What are the treatment options for steatohepatitis (non-alcoholic fatty liver disease)?

Treatment of Steatohepatitis (NASH)

Lifestyle modification targeting 7-10% weight loss through diet and exercise is the cornerstone of steatohepatitis treatment, with pharmacotherapy (pioglitazone for diabetics, vitamin E for non-diabetics) reserved exclusively for biopsy-proven NASH with significant fibrosis (stage ≥F2). 1, 2

Risk Stratification Determines Treatment Intensity

Treatment decisions must be guided by fibrosis stage, not just the presence of steatohepatitis 2, 3:

• Low-risk NASH (F0-F1 fibrosis): Lifestyle modifications only, no liver-directed pharmacotherapy 2, 3
• High-risk NASH (F2-F3 fibrosis): Intensive lifestyle modifications PLUS pharmacotherapy 2, 3
• NASH cirrhosis (F4): Hepatologist-coordinated multidisciplinary care with individualized pharmacotherapy and HCC surveillance 1, 3

Patients with FIB-4 >2.67 or liver stiffness >12.0 kPa by transient elastography require hepatologist referral 2.

Lifestyle Interventions: The Foundation for All Patients

Weight Loss Targets

Achieve 7-10% weight loss to significantly improve liver histology and potentially reverse NASH 1, 2, 3. The magnitude of benefit correlates directly with weight loss achieved 4:

• 3-5% weight loss: Improves steatosis 1, 5
• 7% weight loss: Improves necroinflammation 1, 5
• 10% weight loss: Required for fibrosis improvement 1

Weight loss should be gradual at 0.5-1 kg/week (maximum 1 kg/week) to avoid worsening liver disease 5, 3. A randomized controlled trial demonstrated that participants achieving ≥7% weight loss had significant improvements in steatosis, lobular inflammation, ballooning injury, and overall NASH activity score compared to those losing <7% 4.

Dietary Recommendations

Follow a Mediterranean diet as the preferred dietary pattern 1, 3. This diet is characterized by:

• Reduced carbohydrate intake (40% of calories vs. 50-60% in typical low-fat diets) 6
• Increased monounsaturated and omega-3 fatty acid intake (40% of calories as fat) 6
• Rich in fruits, vegetables, whole grains, legumes, nuts, and olive oil 2, 3
• Avoidance of fructose-containing beverages and processed foods 5, 3

The Mediterranean diet can reduce liver fat even without weight loss 6. Implement a hypocaloric diet with 500-1000 kcal energy deficit to achieve target weight loss 5.

Exercise Prescription

Prescribe 150-300 minutes of moderate-intensity aerobic exercise OR 75-150 minutes of vigorous-intensity exercise per week 1, 2. Key points:

• Both aerobic and resistance training effectively reduce liver fat 3, 7
• Exercise improves NAFLD independent of weight loss by improving insulin sensitivity and decreasing hepatic de novo lipogenesis 1, 7
• Even minimal physical activity below recommended thresholds may have beneficial impact 7

Pharmacological Treatment by Patient Profile

For Diabetic Patients with Biopsy-Proven NASH and Significant Fibrosis (≥F2)

First-line: Pioglitazone 30 mg daily 1, 2, 3. Pioglitazone has demonstrated:

• Resolution of steatohepatitis in 47% of patients vs. 21% with placebo 1
• Consistent benefit in patients with prediabetes or type 2 diabetes in studies up to 3 years 1
• Additional cardiovascular benefits 1

Alternative: GLP-1 receptor agonists (particularly semaglutide) 1, 2, 3. The American Diabetes Association recommends considering GLP-1 receptor agonists with demonstrated benefits in NASH as adjunctive therapy to lifestyle interventions 1.

Avoid metformin for liver-directed therapy as it has no significant effect on liver histology, though it may be continued for diabetes management 1, 5.

For Non-Diabetic Patients with Biopsy-Proven NASH and Significant Fibrosis (≥F2)

Vitamin E 800 IU daily 1, 2, 3. Evidence from the PIVENS trial showed:

• Resolution of steatohepatitis in 36% vs. 21% with placebo 1
• Improvement in steatosis, inflammation, and ballooning 1
• No benefit on fibrosis, which is the only variable associated with mortality 1

Important caveat: Vitamin E may be associated with increased risks of prostate cancer and all-cause mortality, limiting its use 1. A retrospective study suggested vitamin E was associated with greater transplant-free survival in patients with bridging fibrosis or cirrhosis 1.

Emerging Therapies

Resmetirom may be considered for non-cirrhotic NASH with significant fibrosis (stage ≥2) if locally approved, due to demonstrated histological effectiveness on steatohepatitis and fibrosis 3.

Management of Cardiovascular and Metabolic Comorbidities

Use statins for dyslipidemia—they are safe in NASH patients with compensated cirrhosis and should be initiated or continued for cardiovascular risk reduction 1, 2. Statins may reduce HCC risk by 37% 5. Use with caution in decompensated cirrhosis 1.

For patients with diabetes, prioritize glucose-lowering medications that provide dual benefits 2:

• GLP-1 receptor agonists
• SGLT2 inhibitors
• Pioglitazone

Avoid sulfonylureas and insulin if possible, as they may increase HCC risk 5.

Advanced Interventions for Select Patients

Consider bariatric surgery for appropriate candidates with NASH and obesity 1, 3. Metabolic surgery can:

• Treat NASH effectively 1
• Improve cardiovascular outcomes 1
• Should be used with caution in compensated cirrhosis 1
• Is contraindicated in decompensated cirrhosis 1

Monitoring and Surveillance

All NASH patients require 3:

• Regular hepatological and cardiovascular follow-up
• HCC surveillance for those with MASH-related cirrhosis
• Assessment of liver function and fibrosis progression

Critical pitfall to avoid: Rapid weight loss may worsen liver disease; ensure gradual weight reduction at maximum 1 kg/week 5.

Alcohol Consumption

Heavy alcohol consumption should be avoided in all NAFLD/NASH patients 1, 5. While some guidelines suggest light-moderate alcohol consumption may have favorable metabolic effects, no guidelines recommend prescribing alcohol as a preventive/therapeutic strategy 1.