Familial Combined Hyperlipidaemia

Familial combined hyperlipidaemia (FCHL) is a common inherited dyslipidaemia in which affected family members show raised LDL-C, raised triglycerides (TG), or both, with raised apolipoprotein B (apoB). It is a major cause of premature coronary disease.

It affects about 1 to 2% of the general population and accounts for 10 to 20% of premature coronary disease. Onset is usually in adulthood, and tendon xanthomas are absent.

Inheritance is oligogenic or polygenic with environmental amplification. The lipid phenotype in one person can change over time, for example from raised TG to raised LDL-C with weight loss or treatment.

Associations include central obesity, insulin resistance, type 2 diabetes, hypertension, hyperuricaemia and fatty liver disease. Secondary factors such as alcohol, hypothyroidism, nephrotic syndrome and drugs worsen the picture.

Pathophysiology.

The core defect is hepatic overproduction of apoB-100 containing VLDL, with delayed clearance of triglyceride rich lipoproteins. This yields increased small dense LDL, which is atherogenic.

ApoB is raised out of proportion to LDL-C, so LDL-C alone underestimates risk. Non-HDL-C and apoB are the better measures.

Adipose tissue insulin resistance increases free fatty acid flux to the liver and drives triglyceride synthesis.

Most patients are asymptomatic. Presentation is usually a premature coronary or peripheral vascular event, or an incidental lipid result.

Examination may show central obesity, hypertension and signs of metabolic syndrome. Xanthomas are usually absent. Eruptive xanthomas and lipaemia retinalis appear only if TG are very high (over 10 mmol/L).

Features favouring FCHL:

• Fasting TG about 1.7 to 10 mmol/L, raised total cholesterol or LDL-C, or both.
• ApoB over 1.2 g/L (120 mg/dL).
• A first degree relative with a different lipid phenotype or premature coronary disease.
• Exclusion of secondary causes.

Tests:

• Fasting lipid profile with non-HDL-C and apoB (non-HDL-C equals total cholesterol minus HDL-C).
• TSH, glucose or HbA1c, creatinine and eGFR, urine protein, ALT, urate.
• Assessment of alcohol intake and drug history.
• Coronary risk assessment, with calcium scoring where it will change treatment.

Differential diagnosis.

• Dysbetalipoproteinaemia.
• Familial hypercholesterolaemia and familial hypertriglyceridaemia.
• Secondary mixed dyslipidaemia (diabetes, hypothyroidism, nephrotic syndrome, alcohol).
• Polygenic hypertriglyceridaemia.

Targets. Non-HDL-C under 2.6 mmol/L (100 mg/dL) in high risk patients and under 2.2 mmol/L (85 mg/dL) in very high risk patients. ApoB under 0.8 g/L (high risk) or under 0.65 g/L (very high risk). LDL-C under 1.8 mmol/L in high risk patients, or under 1.4 mmol/L with established vascular disease.

Lifestyle. Weight loss of 5 to 10%, limited alcohol, reduced refined carbohydrate, regular exercise. Treat diabetes and hypothyroidism.

Drug therapy.

• Atorvastatin: 40 to 80 mg orally once daily, long term; maximum 80 mg; lipids at 6 to 8 weeks, ALT at baseline and if symptomatic; no renal adjustment; maximum 20 mg with clarithromycin or itraconazole.
• Rosuvastatin (alternative): 20 to 40 mg orally once daily; maximum 40 mg; with eGFR under 30 mL/min/1.73 m2 start 5 mg and limit to 10 mg; 40 mg not used with eGFR under 60 or Asian ancestry.
• Ezetimibe: 10 mg orally once daily, added if non-HDL-C target is unmet; maximum 10 mg; not advised in Child-Pugh B or C hepatic impairment.
• Fenofibrate: for TG over 5.6 mmol/L (500 mg/dL), first line to prevent pancreatitis; otherwise add if TG stay over 2.3 mmol/L (200 mg/dL) on maximal statin. Dose 145 mg (nanoparticle tablet) or 200 mg (micronised capsule) orally once daily with food, long term; maximum 200 mg daily. Creatinine, ALT and CK at baseline, 3 months, then every 6 to 12 months (creatinine rise of 10 to 20% is common and reversible). Avoid if eGFR under 30 mL/min/1.73 m2; reduce to the lowest product strength (about 50 mg daily) if eGFR is 30 to 59; avoid in gallbladder disease and severe hepatic impairment. Fenofibrate potentiates warfarin (reduce dose, check INR).
• Gemfibrozil is not combined with a statin.
• Icosapent ethyl: 2 g orally twice daily with food, for TG 1.7 to 5.6 mmol/L (150 to 499 mg/dL) with vascular disease or diabetes and risk factors on a statin; long term; maximum 4 g daily; monitor for atrial fibrillation and bleeding; no renal adjustment.
• Bempedoic acid 180 mg daily, or a PCSK9 monoclonal antibody (evolocumab 140 mg every 2 weeks or 420 mg monthly; alirocumab 75 to 150 mg every 2 weeks), when LDL-C or apoB targets remain unmet.

TG over 10 mmol/L (880 mg/dL). Pancreatitis risk is high. Start fenofibrate, remove alcohol and precipitants (oestrogen, tamoxifen, isotretinoin, thiazides, beta blockers where possible), and treat diabetes and hypothyroidism.

Monitoring. Lipids and apoB 6 to 8 weeks after change, then every 6 to 12 months. HbA1c annually. ALT annually.

Referral and escalation. Refer for TG persistently over 10 mmol/L, suspected genetic subtype, or intolerance. Urgent assessment for abdominal pain with TG over 10 mmol/L.

Special groups.

• Pregnancy: stop statins and fibrates. TG rise physiologically; marked rises (over 10 mmol/L) need dietary fat restriction, omega-3 and specialist care, with plasmapheresis for pancreatitis.
• Kidney impairment: fenofibrate is avoided at eGFR under 30 and reduced at eGFR 30 to 59; rosuvastatin is started at 5 mg and limited to 10 mg at eGFR under 30 mL/min/1.73 m2.
• Older adults: continue a statin; start at moderate dose if frail.