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

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

Papel da cápsula endoscópica na reclassificação da doença inflamatória intestinal em crianças Role of wireless capsule endoscopy in reclassifying inflammatory bowel disease in children

OBJETIVO: Avaliar o papel da cápsula endoscópica na identificação de lesões no intestino delgado em pacientes pediátricos com DII inespecífica (DIII) diagnosticada recentemente e avaliar se os achados da cápsula endoscópica resultam em alterações no tratamento dos pacientes. MÉTODOS: Dez pacientes pediátricos recém-diagnosticados com DIII por meio de investigações padrão foram recrutados da clínica de gastroenterologia pediátrica no McMaster Children's Hospital, para serem submetidos a exame com a cápsula endoscópica Pillcam SB TM (Given Imaging). Achados compatíveis com o diagnóstico da doença de Crohn exigiram a identificação de pelo menos três ulcerações. RESULTADOS: De 10 pacientes, três apresentaram achados novos com a cápsula endoscópica que satisfizeram o critério para a doença de Crohn. Outros três apresentaram achados com suspeita de doença de Crohn, porém não atenderam nossos critérios de diagnóstico. Apresentaram achados mais compatíveis com colite ulcerativa outros três pacientes, e um apresentava possível gastrite com intestino normal. Os achados da cápsula endoscópica possibilitaram mudanças no tratamento médico de três pacientes. Em todos os dez casos, a cápsula endoscópica permitiu uma melhor caracterização do tipo e da extensão da doença. Não houve resultado adverso em nossa coorte. CONCLUSÃO: Este estudo prospectivo revela que a cápsula endoscópica é viável, útil e não invasiva, que oferece a possibilidade de melhor caracterização de casos de DIII pediátricos recém-diagnosticados ao identificar lesões no intestino delgado e reclassificá-las como doença de Crohn.<br>OBJECTIVE: To evaluate the role of wireless capsule endoscopy in identifying small bowel lesions in pediatric patients with newly diagnosed colonic inflammatory bowel disease (IBD) type unclassified (IBDU), and to assess whether capsule endoscopy findings result in altered patient management. METHODS: Ten pediatric patients recently diagnosed with IBDU through standard investigations were recruited from the pediatric gastroenterology clinic at McMaster Children's Hospital to undergo capsule endoscopy using the Pillcam SB TM (Given Imaging) capsule. Findings consistent with a diagnosis of Crohn's disease required the identification of at least three ulcerations. RESULTS: Three out of ten patients had newly identified findings on capsule endoscopy that met criteria for Crohn's disease. Three more patients had findings suspicious for Crohn's disease, but failed to meet the diagnostic criteria. Three additional patients had findings most consistent with ulcerative colitis, and one had possible gastritis with a normal intestine. Findings from capsule endoscopy allowed for changes in the medical management of three patients. In all ten cases, capsule endoscopy allowed for a better characterization of the type and extent of disease. No adverse outcomes occurred in the present cohort. CONCLUSIONS: This prospective study reveals that wireless capsule endoscopy is feasible, valuable, and non-invasive, offering the ability to potentially better characterize newly diagnosed pediatric IBDU cases by identifying lesions in the small bowel and reclassifying these as Crohn's disease. Further investigation is warranted

Role of wireless capsule endoscopy in reclassifying inflammatory bowel disease in children

Objective: To evaluate the role of wireless capsule endoscopy in identifying small bowel lesions in pediatric patients with newly diagnosed colonic inflammatory bowel disease (IBD) type unclassified (IBDU), and to assess whether capsule endoscopy findings result in altered patient management. Methods: Ten pediatric patients recently diagnosed with IBDU through standard investigations were recruited from the pediatric gastroenterology clinic at McMaster Children's Hospital to undergo capsule endoscopy using the Pillcam SBTM (Given Imaging) capsule. Findings consistent with a diagnosis of Crohn's disease required the identification of at least three ulcerations. Results: Three out of ten patients had newly identified findings on capsule endoscopy that met criteria for Crohn's disease. Three more patients had findings suspicious for Crohn's disease, but failed to meet the diagnostic criteria. Three additional patients had findings most consistent with ulcerative colitis, and one had possible gastritis with a normal intestine. Findings from capsule endoscopy allowed for changes in the medical management of three patients. In all ten cases, capsule endoscopy allowed for a better characterization of the type and extent of disease. No adverse outcomes occurred in the present cohort. Conclusion: This prospective study reveals that wireless capsule endoscopy is feasible, valuable, and non-invasive, offering the ability to potentially better characterize newl

Papel da cápsula endoscópica na reclassificação da doença inflamatória intestinal em crianças

OBJETIVO: Avaliar o papel da cápsula endoscópica na identificação de lesões no intestino delgado em pacientes pediátricos com DII inespecífica (DIII) diagnosticada recentemente e avaliar se os achados da cápsula endoscópica resultam em alterações no tratamento dos pacientes. MÉTODOS: Dez pacientes pediátricos recém-diagnosticados com DIII por meio de investigações padrão foram recrutados da clínica de gastroenterologia pediátrica no McMaster Children's Hospital, para serem submetidos a exame com a cápsula endoscópica Pillcam SB TM (Given Imaging). Achados compatíveis com o diagnóstico da doença de Crohn exigiram a identificação de pelo menos três ulcerações. RESULTADOS: De 10 pacientes, três apresentaram achados novos com a cápsula endoscópica que satisfizeram o critério para a doença de Crohn. Outros três apresentaram achados com suspeita de doença de Crohn, porém não atenderam nossos critérios de diagnóstico. Apresentaram achados mais compatíveis com colite ulcerativa outros três pacientes, e um apresentava possível gastrite com intestino normal. Os achados da cápsula endoscópica possibilitaram mudanças no tratamento médico de três pacientes. Em todos os dez casos, a cápsula endoscópica permitiu uma melhor caracterização do tipo e da extensão da doença. Não houve resultado adverso em nossa coorte. CONCLUSÃO: Este estudo prospectivo revela que a cápsula endoscópica é viável, útil e não invasiva, que oferece a possibilidade de melhor caracterização de casos de DIII pediátricos recém-diagnosticados ao identificar lesões no intestino delgado e reclassificá-las como doença de Crohn

First fully laparoscopic donor hepatectomy for pediatric liver transplantation using the indocyanine green near-infrared fluorescence imaging in the Middle East : a case report

Living donor liver transplantation (LDLT) is a well-established treatment modality for several pediatric end-stage liver diseases owning excellent long-term results. Left lateral sectionectomy (LLS) through an open approach is a well-standardized procedure. This technique has been modified for a fully laparoscopic approach and gaining more and more interest worldwide. We report herein the first fully laparoscopic LLS for pediatric LDLT in the Middle East with the use of indocyanine green dye and near-infrared fluorescence imaging to identify the biliary ducts intraoperatively. The recipient was a 2-year-old. girl affected by glycogen storage disease type IV. The mother, aged 21 years, was her donor. The surgical technique, key-points of this procedure, and outcome are hereby discussed