What are the treatment options for Non-Alcoholic Steatohepatitis (NASH)?

Treatment Options for Non-Alcoholic Steatohepatitis (NASH)

Lifestyle modifications are the cornerstone of NASH treatment, with a target weight loss of 7-10% being most effective for improving liver histology, inflammation, and fibrosis. 1, 2

First-Line Treatment: Lifestyle Modifications

Dietary Recommendations

• Mediterranean diet is strongly recommended, focusing on:
  • Vegetables, fruits, whole grains, legumes, and healthy fats
  • Replacing saturated fats with monounsaturated and polyunsaturated fatty acids
  • Using extra virgin olive oil as primary fat source
  • Limiting fructose and sugar-sweetened beverages 1, 2
• Caloric restriction:
  • 500-1000 kcal daily reduction from baseline
  • Target weight loss goals:
    • 3-5% weight loss: improves steatosis
    • 7-10% weight loss: improves liver inflammation and biochemistry

    • 10% weight loss: improves fibrosis 1, 2

Exercise Recommendations

• Minimum 150-200 minutes/week of moderate-intensity aerobic activities in 3-5 sessions
• Combination of aerobic exercise and resistance training is most effective
• Any physical activity is better than inactivity 1, 2

Pharmacological Options for Biopsy-Confirmed NASH

First-Line Pharmacotherapy

1. Vitamin E (800 IU daily)

   • Recommended for non-diabetic NASH patients without cirrhosis
   • Improves liver biochemistry, inflammation, and histology
   • Caution: Potential concerns about increased all-cause mortality, hemorrhagic stroke, and prostate cancer 1

2. Pioglitazone (30 mg daily)

   • Consider for NASH patients without cirrhosis
   • Improves NASH histology in patients with or without diabetes
   • Caution: Associated with weight gain, peripheral edema, heart failure, and fractures 1

Emerging Therapies

1. Resmetirom

   • First choice for non-cirrhotic NASH with significant liver fibrosis (stage ≥2)
   • Demonstrated histological efficacy on steatohepatitis and fibrosis 2

2. GLP-1 Receptor Agonists (semaglutide, liraglutide, dulaglutide)

   • Safe in NASH, including compensated cirrhosis
   • Primarily indicated for type 2 diabetes and obesity
   • Substantial weight loss provides potential hepatic histological benefit
   • Not yet approved specifically for NASH 2

3. SGLT2 Inhibitors (empagliflozin, dapagliflozin)

   • Safe in NASH but should be used for their primary indications (type 2 diabetes, heart failure, chronic kidney disease)
   • Insufficient evidence to recommend as NASH-targeted therapy 2

Bariatric Surgery

• Consider for non-cirrhotic NASH patients with obesity who meet standard criteria for bariatric surgery
• Induces long-term beneficial liver effects
• Associated with remission of type 2 diabetes and improvement of cardiometabolic risk factors
• For compensated cirrhosis, requires careful evaluation by a multidisciplinary team 1, 2

Monitoring and Follow-up

• Liver enzymes: Monitor every 3 months
• Imaging: Repeat at 6-12 months
• Liver biopsy: Consider after 1-2 years of therapy to assess histological response
• HCC surveillance: Ultrasound examination every 6 months for patients with advanced fibrosis or cirrhosis
• Non-invasive fibrosis assessment (FibroScan, FIB-4): Every 1-2 years to monitor disease progression 2

Treatment Algorithm

1. All NASH patients: Implement lifestyle modifications (diet + exercise)
2. For patients with biopsy-confirmed NASH without cirrhosis:
   • Without diabetes: Add vitamin E 800 IU daily
   • With or without diabetes: Consider pioglitazone 30 mg daily
3. For patients with significant fibrosis (stage ≥2): Consider resmetirom (when available)
4. For patients with obesity: Consider GLP-1 receptor agonists if diabetic or meeting criteria for weight management
5. For patients with obesity meeting criteria: Consider bariatric surgery

Common Pitfalls and Caveats

1. Insufficient weight loss: Many patients achieve <5% weight loss, which may not be enough to improve NASH. Structured weight loss programs are more effective than general advice.

2. Vitamin E safety concerns: Long-term use may increase all-cause mortality, hemorrhagic stroke, and prostate cancer risk. Use with caution and monitor.

3. Pioglitazone side effects: Weight gain, fluid retention, and bone fractures can limit use. Individualized risk assessment is necessary.

4. Overreliance on liver enzymes: Normal ALT/AST doesn't exclude NASH progression. Regular monitoring with non-invasive tests is essential.

5. Lack of approved therapies: Despite promising research, no drugs are FDA-approved specifically for NASH treatment. Current pharmacotherapy is off-label.