What is the appropriate workup for elevated liver enzymes (elevated Alanine Transaminase (ALT), Aspartate Transaminase (AST), alkaline phosphatase, and total and direct bilirubin)?

Workup for Elevated Liver Enzymes

Begin with a comprehensive liver panel including ALT, AST, alkaline phosphatase, total and direct bilirubin, albumin, and prothrombin time/INR, and repeat within 2-5 days to confirm the elevation and establish a trend. 1

Determine the Pattern of Liver Injury

Calculate the R value to classify the injury pattern: R = (ALT/ALT ULN)/(ALP/ALP ULN) 1, 2

• R ≥5: Hepatocellular pattern (ALT/AST predominant elevation) 1
• R ≤2: Cholestatic pattern (alkaline phosphatase predominant elevation) 1
• R >2 but <5: Mixed pattern 1

Fractionate total bilirubin into direct and indirect components, as elevated direct (conjugated) bilirubin indicates hepatocellular disease or biliary obstruction 3, 2

Confirm alkaline phosphatase is of hepatobiliary origin by ordering gamma-glutamyl transferase (GGT) and/or alkaline phosphatase isoenzymes, as ALP can be elevated from bone or other non-hepatic sources 3

Initial Laboratory Workup

For All Patients:

• Viral hepatitis panel: Hepatitis B surface antigen (HBsAg), anti-HBc (IgG and IgM), HBV DNA, anti-HCV antibody, and HCV RNA 1, 4, 5, 2
• Autoimmune markers: Antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), anti-neutrophil cytoplasmic antibody (ANCA), anti-mitochondrial antibody (AMA), liver-kidney microsomal antibody type 1 (LKM-1), and soluble liver antigen (SLA) 1, 5, 2
• Metabolic workup: Fasting lipid profile, fasting glucose or hemoglobin A1C, assess for metabolic syndrome components (waist circumference, blood pressure) 1, 4, 5
• Iron studies: Serum iron, total iron-binding capacity, and ferritin to screen for hereditary hemochromatosis 1, 4, 5, 2
• Creatine kinase: To rule out muscle disorders as a cause of AST elevation 3, 1, 6
• Serum acetaminophen level if acute hepatocellular injury is present 1
• Alcohol markers: Consider urinary ethyl-glucuronide, ethyl-sulfate, or serum phosphatidylethanol if alcohol use is suspected 1

Additional Testing Based on Clinical Context:

• Ceruloplasmin and serum copper for Wilson disease (especially in patients <40 years) 1, 5, 2
• Alpha-1 antitrypsin level for alpha-1 antitrypsin deficiency 1, 5, 2
• Thyroid function tests to exclude thyroid disorders 6, 4, 5
• Immunoglobulin G level if autoimmune hepatitis or overlap syndrome is suspected 3
• Testing for less common viral causes (EBV, CMV, HSV, VZV) if initial workup is negative 1

Imaging Studies

Obtain hepatobiliary ultrasound with Doppler as the first-line imaging modality to assess for: 3, 1, 6, 4

• Biliary obstruction and gallstones
• Portal or hepatic vein thrombosis
• Hepatic metastases
• Fatty liver disease
• Structural abnormalities

Consider MRCP or ERCP if a cholestatic pattern is identified and biliary obstruction or dominant stricture is suspected 3

Medication and Exposure History

Review all medications, supplements, and herbal products for potential hepatotoxicity, as drug-induced liver injury is a common cause of elevated liver enzymes 3, 1, 6, 4, 5

Obtain detailed alcohol consumption history, as alcoholic liver disease is one of the most common causes of elevated transaminases 1, 6, 4, 5

Management Algorithm Based on Severity

Mild Elevations (<5× ULN):

• Repeat liver panel within 1-2 weeks to establish trend 6
• If persistent, initiate workup as outlined above 4, 5
• Consider trial of lifestyle modification if consistent with nonalcoholic fatty liver disease and other causes excluded 4, 5

Moderate Elevations (5-10× ULN):

• Repeat comprehensive liver panel within 2-5 days 3, 1, 6
• Initiate full diagnostic workup immediately 3, 1
• Consider hepatology consultation if no clear cause identified 1

Severe Elevations (>10× ULN) or ALT ≥3× ULN with Bilirubin ≥2× ULN:

• Repeat liver panel within 2-3 days 1, 6
• Immediate comprehensive evaluation including direct bilirubin and INR 1, 6
• Urgent hepatology consultation 1
• Consider hospitalization if synthetic dysfunction present (elevated INR, low albumin) 6

For Patients with Elevated Baseline ALT (≥1.5× ULN):

• Repeat testing within 2-5 days if ALT rises to >2× baseline or >300 U/L 3, 1, 6
• If ALT >3× baseline, repeat within 2-3 days and initiate close monitoring 3, 6

Assessment of Liver Fibrosis

Consider non-invasive assessment of liver fibrosis using FIB-4 score, NAFLD fibrosis score, APRI score, or elastography if chronic liver disease is suspected 1, 6, 4

Liver biopsy should be considered if: 1, 6, 2

• Diagnosis remains unclear after non-invasive evaluation
• Multiple diagnoses are possible
• Steroid-refractory hepatitis
• Staging of disease severity is needed

Follow-up and Referral

• For mild elevations without identified cause: Repeat liver enzymes in 2-4 weeks 6
• Hepatology referral is indicated if transaminases remain elevated for ≥6 months, evidence of synthetic dysfunction is present, or if there is concern for advanced liver disease 6, 5
• Monitor 2-3 times weekly initially if moderate to severe elevation, then reduce to once every 1-2 weeks once stabilized 3, 6

Important Pitfalls to Avoid

Do not attribute significant ALT elevation (>5× ULN) to NAFLD alone without ruling out other causes, as this degree of elevation is uncommon in isolated fatty liver disease 3, 1, 4

Recognize that severe abdominal pain with markedly elevated transaminases may indicate biliary disease (such as choledocholithiasis) rather than primary hepatocellular disease, avoiding unnecessary liver biopsy 7

Remember that ALT reference ranges vary significantly between laboratories (ULN may range from <30 U/L to >70 U/L), and true healthy normal ALT is 29-33 IU/L for males and 19-25 IU/L for females 3, 2

Do not delay repeat testing in symptomatic patients: New hepatic symptoms (fatigue, nausea, vomiting, right upper quadrant pain, jaundice) warrant repeat testing within 2-3 days regardless of enzyme levels 3, 6