Partial Biliary Diversion May Promote Long-Term Relief of Pruritus and Native Liver Survival in Children with Cholestatic Liver Diseases

Introduction Rare cholestatic liver diseases may cause debilitating pruritus in children. Partial biliary diversion (PBD) may relieve pruritus and postpone liver transplantation which is the only other alternative when conservative treatment fails. The aim was to report long-term outcome after PBD in a population of 26 million people during a 25-year period. Materials and Methods This is an international, multicenter retrospective study reviewing medical journals. Complications were graded according to the Clavien-Dindo classification system. Results Thirty-three patients, 14 males, underwent PBD at a median of 1.5 (0.3-13) years at four Nordic pediatric surgical centers. Progressive familial intrahepatic cholestasis was the most common underlying condition. Initially, all patients got external diversion, either cholecystojejunostomy (25 patients) or button placed in the gallbladder or a jejunal conduit. Early complications occurred in 14 (42%) patients, of which 3 were Clavien-Dindo grade 3. Long-term stoma-related complications were common (55%). Twenty secondary surgeries were performed due to stoma problems such as prolapse, stricture, and bleeding, or conversion to another form of PBD. Thirteen children have undergone liver transplantation, and two are listed for transplantation due to inefficient effect of PBD on pruritus. Serum levels of bile acids in the first week after PBD construction were significantly lower in patients with good relief of pruritus than in those with poor effect (13 [2-192] vs. 148 [5-383] mu mol/L; p =0.02). Conclusion PBD may ensure long-term satisfactory effect on intolerable pruritus and native liver survival in children with cholestatic liver disease. However, stoma-related problems and reoperations are common.Peer reviewe

Practical management in Wolcott-Rallison syndrome with associated hypothyroidism, neutropenia, and recurrent liver failure: A case report

Wolcott-Rallison syndrome is a rare genetic syndrome of neonatal diabetes, liver failure, and growth retardation. We present a case with a EIF2AK3 p.(Arg902Ter) mutation, additionally complicated by hypothyroidism, impaired renal function, and exocrine pancreas insufficiency, focusing on clinical management. For its optimization, thorough care of multiple organ systems is needed.This article is freely available via Open Access. Click on the Publisher URL to access the full-text from the publisher's site

Altered peripheral amino acid profile indicate a systemic impact of active celiac disease and a possible role of amino acids in disease pathogenesis

Background: We have previously performed a Genome Wide Association and linkage study that indicated a new disease triggering mechanism involving amino acid metabolism and nutrient sensing signaling pathways. Objective: The aim of this study was to investigate if plasma amino acid levels differed among children with celiac disease compared with disease controls. Materials and methods: Fasting plasma samples from 141 children with celiac disease and 129 non-celiac disease controls, were analyzed for amino acid levels by liquid chromatography-tandem mass spectrometry (LC/MS). A general linear model using age and experimental effects as covariates was used to compare amino acid levels between children with a diagnosis of celiac disease and controls. Results: Seven out of twenty-three analyzed amino acids were elevated in children with celiac disease compared with controls (tryptophan, taurine, glutamic acid, proline, ornithine, alanine and methionine). The significance of the individual amino acids do not survive multiple correction, however, multivariate analyses of the amino acid profile showed significantly altered amino acid levels in children with celiac disease overall and after correction for age, sex and experimental effects (p = 8.4 7 10 -8 ). Conclusion: These findings support the idea that amino acids could influence systemic inflammation and play a possible role in disease pathogenesis

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

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

The national value-system in Swedish elder care from bosses points of view

Denna studie baseras på sex kvalitativa semistrukturerade intervjuer med chefer inom särskilt boende i äldreomsorgen. Studien har genomförts utifrån syftet att undersöka chefers attityder och värderingar till den nationella värdegrunden inom äldreomsorgen och vad de anser om möjligheterna att genomdriva förändringar i linje med densammaIntervjuerna har analyserats genom en kvalitativ innehållsanalys. I analysen har även systemteori och organisationsteori använts som teoretiska utgångspunkter. Resultatet visade att kunskapen kring värdegrunden ansågs vara god. Inställningen till värdegrunden varierade men ett av de mest frekventa svaren var att det föreligger ett behov av en nationell värdegrund inom äldreomsorgen. Den ansågs även bland annat kunna kvalitetssäkra och utgöra ett påtryckningsmedel för förändring. Vad som även framkom i resultatet var att det ansågs föreligga vissa faktorer som antingen möjliggör eller hindrar implementering av den nationella värdegrunden. Hindren kunde med hjälp av systemteori kopplas till olika nivåer. Resultatet visade även att det ansågs ha genomförts förändringar i linje med värdegrunden. Dock poängterades även att det fanns vissa utvecklingsområden för förändring.Det råder brist på forskning kring den nationella värdegrundens inom äldreomsorgen och dess mottagande och effektivitet. Studien bör således endast ses som ett första nedslag i en lokal kontext

The national value-system in Swedish elder care from bosses points of view

Denna studie baseras på sex kvalitativa semistrukturerade intervjuer med chefer inom särskilt boende i äldreomsorgen. Studien har genomförts utifrån syftet att undersöka chefers attityder och värderingar till den nationella värdegrunden inom äldreomsorgen och vad de anser om möjligheterna att genomdriva förändringar i linje med densammaIntervjuerna har analyserats genom en kvalitativ innehållsanalys. I analysen har även systemteori och organisationsteori använts som teoretiska utgångspunkter. Resultatet visade att kunskapen kring värdegrunden ansågs vara god. Inställningen till värdegrunden varierade men ett av de mest frekventa svaren var att det föreligger ett behov av en nationell värdegrund inom äldreomsorgen. Den ansågs även bland annat kunna kvalitetssäkra och utgöra ett påtryckningsmedel för förändring. Vad som även framkom i resultatet var att det ansågs föreligga vissa faktorer som antingen möjliggör eller hindrar implementering av den nationella värdegrunden. Hindren kunde med hjälp av systemteori kopplas till olika nivåer. Resultatet visade även att det ansågs ha genomförts förändringar i linje med värdegrunden. Dock poängterades även att det fanns vissa utvecklingsområden för förändring.Det råder brist på forskning kring den nationella värdegrundens inom äldreomsorgen och dess mottagande och effektivitet. Studien bör således endast ses som ett första nedslag i en lokal kontext

The national value-system in Swedish elder care from bosses points of view

Denna studie baseras på sex kvalitativa semistrukturerade intervjuer med chefer inom särskilt boende i äldreomsorgen. Studien har genomförts utifrån syftet att undersöka chefers attityder och värderingar till den nationella värdegrunden inom äldreomsorgen och vad de anser om möjligheterna att genomdriva förändringar i linje med densammaIntervjuerna har analyserats genom en kvalitativ innehållsanalys. I analysen har även systemteori och organisationsteori använts som teoretiska utgångspunkter. Resultatet visade att kunskapen kring värdegrunden ansågs vara god. Inställningen till värdegrunden varierade men ett av de mest frekventa svaren var att det föreligger ett behov av en nationell värdegrund inom äldreomsorgen. Den ansågs även bland annat kunna kvalitetssäkra och utgöra ett påtryckningsmedel för förändring. Vad som även framkom i resultatet var att det ansågs föreligga vissa faktorer som antingen möjliggör eller hindrar implementering av den nationella värdegrunden. Hindren kunde med hjälp av systemteori kopplas till olika nivåer. Resultatet visade även att det ansågs ha genomförts förändringar i linje med värdegrunden. Dock poängterades även att det fanns vissa utvecklingsområden för förändring.Det råder brist på forskning kring den nationella värdegrundens inom äldreomsorgen och dess mottagande och effektivitet. Studien bör således endast ses som ett första nedslag i en lokal kontext