Sitosterolaemia

Sitosterolaemia is a rare autosomal recessive disorder of plant sterol handling. It causes accumulation of plant sterols (sitosterol, campesterol), xanthomas, premature atherosclerosis, and haematological abnormalities.

It results from biallelic loss-of-function variants in ABCG5 or ABCG8. Fewer than 200 cases are reported, though it is likely under diagnosed and prevalence is estimated at about 1 in 200,000.

Presentation is usually in childhood with xanthomas or unexplained hypercholesterolaemia. Cholesterol levels range from normal to markedly raised, and LDL-C often falls abruptly with dietary change.

Pathophysiology.

ABCG5 and ABCG8 form a transporter that returns absorbed plant sterols from enterocytes to the gut lumen and secretes sterols into bile. Failure of this system leads to hyperabsorption of dietary plant sterols and impaired hepatobiliary excretion.

Retained plant sterols deposit in tendons, skin, arteries and valves and incorporate into red cell and platelet membranes. This causes stomatocytic haemolysis, macrothrombocytopenia and premature atherosclerosis. Suppression of hepatic HMG-CoA reductase makes statins less effective.

• Tendon and tuberous xanthomas (Achilles, extensor tendons, elbows, knees, buttocks), sometimes before age 10.
• Premature coronary disease and aortic valve and root involvement.
• Haemolytic anaemia, stomatocytosis, macrothrombocytopenia, and splenomegaly.
• Arthralgia and arthritis of large joints.

Suspect sitosterolaemia in a child or young adult with xanthomas and hypercholesterolaemia with poor statin response, or with unexplained stomatocytic haemolytic anaemia and macrothrombocytopenia.

Tests:

• Plasma plant sterols (gas chromatography or mass spectrometry): sitosterol typically over 1 mg/dL and often 10 to 60 mg/dL, against under 1 mg/dL in healthy people.
• Genetic testing for biallelic ABCG5 or ABCG8 variants.
• Full blood count and film (stomatocytes, large platelets), reticulocytes, bilirubin, haptoglobin.
• Lipid profile, echocardiography for aortic valve and root, and coronary and carotid assessment.

Differential diagnosis.

• Familial hypercholesterolaemia (especially homozygous).
• Cerebrotendinous xanthomatosis and lysosomal acid lipase deficiency.
• Hereditary stomatocytosis and other causes of macrothrombocytopenia.
• Autosomal recessive hypercholesterolaemia.

Diet. Avoid foods rich in plant sterols: vegetable oils (particularly corn, sunflower, soy), margarines, nuts, seeds, avocado, chocolate, shellfish. Avoid plant sterol fortified products. Diet alone can reduce plasma sterols by 20 to 30%.

Drug therapy.

• Ezetimibe: 10 mg orally once daily, age 10 years or over (used earlier in specialist care); long term; maximum 10 mg; reduces plasma plant sterols by about 50%; ALT with a statin; not advised in Child-Pugh B or C; give 2 hours before or 4 hours after a bile acid sequestrant.
• Colesevelam (add on): 3.75 g orally once daily or 1.875 g twice daily; maximum 4.5 g daily; give other drugs 4 hours before; monitor triglycerides, vitamin levels; contraindicated in bowel obstruction and TG over 10 mmol/L.
• Statins: used as an add on for LDL-C if needed (atorvastatin 40 to 80 mg daily, maximum 80 mg), but response is weak when used alone.
• Lipoprotein apheresis is reserved for refractory disease, and haematological features usually resolve with sterol lowering.

Monitoring. Plasma sterols and lipids every 3 to 6 months initially, then every 6 to 12 months. Full blood count, haemolysis markers, echocardiography (aortic valve) every 1 to 2 years, and coronary or carotid imaging by risk.

Referral and escalation. All suspected cases to a lipid specialist or paediatric metabolic service. Refer urgently for aortic valve disease, symptomatic coronary disease, or severe haemolysis.

Special groups.

• Pregnancy: stop statins; ezetimibe is generally avoided; sequestrants and diet are used; specialist care needed.
• Children: dietary management is central, ezetimibe from age 10 years or earlier in specialist care, with growth monitoring.