Treatment of Steatohepatitis (NASH)
For patients with nonalcoholic steatohepatitis, prioritize structured lifestyle modification targeting 7-10% weight loss through Mediterranean diet and regular exercise, with pioglitazone or GLP-1 receptor agonists as preferred pharmacologic agents for those with biopsy-proven NASH and significant fibrosis. 1, 2
Lifestyle Interventions: The Foundation of Treatment
Weight loss is the only intervention with Level 1 evidence for improving liver histology in NASH. 3 The magnitude of weight loss directly correlates with histologic improvement:
- 5% weight loss reduces hepatic steatosis 4
- 7-10% weight loss improves liver inflammation and achieves NASH resolution in many patients 1, 2, 3
- ≥10% weight loss produces the highest rates of NASH resolution (90%), NAS reduction (100%), and fibrosis regression (45%) 5
Dietary Recommendations
Adopt a Mediterranean dietary pattern emphasizing vegetables, fruits, unsweetened high-fiber cereals, nuts, fish or white meat, and olive oil—this has the strongest evidence for improving liver and cardiometabolic health. 1, 2, 4
Key dietary modifications include:
- Completely eliminate sugar-sweetened beverages 3
- Limit ultra-processed foods rich in sugars and saturated fat 3, 4
- Reduce saturated fat, starch, and added sugar while increasing monounsaturated and omega-3 fatty acids 2
- Avoid excess fructose consumption from processed foods 2
Exercise Requirements
Prescribe at least 150 minutes per week of moderate-intensity aerobic exercise or 75 minutes per week of vigorous-intensity activity. 2, 3, 4 Both aerobic and resistance training improve NAFLD, with benefits proportional to treatment engagement and intensity. 1, 2 Importantly, physical activity reduces steatosis even without significant weight loss. 3, 4
Pharmacologic Treatment
Preferred Agents for Biopsy-Proven NASH
Pioglitazone or GLP-1 receptor agonists are the preferred agents for treating hyperglycemia in adults with type 2 diabetes who have biopsy-proven NASH or high risk for clinically significant liver fibrosis. 1
GLP-1 Receptor Agonists
Consider GLP-1 receptor agonists (semaglutide, liraglutide) as adjunctive therapy to lifestyle interventions, particularly in patients with type 2 diabetes and overweight/obesity. 1, 2 These agents improve cardiometabolic outcomes and are safe in NASH, including compensated cirrhosis. 3
Pioglitazone
Pioglitazone 30 mg daily is effective for patients with biopsy-proven NASH, with or without diabetes. 2 This thiazolidinedione improves insulin sensitivity and has demonstrated histologic benefit. 2
Resmetirom (Newest Option)
Consider Resmetirom for non-cirrhotic NASH with significant fibrosis (stage ≥2) if locally approved, as it demonstrated histological effectiveness on steatohepatitis and fibrosis with acceptable safety in phase III trials. 2, 3 This represents the most recent pharmacologic advance.
Vitamin E
Vitamin E (800 IU/day) should be considered for non-diabetic adults with biopsy-confirmed NASH, as it improves liver histology through antioxidant properties. 2 However, it should not be used in diabetic patients due to lack of proven benefit and potential safety concerns. 2
Important Caveat on Other Diabetes Medications
Other glucose-lowering therapies may be continued as clinically indicated, but lack evidence of benefit specifically for NASH. 1 The exception is insulin, which becomes the preferred agent in decompensated cirrhosis. 1
Cardiovascular Risk Management
Comprehensive management of cardiovascular risk factors is mandatory because patients with NASH and type 2 diabetes face increased cardiovascular risk. 1
Statin Therapy
Statins are safe and should be initiated or continued for cardiovascular risk reduction in patients with NASH and compensated cirrhosis. 1, 3 However, use statins with caution and close monitoring in decompensated cirrhosis given limited safety data. 1
Important: Statins should not be used to specifically treat NASH histology, but their cardiovascular benefits and safety profile make them appropriate for managing dyslipidemia in this population. 1
Surgical Interventions
Consider metabolic (bariatric) surgery in appropriate candidates with NASH and obesity to treat steatohepatitis and improve cardiovascular outcomes. 1, 2, 3 This intervention can achieve the substantial weight loss (≥10%) needed for maximal histologic improvement. 6, 5
Critical caveat: Metabolic surgery should be used with caution in compensated cirrhosis and is contraindicated in decompensated cirrhosis. 1
Medications to Avoid
Discontinue or avoid medications that worsen steatosis, including:
Risk Stratification and Monitoring
Stratify patients using FIB-4 score, liver stiffness measurement (LSM), or liver biopsy to identify those at high risk for advanced fibrosis. 3, 4 High-risk patients have FIB-4 >2.67, LSM >12.0 kPa, or significant fibrosis on biopsy. 3, 4
Patients with indeterminate or high risk of fibrosis should be referred to a gastroenterologist or hepatologist for further workup within a multidisciplinary team framework. 1
Cirrhosis Surveillance
For patients with NASH cirrhosis:
- Screen for hepatocellular carcinoma with right upper quadrant ultrasound every 6 months 1, 2, 3
- Screen for esophageal varices with esophagogastroduodenoscopy per AASLD guidelines 1
- Refer to transplant center when appropriate, as NASH is becoming the leading indication for liver transplantation 1, 6
Common Pitfalls to Avoid
- Do not wait for symptoms—NASH is often asymptomatic until advanced disease develops 6
- Do not underestimate the importance of weight loss magnitude—modest weight loss (3-5%) only improves steatosis, not inflammation or fibrosis 4
- Do not use vitamin E in diabetic patients with NASH due to lack of proven benefit 2
- Do not assume all diabetes medications help NASH—only pioglitazone and GLP-1 receptor agonists have evidence for histologic benefit 1
- Do not withhold statins due to concerns about liver disease—they are safe and necessary for cardiovascular protection 1, 3