Effects of Dietary Intervention and Surgery on NAFLD (Non-Alcoholic Fatty Liver Disease) (EDISON)

Approximately 90% of people undergoing bariatric surgery have NAFLD, which is a condition where fat accumulates in the liver and can lead to inflammation and scarring. It mostly causes no symptoms, however, in the most advanced cases there is an increased risk of liver cancer or liver failure.

NAFLD is currently managed by weight loss and treating associated diseases such as diabetes. No medicines have been licensed to directly treat it but bariatric surgery has been shown to be usually beneficial, although it is unknown whether some operations are better than others. It is also unclear whether this is due to general weight loss or other factors.

This study will be conducted in a hospital setting and aims to determine what changes in liver fat and fat processing occur after pre-operative low calorie diet and the two most common types of bariatric surgery (Roux-en-Y Gastric Bypass and Sleeve Gastrectomy.

Participants will have ten study visits, four of which may be combined with NHS appointments. Participants will undergo investigations including MRI scans to measure changes in NAFLD and DEXA scans to measure changes in fat and fat-free mass (FFM). Participants will also undergo mixed meal testing to which stable isotopes (deuterated water and 13c-palmitate) will be added to allow changes in fat processing to be detected. In addition to samples taken as part of NHS care, blood, urine, liver and fat (visceral and subcutaneous (abdominal and gluteal)) will be used for research. Visits will take place before and after low calorie diet and bariatric surgery.

Study Overview

• Status: Completed
• Conditions: Obesity, Morbid; Bariatric Surgery Candidate; Non-Alcoholic Fatty Liver Disease; Non Alcoholic Fatty Liver
• Intervention / Treatment: Procedure: Roux-en-Y Gastric Bypass (RYGB) surgery; Procedure: Sleeve Gastrectomy (SG) surgery

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jeremy Tomlinson, MD PhD; Phone Number: 0044 1865 857359; Email: jeremy.tomlinson@ocdem.ox.ac.uk
• Study Contact Backup: Name: Niall Dempster, MD; Phone Number: 0044 751 5437956; Email: niall.dempster@balliol.ox.ac.uk

Study Locations

• United Kingdom
  • Oxford, United Kingdom
    • University of Oxford

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Bariatric surgery is already planned for the participant
• Participant is willing and able to give informed consent for participation in the study.
• Aged ≥18 or ≤75 years.
• Body Mass Index ≥35 ≤55 kg/m2

Exclusion Criteria:

• Contraindication to MRI
• Prior or current participation in a CTIMP that could affect study results
• History of alcoholism or a greater than recommended weekly alcohol intake (14 units per week)
• History of albumin allergy
• Anticoagulant treatment
• Pregnant or nursing mothers
• Type 2 Diabetes
• A liver disease other than NAFLD
• Histological confirmation of lack of NAFLD on liver biopsy
• Large hiatus hernia (that would prohibit Sleeve Gastrectomy)
• Active gastrooesophageal reflux disease (that would prohibit Sleeve Gastrectomy)
• Active malabsorptive intestinal disease (that would prohibit Roux-en-Y Gastric Bypass surgery)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Roux-en-Y Gastric Bypass (RYGB) surgery	Procedure: Roux-en-Y Gastric Bypass (RYGB) surgery; RYGB operation using surgeons' standard technique
Active Comparator: Sleeve Gastrectomy (SG) surgery	Procedure: Sleeve Gastrectomy (SG) surgery; SG surgery using surgeons' standard technique

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in liver fat content	Change in liver fat content as measured on MRI scan +/- fibroscan	Baseline measurement just prior to initiation of routine preoperative low calorie diet (this starts 3-4 weeks before surgery) compared to measurements on completion of this (within a week of surgery) and at 20% weight loss and 1 year after SG or RYGB

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hepatic fatty acid synthesis	measured by incorporation of 2H2 palmitate from 2H2O into very low density lipoprotein triglyceride (VLDL-TG) and contribution of de novo lipogenesis and uptake and re-esterification to the hepatic triglyceride pool in liver biopsy	liver biopsy taken during SG or RYGB
Changes in relative contributions of pathways involved in lipid homeostasis	measured using mathematical modelling of results from stable isotope mixed meal test	Baseline measurement just prior to initiation of routine preoperative low calorie diet (this starts 3-4 weeks before surgery) compared to measurements on completion of this (within a week of surgery) and at 20% weight loss and 1 year after SG or RYGB
Changes in fasting and postprandial plasma lipid concentration	measured using a clinical analyser (in fasting states and in response to mixed meal test)	Baseline measurements just prior to initiation of routine preoperative low calorie diet (this starts 3-4 weeks before surgery) compared to measurements on completion of this (within a week of surgery) and at 20% weight loss and 1 year after SG or RYGB
Changes in fasting and postprandial plasma glucose concentration	measured using a clinical analyser measured using a clinical analyser (in fasting state and in response to mixed meal test)	Baseline measurement just prior to initiation of routine preoperative low calorie diet (this starts 3-4 weeks before surgery) compared to measurements on completion of this (within a week of surgery) and at 20% weight loss and 1 year after SG or RYGB
Change in the incorporation of 13C (from dietary fat) into CO2	measured using a breath analyser (in fasting state and in response to mixed meal test)	Baseline measurement just prior to initiation of routine preoperative low calorie diet (this starts 3-4 weeks before surgery) compared to measurements on completion of this (within a week of surgery) and at 20% weight loss and 1 year after SG or RYGB
Expression changes (gene/protein) in adipose tissue biopsies	measured using techniques such as quantitative real-time PCR (polymerase chain reaction) and ELISA (enzyme- linked immunosorbent assay)	Baseline measurement just prior to initiation of routine preoperative low calorie diet (this starts 3-4 weeks before surgery) compared to measurements on completion of this (within a week of surgery) and at 20% weight loss and 1 year after SG or RYGB
Change in fat mass	Proportional (% relative to baseline and lean mass) and absolute changes measured using DXA scan and bioimpedence analysis	Baseline measurement just prior to initiation of routine preoperative low calorie diet (this starts 3-4 weeks before surgery) compared to measurements on completion of this (within a week of surgery) and at 20% weight loss and 1 year after SG or RYGB
Change in lean mass	Proportional (% relative to baseline and fat mass) and absolute changes measured using DXA scan and bioimpedence analysis	Baseline measurement just prior to initiation of routine preoperative low calorie diet (this starts 3-4 weeks before surgery) compared to measurements on completion of this (within a week of surgery) and at 20% weight loss and 1 year after SG or RYGB
Change in functional strength	measured using hand dynamometer	Baseline measurement just prior to initiation of routine preoperative low calorie diet (this starts 3-4 weeks before surgery) compared to measurements on completion of this (within a week of surgery) and at 20% weight loss and 1 year after SG or RYGB
changes in fasting and post-prandial peptides/proteins (e.g. PYY, GLP-1, insulin)	measured using ELISA (in fasting state and in response to mixed meal test)	Baseline measurement just prior to initiation of routine preoperative low calorie diet (this starts 3-4 weeks before surgery) compared to measurements on completion of this (within a week of surgery) and at 20% weight loss and 1 year after SG or RYGB
change in weight	measured in kilograms using weighing scales	Baseline measurement just prior to initiation of routine preoperative low calorie diet (this starts 3-4 weeks before surgery) compared to measurements on completion of this (within a week of surgery) and at 20% weight loss and 1 year after SG or RYGB
change in body mass index (BMI)	weight measured in kilograms using weighing scales and combined with height in metres to report BMI in kg/m^2	Baseline measurement just prior to initiation of routine preoperative low calorie diet (this starts 3-4 weeks before surgery) compared to measurements on completion of this (within a week of surgery) and at 20% weight loss and 1 year after SG or RYGB
change in status of metabolic diseases (e.g. diabetes) / metabolic disease risk scores	measured with blood tests (e.g. hba1c), by recording clinical changes including medication requirements and clinical data (e.g. blood pressure)	Baseline measurement just prior to initiation of routine preoperative low calorie diet (this starts 3-4 weeks before surgery) compared to measurements on completion of this (within a week of surgery) and at 20% weight loss and 1 year after SG or RYGB
complications, re-operation, mortality	clinical events will be recorded	Baseline measurement just prior to initiation of routine preoperative low calorie diet (this starts 3-4 weeks before surgery) compared to measurements on completion of this (within a week of surgery) and at 20% weight loss and 1 year after SG or RYGB
changes in subcutaneous, visceral and pancreatic fat	measured on MRI scan	Baseline measurement just prior to initiation of routine preoperative low calorie diet (this starts 3-4 weeks before surgery) compared to measurements on completion of this (within a week of surgery) and at 20% weight loss and 1 year after SG or RYGB

Collaborators and Investigators

• Sponsor: University of Oxford
• Investigators: Principal Investigator: Jeremy Tomlinson, MD PhD, University of Oxford

Study record dates

Study Major Dates

• Study Start (Actual): June 9, 2017
• Primary Completion (Actual): August 30, 2020
• Study Completion (Actual): August 30, 2020

Study Registration Dates

• First Submitted: May 23, 2017
• First Submitted That Met QC Criteria: June 13, 2017
• First Posted (Actual): June 14, 2017

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: bariatric surgery; non-alcoholic fatty liver disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Obesity, Morbid
• Other Study ID Numbers: 219190

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No