Causes and Differential Diagnosis of Splenomegaly
Primary Diagnostic Categories
Splenomegaly results from five major pathophysiologic mechanisms: hepatic disease with portal hypertension, hematologic disorders, infectious processes, infiltrative/storage diseases, and vascular abnormalities. 1, 2
Hepatic Causes
- Cirrhosis with portal hypertension is the most common hepatic cause of splenomegaly, frequently presenting as isolated splenomegaly even when cirrhosis is clinically inapparent 1, 2
- Wilson's disease can manifest with isolated splenomegaly due to underlying cirrhosis before other hepatic signs become evident 2, 3
- Non-cirrhotic portal hypertension causes significant splenomegaly without typical cirrhotic features 2
- Associated findings include thrombocytopenia, esophageal varices, ascites, and decreased portal blood flow velocity on Doppler ultrasound 2, 3
Hematologic Causes
Myeloproliferative Disorders
- Myelofibrosis is the leading cause of massive splenomegaly (>10 cm below costal margin) in adults, particularly elderly patients 1, 3
- Polycythemia vera and essential thrombocythemia cause splenomegaly, with progression to post-PV or post-ET myelofibrosis defined by increasing splenomegaly ≥5 cm from left costal margin 4
- Chronic myeloid leukemia presents with splenomegaly in the majority of cases 5
Lymphoproliferative Disorders
- Lymphomas (both Hodgkin and non-Hodgkin) are important causes, representing 32% of hematologic splenomegaly cases 5
- Hairy cell leukemia characteristically presents with splenomegaly; resolution of palpable splenomegaly is required for complete remission 4
- Chronic lymphocytic leukemia commonly causes splenomegaly 5
Other Hematologic Conditions
- Smoldering multiple myeloma should be considered in patients over 65 years (median age 65-70 years at diagnosis) 1
- Important caveat: Less than 3% of immune thrombocytopenia (ITP) patients have splenomegaly; moderate or massive splenomegaly excludes ITP as the primary diagnosis 1, 2
Infectious Causes
Common in United States
- Infectious mononucleosis (Epstein-Barr virus) is a frequent cause in younger patients 6
- Endocarditis with splenic abscess presents with persistent fever and left upper quadrant pain 1, 3
- HIV/AIDS accounts for over 50% of infectious splenomegaly cases in urban centers; when massive splenomegaly occurs with AIDS, Mycobacterium avium complex is present in 73% of cases 5
Tropical/Endemic Regions
- Malaria and schistosomiasis cause splenomegaly in up to 80% of affected populations in tropical regions 2, 6
Infiltrative and Storage Disorders
- Acid sphingomyelinase deficiency (ASMD/Niemann-Pick disease) presents with massive hepatosplenomegaly (>10x normal size), often with bone and joint pain 1, 2, 3
- Gaucher disease is a common cause of significant splenomegaly among lysosomal storage disorders 1, 2
- Niemann-Pick disease type C and lysosomal acid lipase deficiency (LALD) also present with splenomegaly 2, 3
- Genetic testing (SMPD1 gene for ASMD) is recommended for unexplained hepatosplenomegaly 2
Vascular Causes
- Splenic vein thrombosis leads to isolated splenomegaly through localized portal hypertension and may cause esophageal varices 1, 3
- Portal vein thrombosis causes splenomegaly and carries poor prognosis in certain conditions 1, 3
- Congestive heart failure accounts for 10% of splenomegaly cases through passive congestion 5
Autoimmune/Inflammatory Causes
- Felty syndrome (rheumatoid arthritis with splenomegaly and neutropenia) 2
- Systemic lupus erythematosus may present with splenomegaly 2
Diagnostic Algorithm
Initial Evaluation
- Complete blood count to assess for cytopenias (anemia, thrombocytopenia, leukopenia) indicating portal hypertension, hypersplenism, or primary hematologic disease 1, 2, 3
- Abdominal ultrasound to confirm splenomegaly, measure spleen size, assess for portal hypertension signs, and evaluate liver parenchyma 1, 2
- Liver function tests to identify hepatic causes 1, 2
- Peripheral blood smear to identify abnormal cells, hairy cells, or leukoerythroblastic picture 4
Second-Line Testing Based on Initial Findings
If hepatic disease suspected:
If hematologic disease suspected:
- Bone marrow biopsy, particularly in patients >60 years or with constitutional symptoms 1, 2
- Flow cytometry for lymphoproliferative disorders (CD19, CD20, CD11c, CD25, CD103, CD123, CD200 for hairy cell leukemia) 4
- JAK2V617F, MPL, and CALR mutation testing for myeloproliferative neoplasms 4
If infectious disease suspected:
- Lymph node biopsy when lymphadenopathy present 5
- Blood cultures for endocarditis 3
- HIV testing in appropriate clinical context 5
If storage disease suspected:
If vascular cause suspected:
Clinical Patterns by Spleen Size
Mild Splenomegaly (palpable 1-4 cm below costal margin)
- Most commonly hepatic causes with portal hypertension 6
- Early lymphoproliferative disorders 6
- Infectious mononucleosis 6
Moderate Splenomegaly (5-10 cm below costal margin)
Massive Splenomegaly (>10 cm below costal margin)
- Myelofibrosis is the most common cause 1, 7
- Chronic myeloid leukemia 7
- Hairy cell leukemia 4
- Gaucher disease and ASMD 1, 2
- AIDS with Mycobacterium avium complex 5
Critical Clinical Pearls
- Constitutional symptoms (fever >37.5°C, >10% weight loss in 6 months, night sweats) suggest myeloproliferative disorders, lymphoma, or infectious causes 4, 1
- Hepatomegaly, lymphadenopathy, or jaundice accompanying splenomegaly narrows the differential toward lymphoproliferative disease, storage disorders, or hepatic causes 1, 3
- Leukoerythroblastic blood picture (immature myeloid cells and nucleated red cells) indicates myelofibrosis or marrow infiltration 4
- Thrombocytopenia with splenomegaly suggests portal hypertension or hypersplenism rather than primary ITP 1, 2
- Left upper quadrant pain with fever suggests splenic infarction or abscess requiring urgent imaging 3