The portal for rare diseases and orphan drugs

Estimated prevalence at birth of PFIC types 1-3 varies between 1/50,000 and 1/100,000. PFIC3 represents one third of PFIC cases.

Clinical signs of cholestasis (discolored stools, dark urine) appear within the first year of life in about one third of patients, or later with recurrent episodes of jaundice and mild pruritus. PFIC3 evolves into secondary biliary cirrhosis. Gastrointestinal bleeding due to portal hypertension might be the presenting symptom in adolescents or young adults.

PFIC3 is due to mutations in the ABCB4 gene (7q21), encoding the multi-drug resistant 3 protein (MDR3), resulting in impaired biliary phospholipid (PL) secretion. Detergent effects of hydrophobic bile salts are not countered by biliary PLs and lead to cholangitis. Low biliary PL levels are insufficient to maintain solubility of cholesterol and promote bile lithogenicity.

PFIC3 should be suspected in children, adolescents, or young adults with a clinical history of cholestasis of unknown origin after exclusion of the other main causes of cholestasis. Patients present with high serum gamma-GT activity, normal cholesterol levels and moderately elevated bile acid concentrations. Liver ultrasonography is usually normal but may reveal a huge gallbladder and sometimes biliary stones. Liver histology reveals portal fibrosis and true ductular proliferation with mixed inflammatory infiltrate and, at a later stage, signs of biliary cirrhosis. MDR3 immunostaining is helpful for diagnosis. Cholangiography shows a normal biliary tree making it possible to rule out sclerosing cholangitis. Bile collection allows biliary lipid analysis showing decreased biliary phospholipid levels. Genotyping confirms the diagnosis.

Differential diagnosis includes biliary tract diseases and causes of intrahepatic cholestasis and of cirrhosis with elevated gamma-GT.

Prenatal diagnosis can be proposed if a mutation has been identified in each parent.

Transmission is autosomal recessive.

Ursodeoxycholic acid therapy (UDCA) should be initiated in all patients to prevent liver damage. Beneficial effects of UDCA are usually observed in patients who harbored at least one missense mutation. In half of the patients, UDCA therapy fails and liver transplantation is required due to liver failure. In patients responding to UDCA, PFIC3 may be complicated by cirrhosis, portal hypertension and hepatocellular carcinoma. Furthermore, patients are at high risk of biliary stones, drug-induced cholestasis, and/or intrahepatic cholestasis of pregnancy (see this term) further in the disease course, especially if UDCA therapy is stopped. Specialized follow-up is mandatory and lifelong.