Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC-1] and Byler syndrome): Evidence for heterogeneity

Abstract

Byler disease (ByD) is an autosomal recessive disorder in which cholestasis of onset in infancy leads to hepatic fibrosis and death. Children who have a clinically similar disorder, but are not members of the Amish kindred in which ByD was described, are said to have Byler syndrome (ByS). Controversy exists as to whether ByD and ByS (subtypes of progressive familial intrahepatic cholestasis [PFIC]) represent one clinicopathological entity. The gene for ByD has been mapped to a 19-cM region of 18q21-q22. PFIC caused by a lesion in this region, including ByD, can be designated PFIC-1. Examination of haplotypes in siblings with ByS in two unrelated non-Amish families showed that the gene(s) responsible for their disorder(s) did not lie in the PFIC-1 candidate region. On light microscopy and transmission electron microscopy (TEM), liver tissue differed between Amish children with PFIC-1, who had coarsely granular bile and at presentation had bland intracanalicular cholestasis, and the children with ByS in the two non-Amish families, who had amorphous or finely filamentous bile and at presentation had neonatal hepatitis. Bile acid composition of bile also differed: In the Amish children with PFIC-1 and in one ByS family, the proportional concentration of chenodeoxycholic acid (CDCA) in bile was low compared with normal bile; in the other ByS family, it was only slightly reduced. Genetic analysis and light microscopy and TEM of liver may help distinguish PFIC-1 from other forms of ByS.

Fine-resolution mapping by haplotype evaluation: the examples of PFIC1 and BRIC

“…Forty-four BRIC and 53 PFIC families were studied; the diagnostic criteria were described previously (Sinke et al 1997;Bull et al 1997). Family B3 was previously described as German (Sinke et al 1997), but new genealogical information indicates that the family is of Italian descent.…”

“…Two distantly related Amish patients shared a homozygous haplotype placing the disease locus in a 16-cM interval (between markers D18S41 and D18S68) within the BRIC region (Carlton et al 1995). Locus heterogeneity for PFIC has subsequently been demonstrated (Strautnieks et al 1996(Strautnieks et al , 1997Bull et al 1997;Arnell et al 1997), and so the 18q21-q22 locus is termed PFIC1.…”

Clinical aspects of familial cholestasis (with molecular explanations)

“…The difference in the severity of the phenotypes may represent different mutations in the BRIC/PFIC gene. Another characteristic of PFIC-1 is the distinct morphologic features seen by transmission electron microscopy of dilatation of the canalicular lumen containing coarsely granular bile [7].…”

Gallensäuren- und Gallelipidtransportdefekte

“…Elektronenmikroskopisch wurden eine granuläre Galle mit Dilatation der Gallekanälchen und Verlust der Mikrovilli gefunden [1,2] (Tabelle 1). Durch molekulargenetische Untersuchungen konnte eine Mutation auf dem Chromosom 18 q21-22 nachgewiesen werden, dem familiäre intrahepatische Cholestase (FIC-1)-Locus [1,2]. Man nimmt an, dass das defekte FIC-1-Gen einen Defekt in einer…”

“…Bei Patienten mit BRIC liegt eine nur partielle Stö-rung dieses Transporters vor. Die Patienten sind deshalb davor geschützt, eine progressive Erkrankung bis hin zur Zirrhose und die Entwicklung eines hepatozellulären Karzinoms zu erleiden, die bei den Patienten mit PFIC-1 beobachtet werden kann [1,6].…”