What are the causes of massive splenomegaly?

Massive Splenomegaly: Primary Causes

Massive splenomegaly (spleen extending >20 cm below the costal margin or weighing >1000 grams) is most commonly caused by myeloproliferative disorders, particularly chronic myeloid leukemia and myelofibrosis, followed by chronic liver disease with portal hypertension, lymphoproliferative disorders, and in tropical regions, parasitic infections such as malaria and schistosomiasis. 1, 2, 3, 4

Hematologic/Myeloproliferative Disorders

This is the dominant category for massive splenomegaly:

• Myelofibrosis has the highest incidence of massive splenomegaly, occurring in 78% of cases, making it the single most likely diagnosis when encountering massive splenomegaly 4
• Chronic myeloid leukemia (CML) and other chronic leukemias are among the most frequent causes of massive splenomegaly 4
• Chronic myelomonocytic leukemia (CMML) frequently presents with splenomegaly, though often limited; however, some patients develop massive splenomegaly requiring intervention 5
• Polycythemia vera and essential thrombocythemia can progress to post-PV or post-ET myelofibrosis, defined by increasing splenomegaly ≥5 cm from left costal margin 1
• Hairy cell leukemia characteristically presents with splenomegaly 1
• Hematologic disorders account for 81% of massive splenomegaly cases and are significantly associated with lymphadenopathy, cytoses, and progressive splenic enlargement 4

Hepatic Diseases with Portal Hypertension

Chronic liver disease is the second major category:

• Cirrhosis with portal hypertension from any cause (viral hepatitis B/C, alcoholic liver disease, non-alcoholic steatohepatitis, autoimmune hepatitis, hereditary hemochromatosis, Wilson's disease, primary biliary cirrhosis) commonly causes splenomegaly 5, 1, 6
• Idiopathic non-cirrhotic portal hypertension (INCPH) causes significant splenomegaly more commonly than other causes of portal hypertension, including cirrhosis and portal vein thrombosis 5
• Splenic vein thrombosis can cause isolated massive splenomegaly due to localized portal hypertension 7
• Hepatic diseases account for 11-41% of splenomegaly cases depending on the population studied 2

Lymphoproliferative Disorders

• Lymphomas (both Hodgkin and non-Hodgkin) are important causes of massive splenomegaly in adults 1, 7
• These disorders are significantly associated with generalized lymphadenopathy 4

Infectious Diseases

Geographic location dramatically influences infectious causes:

• Malaria and schistosomiasis are the most common causes of massive splenomegaly in tropical regions, where up to 80% of the population may have splenomegaly 1, 6, 8
• Schistosomiasis (S. mansoni, S. japonicum) results in hepatosplenic disease with hepatic 'pipestem' fibrosis and portal hypertension 6
• Mycobacterium avium complex (MAC) in AIDS patients: among 11 AIDS patients with massive splenomegaly, 73% had MAC infection 2
• Splenic abscess presents with persistent fever and left upper quadrant pain, particularly in patients with endocarditis 7
• Infectious diseases account for 16-36% of splenomegaly cases, with AIDS being four times more frequent in certain populations 2

Metabolic Storage Disorders

Consider in unexplained hepatosplenomegaly, especially with family history:

• Gaucher disease is a common cause of significant splenomegaly 1
• Acid sphingomyelinase deficiency (ASMD/Niemann-Pick disease) can present with massive, painful hepatosplenomegaly 1, 7
• Niemann-Pick disease type C and lysosomal acid lipase deficiency (LALD) are also associated with splenomegaly 1
• Genetic testing (SMPD1 gene for ASMD) is recommended for suspected storage disorders 1

Congestive/Inflammatory Causes

• Congestive heart failure can cause congestive splenomegaly, accounting for 4-10% of cases 2
• Thyrotoxicosis has been associated with splenomegaly 4

Clinical Pearls and Diagnostic Approach

Key distinguishing features:

• Massive splenomegaly occurred in 27% of combined series patients, particularly with hematologic diseases 2
• Myeloproliferative disorders were the most predominant cause in surgical series of massive splenomegaly 3
• In patients with suspected immune thrombocytopenia (ITP), moderate or massive splenomegaly suggests an alternative diagnosis 1
• INCPH patients often have low liver stiffness (<12 kPa) on transient elastography, helping distinguish from cirrhosis 5

Common pitfall: Patients with INCPH are often radiologically misclassified as cirrhotic on ultrasound due to liver surface nodularity and portal vein wall thickening 5