Familial hypercholesterolemia: Review of diagnosis, screening, and treatment

Ricky D. Turgeon; Arden R. Barry; Glen J. Pearson

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Table 1.

Summary of recommendations

RECOMMENDATIONS	LEVEL OF EVIDENCE
Screening and diagnosis of FH
Who should be screened?
• In adults, screen plasma lipid levels in all men aged ≥ 40 y and all women aged ≥ 50 y or after menopause	III
• In pediatric patients, consider routine universal screening of plasma lipid levels at age 11 y or as early as 12 mo in children with a first-degree family history of ASCVD or FH	III
• Once an FH proband has been identified, perform cascade screening on their relatives	II
When should FH be suspected?
• Any patient with premature ASCVD, physical stigmata of hypercholesterolemia, or a plasma LDL level of ≥ 5 mmol/L should be suspected of having FH	II
How should the diagnosis of FH be confirmed?
• In patients with hypercholesterolemia, 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 sedentary lifestyle	III
• Diagnose FH using the Simon Broome Register or the Dutch Lipid Network criteria	II
Management
Management of FH
• Do not use cardiovascular risk calculators (eg, Framingham risk score) in patients with FH, as these do not reflect the true risk of ASCVD	II
• Consider enrolling patients with FH in the Canadian FH Registry^* by referring them to a participating clinician or centre	III
• Aggressively manage traditional ASCVD risk factors, such as cessation of tobacco use and treatment of hypertension and diabetes	II
Management of HeFH
• Reduce LDL level by ≥ 50% from baseline	III
• Use high-dose statin as first-line therapy	II
• In patients who fail to achieve a ≥ 50% reduction in LDL levels with maximally tolerated statin therapy, add other LDL-lowering agents, such as ezetimibe, bile-acid sequestrants (eg, cholestyramine, colesevelam), fibrates, or niacin	II
Management of HoFH
• Refer patients with HoFH to a specialized centre	III

ASCVD—atherosclerotic cardiovascular disease, FH—familial hypercholesterolemia, HeFH—heterozygous familial hypercholesterolemia, HoFH—homozygous familial hypercholesterolemia, LDL—low-density lipoprotein.
↵* For more information, visit the FH Canada website at www.fhcanada.net/fh-canada-registry.

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Table 2.

Diagnostic criteria of FH

DIAGNOSTIC CRITERIA

DESCRIPTION

DIAGNOSIS

Simon Broome Register

DNA mutation consistent with FH (category A)
Lipid panel (category B): in adults, a TC level of > 7.5 mmol/L or LDL level of > 4.9 mmol/L; in pediatric patients, TC level of > 6.7 mmol/L or LDL level of > 4.0 mmol/L
Tendinous xanthoma in the patient or any first- or second-degree relative (category C)
Family history of myocardial infarction (category D): age < 60 y in first-degree relative; age < 50 y in second-degree relative
Family history of a TC level of > 7.5 mmol/L in a first- or second- degree relative (category E)

Definite FH:

Category A
Category B + category C

Probable FH:

Category B + category D or E

Dutch Lipid Network

History and physical characteristics:

Personal history of CAD, or first-degree relative < 18 y with LDL values > 95th percentile or with tendinous xanthoma or arcus senilis (2 points)
Personal history of premature cerebral or peripheral vascular disease or first-degree adult relative with premature CAD or LDL values > 95th percentile (1 point)
Tendinous xanthoma (6 points)
Arcus senilis at age < 45 y (4 points)

LDL levels:

> 8.5 mmol/L (8 points)
6.51–8.5 mmol/L (5 points)
4.9–6.5 mmol/L (1 point)

Genetic testing:

LDL-R gene functional mutation (8 points)

Definite FH:

≥ 8 points

Probable FH:

6–7 points

Possible FH:

3–5 points

CAD—coronary artery disease, FH—familial hypercholesterolemia, LDL—low-density lipoprotein, LDL-R—low-density lipoprotein receptor, TC—total cholesterol. Data from Varghese.¹⁶

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Table 3.

Summary of new lipid-lowering agents for the treatment of HoFH

LIPID-LOWERING AGENT	CHARACTERISTICS
	AVAILABILITY IN CANADA	MECHANISM	DOSING REGIMEN	MEAN LDL REDUCTION FROM BASELINE	CLINICAL OUTCOME EVIDENCE	CONTRAINDICATIONS	ADVERSE EFFECTS	POTENTIAL DRUG INTERACTIONS
	Lomitapide^*	Yes (approved February 4, 2014)	An MTP inhibitor that prevents assembly of VLDL thereby reducing LDL levels	5–60 mg orally once daily	38%–50%	None	Pregnancy; chronic bowel disease (eg, IBD, malabsorption); moderate or severe hepatic impairment; use of a moderate or strong CYP 3A4 inhibitor; coadministration with simvastatin ≥ 40 mg/d	Gastrointestinal intolerance, liver enzyme elevations, hepatic steatosis	Inhibits CYP 3A4 (eg, interacts with atorvastatin, lovastatin, simvastatin, warfarin) Inhibits P-glycoprotein (eg, interacts with colchicine, dabigatran, digoxin) CYP 3A4 substrate
Mipomersen^†	No	An antisense oligonucleotide targeted against Apo B mRNA, which prevents synthesis of Apo B thereby decreasing LDL levels	200 mg SC once weekly	25%	None	Moderate or severe hepatic impairment	Injection-site reaction, flulike symptoms, liver enzyme elevations, hepatic steatosis	None known
PCSK9 inhibitors (alirocumab, bococizumab, evolocumab)^‡	No	A PCSK9 inhibitor that prevents the breakdown of LDL receptors thereby enhancing LDL elimination	75–150 mg of alirocumab SC every 2 wk 150 mg of bococizumab SC every 2 wk 140 mg of evolocumab SC every 2 wk or 420 mg SC every 4 wk	48%–65% for HeFH; 23% for HoFH	None	None known	Injection-site reaction; musculoskeletal symptoms	None known

Apo B—apolipoprotein B, CYP 3A4—cytochrome P450 enzyme subtype 3A4, HeFH—heterozygous familial hypercholesterolemia, HoFH—homozygous familial hypercholesterolemia, IBD—inflammatory bowel disease, LDL—low-density lipoprotein, mRNA—messenger ribonucleic acid, MTP—microsomal triglyceride transfer protein, PCSK9—proprotein convertase subtilisin-kexin type 9, SC—subcutaneously, VLDL—very low–density lipoprotein.
↵* Data for lomitapide characteristics from Rader and Kastelein,³² Aegerion Pharmaceuticals,³³ and Cuchel et al.³⁴
↵† Data for mipomersen characteristics from Rader and Kastelein,³² Genzyme,³⁵ Raal et al,³⁶ and Akdim et al.³⁷
↵‡ Data for characteristics of PCSK9 inhibitors from Navarese et al.³⁸