have recently provided support for the heterogeneity of this Progressive familial intrahepatic cholestasis (PFIC) is clinical entity, suggesting different causes: clinical, biochemia lethal inherited childhood cholestasis of hepatocellucal, and liver histological features suggest at least two subcatlar origin. Different subtypes of PFIC have been deegories. [4][5][6][7][8][9] It has been shown that one subtype of PFIC may scribed according to serum gamma-glutamyl transpeptibe attributable to a defect in primary bile acid secretion. 5 The dase (GGT) activity. There is currently no effective gene responsible for this subtype of PFIC is not identified, medical therapy available for children with PFIC. We but recently a locus has been mapped to chromosome 18. 10 report on 39 patients with PFIC who received ursode-In this subtype, cholestasis is associated with normal serum oxycholic acid (UDCA) orally (20-30 mg/kg b.w./day) for gamma-glutamyl transpeptidase (GGT) activity and there is a period of 2 to 4 years. Group 1 (n Γ
26) consisted of no ductular proliferation as assessed by standard liver histolchildren with normal GGT activity, and group 2 (n Γ
13) ogy. 5,6 By contrast, the second subtype is characterized by of children with high GGT activity. Within group 1, liver high serum GGT activity and ductular proliferation. 6-8 It has tests normalized in 11 children, improved in 5, and stabibeen shown that children affected with this subtype may lized or worsened in 10. Within group 2, liver tests norhave a defect of phospholipid secretion in bile due to a defect malized in six children, improved in four, and stabilized of Multidrug Resistance 3 gene expression. 7,11,12 Children or worsened in three. Improvement of parameters was with PFIC most often require liver transplantation but in associated with an enrichment of the circulating pool of some instances may benefit from partial external biliary dibile acids with UDCA. Hepatosplenomegaly and pruritus version, which may reverse clinical symptomatology and imdisappeared or diminished in children in whom liver prove liver function tests. [13][14][15] There is currently no effective tests normalized. In nine of these children, liver tests medical therapy available for children with PFIC. worsened and normalized again after stopping and re-Over the last few years, several studies have reported that starting UDCA. Liver histology assessed in four children the long-term oral administration of ursodeoxycholic acid after normalization of liver tests and 2 years of treat-(UDCA), a hydrophilic bile acid which is not hepatotoxic in ment showed a decrease in fibrosis. We conclude that vitro or in human, improves the clinical and biochemical man-UDCA should be considered in the initial therapeutic ifestations of chronic cholestatic liver diseases in adult pamanagement of children with PFIC, because it appears tients, such as primary biliary cirrhosis and sclerosing choleffective in resolving or improving the liver function and angitis. [16][17][18] In pediatric patients, recent data have provided the clinical status of a fair proportion of children.
evidence that UDCA may induce clinical and biochemical Chronic UDCA therapy might thus avoid the need for improvements in cholestatic diseases such as liver disease liver transplantation in some children with PFIC. (HEPAassociated with cystic fibrosis and inborn errors in bile acid TOLOGY 1997;25:519-523.) synthesis. 6,19,20 In addition, a preliminary study has suggested that UDCA may be efficient in the management of Progressive familial intrahepatic cholestasis (PFIC), also children with chronic intrahepatic cholestasis, including chilknown as Byler disease, is a recessive inherited childhood dren with PFIC. 21 We report the evaluation of the clinical and cholestasis of hepatocellular origin, which is characterized biochemical effects of long-term oral UDCA administration in by pruritus, chronic cholestasis, progression toward cirrhosis, 39 children with PFIC. and death due to hepatocellular insufficiency before adolescence. [1][2][3][4] Its etiology is poorly understood, but several studies
PATIENTS AND METHODS
Thirty-nine children (male Γ
20) with PFIC followed in the pediatric hepatology unit of Bice Λtre hospital and Cliniques St Luc from Abbreviations: PFIC, progressive familial intrahepatic cholestasis; GGT, gamma-gluta-March 1988 to April 1995 were prospectively studied. Criteria for myl transpeptidase; UDCA, ursodeoxycholic acid; LT, liver tests; ASAT, aspartate amino-PFIC included the following: 1) a history of chronic cholestatic liver transaminase; ALAT, alanine aminotransaminase.