Background & Aims Repair from biliary damages requires the biliary specification of hepatic progenitor cells and the remodeling of ductular reactive structures into branching biliary tubules. We hypothesized that the morphogenetic role of Notch signaling is maintained during the repair process and have addressed this hypothesis using pharmacologic and genetic models of defective Notch signaling. Methods Treatment with DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine) or ANIT (alpha-naphthyl-isothiocyanate) was used to induce biliary damage in wild type mice and in mice with a liver specific defect in the Notch-2 receptor (Notch-2-cKO) or in RPB-Jk. Hepatic progenitor cells, ductular reaction, and mature ductules were quantified using K19 and SOX-9. Results In DDC treated wild type mice, pharmacologic Notch inhibition with dibenzazepine decreased the number of both ductular reaction and hepatic progenitor cells. Notch-2-cKO mice treated with DDC or ANIT accumulated hepatic progenitor cells that failed to progress into mature ducts. In RBP-Jk-cKO mice, mature ducts and hepatic progenitor cells were both significantly reduced with respect to similarly treated wild type mice. The mouse progenitor cell line BMOL cultured on matrigel, formed a tubular network allowing the study of tubule formation in vitro; γ-secretase inhibitor treatment and siRNAs silencing of Notch-1, Notch-2 or Jagged-1 significantly reduced both the length and number of tubular branches. Conclusions These data demonstrate that Notch signaling plays an essential role in biliary repair. Lack of Notch-2 prevents biliary tubule formation, both in vivo and in vitro. Lack of RBP-Jk inhibits the generation of biliary-committed precursors and tubule formation.
Objective Necrotizing pancreatitis is very rare in children. In this case series, we describe the etiologic factors, course, and outcome of acute necrotizing pancreatitis in children. Study Design We performed a retrospective study of children with necrotizing pancreatitis diagnosed over the last 21 years at Yale New Haven Children’s Hospital. Computed tomography (CT) scan criteria were used to diagnose necrotizing pancreatitis and to assess severity index. Charts were reviewed to collect demographic data, etiology, details of hospital stay, complications, and outcome. Results Eight children (mean age 12.8 years; range 4 to 20.7 years) had necrotizing pancreatitis. Etiologic factors were medications, diabetes, gallstones, and alcohol. All patients had a prolonged hospitalization (9 to 40 days; mean 18 days) and five patients required admission to the pediatric intensive care unit. During the hospital stay, patients developed complications involving the respiratory, hematological, renal, metabolic, and circulatory systems. All patients had aggressive supportive medical therapy and none required surgical intervention. There were no deaths attributable to pancreatitis. Late complications following hospital discharge occurred in six patients and included pseudocysts, transient hyperglycemia, diabetes, and pancreatic exocrine insufficiency. The CT severity index correlated with the risk of complications. Conclusions Acute necrotizing pancreatitis has a variable etiology in children. CT scan is useful for the diagnosis and assessment of severity. Necrotizing pancreatitis in children is associated with severe acute and late complications and requires intensive medical therapy.
Objectives Transient elastography (TE) measures liver stiffness to assess fibrosis. Studies in adults have shown that inflammation increases stiffness, leading to an overestimation of fibrosis. We investigated the contribution of inflammation to liver stiffness measurements (LSM) in children/young adults. Methods This was a cohort analysis of children/young adults who underwent TE within 1 year of liver biopsy. ALT was obtained within 30d of the biopsy and LSM. Fibrosis was assessed by METAVIR stage and inflammation by ALT and Ishak score. Data were stratified into METAVIR F0–F2 vs. F3–F4. Change between ALT and LSM over time was also assessed. Results 154 patients (50% male) age 3wk to 24y (18% <3 years) were studied. Diagnoses included autoimmune (N=38, 25%), viral (N=25, 16%), cholestasis (N=17, 11%), fatty liver (N=9, 6%), biliary atresia (N=8, 5%), metabolic (N=5, 3%), allograft rejection (N=4, 3%), and other (N=48, 31%). 34% of patients had F3–F4. In patients with F0–F2, the proportion of those with LSM >8.6kPa increased with increasing ALT (P=0.002). In patients with F3–F4, there was no association between ALT and LSM (P=0.17). A correlation between change in ALT and LSM was observed in patients with no/minimal fibrosis and inflammatory liver diseases (r=0.33). Conclusions In children with no/minimal hepatic fibrosis and inflammatory liver disease, high ALT values are associated with LSM in the range typical of advanced fibrosis. However, with more advanced fibrosis, inflammation does not appear to contribute to LSM. Caution must be taken when interpreting LSM for assessing fibrosis severity in the setting of inflammation.
Background and objectivePersistent hepatic progenitor cells (HPC) activation resulting in ductular reaction (DR) is responsible for pathologic liver repair in cholangiopathies. Also, HPC/DR expansion correlates with fibrosis in several chronic liver diseases, including steatohepatitis. Increasing evidence indicates Notch signaling as a key regulator of HPC/DR response in biliary and more in general liver injuries. Therefore, we aimed to investigate the role of Notch during HPC/DR activation in a mouse model of steatohepatitis.MethodsSteatohepatitis was generated using methionine-choline deficient (MCD) diet. For hepatocyte lineage tracing, R26R-YFP mice were infected with AAV8-TBG-Cre.ResultsMCD diet promoted a strong HPC/DR response that progressively diffused in the lobule, and correlated with increased fibrosis and TGF-β1 expression. Notch signaling was unchanged in laser-capture microdissected HPC/DR, whereas Notch receptors were down regulated in hepatocytes. However, in-vivo lineage tracing experiments identified discrete hepatocytes showing Notch-1 activation and expressing (the Notch-dependent) Sox9. Stimulation of AML-12 hepatocyte-cell line with immobilized Jag1 induced Sox9 and down-regulated albumin and BSEP expression. TGF-β1 treatment in primary hepatic stellate cells (HSC) induced Jag1 expression. In MCD diet-fed mice, αSMA-positive HSC were localized around Sox9 expressing hepatocytes, suggesting that Notch activation in hepatocytes was promoted by TGF-β1 stimulated HSC. In-vivo Notch inhibition reduced HPC response and fibrosis progression.ConclusionOur data suggest that Notch signaling is an important regulator of DR and that in steatohepatitis, hepatocytes exposed to Jag1-positive HSC, contribute to pathologic DR by undergoing Notch-mediated differentiation towards an HPC-like phenotype. Given the roles of Notch in fibrosis and liver cancer, these data suggest mesenchymal expression of Jag1 as an alternative therapeutic target.
Liver abnormalities in severe acute respiratory syndrome-coronavirus 2 infection, including hepatitis and cholestasis, have been observed in adults and are associated with worse outcomes. We describe 2 adolescents with cholestasis and hepatitis with mild presentation of severe acute respiratory syndrome-coronavirus 2 lacking typical symptoms. Our intention is to raise index of suspicion for testing and protective equipment use.
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