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.

Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS. APPROACH AND RESULTS: This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced ≥1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dl had a 4.1-fold (95% confidence interval [CI], 1.6-10.8), and those ≥10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those <5.0 mg/dl. Median TB levels between ≥5.0 and <10.0 mg/dl and >10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with higher NLS rates relative to ≥5.0 mg/dl, with 79% reaching adulthood with native liver ( p < 0.001). CONCLUSIONS: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of therapies.

Australasian paediatric gastroenterologist practices of coeliac disease diagnosis before and during the COVID-19 pandemic.

AIM: To explore the perceptions and practices of Australasian paediatric gastroenterologists in diagnosing coeliac disease (CD) before and during the COVID-19 pandemic. METHODS: Paediatric gastroenterologists in Australasia were invited via email to complete an anonymous online questionnaire over a 2-week period in 2021. RESULTS: The questionnaire was completed by 39 respondents: 33 from Australia and six from New Zealand (NZ) equating to a 66% response rate. Thirty-four (87%) of the 39 respondents reported they currently practised non-biopsy diagnosis of CD in eligible children, while the rest diagnosed CD using biopsy confirmation only. All NZ respondents practised non-biopsy CD diagnosis. A majority of responders (76%) who practised non-biopsy CD diagnosis followed the 2020 European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines. Twenty-two (56%) respondents reported that they started using a non-biopsy CD diagnosis protocol before the pandemic and did not change their practice during the pandemic, 10 (26%) started diagnosing non-biopsy CD during the pandemic, 5 (13%) stated their practices of CD were not impacted by the pandemic and 2 (5%) did not respond on whether the pandemic changed their practice. CONCLUSION: The majority of Australasian gastroenterologist respondents reported they routinely utilised the 2020 ESPGHAN diagnostic criteria in eligible children; half of them started prior to the pandemic and another quarter started this approach due to the pandemic. A minority of practitioners routinely rely only on biopsy confirmation to diagnose CD.

An Atypical Case of Very Early-onset Familial Adenomatous Polyposis Associated With Focal Cortical Dysplasia.

We describe a female toddler with rectal bleeding from extensive colonic polyposis, and diagnosed with familial adenomatous polyposis. She has epilepsy from infancy attributed to focal cortical dysplasia. Hepatoblastoma was diagnosed at 13 months of age. Germline testing detected a pathogenic APC (adenomatous polyposis coli gene) variant. We discuss the anecdotal management of this case, including the clinical utility of genetic confirmation. We review the genotype-phenotype correlation of the APC mutational spectrum, and the existing evidence supporting the hypothesis that cortical dysplasia is part of the APC-related spectrum.

Diagnostic utility of upper and lower gastrointestinal endoscopy for the diagnosis of acute graft-versus-host disease in children following stem cell transplantation: A 12-year experience.

BACKGROUND: Endoscopically obtained mucosal biopsies are the gold standard for diagnosing acute graft-versus-host disease of the gastrointestinal tract (GI-GVHD). There is no consensus on the ideal endoscopic approach in children. We aimed to ascertain which gastrointestinal sites and endoscopic approaches were most helpful for diagnosing acute GVHD and whether clinical symptoms can guide the endoscopic approach. METHOD: A single-center retrospective review of all pediatric stem cell transplants (SCT) between January 1, 2007, and December 31, 2018. Of those with histologically diagnosed GI-GVHD, sensitivities of individual GI sites for making the diagnosis were calculated. Clinical symptoms were compared with GI site yielding diagnosis. RESULTS: 216 allogeneic SCTs were performed in 199 patients. 37 of 52 suspected GI-GHVD cases underwent endoscopy. There was marked variability in the endoscopic approaches chosen. 82% of these cases had lower gastrointestinal symptoms. 21 cases had histologically proven GI-GVHD. 19 (90%) of these had GVHD of non-gastrointestinal sites; 10 (48%) had concurrent infections. The most-sensitive GI sites were the rectosigmoid and duodenum (86% and 76%, respectively). Overall sensitivity of upper GI endoscopy (UGIE) and lower GI endoscopy (LGIE) was 86% and 90%, respectively. There was no statistically significant association between clinical symptoms and site at which histological diagnosis was obtained. CONCLUSION: We observed variability in the endoscopic approach used by clinicians. UGIE and sigmoidoscopy had high sensitivities for diagnosing GVHD, regardless of symptoms. LGIE had minimal additional diagnostic value. This would support a standardized approach with UGIE and sigmoidoscopy for all children with suspected GI-GVHD.

Three-year outcomes of childhood inflammatory bowel disease in New Zealand: A population-based cohort study.

BACKGROUND AND AIM: High rates of inflammatory bowel disease (IBD) have been documented in New Zealand (NZ) children. The objectives of this study were to describe the outcomes and disease course of childhood IBD in the first 3 years following diagnosis. METHODS: All children diagnosed with IBD in 2015 in NZ were included. Clinical data obtained during routine care for 3 years following diagnosis were analyzed. Growth parameters, disease activity scores, and blood parameters were compared at diagnosis and follow up. RESULTS: Three-year outcome data were available for 48 of 51 children. At follow up, median age was 15.1 years, and 34 had Crohn's disease (CD), 11 had ulcerative colitis (UC), and three had IBD-unclassified (IBDU). Although disease progression including development of perianal disease occurred in 13 (38%) of 34 children with CD, the majority (n = 30) had inflammatory disease at follow up. Disease extension occurred in 25% (2/8) of children initially diagnosed with UC. Of all IBD patients, the mean body mass index z-score increased from -0.40 to +0.10 (P = 0.01). Disease activity scores reduced from diagnosis to follow up in both CD (mean pediatric Crohn's disease activity index 35-6, P < 0.001) and UC (mean pediatric ulcerative colitis activity index 44-6, P < 0.001). Overall, 56% of children received steroids, 44% of children with CD received biologic therapy, and four children with CD or UC had intestinal surgery. CONCLUSIONS: Most children with IBD were in remission with improved growth 3 years after diagnosis. Biologic therapies were commonly prescribed. This is the first NZ study assessing disease course in pediatric IBD. Ongoing follow up will continue to inform outcomes.