What are the diagnostic criteria and management options for non-alcoholic fatty liver disease (NAFLD)?

Diagnosis of Non-Alcoholic Fatty Liver Disease (NAFLD)

NAFLD diagnosis requires two essential criteria: (1) evidence of hepatic steatosis by imaging or histology, AND (2) exclusion of secondary causes including significant alcohol consumption (>21 drinks/week for men, >14 drinks/week for women), steatogenic medications, and hereditary disorders. 1

Diagnostic Criteria

Primary Requirements

• Hepatic steatosis must be documented either by imaging (ultrasound, CT, MRI) or liver biopsy 1
• Exclude significant alcohol consumption as defined above - this is mandatory and non-negotiable 1, 2
• Rule out competing etiologies including hepatitis C (especially genotype 3), Wilson's disease, medications (amiodarone, methotrexate), lipodystrophy, and parenteral nutrition 1

Initial Laboratory Evaluation

The following tests are essential for every suspected NAFLD patient:

• Complete liver chemistry panel (ALT, AST, alkaline phosphatase, bilirubin, albumin, prothrombin time) 2
• Complete blood count with platelets - thrombocytopenia suggests advanced fibrosis 2
• Fasting glucose, HbA1c, and lipid profile to assess metabolic syndrome components 2
• Viral hepatitis serology (HBV, HCV) to exclude viral causes 2
• Iron studies (ferritin, transferrin saturation) - persistently elevated levels, especially with C282Y HFE mutations, warrant liver biopsy 1, 2

Important caveat: Up to 50% of NAFLD patients have normal liver enzymes, so normal ALT/AST does not exclude the diagnosis 2, 3

Imaging Studies

• Abdominal ultrasound is the first-line screening test for detecting hepatic steatosis 2, 4
• MRI or MR spectroscopy provides more accurate quantification of steatosis when ultrasound is inadequate 2
• Standard imaging cannot reliably distinguish simple steatosis from steatohepatitis or assess fibrosis 1

Risk Stratification for Advanced Disease

Non-Invasive Fibrosis Assessment

The NAFLD Fibrosis Score is the most clinically useful tool for identifying patients with bridging fibrosis or cirrhosis 1:

• Calculate using: age, BMI, hyperglycemia, platelet count, albumin, AST/ALT ratio (available at http://nafldscore.com) 1
• Score <-1.455: 90% sensitivity to exclude advanced fibrosis - low risk 1, 2
• Score >0.676: 97% specificity to identify advanced fibrosis - high risk 1, 2

FIB-4 index is an alternative using 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

Metabolic Syndrome as a Predictor

The presence of metabolic syndrome strongly predicts steatohepatitis and should be used to identify patients who would benefit from liver biopsy 1

Emerging Biomarkers

• Serum cytokeratin-18 (CK18) fragments show promise (78% sensitivity, 87% specificity for NASH) but are not yet recommended for routine practice as the assay is not commercially available and lacks standardized cut-off values 1

When to Perform Liver Biopsy

Liver biopsy remains the gold standard for distinguishing NAFL from NASH and staging fibrosis, but should be reserved for specific situations 1, 5:

Strong Indications for Biopsy:

• Patients at increased risk for steatohepatitis and advanced fibrosis based on metabolic syndrome presence and NAFLD Fibrosis Score 1
• Competing etiologies cannot be excluded without histologic confirmation 1
• Persistently elevated ferritin with increased iron saturation, especially with C282Y HFE mutations 1, 2
• High-titer autoantibodies (ANA >1:160 or ASMA >1:40) with very high aminotransferases and elevated globulin suggesting possible autoimmune liver disease 1

Critical distinction: Low-titer autoantibodies are present in 21% of NAFLD patients and are generally an epiphenomenon, not indicative of autoimmune disease 1

Histologic Classification

Once biopsy is performed, NAFLD is categorized as:

• NAFL (nonalcoholic fatty liver): hepatic steatosis without hepatocellular injury or ballooning - benign prognosis 1
• NASH (nonalcoholic steatohepatitis): steatosis plus inflammation with hepatocyte ballooning, with or without fibrosis - can progress to cirrhosis 1, 6

Common Diagnostic Pitfalls

• Do not rely solely on liver enzymes - normal ALT/AST occurs in half of NAFLD patients 2, 3
• Do not misinterpret low-titer autoantibodies as autoimmune disease - they are common in NAFLD and clinically insignificant 1
• Do not assume fatty liver causes abdominal pain - NAFLD is typically asymptomatic and pain requires separate evaluation 3, 7
• Do not forget to quantify alcohol consumption precisely - this is the most critical exclusion criterion 1, 2

Follow-Up Monitoring

• Monitor liver enzymes every 3-6 months to assess disease progression 2, 3
• Reassess fibrosis risk periodically using non-invasive scores 2
• Aggressively manage metabolic comorbidities (obesity, diabetes, dyslipidemia) as these drive disease progression 1, 2
• Refer to hepatology if evidence of advanced fibrosis or cirrhosis is present 2