Familial hypercholesterolemia

Quality of evidence

We conducted a PubMed search (inception to July 2014), supplemented with hand searches of bibliographies of clinical practice guidelines, position papers, and reviews. Recommendations from Canadian authorities, when available, were prioritized. Recommendations were rated from levels I to III: level I evidence included 1 or more properly conducted randomized controlled trials (RCTs) or systematic reviews of RCTs with or without meta-analysis; level II evidence included 1 or more controlled observational studies (cohort, case-control, or other relevant epidemiologic studies); and level III evidence included all opinion-based statements with no empiric supporting evidence.

Main message

Pathophysiology and epidemiology. Genetic mutations cause FH.³ Defects in the genes that code for the LDL receptor, apolipoprotein B, or proprotein convertase subtilisin-kexin type 9 (PCSK9) ultimately lead to impaired clearance of LDL cholesterol from the plasma. Low-density lipoprotein receptors, found primarily on hepatocyte cell membranes, are responsible for uptake of LDL particles and thus removal of cholesterol from plasma. Apolipoprotein B is the LDL-bound protein that binds to the LDL receptor. Finally, PCSK9 is responsible for the degradation of LDL receptors; thus, genetic defects leading to elevated PCSK9 levels will result in decreased LDL receptors on hepatocytes, and thus hyperlipidemia. A single copy of the defective gene (heterozygous) leads to moderate accumulation of plasma LDL, whereas 2 copies of the same defective gene (homozygous) or 2 coexisting mutations (compound heterozygous) lead to extensive accumulation due to minimal or no LDL cholesterol clearance. Clinically, patients with heterozygous FH (HeFH) typically have an LDL plasma concentration of 5 to 13 mmol/L, whereas patients with homozygous FH (HoFH) have an LDL level well above 13 mmol/L.⁴

Approximately 1 in 500 Canadians has HeFH. Prevalence of FH varies based on ethnic background, with higher rates among Québécois French Canadians (1 in 270), Lebanese (1 in 85), Afrikaners (1 in 72), and Ashkenazi Jews (1 in 67).⁵ Homozygous FH, the more severe form, affects approximately 1 out of every 1 million individuals.⁵

Complications and prognosis. Without early and aggressive treatment, FH manifests as premature ASCVD events, often affecting the coronary arteries. Patients with untreated HeFH tend to experience a first coronary event 20 or more years earlier than the general population (mean age 42 vs 64).⁶ Consequently, their cumulative risk of a coronary event by age 50 is up to 44% in men and 20% in women.^6,7 This cardiovascular risk is far greater than that predicted by cardiovascular risk calculators (eg, Framingham risk score), and therefore these calculators should not be used in patients with FH.⁸ Untreated HoFH is associated with an even worse prognosis, with many patients experiencing coronary events in childhood or adolescence.^9,10

Lipid screening. Table 1 provides a summary of the recommendations on screening for FH. The Canadian Cardiovascular Society (CCS) dyslipidemia guidelines and FH position statement recommend universal screening of plasma lipids in all men 40 years of age or older and all women 50 years of age or older or after menopause.^1,8 Furthermore, they recommend screening individuals with conditions that increase their risk of cardiovascular disease (eg, those who have hypertension, diabetes mellitus, chronic kidney disease, or who are current smokers) regardless of age.

For pediatric screening, guidelines released by the National Heart Lung and Blood Institute recommend routine universal screening of plasma lipids at 11 years of age, or as early as 12 months in children with a first-degree family history of ASCVD or FH.¹¹ As atherosclerosis begins early in life for individuals with FH (especially in HoFH), childhood screening is intended to facilitate early identification and treatment. Despite the theoretical benefits of the National Heart Lung and Blood Institute screening program, there are complex logistical challenges in implementation, as well as limited data for the optimal time to initiate treatment, which have stimulated controversy.¹²

Once a proband (or index case) of FH has been identified, the CCS position statement on FH recommends further “cascade screening.”¹ This involves the screening of first-degree relatives of individuals with confirmed FH to identify undiagnosed cases. If a relative is found to have FH, their relatives should also be screened, and so forth. This strategy is based on the autosomal dominant inheritance pattern of FH. Individuals who are first-, second-, and third-degree relatives of an individual with HeFH will have a 50%, 25%, and 12.5% likelihood, respectively, of also having FH. On average, cascade screening identifies 8 new cases of FH for every proband.¹³ A number of countries have initiated different variations of cascade screening, which have demonstrated favourable cost-effectiveness.¹⁴ Patients can be enrolled into the Canadian FH registry through referral to a participating clinician or centre. Information can be obtained from the FH Canada website (www.fhcanada.net/fh-canada-registry).

Diagnosis. In practice, clinicians frequently miss FH. Of the estimated 83 500 individuals with FH in Canada, only approximately 5% have received an appropriate diagnosis.^1,2 Clinicians should suspect FH in any patient with a premature cardiovascular event, physical stigmata of hypercholesterolemia (ie, arcus senilis, xanthoma, or tendinous xanthoma) or a plasma LDL level of 5 mmol/L or higher.¹⁵

Once hypercholesterolemia is identified, physicians should rule out secondary causes, such as medical conditions (eg, hypothyroidism, diabetes mellitus, nephrotic syndrome, obstructive liver disease), drugs (eg, corticosteroids, diuretics), excess alcohol consumption, very poor diet, and a sedentary lifestyle (Table 1).

The CCS position statement on FH recommends making the diagnosis of FH using 1 of 2 score-based diagnostic criteria: the Simon Broome Register or the Dutch Lipid Network criteria (Table 2).^1,16 Both sets of diagnostic criteria perform reasonably well with no clear criterion standard.¹⁷ The diagnosis of FH does not require genetic testing, as approximately 1 in 5 patients with a clinical diagnosis of HeFH have negative test results for all currently known genetic mutations.

Treatment. Despite the high ASCVD risk associated with FH, as many as 50% of patients with a proper diagnosis fail to receive adequately aggressive treatment, possibly owing to an underappreciation of the magnitude of the risk.^18,19 The primary goal for the treatment of FH is to reduce mortality and ASCVD events, which is achieved by reducing plasma LDL levels.^1,20,21

Although there is no evidence to support any specific LDL target in this population, guidelines generally recommend a reduction of 50% or more from baseline,^1,20,21 similar to recommendations for the general population.⁸ Dietary modifications are important to lower LDL levels; however, it is not possible for most FH patients to achieve their lipid level targets without additional interventions.²² Management of traditional ASCVD risk factors, such as cessation of tobacco use and treatment of hypertension and diabetes, are crucial in FH patients owing to their high baseline ASCVD risk.²³

In terms of the pharmacotherapeutic management of HeFH, high-dose statins are first-line therapy. In an RCT of patients with HeFH, treatment with 80 mg of atorvastatin daily reduced LDL levels by an average of 50% from baseline,²⁴ similar to results obtained in the population without FH.²⁵ Beyond LDL reduction, evidence supporting a reduction in clinically relevant outcomes with statin therapy (or any lipid-lowering therapy) in HeFH is primarily observational. One cohort study demonstrated that a moderate dose of statin therapy (eg, 40 mg of atorvastatin daily) reduced the 10-year risk of coronary heart disease from 60% to 10% (adjusted hazard ratio 0.18, 95% CI 0.13 to 0.25).¹⁹ Furthermore, patients with HeFH taking statin therapy had an ASCVD risk that was only slightly higher than an age-matched sample of the general population (6.7 vs 4.1 events per 1000 patient-years). Other studies show similar improvements in prognosis with statin treatment.^26,27

In patients who fail to achieve a 50% or greater reduction in LDL levels with maximally tolerated statin therapy, the CCS position statement on FH recommends adding other LDL-lowering agents.¹ Ezetimibe lowers LDL levels by an additional 15% to 20% and generally has few adverse effects when combined with statin therapy.^28,29 The Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression trial (known as the ENHANCE trial), which enrolled patients with HeFH, had insufficient power to detect changes in clinically relevant outcomes.²⁸ The largest ezetimibe RCT, IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), evaluated the use of ezetimibe in addition to 40 mg of simvastatin daily in 18 144 postacute coronary syndrome patients with LDL levels of 1.3 to 3.2 mmol/L.²⁹ In this secondary prevention population without FH, the addition of ezetimibe to statin therapy reduced the absolute risk of cardiovascular events— primarily nonfatal myocardial infarction or stroke—by 2% over the course of 7 years, with no increased risk of adverse events. The strong pathologic role of LDL levels in the development of ASCVD in FH would predict similar relative benefit in this population.

Additional options include bile-acid sequestrants (eg, cholestyramine, colesevelam), fibrates, or niacin.²⁰ Bile-acid sequestrants and niacin are often poorly tolerated owing to gastrointestinal adverse effects and skin flushing, respectively. Clinicians must use caution when combining a fibrate or niacin with statin therapy owing to the increased risk of myopathies.^30,31 Finally, PCSK9 inhibitors such as evolocumab might provide additional options to further lower LDL levels in the future, pending Health Canada approval. Table 3^32–38 summarizes the new lipid-lowering agents for the treatment of HoFH.

Limited data exist for the treatment of HeFH in children. Randomized controlled trials of lipid-lowering agents in pediatric patients have thus far demonstrated an LDL reduction consistent with that seen in adults but, owing to limited enrollment and follow-up, have not demonstrated an effect on clinical outcomes.^39–41 In general, the management of pediatric patients with HeFH is similar to treatment of adults.

The management of HoFH requires specialist care with aggressive pharmacologic lipid-lowering treatment, as well as lipoprotein apheresis in select patients.¹ Lipoprotein apheresis is an expensive procedure that involves extracorporeal filtering of lipoproteins from blood, generally performed over a few hours on a weekly or twice-monthly basis. As with HeFH, statins and ezetimibe are first- and second-line therapy, with bile-acid sequestrants, fibrates, and niacin used less frequently. Two new agents, lomitapide and mipomersen (Table 3),^32–38 show promise in the treatment of HoFH. In 2014, Health Canada approved lomitapide for use in HoFH, whereas mipomersen is not yet commercially available in Canada. There might also be a future role for PCSK9 inhibitors in the treatment of HoFH patients.