Splenomegaly Differential Diagnoses

Updated: Jun 08, 2022
  • Author: Robert A Franklin, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Diagnostic Considerations

Traditionally, splenomegaly was classified as mild, moderate, or massive. This distinction can help with etiologic diagnosis.

Conditions to consider in the differential diagnosis of massive splenomegaly include the following:

  • Leishmaniasis
  • Malaria
  • Myeloproliferative disease
  • Portal vein obstruction/portal hypertension
  • Schistosomiasis
  • Niemann-Pick disease
  • Mucopolysaccharidosis
  • Lymphomas
  • Gaucher disease [13]
  • Hereditary spherocytosis
  • Thalassemias major
  • Histiocytosis X

Conditions to consider in the differential diagnosis of mild to moderate splenomegaly include all of the above, as well as the following:

  • Bacterial sepsis
  • Infective endocarditis
  • Sickle cell disease
  • Splenic abscess
  • Acute infectious illnesses (eg, typhoid, malaria, other tropical diseases)
  • Acute viral infections (eg, infectious mononucleosis)
  • Systemic lupus erythematosus
  • Tuberculosis
  • Angioimmunoblastic lymphadenopathy
  • Banti disease
  • Congestive heart failure
  • Drug reactions with serum sickness syndromes
  • Hyperlipidemias
  • Idiopathic splenomegaly
  • Immune hemolytic anemias
  • Immune thrombocytopenic disorders
  • Leukocyte disorders
  • Ovalocytosis
  • Splenic vein obstruction
  • Symptomatic human immunodeficiency virus (HIV) infection
  • Trypanosomiasis

While certain causes of splenomegaly are usually obvious due to the concurrent illness (eg, endocarditis, malaria, infections), etiologic diagnosis of splenomegaly in the outpatient setting involves extensive history taking, with inquiries about the range of possible causes, including any history of liver disease, hereditary anemias, or infiltrative disorders. The presence of B symptoms and constitutional symptoms may indicate a primary bone marrow malignancy or myeloproliferative disorders.

On laboratory testing, if the erythrocyte sedimentation rate is high, the differential diagnosis includes the following:

  • Infection
  • Acute leukemias
  • Sarcoidosis
  • Other inflammatory disorders

If the sedimentation rate is low, the differential diagnosis includes the following:

  • Chronic myeloproliferative disorders
  • Hereditary hemolytic anemias
  • Infiltrative disorders

Anemia with peripheral smear findings showing spherocytosis, sickle cells, hemoglobin SC, or elliptocytosis would indicate splenomegaly due to those disorders. Anemia with a high lactate dehydrogenase (LDH) or low haptoglobulin level and a high bilirubin level may indicate a hemolytic disorder or liver disease.

An abnormal coagulation profile with a high prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT) usually indicates an associated liver disorder, with cirrhosis and portal hypertension as the etiology of splenomegaly. It may also indicate an underlying acute bone marrow malignancy or disseminated intravascular coagulation (DIC). 

Splenomegaly with fevers may indicate one of the following:

  • Epstein-Barr virus (EBV) infection
  • Acute bacterial or fungal infection
  • Acute leukemia or lymphoma

Differential Diagnoses