What is the appropriate workup for a patient with elevated liver enzymes, including laboratory tests and imaging studies?

Workup for Elevated Liver Enzymes

Initial Laboratory Testing

Begin with a complete liver panel including AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, and prothrombin time/INR to establish the pattern of injury and assess synthetic function. 1, 2

Essential First-Line Labs

• Complete blood count with platelets to identify cytopenias suggesting advanced liver disease or portal hypertension 2
• Viral hepatitis panel including HBsAg, anti-HBc IgM, and anti-HCV antibody to exclude viral etiologies 1, 2
• Metabolic parameters including fasting glucose or HbA1c and fasting lipid panel, as metabolic syndrome is present in 70% of obese patients and 90% of diabetics with NAFLD 1, 2
• Iron studies (ferritin and transferrin saturation) to screen for hemochromatosis 2
• Autoimmune markers (ANA, anti-smooth muscle antibody, immunoglobulin G) if other causes excluded 2

Pattern Recognition for Targeted Workup

• AST:ALT ratio <1 suggests NAFLD, viral hepatitis, or medication-induced injury 1
• AST:ALT ratio >2 indicates alcoholic liver disease with 70% specificity, particularly if AST and ALT do not exceed 400 IU/mL 1
• Predominant alkaline phosphatase elevation requires imaging first to distinguish intra- from extrahepatic cholestasis 1

Detailed Alcohol and Medication History

Obtain quantitative alcohol consumption history, as intake of ≥14-21 drinks/week in men or ≥7-14 drinks/week in women suggests alcoholic liver disease. 1, 3

• Review all medications against the LiverTox® database, including prescription drugs, over-the-counter products, and herbal supplements, as medication-induced injury causes 8-11% of cases 3, 2
• Document recent exercise intensity, as vigorous activity can transiently elevate transaminases 3

First-Line Imaging

Order abdominal ultrasound as the initial imaging study, which has 84.8% sensitivity and 93.6% specificity for detecting moderate to severe hepatic steatosis. 1, 3

Ultrasound identifies:

• Hepatic steatosis (graded as mild, moderate, or severe based on echogenicity) 1
• Biliary obstruction or dilation 3, 2
• Focal liver lesions 3
• Portal hypertension features (splenomegaly, ascites) 3
• Structural abnormalities 1

Quantitative Assessment

• Hepatorenal index provides objective measurement with 99.2-99.6% correlation to MR spectroscopy and liver biopsy, independent of BMI, inflammation, or fibrosis 1

Risk Stratification for Fibrosis

Calculate the FIB-4 score using age, ALT, AST, and platelet count to determine need for hepatology referral. 3, 2

• FIB-4 <1.3 (<2.0 if age >65): Low risk for advanced fibrosis, negative predictive value ≥90% 3
• FIB-4 >2.67: High risk for advanced fibrosis, requires hepatology referral 3, 2

Additional Testing Based on Clinical Context

• Creatine kinase if AST elevation predominates, to exclude muscle injury as source 1, 3
• Thyroid function tests to rule out thyroid disorders causing transaminase elevation 3
• Alpha-1-antitrypsin level if family history or early-onset emphysema 2
• Ceruloplasmin in patients <40 years to exclude Wilson disease 2
• Hepatitis A and E serology if ALT markedly elevated (>400 IU/L) 2

Monitoring Strategy Based on Severity

Mild Elevation (<2× ULN)

• Repeat liver enzymes in 2-4 weeks to establish trend 3
• If normalizing, continue monitoring every 4-8 weeks until stable 3

Moderate Elevation (2-5× ULN)

• Monitor weekly for 2 weeks, then biweekly until normalized or cause identified 3
• Intensify evaluation for underlying causes 3

Severe Elevation (>5× ULN)

• Urgent evaluation within 2-3 days required 3
• Consider acute viral hepatitis, ischemic hepatitis, drug-induced liver injury, or autoimmune hepatitis 1

Hepatology Referral Criteria

Refer to hepatology if: 3, 2

• Liver enzymes remain elevated ≥6 months without identified cause
• ALT increases to >5× ULN (>235 IU/L for males, >125 IU/L for females)
• Bilirubin >2× ULN
• Evidence of synthetic dysfunction (low albumin, elevated INR)
• FIB-4 score >2.67

Common Pitfalls to Avoid

• Do not attribute elevations to NAFLD alone if ALT ≥5× ULN, as this level is rare in NAFLD and warrants investigation for viral hepatitis, autoimmune hepatitis, or drug-induced injury 3
• Do not overlook sex-specific normal ranges: ALT 29-33 IU/L for males, 19-25 IU/L for females—commercial lab cutoffs are often too high 1, 3
• Do not assume AST elevation is hepatic in origin without checking CK, as AST is present in cardiac muscle, skeletal muscle, kidneys, and red blood cells 1, 3
• Do not simply repeat testing without investigation, as 84% of abnormal tests remain abnormal at 1 month and 75% at 2 years 2
• Do not order liver biopsy for mild elevations unless non-invasive evaluation suggests significant disease or autoimmune hepatitis 3, 2