What is splenomegaly, its causes, types, and relationship to hypersplenism?

Splenomegaly: Definition, Causes, Types, and Hypersplenism

Definition and Measurement

Splenomegaly is defined as an enlarged spleen, typically measured as greater than 13 cm in vertical length on coronal imaging. 1

• The vertical length should be measured on coronal CT images or calculated by multiplying the number of spleen slices in transverse CT views by slice thickness 1
• Physical examination detects a palpable spleen in only 40-50% of cases, making imaging essential for confirmation 2
• Abdominal ultrasound is the recommended first-line imaging modality to confirm splenomegaly and measure spleen size 1, 3

Major Causes of Splenomegaly

Hepatic Diseases (Most Common in United States)

• Cirrhosis with portal hypertension is the most common hepatic cause of splenomegaly 3, 4
• Non-cirrhotic portal hypertension causes more significant splenomegaly than cirrhotic portal hypertension 3
• Wilson's disease may present with isolated splenomegaly due to clinically inapparent cirrhosis 3, 2
• Portal hypertension is typically associated with thrombocytopenia, esophageal varices, and ascites 3, 2

Hematologic/Malignant Causes (Second Most Common in United States)

• Myeloproliferative neoplasms, particularly myelofibrosis, cause massive splenomegaly (>10 cm below costal margin) 3, 2
• Chronic myelomonocytic leukemia (CMML) frequently presents with splenomegaly 3
• Hairy cell leukemia characteristically presents with splenomegaly; flow cytometry showing CD19, CD20, CD11c, CD25, CD103, CD123, CD200 is diagnostic 3
• Polycythemia vera and essential thrombocythemia with progression to myelofibrosis defined by splenomegaly ≥5 cm from left costal margin 3
• Lymphoproliferative disorders including lymphomas are important causes in adults 3, 5

Infectious Causes (Third Most Common in United States)

• Infectious mononucleosis is an apparent cause requiring minimal workup 4
• Malaria and schistosomiasis are the most common causes in tropical regions, affecting up to 80% of people in endemic areas 3, 4
• Splenic abscess, particularly in endocarditis patients, presents with persistent fever and left upper quadrant pain 2, 5

Lysosomal Storage Disorders

• Gaucher disease is the most common cause of significant splenomegaly among storage disorders 3, 2
• Acid sphingomyelinase deficiency (ASMD/Niemann-Pick disease) presents with massive hepatosplenomegaly (>10x normal size) 2, 5
• Niemann-Pick disease type C and lysosomal acid lipase deficiency (LALD) also cause splenomegaly 3, 2

Autoimmune Disorders

• Rheumatoid arthritis with Felty syndrome causes splenomegaly 3
• Systemic lupus erythematosus may present with splenomegaly 3

Types/Classification of Splenomegaly

By Size

• Mild splenomegaly: Palpable but <5 cm below costal margin 3
• Moderate splenomegaly: 5-10 cm below costal margin 3
• Massive splenomegaly: >10 cm below costal margin, typically seen in myelofibrosis, chronic myeloid leukemia, Gaucher disease, and idiopathic non-cirrhotic portal hypertension 3, 2

By Etiology (Hypersplenism Classification)

• Primary hypersplenism: Intrinsic splenic disorder without identifiable cause 6
• Secondary hypersplenism: Due to identifiable systemic disease (cirrhosis, infections, malignancies, storage disorders) 6
• Occult hypersplenism: Functional hypersplenism without apparent splenomegaly 6

Hypersplenism

Hypersplenism is characterized by splenomegaly causing rapid and premature destruction of blood cells, resulting in peripheral cytopenias (anemia, thrombocytopenia, leukopenia). 6

Mechanisms of Hypersplenism

• Splenic sequestration and retention of blood cells in the enlarged spleen 6
• Increased phagocytosis of blood cells by splenic macrophages 6
• Autoimmune destruction of blood cells within the spleen 6

Clinical Manifestations

• Thrombocytopenia is the most frequent manifestation and may contribute to portal hypertension-related bleeding 3, 7
• Anemia is common in patients with hypersplenism 2, 7
• Leukopenia may be present, especially in myeloproliferative disorders 2
• Fatigue and weight loss occur in up to 46% of patients 2
• Left upper quadrant pain, fullness, or discomfort is typical 2, 5

Diagnostic Approach to Hypersplenism

• Complete blood count to assess for cytopenias is essential 3, 2
• Liver function tests (total bilirubin, AST, ALT, alkaline phosphatase, GGT) should be performed annually 1
• Fibrosis indices including APRI (AST-to-Platelet Ratio Index) can detect advanced fibrosis and portal hypertension 1
• Peripheral blood smear to identify abnormal cells or leukoerythroblastic picture 3
• JAK2V617F, MPL, and CALR mutation testing for suspected myeloproliferative neoplasms 3
• Bone marrow examination may be informative in patients >60 years or those with systemic symptoms 3, 5
• Genetic testing (SMPD1 gene for ASMD) for suspected storage disorders 3

Treatment of Hypersplenism

• Treat the underlying disease process as primary management 4, 6
• JAK inhibitors (ruxolitinib) are first-line for symptomatic splenomegaly in myeloproliferative neoplasms 5
• Splenectomy is indicated when JAK inhibitors are unavailable or ineffective for large, painful splenomegaly 5, 7
• Partial splenic embolization is an alternative to splenectomy 7
• Splenic irradiation for patients who cannot tolerate JAK inhibitors and are poor surgical candidates, though benefit is transient 5
• Hypersplenism usually improves following liver transplantation in cirrhotic patients 7

Important Caveats

• Patients with limited splenic function require increased vaccination and prophylactic antibiotics for respiratory tract procedures 4
• Patients should refrain from contact sports to decrease risk of splenic rupture 4
• Acute infections, anemia, and splenic rupture are the most common complications 4
• In suspected immune thrombocytopenia (ITP), moderate or massive splenomegaly suggests an alternative diagnosis 3