Recurrent familial intrahepatic cholestasis in the faeroe islands. phenotypic heterogeneity but genetic homogeneity

Abstract

Recurrent familial intrahepatic cholestasis is an autosomal recessive disorder characterized by episodes of severe pruritus and jaundice lasting for weeks to months without extrahepatic bile duct obstruction. Symptom-free intervals may last for months to years, and chronic liver damage does not develop. We recently studied four of the five patients from the Faeroe Islands described by us 30 years ago (one had recently died) and an additional five patients that were identified after the initial report. The episodes of cholestasis were more frequent and severe in patients with early onset, but tended to reduce in frequency with age. The youngest patient, aged 25 years, who had had 16 episodes each lasting about 6 months, had a liver transplant after which no further episodes were recorded (1 year after surgery). Signs of chronic liver disease were absent in all patients. The FIC1 gene was investigated for mutations in the surviving patients. A single mutation (I661T) was found on both chromosomes in all nine patients, indicating that they are genetically identical for the disease-causing defect. Nevertheless, considerable differences among patients were observed clinically. (HEPATOLOGY 1999;29:506-508.)

Benign Recurrent Intrahepatic Cholestasis with a Single Heterozygote Mutation in the ATP8B1 Gene

“…The mutations G308V, D554N, and I661T are among the most frequently detected [5]. Seventy nine percent (27 of 34 combining this and our previous studies) [10,14,15] of Western European BRIC patients harbor ATP8B1 mutations carrying at least one copy of I661T4). However, a mutation in p.K871QfsX has not previously been reported, and so represents a novel mutation.…”

Altered hepatobiliary gene expressions in PFIC1: ATP8B1 gene defect is associated with CFTR downregulation

“…7,26 ATP8B1-related CFTR downregulation in extrahepatic epithelia could also explain that diarrhea, pancreatitis, and in some cases, elevated sweat chloride concentrations, that are common manifestations in cystic fibrosis, may also occur in PFIC1. 7,8,27,44,45 We conclude from this study that a downregulation of CFTR expression in patients with PFIC1 might be associated with a defect in the ATP8B1 gene. This may impair the contribution of cholangiocytes to bile secretion and also potentially explain some of the extrahepatic manifestations in PFIC1 and related disorders.…”

FIC1 Is Expressed at Apical Membranes of Different Epithelial Cells in the Digestive Tract and Is Induced in the Small Intestine During Postnatal Development of Mice

“…The cholestasis completely resolved in two PFIC1 patients after biliary diversion (21) and in several patients treated by liver transplantation (18), but the children displayed severe diarrhea, failure to achieve catch-up growth, and appearance of steatosis in the new liver (20). Interestingly, many FIC1 disease patients also develop pancreatitis (33)(34)(35)(36)(37). Further evidence for the involvement of extrahepatic tissues in the etiology of FIC1 disease was obtained by analysis of mice with a homozygous missense mutation in Atp8b1; this mutation resulted in an amino acid residue replacement from glycine to valine (G308V), a mutation also found in PFIC1 patients from Amish decent (4).…”