FIC1 DISEASE: A CONTINUUM
ENCOMPASSING BRIC, PFIC1 AND GFC
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.