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

Treatment Options for Non-Alcoholic Steatohepatitis (NASH)

Lifestyle modification is the cornerstone of treatment for all NASH patients, with a target weight loss of 7-10% of total body weight being the most effective intervention to improve liver histology. 1

First-Line Treatment: Lifestyle Modifications

Diet Recommendations

• Mediterranean diet pattern is strongly recommended, including:
  • Daily consumption of vegetables, fruits, fiber-rich cereals, nuts, fish/white meat, and olive oil
  • Limited intake of simple sugars, red/processed meats, and ultra-processed foods
  • Complete alcohol abstinence, especially in those with cirrhosis 1
• Caloric restriction:
  • 1,500-1,800 kcal/day for men and 1,200-1,500 kcal/day for women
  • Hypocaloric diet with 500-1000 kcal daily deficit 1
  • Reduced carbohydrate intake, especially fructose 1

Physical Activity

• At least 150 minutes/week of moderate-intensity or 75 minutes/week of vigorous-intensity physical activity 1
• Both aerobic exercise and resistance training effectively reduce liver fat 1
• Exercise alone may reduce hepatic steatosis even without significant weight loss 1

Weight Loss Goals

• Even modest weight loss (5%) reduces liver fat 1
• 7-10% weight loss is needed to improve steatohepatitis and fibrosis 1, 2
• Weight loss achieved through lifestyle intervention leads to significant improvements in liver histology 2

Pharmacological Treatments

Pharmacological treatments should be applied selectively, as NAFLD typically progresses slowly 1:

1. Vitamin E (800 IU/day):

   • May be considered for non-diabetic NASH patients
   • Improves liver histology but long-term risks remain to be studied 1, 3
   • Not recommended as a targeted therapy for steatohepatitis according to recent guidelines 1

2. Pioglitazone:

   • Can improve all histological features except fibrosis
   • Side effects include weight gain, bone fractures, and rarely congestive heart failure
   • Not recommended as a specific therapy due to lack of robust demonstration of histological efficacy 1, 3

3. GLP-1 receptor agonists (particularly semaglutide, tirzepatide):

   • Consider for patients with type 2 diabetes
   • Have shown histological improvement in NASH patients with or without diabetes
   • Not recommended as first-line treatment for liver disease in NASH 1

4. Resmetirom:

   • May be considered for non-cirrhotic NASH with significant liver fibrosis (stage ≥2), if locally approved 1

Surgical Options

Bariatric surgery:

• Consider for patients with obesity and hepatic steatosis 1, 4
• Can lead to significant weight loss and improvement in liver disease 1
• Improves metabolic conditions associated with NAFLD and liver histology 5

Monitoring and Follow-up

• Monitor liver enzymes every 3-6 months 1
• Repeat non-invasive fibrosis assessment (FIB-4, transient elastography) every 1-2 years 1
• HCC surveillance every 6 months for patients with advanced fibrosis or cirrhosis 1
• Monitor metabolic parameters (glucose, lipids, blood pressure) 1
• Perform surveillance for portal hypertension in patients with cirrhosis 1

Common Pitfalls and Caveats

1. Weight loss challenges: While weight loss is the most effective treatment, it is difficult for many patients to achieve and sustain 6, 5. Consider structured programs with behavioral support to improve adherence.

2. Diagnosis confirmation: Liver biopsy remains the only definitive method for NASH diagnosis 4. Non-invasive tests can help identify patients at risk but cannot replace biopsy for definitive diagnosis.

3. Disease progression: Approximately 20% of patients with NASH will develop cirrhosis 4. Early identification and targeted treatment are essential to improve outcomes.

4. Medication limitations: Currently, no FDA-approved medications specifically for NASH exist 6, 5, 3. Pharmacological treatments should be considered adjunctive to lifestyle modifications.

5. Personalized approach: Multiple pathogenic mechanisms may lead to NASH, suggesting that optimal treatment may eventually involve personalized therapy based on individual disease mechanisms 6.

The evidence strongly supports that achieving and maintaining weight loss through lifestyle modifications remains the most effective intervention for NASH, with pharmacological and surgical options serving as adjunctive therapies in specific patient populations.