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Fatty Acids, Genes and Microbiota in Fatty Liver

10. maj 2016 opdateret af: 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.

Studieoversigt

Status

Afsluttet

Betingelser

Detaljeret beskrivelse

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.

Undersøgelsestype

Observationel

Tilmelding (Faktiske)

205

Kontakter og lokationer

Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.

Studiesteder

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5G 1Z5
        • Toronto General Hospital

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

18 år til 70 år (Voksen, Ældre voksen)

Tager imod sunde frivillige

Ingen

Køn, der er berettiget til at studere

Alle

Prøveudtagningsmetode

Ikke-sandsynlighedsprøve

Studiebefolkning

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.

Beskrivelse

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

Studieplan

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Observationsmodeller: Kohorte
  • Tidsperspektiver: Tværsnit

Kohorter og interventioner

Gruppe / kohorte
Healthy controls
Healthy living liver donors with healthy liver on imaging and/or liver histology
Simple steatosis
Patients with non-alcoholic fatty liver disease confirmed by liver biopsy with a diagnosis of simple steatosis
Nonalcoholic steatohepatitis
Patients with non-alcoholic fatty liver disease confirmed by liver biopsy with a diagnosis of steatohepatitis
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.

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Hepatic fatty acid composition in total lipids in liver biopsy
Tidsramme: Baseline
Gas chromatography
Baseline
Hepatic gene expression
Tidsramme: Baseline
mRNA by microarray
Baseline
Intestinal microbiota composition
Tidsramme: Baseline
Illumina 16S technology
Baseline

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Lipid peroxides in the liver
Tidsramme: Baseline
Test kit
Baseline
Hepatic liver antioxidant power
Tidsramme: Baseline
Test kit
Baseline
Hepatic microRNA expression in the liver
Tidsramme: Baseline
NanoString
Baseline
Intestinal microbiota - specific organisms and groups
Tidsramme: Baseline
Quantitative real-time polymerase chain reaction
Baseline
Intestinal microbiome on a genetic level
Tidsramme: Baseline
Illumina sequencing technology
Baseline
Short-chain fatty acids in stool
Tidsramme: Baseline
Gas chromatography
Baseline
Plasma endotoxin
Tidsramme: Baseline
Limulus assay
Baseline

Andre resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Hepatic phospholipid composition
Tidsramme: Baseline
Gas chromatography
Baseline
Red blood cell fatty acid and phospholipid composition
Tidsramme: Baseline
Gas chromatography
Baseline
Plasma fatty acid composition
Tidsramme: Baseline
Gas chromatography
Baseline
Plasma lipid peroxides
Tidsramme: Baseline
Test kit
Baseline
Plasma antioxidant vitamins
Tidsramme: Baseline
Vitamin C colorimetric, alpha- and gamma-tocopherol and beta-carotene by high-performance liquid chromatography
Baseline
Serum antioxidant power
Tidsramme: Baseline
Test kit
Baseline
TNF-alpha in the liver
Tidsramme: Baseline
Enzyme linked immunosorbent assay
Baseline
Immunohistochemistry
Tidsramme: Baseline
Staining for malondialdehyde, alpha-smooth muscle actin, transforming growth factor beta
Baseline
Free choline in serum
Tidsramme: Baseline
liquid chromatography/electrospray ionization-isotope dilution mass spectrometry (LC/ESI-IDMS)
Baseline
Bacterial DNA in plasma
Tidsramme: Baseline
Quantitative polymerase chain reaction for bacterial 16S rDNA
Baseline
Insulin resistance
Tidsramme: Baseline
Fasting glucose and insulin to calculate insulin resistance (HOMA-IR), C-peptide, hemoglobin A1c, all by standard laboratory methods
Baseline
Plasma ethanol
Tidsramme: Baseline
standard laboratory measurement
Baseline
Anthropometry
Tidsramme: Baseline
Weight, height, skinfolds, bioelectrical impedance analysis
Baseline
Food intake
Tidsramme: Baseline
7-day food records
Baseline
Physical activity
Tidsramme: Baseline
7 day activity logs
Baseline
Factors influencing intestinal microbiota
Tidsramme: Baseline
Environmental questionnaire
Baseline
Liver function tests
Tidsramme: Baseline
Alanine transaminase, aspartate transaminase, alkaline phosphatase, standard laboratory tests
Baseline

Samarbejdspartnere og efterforskere

Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.

Sponsor

Johane Allard

Samarbejdspartnere

Canadian Institutes of Health Research (CIHR)
Canadian Liver Foundation
American College of Gastroenterology

Efterforskere

  • Ledende efterforsker: Johane Allard, MD,FRCPC, University Health Network, Toronto

Publikationer og nyttige links

Den person, der er ansvarlig for at indtaste oplysninger om undersøgelsen, leverer frivilligt disse publikationer. Disse kan handle om alt relateret til undersøgelsen.

Generelle publikationer

Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart

1. oktober 2003

Primær færdiggørelse (Faktiske)

1. august 2015

Studieafslutning (Faktiske)

1. august 2015

Datoer for studieregistrering

Først indsendt

23. maj 2014

Først indsendt, der opfyldte QC-kriterier

23. maj 2014

Først opslået (Skøn)

28. maj 2014

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Skøn)

12. maj 2016

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

10. maj 2016

Sidst verificeret

1. maj 2016

Mere information

Begreber relateret til denne undersøgelse

Nøgleord

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • 03-0505-A

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