Comparative pharmacokinetics of tacrolimus in stable pediatric allograft recipients converted from immediate-release tacrolimus to prolonged-release tacrolimus formulation.

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Anthropometric assessment: ESPGHAN quality of care survey from paediatric hospitals in 28 European countries

Objectives Assessment of anthropometric data is essential for paediatric healthcare. We surveyed the implementation of European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) evidence-based guidelines and practical recommendations on nutritional care, particularly regarding anthropometric measurements. Methods Paediatric hospitals from 28 European countries provided pseudonymized data through online questionnaires on hospital characteristics and their standards of nutritional care. Practical tasks assessed an unbiased collection and reporting of anthropometric measurements in random patients' files and discharge letters. Results Of 114 hospitals (67% academic), 9% have no nutritionist/dietitian available, 18% do not provide standard policy to assess weight and height and 15% lack training for nursing staff for accurate performance. A wall-mounted stadiometer to measure standing height and equipment for sitting weight is unavailable in 9% and 32%, respectively. Infant length is measured by one instead of two healthcare professionals and with a tape instead of a rigid length measuring board in 58% and 15% of hospitals, respectively. The practical tasks reviewed 1414 random patients, thereof 446 younger than 2 years of age. Missing documentation occurred significantly more often for height versus weight and their percentiles in infants ≤2 years versus older children, and in general paediatric versus gastrointestinal patients, with no difference between academic and nonacademic hospitals. Review of documented anthropometric data in discharge letters disclosed that consultants significantly underestimated the deficits in their units compared to documented data. Conclusions The survey revealed significant gaps in performance and documentation of anthropometry in the participating hospitals. A resurvey will assess changes in quality of care over time

Outcomes of Surgical Management of Familial Intrahepatic Cholestasis 1 and Bile Salt Export Protein Deficiencies

Progressive familial intrahepatic cholestasis (PFIC) with normal circulating gamma-glutamyl transpeptidase levels can result from mutations in the ATP8B1 gene (encoding familial intrahepatic cholestasis 1 [FIC1] deficiency) or the ABCB11 gene (bile salt export protein [BSEP] deficiency). We investigated the outcomes of partial external biliary diversion, ileal exclusion, and liver transplantation in these two conditions. We conducted a retrospective multicenter study of 42 patients with FIC1 deficiency (FIC1 patients) and 60 patients with BSEP deficiency (BSEP patients) who had undergone one or more surgical procedures (57 diversions, 6 exclusions, and 57 transplants). For surgeries performed prior to transplantation, BSEP patients were divided into two groups, BSEP-common (bearing common missense mutations D482G or E297G, with likely residual function) and BSEP-other. We evaluated clinical and biochemical outcomes in these patients. Overall, diversion improved biochemical parameters, pruritus, and growth, with substantial variation in individual response. BSEP-common or FIC1 patients survived longer after diversion without developing cirrhosis, being listed for or undergoing liver transplantation, or dying, compared to BSEP-other patients. Transplantation resolved cholestasis in all groups. However, FIC1 patients commonly developed hepatic steatosis, diarrhea, and/or pancreatic disease after transplant accompanied by biochemical abnormalities and often had continued poor growth. In BSEP patients with impaired growth, this generally improved after transplantation. Conclusion: Diversion can improve clinical and biochemical status in FIC1 and BSEP deficiencies, but outcomes differ depending on genetic etiology. For many patients, particularly BSEP-other, diversion is not a permanent solution and transplantation is required. Although transplantation resolves cholestasis in patients with FIC1 and BSEP deficiencies, the overall outcome remains unsatisfactory in many FIC1 patients; this is mainly due to extrahepatic manifestations.Peer reviewe

Immune Status in Children Before Liver Transplantation—A Cross-Sectional Analysis Within the ChilsSFree Multicentre Cohort Study

Background: Both, markers of cellular immunity and serum cytokines have been proposed as potential biomarkers for graft rejection after liver transplantation. However, no good prognostic model is available for the prediction of acute cellular rejection. The impact of underlying disease and demographic factors on immune status before pediatric liver transplantation (pLTx) is still poorly understood. We investigated expression of immune markers before pLTx, in order to better understand the pre-transplant immune status. Improved knowledge of the impact of pre-transplant variables may enhance our understanding of immunological changes post pLTx in the future.Methods: This is a cross-sectional analysis of data from the ChilSFree study, a European multicentre cohort study investigating the longitudinal patterns of immune response before and after pLTx. Immune cell counts and soluble immune markers were measured in 155 children 1–30 days before pLTx by TruCount analysis and BioPlex assays. Results were logarithmised due to skewed distributions and then compared according to age, sex, and diagnosis using t-tests, ANOVAs, and Tukey post-hoc tests. The association between immune markers at time of pLTx and patients' age was assessed using a fractional polynomial approach. Multivariable regression models were used to assess the relative contribution of each factor.Results: Sex had no effect on immune status. We found strong evidence for age-specific differences in the immune status. The majority of immune markers decreased in a log-linear way with increasing age. T and B cells showed a sharp increase within the first months of life followed by a log-linear decline in older age groups. Several immune markers were strongly associated with underlying diagnoses. The effects of age and underlying disease remained virtually unchanged when adjusting for each other in multivariable models.Discussion: We show for the first time that age and diagnosis are major independent determinants of cellular and soluble immune marker levels in children with end-stage liver disease. These results need to be considered for future research on predictive immune monitoring after pLTx

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Background &amp; Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p &lt;0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p &lt;0.001). Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.</p

Natural History of Liver Disease in a Large International Cohort of Children with Alagille syndrome:Results from The GALA Study

BACKGROUND: 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.METHODS: Multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born Jan-1997 - Aug-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.RESULTS: 1433 children (57% male) from 67 centers in 29 countries were included. 10 and 18-years NLS rates were 54.4% and 40.3%. By 10 and 18-years, 51.5% and 66.0% of ALGS children experienced ≥1 adverse liver-related event (CEPH, transplant or death). Children (&gt;6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and &lt;10.0 mg/dL had a 4.1-fold (95% 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 &lt;5.0 mg/dL. Median TB levels between ≥5.0 and &lt;10.0 mg/dL and &gt;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 &lt;5.0 mg/dL. Median TB &lt;5.0 mg/dL were associated with higher NLS rates relative to ≥5.0 mg/dL, with 79% reaching adulthood with native liver (p&lt;0.001).CONCLUSIONS: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB &lt;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 novel therapies.</p

Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial

Background: In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver transplantation. We aimed to evaluate the efficacy and safety of the ileal bile acid transporter inhibitor odevixibat versus placebo in patients with Alagille syndrome. Methods: The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries (Belgium, France, Germany, Italy, Malaysia, the Netherlands, Poland, Türkiye, the UK, and the USA). Eligible patients had a genetically confirmed diagnosis of Alagille syndrome, a history of significant pruritus, and elevated serum bile acids. Patients were randomly assigned (2:1) to receive oral odevixibat 120 μg/kg per day or placebo for 24 weeks (in a block size of six and stratified by age: <10 years and ≥10 years to <18 years) via a web-based system. Patients, clinicians, study staff, and people analysing the data were masked to treatment allocation. The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0–4) from baseline to weeks 21–24. The prespecified key secondary efficacy endpoint was change in serum bile acid concentration from baseline to the average of weeks 20 and 24. Outcomes were analysed in patients who received at least one dose of study drug (the full analysis set for efficacy outcomes and the safety analysis set for safety outcomes). This trial is registered on ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28), and is completed. Findings: Between Feb 26, 2021, and Sept 9, 2022, 52 patients were randomly assigned to receive odevixibat (n=35) or placebo (n=17), all of whom were included in the analysis sets. The median age was 5·5 years (IQR 3·2 to 8·9). 27 (52%) of 52 patients were male and 25 (48%) were female. The mean scratching score was elevated at baseline in both groups (2·8 [SD 0·5] for odevixibat vs 3·0 [0·6] for placebo). Mean scratching scores at weeks 21–24 were 1·1 (0·9) for odevixibat and 2·2 (1·0) for placebo, representing a least-squares (LS) mean change of –1·7 (95% CI –2·0 to –1·3) for odevixibat and –0·8 (–1·3 to –0·3) for placebo, which was significantly greater for odevixibat than for placebo (difference in LS mean change from baseline –0·9 [95% CI –1·4 to –0·3]; p=0·0024). Odevixibat also resulted in significantly greater reductions in mean serum bile acids from baseline versus placebo (237 μmol/L [SD 115] with odevixibat vs 246 μmol/L [121] with placebo) to the average of weeks 20 and 24 (149 μmol/L [102] vs 271 μmol/L [167]; LS mean change –90 μmol/L [95% CI –133 to –48] with odevixibat vs 22 μmol/L [–35 to 80] with placebo; difference in LS mean change –113 μmol/L [95% CI –179 to –47]; p=0·0012). The most common treatment-emergent adverse events were diarrhoea (ten [29%] of 35 patients in the odevixibat group vs one [6%] of 17 in the placebo group) and pyrexia (eight [23%] vs four [24%]). Seven patients had serious treatment-emergent adverse events during the treatment period: five (14%) in the odevixibat group and two (12%) in the placebo group. No patients discontinued treatment and there were no deaths. Interpretation: Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome. Longer-term safety and efficacy data of odevixibat in this population are awaited from the ongoing, open-label ASSERT-EXT study. Funding: Albireo Pharma, an Ipsen company

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. Homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC), in contrast to patients with two predicted protein truncating mutations (PPTM). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n=31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n=30), and with two PPTMs (BSEP3/3; n=77). We compared presentation, native liver survival (NLS), and effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (P<0.001). Without siEHC in their follow-up, NLS of BSEP1/3 was similar to BSEP3/3 patients, but considerably lower than BSEP1/1 patients (at age 10 years: 38%, 30%, and 71%, resp; P=0.003). After siEHC, BSEP1/3 and BSEP3/3 patients had similarly low NLS, while this was much higher in BSEP1/1 patients (10 years after siEHC, 27%, 14%, and 92%, resp.; P<0.001). Conclusions: BSEP deficiency patients with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as patients with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment

Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis

Background & Aims: PEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis. Methods: PEDFIC 2 enrolled and dosed 69 patients across two cohorts; all received odevixibat 120 μg/kg per day. Cohort 1 comprised children from PEDFIC 1, and cohort 2 comprised new patients (any age). We report data through 15 July 2020, with Week 24 of PEDFIC 2 the main time point analysed. This represents up to 48 weeks of cumulative exposure for patients treated with odevixibat from the 24-week PEDFIC 1 study (cohort 1A) and up to 24 weeks of treatment for those who initiated odevixibat in PEDFIC 2 (patients who received placebo in PEDFIC 1 [cohort 1B] or cohort 2 patients). Primary endpoints for this prespecified interim analysis were change from baseline to Weeks 22–24 in serum bile acids (sBAs) and proportion of positive pruritus assessments (≥1-point drop from PEDFIC 2 baseline in pruritus on a 0–4 scale or score ≤1) over the 24-week period. Safety monitoring included evaluating treatment-emergent adverse events (TEAEs). Results: In cohort 1A, mean change from PEDFIC 1 baseline to Weeks 22–24 of PEDFIC 2 in sBAs was -201 μmol/L (p <0.0001). For cohort 1B and cohort 2, mean changes from odevixibat initiation to weeks 22–24 in sBAs were -144 and -104 μmol/L, respectively. The proportion of positive pruritus assessments in the first 24-week period of PEDFIC 2 was 33%, 56%, and 62% in cohorts 1A, 1B, and 2, respectively. Most TEAEs were mild or moderate. No drug-related serious TEAEs occurred. Conclusions: Odevixibat in patients with progressive familial intrahepatic cholestasis was generally well tolerated and associated with sustained reductions in sBAs and pruritus. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT03659916). Impact and Implications: Disrupted bile flow is a hallmark feature of patients with progressive familial intrahepatic cholestasis and can result in build-up of bile constituents in the liver with spill over into the bloodstream; other effects that patients can experience include extremely itchy skin, and because not enough bile reaches the gut, patients can have problems digesting food, which may lead to poor growth. Odevixibat is an orally administered medication that shunts bile acids away from the liver. The current study, called PEDFIC 2, suggested that odevixibat can improve the problematic signs and symptoms of progressive familial intrahepatic cholestasis and was generally safe for patients