What is the initial workup for an adult patient with no significant past medical history presenting with splenomegaly?

Initial Workup for Adult Splenomegaly

Begin with a complete blood count with differential to assess for cytopenias (particularly thrombocytopenia suggesting portal hypertension or hematologic malignancy), comprehensive metabolic panel, liver function tests, and abdominal ultrasound with Doppler to confirm splenomegaly and assess for portal hypertension. 1, 2

Essential First-Line Laboratory Tests

• Complete blood count with differential is mandatory to identify thrombocytopenia (suggesting portal hypertension or bone marrow infiltration), anemia, or leukocytosis/leukopenia that may indicate underlying hematologic disorders 1, 3
• Liver function tests including transaminases, gamma-glutamyl transferase, alkaline phosphatase, and bilirubin are essential to assess for hepatocellular injury and cholestasis, as liver disease is one of the most common causes of splenomegaly in the United States 1, 4
• Lipid profile should be obtained to identify mixed dyslipidemia with decreased HDL, which is characteristic of storage disorders like acid sphingomyelinase deficiency (ASMD) 1, 2
• Peripheral blood smear examination is critical to exclude other causes and assess red blood cell morphology, white blood cell abnormalities, and platelet characteristics 5

First-Line Imaging

• Abdominal ultrasound with Doppler is the initial imaging modality of choice to confirm splenomegaly, measure spleen size (document centimeters below costal margin), assess liver morphology, detect focal lesions, and evaluate for portal hypertension 1, 2
• Doppler ultrasonography provides crucial information about portal blood flow velocity, respiratory flow changes, and can detect portal hypertension by identifying reduced flow velocity or flow reversal 1, 2

Risk Stratification Based on Initial Findings

If thrombocytopenia is present with hepatosplenomegaly:

• This suggests portal hypertension, bone marrow infiltration, or consumption 3
• Consider vibration-controlled transient elastography (VCTE) to assess liver stiffness, which has excellent diagnostic performance for clinically significant portal hypertension (AUC 0.90) 2
• Calculate the LSPS score (combining liver stiffness, spleen size, and platelet count) to improve diagnostic accuracy for portal hypertension 2

If normal liver function tests with hepatosplenomegaly:

• Strongly consider acid sphingomyelinase deficiency (ASMD), particularly in young adults, as this commonly presents with hepatosplenomegaly, normal LFTs, and mixed dyslipidemia 1, 2
• Order genetic testing for the SMPD1 gene if clinical suspicion is high 1, 2
• Obtain chest X-ray or CT to evaluate for interstitial lung disease, which commonly accompanies ASMD 2

If fever, malaise, or constitutional symptoms:

• Obtain HIV antibody testing in patients with risk factors 5
• Consider infectious causes including infectious mononucleosis (most common infectious cause in developed countries) 4
• In patients with travel history to tropical regions, evaluate for malaria and schistosomiasis 4

Additional Testing Based on Clinical Context

• Bone marrow aspiration should be performed if pancytopenia is present, if an infiltrative process is suspected, or if hematologic malignancy cannot be excluded by other means 5, 3
• CT or MRI of the abdomen provides detailed assessment when ultrasound is inconclusive and can detect portosystemic shunting 2
• Inflammatory markers (ESR, CRP) should be obtained if autoinflammatory conditions are suspected 1

Common Diagnostic Pitfalls to Avoid

• Do not dismiss normal liver function tests as excluding serious pathology; ASMD and other storage disorders commonly present with hepatosplenomegaly and normal LFTs 1
• Do not order extensive imaging before basic hematologic evaluation, as this delays diagnosis of potentially life-threatening hematologic conditions 3
• Recognize that massive splenomegaly (>10x normal size) with hepatomegaly strongly suggests storage disorders (Gaucher disease, Niemann-Pick disease, ASMD) rather than glycogen storage diseases 1, 2
• Be aware that 25% of patients with splenomegaly may remain without a causal diagnosis despite extensive workup, representing "idiopathic splenomegaly" 6

Most Common Etiologies in the United States

The three most common causes of splenomegaly in developed countries are:

1. Liver disease with portal hypertension (most common) 4
2. Hematologic malignancies (lymphoma being the most common hematologic cause) 6
3. Infections (infectious mononucleosis being most common in developed countries) 4

Approximately 39% of cases are due to hematological diseases, 18% hepatic diseases, 10% infectious diseases, and 25% remain idiopathic despite workup 6