Dysbetalipoproteinaemia

Dysbetalipoproteinaemia (type III hyperlipoproteinaemia, remnant removal disease) is a disorder of impaired clearance of triglyceride rich lipoprotein remnants. It causes mixed hyperlipidaemia, characteristic xanthomas, and premature coronary and peripheral vascular disease.

About 1% of the population is homozygous for the apoE2 isoform (E2/E2), but only 1 in 100 to 1 in 20 of these develop the disease. Clinical prevalence is about 1 in 5,000 to 1 in 10,000.

A second metabolic hit is usually required: obesity, diabetes, hypothyroidism, heavy alcohol use, chronic kidney disease, oestrogen deficiency or drugs such as retinoids. Rare dominant apoE variants cause disease without a second hit.

Onset is usually in adulthood (men in the 30s to 40s, women after menopause).

Pathophysiology.

ApoE2 binds poorly to the LDL receptor and receptor related proteins, so VLDL and chylomicron remnants and IDL accumulate instead of being cleared.

These remnants are cholesterol rich and highly atherogenic. Plasma cholesterol and TG are raised in roughly equal proportion, and LDL-C is often low or normal because LDL production is reduced.

Palmar crease (striae palmaris) xanthomas are the most specific sign. Tuberoeruptive xanthomas over elbows and knees, and tendon xanthomas, are also seen. Xanthelasma may be present.

Atherosclerosis involves coronary, carotid and femoral arteries, with peripheral vascular disease proportionally more common than in other dyslipidaemias. Obesity, glucose intolerance and hyperuricaemia are common.

Features: total cholesterol and TG both raised (often 7.5 to 15 mmol/L each) with a disproportionately low apoB (often under 1.2 g/L despite the high lipid levels), low or normal LDL-C, and low HDL-C.

Confirmation:

• ApoE genotyping showing E2/E2 (or a rare dominant variant).
• Ultracentrifugation ratio of VLDL-C to total TG over 0.30 (mg/dL basis) is classic where available.
• Calculated LDL-C is unreliable when TG are raised, so use non-HDL-C and apoB.

Also check TSH, glucose or HbA1c, creatinine and eGFR, urine protein, ALT, urate, and coronary and peripheral vascular status.

Differential diagnosis.

• Familial combined hyperlipidaemia and familial hypercholesterolaemia.
• Hypertriglyceridaemia of other cause.
• Secondary mixed dyslipidaemia (hypothyroidism, nephrotic syndrome, diabetes).
• Cerebrotendinous xanthomatosis and sitosterolaemia (xanthomas).

Targets. Non-HDL-C under 2.6 mmol/L (100 mg/dL), or under 2.2 mmol/L (85 mg/dL) in very high risk patients. ApoB under 0.8 g/L (0.65 g/L in very high risk). TG under 1.7 mmol/L.

Lifestyle and secondary causes. Weight loss, alcohol restriction, low saturated fat and refined carbohydrate intake, and exercise. Treat hypothyroidism and diabetes: many patients respond fully to this alone, and levothyroxine often normalises the lipids. Withdraw offending drugs.

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.
• Fenofibrate: 145 mg (nanoparticle tablet) or 200 mg (micronised capsule) orally once daily with food, long term, as monotherapy if a statin is not tolerated or as an add on when non-HDL-C or TG remain raised; maximum 200 mg daily; creatinine, ALT and CK at baseline, 3 months, then every 6 to 12 months; avoid if eGFR under 30 mL/min/1.73 m2, reduce to the lowest strength if eGFR 30 to 59; potentiates warfarin.
• Ezetimibe 10 mg orally once daily as add on; not advised in Child-Pugh B or C.
• Statin and fibrate combination is often needed and is well tolerated with a fibrate other than gemfibrozil.

Response is usually excellent, with a fall in cholesterol and TG of 50% or more.

Monitoring. Lipids, apoB and non-HDL-C at 6 to 8 weeks, then every 6 to 12 months. Reassess xanthomas, vascular status and glycaemia annually.

Referral and escalation. Refer to a lipid specialist for suspected diagnosis, resistant disease, or vascular disease. Urgent review for TG over 10 mmol/L or acute abdominal pain.

Special groups.

• Pregnancy: stop statins and fibrates; monitor TG, which rise in pregnancy; omega-3 and diet are used.
• Menopause: oestrogen deficiency can unmask disease, but systemic oestrogen can also raise TG, so choose transdermal options and monitor.
• 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.