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

Treatment Options for Non-Alcoholic Steatohepatitis (NASH)

Lifestyle modification through diet, exercise, and weight loss is the cornerstone of NASH treatment, with pharmacological options like resmetirom showing promise for non-cirrhotic patients with significant liver fibrosis (stage ≥2).

First-Line Treatment: Lifestyle Modifications

Weight Loss

• Weight loss of 7-10% is strongly associated with histological improvement in NASH 1, 2
• Progressive weight loss (<1kg/week) is preferred over rapid weight loss 3
• The degree of histological improvement correlates directly with the amount of weight lost:
  • 3-5% weight loss: Recommended for lean persons with NAFLD 1
  • 7-10% weight loss: Significant improvements in steatosis, inflammation, ballooning, and overall NASH activity score 2

Diet Recommendations

• Mediterranean diet pattern is recommended with 1, 3:
  • Daily consumption of vegetables, fruits, fiber-rich cereals, nuts, fish/white meat
  • Limited intake of simple sugars, red/processed meats, and ultra-processed foods
  • Olive oil as the primary fat source
• Reduce carbohydrate intake, especially fructose 1, 4
• Limit sugar-sweetened beverages, which can increase NAFLD risk up to four-fold 1
• Calorie restriction of 30% or approximately 750-1,000 kcal/day 1

Physical Activity

• 150-300 minutes/week of moderate-intensity exercise or 75-150 minutes/week of vigorous-intensity exercise 1, 3
• Combination of aerobic and resistance training is more effective than either alone 1
• Vigorous activity (≥6 METs) is required for improvement in NASH and fibrosis 1
• Even without significant weight loss, regular exercise can reduce aminotransferases and steatosis 1

Pharmacological Options

FDA-Approved Therapies

• Resmetirom: Currently the most promising MASH-targeted therapy for non-cirrhotic patients with significant liver fibrosis (stage ≥2) 3

Other Pharmacological Options (Not FDA-Approved for NASH)

• Vitamin E (800 IU/day): May be considered in non-diabetic patients with biopsy-confirmed NASH without cirrhosis 1

  • Improves liver histology but has potential concerns regarding all-cause mortality, hemorrhagic shock, and prostate cancer 1

• Pioglitazone: May be considered in patients with biopsy-confirmed NASH without cirrhosis 1

  • Improves liver histology but has side effects including weight gain, peripheral edema, heart failure, and fractures 1

• GLP-1 Receptor Agonists (e.g., semaglutide, liraglutide):

  • Semaglutide improved NASH resolution in 59% of patients vs 17% on placebo 1
  • Particularly effective for patients with comorbid type 2 diabetes or obesity 3
  • Liraglutide has shown promise in improving steatosis and reversing steatohepatitis 1

• SGLT2 inhibitors: May improve cardiometabolic profile and reverse steatosis in patients with diabetes and NAFLD 1

Surgical Options

• Bariatric surgery: Consider for patients with obesity and NASH who have not responded to lifestyle interventions 3, 5
  • Leads to significant weight loss and improvement in liver histology 3

Monitoring and Follow-up

• Regular monitoring of liver function tests 3
• Evaluation of fibrosis progression using non-invasive methods (elastography, biomarkers) 3
• HCC surveillance every 6 months for patients with advanced fibrosis or cirrhosis 3

Treatment Algorithm Based on Disease Stage

For Patients with Simple Steatosis or Early NASH:

1. Lifestyle modifications (diet, exercise, weight loss)
2. Management of metabolic comorbidities (diabetes, hypertension, dyslipidemia)

For Patients with NASH and Significant Fibrosis (Stage ≥2):

1. Intensive lifestyle modifications with structured weight loss program
2. Consider resmetirom if locally approved 3
3. Consider vitamin E (800 IU/day) for non-diabetic patients 1
4. Consider pioglitazone with careful monitoring of side effects 1
5. For patients with diabetes, consider GLP-1RAs or SGLT2 inhibitors 1, 3

For Patients with NASH Cirrhosis:

1. Nutritional counseling and lifestyle modifications
2. Surveillance for portal hypertension and HCC
3. Consider liver transplantation for decompensated cirrhosis 3

Key Pitfalls to Avoid

• Relying solely on liver enzymes for diagnosis or monitoring (can be normal in NASH)
• Initiating pharmacotherapy without biopsy confirmation of NASH
• Neglecting comorbid metabolic conditions that contribute to disease progression
• Rapid weight loss, which may worsen liver injury
• Alcohol consumption, which should be completely avoided, especially in cirrhosis 3