Debra Smith

Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy

OBJECTIVE To determine the outcome, in index patients followed at an American Center, of syndromic paucity of interlobular bile ducts (sPILBD; Alagille syndrome), with onset of cholestasis in infancy. DESIGN Cohort. SETTING Regional referral center for infants and children with liver disease. RESULTS During the past 10 years, 26 unrelated children with sPILBD were identified. Fifteen (58%) are alive without liver transplantation at a median age of 12.1 years. Three (11%) died, all before 2 years of age. Eight patients (31%) underwent liver transplantation at a median age of 6.5 years; all eight are alive a median 5.4 years after transplantation. The most common factors contributing to the decision for transplantation were bone fractures, pruritus, and severe xanthoma. The predicted probability of reaching 19 years of age without transplantation is about 50%; however, with transplantation, the predicted probability of long-term survival is 87%. Of 26 patients 4 (15%) have had significant central nervous system disease, and two of them have died of intracranial hemorrhage. Of the four patients who underwent cholecystoportostomy or portoenterostomy, three required liver transplantation. CONCLUSIONS Children with sPILBD identified in infancy because of cholestasis have a 50% probability of long-term survival without liver transplantation, a worse prognosis than other follow-up studies have reported. In selected patients, liver transplantation provides the opportunity for long-term survival with improved quality of life. Patients with sPILBD are at risk of having intracranial hemorrhage.

Improvement of cyclosporin absorption in children after liver transplantation by means of water-soluble vitamin E

Many childhood recipients of liver transplantation require massive doses of cyclosporin to achieve therapeutic blood concentrations of the drug. The impaired absorption of this strongly lipophilic drug may be due to reduced intestinal absorptive area, suboptimal mixing of the drug with hepatobiliary secretions, or residual cholestasis. Improvement of cyclosporin absorption was sought by means of oral coadministration of d-alpha-tocopheryl-polyethylene-glycol-1000 succinate (TPGS), a water-soluble form of vitamin E which can form micelles. 25 mg/kg daily of TPGS was given to six paediatric liver transplant recipients and one young adult with severe hepatobiliary graft-vs-host disease after bone-marrow transplantation, who required 29-136 mg/kg cyclosporin daily to achieve therapeutic cyclosporin blood concentrations. Five responded; the oral cyclosporin dose could be reduced by 40-72% within 2 months. In addition, intravenous cyclosporin was stopped in two of the responders. In the two non-responders the cyclosporin doses at entry were similar to those in the responders after TPGS treatment. Oral cyclosporin absorption tests correctly predicted the outcome of treatment in three responders and one non-responder tested. Treatment with TPGS to enhance cyclosporin absorption might be a useful way of reducing the high cost of immunosuppression in paediatric liver transplant recipients.

Use of rifampin for severe pruritus in children with chronic cholestasis.

BACKGROUND Rifampin has been proposed to reduce pruritus in children and adults with chronic cholestasis; however, there is a paucity of published data regarding the use of rifampin in children. METHODS In an open trial, 24 children were evaluated during a 6-year period. Diagnoses included 13 patients with extrahepatic biliary atresia (54%), six with Alagilles syndrome, three with Bylers disease, and one each with primary sclerosing cholangitis and alpha1-antitrypsin deficiency. All patients had severe pruritus that had not responded adequately to at least 2 months of therapy with ursodeoxycholic acid, diphenhydramine, or phenobarbital and local skin care measures. Treatment was initiated with rifampin, 10 mg/kg per day in two divided doses for 18+/-20 months, and the effect on the severity of pruritus was assessed by a clinical scoring system. RESULTS Ten patients showed a complete response, 12 a partial response, and 2 no response. Complete response was more common in extrahepatic cholestasis (64% vs. 10%), whereas partial response was more common in intrahepatic cholestasis (80% vs. 29%). Treatment was associated with reduction of gamma-glutamyl transpeptidase. No clinical or biochemical toxicity of rifampin was observed. CONCLUSIONS We conclude that for more than 90% of children with chronic cholestasis and severe pruritus unresponsive to other treatments, rifampin appears to be a safe and effective therapy.

Niemann-Pick disease type C in neonatal cholestasis at a North American center

Objective To determine the frequency of Niemann-Pick disease type C (NPC) among children being evaluated for neonatal cholestasis during a 2-year period. Methods Medical records were reviewed from all infants with cholestasis and all patients with NPC evaluated at our center from January 1997 through December 1998. Results Forty neonates with cholestasis were evaluated, including three patients diagnosed with NPC (age at diagnosis, 5–21 months) who were originally labeled as having idiopathic neonatal cholestasis (INH). Two adolescents (ages 14 and 16 years) were also diagnosed with NPC during this period, one who originally had neonatal hepatitis and cirrhosis, and the other who had hepatosplenomegaly throughout childhood. Three of the patients with NPC were Hispanic. At time of NPC diagnosis, infants had mildly delayed motor development and persistent splenomegaly with or without hepatomegaly, and the adolescents had ataxia, dysarthria, hepatosplenomegaly, and paresis of vertical gaze. The diagnosis of NPC was established by demonstrating defective cellular cholesterol esterification in cultured skin fibroblasts in three patients and a specific genetic mutation in three patients. Niemann-Pick disease type C was found in 27% of infants initially diagnosed with INH and 8% of all infants evaluated for cholestasis. Conclusion Niemann-Pick disease type C should be considered in all infants with cholestasis, particularly those with splenomegaly or who are of Hispanic descent. Electron microscopy and lipid analysis of liver biopsy specimens obtained during the evaluation of neonatal cholestasis may suggest this diagnosis.

Effect of ursodeoxycholic acid therapy on hepatic function in children with intrahepatic cholestatic liver disease

BACKGROUND Ursodeoxycholic acid (UDCA) has been shown to improve pruritus, alanine aminotransferase (ALT), and cholesterol levels in children with intrahepatic cholestatic liver disease. However, the effect of UDCA on quantitative tests of hepatic function in children is uncertain. METHODS A 2.5-year, open label, crossover study, was designed to determine the effect of UDCA (15-20 mg/kg per day for 12 months, off for 6 months, and on again for 12 months) on clinical symptoms, biochemical test results, galactose and caffeine elimination half-lives (t1/2), and quantitative hepatic scintigraphy in 13 subjects aged 13.1 +/- 2.1 years (10 of whom completed the entire study), with intrahepatic cholestasis. RESULTS Pruritus improved with UDCA in the 6 patients with pruritus on entry into the study. At 12 months, there was a significant decline in ALT, gamma-glutamyl transpeptidase, and plasma levels of copper and manganese, with no further decline in these levels at 24 months. There were no changes in bilirubin or cholylglycine levels. After therapy was discontinued at 12 months, UDCA was restarted within 1 month in 9 of 12 patients in response to a doubling of ALT (n = 6) or worsening pruritus (n = 3). Galactose t1/2 increased after 12 months, with no further increases after 24 months of UDCA therapy, whereas caffeine t1/2 did not change. There were no significant changes in hepatic scintigraphy throughout the study. CONCLUSIONS These data suggest that although UDCA therapy improves pruritus and results in a reduction in ALT and gamma-glutamyl transpeptidase, UDCA therapy did not improve quantitative measures of hepatic function in children with intrahepatic cholestasis.

Clearance of chronic hepatitis B virus infection in young children after alpha interferon treatment

Nine children aged 18 months to 17 years (mean 5.7 years) with chronic hepatitis b virus infection and chronic active hepatitis were treated with 5 to 6 million units/m2 of body surface area of interferon -alpha 2b administered subcutaneously three times per week for 4 months (n = 1) or 6 months (n = 8). At 12 months after the start of therapy, six children less than 3 years of age responded to the treatment (three completely and three partially), whereas only one of three children older than 7 years of age responded. We conclude that IFN treatment may be effective in children with chronic HBV infection, especially when administered while they are young.

Tocopheryl polyethylene glycol 1000succinate therapy for vitamin E deficiency during chronic childhood cholestasis: Neurologic outcome

Treatment of the vitamin E deficiency neurologic syndrome in children with chronic cholestasis is hampered by the very poor intestinal absorption of available forms of vitamin E, thus requiring prolonged treatment with intramuscular injections of vitamin E in many patients. D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) is a water-soluble investigational form of vitamin E that is well absorbed during cholestasis. We studied the effect of TPGS therapy on the neurologic function in 12 children with vitamin E deficiency (aged 9 months to 6 years) with prolonged forms of neonatal cholestasis. Each child had failed to respond to up to 100 to 200 IU/kg/d of standard oral preparations of vitamin E. Treatment with 15 to 25 IU/kg/d TPGS for a mean of 19.3 months normalized the biochemical indices of vitamin E status and was well tolerated by all patients. Neurologic function, assessed by serial neurologic examinations, remained normal during therapy in the two children with no neurologic symptoms younger than age 3 years at onset of therapy. Neurologic function, which had deteriorated before this study, improved in six of seven patients with symptoms who were younger than 3 years and in all three with symptoms older than 3 years. TPGS appears to be a safe and effective form of orally administered vitamin E for use in children with chronic cholestasis who are unresponsive to available oral preparations of vitamin E.