Causes of Splenomegaly
Primary Etiologic Categories
Splenomegaly results from hepatic disease with portal hypertension, hematologic malignancies, infections, and infiltrative storage disorders, with the specific etiology varying by geographic region and patient demographics. 1
Hepatic Diseases with Portal Hypertension
- Cirrhosis from any cause is the most common hepatic etiology in developed countries, producing splenomegaly through portal hypertension and venous congestion 1
- Idiopathic non-cirrhotic portal hypertension (INCPH) causes more significant splenomegaly than other portal hypertension etiologies and is often misclassified as cirrhosis on ultrasound due to liver surface nodularity 1
- Wilson's disease may present with isolated splenomegaly from clinically inapparent cirrhosis before other hepatic manifestations become evident 1, 2
- Non-cirrhotic portal hypertension from splenic or portal vein thrombosis can produce marked splenic enlargement 1
- Progressive spleen enlargement over time in cirrhotic patients predicts higher risk of esophageal varices formation (84.6% vs 16.6%) and first clinical decompensation (51.1% vs 19.5%) 3
Hematologic Malignancies and Myeloproliferative Disorders
Myeloproliferative Neoplasms
- Primary myelofibrosis is the most common hematologic cause of massive splenomegaly (>10 cm below costal margin) 4, 2
- Chronic myeloid leukemia (CML) characteristically presents with splenomegaly quantified by distance below the costal margin 1, 4
- Polycythemia vera and essential thrombocythemia progress to post-PV or post-ET myelofibrosis when splenomegaly increases ≥5 cm from the left costal margin 1, 4
- Chronic myelomonocytic leukemia (CMML) can develop massive splenomegaly requiring splenectomy, splenic irradiation, or JAK-inhibitor therapy 1, 4
- JAK2 V617F mutation is 100% specific and can be detected before hematologic abnormalities appear; normal blood counts do not exclude myeloproliferative neoplasms because splenic sequestration masks marrow proliferation 4
Lymphoproliferative Disorders
- Hairy cell leukemia presents with splenomegaly in approximately 90% of patients; resolution of palpable splenomegaly is required for complete remission 1, 4
- Lymphomas represent a major proportion of malignant causes in adults, particularly when accompanied by lymphadenopathy or B-symptoms 4
Infectious Causes
Endemic/Tropical Infections
- Malaria and schistosomiasis are the leading causes in tropical regions, where up to 80% of the population may have splenomegaly 1, 5
- Hyperreactive malarial splenomegaly (HMS) results from chronic antigenic stimulation in malaria-endemic areas 4
- Visceral leishmaniasis (kala-azar) presents with chronic fever, weight loss, splenomegaly, pancytopenia, hypoalbuminemia, and elevated inflammatory markers 1, 4
Other Infections
- Infectious mononucleosis is a common acute infectious cause in developed countries 5
- Endocarditis can lead to splenic abscess and splenomegaly, presenting with persistent fever and left upper quadrant pain 2
- Tuberculosis should be considered when splenomegaly is accompanied by fever and a positive tuberculin skin test or interferon-γ release assay 4
Lysosomal Storage Disorders
- Gaucher disease (type 1) is the most common lysosomal storage disorder causing significant splenomegaly, affecting approximately 90% of patients 1, 4
- Acid sphingomyelinase deficiency (ASMD/Niemann-Pick disease) produces massive hepatosplenomegaly often exceeding 10-fold normal organ size 1, 4, 2
- Niemann-Pick disease type C and lysosomal acid lipase deficiency (LALD) are associated with notable splenomegaly 1, 4
- Mixed dyslipidemia pattern (elevated LDL, VLDL, triglycerides with reduced HDL) provides a laboratory clue for metabolic storage disorders 4
Autoimmune and Inflammatory Disorders
- Rheumatoid arthritis with Felty syndrome causes splenomegaly with neutropenia 1
- Systemic lupus erythematosus (SLE) may present with splenomegaly 1
Drug-Induced Splenomegaly
- Medications can provoke splenic enlargement through direct effects on splenic cells, drug-induced hemolysis, or venous congestion from hepatic disturbance with portal vein occlusion 6
- Drug-induced splenomegaly is usually transitory and resolves when the medication is discontinued 6
Sickle Cell Disease Complications
- Chronic splenomegaly in sickle cell disease may necessitate splenectomy to manage complications 1
- Acute splenic sequestration presents with sudden pallor and risk of severe anemia from rapid blood pooling in the spleen 1
Critical Diagnostic Pitfalls
- Moderate or massive splenomegaly essentially excludes idiopathic thrombocytopenic purpura (ITP) as a diagnosis; palpable splenomegaly exceeding 3% of the abdomen mandates investigation for alternative etiologies 1, 4
- Normal complete blood counts do not exclude myeloproliferative neoplasms; JAK2 V617F, CALR, and MPL mutation testing should be performed immediately in massive splenomegaly with otherwise normal laboratory studies 4
- Bone marrow examination is essential for patients ≥60 years or those with systemic symptoms when molecular tests are negative, as dystrophic megakaryocytes can confirm myeloproliferative neoplasms even without detectable JAK2 mutation 4