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

Treatment of NASH

Lifestyle modification with a target weight loss of 7-10% is the cornerstone of NASH treatment, with pharmacotherapy (vitamin E for non-diabetics, pioglitazone for diabetics) reserved for biopsy-proven NASH with significant fibrosis (≥F2). 1, 2

Risk Stratification Determines Treatment Intensity

Your treatment approach should be guided by fibrosis stage, as this directly impacts morbidity and mortality:

Low-Risk NASH (F0-F1 Fibrosis)

• Focus exclusively on lifestyle modifications without liver-directed pharmacotherapy 1
• No medications are recommended at this stage, as the risk-benefit ratio does not favor pharmacological intervention 1

High-Risk NASH (F2-F3 Fibrosis)

• Intensive lifestyle modifications PLUS pharmacotherapy 1
• This population has approximately 10% risk of progression and requires hepatologist-coordinated multidisciplinary care 3

NASH Cirrhosis (F4)

• Lifestyle modifications with careful monitoring, limited pharmacotherapy evidence, and mandatory HCC surveillance every 6 months with ultrasound ± AFP 1

Lifestyle Modifications: The Foundation

Weight Loss Targets

• Achieve 7-10% weight loss to significantly improve liver histology, reduce steatosis and inflammation, and potentially reverse NASH 1, 2
• Even 5-7% weight loss improves hepatic steatosis and NAFLD activity scores 1
• Weight reduction of 9.3% achieved through intensive lifestyle intervention reduced NASH histological activity scores from 4.4 to 2.0 (P=0.05) 4
• Participants achieving ≥7% weight loss had significant improvements in all histological parameters: steatosis (-1.36 vs -0.41, P<0.001), lobular inflammation (-0.82 vs -0.24, P=0.03), and ballooning injury (-1.27 vs -0.53, P=0.03) 4

Dietary Modifications

• Implement a Mediterranean diet: reduced carbohydrates, increased monounsaturated and omega-3 fatty acids, rich in fruits, vegetables, whole grains, legumes, nuts, and olive oil 1, 2
• Limit excess fructose consumption and avoid processed foods with added sugars 1, 2
• Replace saturated fats with polyunsaturated and monounsaturated fats 1, 2
• Avoid fast food and commercial bakery goods 1, 2

Exercise Prescription

• Prescribe 150-300 minutes of moderate-intensity exercise (3-6 metabolic equivalents) OR 75-150 minutes of vigorous-intensity exercise per week 3
• Both aerobic and resistance training effectively reduce liver fat 1, 2
• Vigorous exercise provides greater benefit than moderate exercise for NASH and fibrosis 1
• Exercise reduces hepatic triglyceride content by 16% and visceral fat by 22 cm² even without weight loss 5
• Physical activity decreases aminotransferases and steatosis even without significant weight loss 3

Structured Programs

• Refer to formal weight loss programs rather than relying on office-based counseling alone, as structured programs achieve superior outcomes 3
• Consider bariatric surgery for appropriate individuals with clinically significant fibrosis and obesity with comorbidities 3, 2

Pharmacological Treatment by Patient Profile

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

Vitamin E 800 IU daily is recommended 3, 1, 2

• Improves liver histology through antioxidant properties 1, 2
• Improved steatohepatitis in a large randomized trial of non-diabetic NASH patients 3
• A retrospective study showed improved transplant-free survival and lower hepatic decompensation rates 3

Critical caveats:

• Potential increased risk of all-cause mortality, hemorrhagic stroke, and prostate cancer with long-term use 1
• Mixed results in diabetic patients 3
• Monitor for these adverse effects during treatment 1

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

Pioglitazone 30 mg daily is the first-line pharmacotherapy 1, 2

• Five RCTs demonstrate improvement in liver histology, primarily steatohepatitis 3
• Improves all histological features except fibrosis 1
• Effective in patients with or without diabetes 1, 2

Critical caveats:

• Causes weight gain (which seems paradoxical but histology still improves) 1
• Increased risk of bone fractures in women 1
• Rarely causes congestive heart failure 1
• Screen for these complications before and during treatment 1

GLP-1 Receptor Agonists: Emerging Evidence

Consider GLP-1RAs for diabetic NASH patients, particularly semaglutide 3, 1, 2

• Daily semaglutide 0.4 mg achieved NASH resolution without worsening fibrosis in 59% vs 17% placebo (P<0.001) in 320 patients 3
• Fewer patients experienced worsening fibrosis compared to placebo 3
• Liraglutide showed reversal of steatohepatitis and amelioration of fibrosis progression in proof-of-concept studies 3
• Use should follow American Diabetes Association guidelines for T2D and NAFLD 3

Critical caveats:

• Dose-dependent gastrointestinal adverse effects: nausea, constipation, vomiting 3
• No significant improvement in fibrosis stage (though progression was slowed) 3

SGLT2 Inhibitors

Consider SGLT2 inhibitors for diabetic NASH patients to improve cardiometabolic profile and reverse steatosis 3, 2

• Use should follow American Diabetes Association guidelines 3

Resmetirom: Newest Option

Consider resmetirom for non-cirrhotic NASH with significant fibrosis (≥F2) if locally approved 2

• Demonstrated histological effectiveness on both steatohepatitis and fibrosis 2
• Acceptable safety profile 2
• This represents the most recent guideline-recommended pharmacotherapy 2

Management of Cardiovascular and Metabolic Comorbidities

Statins

• Use statins for dyslipidemia management—they are safe in NASH patients and have beneficial pleiotropic properties 3
• Follow standard cardiovascular risk management guidelines 3

Hypertension

• Manage according to standard guidelines 3
• The renin-angiotensin system may contribute to hepatic inflammation and fibrosis 6

Diabetes Management

• Optimize glycemic control with glucose-lowering medications 3
• Prioritize GLP-1RAs, SGLT2 inhibitors, and pioglitazone as they provide dual benefits for diabetes and NASH 3

High-Risk Patients Requiring Hepatologist Management

Patients with FIB-4 >2.67, liver stiffness >12.0 kPa by transient elastography, or biopsy-proven clinically significant fibrosis should be managed by a hepatologist-coordinated multidisciplinary team 3

These patients require:

• Monitoring for cirrhosis complications 3
• HCC surveillance 3, 1
• Aggressive lifestyle interventions 3
• Greater use of formal weight loss programs 3
• Consideration of bariatric surgery in appropriate candidates 3

Critical Clinical Pitfalls

• Do not wait for symptoms to initiate treatment—NASH is often asymptomatic until advanced 7
• Do not use pharmacotherapy for simple steatosis (F0-F1)—lifestyle modification alone is appropriate 1
• Do not prescribe vitamin E to diabetic patients as first-line—use pioglitazone instead 3, 1
• Do not forget that 20% of NASH patients will develop cirrhosis, making early identification crucial 7
• Do not overlook that NASH has substantially higher mortality than the general population (25.56 per 1000 person-years all-cause, 11.77 per 1000 person-years liver-specific) 7
• Do not assume exercise requires weight loss to be beneficial—exercise independently reduces hepatic triglyceride content and visceral fat 5