Fatty Acids, Genes and Microbiota in Fatty Liver
10 mai 2016 mis à jour par: Johane Allard
Non-alcoholic Steatohepatitis Versus Simple Hepatic Steatosis: Is There a Difference in the Nutritional Factors Influencing Lipid Perioxidation and Inflammation?
The first aim of this study is to assess oxidative stress and nutritional status in patients with elevated liver enzymes who were found to have either simple steatosis (SS) or nonalcoholic steatohepatitis (NASH) or normal histological findings on liver biopsy by measuring liver lipid peroxides and tumor necrosis factor (TNF)-α, liver pathology and immunohistochemistry, liver function tests, liver and red blood cell membrane fatty composition, insulin resistance (IR) parameters, plasma lipid peroxides, plasma antioxidant vitamins and antioxidant power, lipid profile, subject demographics, medical history and medication use.
The second aim is to detect differences in hepatic gene expression (messenger RNA, mRNA) and epigenetic regulation (micro RNA, miRNA) between patients with SS or NASH and healthy controls, in addition to determine in patients with non-alcoholic fatty liver disease (NAFLD = SS+NASH combined) whether there is an association between hepatic n-3 PUFA content and gene expression.
The third aim is to determine the intestinal microbiome (microbial composition and metagenome) in patients with SS or NASH and healthy controls.
Aperçu de l'étude
Statut
Complété
Description détaillée
NASH is associated with obesity, diabetes and hyperlipidemia. Fat accumulation in the liver is likely due to variable degrees of disordered fatty-acid metabolism and insulin resistance (IR). Liver steatosis, especially polyunsaturated fatty acids (PUFA) in the liver, increases lipid peroxidation and is associated with a reduction in the antioxidant defense system. This oxidative stress can lead to increased production of pro-inflammatory cytokines (TNF-α, transforming growth factor-beta) contributing to the development of steatohepatitis and fibrosis.TNF-α - may further contribute to IR. In addition, changes in fatty acid composition within the liver may influence lipid metabolism and inflammation. In particular, n-3 PUFA have an effect on the insulin sensitivity, transcription of antioxidant genes, inflammatory response and production of reactive oxygen species. Differences might be seen on the gene expression level (mRNA) and also in epigenetic regulation (miRNA).
Microbiota composition might influence energy metabolism, and inflammatory tone and IR through increased endotoxemia and therefore could also play a role in the development of NAFLD.
Type d'étude
Observationnel
Inscription (Réel)
205
Contacts et emplacements
Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.
Lieux d'étude
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Ontario
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Toronto, Ontario, Canada, M5G 1Z5
- Toronto General Hospital
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Critères de participation
Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.
Critère d'éligibilité
Âges éligibles pour étudier
18 ans à 70 ans (Adulte, Adulte plus âgé)
Accepte les volontaires sains
Non
Sexes éligibles pour l'étude
Tout
Méthode d'échantillonnage
Échantillon non probabiliste
Population étudiée
Healthy living liver donors from the Multiorgan transplant program at the University Health Network Patients with nonalcoholic fatty liver disease (SS or NASH on liver biopsy) or patients with elevated liver enzymes but no significant findings on liver biopsy.
La description
Inclusion criteria:
- Male and female patients, age >18 y
- A liver biopsy with a diagnosis of SS or NASH OR No signs of steatosis, fibrosis or any other kind of liver disease on histology (minimal findings) OR For healthy control subjects, those with normal liver enzymes and normal liver imaging on ultrasound
- alcohol consumption (<20g of ethanol per day);
- absence of any other possible cause for liver dysfunction.
Exclusion criteria:
- any other liver disease apart from NAFLD
- anticipated need for liver transplantation in one year or complications of liver disease;
- any reasons contraindicating a liver biopsy (patients) or liver donation (healthy donors)
- chronic gastrointestinal diseases, previous gastrointestinal surgery modifying the anatomy, patients with diabetes requiring insulin.
- medications known to precipitate steatohepatitis (corticosteroids, high dose estrogens, methotrexate, amiodarone, spironolactone, sulfasalazine, perhexiline maleate, diethylamino- ethoxyhexestrol (DH), tamoxifen, diethylstilbestrol, naproxen or oxacillin) or regular intake of non-steroidal anti-inflammatory drugs (except for low dose aspirin), use of ursodeoxycholic acid or any experimental drug in the 6 months prior to entry.
- regular intake of prebiotics, probiotics, antibiotics, or laxatives; in the 3 months prior to study entry
- Pregnant or lactating
Plan d'étude
Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.
Comment l'étude est-elle conçue ?
Détails de conception
- Modèles d'observation: Cohorte
- Perspectives temporelles: Transversale
Cohortes et interventions
Groupe / Cohorte |
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Healthy controls
Healthy living liver donors with healthy liver on imaging and/or liver histology
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Simple steatosis
Patients with non-alcoholic fatty liver disease confirmed by liver biopsy with a diagnosis of simple steatosis
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Nonalcoholic steatohepatitis
Patients with non-alcoholic fatty liver disease confirmed by liver biopsy with a diagnosis of steatohepatitis
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Minimal findings
Patients undergoing liver biopsy because of suspected fatty liver but nonspecific findings on liver histology.
This group was initially used as a control group.
Later in the study, this group was replaced by healthy donors as true healthy controls.
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Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
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Hepatic fatty acid composition in total lipids in liver biopsy
Délai: Baseline
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Gas chromatography
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Baseline
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Hepatic gene expression
Délai: Baseline
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mRNA by microarray
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Baseline
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Intestinal microbiota composition
Délai: Baseline
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Illumina 16S technology
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Baseline
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Mesures de résultats secondaires
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
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Lipid peroxides in the liver
Délai: Baseline
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Test kit
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Baseline
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Hepatic liver antioxidant power
Délai: Baseline
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Test kit
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Baseline
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Hepatic microRNA expression in the liver
Délai: Baseline
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NanoString
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Baseline
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Intestinal microbiota - specific organisms and groups
Délai: Baseline
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Quantitative real-time polymerase chain reaction
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Baseline
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Intestinal microbiome on a genetic level
Délai: Baseline
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Illumina sequencing technology
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Baseline
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Short-chain fatty acids in stool
Délai: Baseline
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Gas chromatography
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Baseline
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Plasma endotoxin
Délai: Baseline
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Limulus assay
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Baseline
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Autres mesures de résultats
Mesure des résultats |
Description de la mesure |
Délai |
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Hepatic phospholipid composition
Délai: Baseline
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Gas chromatography
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Baseline
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Red blood cell fatty acid and phospholipid composition
Délai: Baseline
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Gas chromatography
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Baseline
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Plasma fatty acid composition
Délai: Baseline
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Gas chromatography
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Baseline
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Plasma lipid peroxides
Délai: Baseline
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Test kit
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Baseline
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Plasma antioxidant vitamins
Délai: Baseline
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Vitamin C colorimetric, alpha- and gamma-tocopherol and beta-carotene by high-performance liquid chromatography
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Baseline
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Serum antioxidant power
Délai: Baseline
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Test kit
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Baseline
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TNF-alpha in the liver
Délai: Baseline
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Enzyme linked immunosorbent assay
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Baseline
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Immunohistochemistry
Délai: Baseline
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Staining for malondialdehyde, alpha-smooth muscle actin, transforming growth factor beta
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Baseline
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Free choline in serum
Délai: Baseline
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liquid chromatography/electrospray ionization-isotope dilution mass spectrometry (LC/ESI-IDMS)
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Baseline
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Bacterial DNA in plasma
Délai: Baseline
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Quantitative polymerase chain reaction for bacterial 16S rDNA
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Baseline
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Insulin resistance
Délai: Baseline
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Fasting glucose and insulin to calculate insulin resistance (HOMA-IR), C-peptide, hemoglobin A1c, all by standard laboratory methods
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Baseline
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Plasma ethanol
Délai: Baseline
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standard laboratory measurement
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Baseline
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Anthropometry
Délai: Baseline
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Weight, height, skinfolds, bioelectrical impedance analysis
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Baseline
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Food intake
Délai: Baseline
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7-day food records
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Baseline
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Physical activity
Délai: Baseline
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7 day activity logs
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Baseline
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Factors influencing intestinal microbiota
Délai: Baseline
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Environmental questionnaire
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Baseline
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Liver function tests
Délai: Baseline
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Alanine transaminase, aspartate transaminase, alkaline phosphatase, standard laboratory tests
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Baseline
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Collaborateurs et enquêteurs
C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.
Parrainer
Collaborateurs
Les enquêteurs
- Chercheur principal: Johane Allard, MD,FRCPC, University Health Network, Toronto
Publications et liens utiles
La personne responsable de la saisie des informations sur l'étude fournit volontairement ces publications. Il peut s'agir de tout ce qui concerne l'étude.
Publications générales
- Schwenger KJ, Allard JP. Clinical approaches to non-alcoholic fatty liver disease. World J Gastroenterol. 2014 Feb 21;20(7):1712-23. doi: 10.3748/wjg.v20.i7.1712.
- Monteiro J, Leslie M, Moghadasian MH, Arendt BM, Allard JP, Ma DW. The role of n - 6 and n - 3 polyunsaturated fatty acids in the manifestation of the metabolic syndrome in cardiovascular disease and non-alcoholic fatty liver disease. Food Funct. 2014 Mar;5(3):426-35. doi: 10.1039/c3fo60551e.
- Mouzaki M, Allard JP. The role of nutrients in the development, progression, and treatment of nonalcoholic fatty liver disease. J Clin Gastroenterol. 2012 Jul;46(6):457-67. doi: 10.1097/MCG.0b013e31824cf51e.
- Mouzaki M, Allard J. Non-alcoholic steatohepatitis: the therapeutic challenge of a global epidemic. Ann Gastroenterol. 2012;25(3):207-217.
- Da Silva HE, Arendt BM, Noureldin SA, Therapondos G, Guindi M, Allard JP. A cross-sectional study assessing dietary intake and physical activity in Canadian patients with nonalcoholic fatty liver disease vs healthy controls. J Acad Nutr Diet. 2014 Aug;114(8):1181-94. doi: 10.1016/j.jand.2014.01.009. Epub 2014 Mar 14.
- Arendt BM, Ma DW, Simons B, Noureldin SA, Therapondos G, Guindi M, Sherman M, Allard JP. Nonalcoholic fatty liver disease is associated with lower hepatic and erythrocyte ratios of phosphatidylcholine to phosphatidylethanolamine. Appl Physiol Nutr Metab. 2013 Mar;38(3):334-40. doi: 10.1139/apnm-2012-0261. Epub 2012 Oct 15.
- Mouzaki M, Comelli EM, Arendt BM, Bonengel J, Fung SK, Fischer SE, McGilvray ID, Allard JP. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology. 2013 Jul;58(1):120-7. doi: 10.1002/hep.26319. Epub 2013 May 14.
- Allard JP, Aghdassi E, Mohammed S, Raman M, Avand G, Arendt BM, Jalali P, Kandasamy T, Prayitno N, Sherman M, Guindi M, Ma DW, Heathcote JE. Nutritional assessment and hepatic fatty acid composition in non-alcoholic fatty liver disease (NAFLD): a cross-sectional study. J Hepatol. 2008 Feb;48(2):300-7. doi: 10.1016/j.jhep.2007.09.009. Epub 2007 Nov 20.
- Arendt BM, Comelli EM, Ma DW, Lou W, Teterina A, Kim T, Fung SK, Wong DK, McGilvray I, Fischer SE, Allard JP. Altered hepatic gene expression in nonalcoholic fatty liver disease is associated with lower hepatic n-3 and n-6 polyunsaturated fatty acids. Hepatology. 2015 May;61(5):1565-78. doi: 10.1002/hep.27695. Epub 2015 Feb 27.
- Pettinelli P, Arendt BM, Schwenger KJP, Sivaraj S, Bhat M, Comelli EM, Lou W, Allard JP. Relationship Between Hepatic Gene Expression, Intestinal Microbiota, and Inferred Functional Metagenomic Analysis in NAFLD. Clin Transl Gastroenterol. 2022 Jul 1;13(7):e00466. doi: 10.14309/ctg.0000000000000466. Epub 2022 Feb 10.
Dates d'enregistrement des études
Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.
Dates principales de l'étude
Début de l'étude
1 octobre 2003
Achèvement primaire (Réel)
1 août 2015
Achèvement de l'étude (Réel)
1 août 2015
Dates d'inscription aux études
Première soumission
23 mai 2014
Première soumission répondant aux critères de contrôle qualité
23 mai 2014
Première publication (Estimation)
28 mai 2014
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Estimation)
12 mai 2016
Dernière mise à jour soumise répondant aux critères de contrôle qualité
10 mai 2016
Dernière vérification
1 mai 2016
Plus d'information
Termes liés à cette étude
Termes MeSH pertinents supplémentaires
Autres numéros d'identification d'étude
- 03-0505-A
Informations sur les médicaments et les dispositifs, documents d'étude
Étudie un produit pharmaceutique réglementé par la FDA américaine
Non
Étudie un produit d'appareil réglementé par la FDA américaine
Non
produit fabriqué et exporté des États-Unis.
Non
Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .