How to treat a patient with non-alcoholic steatohepatitis (NASH) and metabolic associated steatohepatitis liver disease (MASLD) with persistent alanine transaminase (ALT) elevation who has failed to lose weight?

Treatment of MASLD with Persistent ALT Elevation Despite Failed Weight Loss Attempts

For patients with MASLD who have persistent ALT elevation and have failed weight loss attempts, pharmacological therapy with resmetirom should be considered if they have non-cirrhotic MASH with significant fibrosis (stage ≥2), while simultaneously intensifying lifestyle interventions through structured programs and addressing all cardiometabolic risk factors. 1, 2

Immediate Pharmacological Considerations

Resmetirom (First-Line Liver-Targeted Therapy)

• Resmetirom is the first FDA-approved medication specifically for MASH and should be considered for patients with non-cirrhotic MASH and fibrosis stage ≥2. 1, 2
• This thyroid hormone receptor-beta agonist has demonstrated histological efficacy on both steatohepatitis and fibrosis in phase III trials with an acceptable safety profile. 2
• Importantly, resmetirom improves MASLD outcomes without requiring weight loss, making it ideal for patients who have failed weight reduction attempts. 3

Incretin-Based Therapies (GLP-1 Receptor Agonists)

• Consider semaglutide or tirzepatide, particularly if the patient has comorbid type 2 diabetes or obesity. 2
• These agents provide dual benefits: significant weight loss (which many patients struggle to achieve through lifestyle alone) and direct improvements in hepatic steatosis and inflammation. 3, 4
• GLP-1 receptor agonists are the most commonly prescribed weight loss medications by hepatology providers (66% preference among prescribers). 4

Alternative Pharmacological Options

• Vitamin E (800 IU/day) may be considered for non-diabetic patients with biopsy-proven NASH, though it remains off-label and is commonly prescribed (30% of providers use it). 4
• Pioglitazone can improve MASLD and potentially fibrosis without requiring weight loss, though it may cause modest weight gain and requires careful patient selection. 3

Intensified Lifestyle Intervention Strategy

Structured Digital or Supervised Programs

• Patients who have "failed" unstructured weight loss attempts may benefit from formal, MASLD-specific digital behavioral interventions or supervised programs. 5
• These programs should include MASLD-specific education, self-regulation tools (goal setting, food monitoring, step tracking), and regular health coaching appointments. 5
• Even modest weight loss of 3.5% achieved through structured programs can reduce ALT by 27%. 5

Dietary Modifications (Mediterranean Pattern)

• Strongly recommend a Mediterranean dietary pattern with specific emphasis on limiting ultra-processed foods rich in sugars and saturated fats, and avoiding sugar-sweetened beverages. 1, 2
• This dietary approach can improve liver injury even without significant weight loss. 2
• Increase intake of fruits, vegetables, whole grains, legumes, nuts, and olive oil. 2
• Encourage coffee consumption, as observational studies show associations with improvements in liver damage and reduced liver-related clinical outcomes. 2

Exercise Prescription

• Prescribe at least 150 minutes/week of moderate-intensity aerobic activity or 75 minutes/week of vigorous-intensity activity. 1, 2
• Include resistance training as both aerobic and resistance exercise effectively reduce liver fat. 1
• Physical activity can reduce steatosis even when weight loss goals are not met. 1

Addressing Cardiometabolic Comorbidities

Comprehensive Metabolic Management

• A multidisciplinary approach is mandatory given the bidirectional connections between MASLD and cardiometabolic conditions. 1, 2
• Screen for and aggressively treat type 2 diabetes, hypertension, and dyslipidemia, as controlling these conditions impacts hepatic disease course. 1, 6
• Optimize glycemic control in diabetic patients, as type 2 diabetes is one of the metabolic diseases with the greatest impact on MASLD natural history. 1

Medication Review

• Discontinue or substitute medications that may worsen steatosis including corticosteroids, amiodarone, methotrexate, tamoxifen, estrogens, tetracyclines, and valproic acid. 6

Monitoring Strategy

Non-Invasive Test Follow-Up

• Follow up with liver enzyme tests (particularly ALT) every 3-6 months to assess response to interventions. 6
• Consider repeat non-invasive fibrosis assessment (such as FIB-4 or transient elastography) after 1 year of treatment. 6
• An ALT reduction of >17 U/L has been associated with resolution of steatohepatitis in clinical trials. 1

Liver Biopsy Consideration

• While not suited for routine monitoring, liver biopsy can be used in individual cases to monitor disease progression or confirm treatment response, particularly when considering escalation of therapy. 1

Bariatric Surgery Consideration

• Bariatric surgery should be considered for patients with obesity (BMI ≥35 or ≥30 with comorbidities) who do not respond to lifestyle interventions and pharmacotherapy. 2
• This represents a definitive option for patients with multiple failed weight loss attempts, as it provides sustained weight reduction and improvement in MASLD histology. 7, 8

Critical Pitfalls to Avoid

• Do not delay pharmacological intervention in patients with significant fibrosis (≥F2) simply because they haven't achieved weight loss targets. The presence of fibrosis stage ≥2 with persistent ALT elevation warrants consideration of liver-targeted therapy regardless of weight loss success. 1, 2
• Do not assume that "failed weight loss" means the patient is non-compliant or that lifestyle intervention is futile. Many patients require structured programs, pharmacological support, or bariatric intervention to achieve meaningful results. 5, 4
• Avoid prescribing weight loss medications without adequate knowledge or comfort. 81% of providers report low comfort with these medications despite 96% believing they could benefit patients, highlighting a critical treatment gap. 4
• Do not focus solely on liver outcomes while neglecting cardiovascular risk, as individuals with MASLD have increased risk of cardiovascular disease (HR 1.40), which often represents a greater mortality threat than liver disease itself. 1