implementation of lipid screening guidelines in children by primary pediatric providers.
      There will likely never be direct evidence that lipid screening in childhood reduces cardiovascular disease risk in adulthood, despite a compelling chain of observational evidence. Atherosclerosis does not progress uniformly across the lifespan, and is likely preventable and reversible during childhood. Optimizing risk factors during adolescence was associated with reduced odds of cardiometabolic risk factors and early atherosclerosis on carotid ultrasound 21 years later.
      • Laitinen T.T.
      • Pahkala K.
      • Magnussen C.G.
      • et al.
      Ideal cardiovascular health in childhood and cardiometabolic outcomes in adulthood: tThe cardiovascular risk in young Finns study.
      Trials of statin therapy in children and adolescents with FH have shown normalized endothelial function,
      • de Jongh S.
      • Lilien M.R.
      • op’t Roodt J.
      • et al.
      Early statin therapy restores endothelial function in children with familial hypercholesterolemia.
      and regression of carotid intima-media thickness,
      • Wiegman A.
      • Hutten B.A.
      • de Groot E.
      • et al.
      Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial.
      which is effective when initiated at younger ages.
      • Rodenburg J.
      • Vissers M.N.
      • Wiegman A.
      • et al.
      Statin treatment in children with familial hypercholesterolemia: the younger, the better.
      The case for screening children to detect FH and initiate treatment is reasonably strong.
      • Gillman M.W.
      Screening for familial hypercholesterolemia in childhood.
      • Gillman M.W.
      Changing the conversation regarding pediatric cholesterol screening: the rare disease paradigm.
      As with adults, screening for FH in children can be accomplished using universal, targeted, or cascade screening. Universal screening potentially allows for complete case ascertainment. Although cascade screening appears cost-effective, there are many uncertainties in the modelling. Because there are even more uncertainties in modelling its cost-effectiveness, we cannot recommend universal screening in children. Advice for pediatric screening for FH from other bodies is discussed in the Supplemental material section “ADDITIONAL POINTS ON SCREENING”.
      Recommendation
      • 4.
        We suggest targeted screening in children and adolescents with such cardiovascular risk factors as a positive family history of dyslipidemia or cardiovascular disease, obesity, smoking, hypertension, or type 2 diabetes (Conditional Recommendation, Low-Quality Evidence).
      Values and Preferences. Screening the plasma lipid profile in children with a positive family history, and with poor lifestyle or cardiovascular risk factors might help motivate the adoption of preventive strategies.

      Management of FH in Adults

      Overall goals of treatment

      Although no randomized trials exist to prove that lowering LDL-C is the primary treatment target in FH patients, overwhelming evidence from the general population shows the effectiveness of reducing LDL-C: a 1 mmol/L reduction reduces major cardiovascular disease events by approximately 20% after 5 years.
      • Baigent C.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists Collaborators
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      Nonetheless, coronary heart disease risk is increased by up to 20-fold in untreated FH patients,
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • 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.
      and cardiovascular disease events are dramatically reduced in observational studies of statin-treated FH patients.
      • Versmissen J.
      • Oosterveer D.M.
      • Yazdanpanah M.
      • et al.
      Efficacy of statins in familial hypercholesterolaemia: a long term cohort study.
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Humphries S.E.
      A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia.
      Extrapolating from the general population in the context of the high cardiovascular disease risk level in adult FH heterozygotes, it is reasonable to recommend > 50% reduction from baseline LDL-C as a minimal target for primary prevention.
      • Anderson T.J.
      • Gregoire J.
      • Hegele R.A.
      • et al.
      2012 Update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult.
      If cardiovascular disease is present, the LDL-C target to be strived for is < 2.0 mmol/L, although patients with severe HeFH or HoFH will likely not reach this target without more aggressive and complex therapy.
      Recommendation
      • 5.
        Conventional cardiovascular risk calculators that assess short-term risk are inaccurate in FH patients. We recommend considering all adults with FH as being at “high risk” as a result of lifelong exposure of arteries to high LDL-C (Strong Recommendation, Moderate-Quality Evidence).
      Values and Preferences. Because FH patients are often young, with few other risk factors, risk calculators such as Framingham, Systematic Coronary Risk Evaluation (SCORE), and others will underestimate their lifetime cardiovascular risk, and should not be used for risk assessment.
      • 6.
        For primary prevention in adult FH patients, beginning at 18 years of age, we recommend a > 50% reduction of LDL-C from baseline. For secondary prevention, we recommend striving toward a target LDL-C < 2.0 mmol/L (Strong Recommendation, Low-Quality Evidence).
      Values and Preferences. LDL-C is a strong surrogate for end points such as cardiovascular death, myocardial infarction, and the need for arterial revascularization.

      Lifestyle factors

      In addition to increased LDL-C levels, FH patients are also vulnerable to other risk factors. Thus, FH patients and families would benefit from lifestyle management education, including advice regarding diet, exercise, weight control, blood pressure control, diabetes control, and smoking cessation.
      • Harris W.S.
      • Mozaffarian D.
      • Rimm E.
      • et al.
      Omega-6 fatty acids and risk for cardiovascular disease: a science advisory from the American Heart Association nutrition subcommittee of the council on nutrition, physical activity, and metabolism; council on cardiovascular nursing; and council on epidemiology and prevention.

      Dietary reference intakes tables, Health Canada. Available at: http://www.hc-sc.gc.ca/fn-an/nutrition/reference/table/index-eng. Accessed August 31, 2012.

      Advice to children and young adults to refrain from starting smoking is especially important. Structured smoking cessation programs should be offered to smokers with FH.
      Recommendation
      • 7.
        We suggest that a healthy lifestyle including smoking cessation, prudent diet, caloric intake to maintain ideal body weight, daily exercise, and stress reduction be recommended for FH patients (Conditional Recommendation, Low-Quality Evidence).
      Values and Preferences. Randomized trials of lifestyle modification in FH subjects are unlikely to be performed. However, nonlipid cardiovascular disease risk factors amplify the already high risk in FH patients and should be managed.

      Pharmaceutical therapies

      Statins are the drug class of choice for HeFH, although clinical end point evidence for specific levels of absolute or relative reductions in plasma LDL-C is lacking. Following from the Canadian Cardiovascular Society guideline recommendations for adults with dyslipidemia, a reasonable therapeutic goal for primary prevention in adults with HeFH is to achieve a > 50% reduction in LDL-C levels,
      • Anderson T.J.
      • Gregoire J.
      • Hegele R.A.
      • et al.
      2012 Update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult.
      a goal that in many cases is achievable with high-dose statins alone. When LDL-C still requires reduction, addition of adjunctive agents is recommended on an individualized basis. In HeFH patients with established atherosclerotic cardiovascular disease, the Canadian Cardiovascular Society guideline recommended a goal of LDL-C < 2.0 mmol/L should be at the top-of-mind, but might not be feasible with currently available drugs.
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • 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.
      Recommendation
      • 8.
        We recommend that statins should be first-line therapy in FH patients, with the aim of lowering LDL-C by > 50%. In patients with atherosclerosis, maximally tolerated doses of statins with or without ezetimibe or bile acid sequestrants (cholestyramine, colestipol, or colesevelam) might further decrease LDL-C (Strong Recommendation, Low-Quality Evidence).
      Values and Preferences. Statins have modified the natural course of FH. When treated early in life, event-free survival is essentially normalized in HeFH patients.

      Statin intolerance or adverse effects in FH

      Although statins are safe and easy to use, compliance can be an issue in up to 10% of patients because of side effects. Statin-related adverse effects have been extensively reviewed: muscle-related symptoms and early diabetes onset in diabetes-prone individuals are most consistent, and evidence of effects on liver function and cognitive function is much weaker.
      • Mancini G.B.
      • Baker S.
      • Bergeron J.
      • et al.
      Diagnosis, prevention, and management of statin adverse effects and intolerance: proceedings of a Canadian working group consensus conference.
      • Mancini G.B.
      • Tashakkor A.Y.
      • Baker S.
      • et al.
      Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian working group consensus update.
      A large meta-analysis found no difference between statins and placebo with respect to side effect-related discontinuations, myalgia, or the incidence of cancer, and there were differences among individual statins regarding creatine kinase and liver function abnormalities.
      • Naci H.
      • Brugts J.
      • Ades T.
      Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246 955 participants from 135 randomized, controlled trials.
      Additionally, statins appear to be associated with a small risk of new-onset type 2 diabetes.
      • Mancini G.B.
      • Tashakkor A.Y.
      • Baker S.
      • et al.
      Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian working group consensus update.
      The latter effects were seen with the higher-potency doses and were related to presence of metabolic risk factors for new-onset diabetes, such as obesity, impaired fasting glucose, hypertriglyceridemia, and hypertension.
      • Waters D.D.
      • Ho J.E.
      • DeMicco D.A.
      • et al.
      Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials.
      Moreover, the cardiovascular risk reduction benefit of statins far outweigh the risk of new-onset diabetes.
      Concerns are often amplified when long-term therapy is considered for young and prepubertal patients with FH. Safety evidence specific to FH patients is not plentiful, but several meta-analyses show statins are generally very well tolerated without significant effects on growth or maturation.
      • O’Gorman C.S.
      • Higgins M.F.
      • O’Neill M.B.
      Systematic review and metaanalysis of statins for heterozygous familial hypercholesterolemia in children: evaluation of cholesterol changes and side effects.
      • Arambepola C.
      • Farmer A.J.
      • Perera R.
      • Neil H.A.
      Statin treatment for children and adolescents with heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis.
      • Avis H.J.
      • Vissers M.N.
      • Stein E.A.
      • et al.
      A systematic review and meta-analysis of statin therapy in children with familial hypercholesterolemia.
      Although further evidence would be desirable, the current evidence base suggests that statins can be as safely used in the FH population as in the general population, but with care in special circumstances, including treatment of children younger than 8 years of age, and avoidance of use in women intending to conceive or who are pregnant or breast-feeding.
      • Watts G.F.
      • Gidding S.
      • Wierzbicki A.S.
      • et al.
      Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation.

      Emerging therapies

      Because of the importance of LDL-C as a cardiovascular disease risk factor, and because FH is the ultimate human model of extreme increased LDL-C level that increases cardiovascular disease risk, new classes of drugs to decrease LDL-C level have been or are being evaluated in FH. Discussed in detail in the Supplemental material section “EMERGING THERAPIES IN FH”, these include: (1) oral microsomal triglyceride transfer protein inhibitors, of which lomitapide was recently approved in Canada for the restricted indication of treatment of HoFH
      • Cuchel M.
      • Meagher E.A.
      • du Toit T.H.
      • et al.
      Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study.
      ; (2) subcutaneously administered apolipoprotein B antisense strategies, of which mipomersen was recently approved in the United States but not Canada
      • Raal F.J.
      • Santos R.D.
      • Blom D.J.
      • et al.
      Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial.
      ; (3) orally administered cholesterol ester transfer protein inhibitors
      • Rader D.J.
      • deGoma E.M.
      Future of cholesteryl ester transfer protein inhibitors.
      ; and (4) subcutaneously administered proprotein convertase subtilisin/kexin type 9 inhibitors.
      • Stein E.A.
      Low-density lipoprotein cholesterol reduction by inhibition of PCSK9.

      Management of FH in Children

      Because atherosclerosis in FH starts early in life,
      • Berenson G.S.
      • Srinivasan S.R.
      • Bao W.
      • et al.
      Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa heart study.
      • McGill Jr., H.C.
      • McMahan C.A.
      • Zieske A.W.
      • et al.
      Effects of nonlipid risk factors on atherosclerosis in youth with a favorable lipoprotein profile.
      untreated children with FH will develop endothelial dysfunction, premature plaques, and early coronary heart disease.
      • Raitakari O.T.
      • Juonala M.
      • Kahonen M.
      • et al.
      Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the cardiovascular risk in young Finns study.
      • Davis P.H.
      • Dawson J.D.
      • Riley W.A.
      • Lauer R.M.
      Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: the Muscatine study.
      • Mabuchi H.
      • Koizumi J.
      • Shimizu M.
      • Takeda R.
      Development of coronary heart disease in familial hypercholesterolemia.
      • Mouratidis B.
      • Vaughan-Neil E.F.
      • Gilday D.L.
      • et al.
      Detection of silent coronary artery disease in adolescents and young adults with familial hypercholesterolemia by single-photon emission computed tomography thallium-201 scanning.
      Levels of LDL-C in FH children, even at birth, were increased 2- to 3-fold above the normal range. Counselling on lifestyle modification remains the essential starting point in the care of children and adolescents with FH.
      Recommendation
      • 9.
        We suggest that all children with a presumptive diagnosis of FH first undergo at least 12 months of lifestyle changes, including diet, exercise, and a tobacco-free environment (Conditional Recommendation, Low-Quality Evidence).
      Values and Preferences. Lifestyle remains the cornerstone of cardiovascular disease prevention in children and adolescents with HeFH.

      Pharmaceutical therapies

      Clinical studies support the efficacy of statin therapy during childhood.
      • Avis H.J.
      • Vissers M.N.
      • Stein E.A.
      • et al.
      A systematic review and meta-analysis of statin therapy in children with familial hypercholesterolemia.
      A meta-analysis of clinical trials of statins in children showed an average LDL-C reduction of 30% (95% confidence interval, −36% to −24%), with no increased risk of adverse events, including no increase of hepatic transaminase, a statistically significant change in height (0.33 cm; 95% confidence interval, 0.03-0.63 cm) favouring the treatment group, but no effect on pubertal development.
      • Avis H.J.
      • Vissers M.N.
      • Stein E.A.
      • et al.
      A systematic review and meta-analysis of statin therapy in children with familial hypercholesterolemia.
      Similar data were reported for a longer follow-up period.
      • Rodenburg J.
      • Vissers M.N.
      • Wiegman A.
      • et al.
      Statin treatment in children with familial hypercholesterolemia: the younger, the better.
      In children with HeFH, ezetimibe monotherapy was well tolerated and significantly reduced LDL-C.
      • Hamilton-Craig I.
      • Kostner K.
      • Colquhoun D.
      • Woodhouse S.
      Combination therapy of statin and ezetimibe for the treatment of familial hypercholesterolemia.
      Lipoprotein apheresis should be pursued in children with HoFH, managed at a lipid specialist centre.
      • Schuff-Werner P.
      • Fenger S.
      • Kohlschein P.
      Role of lipid apheresis in changing times.
      Initiation of statin therapy, after ≥ 12 months of lifestyle changes as discussed herein, is now recommended at ages 8-10, when FH is believed to be “definite.”
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • 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.
      • McCrindle B.W.
      • American Heart Association Writing Group
      • Urbina E.M.
      • et al.
      Summary of the American Heart Association's scientific statement on drug therapy of high-risk lipid abnormalities in children and adolescents.
      The LDL-C target in children is < 3.5 mmol/L, but the presence of additional risk factors or high-risk conditions might decrease this target to < 2.5 mmol/L or could prompt initiation of statin therapy at an age younger than 10 years.
      Recommendation
      • 10.
        If drug treatment is believed to be necessary, assessed on an individual basis, statins are first-line therapy, with ezetimibe and bile acid binding resins considered as next-line therapies. Niacin is no longer recommended (Conditional Recommendation, Low-Quality Evidence).
      Values and Preferences. A healthy lifestyle is the therapeutic cornerstone for all children with HeFH, and initiation of statins on an individualized basis as first-line pharmacological agents depends on additional variables, such as a high burden of cardiovascular disease risk factors and the absolute degree of the increase in LDL-C level.

      Secondary Testing and Imaging in FH

      Because the lifetime cardiovascular disease risk ranges from exceptionally high in HoFH to high in HeFH patients, there is no risk refinement or reclassification based on imaging, because all patients warrant therapy. Several specific situations might, however, warrant imaging. Methods to assess symptomatic FH patients should be relevant to the nature of the symptoms (eg, carotid duplex scanning for assessment of transient ischemic attacks or exercise testing for evaluation of chest pain, etc). Assessment of the aortic valve and root using echocardiography is warranted in patients with HoFH and perhaps also in those with severe HeFH and concomitant increased level of Lipoprotein(a) [Lp(a)], which is associated with aortic valve disease.
      • Jansen A.C.
      • van Aalst-Cohen E.S.
      • Tanck M.W.
      • et al.
      The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: Data in 2400 patients.
      • Oosterveer D.M.
      • Versmissen J.
      • Schinkel A.F.
      • et al.
      Clinical and genetic factors influencing cardiovascular risk in patients with familial hypercholesterolemia.
      • Nordestgaard B.G.
      • Chapman M.J.
      • Ray K.
      • et al.
      Lipoprotein(a) as a cardiovascular risk factor: current status.
      • Thanassoulis G.
      • Campbell C.Y.
      • Owens D.S.
      • et al.
      Genetic associations with valvular calcification and aortic stenosis.
      Detection of premature atherosclerosis might be warranted in a patient suspected of having FH and without family history of cardiovascular disease.
      • Michos E.D.
      • Nasir K.
      • Rumberger J.A.
      • et al.
      Relation of family history of premature coronary heart disease and metabolic risk factors to risk of coronary arterial calcium in asymptomatic subjects.
      Additionally, among individuals who meet “possible FH” criteria using the Simon Broome Registry or Dutch Lipid Clinic Network algorithms, detection of increased atheroma using carotid ultrasound or coronary artery calcium scoring could increase the chance of finding a discrete monogenic cause.
      • Clarke R.E.
      • Padayachee S.T.
      • Preston R.
      • et al.
      Effectiveness of alternative strategies to define index case phenotypes to aid genetic diagnosis of familial hypercholesterolaemia.
      Stress testing, including stress imaging studies, might be warranted to rule out silent ischemia in patients who engage in rigorous exercise.
      • Descamps O.S.
      • de Meester A.
      • Cheron P.
      • Kastelein J.J.
      • Heller F.R.
      Silent ischaemia in familial hypercholesterolemia.
      Finally, suspicion of hepatic steatosis as a cause of increased levels of transaminases might require hepatic ultrasound evaluation.
      • Mancini G.B.
      • Baker S.
      • Bergeron J.
      • et al.
      Diagnosis, prevention, and management of statin adverse effects and intolerance: proceedings of a Canadian working group consensus conference.
      • Mancini G.B.
      • Tashakkor A.Y.
      • Baker S.
      • et al.
      Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian working group consensus update.
      Vascular imaging is not recommended to monitor vascular effects of lipid-lowering therapy even though diverse imaging methods have been used in mechanistic, surrogate end point trials. The presence of severe vascular disease in an asymptomatic patient might prompt more aggressive intervention.

      Homozygous FH: Identification and Treatment

      Depending on the population and definition used, the prevalence of HoFH ranges from 1 in 250,000 to 1 in 1,000,000 individuals globally, and is increased in founder populations, such as French-Canadians.
      • Moorjani S.
      • Roy M.
      • Gagne C.
      • et al.
      Homozygous familial hypercholesterolemia among French Canadians in Quebec province.
      Diagnostic criteria are typically based on family history, which include HeFH in both parents, presence of cutaneous and tendinous manifestations at ages younger than 10 years, severe increased level of LDL-C (ie, untreated LDL-C > 12-13 mmol/L) and molecular diagnosis.
      • Moorjani S.
      • Roy M.
      • Gagne C.
      • et al.
      Homozygous familial hypercholesterolemia among French Canadians in Quebec province.
      • Cuchel M.
      • Bruckert E.
      • Ginsberg H.N.
      • 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.
      HoFH patients are at extremely high risk of cardiovascular disease and should be evaluated at younger than 2 years of age for optimal prevention.
      • Cuchel M.
      • Bruckert E.
      • Ginsberg H.N.
      • 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.
      • Umans-Eckenhausen M.A.
      • Defesche J.C.
      • Sijbrands E.J.
      • Scheerder R.L.
      • Kastelein J.J.
      Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands.
      HoFH patients should be referred to a lipid specialist centre for cholesterol-lowering therapies, including extracorporeal LDL removal, which has demonstrated beneficial effects on aortic and coronary atherosclerosis in HoFH
      • Thompson G.R.
      HEART-UK LDL Apheresis Working Group
      Recommendations for the use of LDL apheresis.
      • Kolansky D.M.
      • Cuchel M.
      • Clark B.J.
      • et al.
      Longitudinal evaluation and assessment of cardiovascular disease in patients with homozygous familial hypercholesterolemia.
      • Sachais B.S.
      • Katz J.
      • Ross J.
      • Rader D.J.
      Long-term effects of LDL apheresis in patients with severe hypercholesterolemia.
      • Raal F.J.
      • Pilcher G.J.
      • Panz V.R.
      • et al.
      Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy.
      • Stefanutti C.
      • Julius U.
      Lipoprotein apheresis: state of the art and novelties.
      and possibly for trials with new therapies (see Supplemental material section “EMERGING THERAPIES IN FH”). Apheresis is recommended in adults with HoFH with refractory LDL-C > 8.5 mmol/L and in children (> 15 kg in weight or older than 7 years of age) with refractory LDL-C > 5.0 mmol/L on maximally tolerated medical therapy.
      • Thompson G.R.
      HEART-UK LDL Apheresis Working Group
      Recommendations for the use of LDL apheresis.
      • Kolansky D.M.
      • Cuchel M.
      • Clark B.J.
      • et al.
      Longitudinal evaluation and assessment of cardiovascular disease in patients with homozygous familial hypercholesterolemia.
      • Sachais B.S.
      • Katz J.
      • Ross J.
      • Rader D.J.
      Long-term effects of LDL apheresis in patients with severe hypercholesterolemia.
      • Raal F.J.
      • Pilcher G.J.
      • Panz V.R.
      • et al.
      Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy.
      • Stefanutti C.
      • Julius U.
      Lipoprotein apheresis: state of the art and novelties.
      • Thompson G.R.
      The evidence-base for the efficacy of lipoprotein apheresis in combating cardiovascular disease.
      Lipid-lowering therapy is associated with delayed cardiovascular disease events and prolonged survival, and low-fat diet and optimization of other risk factors have less effect on the disease course.
      • Cuchel M.
      • Bruckert E.
      • Ginsberg H.N.
      • 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.
      • Hopkins P.N.
      • Toth P.P.
      • Ballantyne C.M.
      • Rader D.J.
      National Lipid Association Expert Panel on Familial H. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid association expert panel on familial hypercholesterolemia.
      Calcific valvular and supravalvular aortic stenoses are almost universal and frequently require aortic valve replacement.
      • Awan Z.
      • Alrasadi K.
      • Francis G.A.
      • et al.
      Vascular calcifications in homozygote familial hypercholesterolemia.
      Patients with HoFH who require intensive LDL-C-lowering therapy with apheresis are generally monitored every 1-2 years to determine progression of carotid atherosclerosis (carotid ultrasound), progression of aortic valve/root disease (echocardiography), and progression of coronary atherosclerosis (stress exercise tests).
      • Cuchel M.
      • Bruckert E.
      • Ginsberg H.N.
      • 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.
      • Stefanutti C.
      • Julius U.
      Lipoprotein apheresis: state of the art and novelties.
      Additional details on aetiology, diagnosis, and treatment of HoFH can be found in the Supplemental material section “ADDITIONAL POINTS RELATED TO HOMOZYGOUS FH.”
      Recommendation
      • 11.
        HoFH patients older than 7 years of age and > 15 kg in weight should be referred to a specialized centre and considered for extracorporeal plasma exchange or LDL apheresis and emerging therapies (Conditional Recommendation, Low-Quality Evidence).
      Values and Preferences. Clinical observation has shown that with apheresis, life expectancy of HoFH patients has more than doubled in the past 3 decades; this must be made available in specialized centres across Canada.

      Pregnancy and Contraception in FH

      Because of teratogenicity, women with FH who are planning pregnancy must interrupt statin therapy at least 1 month before stopping contraception, and remain without therapy until breastfeeding is completed. Adolescent and adult women with HeFH of childbearing potential should receive counselling on contraception and pregnancy. For couples planning a pregnancy in which one member has FH, the partner's lipid profile should be screened before conception to exclude coincident FH and the possibility of a child with HoFH; when both parents have HeFH, prenatal counselling might be sought. Barrier methods, intrauterine devices, tubal ligation, or partner vasectomy are preferred because in theory these have no effect on blood lipid levels and cardiovascular disease risk. However, oral contraceptives are the usual default method, for various reasons including convenience. No study has examined cardiovascular disease risk in women with FH who use oral contraceptives. If pregnancy occurs during statin therapy, it must be stopped immediately and an obstetrician consulted for early fetal evaluation, although the risk of fetal complications is low.
      • Edison R.J.
      • Muenke M.
      Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins.
      Cholestyramine, colestipol, or colesevelam can be safely prescribed during pregnancy and breastfeeding, but these reduce LDL-C by approximately 15% at most and have tolerability issues. For HoFH subjects and FH subjects with cardiovascular disease, LDL apheresis can decrease LDL-C and prevent complications.
      • Cashin-Hemphill L.
      • Noone M.
      • Abbott J.F.
      • Waksmonski C.A.
      • Lees R.S.
      Low-density lipoprotein apheresis therapy during pregnancy.
      For these women, shared care and cardiovascular assessment are strongly advised.
      Recommendation
      • 12.
        We recommend that women with FH who are considering pregnancy stop lipid-lowering therapy, with the exception of bile acid-binding resins, at least 4 weeks before conception and until cessation of breastfeeding (Strong Recommendation, Moderate-Quality Evidence).
      Values and Preferences. Statin therapy during pregnancy is contraindicated.

      Utility of an FH Registry

      FH registries have been established in several European countries, of which the Dutch registry is the most successful. Using a cascade screening approach, 1500-2000 new FH cases are diagnosed yearly in the Netherlands; about half of that nation's expected FH cases have been enrolled in the FH registry. On average, 8 new cases are detected per family, and treatment starts at a mean age of 37 years. The 98% participation rate reflects a positive attitude toward the screening program.
      • Umans-Eckenhausen M.A.
      • Defesche J.C.
      • Sijbrands E.J.
      • Scheerder R.L.
      • Kastelein J.J.
      Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands.
      Results were impressive with early initiation of treatment, with virtually complete avoidance of excess coronary heart disease morbidity and mortality. Furthermore, morbidity and mortality from other diseases (particularly cancer) also significantly decreased, attributed to the lifestyle counselling.
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • et al.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      The United Kingdom National Institutes for Health and Clinical Excellence (NICE) registry also uses cascade screening with genetic testing and LDL-C measurement to identify affected relatives of FH index cases. This approach: (1) reduced the average age at which the patients are diagnosed and treated; (2) increased the proportion of patients with FH who are receiving statin therapy, and who significantly decreased their lipid levels; (3) markedly reduced morbidity and mortality from coronary heart disease when statin treatment was initiated; (4) resulted in improved lipid levels in children with FH; and (5) yielded cost-effective interventions, with important economic benefits for society.

      NICE. National Institute for Health and Care Excellence. Identification and management of familial hypercholesterolaemia. Available at: www.nice.org.uk/CG071. Accessed August 28, 2014.

      Recommendation
      • 13.
        We recommend that a FH registry be implemented in Canada to improve health outcomes in patients with FH (Strong Recommendation, Moderate-Quality Evidence).
      Values and Preferences. FH registries in several European countries have shown improvements in health services utilization and cardiovascular outcomes. A similar effort should be supported in Canada.

      Acknowledgements

      David Bewick, MD, Sabyasachi Bose, MD, Francois Bussieres, Claude Gagne, MD, Sophie Guerin, Pamela Katz, MD, Anne-Marie Laberge, MD, PhD, Lawrence A. Leiter, MD, Katherine Morrison, MD, Teik Chye Ooi, MD, Glen Pearson, Pharm D, and Tom Ransom, MD, participated in this work as members of the Secondary Panel.

      Supplementary Material

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