What are the differential diagnoses and initial work‑up for splenomegaly?

Splenomegaly: Differential Diagnosis and Initial Work-Up

The differential diagnosis of splenomegaly is best organized by mechanism and geography: in developed countries, hematologic malignancies (37% of adults), liver disease with portal hypertension, and infections dominate, while in tropical regions, malaria and schistosomiasis account for up to 80% of cases. 1, 2, 3, 4

Differential Diagnosis by Category

Hematologic Malignancies and Myeloproliferative Disorders

Myeloproliferative neoplasms are the leading cause of massive splenomegaly (>20 cm below left costal margin) in developed countries:

• Chronic myeloid leukemia (CML) characteristically presents with splenomegaly quantified by distance below the costal margin 1
• Myelofibrosis frequently produces massive splenomegaly exceeding 10 cm below the costal margin 1, 5
• Polycythemia vera and essential thrombocythemia can progress to post-PV/post-ET myelofibrosis, defined by splenomegaly increase ≥5 cm from baseline 1
• Chronic myelomonocytic leukemia (CMML) may evolve to massive splenomegaly 1
• Hairy cell leukemia requires resolution of palpable splenomegaly for complete remission 1
• Lymphomas constitute a significant portion of malignant causes 6, 3

Critical pitfall: Moderate or massive splenomegaly in suspected immune thrombocytopenic purpura (ITP) essentially excludes ITP and mandates evaluation for alternative diagnoses, particularly lymphoproliferative disorders 1

Infectious Causes

In endemic regions:

• Visceral leishmaniasis (kala-azar) presents with chronic fever, weight loss, splenomegaly, pancytopenia, hypoalbuminemia, and elevated inflammatory markers 6, 1
• Hyperreactive malarial splenomegaly (HMS) is a leading cause in malaria-endemic areas, driven by chronic antigenic stimulation 1
• Schistosomiasis is common in tropical regions 1, 2

In developed countries:

• Infectious mononucleosis is the most common infectious cause 2
• Endocarditis can lead to splenic abscess and splenomegaly 7, 5
• Bone marrow examination may reveal malarial parasites in 20.5% of cases even when peripheral smears are negative 4

Hepatic Diseases with Portal Hypertension

• Cirrhosis (any etiology) commonly causes splenomegaly, though massive enlargement is rare 1, 7
• Wilson disease can present with isolated splenomegaly due to subclinical cirrhosis with portal hypertension, often with Kayser-Fleischer rings and neuropsychiatric symptoms 1, 7, 5
• Idiopathic non-cirrhotic portal hypertension (INCPH) produces more significant splenomegaly than other portal hypertension causes 1
• Hepatic causes account for 18% of splenomegaly cases in registry studies 3

Lysosomal Storage Disorders

These are critical not-to-miss diagnoses:

• Gaucher disease (type 1) causes splenomegaly in approximately 90% of patients 1
• Acid sphingomyelinase deficiency (ASMD/Niemann-Pick disease) typically produces massive hepatosplenomegaly, often >10× normal organ size 1, 7, 5
• Niemann-Pick disease type C and lysosomal acid lipase deficiency (LALD) present with notable splenomegaly 1, 7
• Mixed dyslipidemia on lipid panel should raise suspicion for storage disorders 1, 7

Other Causes

• Autoimmune disorders, including rheumatoid arthritis with Felty syndrome 7
• Hemolytic anemias (particularly beta-thalassemia in children, accounting for 55% of pediatric cases) 4
• Megaloblastic anemia (13% of adult cases) 4

Initial Work-Up Algorithm

Step 1: Targeted History

• Geographic exposure: Travel to malaria or schistosomiasis-endemic regions 6, 1, 2
• Constitutional symptoms: Fever (25% of cases), weight loss (46%), fatigue (46%), night sweats 5, 2
• Left upper quadrant pain or fullness (40-50% of cases) 5
• Risk factors: HIV status, immunosuppression, family history of storage disorders or hemoglobinopathies 6, 2

Step 2: Physical Examination

• Measure spleen size: Document distance in centimeters below left costal margin during deep inspiration 1, 7
  • Splenomegaly threshold: >13 cm vertical length on imaging 6, 1
  • Massive splenomegaly: >20 cm below costal margin 1
• Assess for hepatomegaly: Measure liver span and distance below right costal margin 7
• Look for stigmata of liver disease: Jaundice, ascites, spider angiomata, palmar erythema 5, 2
• Examine for lymphadenopathy suggesting lymphoproliferative disorder 2
• Check for Kayser-Fleischer rings (Wilson disease) 7

Step 3: First-Line Laboratory Studies

Obtain these tests in all patients:

• Complete blood count with differential to detect cytopenias (anemia, thrombocytopenia, leukopenia) or leukocytosis 1, 7, 5
• Peripheral blood smear for abnormal cells, hairy cells, or leukoerythroblastic picture 6, 1
• Liver function tests: AST, ALT, alkaline phosphatase, GGT, bilirubin, albumin 1, 7
• Lipid profile (mixed dyslipidemia suggests storage disorders) 1, 7
• Lactate, uric acid, and glucose levels 7

Step 4: Imaging Confirmation

• Abdominal ultrasound is the first-line imaging modality to confirm splenomegaly, measure size, and evaluate for portal hypertension signs 1, 7, 2
• CT or MRI for precise volumetric measurement and assessment of associated intra-abdominal pathology 1, 7

Step 5: Targeted Second-Line Testing Based on Initial Results

If hematologic malignancy suspected (abnormal CBC, peripheral smear):

• JAK2 V617F, MPL, CALR mutation analysis for myeloproliferative neoplasms 6, 1
• Flow cytometry (CD19, CD20, CD11c, CD25, CD103, CD123, CD200) for hairy cell leukemia and lymphoproliferative disorders 1
• Bone marrow examination in patients >60 years or with systemic symptoms 1, 4

If liver disease suspected:

• Hepatitis serologies, ceruloplasmin (Wilson disease), autoimmune markers 7, 2
• Liver elastography to assess fibrosis 7

If storage disorder suspected (hepatosplenomegaly + dyslipidemia):

• Genetic testing for SMPD1 (ASMD), glucocerebrosidase activity (Gaucher), enzymatic analysis 1, 7

If infectious cause suspected:

• Thick and thin blood smears for malaria (may require bone marrow if peripheral smears negative) 4
• Leishmania serology or tissue diagnosis in endemic exposure 6
• Blood cultures, echocardiography if endocarditis suspected 5

Key Clinical Pitfalls

• Do not assume ITP if splenomegaly is moderate or massive; this finding excludes ITP and mandates hematologic work-up 1
• Bone marrow examination may reveal malarial parasites even when peripheral smears are negative (20.5% of cases) 4
• In 25% of cases, no causal diagnosis is found despite extensive work-up; these patients require ongoing surveillance 3
• Palpable spleen in children occurs in 12% of healthy children aged 1-3 years; ultrasound with age-appropriate reference values is required for definitive diagnosis 7
• Splenic rupture risk increases with splenomegaly; patients should avoid contact sports 2

Referral Considerations

• Initial referral to hepatology/gastroenterology is appropriate when liver disease is suspected, as the liver is often the primary affected organ 7
• Hematology referral is indicated for suspected myeloproliferative disorders, lymphoproliferative disorders, or hemolytic anemias 7, 3
• Metabolic specialist referral when storage disorders are suspected based on hepatosplenomegaly with dyslipidemia 7