Fatty Acids, Genes and Microbiota in Fatty Liver

NCT ID: NCT02148471

Last Updated: 2016-05-12

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 205 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2003-10-31
• Study Completion Date: 2015-08-31

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.

Detailed Description

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.

Conditions

Nonalcoholic Fatty Liver Disease; Steatosis; Nonalcoholic Steatohepatitis

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: CROSS_SECTIONAL

Study Groups

Healthy controls

Healthy living liver donors with healthy liver on imaging and/or liver histology

No interventions assigned to this group

Simple steatosis

Patients with non-alcoholic fatty liver disease confirmed by liver biopsy with a diagnosis of simple steatosis

No interventions assigned to this group

Nonalcoholic steatohepatitis

Patients with non-alcoholic fatty liver disease confirmed by liver biopsy with a diagnosis of steatohepatitis

No interventions assigned to this group

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.

No interventions assigned to this group

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Canadian Liver Foundation

UNKNOWN

Sponsor Role: collaborator

Canadian Institutes of Health Research (CIHR)

OTHER_GOV

Sponsor Role: collaborator

American College of Gastroenterology

OTHER

Sponsor Role: collaborator

Johane Allard

OTHER

Sponsor Role: lead

Responsible Party

Johane Allard

Prof. Dr.

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Johane Allard, MD,FRCPC

Role: PRINCIPAL_INVESTIGATOR

University Health Network, Toronto

Locations

Toronto General Hospital

Toronto, Ontario, Canada

Countries

Canada

References

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Reference Type: BACKGROUND

PMID: 24587650 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24496399 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22469640 (View on PubMed)

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

Reference Type: BACKGROUND

PMID: 24713803 (View on PubMed)

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.

Reference Type: RESULT

PMID: 24631112 (View on PubMed)

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.

Reference Type: RESULT

PMID: 23537027 (View on PubMed)

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.

Reference Type: RESULT

PMID: 23401313 (View on PubMed)

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.

Reference Type: RESULT

PMID: 18086506 (View on PubMed)

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.

Reference Type: RESULT

PMID: 25581263 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 39624175 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 38353022 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35166723 (View on PubMed)

Other Identifiers

03-0505-A

Identifier Type: -

Identifier Source: org_study_id