RGD Reference Report - Downregulation of the endothelial genes Notch1 and ephrinB2 in patients with nodular regenerative hyperplasia. - Rat Genome Database

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Downregulation of the endothelial genes Notch1 and ephrinB2 in patients with nodular regenerative hyperplasia.

Authors: Rothweiler, Sonja  Terracciano, Luigi  Tornillo, Luigi  Dill, Michael T  Heim, Markus H  Semela, David 
Citation: Rothweiler S, etal., Liver Int. 2014 Apr;34(4):594-603. doi: 10.1111/liv.12261. Epub 2013 Jul 21.
RGD ID: 155646133
Pubmed: PMID:23870033   (View Abstract at PubMed)
DOI: DOI:10.1111/liv.12261   (Journal Full-text)


BACKGROUND & AIMS: 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Focal Nodular Hyperplasia  IEP 155646133; 155646133; 155646133; 155646133; 155646133mRNA:decreased expression:liverRGD 
Focal Nodular Hyperplasia  ISODLL4 (Homo sapiens)155646133; 155646133mRNA:decreased expression:liverRGD 
Focal Nodular Hyperplasia  ISOEFNB2 (Homo sapiens)155646133; 155646133mRNA:decreased expression:liverRGD 
Focal Nodular Hyperplasia  ISOEPHB4 (Homo sapiens)155646133; 155646133mRNA:decreased expression:liverRGD 
Focal Nodular Hyperplasia  ISONOTCH1 (Homo sapiens)155646133; 155646133mRNA:decreased expression:liverRGD 
Focal Nodular Hyperplasia  ISOTEK (Homo sapiens)155646133; 155646133mRNA:decreased expression:liverRGD 

Objects Annotated

Genes (Rattus norvegicus)
Dll4  (delta like canonical Notch ligand 4)
Efnb2  (ephrin B2)
Ephb4  (EPH receptor B4)
Notch1  (notch receptor 1)
Tek  (TEK receptor tyrosine kinase)

Genes (Mus musculus)
Dll4  (delta like canonical Notch ligand 4)
Efnb2  (ephrin B2)
Ephb4  (Eph receptor B4)
Notch1  (notch 1)
Tek  (TEK receptor tyrosine kinase)

Genes (Homo sapiens)
DLL4  (delta like canonical Notch ligand 4)
EFNB2  (ephrin B2)
EPHB4  (EPH receptor B4)
NOTCH1  (notch receptor 1)
TEK  (TEK receptor tyrosine kinase)


Additional Information