What are the treatment options for steatotic hepatitis (Non-Alcoholic Fatty Liver Disease, NAFLD)?

Treatment for Steatotic Hepatitis (NASH)

Lifestyle modification with 7-10% weight loss is the cornerstone of treatment for all patients with steatotic hepatitis, combined with a Mediterranean diet and 150-300 minutes of moderate-intensity exercise weekly. 1, 2 Pharmacotherapy should be reserved exclusively for patients with biopsy-proven NASH and significant fibrosis (≥F2): 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:

• Low-risk patients (F0-F1 fibrosis): Focus exclusively on lifestyle modifications without liver-directed pharmacotherapy 2, 3
• High-risk patients (F2-F3 fibrosis): Intensive lifestyle modifications PLUS pharmacotherapy 1, 2
• Cirrhosis (F4): Lifestyle modifications with careful monitoring, limited evidence for pharmacotherapy, and hepatocellular carcinoma surveillance with ultrasound ± AFP every 6 months 1

Use FIB-4 score or transient elastography to assess fibrosis severity non-invasively. 3 Patients with FIB-4 >2.67 or liver stiffness >12.0 kPa require hepatologist-coordinated multidisciplinary care. 2

Lifestyle Modifications: The Non-Negotiable Foundation

Weight Loss Targets:

• 7-10% weight reduction is the primary goal for all overweight/obese patients, as this significantly improves liver histology, reduces steatosis and inflammation, and can reverse NASH 1, 2
• Even 5-7% weight loss improves hepatic steatosis and components of the NAFLD activity score 1
• 3-5% weight loss improves steatosis alone, while >7% is needed to decrease necroinflammation 4, 1
• Weight loss of ≥10% may be necessary to improve hepatic fibrosis 4, 5

Dietary Interventions:

• Mediterranean diet is the most strongly recommended dietary pattern for NASH: reduced carbohydrates, increased monounsaturated and omega-3 fatty acids, rich in fruits, vegetables, whole grains, legumes, nuts, and olive oil 4, 1, 2
• Limit excess fructose consumption and avoid processed foods with added sugars 1
• Replace saturated fats with polyunsaturated and monounsaturated fats 4, 1
• Avoid processed foods, fast food, and commercial bakery goods 4, 1
• Hypocaloric diet with 500-1000 kcal daily reduction for obese adults 4

Physical Activity:

• 150-300 minutes of moderate-intensity exercise (3-6 metabolic equivalents) OR 75-150 minutes of vigorous-intensity exercise per week 4, 2, 3
• Vigorous exercise provides greater benefit than moderate exercise for NASH and fibrosis 1
• Both aerobic and resistance training are effective at reducing liver fat 1
• Exercise alone can reduce hepatic steatosis even without weight loss 4, 5

Alcohol Restriction:

• Restrict alcohol consumption to reduce liver-related events, as even low alcohol intake (9-20 g daily) doubles the risk for adverse liver-related outcomes in NAFLD patients 4
• All guidelines recommend avoiding heavy alcohol consumption 4

Pharmacological Treatment: Only for Biopsy-Proven NASH with Significant Fibrosis

Critical caveat: All pharmacologic treatments require histologic diagnosis (liver biopsy) prior to initiation. 1 Do not prescribe these medications based on imaging or laboratory findings alone.

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

Vitamin E 800 IU daily is the recommended first-line pharmacotherapy 1, 2, 3

• Improves liver histology through antioxidant properties 1
• Potential concerns: Increased risk of all-cause mortality, hemorrhagic stroke, and prostate cancer with long-term use 1
• Should be used only in non-diabetic adults with biopsy-confirmed NASH 1

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

Pioglitazone 30 mg daily is the first-line pharmacotherapy 1, 2, 3

• Improves all histological features except fibrosis 1
• Has the strongest evidence for NASH treatment in diabetic patients 1
• Side effects: Weight gain, bone fractures in women, and rarely congestive heart failure 1

GLP-1 receptor agonists (e.g., semaglutide) should be considered as an alternative or addition, particularly for diabetic NASH patients with significant fibrosis 2

• Show promise for NASH treatment, though evidence is still emerging 1
• Provide dual benefits for diabetes and NASH 2

Management of Metabolic Comorbidities

Aggressively treat all metabolic comorbidities, as cardiovascular disease is the main driver of morbidity and mortality in NAFLD patients before cirrhosis develops: 3

• Statins for dyslipidemia: Safe in NASH patients and have beneficial pleiotropic properties 4, 1, 2
• Optimize glycemic control: Prioritize GLP-1RAs, SGLT2 inhibitors, and pioglitazone as they provide dual benefits for diabetes and NASH 4, 2
• Manage hypertension according to standard guidelines 2

Discontinue hepatotoxic medications: Corticosteroids, amiodarone, methotrexate, tamoxifen, estrogens, tetracyclines, and valproic acid 4, 1, 3

Special Considerations

Bariatric surgery may be considered for morbidly obese patients who meet other medical criteria, with nearly 85% of obese patients with biopsy-proven NASH having histologic resolution at one year following surgery 1

Structured weight loss programs are superior to general education alone, with two-thirds of patients in an intensive intervention group no longer meeting NASH criteria after 48 weeks 1

Monitoring and Follow-Up

• Reassess fibrosis using non-invasive tests every 1-3 years to monitor treatment response or disease progression 3
• Monitor cardiovascular disease risk factors closely, as this is the primary cause of death in NAFLD patients 3
• For cirrhotic patients, hepatocellular carcinoma surveillance with ultrasound ± AFP every 6 months is mandatory 1