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

Study Overview
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Brief Summary
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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.

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

Conditions
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Non-Alcoholic Fatty Liver Disease, Non Alcoholic Fatty Liver, Bariatric Surgery Candidate, Obesity, Morbid

Intervention / Treatment
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* Procedure: Roux-en-Y Gastric Bypass (RYGB) surgery
* Procedure: Sleeve Gastrectomy (SG) surgery


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non-alcoholic fatty liver disease, bariatric surgery