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.

Long-term outcomes of liver transplantation for homozygous familial hypercholesterolaemia in Australia and New Zealand.

BACKGROUND AND AIMS: Homozygous familial hypercholesterolaemia (FH) causes severe cardiovascular disease from childhood. Conventional drug therapy is usually ineffective; lipoprotein apheresis (LA) is often required. Liver transplantation (LT) can correct the metabolic defect but is considered a treatment of last resort. Newer drugs including lomitapide and evinacumab might reduce the need for apheresis and LT. We sought to determine the long-term outcomes following LT in Australia and New Zealand. METHODS: We analysed demographic, biochemical and clinical data from all patients in Australia and New Zealand who have received LT for homozygous FH, identified from the Australia and New Zealand Liver and Intestinal Transplant Registry. RESULTS: Nine patients (five female; one deceased; seven aged between 3 and 6 years at the time of LT and two aged 22 and 26 years) were identified. Mean follow-up was 14.1 years (range 4-27). Baseline LDL-cholesterol off all treatment was 23 ± 4.1 mmol/L. Mean LDL-cholesterol on medical therapy (including maximal statin therapy in all patients, ezetimibe in three and LA in five) was 11 ± 5.7 mmol/L (p < 0.001). After LT, mean LDL-cholesterol was 2.6 ± 0.9 mmol/L (p = 0.004) with three patients remaining on statin therapy and none on LA. One patient died from acute myocardial infarction (AMI) three years after LT. Two patients required aortic valve replacement, more than 10 years after LT. The remaining six patients were asymptomatic after eight to 21 years of follow-up. No significant adverse events associated with immunosuppression were reported. CONCLUSIONS: LT for homozygous FH was highly effective in achieving substantial long-term reduction in LDL-cholesterol concentrations in all nine patients. LT remains an option for severe cases of homozygous FH where drug therapy combined with apheresis is ineffective or unfeasible.

Long-term Outcome of Asymptomatic Patients With Graft Fibrosis in Protocol Biopsies After Pediatric Liver Transplantation.

BACKGROUND: The histological prevalence of allograft fibrosis in asymptomatic children after liver transplantation (LT) is well documented. However, long-term graft and patient survival remain unclear. This retrospective multicenter study aims to determine the prevalence of allograft fibrosis and analyze the long-term outcome for patients transplanted in childhood. METHODS: We reviewed clinical data of children who had undergone 10-y protocol liver biopsies. We excluded patients with autoimmune hepatitis, primary sclerosing cholangitis, hepatitis B or C, and retransplantation. In total, 494 patients transplanted in childhood across 12 international transplant centers were included. We evaluated the development of fibrosis by comparing the results with biopsies obtained 5 and 15 y post-LT. Histological findings were correlated with graft and patient survival up to 20 y post-LT. RESULTS: In the 10-y biopsies, periportal or pericentral fibrosis was observed in 253 patients (51%), 87 (18%) had bridging fibrosis, 30 (6%) had cirrhosis, and 124 (25%) had no fibrosis. The prevalence and stage of graft fibrosis significantly progressed from 5 to 10 y. At 10 y, the severity of fibrosis correlated significantly with inflammation. Patients with graft cirrhosis in the 10-y biopsy were more likely to die or require retransplantation subsequently ( P = 0.027). CONCLUSIONS: At 10 y post-LT, most patients transplanted in childhood developed fibrosis, based on the protocol liver biopsies. Although mild-to-moderate graft fibrosis did not largely affect patient or graft survival up to 20 y post-LT, this progressive fibrosis finding has substantial implications for developing cirrhosis and portal hypertension in adult care.

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.

Paediatric liver transplantation in Australia and New Zealand: 1985-2018.

Liver transplantation has become the standard of care for children with end-stage liver disease. In Australia and New Zealand, there are four paediatric liver transplant units, in Sydney, Melbourne, Brisbane and Auckland. Over the past 30 years, there have been significant changes to indications for transplant, as well as medical and surgical advances. In this paper, using retrospective data from the Australia and New Zealand Liver Transplant Registry, we review 977 children (less than 16 years of age) who underwent liver transplant from 1985 to 2018. The most common indication was biliary atresia (54%), although there has been an increase in other indications, including inborn errors of metabolism, fulminant hepatic failure and malignant liver tumours. Over the past 3 decades, areas of change and innovation include: the use of 'split grafts' to enable an adult and a child to receive the same donor liver, live donation, improvements in immunosuppressive regimens and infectious prophylaxis protocols and innovative surgical techniques allowing transplantation in smaller infants. The outcomes for children who undergo liver transplant in ANZ are excellent, with current 10-year patient survival rates of 95%, comparable to other larger centres around the world.

Combined liver and pancreas transplantation in two children with cystic fibrosis-First experience in Australia and New Zealand.

We report the first two pediatric patients with CF who underwent successful combined liver-pancreas transplantation in Australia and New Zealand for CF liver disease and CF-related diabetes mellitus.

Prospective Evaluation of the ESPGHAN Guidelines for Diagnosis of Celiac Disease in New Zealand Children.

OBJECTIVE: The 2012 European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guideline for diagnosis of celiac disease (CD) questioned the requirement for intestinal biopsy to confirm the diagnosis. The guideline recommends that in symptomatic patients with consistent human leukocyte antigen (HLA) subtypes, the diagnostic accuracy of strongly positive serology is sufficient to confirm the diagnosis. We prospectively assessed these guidelines in a "real-life" clinical setting. METHODS: One hundred and four children referred for evaluation of possible CD were prospectively recruited. Following informed consent, blood was drawn for serological testing and HLA analysis at upper gastrointestinal endoscopy. Histological findings according to Marsh criteria were correlated with blood results and the accuracy of the guideline analyzed.The study also examined the role of deamidated gliadin peptide (DGP) in the diagnosis of CD. RESULTS: For symptomatic patients with consistent HLA subtypes, strongly positive serology (as described in the ESPGHAN guidelines) accurately predicted biopsy-proven CD in >95% of cases. DGP was positive in fewer patients than anti-TG2 or EMA. Incorporation of DGP as a second confirmatory serological test in place of EMA was associated with maintained predictive value of guideline, but fewer patients fulfilling criteria for biopsy-free diagnosis. CONCLUSIONS: The ESPGHAN guideline performs well in our population. Adoption of the guideline would reduce the number of patients requiring endoscopy without compromise in diagnostic accuracy. The involvement of pediatric gastroenterological expertise, however, remains key to diagnosis of CD.

Histological findings in protocol biopsies following pediatric liver transplant: Low incidence of abnormalities at 5 years.

Histological abnormalities, including chronic hepatitis, fibrosis, and steatosis, are increasingly reported in liver biopsies of children after LT. These changes may be progressive and represent a form of rejection. Liver biochemistry is often initially normal. Our LT program began in 2002, utilizing tacrolimus and low-dose steroids for the first year post-LT. Patients undergo a protocol biopsy at 1 year post-LT prior to stopping steroids, then at 5 years and every 5 years thereafter. Target tacrolimus levels are 5-8 µg/L and 3-5 µg/L after 3 and 12 months, respectively. Between 2002 and 2009, 51 LT were performed; 50 (98%) and 49 (96%) patients survived for 1 and 5 years, respectively. A total of 43 patients (median age at LT 2.3 years) underwent a protocol biopsy at 1 year (16 male; median time post-LT 12.5 months), and 44 (20 male; median time post-LT 5.1 years) at 5 years. By 5 years, 3 had transferred to adult services; 1 was re-transplanted for graft failure and 1 moved overseas. Biopsies were reviewed by 2 pathologists. Most patients (31/44) were on tacrolimus monotherapy at 5 years. At 1 and 5 years, 29 of 43 (67.5%) and 31 of 44 (71%) biopsies were normal, respectively. Two of 44 had chronic allograft hepatitis at 5 years. Two of 43 and 1 of 44 had isolated fibrosis, 3 of 43 and 3 of 44 steatosis, and 3 of 43 and 4 of 44 acute rejection at 1 and 5 years, respectively. Other findings included predominantly biliary changes (6/43 & 3/44 at 1 and 5 years, respectively). Tacrolimus levels at 5 years were slightly higher than anticipated (median trough level 5.8 µg/L). With an immunosuppressive regimen of tacrolimus and low-dose steroids for 1 year followed by tacrolimus monotherapy thereafter, the majority of PLB were normal and no progressive changes were observed at 5 years. Compared to other LT programs, we have lower rates of chronic allograft hepatitis, steatosis, and fibrosis at 5 years. However, the tacrolimus levels at 5 years were higher than planned and this may have played a role. Further evaluation is also required to determine the potential long-term adverse effects of corticosteroid use on linear growth and bone mineral density.

Diagnostic utility of modified gliadin peptide antibody assays in New Zealand children.

OBJECTIVE: The aim of the present study was to evaluate a panel of different antibody assays, including second-generation antigliadin kits, in a local paediatric population thought to be at risk for coeliac disease (CD). METHODS: Seventy-nine children, who tested positive for immunoglobulin A (IgA) antibodies to tissue transglutaminase (TG), underwent duodenal biopsy. At endoscopy, serum was collected from all of the patients, and 9 different coeliac antibody assays were performed, both as isolated assays and in combination. These included immunoglobulin A (IgA) anti-tissue transglutaminase (TGA), and IgA plus IgG anti-deamidated gliadin peptide (DGPAG). A diagnosis of CD was made if the biopsies showed Marsh grade 3 lesions. RESULTS: Twenty-four of 79 children had CD confirmed histologically. Only 39 of 79 were positive for Inova TGA, and 35 of 79 were positive for Inova DGPAG. Twenty-four of 39 who were TGA positive and 24 of 35 who were DGPAG positive had confirmed CD on biopsy. There was good correlation between TGA and DGPAG-positive predictive values. None of the modified gliadin tests produced false-negative results, and neither did the TGA. CONCLUSIONS: The Inova DGPAG and TGA assays have similar use in predicting CD in a selected paediatric population; however, in children who are positive for TGA when screened for CD, more than half have negative TGA serology when repeat testing is done at the time of biopsy. Those with persistent TGA positivity have only a 61.5% probability of having histologic CD, compared with 68.6% of those children positive for DGPAG.

Massive hepatic hemangioendothelioma and consumptive hypothyroidism.

Hypothyroidism was diagnosed in an infant with massive hepatic hemangioendothelioma. Markedly elevated serum reverse-triiodothyronine levels confirmed consumptive hypothyroidism. Large doses of thyroxine were initially required to normalise TSH. Thyroxine was tapered as the tumor regressed and was discontinued at 16 months old. Thyroid function remains normal without treatment.

Paediatric liver transplantation in New Zealand: the first 5 years.

AIM: To report the first 5 years of paediatric liver transplantation (LTx) undertaken by the New Zealand Liver Transplant Unit. METHODS: The records of all patients aged 0 to 15 years assessed for LTx between 1 January 2002 and 1 November 2006 were examined. Demographics, criteria for listing, waiting time, transplant-hospitalisation details, and outcome to date are reported. RESULTS: Thirty-eight children were assessed for LTx, of whom 33 were listed. One improved and was de-listed, 3 died on the waiting-list, and 1 remains on the list currently. Twenty-eight children have undergone 29 transplants; there were 25 primary and 4 re-transplants (3 had their primary transplant in Australia). The median wait-time was 122 days and median age at transplantation was 2 years 6 months. Fourteen (50%) were European, 10 (36%) Maori, 3 (11%) Pacific (mostly of Samoan, Tongan, Niuean, or Cook Islands origin), and 1 (3%) Asian. The most common diagnosis was extra-hepatic biliary atresia (59%) followed by alpha-1 antitrypsin deficiency and acute liver failure (14% each). There were 6 whole liver grafts and 23 partial liver grafts including 7 live donor and 10 split LTx. Median time in the Paediatric Intensive Care Unit (PICU) was 2 days and median hospital stay after LTx was 25 days. Time spent in Auckland immediately pre- and post-transplant for families from outside the region was a median of 14 weeks. Postoperative morbidity includes biliary leaks or strictures in 10 (36%), vascular thromboses in 7 (24%), and culture positive bacterial infection in 14 (50%). Twelve (43%) experienced one or more episodes of acute rejection, 3 developed chronic rejection, and post-transplant lymphoproliferative disorder (PTLD) occurred in 2 patients. Despite these problems, graft survival is 97% and patient survival is currently 100%. All patients of school age are currently attending school. CONCLUSION: Liver transplantation is now established in New Zealand as the treatment of choice for end-stage liver disease and acute liver failure in the paediatric population. Excellent outcomes that compare well with large overseas centres have been achieved.