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MCID: NDL013
MIFTS: 46

Nodular Regenerative Hyperplasia

Categories: Blood diseases, Immune diseases, Liver diseases, Rare diseases
Genes Tissues Related diseases Publications Pathways Symptoms & Phenotypes Drugs
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Aliases & Classifications for Nodular Regenerative Hyperplasia

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MalaCards integrated aliases for Nodular Regenerative Hyperplasia:

Name: Nodular Regenerative Hyperplasia 20 70
Nodular Regenerative Hyperplasia of the Liver 20 58
Non-Cirrhotic Nodulation 20 58
Non-Cirrhotic Nodular Transformation 20
Miliary Hepatocellular Adenomatosis 20
Non-Cirrhotic Portal Hypertension 20
Nodular Hyperplasia 70

Characteristics:

Orphanet epidemiological data:

58
nodular regenerative hyperplasia of the liver
Inheritance: Not applicable; Age of onset: Adult;

Classifications:

MalaCards categories:
Global: Rare diseases
Anatomical: Liver diseases Immune diseases Blood diseases
See all MalaCards categories (disease lists)
ICD10: 33
Orphanet: 58  
Rare hepatic diseases


External Ids:

ICD10 via Orphanet 33 K76.8
Orphanet 58 ORPHA48372
SNOMED-CT via HPO 68 34742003
UMLS 70 C0020510 C4048264
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Summaries for Nodular Regenerative Hyperplasia

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GARD : 20 Nodular regenerative hyperplasia (NRH) is a rare liver disease in which normal liver tissue transforms into multiple, small clusters (nodules) of replicating liver cells (regenerating hepatocytes). It can develop in people of all ages but is more common in older adults. NRH often does not cause signs or symptoms (so is likely underdiagnosed), but in some people, it leads to a type of portal hypertension called non-cirrhotic portal hypertension (NCPH). NCPH refers to abnormally high blood pressure in the portal vein (the vein that carries blood from the intestine to the liver) that is not caused by cirrhosis (scarring of liver tissue that impairs its function). NCPH typically is less severe than portal hypertension caused by cirrhosis. Symptoms of portal hypertension may include fatigue, edema, itching, jaundice, and abdominal discomfort or swelling due to fluid build-up ( ascites ). Complications that may develop include bleeding esophageal varices and an enlarged and overactive spleen ( hypersplenism ). Liver function in most people with NRH remains normal (even in those who develop NCPH), and liver failure in people with NRH and NCPH is rare. The cause of NRH is not well-understood. It is thought that the liver's blood vessels somehow become damaged or inflamed, impairing blood flow to parts of the liver. This in turn may cause cells in adjacent parts to "overcompensate" and replicate more than they should, leading to NRH. While some people with NRH have no known underlying health problems, NRH is often associated with rheumatic, autoimmune, hematologic (blood-related), and myeloproliferativ e disorders; chronic or recurrent infections; immune deficiency; or exposure to certain medications or toxins. NRH may be diagnosed based on signs and symptoms (when present), liver function tests (which usually are normal), medical history (including drug or toxin exposure), imaging studies, and liver biopsy (to rule out cirrhosis). Treatment for people with NCPH may involve starting medications to prevent or treat bleeding esophageal varices, stopping medications associated with NCPH, and treating underlying health conditions associated with NCPH. The long-term outlook for people with NRH depends on whether an underlying health problem is present and whether NCPH and its complications develop (which cannot be predicted). A small proportion of people eventually need a liver transplant.

MalaCards based summary : Nodular Regenerative Hyperplasia, also known as nodular regenerative hyperplasia of the liver, is related to hepatic veno-occlusive disease and budd-chiari syndrome. An important gene associated with Nodular Regenerative Hyperplasia is NOTCH1 (Notch Receptor 1), and among its related pathways/superpathways are Th17 cell differentiation and Notch Signaling Pathway (WikiPathways). The drugs Caffeine and Antirheumatic Agents have been mentioned in the context of this disorder. Affiliated tissues include liver, spleen and heart, and related phenotypes are portal hypertension and abnormality of the hepatic vasculature

Wikipedia : 73 Nodular regenerative hyperplasia is a form of liver hyperplasia associated with portal... more...

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Related Diseases for Nodular Regenerative Hyperplasia

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Diseases related to Nodular Regenerative Hyperplasia via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 246)
# Related Disease Score Top Affiliating Genes
1 hepatic veno-occlusive disease 30.3 TPMT F3
2 budd-chiari syndrome 30.2 GFER F3
3 adams-oliver syndrome 29.7 NOTCH2 NOTCH1 JAG1
4 alagille syndrome 1 29.6 NOTCH2 NOTCH1 JAG1
5 portal hypertension 11.1
6 varicose veins 10.8
7 splenomegaly 10.7
8 esophageal varix 10.7
9 liver cirrhosis 10.6
10 felty syndrome 10.6
11 primary biliary cholangitis 10.6
12 liver disease 10.6
13 inflammatory bowel disease 10.5
14 cholestasis 10.5
15 immune deficiency disease 10.5
16 hepatoportal sclerosis 10.5
17 common variable immunodeficiency 10.5
18 autoimmune disease 10.4
19 systemic lupus erythematosus 10.4
20 vascular disease 10.4
21 hypersplenism 10.4
22 lupus erythematosus 10.4
23 pulmonary hypertension 10.4
24 hepatic coma 10.4
25 hepatic encephalopathy 10.4
26 peliosis hepatis 10.4
27 celiac disease 1 10.4
28 crest syndrome 10.4
29 portal vein thrombosis 10.4
30 telangiectasis 10.4
31 banti's syndrome 10.4
32 portosinusoidal vascular disease 10.3
33 scleroderma, familial progressive 10.3
34 hepatocellular adenoma 10.3
35 neutropenia 10.3
36 thrombocytopenia 10.3
37 glomerulonephritis 10.3
38 antiphospholipid syndrome 10.3
39 vasculitis 10.3
40 polyarteritis nodosa 10.3
41 pulmonary hypertension, primary, 1 10.2
42 portal hypertension, noncirrhotic 10.2
43 autoimmune hepatitis 10.2
44 connective tissue disease 10.2
45 adenoma 10.2
46 crohn's disease 10.2
47 macroglobulinemia 10.2
48 cholangitis 10.2
49 encephalopathy 10.2
50 fibrosis of extraocular muscles, congenital, 1 10.2

Graphical network of the top 20 diseases related to Nodular Regenerative Hyperplasia:



Diseases related to Nodular Regenerative Hyperplasia
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Symptoms & Phenotypes for Nodular Regenerative Hyperplasia

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Human phenotypes related to Nodular Regenerative Hyperplasia:

58 31
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 portal hypertension 58 31 occasional (7.5%) Occasional (29-5%) HP:0001409
2 abnormality of the hepatic vasculature 58 Very frequent (99-80%)

MGI Mouse Phenotypes related to Nodular Regenerative Hyperplasia:

46
# Description MGI Source Accession Score Top Affiliating Genes
1 growth/size/body region MP:0005378 10.02 EFNB2 F3 GFER ITPA JAG1 NOTCH1
2 cellular MP:0005384 9.95 EFNB2 F3 GFER ITPA JAG1 NOTCH1
3 hematopoietic system MP:0005397 9.92 EFNB2 F3 ITPA JAG1 NOTCH1 NOTCH2
4 mortality/aging MP:0010768 9.81 EFNB2 F3 GFER ITPA JAG1 NOTCH1
5 integument MP:0010771 9.73 EFNB2 F3 ITPA JAG1 NOTCH1 NOTCH2
6 muscle MP:0005369 9.43 EFNB2 F3 ITPA JAG1 NOTCH1 NOTCH2
7 respiratory system MP:0005388 9.02 EFNB2 F3 ITPA NOTCH1 NOTCH2
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Drugs & Therapeutics for Nodular Regenerative Hyperplasia

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Drugs for Nodular Regenerative Hyperplasia (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):

(show all 32)
# Name Status Phase Clinical Trials Cas Number PubChem Id
1
Caffeine Approved Phase 4 58-08-2 2519
2 Antirheumatic Agents Phase 4
3 Anti-Inflammatory Agents Phase 4
4 Mesalamine Phase 4 89-57-6
5 Calcium Supplement Phase 4
6 Calcium, Dietary Phase 4
7 Anti-Inflammatory Agents, Non-Steroidal Phase 4
8 Analgesics Phase 4
9 Analgesics, Non-Narcotic Phase 4
10
Calcium Nutraceutical Phase 4 7440-70-2 271
11
Propranolol Approved, Investigational Phase 3 525-66-6 4946
12
Apixaban Approved Phase 3 503612-47-3 10182969
13 Vasodilator Agents Phase 3
14 Anti-Arrhythmia Agents Phase 3
15 Adrenergic Antagonists Phase 3
16 Adrenergic beta-Antagonists Phase 3
17 Adrenergic Agents Phase 3
18 Neurotransmitter Agents Phase 3
19 Antihypertensive Agents Phase 3
20 Serine Proteinase Inhibitors Phase 3
21 Antithrombins Phase 3
22 Antithrombin III Phase 3
23 Liver Extracts Phase 3
24 Factor Xa Inhibitors Phase 3
25 HIV Protease Inhibitors Phase 3
26 Anticoagulants Phase 3
27
protease inhibitors Phase 3
28
Serine Investigational, Nutraceutical Phase 3 56-45-1 5951
29
Epinephrine Approved, Vet_approved 51-43-4 5816
30
Racepinephrine Approved 329-65-7 838
31 Epinephryl borate
32 Hemostatics

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 CLINICAL MANAGEMENT OF CHILDHOOD INTESTINAL LYMPHOID NODULAR HYPERPLASIA: A RANDOMIZED CONTROLLED CLINICAL TRIAL. Unknown status NCT01789294 Phase 4 Mesalamine
2 Comparison of Endoscopic Variceal Ligation (EVL) and Propranolol in Secondary Prophylaxis of Variceal Bleeding in Patients With Non Cirrhotic Portal Hypertension (NCPH): A Prospective Randomized Controlled Trial Completed NCT01000779 Phase 3 Propranolol
3 Apixaban for Intrahepatic Non Cirrhotic Portal Hypertension Recruiting NCT04007289 Phase 3 Apixaban;Placebo
4 Exploratory Phase IV Randomized Single Blind Study Evaluating the Efficacy and Tolerability of Hemopatch in Improving Time of Hemostasis and Preventing Post-operative Complications After Hepatic Resection Unknown status NCT03323359
5 Contrast Enhanced Ultrasound for the Evaluation of Focal Liver Lesions - a Multi-center Study on the Usefulness in the Clinical Practice Unknown status NCT01329458
6 Risk Factors for Variceal Bleeding in Egyptian Patients With Non-Cirrhotic Portal Hypertension Completed NCT02635815
7 "The Fingerprint: Spoke-wheel Sign" of Focal Nodular Hyperplasia: Assessment of Novel Ultrasound Approach Using Superb Microvascular Imaging Technique Completed NCT02737865 Sonazoid
8 Quantitative Real-time Ultrasound Elastography (Shear Wave Elastography - SWEâ„¢) for Characterisation of Liver Tumors Completed NCT02156700

Search NIH Clinical Center for Nodular Regenerative Hyperplasia

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Genetic Tests for Nodular Regenerative Hyperplasia

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Anatomical Context for Nodular Regenerative Hyperplasia

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MalaCards organs/tissues related to Nodular Regenerative Hyperplasia:

40
Liver, Spleen, Heart, Bone Marrow, Lung, Myeloid, Endothelial
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Publications for Nodular Regenerative Hyperplasia

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Articles related to Nodular Regenerative Hyperplasia:

(show top 50) (show all 620)
# Title Authors PMID Year
1
Drug-induced nodular regenerative hyperplasia. 20 61
24879987 2014
2
Hepatic hemodynamics in 24 patients with nodular regenerative hyperplasia and symptomatic portal hypertension. 61 20
22554152 2012
3
Transportal Technetium-99m Labeled Macroaggregated Albumin Scintigraphy to Quantify Occult Intrahepatic Microvascular Portosystemic Shunting. 61
33664925 2021
4
Identification of tissue sections from decellularized liver scaffolds for repopulation experiments. 61
33644446 2021
5
Recurrent nodular regenerative hyperplasia post-liver transplantation in common variable immunodeficiency. 61
33638875 2021
6
Thioguanine Therapy in Inflammatory Bowel Diseases. A Practical Guide. 61
33331335 2020
7
Portal hypertension in primary biliary cholangitis: prevalence, natural history and histological correlates. 61
33323761 2020
8
Reply to "Letter to the Editor: Post-Liver Transplantation Sinusoidal Obstruction Syndrome and immunosuppressive drugs: causality of MMF or tacrolimus?" 61
33200416 2020
9
Autoimmune Hepatitis in a Patient With Common Variable Immunodeficiency. 61
33204738 2020
10
The prevalence of nodular regenerative hyperplasia of the liver in long-term thiopurine-treated inflammatory bowel disease patients. 61
33136726 2020
11
Nodular regenerative hyperplasia and portal hypertension are the characteristics of liver abnormalities in patients with selective immunoglobulin A deficiency. 61
32146091 2020
12
Living donor liver transplantation for idiopathic portal hypertension with extrahepatic portal vein stenosis and splenic artery aneurysms: a case report and review of the literature. 61
33121468 2020
13
Safety of trastuzumab after trastuzumab emtansine-induced nodular regenerative hyperplasia: A case report. 61
32192389 2020
14
Hereditary Hemorrhagic Telangiectasia and Refractory Ascites. 61
33134402 2020
15
Sinusoidal obstruction syndrome. 61
32253162 2020
16
Efficacy, safety and drug survival of thioguanine as maintenance treatment for inflammatory bowel disease: a retrospective multi-centre study in the United Kingdom. 61
32917155 2020
17
The Clinical Spectrum and Diagnosis of Oxaliplatin Liver Injury in the Era of Nonalcoholic Fatty Liver Disease. 61
33007507 2020
18
Sinusoidal Hepatic Angiosarcoma on a Background of Non-cirrhotic Portal Hypertension and Nodular Regenerative Hyperplasia Masquerading as Acute on Chronic Liver Failure. 61
32880042 2020
19
Biliary Atresia Patients With Successful Kasai Portoenterostomy Can Present With Features of Obliterative Portal Venopathy. 61
32187144 2020
20
Aberrant von Willebrand factor expression of sinusoidal endothelial cells and quiescence of hepatic stellate cells in nodular regenerative hyperplasia and obliterative portal venopathy. 61
31994248 2020
21
Does Chemotherapy-Induced Liver Injury Impair Postoperative Outcomes After Laparoscopic Liver Resection for Colorectal Metastases? 61
32410180 2020
22
Spectrum of Hepatic Manifestations of Common Variable Immunodeficiency. 61
32187043 2020
23
Transjugular intrahepatic portosystemic shunt placement for symptomatic non- bleeding anorectal varices in nodular regenerative hyperplasia. 61
32603056 2020
24
Pathologic Manifestations of Gastrointestinal and Hepatobiliary Injury in Immune Checkpoint Inhibitor Therapy. 61
32338534 2020
25
Nodular regenerative hyperplasia - An under-recognized vascular disorder of liver. 61
32164988 2020
26
Nodular Regenerative Hyperplasia: Expression Pattern of Glutamine Synthetase and a Potential Role for Hepatic Progenitor Cells. 61
31335486 2020
27
Nodular Regenerative Hyperplasia Associated With Primary Liver Malignancies. 61
31429968 2020
28
Liver stiffness measurement in patients with nodular regenerative hyperplasia undergoing magnetic resonance elastography. 61
31834457 2020
29
Hepatocellular adenoma(s) arising in nodular regenerative hyperplasia in a patient with systemic lupus erythematosus. 61
31810588 2020
30
The continuous rediscovery and the benefit-risk ratio of thioguanine, a comprehensive review. 61
32090622 2020
31
Heterogeneity of Liver Disease in Common Variable Immunodeficiency Disorders. 61
32184784 2020
32
Non-infectious Complications of Common Variable Immunodeficiency: Updated Clinical Spectrum, Sequelae, and Insights to Pathogenesis. 61
32117289 2020
33
Abernethy malformation and hepatocellular carcinoma: a serious consequence of a rare disease. 61
31911408 2020
34
Noncirrhotic Portal Hypertension Secondary to Nodular Regenerative Hyperplasia Postrenal Transplant. 61
32042840 2019
35
Recurrent metastatic breast cancer presenting with portal hypertension and pseudocirrhosis. 61
31767605 2019
36
Porto-Sinusoidal Vascular Disease Associated to Oxaliplatin: An Entity to Think about It. 61
31771307 2019
37
[Unknown liver lesions]. 61
31752038 2019
38
Patients With Signs of Advanced Liver Disease and Clinically Significant Portal Hypertension Do Not Necessarily Have Cirrhosis. 61
30625404 2019
39
Budd-Chiari Syndrome in a Patient With Simultaneous Diagnosis of Hepatic Sarcoidosis and Nodular Regenerative Hyperplasia. 61
31750374 2019
40
Clinical features of idiopathic portal hypertension in China: A retrospective study of 338 patients and literature review. 61
30462857 2019
41
Paraneoplastic nodular regenerative hyperplasia of the liver associated with placental site trophoblastic tumor. 61
31193692 2019
42
Clinicopathologic characteristics of de novo nodular regenerative hyperplasia in pediatric liver transplant. 61
31124197 2019
43
Sustained effectiveness, safety and therapeutic drug monitoring of tioguanine in a cohort of 274 IBD patients intolerant for conventional therapies. 61
31094013 2019
44
Letter to the Editor: Is Nodular Regenerative Hyperplasia an Immune-Mediated Phenomenon? 61
30820967 2019
45
The Spectrum of Hepatic Involvement in Patients With Telomere Disease. 61
30791107 2019
46
Limited relevance and progression of histological alterations in the liver during thioguanine therapy in inflammatory bowel disease patients. 61
31203688 2019
47
Novel IL2RG Mutation Causes Leaky TLOWB+NK+ SCID With Nodular Regenerative Hyperplasia and Normal IL-15 STAT5 Phosphorylation. 61
29939941 2019
48
Porto-sinusoidal vascular disease: proposal and description of a novel entity. 61
30957754 2019
49
Successful treatment of noncirrhotic portal hypertension with eculizumab in paroxysmal nocturnal hemoglobinuria: A case report. 61
31183008 2019
50
A case of incontinentia pigmenti associated with congenital absence of portal vein system and nodular regenerative hyperplasia. 61
30328117 2019
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Variations for Nodular Regenerative Hyperplasia

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Expression for Nodular Regenerative Hyperplasia

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Search GEO for disease gene expression data for Nodular Regenerative Hyperplasia.
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Pathways for Nodular Regenerative Hyperplasia

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Pathways related to Nodular Regenerative Hyperplasia according to GeneCards Suite gene sharing:

(show all 13)
# Super pathways Score Top Affiliating Genes
1
Th17 cell differentiation 36
Show member pathways
 12.24 NOTCH2 NOTCH1 JAG1
2
Notch Signaling Pathway (WikiPathways) 36
Show member pathways
 12.2 NOTCH2 NOTCH1 JAG1
3
Wnt / Hedgehog / Notch 4
11.87 NOTCH2 NOTCH1 JAG1
4
NOTCH2 Activation and Transmission of Signal to the Nucleus 65
Show member pathways
 11.65 NOTCH2 NOTCH1 JAG1
5
Primary Focal Segmental Glomerulosclerosis FSGS 1
11.3 PCNA NOTCH1 JAG1
6
Th2 Differentiation Pathway 64
11.16 NOTCH1 JAG1
7
Notch Signaling Pathway (sino) 66
11.11 NOTCH2 NOTCH1 JAG1
8
Angiogenesis (CST) 4
10.97 NOTCH2 NOTCH1 JAG1 F3 EFNB2
9
Notch Signaling 63
10.95 NOTCH2 NOTCH1
10
Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics 60
10.89 TPMT ITPA
11
NOTCH1 regulation of human endothelial cell calcification 1
10.66 NOTCH1 JAG1
12
Amplification and Expansion of Oncogenic Pathways as Metastatic Traits 1
10.6 NOTCH1 JAG1
13
Canonical and Non-canonical Notch signaling 1
10.56 NOTCH2 NOTCH1 JAG1
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GO Terms for Nodular Regenerative Hyperplasia

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Cellular components related to Nodular Regenerative Hyperplasia according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 adherens junction GO:0005912 8.8 NOTCH1 JAG1 EFNB2

Biological processes related to Nodular Regenerative Hyperplasia according to GeneCards Suite gene sharing:

(show all 30)
# Name GO ID Score Top Affiliating Genes
1 angiogenesis GO:0001525 9.79 NOTCH1 JAG1 EFNB2
2 axon guidance GO:0007411 9.77 NOTCH2 NOTCH1 EFNB2
3 Notch signaling pathway GO:0007219 9.67 NOTCH2 NOTCH1 JAG1
4 heart looping GO:0001947 9.65 NOTCH2 NOTCH1
5 negative regulation of neuron differentiation GO:0045665 9.64 NOTCH1 JAG1
6 negative regulation of cell differentiation GO:0045596 9.64 NOTCH1 JAG1
7 keratinocyte differentiation GO:0030216 9.63 NOTCH1 JAG1
8 humoral immune response GO:0006959 9.63 NOTCH2 NOTCH1
9 positive regulation of Notch signaling pathway GO:0045747 9.62 NOTCH1 JAG1
10 embryonic limb morphogenesis GO:0030326 9.62 NOTCH2 NOTCH1
11 positive regulation of BMP signaling pathway GO:0030513 9.61 NOTCH2 NOTCH1
12 liver development GO:0001889 9.61 NOTCH2 NOTCH1 GFER
13 positive regulation of Ras protein signal transduction GO:0046579 9.6 NOTCH2 NOTCH1
14 aortic valve morphogenesis GO:0003180 9.58 NOTCH1 JAG1
15 inflammatory response to antigenic stimulus GO:0002437 9.58 NOTCH2 NOTCH1
16 neuronal stem cell population maintenance GO:0097150 9.57 NOTCH1 JAG1
17 cell fate determination GO:0001709 9.56 NOTCH2 JAG1
18 negative regulation of stem cell differentiation GO:2000737 9.55 NOTCH1 JAG1
19 cardiac septum morphogenesis GO:0060411 9.54 NOTCH1 JAG1
20 left/right axis specification GO:0070986 9.52 NOTCH2 NOTCH1
21 response to muramyl dipeptide GO:0032495 9.51 NOTCH1 JAG1
22 morphogenesis of an epithelial sheet GO:0002011 9.48 NOTCH2 JAG1
23 glomerular visceral epithelial cell development GO:0072015 9.46 NOTCH2 JAG1
24 ciliary body morphogenesis GO:0061073 9.4 NOTCH2 JAG1
25 regulation of developmental process GO:0050793 9.37 NOTCH2 NOTCH1
26 distal tubule development GO:0072017 9.32 NOTCH1 JAG1
27 negative regulation of growth rate GO:0045967 9.26 NOTCH2 NOTCH1
28 positive regulation of cardiac epithelial to mesenchymal transition GO:0062043 9.16 NOTCH1 JAG1
29 pulmonary valve morphogenesis GO:0003184 9.13 NOTCH2 NOTCH1 JAG1
30 Notch signaling involved in heart development GO:0061314 8.8 NOTCH2 NOTCH1 JAG1

Molecular functions related to Nodular Regenerative Hyperplasia according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 Notch binding GO:0005112 8.62 NOTCH1 JAG1
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Sources for Nodular Regenerative Hyperplasia

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3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
20 GARD
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
53 NINDS
54 Novoseek
56 OMIM via Orphanet
57 OMIM® (Updated 20-May-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 Tocris
70 UMLS
71 UMLS via Orphanet
The MalaCards human disease database index: 1-9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
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