What is the appropriate workup for elevated Liver Function Tests (LFTs)?

Evaluation and Management of Elevated Liver Function Tests

The appropriate workup for elevated liver function tests (LFTs) should include a systematic evaluation for common liver diseases, with initial laboratory testing, imaging, and lifestyle modifications, followed by targeted investigations based on the pattern of elevation.

Initial Assessment

Pattern Recognition

• Categorize the pattern of LFT elevation:
  • Hepatocellular pattern: Predominant elevation of AST/ALT
  • Cholestatic pattern: Predominant elevation of alkaline phosphatase and GGT
  • Mixed pattern: Elevation of both hepatocellular and cholestatic enzymes

Severity Classification

• Mild: <5× upper limit of normal (ULN)
• Moderate: 5-10× ULN
• Severe: >10× ULN 1

First-Line Investigations

Essential Laboratory Testing

1. Complete blood count with differential
2. Comprehensive metabolic panel (including fractionated bilirubin)
3. Coagulation studies (PT/INR)
4. Viral hepatitis screening:
   • Hepatitis B surface antigen (HBsAg)
   • Hepatitis B core antibody (anti-HBc)
   • Hepatitis C antibody (anti-HCV) 1

Imaging

• Abdominal ultrasound to assess liver structure and rule out biliary obstruction 1

Targeted Investigations Based on Clinical Context

For Suspected Alcoholic Liver Disease

• AST:ALT ratio >2 suggests alcoholic liver disease
• MCV elevation is common
• Consider the ALD/NAFLD index (based on MCV, AST/ALT ratio, BMI, and gender) 2

For Suspected NAFLD

• Lipid profile
• Fasting glucose/HbA1c
• AST:ALT ratio typically <1 1

For Suspected Autoimmune or Metabolic Liver Disease

• Autoimmune markers (ANA, ASMA, ANCA)
• Iron studies (transferrin and transferrin saturation)
• Alpha-1-antitrypsin
• Ceruloplasmin (in younger patients) 2

For Suspected Drug-Induced Liver Injury

• Complete medication review including prescription medications, over-the-counter drugs, and supplements
• Consider temporary discontinuation of potential hepatotoxic medications 1

Management Approach

For Mild Elevations (<5× ULN)

1. Monitor LFTs every 2-4 weeks until normalization
2. Implement lifestyle modifications:
   • Mediterranean diet with limited fat (25-30% of total calories)
   • Regular exercise (30 minutes of moderate-intensity activity most days)
   • Weight loss targeting 5-10% if overweight/obese 1
3. Avoid hepatotoxic substances including alcohol

For Moderate to Severe Elevations (>5× ULN)

1. More urgent evaluation with expanded laboratory testing
2. Consider hepatology referral, especially with jaundice or signs of hepatic decompensation
3. Consider liver biopsy for diagnosis confirmation in cases of suspected autoimmune hepatitis or conflicting findings 1

Special Considerations

Medication-Related LFT Elevations

• For patients on medications known to affect liver enzymes (e.g., methotrexate, sulfasalazine, leflunomide):
  • Monitor CBC, LFTs within first 1-2 months of usage and every 3-4 months thereafter
  • Consider dose reduction or temporary discontinuation for clinically relevant elevations 2

Immune Checkpoint Inhibitor Therapy

• For patients on immunotherapy with elevated LFTs:
  • Grade ≥2 elevation: Hold immunotherapy temporarily
  • Consider steroids (0.5-1 mg/kg/d prednisone) if no improvement after 3-5 days
  • For grade ≥3: Consider mycophenolate mofetil if inadequate improvement with steroids 2

Indications for Referral to Hepatology

• Persistent elevation (>6 months) despite interventions
• Severe elevations (>10× ULN)
• Development of jaundice or signs of hepatic decompensation
• Suspected autoimmune hepatitis requiring histological confirmation
• Conflicting clinical, laboratory, and imaging findings 1

Monitoring and Follow-up

• If LFTs normalize, continue lifestyle modifications and repeat testing in 3-6 months
• If LFTs remain elevated after 3-6 months despite interventions, refer to hepatology 1
• For patients with cirrhosis, perform upper gastrointestinal endoscopy to screen for esophageal varices unless low risk (platelets >150,000 and Fibroscan <20) 2

The systematic approach to elevated LFTs helps identify the underlying cause early, allowing for timely intervention and potentially preventing progression to advanced liver disease 3.