What is the management of non-alcoholic steatohepatitis (NASH)?

Management of Non-Alcoholic Steatohepatitis (NASH)

All patients with NAFLD require lifestyle modifications regardless of disease stage, but pharmacological treatment should be reserved exclusively for those with biopsy-proven NASH and significant fibrosis (≥F2). 1, 2

Risk Stratification Determines Treatment Intensity

The cornerstone of NASH management is identifying which patients need aggressive intervention versus conservative management:

• Low-risk patients (F0-F1 fibrosis) have excellent prognosis from a liver standpoint and should receive lifestyle modifications only, with no liver-directed pharmacotherapy. 1, 2

• High-risk patients (≥F2 fibrosis or biopsy-proven NASH) require intensive lifestyle modifications plus consideration of pharmacotherapy, as fibrosis stage ≥F2 is an independent predictor of liver-related complications and mortality. 1, 2

• Patients with NASH cirrhosis (F4) need hepatocellular carcinoma surveillance with ultrasound ± AFP every 6 months, variceal screening if LSM ≥20 kPa or thrombocytopenia is present, and careful monitoring with limited evidence for pharmacotherapy. 1, 3

Lifestyle Modifications: The Foundation for All Patients

Weight Loss Targets

Achieve 7-10% weight loss as the primary therapeutic goal, with a dose-response relationship where greater weight loss produces greater histological improvement. 1, 2, 3

• Weight loss of 5-7% improves hepatic steatosis and inflammation. 1
• Weight loss of ≥7% significantly improves necroinflammation. 1, 3, 4
• Weight loss of ≥10% improves liver fibrosis in 45% of patients. 1
• Progressive weight loss should not exceed 1 kg/week, as rapid weight loss (>1.6 kg/week) can worsen portal inflammation and fibrosis in morbidly obese patients. 1

Dietary Interventions

Implement a Mediterranean diet pattern with reduced carbohydrates, increased monounsaturated and omega-3 fatty acids, rich in fruits, vegetables, whole grains, legumes, nuts, and olive oil. 2, 3

• Reduce total daily caloric intake by 500-750 kcal/day: target 1,200-1,500 kcal/day for women and 1,500-1,800 kcal/day for men, adjusted for age, sex, weight, and physical activity. 1
• Limit excess fructose consumption and avoid processed foods with added sugars. 3
• Replace saturated fats with polyunsaturated and monounsaturated fats. 3
• Low-carbohydrate diets are more effective than low-fat diets in reducing liver fat content. 1

Exercise Prescription

Prescribe 150-300 minutes of moderate-intensity exercise (3-6 metabolic equivalents) OR 75-150 minutes of vigorous-intensity exercise (≥6 METs) per week. 2, 3

• Vigorous exercise (≥6 METs) provides greater benefit for NASH and fibrosis improvement compared to moderate exercise. 1, 3
• Both aerobic and resistance training are effective at reducing liver fat. 3
• Any increase in physical activity over previous levels is beneficial compared to continued inactivity. 3

Pharmacological Treatment: Reserved for High-Risk Patients

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

Vitamin E 800 IU daily is the recommended first-line pharmacotherapy, improving steatohepatitis and liver histology through antioxidant properties. 2, 5, 3

• Vitamin E should NOT be used in diabetic patients or those with cirrhosis due to mixed or lacking evidence. 5
• Potential concerns include increased risk of all-cause mortality, hemorrhagic stroke, and prostate cancer with long-term use, requiring informed patient discussion. 3

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

Pioglitazone 30 mg daily is the first-line pharmacotherapy, improving all histological features of NASH except fibrosis. 2, 5, 3

• Pioglitazone has the strongest evidence for NASH treatment in diabetic patients. 3
• Side effects include weight gain (which may counteract benefits), bone fractures in women, and rarely congestive heart failure. 3
• Monitor for fluid retention and avoid in patients with heart failure. 3

GLP-1 receptor agonists (particularly semaglutide) should be considered as an alternative, especially for patients with significant fibrosis (≥F2), as they provide dual benefits for diabetes and NASH. 2, 5

• Semaglutide has the strongest evidence for liver histological benefit among GLP-1 receptor agonists. 5
• GLP-1 receptor agonists are preferred glucose-lowering medications in diabetic NASH patients alongside SGLT2 inhibitors and pioglitazone. 2, 5

Management of Cardiovascular and Metabolic Comorbidities

Use statins for dyslipidemia management—they are safe in NASH patients and have beneficial pleiotropic properties beyond lipid lowering. 2, 5

• Statins do not worsen liver disease and should not be withheld due to NASH diagnosis. 5

Optimize glycemic control with glucose-lowering medications, prioritizing GLP-1 receptor agonists, SGLT2 inhibitors, and pioglitazone as they provide dual benefits for diabetes and NASH. 2, 5

Manage hypertension according to standard guidelines. 2

Bariatric Surgery for Select Patients

Bariatric surgery should be strongly considered for high-risk patients with obesity (BMI ≥35 kg/m² with comorbidities or ≥40 kg/m²) who meet standard surgical criteria, as nearly 85% of obese patients with biopsy-proven NASH have histologic resolution at one year following surgery. 3, 6

• Bariatric surgery should be performed by well-established programs with multidisciplinary support. 5
• Weight loss medications should be considered for patients who do not meet bariatric surgery criteria or prefer medical management. 5

Medications NOT Recommended

Metformin, ursodeoxycholic acid, and orlistat are NOT recommended for NASH treatment due to lack of significant histological benefit. 1, 5

• Metformin does not improve liver histology despite improving insulin resistance. 1
• Orlistat did not improve body weight or liver histology in controlled trials. 1

Hepatologist Referral Criteria

Refer patients to hepatology for multidisciplinary management if they have FIB-4 >2.67, liver stiffness >12.0 kPa by transient elastography, or biopsy-proven clinically significant fibrosis (≥F2). 1, 2

• Patients with discordant or indeterminate liver stiffness measurements (8.0-12.0 kPa) should also be referred for further diagnostic evaluation with liver biopsy or MR elastography. 1
• High-risk patients have approximately 10% risk of disease progression and require hepatologist-coordinated multidisciplinary care. 2

Common Pitfalls to Avoid

• Do not prescribe liver-directed pharmacotherapy for simple steatosis (NAFL) without inflammation or fibrosis—these patients have excellent prognosis and only need lifestyle modifications. 1, 5

• Do not use vitamin E in diabetic patients—pioglitazone or GLP-1 receptor agonists are preferred in this population. 5, 3

• Do not recommend rapid weight loss exceeding 1 kg/week—this can paradoxically worsen portal inflammation and fibrosis. 1

• Do not withhold statins in NASH patients with dyslipidemia—they are safe and beneficial. 2, 5

• Do not use pharmacotherapy in NASH cirrhosis outside of clinical trials—evidence is lacking and safety concerns exist. 5