Fatty Acids, Genes and Microbiota in Fatty Liver
10. Mai 2016 aktualisiert von: 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.
Studienübersicht
Status
Abgeschlossen
Detaillierte Beschreibung
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.
Studientyp
Beobachtungs
Einschreibung (Tatsächlich)
205
Kontakte und Standorte
Dieser Abschnitt enthält die Kontaktdaten derjenigen, die die Studie durchführen, und Informationen darüber, wo diese Studie durchgeführt wird.
Studienorte
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Ontario
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Toronto, Ontario, Kanada, M5G 1Z5
- Toronto General Hospital
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Teilnahmekriterien
Forscher suchen nach Personen, die einer bestimmten Beschreibung entsprechen, die als Auswahlkriterien bezeichnet werden. Einige Beispiele für diese Kriterien sind der allgemeine Gesundheitszustand einer Person oder frühere Behandlungen.
Zulassungskriterien
Studienberechtigtes Alter
18 Jahre bis 70 Jahre (Erwachsene, Älterer Erwachsener)
Akzeptiert gesunde Freiwillige
Nein
Studienberechtigte Geschlechter
Alle
Probenahmeverfahren
Nicht-Wahrscheinlichkeitsprobe
Studienpopulation
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.
Beschreibung
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
Studienplan
Dieser Abschnitt enthält Einzelheiten zum Studienplan, einschließlich des Studiendesigns und der Messung der Studieninhalte.
Wie ist die Studie aufgebaut?
Designdetails
- Beobachtungsmodelle: Kohorte
- Zeitperspektiven: Querschnitt
Kohorten und Interventionen
Gruppe / Kohorte |
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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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Was misst die Studie?
Primäre Ergebnismessungen
Ergebnis Maßnahme |
Maßnahmenbeschreibung |
Zeitfenster |
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Hepatic fatty acid composition in total lipids in liver biopsy
Zeitfenster: Baseline
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Gas chromatography
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Baseline
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Hepatic gene expression
Zeitfenster: Baseline
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mRNA by microarray
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Baseline
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Intestinal microbiota composition
Zeitfenster: Baseline
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Illumina 16S technology
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Baseline
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Sekundäre Ergebnismessungen
Ergebnis Maßnahme |
Maßnahmenbeschreibung |
Zeitfenster |
|---|---|---|
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Lipid peroxides in the liver
Zeitfenster: Baseline
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Test kit
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Baseline
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Hepatic liver antioxidant power
Zeitfenster: Baseline
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Test kit
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Baseline
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Hepatic microRNA expression in the liver
Zeitfenster: Baseline
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NanoString
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Baseline
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Intestinal microbiota - specific organisms and groups
Zeitfenster: 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
Zeitfenster: Baseline
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Illumina sequencing technology
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Baseline
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Short-chain fatty acids in stool
Zeitfenster: Baseline
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Gas chromatography
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Baseline
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Plasma endotoxin
Zeitfenster: Baseline
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Limulus assay
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Baseline
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Andere Ergebnismessungen
Ergebnis Maßnahme |
Maßnahmenbeschreibung |
Zeitfenster |
|---|---|---|
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Hepatic phospholipid composition
Zeitfenster: Baseline
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Gas chromatography
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Baseline
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Red blood cell fatty acid and phospholipid composition
Zeitfenster: Baseline
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Gas chromatography
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Baseline
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Plasma fatty acid composition
Zeitfenster: Baseline
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Gas chromatography
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Baseline
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Plasma lipid peroxides
Zeitfenster: Baseline
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Test kit
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Baseline
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Plasma antioxidant vitamins
Zeitfenster: 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
Zeitfenster: Baseline
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Test kit
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Baseline
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TNF-alpha in the liver
Zeitfenster: Baseline
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Enzyme linked immunosorbent assay
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Baseline
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Immunohistochemistry
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: Baseline
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Quantitative polymerase chain reaction for bacterial 16S rDNA
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Baseline
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Insulin resistance
Zeitfenster: 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
Zeitfenster: Baseline
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standard laboratory measurement
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Baseline
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Anthropometry
Zeitfenster: Baseline
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Weight, height, skinfolds, bioelectrical impedance analysis
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Baseline
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Food intake
Zeitfenster: Baseline
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7-day food records
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Baseline
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Physical activity
Zeitfenster: Baseline
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7 day activity logs
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Baseline
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Factors influencing intestinal microbiota
Zeitfenster: Baseline
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Environmental questionnaire
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Baseline
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Liver function tests
Zeitfenster: Baseline
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Alanine transaminase, aspartate transaminase, alkaline phosphatase, standard laboratory tests
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Baseline
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Mitarbeiter und Ermittler
Hier finden Sie Personen und Organisationen, die an dieser Studie beteiligt sind.
Sponsor
Mitarbeiter
Ermittler
- Hauptermittler: Johane Allard, MD,FRCPC, University Health Network, Toronto
Publikationen und hilfreiche Links
Die Bereitstellung dieser Publikationen erfolgt freiwillig durch die für die Eingabe von Informationen über die Studie verantwortliche Person. Diese können sich auf alles beziehen, was mit dem Studium zu tun hat.
Allgemeine Veröffentlichungen
- 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.
Studienaufzeichnungsdaten
Diese Daten verfolgen den Fortschritt der Übermittlung von Studienaufzeichnungen und zusammenfassenden Ergebnissen an ClinicalTrials.gov. Studienaufzeichnungen und gemeldete Ergebnisse werden von der National Library of Medicine (NLM) überprüft, um sicherzustellen, dass sie bestimmten Qualitätskontrollstandards entsprechen, bevor sie auf der öffentlichen Website veröffentlicht werden.
Haupttermine studieren
Studienbeginn
1. Oktober 2003
Primärer Abschluss (Tatsächlich)
1. August 2015
Studienabschluss (Tatsächlich)
1. August 2015
Studienanmeldedaten
Zuerst eingereicht
23. Mai 2014
Zuerst eingereicht, das die QC-Kriterien erfüllt hat
23. Mai 2014
Zuerst gepostet (Schätzen)
28. Mai 2014
Studienaufzeichnungsaktualisierungen
Letztes Update gepostet (Schätzen)
12. Mai 2016
Letztes eingereichtes Update, das die QC-Kriterien erfüllt
10. Mai 2016
Zuletzt verifiziert
1. Mai 2016
Mehr Informationen
Begriffe im Zusammenhang mit dieser Studie
Schlüsselwörter
Zusätzliche relevante MeSH-Bedingungen
Andere Studien-ID-Nummern
- 03-0505-A
Arzneimittel- und Geräteinformationen, Studienunterlagen
Studiert ein von der US-amerikanischen FDA reguliertes Arzneimittelprodukt
Nein
Studiert ein von der US-amerikanischen FDA reguliertes Geräteprodukt
Nein
Produkt, das in den USA hergestellt und aus den USA exportiert wird
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