Hypobetalipoproteinaemia

Hypobetalipoproteinaemia is low LDL cholesterol and apolipoprotein B (under the 5th percentile for age and sex, usually LDL cholesterol under 1.3 mmol/L, 50 mg/dL). It is primary (genetic) or secondary.

Familial hypobetalipoproteinaemia is caused by APOB truncating variants (most), PCSK9 or ANGPTL3 loss of function, and other genes. Heterozygous disease is common (about 1 in 1,000 to 3,000) and often asymptomatic. Homozygous disease is rare and resembles abetalipoproteinaemia.

Secondary causes are malabsorption, malnutrition, hyperthyroidism, chronic liver disease, cancer, infection (HIV) and drugs.

Pathophysiology.

Truncated apolipoprotein B is secreted at low levels or degraded, reducing VLDL secretion and hepatic fat export, so liver fat accumulates. PCSK9 and ANGPTL3 variants increase LDL receptor activity or lipoprotein lipase activity, lowering LDL without liver fat.

Fat soluble vitamin absorption is mildly impaired in homozygotes.

• Heterozygotes: usually no symptoms, with hepatic steatosis found on imaging or from raised aminotransferases.
• Homozygotes: steatorrhoea, failure to thrive, acanthocytosis, retinitis pigmentosa, ataxia, neuropathy, vitamin E and K deficiency, and liver disease.

Red flags.

• Neurological or visual deterioration.
• Bleeding or progressive liver disease.

• LDL cholesterol and apolipoprotein B under the 5th percentile on repeated fasting samples, after excluding secondary causes (thyroid function, liver tests, nutrition, malabsorption screen, HIV test, cancer assessment).
• Family lipid testing: heterozygous parents of a homozygote have LDL cholesterol about half the normal level. Homozygotes have very low levels like abetalipoproteinaemia.
• Liver ultrasound or elastography, vitamin E, A and K levels, blood film (acanthocytes) and prothrombin time.
• APOB, PCSK9, ANGPTL3 and MTTP sequencing.

Differential diagnosis.

• Abetalipoproteinaemia (parents normal) and chylomicron retention disease.
• Secondary hypocholesterolaemia (hyperthyroidism, malabsorption, malnutrition, liver or inflammatory disease, malignancy).
• Familial combined hypolipidaemia (ANGPTL3) and Tangier disease (HDL low).

• Heterozygotes need no specific treatment. Advise a healthy diet, weight control and alcohol limitation to reduce hepatic steatosis, and monitor liver tests.
• Homozygotes: use a fat restricted diet, vitamin E 100 to 300 mg/kg daily, vitamin A 100 to 400 units/kg daily, vitamin K 5 to 10 mg weekly in adults (1 to 2 mg daily in children), and vitamin D at usual doses.
• Avoid drugs that lower lipids further (lomitapide, mipomersen). Statins are not needed.
• Treat secondary causes.
• Low LDL cholesterol is not harmful for cardiovascular risk; lifelong low LDL is associated with lower cardiovascular events.

Special groups. Pregnancy: homozygous women need specialist care and limited vitamin A dosing.

Monitoring. Heterozygotes: liver tests and imaging every 1 to 2 years if steatosis is present. Homozygotes: vitamin levels, prothrombin time and liver tests every 3 to 6 months, and ophthalmology and neurology yearly.

Referral and escalation. Lipid or metabolic specialist for homozygous disease or unexplained liver disease; hepatology for fibrosis.