What's the next step in evaluating a middle-aged patient with right lower quadrant abdominal pain, incidentally found to have hepatosplenomegaly (enlarged liver and spleen) on a computed tomography (CT) scan, with a liver size of up to 20.7 cm and a spleen size of up to 12.9 cm, compared to a normal size six months prior?

Workup of Incidental Hepatosplenomegaly

Order a complete blood count (CBC), comprehensive metabolic panel with liver function tests, and abdominal ultrasound with Doppler as the immediate next steps to evaluate this rapidly progressive hepatosplenomegaly. 1, 2

Initial Laboratory Evaluation

The rapid progression from normal organ size to significant hepatosplenomegaly over 6 months demands urgent systematic evaluation. Begin with:

• CBC to assess for cytopenias (particularly thrombocytopenia suggesting portal hypertension) and leukocytosis (suggesting hematologic malignancy) 1, 2
• Liver function tests including AST, ALT, alkaline phosphatase, GGT, and bilirubin to identify hepatocellular injury patterns 1
• Lactate dehydrogenase (LDH) - markedly elevated LDH with hepatosplenomegaly raises concern for lymphoma even without discrete masses 3
• Lipid profile to screen for storage disorders, which commonly show mixed dyslipidemia with decreased HDL 2

Imaging Strategy

Abdominal ultrasound with Doppler is the appropriate next imaging study to confirm hepatosplenomegaly, assess liver morphology, detect focal lesions, and identify signs of portal hypertension through portal blood flow assessment 1, 2. This is more appropriate than repeating CT given radiation exposure and the need for functional vascular information.

The Doppler component specifically evaluates for:

• Reduced portal blood flow velocity
• Loss of respiratory changes in portal flow
• Portal blood flow reversal indicating portal hypertension 2

Critical Differential Diagnoses

Given the rapid 6-month progression, prioritize these time-sensitive diagnoses:

Hematologic Malignancy (Highest Priority)

• Primary hepatic or hepatosplenic lymphoma can present with diffuse hepatosplenomegaly, markedly elevated LDH, and no discrete mass on CT 3
• Non-Hodgkin's lymphoma (particularly diffuse large B-cell type) may show only diffuse organ enlargement with uneven contrast enhancement 3
• This diagnosis requires urgent consideration given the rapid progression and potential for cure with prompt treatment

Portal Hypertension

• Calculate liver fibrosis indices (APRI, FIB-4, GGT-to-Platelet Ratio) from initial labs 1, 2
• Consider cirrhotic causes: viral hepatitis B/C, NASH, autoimmune hepatitis, hemochromatosis, Wilson's disease, primary biliary cirrhosis 1

Storage Disorders

• Acid sphingomyelinase deficiency (ASMD) commonly presents with hepatosplenomegaly and normal LFTs in young adults, though typically has slower progression 2
• Other considerations: Gaucher disease, Niemann-Pick disease type C 2, 4

Advanced Diagnostic Testing Based on Initial Results

If initial workup suggests lymphoma (elevated LDH, cytopenias, abnormal peripheral smear):

• Bone marrow biopsy to assess for marrow involvement 3
• PET-CT to evaluate extent of disease and guide biopsy sites 3
• US-guided liver biopsy for definitive diagnosis when imaging shows no discrete mass 3

If portal hypertension is suspected (thrombocytopenia, elevated fibrosis indices):

• Vibration-controlled transient elastography (VCTE) - values <12 kPa suggest idiopathic non-cirrhotic portal hypertension rather than cirrhosis 1
• Consider hepatic venous pressure gradient (HVPG) measurement at specialized centers 1, 2

If storage disease is suspected (young patient, normal LFTs, lipid abnormalities):

• Genetic testing for SMPD1 gene (ASMD) 1
• Enzymatic analysis on liver biopsy 1

Common Pitfalls to Avoid

• Do not dismiss diffuse hepatosplenomegaly without a mass as benign - lymphoma frequently presents this way 3
• Do not delay hepatology referral - rapid progression over 6 months indicates aggressive pathology requiring subspecialty evaluation 1
• Do not assume cirrhosis based on ultrasound appearance alone - VCTE helps distinguish cirrhosis from non-cirrhotic portal hypertension 1
• Do not order single-phase CT for further characterization - if additional CT imaging is needed, multiphase contrast-enhanced CT is required 5

Red Flags Requiring Urgent Evaluation

• Sudden left upper quadrant pain (splenic rupture or infarction) 1
• Persistent fever with left upper quadrant pain (splenic abscess) 6, 1
• Guarding and rebound tenderness (acute abdomen) 1
• Progressive cytopenias (bone marrow involvement) 3

Timeline for Workup

Given the 6-month progression from normal to significantly enlarged organs, complete the initial laboratory and ultrasound evaluation within 48-72 hours. If lymphoma is suspected based on markedly elevated LDH or cytopenias, expedite hematology consultation and consider same-day bone marrow biopsy to avoid treatment delays that impact mortality 3.