Treatment of Nonalcoholic Steatohepatitis (NASH)
Lifestyle modification with 7-10% weight loss is the cornerstone of NASH treatment, and for patients with biopsy-proven NASH and significant fibrosis (≥F2), add vitamin E 800 IU daily for non-diabetics or pioglitazone 30 mg daily for diabetics. 1, 2
Risk Stratification Determines Treatment Intensity
Your first step is determining fibrosis stage, as this dictates whether pharmacotherapy is warranted:
- F0-F1 (minimal fibrosis): Lifestyle modifications only—no liver-directed pharmacotherapy 1, 2
- F2-F3 (significant fibrosis): Intensive lifestyle modifications PLUS pharmacotherapy 1, 2
- F4 (cirrhosis): Lifestyle modifications with careful monitoring, limited pharmacotherapy evidence, and mandatory HCC surveillance with ultrasound ± AFP every 6 months 1, 3
Patients with FIB-4 >2.67, liver stiffness >12.0 kPa by transient elastography, or biopsy-proven clinically significant fibrosis require hepatologist-coordinated multidisciplinary care 2.
Lifestyle Modifications: The Non-Negotiable Foundation
Target 7-10% weight loss—this is the single most effective intervention, with histologic improvement directly correlating with percent weight reduction 1, 2, 4. A landmark randomized controlled trial demonstrated that 72% of patients achieving this goal had clinically meaningful NAS reduction versus only 30% in controls 4.
Specific dietary prescription:
- Mediterranean diet: Reduced carbohydrates, increased monounsaturated and omega-3 fatty acids, rich in fruits, vegetables, whole grains, legumes, nuts, and olive oil 1, 2, 3
- Limit excess fructose consumption and avoid processed foods with added sugars 1, 3
- Replace saturated fats with polyunsaturated and monounsaturated fats 1, 3
- Avoid processed foods, fast food, and commercial bakery goods 1, 3
Exercise prescription:
- 150-300 minutes of moderate-intensity exercise (3-6 metabolic equivalents) OR 75-150 minutes of vigorous-intensity exercise per week 2
- Both aerobic and resistance training effectively reduce liver fat 1, 3
- Vigorous exercise provides greater benefit than moderate exercise for NASH and fibrosis 1
Critical caveat: Aim for gradual weight loss of approximately 0.5-1 kg/week—rapid weight reduction may paradoxically worsen liver disease 3.
Pharmacotherapy Algorithm Based on Diabetes Status
For Non-Diabetic Patients with F2-F3 Fibrosis:
Vitamin E 800 IU daily is the first-line pharmacotherapy 1, 2, 3. It improves liver histology through antioxidant properties, but counsel patients about potential long-term concerns: increased risk of all-cause mortality, hemorrhagic stroke, and prostate cancer 1.
For Diabetic Patients with F2-F3 Fibrosis:
Pioglitazone 30 mg daily has the strongest evidence for NASH treatment in diabetics 1, 2, 3. It improves all histological features except fibrosis 1. Warn patients about side effects: weight gain, bone fractures in women, and rarely congestive heart failure 1.
Alternative for diabetics: Consider GLP-1 receptor agonists (e.g., semaglutide) for dual benefits on diabetes and NASH, particularly in patients with significant fibrosis 2, 3.
Emerging Option:
Resmetirom may be considered for non-cirrhotic MASH with significant fibrosis (stage ≥2) if locally approved, demonstrating histological effectiveness on steatohepatitis and fibrosis with acceptable safety 3.
Managing Cardiovascular and Metabolic Comorbidities
This is non-optional, as cardiovascular disease is the leading cause of death in NASH patients:
- Use statins for dyslipidemia—they are safe in NASH and have beneficial pleiotropic properties 2
- Manage hypertension according to standard guidelines 2
- Optimize glycemic control prioritizing GLP-1RAs, SGLT2 inhibitors, and pioglitazone for dual diabetes-NASH benefits 2
Bariatric Surgery Consideration
For morbidly obese patients meeting medical criteria, bariatric surgery may be considered—nearly 85% of obese patients with biopsy-proven NASH had histologic resolution at one year post-surgery 1, 3. However, this should be viewed as treatment for obesity with beneficial effects on NASH, not as primary NASH therapy 1.
Critical Pitfalls to Avoid
Do not initiate pharmacotherapy without histologic diagnosis—all currently recommended pharmacologic treatments require biopsy-proven NASH prior to initiation 1. The exception is managing comorbid conditions like diabetes and dyslipidemia, which should be treated regardless.
Do not forget to discontinue hepatotoxic medications: corticosteroids, amiodarone, methotrexate, tamoxifen, estrogens, tetracyclines, valproic acid 5.
Do not overlook cirrhosis screening: If cirrhosis is present or suspected (thrombocytopenia, AST>ALT, hypoalbuminemia), obtain right upper quadrant ultrasound every 6 months for HCC screening and EGD screening for esophageal varices 5, 1.