Fibrosis Reduction in Non Alcoholic Steatohepatitis

Study Overview
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Brief Summary
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Background: Non-Alcoholic Steatohepatitis (NASH) represents one of the stages of Non-Alcoholic Fatty Liver Disease (NAFLD) with a very high risk to evolve in cirrhosis and hepato-carcinoma. Currently, the only diagnostic method is a liver biopsy that remains the gold standard for characterizing liver histologic alterations and fibrosis stages. There is no specific treatment for NASH, in fact no drugs are currently licensed specifically for treating this disease. Aim: Our aim is to conduct a non-inferiority, randomized-controlled trial (RCT) comparing Roux-en-Y Gastric bypass (RYGB) with an intensive lifestyle modification plan (Very low-calorie diet, VLCD) for the reduction of advanced stages of fibrosis in subjects with obesity and NASH after 25% weight loss.

Detailed Description
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Materials and Methods: The Investigators will screen patients with obesity, NAFLD fibrosis score (NFS) >0.676 and FibroScan > 9.5 kPA who have a high probability of NASH with advanced stage of fibrosis. Participants will undergo liver biopsy to make diagnosis according to the Steatosis Activity Fibrosis (SAF) score algorithm. Subjects with BMI ≥ 30 and ≤50 kg/m2, age 25-65 years and F3-F4 fibrosis stage at liver biopsy will be included and randomized 1:1 to RYGB or VLCD. Anthropometric parameters, body composition with DEXA and liver function with blood samples will be assessed at the enrolment. A mixed meal metabolic test will be also performed to evaluate insulin sensitivity and secretion. These procedures will be repeated after 25% weight loss. Expectation: The Investigators expect a reduction of 2 points of histological fibrosis after 25% weight loss following either metabolic surgery or dieting. The investigators foresee also reversal of NASH, improvement of metabolic syndrome and glycemic control, changes in insulin sensitivity and secretion, changes in lipid profile, in NASH liver markers, in Fibroscan variables and in body composition

Official Title
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Fibrosis Reduction in Non Alcoholic Steatohepatitis: the Effects of Weight Loss vs Metabolic Surgery

Conditions
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NASH With Fibrosis, Weight Loss, Bariatric Surgery Candidate

Intervention / Treatment
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* Procedure: roux -en-y- gastric bypass
* Dietary Supplement: intensive life style modification


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed Consent signed before starting any procedure foreseen by the study; Liver Ultrasound shoving steatosis and Fibroscan>9,5 KPa; NAFLD fibrosis score>0,676; diagnosis of NASH with stage F3-F4 of fibrosis according to SAF score, documented by liver biopsy and no evidence of another form of liver disease; BMI≥ 30 and ≤50 kg/m2; Age 25-65 years. Exclusion Criteria: Chronic liver disease other than NAFLD (e.g. hemochromatosis, viral or autoimmune hepatitis, Wilson's disease, α1 -antitrypsin deficiency); Presence of esophageal varices and/or ascites; INR ≥ 1,4; Platelet count ≤ 100000; Substantial alcohol consumption (>20 g/day for women or >30 g/day for men) and/or toxin exposure; Coronary event or procedure (myocardial infarction, unstable angina, coronary artery bypass, surgery or coronary angioplasty) in the previous 6 months; End stage renal failure; Participation in any other concurrent therapeutic clinical trial; Any other life-threatening, non-cardiac disease; Pregnancy; Type 1 diabetes, or LADA; Lipodystrophy; Abetalipoproteinemia; Interfering medications (e.g., amiodarone, methotrexate, tamoxifen, corticosteroids); Inability to give informed consent.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 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: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: intensive lifestyle modifications<br>VLCD 800-850 Kcal/day | Dietary Supplement: intensive life style modification<br>* Weight loss will be induced using a VLCD (800-850 kcal/day; 59% carbohydrate, 13% fat, 26% protein, 2% fiber) with replacement meals for 2 months, followed by structured food reintroduction every 2-8 weeks (about 50% carbohydrate, 35% total fat, and 15% protein), and an ongoing structured program with follow-up visits up to 25% body weight loss<br>|
| Active Comparator: Roux-en-y-gastric bypass<br>laparoscopic RYGB | Procedure: roux -en-y- gastric bypass<br>* Roux-&-Y Gastric Bypass (RYGB) involves the use of a surgical stapler to create a small and vertically oriented gastric pouch with a volume of 30 ml. The upper pouch is completely divided by the gastric remnant and is anastomosed to the jejunum, 75 cm distally to the Treitz's ligament, through a narrow gastrojejunal anastomosis in a Roux-en-Y fashion. Bowel continuity is restored by an entero-entero anastomosis, between the excluded biliary limb and the alimentary limb, performed at 100 cm from the gastrojejunostomy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| histological reduction of fibrosis | The primary outcome is the rate of histological reduction of 2 points of fibrosis after 25% weight loss following either metabolic surgery or dieting | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver histology | Reversal of NASH: number of partcipant with a NAFLD activity score (NAS: from 0 to 8) < 3; Changes in Fibroscan evaluation: number of participant with a FibroScan <9.5 kPa. | 2 years | 
| Liver Markers | Changes in liver markers: number of participant with a significant reduction of AST and ALT from baseline; | 2 years | 
| Non-alcoholic Fatty Liver Disease Fibrosis score | Changes in Non-alcoholic Fatty Liver Disease Fibrosis score from baseline | 2 years | 
| Fibrosis-4 (FIB-4) Index | Changes in Fibrosis-4 (FIB-4) Index for Liver Fibrosis from baseline; | 2 years | 
| Fibroscan | Changes in Fibroscan evaluation: number of participant with a FibroScan <9.5 kPa. | 2 years |