Progressive Familial Intrahepatic Cholestasis

Progressive familial intrahepatic cholestasis is a group of autosomal recessive disorders of bile formation that cause cholestasis in infancy and childhood, with progression to cirrhosis and liver failure in the first decades of life.

The incidence is about 1 in 50,000 to 100,000 births. Type 1 (ATP8B1, FIC1) and type 2 (ABCB11, bile salt export pump) have low gamma glutamyl transferase, and type 3 (ABCB4, MDR3) has a high gamma glutamyl transferase. Types 4 to 6 (TJP2, NR1H4, MYO5B) are rarer. Type 2 carries a risk of hepatocellular carcinoma in early childhood.

Pathophysiology.

Impaired bile acid secretion (types 1 and 2) or phospholipid secretion (type 3) leads to retained toxic bile acids, hepatocyte injury, fibrosis and cirrhosis.

Jaundice, severe itching with scratch marks, poor growth, fat malabsorption with fat soluble vitamin deficiency (rickets, coagulopathy), hepatosplenomegaly and, in type 1, extrahepatic features such as diarrhoea, deafness and pancreatitis. Portal hypertension develops in type 3.

Red flags.

• Intractable itch.
• Coagulopathy or bleeding.
• Rising alpha fetoprotein or liver mass (type 2).
• Failure to thrive.

Raised bile acids and conjugated bilirubin, low gamma glutamyl transferase (types 1 and 2) or high gamma glutamyl transferase (type 3). Exclude biliary atresia, Alagille syndrome and metabolic disease. Genetic testing confirms the type. Liver biopsy with immunostaining for BSEP and MDR3 supports the diagnosis. Check INR, vitamins A, D, E and K, and alpha fetoprotein.

Differential diagnosis.

• Biliary atresia.
• Alagille syndrome.
• Bile acid synthesis defects.
• Benign recurrent intrahepatic cholestasis.
• Neonatal sclerosing cholangitis.

Treat pruritus, nutrition and vitamin deficiency, and slow progression with ileal bile acid transporter inhibitors. Partial external biliary diversion or ileal exclusion is for types 1 and 2 with preserved liver architecture, and liver transplant is for end stage disease, intractable itch or tumour.

• Ursodeoxycholic acid: 20 to 30 mg/kg orally daily in two divided doses; maximum 30 mg/kg daily; monitor liver tests; reduce if diarrhoea occurs, and stop if cholestasis worsens.
• Odevixibat (types 1 and 2): 40 micrograms/kg orally once daily in the morning with food, increased after 3 months to 120 micrograms/kg; maximum 7,200 micrograms daily; monitor bile acids, liver tests, diarrhoea and fat soluble vitamins; avoid in decompensated liver disease.
• Rifampicin: 10 mg/kg orally daily in two divided doses; maximum 600 mg daily; monitor liver tests every 2 weeks at first and drug interactions; stop if hepatitis develops.
• Colestyramine: 240 mg/kg orally daily in three divided doses; maximum 16 g daily; monitor vitamins and bowel function; take at a different time from other drugs.
• Phytomenadione: 2.5 to 5 mg orally daily; maximum 10 mg daily; monitor INR.
• Vitamin A, D and E replacement: doses adjusted to serum levels, with specialist dietitian input.

Monitoring. Growth, liver tests, INR, vitamins and bile acids every 3 months; ultrasound and alpha fetoprotein every 6 months.

Referral and escalation. Paediatric hepatology; transplant centre.

Special groups. Children need weight based dosing and nutritional support with medium chain triglycerides.