What are the causes of splenomegaly?

Causes of Splenomegaly

Splenomegaly results from three major disease categories: hepatic diseases with portal hypertension (most common in the United States), hematologic/malignant disorders, and infectious diseases, with the specific etiology determined by systematic evaluation of risk factors, laboratory findings, and imaging studies. 1, 2

Primary Etiologic Categories

Hepatic Diseases with Portal Hypertension

• Cirrhosis from any cause is the most common hepatic etiology, including chronic viral hepatitis B or C, non-alcoholic/alcoholic steatohepatitis, autoimmune hepatitis, hereditary hemochromatosis, Wilson's disease, and primary biliary cirrhosis 1, 3
• Portal hypertension causes splenomegaly through both passive congestion and active tissue hyperplasia with fibrosis, which then increases splenic blood flow and further worsens portal hypertension 4
• Wilson's disease may present with isolated splenomegaly due to clinically inapparent cirrhosis before other manifestations become evident 1, 5
• Idiopathic non-cirrhotic portal hypertension (INCPH) causes more significant splenomegaly than cirrhotic portal hypertension and characteristically shows low liver stiffness (<12 kPa) on transient elastography 1
• Non-cirrhotic portal hypertension, including splenic vein thrombosis, can cause significant splenomegaly with esophageal varices 1

Hematologic and Malignant Disorders

• Myeloproliferative neoplasms are major hematologic causes, including chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and primary myelofibrosis, with myelofibrosis particularly associated with massive splenomegaly (>10 cm below costal margin) 1, 5
• Lymphomas represent a common malignant cause of splenomegaly in the United States 6
• Hairy cell leukemia characteristically presents with splenomegaly as a defining feature 1
• Chronic myelomonocytic leukemia (CMML) frequently presents with splenomegaly, though some patients develop massive enlargement requiring intervention 1

Infectious Diseases

• In tropical regions, malaria and schistosomiasis are the most common causes, affecting up to 80% of the population in endemic areas 1, 2
• Schistosomiasis (S. mansoni, S. japonicum) results in hepatosplenic disease with hepatic 'pipestem' fibrosis and portal hypertension 3
• Infectious mononucleosis is a common viral cause in developed countries 2
• Visceral leishmaniasis (kala-azar) presents with chronic fever, weight loss, splenomegaly, and pancytopenia 1
• AIDS-related infections, particularly Mycobacterium avium complex, cause massive splenomegaly in 73% of AIDS patients with this complication 6
• Endocarditis can lead to splenic abscess and splenomegaly, presenting with persistent fever and left upper quadrant pain 5
• Cytomegalovirus, parvovirus B19, tuberculosis, toxoplasmosis, and Pneumocystis can cause hepatosplenomegaly, particularly in immunocompromised patients 3

Lysosomal Storage Disorders

• Gaucher disease is the most common lysosomal storage disorder causing significant splenomegaly, affecting 90% of type 1 patients 1
• Acid sphingomyelinase deficiency (ASMD/Niemann-Pick disease) commonly presents with massive hepatosplenomegaly (>10x normal size) 5
• Niemann-Pick disease type C and lysosomal acid lipase deficiency (LALD) are also associated with splenomegaly 1
• Glycogen storage diseases frequently present with hepatomegaly, with some types also causing splenomegaly 1

Autoimmune and Inflammatory Disorders

• Rheumatoid arthritis with Felty syndrome causes splenomegaly with neutropenia 1
• Systemic lupus erythematosus (SLE) may present with splenomegaly 1

Sickle Cell Disease

• Chronic splenomegaly may develop and require splenectomy in some patients with sickle cell disease 7
• Acute splenic sequestration presents with pallor and potential severe anemia 7

Drug-Induced Splenomegaly

• Drugs may provoke splenomegaly by direct effect on splenic cells, severe hemolysis, or venous congestion from drug-induced liver disturbance with portal vein occlusion 8
• Drug-induced splenomegaly is usually transitory and resolves when medication is discontinued 8

Rare Genetic Disorders

• Griscelli syndrome type 2 presents with oculocutaneous hypopigmentation, silvery grey hair, recurrent infections, and hepatosplenomegaly, often progressing to fatal hemolymphatic histiocytosis 3
• Chédiak-Higashi syndrome presents with partial albinism, recurrent infections, progressive neurological dysfunction, and hepatosplenomegaly during accelerated phase 3

Clinical Pattern Recognition

Massive Splenomegaly (>10 cm below costal margin)

• Primary myelofibrosis and chronic myeloid leukemia are the most common hematologic causes 1, 5
• Gaucher disease among storage disorders 1
• Mycobacterium avium complex in AIDS patients 6

Splenomegaly with Thrombocytopenia

• Portal hypertension with hypersplenism is the classic presentation 1
• Important caveat: In idiopathic thrombocytopenic purpura (ITP), mild splenomegaly occurs in less than 3% of patients; moderate or massive splenomegaly essentially excludes ITP and suggests an alternative diagnosis 1

Hepatosplenomegaly Pattern

• Suggests cirrhosis with portal hypertension, storage disorders, or infiltrative hematologic malignancies 3
• Storage disorders typically cause massive splenomegaly with hepatomegaly, helping differentiate from glycogen storage diseases which rarely cause significant splenomegaly 1