Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study. APPROACH AND RESULTS: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings. CONCLUSIONS: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.

Gallbladder remnant: A potential source for biliary stones postcholecystectomy; a case report in a child with sickle cell disease.

Stone formation in a gallbladder remnant is a rare postcholecystectomy complication. This report describes the case of gallstones in a gallbladder remnant of an adolescent with sickle cell disease (SCD) years after laparoscopic cholecystectomy. A 15-year-old female with SCD presented to our gastroenterology clinic with concerns of recurrent choledocholithiasis despite cholecystectomy 2 years before presentation. About 4 months before presentation to our clinic, she was evaluated at the referring physician's emergency department for recurrent severe abdominal pain of 1 month duration. After admission to the hospital, common bile duct stones were seen on magnetic resonance cholangiopancreatography (MCRP) imaging and subsequently removed via endoscopic retrograde cholangiopancreatography (ERCP). On review of her MRCP and ERCP at our hospital, a remnant of gallbladder containing multiple stones was identified. She subsequently underwent a laparoscopic resection of the gallbladder remnant. Clinicians should consider biliary duct imaging in children with biliary colic following cholecystectomy, especially those with history of chronic hemolysis.

Association between BMI Change, Transaminases, and Other Metabolic Parameters in Children with Nonalcoholic Fatty Liver Disease.

Background: Weight loss and lifestyle interventions are the mainstay of treatment in pediatric NAFLD. There are gaps in the literature on the objective improvement in BMI to meaningfully impact NAFLD in children. Aim: To determine the decrease in BMI associated with a significant decline in ALT and other metabolic parameters. Methods: Retrospective chart review of pediatric patients with the diagnosis of NAFLD. Data were collected at the baseline and 6 and 12 months. A linear regression model was used to assess the percent change in BMI predictive of change in ALT and other metabolic parameters. Results: 281 charts were included. 71% of patients who had up to a 2.5% loss in BMI at 6 months had a decrease in ALT of up to 10 U/L compared to 43% patients who did not have a decrease in BMI up to 2.5% loss at the same time period (P=0.01). The linear regression model showed that 6-month and 12-month percent changes in BMI are predictive of 6-month and 12-month ALT changes (P=0.01 and 0.02), respectively. ALT normalization was achieved on 12% of patients with a ≥2.5% decrease in BMI at 6 months compared to 1% of patients that had no decrease of ≥2.5% decrease in BMI at 6 months (P=0.01). The mean BMI Z-score decline was 0.18 (P=0.001) in the group with a ≥2.5% decrease in BMI at 6 months. Conclusions: BMI loss of up to 2.5% and the mean BMI Z-score 0.18 are associated with a significant decrease in ALT of up to 10 U/L. BMI percent change at 6 months and 12 months is predictive of changes in ALT. These results should help guide providers in clinical practice set objective goals for the management of children with NAFLD resulting from obesity.