What is the appropriate laboratory workup for a patient with hepatomegaly?

Laboratory Workup for Hepatomegaly

The initial laboratory workup for an enlarged liver should include a comprehensive panel consisting of: bilirubin, albumin, ALT, AST, alkaline phosphatase, GGT, prothrombin time/INR, platelet count, and complete blood count. 1

Core Liver Function Tests

The foundation of hepatomegaly evaluation requires assessment of both hepatocellular injury and synthetic function:

• Bilirubin (total and fractionated) assesses hepatic excretory function and identifies cholestasis 1
• Albumin reflects hepatic synthetic function and indicates chronicity of liver disease 1
• ALT and AST are primary markers of hepatocellular injury, with ALT being more liver-specific 1, 2
• Alkaline phosphatase (ALP) indicates cholestatic or infiltrative disease 1
• GGT increases sensitivity for detecting alcohol-related and fatty liver disease and is associated with increased liver and all-cause mortality 1
• Prothrombin time/INR evaluates hepatic synthetic function and coagulation status 3
• Platelet count serves as a surrogate marker for portal hypertension and advanced fibrosis 3, 1

Etiologic Testing for Underlying Causes

Once hepatomegaly is confirmed, systematic testing should identify the specific etiology:

Viral Hepatitis Serologies

• Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) including IgG and IgM fractions 3, 4
• Hepatitis C antibody (HCV Ab) with reflex PCR if positive 4
• For marked transaminase elevations (ALT >1000 U/L), add hepatitis A IgM, hepatitis E IgM, and CMV serologies 1, 4
• Confirm viral load in patients testing positive for HBsAg, HBcAb IgG, or HCV antibodies 3

Autoimmune Markers

• Antimitochondrial antibody (AMA) for primary biliary cholangitis, particularly if cholestatic pattern present 3, 1
• Antinuclear antibody (ANA) and anti-smooth muscle antibody (ASMA) for autoimmune hepatitis 1
• Serum immunoglobulin G (IgG) which is elevated in autoimmune hepatitis 1

Metabolic and Infiltrative Disease Screening

• Fasting glucose or hemoglobin A1c and lipid panel to assess for NAFLD and metabolic syndrome 1
• Iron studies (serum iron, total iron-binding capacity, ferritin, transferrin saturation) to screen for hemochromatosis 3
• Alpha-fetoprotein (AFP) if hepatocellular carcinoma is suspected, though it can be elevated in chronic hepatitis B/C and other conditions 3

Assessment of Hepatic Functional Reserve

For patients with suspected cirrhosis or advanced liver disease, additional testing is critical:

• Blood urea nitrogen and creatinine to assess kidney function, as creatinine is an established prognostic marker in liver disease 3
• Calculate Child-Pugh score using albumin, bilirubin, prothrombin time, and clinical assessment of encephalopathy and ascites 3
• Calculate MELD score using bilirubin, creatinine, and INR for patients being considered for transplantation 3

Non-Invasive Fibrosis Assessment

Fibrosis indices should be calculated to stratify risk of advanced disease:

• FIB-4 score with values <1.3 indicating low risk of advanced fibrosis (<2.0 for age >65 years) 1
• APRI (AST-to-Platelet Ratio Index) can detect advanced fibrosis and portal hypertension 3
• GPR (GGT-to-Platelet Ratio) may be particularly useful in detecting early biliary disease 3

Critical Pitfalls to Avoid

Do not simply repeat abnormal liver tests without pursuing the underlying etiology, as 75% of abnormal liver enzymes remain abnormal at 2 years without intervention 4. The pattern of enzyme elevation guides the differential diagnosis: hepatocellular injury shows disproportionate ALT/AST elevation, while cholestatic injury shows disproportionate alkaline phosphatase elevation 2.

Ferritin can be falsely elevated in inflammatory conditions, necroinflammatory liver disease (alcoholic liver disease, chronic hepatitis B/C, NAFLD), lymphomas, and other chronic inflammatory conditions, so interpret in context 3. Similarly, AFP lacks specificity and can be elevated in pregnancy, chronic HBV/HCV, intrahepatic cholangiocarcinoma, and other malignancies 3.

Timing and Referral Considerations

Immediate specialist referral is warranted for:

• Unexplained clinical jaundice 1
• Suspicion of hepatic or biliary malignancy 1
• Evidence of hepatitis B, HCV, autoimmune hepatitis, or hemochromatosis 1
• Findings concerning for cirrhosis such as thrombocytopenia, AST>ALT ratio, hypoalbuminemia, or elevated INR 1