Vanishing Bile Duct Syndrome

Vanishing bile duct syndrome is a group of acquired disorders with progressive destruction and disappearance of the intrahepatic interlobular bile ducts, producing chronic cholestasis. Histologically, over half of portal tracts (in a biopsy with at least 20) lack a bile duct.

It may be self-limited or progress to biliary cirrhosis and liver failure. Causes are drugs (amoxicillin-clavulanate, flucloxacillin, chlorpromazine, carbamazepine, azithromycin, ibuprofen, terbinafine), chronic graft rejection after liver transplant, graft-versus-host disease, Hodgkin lymphoma (paraneoplastic), sarcoidosis, primary biliary cholangitis and sclerosing cholangitis, infection (cytomegalovirus), Langerhans cell histiocytosis, ischaemia and congenital disorders such as Alagille syndrome.

Pathophysiology.

Immune mediated or toxic injury to cholangiocytes and the peribiliary vasculature causes duct loss with failed regeneration.

In rejection and graft-versus-host disease, T cell injury of bile duct epithelium is the main mechanism, and in drug injury the reactive metabolite or immune reaction injures duct cells.

Jaundice, pruritus, dark urine, fatigue, steatorrhoea, xanthomata and weight loss. Features of the underlying cause may be present: rash, fever, lymphadenopathy, graft-versus-host features or sarcoid disease.

Red flags.

• Rapidly rising bilirubin.
• Features of liver failure.
• Lymphadenopathy with B symptoms (lymphoma).
• Recent drug exposure with progressive cholestasis.

Cholestatic pattern: alkaline phosphatase and gamma glutamyl transferase raised, with high bilirubin, and cholesterol raised. Liver biopsy is the key test, showing absent ducts in over 50% of portal tracts, with portal inflammation and cholestasis. Magnetic resonance cholangiopancreatography is normal or shows pruning, which separates it from large duct disease. Test antimitochondrial antibodies, immunoglobulins, angiotensin converting enzyme, viral serology (including cytomegalovirus) and carry out imaging for lymphoma.

Differential diagnosis.

• Primary biliary cholangitis.
• Primary sclerosing cholangitis.
• Chronic rejection.
• Drug induced cholestasis without duct loss.
• Biliary obstruction.
• Infiltrative liver disease.

Remove the cause: stop suspected drugs, treat lymphoma, sarcoidosis or infection, and adjust immunosuppression for rejection or graft-versus-host disease.

• Ursodeoxycholic acid: 13 to 15 mg/kg orally daily in 2 to 3 divided doses; long term while cholestasis persists; maximum 20 mg/kg daily; monitor liver tests every 3 months; avoid in complete biliary obstruction; no renal adjustment.
• Colestyramine: 4 g orally once daily, increased to 4 g two to four times daily; long term; maximum 16 g daily in this use; monitor bowel function; take 4 hours before or 1 to 2 hours after other drugs.
• Rifampicin: 150 mg orally once daily, increased to 300 to 600 mg daily; maximum 600 mg daily; monitor liver enzymes every 2 to 4 weeks; avoid in decompensated cirrhosis; many interactions.

Replace fat soluble vitamins and treat bone disease. Chronic rejection and graft-versus-host disease need intensified immunosuppression through specialist care. Liver transplantation is for progressive liver failure.

Monitoring. Liver tests monthly at first, then every 3 months; repeat biopsy when the course changes.

Referral and escalation. Hepatology and transplant centre; haematology for lymphoma or graft-versus-host disease.