Progressive familial intrahepatic cholestasis (PFIC) is a class of chronic cholestasis disorders that begin in infancy and usually progress to cirrhosis within the first decade of life. The average age at onset is 3 months, although some patients do not develop jaundice until later, even as late as adolescence. PFIC can progress rapidly and cause cirrhosis during infancy or may progress relatively slowly with minimal scarring well into adolescence. Few patients have survived into the third decade of life without treatment.
Initially described in Amish descendants of Jacob Byler, PFIC was originally named Byler disease. The condition was inherited in an autosomal recessive manner and was characterized by hepatocellular cholestasis. Subsequently, numerous phenotypically similar non-Amish patients were reported, and the term Byler syndrome was used to describe these patients’ condition. These terms now have been superseded by the term progressive familial intrahepatic cholestasis.
At present, specific gene defects have been identified for 3 subtypes of PFIC (see Table 1 below). PFIC1 (the former Byler disease) and PFIC2 are characterized by low gamma-glutamyl peptidase (GGT) levels. Despite their genetic distinctiveness, PFIC1 and PFIC2 have few clinical differences, and both are caused by the absence of a gene product required for canalicular export and bile formation.
In PFIC3, patients have a similar clinical presentation, but laboratory results reveal an elevated serum GGT. Rather than defective bile acid export, patients with PFIC3 have deficient hepatocellular phospholipid export. The lack of phospholipids produces unstable micelles that have a toxic effect on the bile ducts, leading to bile duct plugs and biliary obstruction.