What are the minimum laboratory tests to order for a patient with elevated alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase?

Minimum Laboratory Tests for Elevated ALP, ALT, and AST

When alkaline phosphatase, ALT, and AST are all elevated, you must order a complete liver panel (including total and direct bilirubin, albumin, prothrombin time/INR), gamma-glutamyl transferase (GGT), and viral hepatitis serologies (HBsAg, anti-HBc, anti-HCV) as the bare minimum initial workup. 1

Essential First-Line Laboratory Tests

Complete Liver Panel

• Measure total and direct bilirubin to calculate the conjugated fraction, which distinguishes cholestatic from hepatocellular patterns and assesses severity 2, 1
• Check albumin and prothrombin time (PT/INR) to evaluate hepatic synthetic function and differentiate acute from chronic liver disease 2
• Include platelet count as a surrogate marker for portal hypertension and to calculate fibrosis risk scores 2

Gamma-Glutamyl Transferase (GGT)

• Order GGT to confirm the hepatic origin of elevated alkaline phosphatase, as ALP can originate from bone, intestine, or placenta 1, 3
• Elevated GGT alongside ALP confirms a cholestatic pattern and directs further hepatobiliary evaluation 3, 4
• Normal GGT with elevated ALP suggests a bone source rather than liver disease 3

Viral Hepatitis Serologies

• Test for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), and hepatitis C antibody (anti-HCV) as viral hepatitis commonly causes fluctuating transaminase elevations 2, 1
• Confirm viral load in patients who test positive for HBsAg or anti-HCV 2

Pattern Recognition and Additional Testing

When Cholestatic Pattern Predominates (ALP >> ALT/AST)

• Calculate the R-value: (ALT/ULN) ÷ (ALP/ULN) to classify injury pattern 1, 5
  • R ≤ 2 indicates cholestatic injury
  • R > 2 and < 5 indicates mixed injury
  • R ≥ 5 indicates hepatocellular injury
• Order abdominal ultrasound as first-line imaging to evaluate for biliary obstruction, gallstones, and structural abnormalities 2, 1, 3

When Hepatocellular Pattern Predominates (ALT/AST >> ALP)

• Obtain metabolic parameters including fasting glucose or HbA1c and fasting lipid panel to assess for nonalcoholic fatty liver disease 1
• Perform detailed alcohol history using validated tools; consumption ≥30 g/day in men or ≥20 g/day in women suggests alcoholic liver disease 2, 1
• Review all medications including over-the-counter drugs and herbal supplements, as medication-induced liver injury causes 8-11% of cases 1

When Mixed Pattern Present

• Check iron studies (serum ferritin and transferrin saturation) to screen for hereditary hemochromatosis 1, 5
• Measure autoimmune markers (ANA, anti-smooth muscle antibody, anti-mitochondrial antibody) if autoimmune liver disease is suspected 1, 5

Critical Pitfalls to Avoid

• Do not assume mild elevations are benign without proper evaluation; even modest increases can reflect significant pathology, especially in women whose normal ALT range is lower (19-25 IU/L versus 29-33 IU/L in men) 1, 5
• Do not overlook non-hepatic causes of AST elevation, such as cardiac injury, skeletal muscle disorders, or hemolysis; consider checking creatine kinase if recent exercise or muscle injury is possible 1
• Do not delay imaging when cholestatic pattern is present, as biliary obstruction requires prompt identification 2, 3
• Normal ultrasound does not exclude significant liver disease; up to 10% of patients with advanced fibrosis may have normal imaging 1

Monitoring Strategy

• Repeat liver enzymes in 2-4 weeks to establish trend and confirm reproducibility 1, 6
• If ALT increases to ≥3× ULN or doubles from baseline, intensify evaluation and repeat testing within 2-5 days 1
• If values remain elevated for ≥6 months without identified cause, refer to hepatology 1