Progressive Familial Intrahepatic Cholestasis

CAUSE AND SYMPTOMS :

The main clinical manifestations are cholestasis, pruritus (itching), jaundice, failure to thrive and hepatomegaly (enlarged liver). Three types of PFIC have been characterized at the molecular level.

PFIC1 :

is associated with mutations in the ATP8B1 gene, which encodes the FIC1 transporter (aminophospholipid flippase). Affected individuals typically develop liver failure before adulthood.

PFIC2 :

is associated with mutations in the ABCB11 gene, which encodes the bile salt export pump (BSEP) transporter that allows the excretion of bile acids from hepatocytes into the bile. The PFIC2 transporter defect is restricted to the liver and tends to be more severe than in PFIC1. Cellular bile accumulation leads to hepatocyte death, bile release in blood, severe pruritus, evolution to cirrhosis, portal hypertension, liver failure and ultimately death within the first few years of life in nontransplanted patients. PFIC2 patients are also at increased risk of developing hepatocellular carcinoma.

PFIC3 :

is associated with mutations in the ABCB4 gene, which encodes the MDR3 phospholipid transporter, resulting in impaired biliary phospholipid secretion. In PFIC3 patients, detergent effects of hydrophobic bile salts in bile canaliculi are not countered by biliary phospholipids. Similar to PFIC2, the functional defect is restricted to the liver. PFIC3 usually does not become apparent until late infancy or early childhood, more rarely people are diagnosed in late childhood. Evolution to liver failure is more insidious than for PFIC2 and may occur in childhood or adulthood.

INHERITANCE :

All 3 PFIC types are inherited in an autosomal recessive manner, which means that each patient has received one copy of the mutated gene from each parent.