Fatty Acids, Genes and Microbiota in Fatty Liver
10 de mayo de 2016 actualizado por: 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.
Descripción general del estudio
Estado
Terminado
Descripción detallada
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.
Tipo de estudio
De observación
Inscripción (Actual)
205
Contactos y Ubicaciones
Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.
Ubicaciones de estudio
-
-
Ontario
-
Toronto, Ontario, Canadá, M5G 1Z5
- Toronto General Hospital
-
-
Criterios de participación
Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.
Criterio de elegibilidad
Edades elegibles para estudiar
18 años a 70 años (Adulto, Adulto Mayor)
Acepta Voluntarios Saludables
No
Géneros elegibles para el estudio
Todos
Método de muestreo
Muestra no probabilística
Población de estudio
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.
Descripción
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 de estudios
Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.
¿Cómo está diseñado el estudio?
Detalles de diseño
- Modelos observacionales: Grupo
- Perspectivas temporales: Transversal
Cohortes e Intervenciones
Grupo / Cohorte |
|---|
|
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.
|
¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Hepatic fatty acid composition in total lipids in liver biopsy
Periodo de tiempo: Baseline
|
Gas chromatography
|
Baseline
|
|
Hepatic gene expression
Periodo de tiempo: Baseline
|
mRNA by microarray
|
Baseline
|
|
Intestinal microbiota composition
Periodo de tiempo: Baseline
|
Illumina 16S technology
|
Baseline
|
Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Lipid peroxides in the liver
Periodo de tiempo: Baseline
|
Test kit
|
Baseline
|
|
Hepatic liver antioxidant power
Periodo de tiempo: Baseline
|
Test kit
|
Baseline
|
|
Hepatic microRNA expression in the liver
Periodo de tiempo: Baseline
|
NanoString
|
Baseline
|
|
Intestinal microbiota - specific organisms and groups
Periodo de tiempo: Baseline
|
Quantitative real-time polymerase chain reaction
|
Baseline
|
|
Intestinal microbiome on a genetic level
Periodo de tiempo: Baseline
|
Illumina sequencing technology
|
Baseline
|
|
Short-chain fatty acids in stool
Periodo de tiempo: Baseline
|
Gas chromatography
|
Baseline
|
|
Plasma endotoxin
Periodo de tiempo: Baseline
|
Limulus assay
|
Baseline
|
Otras medidas de resultado
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Hepatic phospholipid composition
Periodo de tiempo: Baseline
|
Gas chromatography
|
Baseline
|
|
Red blood cell fatty acid and phospholipid composition
Periodo de tiempo: Baseline
|
Gas chromatography
|
Baseline
|
|
Plasma fatty acid composition
Periodo de tiempo: Baseline
|
Gas chromatography
|
Baseline
|
|
Plasma lipid peroxides
Periodo de tiempo: Baseline
|
Test kit
|
Baseline
|
|
Plasma antioxidant vitamins
Periodo de tiempo: Baseline
|
Vitamin C colorimetric, alpha- and gamma-tocopherol and beta-carotene by high-performance liquid chromatography
|
Baseline
|
|
Serum antioxidant power
Periodo de tiempo: Baseline
|
Test kit
|
Baseline
|
|
TNF-alpha in the liver
Periodo de tiempo: Baseline
|
Enzyme linked immunosorbent assay
|
Baseline
|
|
Immunohistochemistry
Periodo de tiempo: Baseline
|
Staining for malondialdehyde, alpha-smooth muscle actin, transforming growth factor beta
|
Baseline
|
|
Free choline in serum
Periodo de tiempo: Baseline
|
liquid chromatography/electrospray ionization-isotope dilution mass spectrometry (LC/ESI-IDMS)
|
Baseline
|
|
Bacterial DNA in plasma
Periodo de tiempo: Baseline
|
Quantitative polymerase chain reaction for bacterial 16S rDNA
|
Baseline
|
|
Insulin resistance
Periodo de tiempo: Baseline
|
Fasting glucose and insulin to calculate insulin resistance (HOMA-IR), C-peptide, hemoglobin A1c, all by standard laboratory methods
|
Baseline
|
|
Plasma ethanol
Periodo de tiempo: Baseline
|
standard laboratory measurement
|
Baseline
|
|
Anthropometry
Periodo de tiempo: Baseline
|
Weight, height, skinfolds, bioelectrical impedance analysis
|
Baseline
|
|
Food intake
Periodo de tiempo: Baseline
|
7-day food records
|
Baseline
|
|
Physical activity
Periodo de tiempo: Baseline
|
7 day activity logs
|
Baseline
|
|
Factors influencing intestinal microbiota
Periodo de tiempo: Baseline
|
Environmental questionnaire
|
Baseline
|
|
Liver function tests
Periodo de tiempo: Baseline
|
Alanine transaminase, aspartate transaminase, alkaline phosphatase, standard laboratory tests
|
Baseline
|
Colaboradores e Investigadores
Aquí es donde encontrará personas y organizaciones involucradas en este estudio.
Patrocinador
Colaboradores
Investigadores
- Investigador principal: Johane Allard, MD,FRCPC, University Health Network, Toronto
Publicaciones y enlaces útiles
La persona responsable de ingresar información sobre el estudio proporciona voluntariamente estas publicaciones. Estos pueden ser sobre cualquier cosa relacionada con el estudio.
Publicaciones Generales
- 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.
Fechas de registro del estudio
Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.
Fechas importantes del estudio
Inicio del estudio
1 de octubre de 2003
Finalización primaria (Actual)
1 de agosto de 2015
Finalización del estudio (Actual)
1 de agosto de 2015
Fechas de registro del estudio
Enviado por primera vez
23 de mayo de 2014
Primero enviado que cumplió con los criterios de control de calidad
23 de mayo de 2014
Publicado por primera vez (Estimar)
28 de mayo de 2014
Actualizaciones de registros de estudio
Última actualización publicada (Estimar)
12 de mayo de 2016
Última actualización enviada que cumplió con los criterios de control de calidad
10 de mayo de 2016
Última verificación
1 de mayo de 2016
Más información
Términos relacionados con este estudio
Términos MeSH relevantes adicionales
Otros números de identificación del estudio
- 03-0505-A
Información sobre medicamentos y dispositivos, documentos del estudio
Estudia un producto farmacéutico regulado por la FDA de EE. UU.
No
Estudia un producto de dispositivo regulado por la FDA de EE. UU.
No
producto fabricado y exportado desde los EE. UU.
No
Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .