What is the recommended approach to diagnose and manage Non-Alcoholic Fatty Liver Disease (NAFLD) in an overweight or obese patient with elevated liver enzymes and suspected insulin resistance?

Diagnosis and Management of NAFLD

Diagnosis

Screen all patients with diabetes mellitus for NAFLD regardless of liver enzyme levels, and screen patients with persistent liver enzyme elevation, metabolic syndrome, or obesity. 1, 2

Who to Screen

• Mandatory screening: Patients with diabetes mellitus, even with normal liver enzymes 1
• Strong consideration: Patients with persistent liver enzyme elevation, metabolic syndrome, obesity, or insulin resistance 1, 2
• Important caveat: Up to 50% of NAFLD patients have normal liver enzymes, so normal ALT/AST does not exclude the diagnosis 2

Initial Diagnostic Workup

Obtain a detailed alcohol history first—consumption must be <30 g/day for men and <20 g/day for women to diagnose NAFLD. 1, 2

Essential Laboratory Tests

• Complete liver chemistry panel (ALT, AST, alkaline phosphatase, bilirubin, albumin, PT/INR) 2
• Complete blood count with platelets (thrombocytopenia suggests advanced fibrosis) 2
• Fasting glucose, HbA1c, and consider 75g oral glucose tolerance test in high-risk patients 1, 2
• Lipid profile (total cholesterol, HDL, triglycerides) 1, 2
• Viral hepatitis serology (HBV, HCV) to exclude other causes 2
• Iron studies (ferritin, transferrin saturation) to exclude hemochromatosis 1, 2

Imaging Studies

Abdominal ultrasonography is the first-line screening test for detecting hepatic steatosis. 1, 2

• Ultrasound has limited sensitivity for steatosis <20% and in patients with BMI >40 kg/m² 1
• Controlled attenuation parameter (CAP) via transient elastography can quantify steatosis (cutoff ~276 dB/m for moderate-severe steatosis in Korean populations) 1
• MRI or MR spectroscopy provides more accurate quantification when ultrasound is inadequate 2

Fibrosis Risk Stratification

Calculate non-invasive fibrosis scores in all NAFLD patients to identify those at risk for advanced fibrosis. 1, 2

NAFLD Fibrosis Score (NFS)

• Uses age, BMI, diabetes/impaired fasting glucose, AST/ALT ratio, platelet count, and albumin 2
• NFS <-1.455: Low risk of advanced fibrosis 2
• NFS >0.676: High risk of advanced fibrosis 2

FIB-4 Index

• Uses age, AST, ALT, and platelet count 2
• FIB-4 <1.45: Low risk of advanced fibrosis 2
• FIB-4 >3.25: High risk of advanced fibrosis 2

Transient Elastography

• Perform in patients who cannot be ruled out for significant fibrosis by serum scores 1
• Liver stiffness measurement <8.0 kPa suggests low risk 3

When to Perform Liver Biopsy

Liver biopsy remains the gold standard but should be reserved for patients at increased risk of steatohepatitis and advanced fibrosis. 1

Indications for Liver Biopsy

• Patients with metabolic syndrome and indeterminate or high-risk non-invasive fibrosis scores 1
• Suspected NAFLD with competing etiologies that cannot be excluded without biopsy 1
• Persistently elevated liver enzymes with high-risk features 2
• Patients with high serum ferritin and increased iron saturation, especially with C282Y HFE mutation 2

Histological Diagnosis

• NAFL (simple steatosis): Steatosis alone, or with inflammation/ballooning but not both 1
• NASH: Requires steatosis + ballooning + lobular inflammation 1
• Perisinusoidal fibrosis is common but not required for NASH diagnosis 1

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Management

Weight loss of 7-10% body weight through hypocaloric diet and exercise is the cornerstone of NAFLD treatment. 1, 3

Lifestyle Interventions (All Patients)

Weight Loss Targets

• 3-5% weight loss: Improves steatosis 1, 3
• 7-10% weight loss: Needed to improve necroinflammation and potentially fibrosis 1, 3
• Rate matters: Gradual weight loss (maximum 1 kg/week) is recommended; rapid weight loss may worsen liver disease 3

Dietary Recommendations

• Hypocaloric diet with 500-1000 kcal energy deficit 3
• Avoid fructose-containing beverages and foods 3
• Limit saturated fat to <7% of total calories 4
• Alcohol consumption should be below risk threshold (30g for men, 20g for women) or consider complete abstinence 3

Physical Activity

• Exercise alone may reduce hepatic steatosis but its effect on necroinflammation is uncertain 1
• Combine with dietary modification for optimal results 1

Pharmacological Treatment

Pharmacological treatment should be considered selectively based on risk stratification—reserve for patients with NASH and significant fibrosis (≥F2). 3

Who Should NOT Receive Pharmacotherapy

• Patients with simple steatosis (NAFL) without NASH or fibrosis should only receive lifestyle counseling 3

Who Should Receive Pharmacotherapy

• Patients with progressive NASH (bridging fibrosis and cirrhosis) 3
• Patients with NASH and ≥F2 fibrosis 3

Specific Medications

Metformin is NOT recommended as a specific treatment for liver disease in NASH, as it has no significant effect on liver histology. 3

• Avoid sulfonylureas and insulin if possible, as they may increase HCC risk 3

Management of Comorbidities

Diabetes Management

• Consider GLP-1 agonists, which can be effective for NASH recovery 3
• Screen for diabetes with fasting glucose, HbA1c, or OGTT in high-risk patients 1

Dyslipidemia Management

• Statins are safe and effective in NAFLD patients and may reduce HCC risk by 37% 3
• Statins are not contraindicated and should be used for cardiovascular risk reduction 4

Cardiovascular Disease

• Comprehensive CVD workup is mandatory, as cardiovascular disease is the main driver of mortality in NAFLD patients before cirrhosis develops 3
• Address all metabolic risk factors (hypertension, dyslipidemia, diabetes) 1

Monitoring and Follow-Up

Follow-up intervals should be based on disease severity and fibrosis stage. 1

Monitoring Schedule

• NAFL without worsening metabolic risk factors: Monitor every 2-3 years 1
• NASH and/or fibrosis: Monitor annually 1
• NASH cirrhosis: Monitor every 6 months 1

What to Monitor

• Liver enzymes every 3-6 months 2
• Periodic reassessment of fibrosis risk using non-invasive tests 2
• Assessment of metabolic comorbidities 2
• Consider repeat liver biopsy after 5 years if indicated on a case-by-case basis 1

Hepatocellular Carcinoma Surveillance

Patients with NAFLD-related cirrhosis require HCC surveillance. 3

• Smoking cessation, alcohol abstinence, and weight loss are strongly recommended to reduce HCC development 3

When to Refer to Hepatology

Refer to hepatology if evidence of advanced fibrosis or cirrhosis is present. 2

Specific Referral Criteria

• ALT >8× ULN or >5× baseline 4
• ALT >3× ULN with total bilirubin >2× ULN 4
• Evidence of synthetic dysfunction (elevated INR, low albumin) 4
• High-risk non-invasive fibrosis scores confirmed by transient elastography 1

Common Pitfalls to Avoid

• Do not rely solely on liver enzymes: Normal ALT/AST does not exclude NAFLD or even advanced fibrosis 2
• Do not assume spontaneous resolution: 84% of abnormal liver tests remain abnormal at 1 month, and 75% at 2 years 4
• Do not misinterpret low-titer autoantibodies: These are common in NAFLD and generally not clinically significant 2
• Do not fail to exclude significant alcohol consumption: This is essential to distinguish NAFLD from alcoholic liver disease 2
• Do not withhold statins: They are safe and beneficial for cardiovascular risk in NAFLD patients 3, 4