1Houwen RHJ, 2Bull LN, 1Klomp LWJ

1University Medical Center Utrecht, The Netherlands and 2Liver Center Laboratory, San Francisco General Hospital, UCSF, CA, USA


The molecular background of Byler disease, more properly referred to as Progressive Familial Intrahepatic Cholestasis type 1 (PFIC1), Greenland Familial Cholestasis (GFC) and Benign Recurrent Intrahepatic Cholestasis (BRIC) has been elusive for many years. We recently described that these entities are all caused by mutations in a single gene, FIC1 (now rechristened as ATP8B1).


BRIC is characterized by recurrent attacks of cholestasis without bile duct obstruction. These attacks can start at any moment after the neonatal period, vary in duration from weeks to months and resolve spontaneously. During an attack patients have intense pruritis, due to the high serum bile acids, which is generally accompanied by jaundice. Normal liver enzymes, including serum GGT, are found both in between and during attacks. No progression of the disease is observed, not even at old age and after many attacks.


Both PFIC1 and GFC are characterized by unremitting cholestasis that starts in the first year of life. Patients present with severe pruritis due to high serum bile acid levels and some degree of jaundice. Characteristically the serum gamma-glutamyl transpeptidase is normal or almost normal. The disease is progressive and fatal within the first decade of life, unless a liver transplantation is performed.


Some patients, including members of the original Byler family, are known that initially present with recurrent attacks of cholestasis, but develop unremitting cholestasis in the course of their disease. For several of those patients we now also have identified mutations in the ATP8B1 gene.


This careful reexamination of the case histories of the patients described to date with either BRIC, PFIC1 and GFC do show that, apart from having mutations in the same gene, the clinical, as well as the biochemical aspects of these disease entities are in fact part of a continuum, for which we propose the name FIC1 disease, which can be either mild or progressive.