Cholesteryl Ester Storage Disease

Cholesteryl ester storage disease (CESD) is the later onset form of lysosomal acid lipase deficiency, an autosomal recessive disorder due to biallelic LIPA variants with some residual enzyme activity. It presents in childhood or adult life with hepatomegaly, raised transaminases and dyslipidaemia, and can progress to cirrhosis and premature atherosclerosis.

Pathophysiology. Residual lysosomal acid lipase activity spares the infant from Wolman disease but is not enough to clear cholesteryl esters and triglycerides from hepatocytes and macrophages. Chronic storage causes steatosis, fibrosis and cirrhosis, and the liver's compensatory cholesterol synthesis raises LDL cholesterol.

The common splice variant c.894G>A (exon 8 skipping) is found in many patients.

The condition is under recognised because it mimics common liver and lipid disease.

• Hepatomegaly, usually from childhood
• Raised alanine and aspartate aminotransferase
• Dyslipidaemia: raised LDL cholesterol, low HDL cholesterol, and often raised triglycerides
• Microvesicular steatosis, progressing to fibrosis and cirrhosis
• Splenomegaly and portal hypertension in advanced disease
• Premature atherosclerosis and cardiovascular events
• Abdominal pain, diarrhoea and malabsorption in some
• Adrenal calcification in a minority
• Gallstones

• Lysosomal acid lipase activity in dried blood spots or leukocytes: markedly reduced.
• LIPA sequencing with deletion and duplication analysis.
• Lipid profile, liver enzymes and ferritin.
• Liver imaging (ultrasound, elastography) or biopsy showing microvesicular steatosis with cholesteryl ester crystals.
• Carotid and cardiac risk assessment in adults.
• Family screening of siblings and parents.

Differential diagnosis.

• Familial hypercholesterolaemia
• Non-alcoholic fatty liver disease
• Combined familial dyslipidaemia
• Wilson disease and autoimmune hepatitis
• Other lysosomal storage disorders with hepatomegaly (Gaucher disease, Niemann-Pick disease)

• Enzyme replacement therapy: sebelipase alfa 1 mg/kg intravenously every other week for children and adults, as a lifelong infusion. Premedicate with an antihistamine (cetirizine 10 mg orally; children 6 to 11 years 5 mg twice daily) if infusion reactions occur. Keep adrenaline 0.5 mg intramuscularly (children 0.01 mg/kg, maximum 0.5 mg) available.
• Lipid lowering: atorvastatin 10 to 80 mg daily (children over 10 years 10 to 20 mg daily), with ezetimibe 10 mg daily added if LDL cholesterol remains high. Statins reduce cholesterol but do not stop liver disease.
• Diet: a low fat diet, weight control and avoidance of alcohol.
• Cirrhosis and portal hypertension: screening endoscopy, propranolol 1 mg/kg daily divided up to 4 mg/kg in children (adults 40 mg twice daily to 160 mg twice daily) and variceal banding. Liver transplantation for decompensated disease.
• Cardiovascular risk: control of blood pressure, no smoking, and low dose aspirin 75 mg daily in adults with established atherosclerosis.
• Surveillance for hepatocellular carcinoma: ultrasound every 6 months in cirrhosis.
• Genetic counselling: a 25% recurrence risk in each pregnancy, and screening of siblings.

Special groups.

• Children with unexplained hepatomegaly and raised LDL cholesterol: measure lysosomal acid lipase before a statin is started and before liver biopsy.

Monitoring. Lipid profile, aminotransferases and platelet count every 3 to 6 months. Liver elastography yearly, upper endoscopy as indicated, and carotid assessment in adults.

Referral and escalation. Refer to clinical genetics, metabolic medicine and hepatology. Urgent for variceal bleeding, liver failure or acute cardiovascular events.