What are the causes and differential diagnosis of splenomegaly?

Causes and Differential Diagnosis of Splenomegaly

Splenomegaly is almost always a manifestation of systemic disease, with the most common causes in the United States being liver disease with portal hypertension, hematologic malignancies, and infections, while in tropical regions parasitic infections predominate. 1, 2

Major Diagnostic Categories

Hepatic Causes (Most Common in US Adults)

• Cirrhosis with portal hypertension is the most frequent hepatic cause, often presenting as isolated splenomegaly even when cirrhosis is clinically inapparent 1, 3
• Wilson's disease can present with isolated splenomegaly due to subclinical cirrhosis 1, 4
• Non-cirrhotic portal hypertension causes significant splenomegaly and is associated with esophageal varices and ascites 1
• Splenic vein thrombosis leads to isolated splenomegaly through localized portal hypertension 3

Hematologic Disorders (Most Common Cause of Massive Splenomegaly)

• Myeloproliferative neoplasms, particularly myelofibrosis, are the leading cause of massive splenomegaly (>10 cm below costal margin), with 78% of myelofibrosis patients developing massive enlargement 1, 3, 5
• Polycythemia vera and essential thrombocythemia, especially when progressing to post-PV or post-ET myelofibrosis with increasing splenomegaly ≥5 cm from left costal margin 1
• Hairy cell leukemia characteristically presents with splenomegaly 1
• Chronic leukemias (both myeloid and lymphoid) are common causes 5
• Lymphoproliferative disorders including lymphomas, particularly in older adults 3, 6

Infectious Causes

• In tropical regions, malaria and schistosomiasis cause up to 80% of splenomegaly cases 1, 2
• In the United States, infectious mononucleosis is the most apparent infectious cause 2
• AIDS-related splenomegaly, with Mycobacterium avium complex found in 73% of AIDS patients with massive splenomegaly 6
• Endocarditis can lead to splenic abscess, presenting with persistent fever and left upper quadrant pain 3, 4
• Tuberculosis remains an important infectious cause 5

Infiltrative and Storage Disorders

• Acid sphingomyelinase deficiency (ASMD/Niemann-Pick disease) presents with massive hepatosplenomegaly (>10x normal size) 3, 4
• Gaucher disease causes significant splenomegaly 1, 7
• Niemann-Pick disease type C and lysosomal acid lipase deficiency (LALD) are associated with splenomegaly 1

Autoimmune and Inflammatory Disorders

• Felty syndrome (rheumatoid arthritis with splenomegaly) 1, 7
• Systemic lupus erythematosus may present with splenomegaly 1

Congestive Causes

• Congestive heart failure leads to passive congestion 5, 6
• Portal vein thrombosis, which carries poor prognosis in certain conditions 3, 4

Algorithmic Diagnostic Approach

Initial Evaluation

• Confirm splenomegaly with abdominal ultrasound to measure spleen size, assess for portal hypertension signs (decreased portal blood flow velocity on Doppler), and evaluate liver parenchyma 1, 3
• Complete blood count to assess for cytopenias (thrombocytopenia, anemia, leukopenia) suggesting hypersplenism or portal hypertension, or cytoses suggesting myeloproliferative disorders 1, 3
• Peripheral blood smear to identify abnormal cells, hairy cells, or leukoerythroblastic picture 1
• Liver function tests to evaluate hepatic causes 3

Degree of Splenomegaly Guides Differential

• Mild splenomegaly may occur in younger patients with immune thrombocytopenia (ITP), but less than 3% of ITP patients have splenomegaly 3
• Moderate or massive splenomegaly (>5-10 cm below costal margin) strongly suggests alternative causes, particularly hematologic malignancies 1, 3

Targeted Testing Based on Clinical Context

For suspected hematologic disease:

• JAK2V617F, MPL, and CALR mutation testing for myeloproliferative neoplasms 1
• Flow cytometry for lymphoproliferative disorders (CD19, CD20, CD11c, CD25, CD103, CD123, CD200 for hairy cell leukemia) 1
• Bone marrow examination in patients older than 60 years or those with systemic symptoms (fever, weight loss) 1, 3

For suspected storage disorders:

• Lipid profile may reveal mixed dyslipidemia 1
• Genetic testing (SMPD1 gene for ASMD) for unexplained hepatosplenomegaly 1

For suspected vascular causes:

• CT angiography or MRI to evaluate vascular structure and potential complications 3, 4

Critical Clinical Pitfalls

• Do not assume ITP in patients with splenomegaly and thrombocytopenia; moderate or massive splenomegaly mandates investigation for alternative causes 3
• Constitutional symptoms (fever, weight loss), hepatomegaly, or lymphadenopathy indicate underlying disorders such as HIV, systemic lupus erythematosus, or lymphoproliferative disease and require comprehensive workup 3
• Travel history is essential, as malaria and schistosomiasis are common in tropical regions 1, 2
• Splenic rupture risk increases with any degree of splenomegaly; patients should refrain from contact sports 2