Familial Hypercholesterolaemia

Familial hypercholesterolaemia (FH) is an inherited disorder of LDL receptor mediated clearance. It causes lifelong elevation of LDL cholesterol (LDL-C) and accelerated atherosclerosis, with premature coronary disease as the main consequence.

Heterozygous FH (HeFH) affects about 1 in 250 to 1 in 310 people. Homozygous FH (HoFH), including compound and double heterozygotes, affects about 1 in 250,000 to 1 in 300,000. Most cases remain undiagnosed in most health systems.

Loss-of-function variants in LDLR account for about 80 to 85% of genetically confirmed cases. APOB variants (defective LDL binding) account for 5 to 10%, gain-of-function PCSK9 variants for about 1%, and recessive LDLRAP1 variants are rare. Up to 20 to 40% of clinically definite cases have no monogenic variant, and part of this group has polygenic LDL-C raising.

Untreated HeFH gives LDL-C of about 5 to 10 mmol/L (190 to 390 mg/dL), with coronary events commonly in the 40s to 50s in men and the 50s to 60s in women. Untreated HoFH gives LDL-C over 13 mmol/L (500 mg/dL), childhood xanthomas, coronary events in the teens to twenties, and aortic root and valve disease.

Pathophysiology.

Hepatic LDL receptors clear LDL particles through apoB-100 binding. Loss of receptor function, defective apoB binding, or excess PCSK9 (which directs receptors to lysosomal degradation) leaves LDL in plasma for longer.

Risk reflects cumulative LDL-C exposure from birth, so early and sustained lowering gives the largest benefit. Modifiers of risk include male sex, smoking, diabetes, hypertension and raised lipoprotein(a).

In HoFH, receptor activity under 2% (receptor negative) behaves more severely than activity of 2 to 25% (receptor defective). Aortic valve and root involvement is a feature unique to the homozygous state.

Most patients are asymptomatic until a vascular event. Tendon xanthomas (Achilles, extensor tendons of the hands) occur in a minority of adults with HeFH. Corneal arcus before age 45 and xanthelasma are supportive signs.

HoFH adds planar and tuberous xanthomas (interdigital webs, buttocks, elbows, knees) in the first decade, supravalvular and valvular aortic stenosis, and coronary ostial disease.

Diagnosis is clinical, genetic, or both. Adult untreated LDL-C over 4.9 mmol/L (190 mg/dL) with a family history of raised LDL-C or premature coronary disease is highly suggestive. In children, LDL-C of 4.0 mmol/L (155 mg/dL) or more on two occasions, or 3.5 mmol/L or more with a positive family history, warrants testing.

The Dutch lipid clinic score allocates points for each feature:

• Family history: first degree relative with premature vascular disease (men under 55, women under 60) or LDL-C over the 95th percentile, 1 point; first degree relative with tendon xanthomas or corneal arcus, or a child under 18 with LDL-C over the 95th percentile, 2 points.
• Personal history: premature coronary disease, 2 points; premature cerebral or peripheral vascular disease, 1 point.
• Examination: tendon xanthomas, 6 points; corneal arcus under age 45, 4 points.
• LDL-C: 4.0 to 4.9 mmol/L, 1 point; 5.0 to 6.4, 3 points; 6.5 to 8.4, 5 points; over 8.5 mmol/L, 8 points.
• Functional pathogenic variant in LDLR, APOB or PCSK9: 8 points.
• Total over 8 is definite, 6 to 8 probable, 3 to 5 possible.

Baseline tests:

• Fasting or non-fasting lipid profile (repeat LDL-C off drugs if possible), apoB and lipoprotein(a).
• TSH, creatinine and eGFR, urine protein, ALT, glucose or HbA1c.
• Secondary causes: hypothyroidism, nephrotic syndrome, cholestasis, and drugs (ciclosporin, corticosteroids, progestins, protease inhibitors).
• ECG and echocardiography. Coronary calcium scoring or CT coronary angiography from the 30s, earlier in HoFH.
• HoFH: aortic root and valve imaging, carotid ultrasound, early coronary imaging.
• Cascade testing of first degree relatives by genotype or LDL-C, from age 5 to 10 years, and from age 2 if HoFH is possible.

Differential diagnosis.

• Polygenic hypercholesterolaemia and secondary hypercholesterolaemia.
• Sitosterolaemia (xanthomas with poor statin response).
• Lysosomal acid lipase deficiency and cerebrotendinous xanthomatosis (tendon xanthomas).
• Autosomal recessive hypercholesterolaemia (LDLRAP1).

Targets. LDL-C reduction of at least 50% from untreated baseline, with LDL-C under 1.8 mmol/L (70 mg/dL) without established vascular disease and under 1.4 mmol/L (55 mg/dL) with vascular disease or other very high risk features. An alternative target in some settings is under 2.6 mmol/L (100 mg/dL).

Lifestyle. Stop smoking, reduce saturated fat, maintain healthy weight, regular activity. Lifestyle alone never achieves target.

Drug therapy (stepwise).

• Atorvastatin: 40 to 80 mg orally once daily, long term; maximum 80 mg daily; lipids at 4 to 8 weeks, ALT at baseline and if symptomatic; no renal adjustment; maximum 20 mg with clarithromycin or itraconazole; avoid with ciclosporin and gemfibrozil; contraindicated in active liver disease.
• Rosuvastatin (alternative): 20 to 40 mg orally once daily, long term; maximum 40 mg; lipids at 4 to 8 weeks, ALT at baseline and if symptomatic; with eGFR under 30 mL/min/1.73 m2 start 5 mg and limit to 10 mg; the 40 mg dose is not used with eGFR under 60 or Asian ancestry (maximum 20 mg).
• Ezetimibe: 10 mg orally once daily, added when target is unmet after 4 to 8 weeks of maximal tolerated statin; maximum 10 mg; ALT when combined with a statin; not advised in moderate to severe hepatic impairment (Child-Pugh B or C); give 2 hours before or 4 hours after a bile acid sequestrant.
• Bempedoic acid: 180 mg orally once daily, long term; maximum 180 mg; monitor uric acid, ALT and for tendon pain; limit simvastatin to 20 mg and pravastatin to 40 mg; limited data at eGFR under 30.
• Evolocumab: 140 mg subcutaneously every 2 weeks, or 420 mg once monthly; long term; lipids at 4 to 12 weeks; no renal or mild to moderate hepatic adjustment. In HoFH the dose is 420 mg monthly (age 10 years or over), increased to every 2 weeks if on apheresis.
• Alirocumab: 75 mg subcutaneously every 2 weeks, increased to 150 mg every 2 weeks (or 300 mg every 4 weeks) if response is inadequate; long term; no renal adjustment.
• Inclisiran: 284 mg subcutaneously at day 0, at 3 months, then every 6 months; long term; lipids at 3 months; no renal adjustment; use with caution in severe hepatic impairment.

HoFH.

• Statin, ezetimibe and a PCSK9 monoclonal antibody (limited effect in receptor negative disease).
• Lomitapide, adults only: start 5 mg orally once daily in the evening, 2 hours after food; increase to 10 mg after at least 2 weeks, then 20, 40 and 60 mg at intervals of at least 4 weeks; maximum 60 mg daily. Low fat diet (under 20% of energy) with vitamin E (about 400 IU daily) and essential fatty acid supplements. ALT, AST, ALP and bilirubin before each increase, monthly in the first year, then every 3 months. Maximum 40 mg in mild hepatic impairment or dialysis; contraindicated in moderate to severe hepatic impairment and with moderate or strong CYP3A4 inhibitors; limit to 30 mg daily with weak CYP3A4 inhibitors such as atorvastatin.
• Evinacumab: 15 mg/kg intravenously over 60 minutes every 4 weeks, age 5 years or over; long term; monitor LDL-C and infusion reactions; no renal adjustment; exclude pregnancy before starting.
• Lipoprotein apheresis every 1 to 2 weeks (acute LDL-C reduction about 50 to 75%) when targets are unmet on drugs, starting in childhood if needed.

Children. Start a statin at 8 to 10 years in HeFH, earlier in HoFH:

• Pravastatin, from 8 years: 20 mg daily at 8 to 13 years and 40 mg daily at 14 to 18 years (maximum 40 mg daily).
• Atorvastatin, from 10 years: start 10 mg daily, maximum 20 mg daily.
• Rosuvastatin: 5 to 10 mg daily at 6 to 9 years (maximum 10 mg), up to 20 mg daily at 10 to 17 years.
• Add ezetimibe 10 mg daily from 6 years if needed. Monitor growth, puberty, ALT and CK if symptomatic.

Monitoring. Lipids 4 to 12 weeks after any change, then every 6 to 12 months. ALT at baseline and as clinically needed. Reassess vascular risk annually, with imaging at intervals set by risk.

Referral and escalation. Refer to a lipid specialist for LDL-C over 5.0 mmol/L despite treatment, any HoFH, children, or intolerance. Urgent referral for LDL-C over 13 mmol/L, xanthomas in a child under 10 years, aortic stenosis, exertional chest pain or syncope with xanthomas, and any acute coronary event under age 55 in a man or under age 60 in a woman.

Special groups.

• Pregnancy and breastfeeding: stop statins before conception or when pregnancy is confirmed. Colesevelam 3.75 g orally once daily (or 1.875 g twice daily; maximum 4.5 g daily) or colestyramine 4 g once or twice daily (maximum 24 g daily) may be used, with other drugs taken 1 hour before or 4 to 6 hours after. Apheresis for HoFH. Effective contraception is needed on statins, lomitapide or evinacumab.
• Older adults: continue statin therapy; start at moderate dose if frailty or interacting drugs.
• Kidney impairment: rosuvastatin is started at 5 mg and limited to 10 mg when eGFR is under 30 mL/min/1.73 m2; fibrates and bempedoic acid need caution.