Low Phospholipid-Associated Cholelithiasis

Low phospholipid associated cholelithiasis is a genetic form of gallstone disease caused by heterozygous ABCB4 mutations, leading to low biliary phospholipid and cholesterol crystal formation. It presents with symptomatic stones before age 40 years and intrahepatic microlithiasis.

It is found in about 1% of young adults with symptomatic gallstones and up to 5% with recurrent symptoms after cholecystectomy. The syndrome combines symptomatic gallstones before 40 years, recurrence after cholecystectomy and intrahepatic hyperechoic foci with comet tail artefact.

Pathophysiology.

The ABCB4 gene encodes the phospholipid flippase MDR3. Reduced phospholipid secretion makes bile toxic to biliary epithelium, which causes cholesterol crystals, stones and cholangiopathy.

Biliary colic, cholangitis, pancreatitis or cholestatic jaundice in a young adult, often with a family history and a history of intrahepatic cholestasis of pregnancy. Pain recurs after cholecystectomy.

Red flags.

• Cholangitis.
• Pancreatitis.
• Progressive cholestasis with fibrosis.

Ultrasound shows hyperechoic foci in the intrahepatic ducts (comet tail artefact) or microlithiasis. Magnetic resonance cholangiopancreatography and endoscopic ultrasound show intrahepatic stones and sludge. Gamma glutamyl transferase is often raised. ABCB4 sequencing confirms the diagnosis. Check for fibrosis by elastography.

Differential diagnosis.

• Common gallstone disease.
• Primary sclerosing cholangitis.
• Benign recurrent intrahepatic cholestasis.
• Caroli disease.
• Postcholecystectomy syndrome from other causes.

Long term ursodeoxycholic acid reduces recurrence of symptoms and stones, and is started after cholecystectomy or as primary treatment in patients unfit for surgery. Clear common duct stones endoscopically. Fibrosis or biliary cirrhosis is managed by hepatology, with transplant in end stage disease.

• Ursodeoxycholic acid: 10 to 15 mg/kg orally daily in two to three divided doses, long term; maximum 20 mg/kg daily; monitor liver tests every 6 months and ultrasound each year; reduce for diarrhoea.

Offer genetic counselling to relatives.

Monitoring. Liver tests and ultrasound each year; fibrosis assessment every 2 years.

Referral and escalation. Hepatology and pancreaticobiliary endoscopy.

Special groups. In pregnancy, ursodeoxycholic acid is continued, and cholestasis is checked each trimester.