Optimizing Portal Hypertension With TIPS and Interval Metabolic Surgery for Advanced Liver Disease

Obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) are now among the leading global causes of cirrhosis. Up to one-third of individuals with cirrhosis also have class II or III obesity, which exacerbates portal hypertension, accelerates liver disease progression, and can limit eligibility for liver transplantation. Metabolic (bariatric) surgery is an established treatment that induces sustained weight loss and improves metabolic and hepatic outcomes. However, the presence of clinically significant portal hypertension (CSPH) increases the risks of surgery, including intraoperative bleeding and postoperative hepatic decompensation. Small retrospective studies suggest that placing a transjugular intrahepatic portosystemic shunt (TIPS) before surgery may reduce these risks by decompressing the portal venous system. To date, no prospective randomized trial has evaluated this approach.

The OPTIMAL Trial (Optimizing Portal Hypertension with TIPS and Interval Metabolic Surgery for Advanced Liver Disease) is a single-center, prospective randomized controlled trial designed to determine whether a staged strategy using TIPS followed by sleeve gastrectomy improves health-related quality of life (HRQoL), weight loss, and safety in patients with cirrhosis, severe obesity, and CSPH compared to medical management alone.

The trial will enroll 70 adults aged 18 to 70 years with a body mass index (BMI) between 35 and 70 kg/m², biopsy-proven or elastography-confirmed cirrhosis, and objective evidence of CSPH. Inclusion criteria include Child-Pugh class A or B liver function, MELD 3.0 score <=15, and platelet count >= 50,000 /µL. Key exclusion criteria include decompensated cirrhosis, defined as moderate-to-large volume ascites, hepatic encephalopathy, or patients undergoing liver transplant evaluation. Patients with a history of variceal hemorrhage or small-volume ascites may still be eligible. Other exclusions include MELD 3.0 > 15, portal vein thrombosis, hepatocellular carcinoma, prior metabolic surgery, pregnancy, active substance use, untreated psychiatric illness, and severe cardiopulmonary disease that would preclude surgery or anesthesia.

After informed consent, participants will be randomized in a 1:1 ratio to one of two arms. The intervention group will undergo TIPS placement, aiming for at least a 50 percent reduction in hepatic venous pressure gradient (HVPG) or a final HVPG less than 12 mmHg, followed by sleeve gastrectomy approximately 4 to 6 weeks later. The control group will receive structured lifestyle counseling and, when clinically indicated, FDA-approved pharmacologic therapies for weight management and diabetes.

Follow-up visits at 1, 3, and 6 months will assess weight, vital signs, adverse events, and MELD 3.0 laboratory values. Liver Doppler ultrasound will be performed in the intervention group to assess TIPS patency per standard of care. Both groups will complete the SF-36 survey to evaluate health-related quality of life. The primary outcome is the change in SF-36 Physical Component Summary (PCS) score from baseline to 6 months. Secondary outcomes include percentage of total body weight loss, incidence of serious liver-related complications such as hepatic encephalopathy, variceal bleeding, and acute-on-chronic liver failure, as well as changes in SF-36 scores at 1 and 3 months. Exploratory outcomes include changes in MELD 3.0 parameters (bilirubin, albumin, INR, sodium, and creatinine); proportion of participants achieving 5% to 25% weight loss; changes in BMI, waist circumference, and body composition; changes in glucose and HbA1c in patients with type 2 diabetes; proportion meeting HbA1c targets (<6.5% without medications, <7% overall); and changes in cardiovascular and diabetes medication use.

Following randomization, all patients who receive TIPS or start nonsurgical management will be analyzed based on the intention-to-treat plan. Furthermore, patients who undergo TIPS placement but not sleeve gastrectomy for any reason, such as the development of de novo portal vein thrombosis, development of de novo acute renal failure, or persistent esophageal varices, will not be included in the per-protocol (on treatment) analysis.

This trial will generate the first prospective data evaluating whether a combined approach of portal pressure reduction and metabolic surgery can safely and effectively improve quality of life, metabolic control, and liver-related outcomes in patients with cirrhosis, severe obesity, and CSPH.

• Transjugular Intrahepatic Portosystemic Shunt (TIPS) (Procedure), also known as TIPS: Fluoroscopically guided placement of a covered stent creating a portosystemic shunt between hepatic and portal veins. Goal: ≥ 50 % HVPG reduction or final HVPG < 12 mmHg. Conducted 4-6 weeks (≤ 6 months allowed) before bariatric surgery; standard post-TIPS surveillance ultrasound and EGD to confirm patency and variceal resolution.
• Sleeve Gastrectomy (Procedure), also known as SG: Longitudinal resection of \~80 % of stomach via laparoscopic or robotic approach, preserving pylorus. Performed after successful TIPS once portal pressures stabilize (< 6 months post-TIPS). Standard peri-operative care, micronutrient supplementation, and bariatric follow-up per ASMBS guidelines.
• Anti-Obesity Pharmacotherapy (Class Effect) (Drug), also known as GLP-1 receptor agonist, Topiramate, Phentermine, Incretin Mimetics: Clinician-selected, evidence-based anti-obesity medications (AOMs) used at the treating provider's discretion. Agents may include incretin-based therapies (e.g., Semaglutide, Tirzepatide) or other FDA-approved AOMs such as Topiramate or Phentermine. Dosing and titration follow standard labeling; no specific drug is mandated. The study assesses the overall class effect of pharmacotherapy rather than any single agent.
• Lifestyle Counseling - Diet & Physical-Activity Program (Behavioral), also known as Dietary modification, Exercise counseling, Behavioral weight-loss coaching: Regular sessions with a registered dietitian or equivalent (in-person or virtual) focusing on adherence to a reduced-calorie diet, structured physical-activity regimen, and behavior-change strategies. Counseling occurs throughout the 6-month study period and is considered standard care for this patient population.

Primary outcomes

• Change in SF-36 Physical Component Summary (PCS) Score From Baseline to 6 Months [At 6 months after treatment initiation (Day 0 = TIPS placement date or start of medical management).]: Difference between baseline and 6-month SF-36 PCS score (0-100 scale; higher values = better physical health-related quality of life). Positive change denotes improvement.

Secondary outcomes

• Percent Total Body-Weight Loss (%TBWL) at 6 Months [At 6 months after treatment initiation]: %TBWL = ((baseline weight - 6-month weight) ÷ baseline weight) × 100.
• Incidence of Serious Complication Composite Within 6 Months [Up to 6 months after treatment initiation]: Proportion of participants experiencing ≥ 1 of the following: severe hepatic encephalopathy (requiring hospitalization/intubation/TIPS revision), variceal hemorrhage, acute-on-chronic liver failure, deep intra-abdominal infection, severe sepsis, blood transfusion, pulmonary embolism, initiation of dialysis, or death.
• Change in SF-36 Physical Component Score From Baseline to 1 Month [Baseline and 1 month]: Differences in SF-36 Physical Component Score at one month versus baseline (higher = better physical health-related quality of life).
• Change in SF-36 Mental Component Score From Baseline to 1 Month. [Baseline and 1 month.]: Differences in SF-36 Mental Component Score at one month versus baseline (higher = better mental health-related quality of life).
• Change in SF-36 Physical Component Score From Baseline to 3 Months [Baseline and 3 months]: Differences in SF-36 Physical Component Score at three months versus baseline (higher = better physical health-related quality of life).
• Change in SF-36 Mental Component Score From Baseline to 3 Months. [Baseline and 3 months.]: Differences in SF-36 Mental Component Score at three months versus baseline (higher = better mental health-related quality of life).

Other outcomes

• Change in HbA1c (%) [Baseline and 6 months (Week 24) after treatment initiation]: Mean absolute change in glycated hemoglobin (HbA1c, percent) between baseline and each follow-up visit

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria

1. Is a candidate for general anesthesia
2. Is ≥18 and ≤70 years old at the time of signing the informed consent
3. Has a BMI ≥35 and ≤85 kg/m2 at the time of first study visit
4. Is eligible for metabolic surgery (SG) based on the ASMBS/IFSO 2022 guidelines \[39\]
5. Has insurance coverage for metabolic surgery
6. Patients who are currently receiving or have previously received anti-obesity medicines will be considered for participation
7. Liver cirrhosis as determined via liver biopsy or noninvasive liver disease assessment
8. CSPH as determined by HVPG of ≥ 10-12 mmHg, presence of esophagogastric varices, moderate-to-severe portal hypertensive gastropathy, dilated portal vein (>13 mm), biphasic or reverse portal vein flow, enlarged paraumbilical veins, splenorenal collaterals, or dilated left and short gastric veins.
9. Has the ability and willingness to participate in the study, provide informed consent, and agree to any of the arms involved in the study.
10. Has a negative urine pregnancy test at the first visit and at the randomization visits for women of childbearing potential.
11. Women of childbearing age must agree to use reliable method of contraception for 2 years.

Exclusion Criteria

1. Prior bariatric and metabolic surgery of any kind

   • Reversed procedures such as gastric band or intragastric balloon that have been removed at least 3 months prior to the first study visit are allowed.
2. Prior complex foregut surgery including any esophageal and gastric surgeries, anti-reflux procedures, biliary diversion, and complex trauma surgery
3. History of solid organ transplant
4. Severe pulmonary disease defined as FEV1 < 50% of predicted value
5. Significant cardiac or atherosclerotic disease (planned to undergo cardiac, coronary, carotid, or peripheral artery revascularization procedures in the next 12 months)
6. Severe uncompensated cardiopulmonary disease leading to American Society of Anesthesiologists Class IV or V
7. Left ventricular ejection fraction <25% at the time of screening
8. Myocardial infarction, unstable angina, stroke, heart surgery, coronary stent placement in the past 6 months
9. Presence of large hiatal hernia (>7 cm)
10. Presence of erosive esophagitis (LA Grade C and D)
11. Presence of active Crohn's disease
12. Psychiatric disorders including (but not limited to) dementia, active psychosis, severe depression requiring 3 or more medications, history of suicide attempts, active alcohol, or substance abuse within the previous 12 months that in the opinion of the investigators could disqualify the patient from metabolic surgery
13. Pregnancy, the intention of becoming pregnant, or not using adequate contraceptive measures
14. Breastfeeding
15. Diagnosis of malignancy within the preceding 1 year, including intra- or extra-hepatic malignancy. This includes known hepatocellular carcinoma or evidence of OPTN-V lesion on imaging (except squamous cell and basal cell cancer of the skin).
16. Clinical judgment that life expectancy is less than 2 years
17. Use of investigational therapy within 3 months prior to signing the consent
18. Acute pancreatitis < 90 days before screening
19. Portal vein thrombosis
20. Decompensated cirrhosis: moderate-to-large volume ascites, hepatic encephalopathy, or patients undergoing liver transplant evaluation.

    • We will include patients with prior variceal hemorrhage or small volume ascites
21. Total bilirubin > 3 mg/dl within 1 month of screening
22. INR > 1.7 within 1 month of screening
23. Platelets <50,000 per microliter within 1 month of screening
24. Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to the first study visit.

    • Defined as more than 14 units/week for females (>1 drink per day) and more than 21 units/week for males (>2 drinks per day) on average, where one unit of alcohol is equivalent to a 12-ounce beer, 4-ounce glass of wine, or 1-ounce shot of hard liquor.
25. Chronic renal insufficiency with estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73 m2 or being on dialysis within 1 month of screening.
26. Known cases of Acquired Immune Deficiency Syndrome (AIDS)
27. Unable to understand the risks, benefits, and compliance requirements of study
28. Lack capacity to give informed consent
29. Plans to move outside the primary location of study (within 3-hour distance of Cleveland) within the next 6 months.
30. Previous participation in this trial and got randomized to one of the study groups but did not proceed.
31. Any condition or major illness that, in the investigator's judgment, places the subject at undue risk by participating in the study

• Ali Aminian, MD, Principal investigator, The Cleveland Clinic