What are the evaluation and management strategies for Fatty Liver Disease (FLD), including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)?

Evaluation and Management of Fatty Liver Disease

Screen all patients with type 2 diabetes, prediabetes, obesity (BMI >25 kg/m²), or metabolic syndrome for NAFLD using the FIB-4 index as your initial fibrosis assessment tool, regardless of whether liver enzymes are normal. 1, 2

Initial Diagnostic Evaluation

Who to Screen

• All adults with type 2 diabetes or prediabetes should undergo NAFLD screening, particularly those with obesity or established cardiovascular disease 1
• Patients over age 40 with type 2 diabetes warrant screening even if lean (BMI <25 kg/m² for non-Asian, <23 kg/m² for Asian) 1
• Any patient with incidental hepatic steatosis on imaging requires further evaluation 1
• Do not exclude NAFLD based on normal ALT alone—half of NAFLD patients have normal transaminases 2

Defining NAFLD

NAFLD requires two criteria: (1) evidence of hepatic steatosis by imaging or histology, and (2) exclusion of secondary causes including alcohol consumption >20-30 g/day in men or >14-20 g/day in women, steatogenic medications (amiodarone, methotrexate, tamoxifen, corticosteroids), viral hepatitis C, Wilson's disease, and lipodystrophy 1

Initial Laboratory Workup

Obtain the following tests at diagnosis 1, 2:

• Complete metabolic panel with ALT, AST, GGT
• Complete blood count with platelets (needed for FIB-4 calculation)
• Fasting glucose or HbA1c
• Fasting lipid profile
• INR
• Hepatitis B and C serologies
• Ferritin and transferrin saturation
• Consider thyroid function, celiac screen, and tests for autoimmune hepatitis, alpha-1 antitrypsin deficiency if clinically indicated 1

Alcohol History

Routinely and carefully query all patients about alcohol consumption patterns—this is essential to distinguish NAFLD from alcoholic liver disease 1

Risk Stratification for Fibrosis

First-Tier: FIB-4 Index

Calculate FIB-4 at diagnosis for every NAFLD patient using age, ALT, AST, and platelet count 1, 2:

• FIB-4 <1.3 (or <2.0 if age >65): Low risk for advanced fibrosis—repeat testing in 2-3 years 2
• FIB-4 1.3-2.67: Indeterminate risk—proceed to second-tier testing 1
• FIB-4 >2.67: High risk for advanced fibrosis—proceed to second-tier testing 1

Second-Tier Testing for Indeterminate or High FIB-4

Patients with FIB-4 ≥1.3 require additional risk stratification with 1, 2:

• Transient elastography (FibroScan) as the preferred modality
• MR elastography if available
• Enhanced Liver Fibrosis (ELF) panel as an alternative blood biomarker

When to Refer to Hepatology/Gastroenterology

Refer patients with indeterminate or high-risk results on second-tier testing (elevated liver stiffness or ELF) to a gastroenterologist or hepatologist for further workup and long-term interprofessional management 1

Imaging for Steatosis Detection

• Ultrasound is the most economical and widely available first-line imaging modality, though it has limited sensitivity for mild steatosis (<30%) 2
• MRI-PDFF (proton density fat fraction) provides excellent quantification of steatosis but is primarily reserved for clinical trials 2
• CT is not recommended for routine steatosis detection due to radiation exposure 1

Role of Liver Biopsy

Consider liver biopsy in the following scenarios 1, 2:

• Uncertainty regarding contributing causes of liver injury
• Indeterminate noninvasive test results despite second-tier testing
• Suspected NASH with advanced fibrosis requiring definitive staging
• When concurrent chronic liver disease cannot be excluded

Liver biopsy remains the gold standard for diagnosing NASH (defined as ≥5% steatosis plus inflammation and hepatocyte ballooning with or without fibrosis) and staging fibrosis (F0-F4) 1

Management Strategies

Lifestyle Modification (First-Line for All Patients)

Target 7-10% weight loss through diet and exercise—this is the most effective intervention for improving histologic outcomes including fibrosis 1, 3:

• Weight loss of 3-5% improves steatosis 1
• Weight loss of 7-10% improves NASH and fibrosis 3
• Mediterranean diet pattern is recommended 4
• Avoid fructose and sugar-sweetened beverages 1
• Regular physical activity independent of weight loss provides benefit 4

Pharmacologic Therapy

For biopsy-confirmed NASH without diabetes or cirrhosis:

• Vitamin E 800 IU daily may be considered 1, 4
• Pioglitazone 30 mg daily may be considered (can be used with or without diabetes, but not in cirrhosis) 1, 4

For patients with type 2 diabetes and NAFLD:

• GLP-1 receptor agonists show promise but require further investigation for NAFLD-specific indications 1, 4
• SGLT-2 inhibitors require further investigation for NAFLD management 1, 4

Important caveat: No NAFLD-specific therapies are currently FDA-approved 3

Bariatric Surgery

Consider bariatric surgery for appropriate candidates with obesity and NAFLD, as substantial weight loss achieved through surgery directly correlates with histologic improvement including fibrosis regression 3

Monitoring and Follow-Up

Low-Risk Patients (FIB-4 <1.3)

• Repeat FIB-4 every 2-3 years, as only 12% show significant progression in liver stiffness over 3 years 2
• Continue monitoring metabolic comorbidities 1

NASH Patients with Fibrosis

• Monitor annually with routine biochemistry and noninvasive fibrosis assessment 1
• Repeat liver biopsy may be considered after 5 years on a case-by-case basis 1

NASH Cirrhosis

• Monitor every 6 months 1
• Hepatocellular carcinoma surveillance with abdominal ultrasound ± AFP every 6 months is essential 1
• Screen for varices per standard cirrhosis protocols 1

Comorbidity Management

Aggressively manage all metabolic comorbidities as NAFLD patients have increased mortality from cardiovascular disease, extrahepatic cancer, and liver-related complications 1:

• Optimize glycemic control in diabetes 1
• Treat dyslipidemia per cardiovascular risk guidelines 1
• Manage hypertension—note that hypertension doubles the rate of fibrosis progression 1
• Address cardiovascular disease risk comprehensively 1

Critical Pitfalls to Avoid

• Never exclude NAFLD based solely on normal liver enzymes—transaminases are normal in approximately 50% of NAFLD patients 2
• Do not assume AST:ALT ratio >1 excludes NAFLD—this ratio reverses in advanced fibrosis and cirrhosis 2
• Do not overlook lean NAFLD—7-20% of NAFLD patients have normal BMI and require the same systematic evaluation 1
• Do not underestimate cardiovascular risk—cardiovascular disease is a leading cause of death in NAFLD, often exceeding liver-related mortality 1