In an adult with biopsy‑proven non‑alcoholic steatohepatitis (NASH) and fibrosis stage F2–F3, what is the recommended resmetirom (MGL‑3196) dose, eligibility criteria, baseline laboratory assessments, monitoring schedule, contraindications (e.g., pregnancy), and common adverse effects?

Resmetirom for Non-Cirrhotic NASH with F2–F3 Fibrosis

Resmetirom is FDA-approved at weight-based doses (80 mg for patients <100 kg, 100 mg for ≥100 kg) for adults with biopsy-proven or non-invasively confirmed non-cirrhotic NASH and moderate-to-advanced fibrosis (F2–F3), used in conjunction with diet and exercise. 1

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Dosing Algorithm

Weight-based dosing:

• 80 mg once daily for patients weighing <100 kg 1
• 100 mg once daily for patients weighing ≥100 kg 1

Dose adjustments with concomitant medications:

• Reduce resmetirom dose when co-administered with moderate CYP2C8 inhibitors 2, 3
• Avoid concomitant use with strong CYP2C8 inhibitors or OATP1B1/OATP1B3 inhibitors 2, 3
• Limit statin doses: rosuvastatin or simvastatin to ≤20 mg/day; pravastatin or atorvastatin to ≤40 mg/day 3, 4

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Eligibility Criteria

Inclusion requirements:

• Adults with non-cirrhotic NASH and fibrosis stage F2 or F3 (moderate to advanced fibrosis) 1
• Diagnosis can be established by liver biopsy OR concordant non-invasive tests (NITs) suggesting F2–F3 disease 1, 2
• Must be used in conjunction with diet and exercise 1

Exclusion criteria:

• Cirrhosis (F4 fibrosis) – resmetirom is contraindicated in decompensated cirrhosis and not approved for any cirrhotic patients 1, 4
• Early fibrosis (F0–F1) – excluded from the approved indication 1
• Other causes of liver disease must be ruled out: alcohol-associated liver disease, viral hepatitis, autoimmune hepatitis, iron overload 1

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Baseline Laboratory Assessments

Before initiating resmetirom, obtain:

• Liver enzymes (ALT, AST) to establish baseline and exclude autoimmune hepatitis if elevated with positive autoantibodies 1
• Lipid panel (LDL-cholesterol, triglycerides, apolipoprotein B) 5, 6
• Thyroid function tests (free T4, TSH, free T3) 1, 3
• Fibrosis assessment via FIB-4 score followed by transient elastography (liver stiffness ≥10 kPa suggests ≥F2) or MRI-elastography if obesity limits FibroScan accuracy 1, 4
• Hepatic fat quantification by MRI-PDFF if available 1, 6
• Exclude other liver diseases: viral hepatitis serologies, ferritin/transferrin saturation, autoimmune markers (ANA, anti-smooth muscle antibody), alcohol biomarkers (phosphatidylethanol if suspicion of underreporting) 1

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Monitoring Schedule

Week 12:

• Liver enzymes (ALT, AST) to detect drug-induced liver injury 4
• Lipid panel (LDL-cholesterol, triglycerides) 5, 6
• MRI-PDFF (if available) – a relative reduction >30% and ALT decrease >17 U/L are associated with histologic MASH resolution 4

Month 6:

• Repeat liver enzymes, lipid panel 3
• Thyroid function tests (free T4, TSH) – resmetirom decreases free T4 levels 2, 3
• Transient elastography or fibrosis biomarkers (e.g., PRO-C3) to assess fibrosis progression 6

Month 12:

• Full efficacy evaluation: liver enzymes, lipid panel, thyroid function, MRI-PDFF, transient elastography 3
• Consider repeat liver biopsy in select cases where precise histologic response is needed, though NITs are preferred for routine monitoring 1, 4

Ongoing:

• Monitor for gallbladder complications (cholelithiasis, acute cholecystitis, obstructive pancreatitis) – educate patients to report abdominal pain, nausea, vomiting, or fever 4
• Annual fibrosis monitoring with FIB-4 and elastography for patients with F2/F3 4

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Contraindications

Absolute contraindications:

• Decompensated cirrhosis (Child-Pugh B or C) 1, 4
• Pregnancy – resmetirom's effects on fetal development are unknown; women of childbearing potential should use effective contraception 2

Relative contraindications/cautions:

• Concomitant strong CYP2C8 inhibitors or OATP1B1/OATP1B3 inhibitors – avoid use 2, 3
• Suspected autoimmune hepatitis – rule out before initiating, as elevated liver enzymes during treatment may confound diagnosis 1

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Common Adverse Effects

Gastrointestinal (most common, mild-to-moderate):

• Diarrhea – most frequent adverse event 1, 2, 3, 7
• Nausea 1, 2, 3, 7, 8
• Vomiting 2, 3

Dermatologic:

• Pruritus 2, 3

Hepatobiliary:

• Transient ALT/AST elevations – especially with concurrent statin use 4
• Gallbladder complications (cholelithiasis, acute cholecystitis, obstructive pancreatitis) – occur more frequently than placebo 4

Endocrine:

• Decreased free T4 levels – resmetirom acts as a liver-selective thyroid hormone receptor-β agonist without central hypothalamic-pituitary-thyroid axis suppression; TSH and free T3 remain unchanged 1
• Elevated sex hormone-binding globulin – free testosterone levels remain unchanged; no impact on bone mineral density observed to date 1

Overall tolerability:

• Adverse events are mostly mild to moderate with good overall tolerability 1, 3, 7, 8
• No evidence of central thyroid axis dysregulation or interference with thyroid hormone replacement therapy 1

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Concomitant GLP-1 or GLP-1/GIP Dual Agonists

For patients already on GLP-1 receptor agonists or tirzepatide:

• Initiate resmetirom if residual active MASH with F2–F3 fibrosis persists 1, 3, 4
• In the MAESTRO-NASH trial, ~14% of patients were on GLP-1 therapy at baseline, and it did not affect resmetirom's tolerability or efficacy 1, 4

For GLP-1-naïve patients:

• Concomitant initiation of GLP-1 therapy and resmetirom is not recommended due to lack of evidence 1, 3
• Balance risk-benefit: only resmetirom has demonstrated MASH resolution and fibrosis regression in a large phase 3 trial; GLP-1 agonists offer metabolic benefits but lack phase 3 histologic data in NASH 1, 4

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Common Pitfalls to Avoid

• Do not use resmetirom in cirrhotic patients (F4) – it is contraindicated in decompensated cirrhosis and not approved for any cirrhotic stage 1, 4
• Do not rely on ultrasound alone to exclude cirrhosis – use FIB-4, transient elastography, or MRI-elastography for accurate staging 4
• Do not ignore gallbladder symptoms – resmetirom increases risk of cholelithiasis and acute cholecystitis; educate patients to report right upper quadrant pain, nausea, or fever 4
• Do not co-administer with strong CYP2C8 inhibitors – this increases resmetirom exposure and toxicity risk 2, 3
• Do not exceed recommended statin doses when using resmetirom – limit rosuvastatin/simvastatin to ≤20 mg/day and pravastatin/atorvastatin to ≤40 mg/day 3, 4
• Do not discontinue lifestyle interventions – resmetirom must be used in conjunction with diet (Mediterranean pattern, 7–10% weight loss target) and ≥150 min/week of moderate-intensity exercise 1, 4