title: Downregulation of the endothelial genes Notch1 and ephrinB2 in patients with nodular regenerative hyperplasia.
abstract: OBJECTIVE
  Nodular regenerative hyperplasia (NRH) is a rare liver disease characterized by small regenerative nodules without fibrosis and can cause portal hypertension. Aetiology and pathogenesis of NRH remain unclear. We have recently shown that Notch1 knockout induces NRH with portal hypertension through vascular remodelling in mice. The aim of this study was to analyse histological and clinical data of NRH patients and to explore if the endothelial pathways identified in our NRH mouse model are also regulated in human NRH.
  
  
  METHODS
  Patients were identified retrospectively from the pathology database. Clinical and laboratory patient data were retrieved. mRNA expression was measured in liver biopsies from a subset of NRH patients.
  
  
  RESULTS
  Diagnosis of NRH was confirmed in needle biopsies of 51 patients, including 31 patients with grade 1, 12 patients with grade 2 and 8 patients with grade 3 NRH. Grade 3 nodularity significantly correlated with the presence of portal hypertension: 50% of the patients with grade 3 NRH vs. 6.5% with grade 1 (P = 0.0105). mRNA expression analysis in liver biopsies from 14 NRH patients and in primary human sinusoidal endothelial cells revealed downregulation of identical genes as in the murine NRH model, which are implicated in vascular differentiation: Notch1, delta-like 4 (Dll4) and ephrinB2.
  
  
  CONCLUSIONS
  In this large NRH needle biopsy cohort, we demonstrated that advanced nodularity correlates with presence of portal hypertension. Downregulation of the endothelial signalling pathways Dll4/Notch1 and ephrinB2/EphB4 supports the hypothesis that human NRH is caused by a sinusoidal injury providing first insights into the molecular pathogenesis of this liver condition.
authors.affiliation: Department of Biomedicine, University Hospital Basel, University Basel, Basel, Switzerland.
authors.forename: Sonja
authors.initials: S
authors.lastname: Rothweiler
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.forename: Luigi
authors.initials: L
authors.lastname: Tornillo
authors.forename: Michael T
authors.initials: MT
authors.lastname: Dill
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
authors.forename: David
authors.initials: D
authors.lastname: Semela
mesh_terms: D001706:Biopsy; D015331:Cohort Studies; D015536:Down-Regulation / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism; D036388:Ephrin-B2 / Q000378:metabolism*; D020518:Focal Nodular Hyperplasia / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006975:Hypertension, Portal / Q000209:etiology*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051881:Receptor, Notch1 / Q000378:metabolism*; D012189:Retrospective Studies; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D036388:Ephrin-B2; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1
keywords: Capillarization; endotheliopathy; portal hypertension