Haemostatic spray in the management of acute nonvariceal upper gastrointestinal bleeding in children: A single-centre experience in Singapore.

Introduction/Objectives: Haemostatic spray (HS; Hemospray) is a powder agent for endoscopic haemostasis in patients with acute upper gastrointestinal bleeding (UGIB). It has been shown to be effective and easy to administer. However, published data on efficacy and safety in children remain scarce. Our aim was to describe our experience with the use of HS in the management of UGIB. Patients and Methods: A retrospective review was conducted of patients aged 0-18 receiving HS for endoscopic haemostasis from January 2017 to December 2021. Information was obtained on demographics, clinical presentation and comorbidities. Outcomes were successful initial haemostasis and rates of re-bleeding. Results: A total of 25 applications of HS occurred in 23 patients. The median patient age was 8 years (range: 4 months to 16 years). HS was used in 17/25 (68%) applications as monotherapy. Other treatments employed were clip application and adrenaline injection. One hundred per cent initial haemostasis was achieved with three (13.0%) patients who experienced re-bleeding. All patients tolerated HS applications with no adverse events. Conclusions: Our finding supports the use of HS in the management of UGIB in children. HS, either as monotherapy or in combination with other conventional therapy, could potentially be the treatment of choice in children with UGIB with its excellent feasibility and good safety profile.

Clinical profile, referral trends, and real-world application of vibration-controlled transient elastography in children with non-alcoholic fatty liver disease in Singapore.

Background and Aim: Pediatric non-alcoholic fatty liver disease (NAFLD) is a progressive disorder that is increasing in incidence globally. The study aims to describe the clinical profile and longitudinal outcome, including the utility of vibration-controlled transient elastography (VCTE), in children with NAFLD at a single tertiary liver unit in Singapore. Methods: Retrospective review of patients aged 0-18 years referred for NAFLD from 2003 to 2020 was conducted. Diagnosis was based on persistent elevation of alanine transaminase ≥2× the upper limit of normal in at-risk patients, and/or radiologic detection of hepatic steatosis, with the exclusion of other etiologies. VCTE-derived liver stiffness measurements (LSMs) ≤7.0 , 7.1-9.0, and ≥9.1 kPa were used to differentiate normal (F0-F1), significant fibrosis (F2), and advanced fibrosis (F3-F4), respectively. Results: The study included 210 patients (72.4% male, mean age 11.6 years). New cases increased from 1.7/1000 referrals in 2003-2008 to 12.7 and 24.5/1000 referrals in 2009-2014 and 2015-2020, respectively. Significant proportion had dyslipidemia (41.4%), impaired glucose tolerance/diabetes (IGT/DM, 26.7%), and hypertension (17.1%). Only 6.2% had resolution of NAFLD after a mean follow-up of 3.7 years. Based on VCTE (n = 65), 41.5% had normal LSM, while 26.2% and 32.3% had increased likelihood of significant and advanced fibrosis, respectively. Age ≥16 years (odds ratio [OR] 8.9), IGT/DM (OR 6.5), and aspartate transaminase >70 U/L (OR 11.0) were independent risk factors associated with increased likelihood of advanced fibrosis. Conclusion: Incidence of pediatric NAFLD has increased dramatically in Singapore. Based on LSM estimation, pediatric NAFLD may be associated with an increased risk of developing advanced fibrosis by late adolescence.

To B(enign) or Not to B: functionalisation of variant in a mild form of argininosuccinate lyase deficiency identified through newborn screening.

Argininosuccinate lyase (ASL) deficiency is an autosomal recessive disorder of the urea cycle with a diverse spectrum of clinical presentation that is detectable in newborn screening. We report an 8-year-old girl with ASL deficiency who was detected through newborn screening and was confirmed using biochemical and functional assay. She is compound heterozygous for a likely pathogenic variant NM_000048.4(ASL):c.283C>T (p.Arg95Cys) and a likely benign variant NM_000048.4(ASL): c.1319T>C (p.Leu440Pro). Functional characterisation of the likely benign genetic variant in ASL was performed. Genomic sequencing was performed on the index patient presenting with non-specific symptoms of poor feeding and lethargy and shown to have increased serum and urine argininosuccinic acid. Functional assay using HEK293T cell model was performed. ASL enzymatic activity was reduced for Leu440Pro. This study highlights the role of functional testing of a variant that may appear benign in a patient with a phenotype consistent with ASL deficiency, and reclassifies NM_000048.4(ASL): c.1319T>C (p.Leu440Pro) variant as likely pathogenic.

Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC. METHODS: MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 µg/kg, then escalated to 570 µg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22. FINDINGS: Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 µmol/L (95% CI -257 to -94) for maralixibat versus 11 µmol/L (-58 to 80) for placebo, also representing a significant difference of -187 µmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred. INTERPRETATION: Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC. FUNDING: Mirum Pharmaceuticals.