Fibrosis Lessens After Metabolic Surgery

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), a major global public health concern, is commonly associated with obesity, diabetes, and dyslipidemia. MASLD is currently the most common cause of chronic liver disease affecting about 80% of people with obesity, ranging from simple fat deposits in the liver to Metabolic Dysfunction-Associated Steatohepatitis (MASH), cellular injury, advanced fibrosis, cirrhosis, or hepatocellular carcinoma. Patients with MASH are also at risk for cardiovascular disease and mortality. There is no universally approved medication for MASH. Weight loss remains the cornerstone of MASH treatment. Patients meeting the inclusion and exclusion criteria and who give informed consent will be enrolled in the trial and undergo the baseline liver biopsy (if none available). Approximately 120 patients with MASH and liver fibrosis (F1-F4 in baseline liver biopsy) will be randomized in a 1:1 ratio to metabolic surgery or medical treatment (incretin-based therapies ± other medical therapies for MASH) and followed for 2 years at which time a repeat liver biopsy will be performed for the assessment of the primary end point.

Inclusion Criteria Entry into the study would require that the patient: 1. Is a candidate for general anesthesia 2. Is eligible for metabolic surgery (RYGB or SG) based on the ASMBS/IFSO 2022 guidelines 3. Has insurance coverage for metabolic surgery (the requirements may vary in each country) 4. Is ≥18 and ≤75 years old at the time of signing the informed consent 5. Has a BMI ≥35 and ≤70 kg/m2 at the time of first study visit 6. FIB-4 ≥ 1.3 7. At least one of the following 5 criteria suggesting presence of advanced fibrosis: * LSM ≥ 12 kPa by VCTE using FibroScan® * LSM ≥ 12 kPa by SWE * LSM ≥ 1.7 m/s by ARFI * LSM ≥ 3.63 kPa MRE * ELF score ≥ 9.8 8. Patients with and without T2DM are eligible for the study. Patients with T2DM should have been on a stable dose of anti-diabetic medication (including insulin but not semaglutide or tirzepatide or liraglutide) for at least 3 months prior to entry, with glycated hemoglobin (HbA1c) ≤12%. 9. Self-reported stable weight in 6 months before the first study visit (no weight loss \>10% within 6 months prior to the first study visit) a. In patients with a historical noninvasive tests or liver biopsy, weight loss of no more than 10% is allowed from 6 months prior to the historical tests until the first study visit 10. Has the ability and willingness to participate in the study, provide informed consent, and agree to any of the arms involved in the study 11. Can understand the options and comply with the requirements of each arm, including one liver biopsy performed during the screening period (if no adequate biopsy within 12 months before screening is available) and one liver biopsy after 2-years 12. Has a negative urine pregnancy test at the first and at the randomization visits for women of childbearing potential. 13. Women of childbearing age must agree to use reliable method of contraception for 2 years 8.2 Exclusion Criteria Patients who meet the following criteria will be excluded from the study: 1. Known history of other chronic liver diseases (drug induced, viral hepatitis, autoimmune, and genetic): * Hepatitis B as detected by presence of hepatitis B surface antigen (HBsAg) * Hepatitis C as detected by presence of hepatitis C virus (HCV) RNA (in case the screening test for hepatitis C is positive, the confirmative test is decisive) * Autoimmune liver disease as diagnosed by antibodies or compatible liver histology * Primary biliary cirrhosis as defined by the presence of at least 2 criteria (elevated alkaline phosphatase, presence of anti-mitochondrial antibody, and histologic evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts) * Primary sclerosing cholangitis * Wilson's disease as diagnosed by low ceruloplasmin or compatible liver histology * Alpha-1-antitrypsin deficiency as diagnosed by alpha1-antitrypsin level or liver histology * Hemochromatosis as diagnosed by HFE mutations (C282Y, H63D), ferritin and transferrin saturation levels, or presence of 3+ or 4+ stainable iron on liver biopsy * Drug-induced liver disease diagnosed by medical history * Known bile duct obstruction * Suspected or proven liver cancer 2. Weight change \>10% within 6 months prior to the first study visit or prior to the historical liver biopsy 3. Treatment with semaglutide, tirzepatide, or liraglutide (for obesity or for T2DM) \13 mm), biphasic or reverse flow in the portal vein, enlarged paraumbilical veins, splenorenal collaterals, or dilated left and short gastric veins. Note: Negative findings on upper endoscopy and liver duplex ultrasound (done within one year of the first study visit for both tests) are necessary to establish eligibility for the FLAMES. * Ruling out clinically significant portal hypertension is particularly important in patients with a liver stiffness ≥20 kPa or with a platelet count \150,000 per μL, or * a (historical) liver biopsy showing absence of cirrhosis, or * a (historical) HVPG \< 5 mmHg 57. Cross-sectional abdominal imaging (if available historically) indicating presence of large portosystemic collaterals or ascites • Splenomegaly alone (in the absence of other radiological and laboratory findings) is not considered to be a sign of clinically significant portal hypertension and is not an exclusion criterion. 58. HVPG ≥ 12 mmHg (if available historically or if measured at the time of de novo liver biopsy) 59. Liver biopsy characteristics: * F0 in de novo biopsy; Enrollment cap of 20% for F1 in de novo biopsy. * F0 and F1 in historical liver biopsy * Absence of all three components of MASH (steatosis, hepatocyte ballooning, and lobular inflammation) in patients with F1, F2, and F3 * Absence of steatosis (\