What is the recommended management for an adult with non‑alcoholic steatohepatitis (NASH) and metabolic risk factors such as obesity, type 2 diabetes mellitus, and dyslipidaemia?

Management of NASH with Metabolic Risk Factors

For adults with NASH and metabolic comorbidities (obesity, type 2 diabetes, dyslipidemia), initiate intensive lifestyle modification targeting 7-10% weight loss through Mediterranean diet and 150-300 minutes weekly of moderate-to-vigorous exercise, while aggressively managing all metabolic conditions with statins for dyslipidemia and GLP-1 agonists or pioglitazone for diabetes. 1, 2

Initial Risk Stratification and Diagnosis

• Calculate FIB-4 score immediately to determine fibrosis risk: <1.3 indicates low risk, 1.3-2.67 intermediate risk, and >2.67 high risk of advanced fibrosis 3, 2
• Patients with FIB-4 ≥1.3 require transient elastography (vibration controlled transient elastography) to measure liver stiffness, with >12.0 kPa indicating high risk 3, 2
• Refer intermediate or high-risk patients to hepatology for consideration of liver biopsy, which remains the gold standard for confirming NASH diagnosis and staging fibrosis 3
• Obtain baseline evaluation including liver ultrasound, complete blood count, comprehensive metabolic panel (AST, ALT, bilirubin, alkaline phosphatase), INR, and creatinine 3
• Assess cardiovascular risk factors: lipid profile, fasting glucose and/or hemoglobin A1c, waist circumference, and BMI 3

Lifestyle Modification: The Cornerstone of Treatment

Weight Loss Targets

• Target 7-10% weight loss to achieve resolution of steatohepatitis and potential fibrosis regression 1, 2
• Even 5% weight loss improves hepatic steatosis, while 10% weight loss results in fibrosis regression or stability 1, 2
• Weight loss of >7% is associated with decreased necroinflammation, while 3-5% improves steatosis alone 1
• Structured weight loss programs are superior to general education, with two-thirds of patients in intensive intervention no longer meeting NASH criteria after 48 weeks 1

Dietary Interventions

• Prescribe Mediterranean diet as the primary dietary pattern: daily vegetables, fresh fruits, whole grain cereals, legumes, nuts, seeds, and extra virgin olive oil as the primary fat source 1, 2
• Consume fish 2-3 times weekly and minimize red meat, processed meats, and simple sugars 2
• Replace saturated fats with monounsaturated and polyunsaturated fatty acids, increase omega-3 PUFAs through fatty fish 2
• Implement a 500-1,000 kcal/day deficit to achieve gradual weight loss 4
• Limit excess fructose consumption and avoid processed foods with added sugars 1

Exercise Prescription

• Prescribe 150-300 minutes of moderate-intensity OR 75-150 minutes of vigorous-intensity aerobic exercise per week 1, 2
• Include resistance training as complementary exercise 2
• Vigorous exercise provides greater benefit than moderate exercise for NASH and fibrosis 1
• Any increase in physical activity over previous levels is beneficial compared to continued inactivity 1

Alcohol Limitation

• Minimize alcohol use to no more than 1 drink/day for women or 2 drinks/day for men 3

Management of Metabolic Comorbidities

Type 2 Diabetes Management

• Prefer GLP-1 receptor agonists (semaglutide, liraglutide) as first-line agents, which improve both glycemic control and liver histology 2, 4
• Consider pioglitazone (30 mg daily) for patients with biopsy-proven NASH with or without diabetes, as it improves all histological features except fibrosis 1
• Pioglitazone has the strongest evidence for NASH treatment in diabetic patients but carries side effects including weight gain, bone fractures in women, and rarely congestive heart failure 1
• Maintain tight glycemic control and avoid medications that increase hepatocellular carcinoma risk 2

Dyslipidemia Management

• Statins are safe and strongly recommended for all patients with dyslipidemia, reducing hepatocellular carcinoma risk by 37% 1, 2, 4
• There is no evidence that NASH patients are at increased risk for serious drug-induced liver injury from statins 4
• Statins have beneficial pleiotropic properties beyond lipid lowering 1

Hypertension and Other Comorbidities

• Aggressively manage hypertension as part of comprehensive metabolic syndrome treatment 3, 2
• Screen for and treat associated conditions including hypothyroidism, polycystic ovary syndrome, and obstructive sleep apnea 3

Pharmacological Treatment for Liver Disease

For Non-Diabetic Patients with Biopsy-Proven NASH

• Consider vitamin E (800 IU/day) for non-diabetic adults with biopsy-confirmed NASH, which improves liver histology through antioxidant properties 1
• Be aware of potential concerns about increased risk of all-cause mortality, hemorrhagic stroke, and prostate cancer with long-term vitamin E use 1

For Patients with Significant Fibrosis (F2-F3)

• Consider resmetirom for non-cirrhotic NASH with significant fibrosis, as it demonstrated histological effectiveness on steatohepatitis and fibrosis with acceptable safety and tolerability 2
• Alternative options include pioglitazone and vitamin E, though long-term efficacy and safety data are limited 2

Important Caveat

• All currently recommended pharmacologic treatments for NASH require histologic diagnosis (liver biopsy) prior to initiation 1

Medications to Discontinue

• Discontinue hepatotoxic medications that may worsen steatosis: corticosteroids, amiodarone, methotrexate, tamoxifen, estrogens, tetracyclines, and valproic acid 3, 1

Bariatric Surgery Consideration

• Consider bariatric surgery for morbidly obese patients who meet other medical criteria, as nearly 85% of obese patients with biopsy-proven NASH have histologic resolution at one year following bariatric surgery 1
• Bariatric surgery may be indicated to achieve and maintain the necessary degree of weight loss required for therapeutic effect 5

Monitoring and Follow-Up Strategy

For Low-Risk Patients (FIB-4 <1.3)

• Annual follow-up with repeated FIB-4 calculation to monitor for fibrosis progression 2, 4
• Focus on lifestyle modifications with no specific liver-directed pharmacotherapy 1

For Intermediate and High-Risk Patients

• More frequent monitoring every 6 months with liver function tests and non-invasive fibrosis markers 2
• Hepatology referral for specialized management 2

For Patients with Cirrhosis (F4)

• Hepatocellular carcinoma surveillance with right upper quadrant ultrasound ± AFP every 6 months 3, 2
• EGD screening for esophageal varices per AASLD guidelines 3
• Referral to transplant center when appropriate 3
• Nutritional counseling for sarcopenia and liver transplantation evaluation for decompensated cirrhosis 2

Common Pitfalls to Avoid

• Do not rely solely on serum aminotransferase levels or imaging to assess disease severity, as they do not reliably reflect the spectrum of liver histology in NASH 3
• Do not assume simple steatosis (NAFL) is benign—some patients may progress directly from NAFL to advanced fibrosis without going through classic NASH 3
• Do not overlook cardiovascular disease as the most common cause of death in NASH patients, not liver-related mortality 3
• Do not screen family members systematically for NAFLD, as this is not currently recommended 3