What is the initial workup for a patient presenting with hepatomegaly (enlarged liver)?

Initial Workup for Hepatomegaly

Begin with a comprehensive metabolic panel including AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, and prothrombin time/INR, combined with abdominal ultrasound as the first-line imaging modality. 1

Essential Laboratory Testing

Core Liver Function Panel

• Obtain AST, ALT, alkaline phosphatase, GGT, total bilirubin, direct bilirubin, albumin, and prothrombin time/INR to characterize the pattern of liver injury (hepatocellular vs. cholestatic) 2, 1
• Measure complete blood count with differential and platelet count to assess for cytopenias suggesting portal hypertension or infiltrative processes 1
• Check serum creatinine and blood urea nitrogen as prognostic markers and to assess kidney function 2

Pattern Recognition in Laboratory Results

• Hepatocellular pattern: Transaminases elevated >5 times upper limit of normal with alkaline phosphatase <2-3 times upper limit of normal 3
• Cholestatic pattern: Alkaline phosphatase 3-5 times upper limit of normal with mild transaminase elevation 3
• Infiltrative pattern: Alkaline phosphatase disproportionately elevated compared to bilirubin 3

Viral Hepatitis Screening

• Test for HBsAg, hepatitis B surface antibody, hepatitis B core antibody (HBcAb), HBcAb IgM (if acute hepatitis suspected), and HCV antibodies 2, 1
• Confirm viral load in patients positive for HBsAg, HBcAb IgG, or HCV antibodies 2

Additional Metabolic and Specialized Testing

• Measure fasting glucose and lipid profile to evaluate for non-alcoholic fatty liver disease 1
• Check iron studies (ferritin, transferrin saturation) for hemochromatosis 1
• Obtain autoimmune markers (ANA, ASMA, immunoglobulin levels) when autoimmune hepatitis is suspected 2, 1
• Measure alpha-fetoprotein (AFP) in patients with cirrhosis or risk factors for hepatocellular carcinoma 2, 1
• Consider ceruloplasmin level in patients <40 years without obvious explanation, as Wilson disease can present with hepatomegaly 2

Context-Specific Laboratory Evaluation

When hepatomegaly presents with hypoglycemia, obtain blood glucose (ideally at time of hypoglycemia), lactate, uric acid, CK, plasma carnitine (total and free), acylcarnitine profile, plasma amino acids, urinalysis, and urine organic acids 2

Imaging Studies

First-Line Imaging

• Abdominal ultrasound is the initial imaging modality of choice, assessing liver size, parenchymal texture, focal lesions, biliary dilation, portal vein patency, and splenomegaly 1, 3
• Ultrasound can identify hepatomegaly, steatosis, masses, and signs of portal hypertension 1

Advanced Imaging Indications

• Obtain triphasic CT or MRI when focal lesions are detected, hepatocellular carcinoma is suspected, or ultrasound findings are inconclusive 2, 1
• Use MRCP when cholestatic liver tests suggest biliary pathology 1
• Consider liver elastography (transient elastography or MRI/ultrasound elastography) for non-invasive assessment of liver fibrosis 1, 4

Critical History and Physical Examination Elements

History Taking Priorities

• Quantify alcohol consumption in detail, as alcohol is a leading cause of liver disease 1, 4
• Document intravenous drug use history as a risk factor for viral hepatitis 1
• Assess for metabolic risk factors including obesity, diabetes, and hyperlipidemia suggesting NAFLD 1
• Obtain family history of hereditary liver diseases (Wilson's disease, hemochromatosis, alpha-1 antitrypsin deficiency) 1
• Review medication and supplement use, including over-the-counter products and herbal preparations 4
• In acute presentations, carefully review possible exposures to viral infection, drugs, or toxins 2

Physical Examination Focus

• Assess liver size by palpation and percussion; inability to palpate or percuss significant liver dullness may indicate massive hepatocyte loss 2
• An enlarged liver may indicate viral hepatitis, malignant infiltration, congestive heart failure, or acute Budd-Chiari syndrome 2
• Evaluate for splenomegaly, which combined with hepatomegaly suggests portal hypertension, storage diseases, or hematologic malignancies 1, 5
• Document signs of chronic liver disease including spider angiomata, palmar erythema, jaundice, ascites, and caput medusae 1
• Assess mental status carefully; any alteration in sensorium with prolonged prothrombin time (INR ≥1.5) establishes acute liver failure requiring immediate hospitalization 2
• Right upper quadrant tenderness is variably present and non-specific 2

Special Clinical Scenarios

Pediatric Considerations

• Maintain higher suspicion for metabolic and storage disorders including glycogen storage diseases 1
• In infants <2 months with hepatomegaly or those with coagulopathy/impending organ failure, defer biopsy until after clinical stabilization 2
• Infants <6 months with L1 adrenal tumors ≤3.1 cm (solid) or ≤5 cm (≥25% cystic) do not require initial biopsy 2

Acute Liver Failure Recognition

• If prothrombin time is prolonged by 4-6 seconds or more (INR ≥1.5) with any evidence of altered sensorium, diagnose acute liver failure and admit immediately to ICU 2
• Measure acetaminophen level and obtain toxicology screen in all cases of acute liver failure 2
• Check arterial blood gas, arterial lactate, and ammonia (arterial preferred) 2
• Obtain pregnancy test in females, as acute fatty liver of pregnancy requires expeditious delivery 4

Hepatomegaly with Splenomegaly

• This combination warrants evaluation for portal hypertension, lysosomal storage diseases, or hematologic malignancies 1, 5
• Massive splenomegaly with hepatomegaly suggests Gaucher disease or Niemann-Pick disease rather than glycogen storage disease 2

Fibrosis Assessment

• Calculate non-invasive fibrosis indices (APRI, FIB-4, GPR) using AST, ALT, GGT, and platelet count 4
• Perform liver elastography when available if abnormal physical exam, persistently elevated liver enzymes, or abnormal ultrasound findings are present 4

Common Pitfalls to Avoid

• Do not rely on AFP elevation alone for diagnosis, as it can be elevated in pregnancy, intrahepatic cholangiocarcinoma, colon cancer metastases, lymphoma, and germ cell tumors 2
• Recognize that up to 30% of patients with hepatocellular carcinoma have normal AFP levels 2
• A growing liver mass with negative biopsy does not rule out malignancy; continued monitoring with multidisciplinary review is essential 2
• In acute presentations, do not delay transfer to ICU once acute liver failure is diagnosed, as mental status can deteriorate hour-by-hour 2
• Failure to identify the underlying cause before initiating treatment leads to poor outcomes 4