Fatty Acids, Genes and Microbiota in Fatty Liver

NCT02148471 | Completed

• 1 other identifier: 03-0505-A
• Study Type: observational
• Target: 205
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Nonalcoholic Fatty Liver Disease; Steatosis; Nonalcoholic Steatohepatitis

Keywords

Nonalcoholic fatty liver disease; Steatosis; Nonalcoholic steatohepatitis

Outcome Measures

Primary Outcomes (3)

• Hepatic fatty acid composition in total lipids in liver biopsy

  Gas chromatography

  Baseline

• Hepatic gene expression

  mRNA by microarray

  Baseline

• Intestinal microbiota composition

  Illumina 16S technology

  Baseline

Secondary Outcomes (7)

• Lipid peroxides in the liver

  Baseline

• Hepatic liver antioxidant power

  Baseline

• Hepatic microRNA expression in the liver

  Baseline

• Intestinal microbiota - specific organisms and groups

  Baseline

• Intestinal microbiome on a genetic level

  Baseline

Other Outcomes (17)

• Hepatic phospholipid composition

  Baseline

• Red blood cell fatty acid and phospholipid composition

  Baseline

• Plasma fatty acid composition

  Baseline

Study Arms (4)

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.

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

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.

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Johane Allard: lead
• Canadian Liver Foundation: collaborator
• Canadian Institutes of Health Research (CIHR): collaborator
• American College of Gastroenterology: collaborator

Study Sites (1)

Toronto General Hospital

Toronto, Ontario, M5G 1Z5, Canada

Location

Related Publications (12)

• 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.

  PMID: 24587650 BACKGROUND

• 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.

  PMID: 24496399 BACKGROUND

• 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.

  PMID: 22469640 BACKGROUND

• Mouzaki M, Allard J. Non-alcoholic steatohepatitis: the therapeutic challenge of a global epidemic. Ann Gastroenterol. 2012;25(3):207-217.

  PMID: 24713803 BACKGROUND

• 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.

  PMID: 24631112 RESULT

• 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.

  PMID: 23537027 RESULT

• 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.

  PMID: 23401313 RESULT

• 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.

  PMID: 18086506 RESULT

• 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.

  PMID: 25581263 RESULT

• Pasini E, Baciu C, Angeli M, Arendt B, Pellegrina D, Reimand J, Patel K, Tomlinson G, Mazhab-Jafari MT, Kotra LP, Fischer S, Allard JP, Humar A, Bhat M. Acyl-CoA Thioesterase 1 Contributes to Transition of Steatosis to Metabolic-Associated Steatohepatitis. Int J Hepatol. 2024 Jul 11;2024:5560676. doi: 10.1155/2024/5560676. eCollection 2024.

  PMID: 39624175 DERIVED

• Schwenger KJP, Sharma D, Ghorbani Y, Xu W, Lou W, Comelli EM, Fischer SE, Jackson TD, Okrainec A, Allard JP. Links between gut microbiome, metabolome, clinical variables and non-alcoholic fatty liver disease severity in bariatric patients. Liver Int. 2024 May;44(5):1176-1188. doi: 10.1111/liv.15864. Epub 2024 Feb 14.

  PMID: 38353022 DERIVED

• 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.

  PMID: 35166723 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

DNA - samples retained, with potential for extraction of DNA from at least one of the types of samples retained (e.g., frozen tissue, whole blood

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Fatty Liver

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases

Study Officials

• Johane Allard, MD,FRCPC

  University Health Network, Toronto

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr.

Study Record Dates

• First Submitted: May 23, 2014
• First Posted: May 28, 2014
• Study Start: October 1, 2003
• Primary Completion: August 1, 2015
• Study Completion: August 1, 2015
• Last Updated: May 12, 2016

Record last verified: 2016-05

Locations

CA (1)