Benign Recurrent Intrahepatic Cholestasis

Benign recurrent intrahepatic cholestasis is an autosomal recessive disorder of episodic cholestasis, with attacks of jaundice and severe itching lasting weeks to months, and full recovery between episodes. It is the milder end of the spectrum that includes progressive familial intrahepatic cholestasis.

Onset is usually in childhood or young adulthood, and men and women are equally affected. Type 1 is due to ATP8B1 and type 2 to ABCB11 mutations. The disease does not usually progress to cirrhosis, but some patients develop persistent cholestasis.

Attacks are triggered by infections, drugs (oestrogens, anabolic steroids), pregnancy or no cause.

Pathophysiology.

Defective bile salt secretion across the canalicular membrane (BSEP) or abnormal phospholipid flipping (FIC1) causes retained bile salts in hepatocytes and cholestasis during attacks.

Prodrome of malaise and nausea, then intense itching, jaundice, dark urine, pale stools, weight loss and steatorrhoea. Gallstones are common, and patients with ATP8B1 mutations may have diarrhoea or pancreatitis.

Red flags.

• Itching causing sleep loss or self-harm.
• Persistent cholestasis for over 6 months.
• Signs of liver failure.

Attacks show raised bilirubin and bile acids with a normal or only mildly raised gamma glutamyl transferase and raised alkaline phosphatase. Exclude obstruction by ultrasound and magnetic resonance cholangiopancreatography, and exclude viral, autoimmune and drug causes. Genetic testing for ATP8B1, ABCB11 and ABCB4 confirms the diagnosis. Liver biopsy shows canalicular cholestasis and no fibrosis.

Differential diagnosis.

• Progressive familial intrahepatic cholestasis.
• Intrahepatic cholestasis of pregnancy.
• Drug induced cholestasis.
• Primary biliary cholangitis and primary sclerosing cholangitis.
• Low phospholipid associated cholelithiasis.

Stop oestrogen containing drugs and other triggers. Treat itching and the cholestasis, and replace fat soluble vitamins. Nasobiliary drainage or plasmapheresis is used for refractory attacks.

• Ursodeoxycholic acid: 13 to 15 mg/kg orally once daily or in two divided doses long term; maximum 20 mg/kg daily; monitor liver tests; no renal adjustment, and reduce if diarrhoea occurs.
• Rifampicin: 150 mg orally once daily, increased to 300 mg twice daily if needed for itching; maximum 600 mg daily (10 mg/kg in children); monitor liver tests every 2 weeks at first and drug interactions; avoid in decompensated liver disease.
• Colestyramine: 4 g orally once daily, increased to 4 g up to four times daily; maximum 16 g daily; monitor bowel function and fat soluble vitamins; take 4 hours before or 1 to 2 hours after other drugs.
• Naltrexone: 12.5 mg orally once daily, increased to 50 mg; maximum 50 mg daily; monitor for opioid withdrawal and liver tests; avoid with opioid use.
• Phytomenadione (vitamin K): 10 mg orally once daily during attacks with steatorrhoea; maximum 10 mg daily; monitor INR.

Monitoring. Liver tests, INR and vitamin levels each 6 to 12 months; ultrasound each year.

Referral and escalation. Hepatology; transplant assessment for chronic disabling itch or progressive disease.

Special groups. In pregnancy use ursodeoxycholic acid and colestyramine, and avoid rifampicin.