In a 72-year-old obese woman with type 2 diabetes on tirzepatide (Mounjaro) 12.5 mg who has lost 20 lb, normal liver enzymes, FibroScan showing stage 2 fibrosis and an ultrasound that cannot exclude cirrhosis, should she start resmetirom (Rezdiffra)?

Should This Patient Start Resmetirom?

No, this patient should not start resmetirom at this time. The ultrasound's inability to exclude cirrhosis creates diagnostic uncertainty that must be resolved before initiating therapy, as resmetirom is contraindicated in cirrhosis and approved only for non-cirrhotic MASH with F2-F3 fibrosis. 1, 2

Critical Diagnostic Gap

The FibroScan F2 result conflicts with the ultrasound concern for possible cirrhosis, creating a diagnostic dilemma that requires resolution before treatment decisions. This discordance is particularly problematic because:

• FibroScan significantly overestimates advanced fibrosis and cirrhosis in patients with class 3 obesity, with studies showing 38.6% discordance rates in this population. 3
• In one study, FibroScan suggested cirrhosis in 57.9% of class 3 obesity patients, but liver biopsy confirmed cirrhosis in only 24.2% of those cases. 3
• Resmetirom is specifically contraindicated in decompensated cirrhosis and not approved for F4 (cirrhotic) disease. 1, 4

Required Next Steps Before Treatment

Obtain definitive fibrosis staging through one of these approaches:

1. Liver biopsy remains the gold standard when non-invasive tests are discordant or unreliable, particularly in class 3 obesity. 2, 3
2. MRI-based elastography (MRE) if available, as it is less affected by obesity than FibroScan. 2
3. Proprietary blood-based non-invasive tests (e.g., Enhanced Liver Fibrosis score, FibroTest) to provide additional data points. 2

If biopsy or additional testing confirms F2-F3 fibrosis (not F4/cirrhosis), then resmetirom becomes appropriate. 1, 2

Resmetirom Eligibility Criteria

FDA-approved indications require ALL of the following: 1, 2

• Non-cirrhotic NASH/MASH with moderate to advanced fibrosis (F2-F3 stages)
• Active steatohepatitis ("at-risk MASH")
• Used in conjunction with diet and exercise
• Explicitly avoid use in decompensated cirrhosis 1

This patient's current status:

• ✓ Has metabolic risk factors (obesity, diabetes)
• ✓ Normal liver enzymes (though this doesn't exclude MASH)
• ✓ FibroScan suggests F2
• ✗ Ultrasound cannot exclude cirrhosis—this is the critical barrier
• ? Active steatohepatitis not confirmed histologically

Current Optimal Management While Awaiting Clarification

Continue and optimize tirzepatide therapy, as she is already on Mounjaro 12.5 mg with documented weight loss. 2

• GLP-1/GIP dual agonists like tirzepatide provide substantial hepatic benefit in addition to glycemic control and weight loss, with demonstrated improvements in liver fat and inflammation. 5, 2
• Tirzepatide was present in ~14% of MAESTRO-NASH trial participants and did not affect resmetirom's tolerability or efficacy. 2
• If resmetirom is eventually started, continuing tirzepatide is recommended for patients with residual active MASH and F2-F3 fibrosis. 2

Target additional weight loss:

• She has lost 20 lbs over 4 years (modest rate); aim for 7-10% total body weight reduction to achieve MASH resolution and potential fibrosis regression. 5, 2
• Weight loss ≥10% is associated with fibrosis improvement. 5

Implement Mediterranean dietary pattern emphasizing vegetables, fruits, olive oil, nuts, legumes, and fish while eliminating sugar-sweetened beverages and ultra-processed foods. 5, 2

Prescribe ≥150 minutes/week of moderate-intensity aerobic activity. 5, 2

Key Safety Considerations If Resmetirom Is Eventually Started

Monitor for hepatotoxicity:

• Check liver enzymes at 12 weeks to assess for drug-induced liver injury (though early transient ALT/AST elevations may occur, especially with concomitant statins). 2, 1
• Educate patient on symptoms: fatigue, nausea, vomiting, right upper quadrant pain, jaundice, fever, rash. 1

Monitor for gallbladder complications:

• Cholelithiasis, acute cholecystitis, and obstructive pancreatitis occur more frequently with resmetirom. 1, 2
• Instruct patient to report severe abdominal pain, nausea, vomiting, or fever. 1

Statin dose adjustments:

• If on rosuvastatin or simvastatin: limit to 20 mg/day
• If on pravastatin or atorvastatin: limit to 40 mg/day 2, 1

Common Pitfalls to Avoid

Do not start resmetirom based solely on FibroScan F2 in a patient with class 3 obesity and conflicting imaging, as obesity causes significant FibroScan overestimation of fibrosis. 3

Do not assume normal liver enzymes exclude active MASH—many patients in MAESTRO-NASH had histologic improvement without ALT normalization. 2

Do not initiate GLP-1 therapy and resmetirom simultaneously due to lack of safety data; however, adding resmetirom to existing GLP-1 therapy is supported. 2

Do not use resmetirom if cirrhosis is confirmed, as it is not approved for F4 disease and should be avoided in decompensated cirrhosis. 1, 4