What is the recommended treatment for a patient with metabolic associated steatohepatitis (NASH)?

Treatment for Metabolic Associated Steatohepatitis (MASH)

Lifestyle modification targeting 7-10% weight loss is the cornerstone of MASH treatment, with pharmacotherapy (resmetirom, vitamin E, or pioglitazone) reserved for biopsy-proven MASH with significant fibrosis (stage ≥2) in non-cirrhotic patients. 1

First-Line Treatment: Lifestyle Interventions

Weight loss remains the most effective therapy for MASH, with histologic improvement directly correlated to the degree of weight reduction 2:

• Target 7-10% total body weight loss to improve liver histology, reduce steatosis and inflammation, and achieve MASH resolution 1
• Aim for gradual weight loss of 0.5-1 kg per week through a caloric deficit of 500-1,000 kcal/day to avoid rapid weight reduction that may worsen liver disease 1
• Weight loss >10% is associated with significant improvement in NAFLD activity score and potential fibrosis regression 3

Dietary recommendations should focus on a Mediterranean diet pattern 1:

• Emphasize monounsaturated and omega-3 fatty acids, fruits, vegetables, whole grains, legumes, nuts, and olive oil 1
• Limit excess fructose consumption, processed foods with added sugars, saturated fats, red meat, and ultra-processed foods 1
• Replace saturated fats with polyunsaturated and monounsaturated fats 1

Exercise prescription should include both aerobic and resistance training 1:

• Prescribe 150-300 minutes of moderate-intensity aerobic exercise per week (or 75-150 minutes of vigorous-intensity) 1
• Include resistance training 2-3 times weekly, as both modalities effectively reduce liver fat 1

Pharmacological Treatment for Biopsy-Proven MASH

Pharmacotherapy should be considered only in patients with biopsy-proven MASH with significant fibrosis (stage ≥2) without cirrhosis 4, 1:

Resmetirom (First-Line Pharmacotherapy)

• Consider resmetirom for non-cirrhotic MASH with fibrosis stage ≥2 if locally approved, as it demonstrates histological effectiveness on steatohepatitis and fibrosis with an acceptable safety profile 1
• Resmetirom is NOT indicated at the cirrhotic stage (F4), as current approval is limited to non-cirrhotic MASH 5

Vitamin E

• Prescribe vitamin E 800 IU daily for non-diabetic adults with biopsy-confirmed MASH to improve liver histology through antioxidant properties 4, 1
• Vitamin E should not be used in diabetic patients due to safety concerns 4

Pioglitazone

• Prescribe pioglitazone 30 mg daily for patients with biopsy-proven MASH with or without diabetes 4, 1
• Pioglitazone improves liver histology but may cause weight gain and bone density loss, requiring monitoring 4

Management of Cardiometabolic Comorbidities

MASH patients have substantially elevated cardiovascular risk, making aggressive management of metabolic comorbidities essential 6:

Diabetes Management

• Prioritize GLP-1 receptor agonists (semaglutide, liraglutide) or tirzepatide for patients with type 2 diabetes, as these agents improve both glycemic control and liver histology 1, 6
• Metformin is not indicated specifically for NASH treatment but is safe and effective for diabetes management in MASH patients 4

Dyslipidemia Management

• Initiate statin therapy for all patients with dyslipidemia, as statins are safe in MASH and reduce hepatocellular carcinoma risk by 37% 1, 6
• Statins do not increase risk of drug-induced liver injury in NAFLD/MASH patients 4, 7

Hypertension Management

• Treat hypertension according to standard guidelines, as it is a key component of metabolic syndrome 4

Bariatric Surgery and Endoscopic Interventions

For patients with MASH and obesity who fail lifestyle modification:

• Consider bariatric surgery as an effective option for achieving sustained weight loss and improving liver histology 1, 2
• Endoscopic sleeve gastroplasty plus lifestyle intervention achieves 9.5% total body weight loss and significant reduction in steatosis and liver stiffness 3
• Intraoperative liver biopsy during bariatric or cholecystectomy surgery is low-risk and should be considered for diagnostic purposes 4

Medications to Avoid

Discontinue medications that may worsen steatosis 4:

• Corticosteroids
• Amiodarone
• Methotrexate
• Tamoxifen
• Estrogens
• Tetracyclines
• Valproic acid

Risk Stratification and Monitoring

Initial Evaluation

• Obtain baseline liver evaluation including ultrasound, complete blood count, comprehensive metabolic panel (AST, ALT, bilirubin, alkaline phosphatase), INR, and creatinine 4
• Assess cardiovascular risk factors: lipid profile, fasting glucose and/or HbA1c, waist circumference, BMI 4
• Calculate FIB-4 score for non-invasive fibrosis risk stratification (FIB-4 <1.3 = low risk, 1.3-2.67 = intermediate risk, >2.67 = high risk) 7

Liver Biopsy Indications

Refer for liver biopsy if 4:

• Patient has risk factors for MASH and advanced fibrosis (diabetes and/or metabolic syndrome)
• Findings concerning for cirrhosis (thrombocytopenia, AST>ALT, hypoalbuminemia)
• FIB-4 score indicates intermediate or high risk (≥1.3) 7

Follow-Up and Surveillance

• Low-risk patients require annual follow-up with repeated FIB-4 calculation to monitor for fibrosis progression 7
• For patients with cirrhosis (F4 fibrosis): perform hepatocellular carcinoma surveillance with ultrasound every 6 months 4, 5
• Screen for esophageal varices with upper endoscopy in cirrhotic patients, particularly if liver stiffness ≥20 kPa or thrombocytopenia present 5
• Monitor liver function tests, complete blood count, and INR every 3-6 months in cirrhotic patients 5

Special Considerations for Cirrhotic Patients (F4 Fibrosis)

Patients with established cirrhosis require immediate hepatology referral and specialized management 5:

• No MASH-targeted pharmacotherapy is currently recommended for F4 cirrhosis, as resmetirom and other agents are approved only for non-cirrhotic disease 5
• Lifestyle modification remains important but fibrosis regression is more challenging at the cirrhotic stage 5
• Refer to registered dietitian for specialized nutritional counseling, as cirrhotic patients require specific protein and calorie targets to prevent sarcopenia 5
• Minimize alcohol use to no more than 1 drink/day for women or 2 drinks/day for men 4

Common Pitfalls to Avoid

• Do not delay lifestyle intervention while awaiting biopsy results—weight loss and dietary changes should begin immediately upon MASH diagnosis 1
• Do not withhold statins due to elevated liver enzymes—statins are safe and beneficial in MASH patients with dyslipidemia 4, 7, 6
• Do not use vitamin E in diabetic patients—pioglitazone is the preferred option in this population 4, 1
• Do not prescribe pharmacotherapy for simple steatosis without biopsy-proven MASH and significant fibrosis—lifestyle modification alone is appropriate for low-risk patients 1, 7