History
Despite the extensive differential diagnosis of splenomegaly, careful history taking and physical examination, along with a CBC and manual differential, often help to narrow down the list of likely causes.
The history should include attention to the following important areas [46] :
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Duration of known enlargement of the spleen
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Exposure to hepatotoxic agents or microorganisms resulting in hepatitis or portal hypertension
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Abdominal trauma that may cause splenic hematoma
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Signs of infection or known infections such as hepatitis, mononucleosis, malaria, or salmonellosis
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Bone pain, fever, malaise, lethargy, pallor, bruising, weight loss, night sweats, or other findings that may indicate malignancy
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Jaundice suggestive of hepatobiliary disease
The patient should also be assessed for the following:
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Complicated neonatal course - Eg, sepsis, hypotension
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Umbilical catheter thrombosis
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Hyperbilirubinemia, anemia - Eg, due to hereditary hemolysis
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Heart disease - Eg, congestive heart failure
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Past surgeries - Eg, leading to infection, thrombosis, portal hypertension and cholecystectomy due to cholelithiasis
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Anemia or transfusions - Eg, due to hematologic abnormalities and/or resulting in hepatitis
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Abdominal trauma - Possibly resulting in splenic pseudocyst or hematoma
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Travel - Possible exposure to malaria, leishmaniasis, schistosomiasis, trypanosomiasis, or other microorganisms
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Sexual behavior - Possible presence of sexually transmitted infections, including human immunodeficiency virus (HIV), cytomegalovirus (CMV), and hepatitis
With regard to family history, carefully document the presence or absence of the following:
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Anemia
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Cholecystectomy
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Splenectomy - Eg, due to hemolytic anemia
The patient’s ethnicity should also be determined:
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Mediterranean ethnicity - Increased incidence of thalassemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency
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African ethnicity - Increased incidence of sickle cell anemia, G6PD deficiency, and hereditary pyropoikilocytosis
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European or American-Amish ancestry - Associated with pyruvate kinase deficiency and hereditary spherocytosis
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Asian ethnicity - Increased incidence of portal hypertension secondary to noncirrhotic portal fibrosis and increased incidence of G6PD deficiency
Physical
The patient should be examined in the supine or right lateral decubitus position. Palpation should start at the pubis and move toward the left upper quadrant to identify the medial and inferior border of the spleen. If the enlarged tip of the spleen is below the examiner's hands, he or she may not detect it. Likewise, light pressure should be used because the spleen can easily be displaced without the clinician identifying the organ’s edge. At times, the superior medial edge of the spleen is more readily palpated than the inferior margin.
The characteristic downward movement of the spleen with inspiration can help in differentiating the spleen from other masses of the left upper quadrant.
Percussion over the left lateral areas of the lower ribs may reveal splenomegaly that is not evident upon palpation. Percussion is particularly helpful in obese or crying patients. [48, 49, 50]
Document weight and height with percentiles for age to identify growth abnormalities, and obtain vital signs, including heart rate and blood pressure. Identify tachycardia, which may be seen in anemia, and fever, which may be present in inflammatory and infectious conditions.
Examine the patient supine with the hips and knees flexed. Place a pillow underneath the neck. Ensure relaxation of the abdominal musculature. Begin palpation at the iliac bone and palpate both lower quadrants. Percuss the lowest intercostal space in the left anterior axillary line; evaluate the space that is bound superiorly by the sixth rib, laterally by the axillary line, and inferiorly by the costal margin. Dullness to percussion in this area may indicate splenomegaly.
Assess the patient’s general appearance to document ill appearance. This will guide evaluation but is nonspecific and may be seen in various conditions, including malignancy, chronic hemolysis, chronic infection, metabolic disease, liver disease, and inflammatory disease.
Dermal findings
These include the following:
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Pallor - Eg, due to anemia, which may indicate hemolysis, bone marrow infiltration, or hypersplenism
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Petechiae, purpura - Eg, due to thrombocytopenia, which may indicate bone marrow failure, autoimmune disorder, or hypersplenism
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Jaundice - Eg, due to hemolytic anemia or liver disease
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Exanthems - Eg, due to acute and chronic infections, systemic lupus erythematosus, rheumatoid arthritis, infective endocarditis, hemangiomata, histiocytosis, or immunodeficiency
Head, eye, ear, nose, and throat findings
These include the following:
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Icterus - Eg, due to hemolytic anemia or liver dysfunction
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Cherry red retinal spots, cloudy corneas - For example, due to lipid-storage diseases
Respiratory and cardiovascular findings
These include the following:
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Dyspnea, fatigue - Eg, due to anemia or congestive heart failure
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Cardiac murmur - Eg, due to anemia or endocarditis
Gastrointestinal findings
These include the following:
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Abdominal tenderness - Eg, due to gallstones, hepatitis, trauma, or acute splenomegaly
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Distention, prominent abdominal veins, ascites - Eg, due to liver disease
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Abnormal size or texture of the liver
Musculoskeletal findings
These include the following:
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Joint abnormalities - Eg, due to systemic lupus erythematosus, rheumatoid arthritis, or autoimmune inflammatory disease
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Bone abnormalities - Eg, due to storage diseases or osteopetrosis
Neurologic abnormalities
These include the following:
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Poor vision - Eg, due to osteopetrosis
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Uveitis, iritis - Eg, due to sarcoidosis or rheumatoid arthritis
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Inappropriate developmental milestones - Eg, due to storage diseases or other chronic illness
Causes
Despite the numerous causes of splenomegaly (see Differentials), the spleen is rarely the primary site of disease.
Splenomegaly is often categorized into the following groupings:
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Sequestration of blood cells - Such as in hemolytic conditions
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Proliferation due to infection or inflammation
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Deposition - Such as in Niemann-Pick and Gaucher disease and in some infections
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Infiltration due to granulomatous, histiocytic, lymphoproliferative, or malignant conditions
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Endowment - As caused by space-occupying lesions
Splenic masses
Hematomas of the spleen may develop after trauma, including birth trauma, and may occur in accessory spleens, as well as in the main spleen. Some splenic hematomas arise as complications of medical procedures, and they may also appear spontaneously as part of disease processes. Splenic hematomas can be associated with symptomatic bleeding and other complications and require evaluation and monitoring. Some cases may be managed medically, but resection is frequently required for splenic hematomas. [51, 19, 52]
Splenic cysts are rare and are often discovered incidentally. Some patients with splenic cysts may report gastrointestinal complaints such as pain, nausea, altered bowel habits, flatulence, fullness, or emesis.
Primary splenic cysts are the most common type of splenic cyst in children. [53] The lesions are broadly categorized based on whether they are parasitic or non-parasitic in origin and by histology and etiology. Size, symptoms, and cause will determine the nature of any required treatment. There is a risk that a splenic cyst may become complicated by thrombocytopenia, bleeding, infection, or rupture. Splenectomy or partial splenectomy is sometimes performed. [53]
Hyperplasia
The most common mechanism of pathologic splenomegaly in children is hyperplasia of the MPS. This is due to a variety of conditions that result in excessive antigenic stimulation, including infection and immune dysfunction, as well as hemolysis. [27, 54]
Excessive antigenic stimulation due to infection is the cause of most cases of splenomegaly in children. Viral infections are the most frequent culprits, and the associated splenomegaly is usually transient and only mild to moderate in severity. Although Epstein-Barr virus (EBV) and CMV are well-known causes of splenomegaly, other, more common viral illnesses of childhood are the most frequent causes of pediatric infectious splenomegaly. (In addition, pediatric hepatosplenomegaly has been reported in patients with complications of severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2] infection. [55] )
Other common infectious etiologies include bacterial, protozoal, and fungal infections. In endemic areas, malaria and schistosomiasis are frequent causes of splenomegaly. Concomitant, generalized lymphadenopathy is common in many of these infectious conditions.
Inflammation and hyperplasia due to collagen vascular diseases such as juvenile rheumatoid arthritis are relatively uncommon, but clinically significant, causes of splenomegaly.
Malignancy
Splenomegaly can be a presenting sign of neoplasia, being a key such feature in leukemia and lymphoma. Histiocytic disorders may also present with infiltration of the spleen. [56]
Metastasis to the spleen, which is uncommon in children, has been reported in neuroblastoma.
Portal venous system abnormalities
Obstructed venous blood flow of intrahepatic or extrahepatic etiology can cause splenomegaly. The most common causes include portal vein thrombosis, hepatic cirrhosis, and congestive heart failure. Children with extrahepatic portal venous obstruction, such as cavernous transformation, often present with splenomegaly as the primary manifestation of their disease. In an Italian multicenter, national study by Di Giorgio et al, children with noncirrhotic portal vein thrombosis were evaluated, and the condition was noted to be diagnosed subsequent to the detection of splenomegaly in 40% of patients. [57]
Deposition causing splenomegaly
Storage diseases may result in splenomegaly, and in Gaucher and Niemann-Pick disease, it is often the first clinical manifestation. [58, 59, 60] Splenomegaly arises from the accumulation of abnormal lipids in splenic macrophages.
A study by McGovern et al of adults and children with Niemann-Pick disease indicated that over the report’s follow-up period, the risk of death for patients with a history of severe splenomegaly or prior splenectomy was 10-fold that of individuals with moderate splenomegaly or intact spleens. With regard to a history of severe splenomegaly alone, the odds ratio for mortality was 6.0. [61]
Masses
After trauma, palpable subcapsular hematomas may form in the spleen, which may eventually develop into clinically palpable pseudocysts. Patients with congenital true splenic cysts usually present with asymptomatic splenomegaly.
Extramedullary hematopoiesis
Although normally found only during the first 6 months of life, extramedullary hematopoiesis may occur in diseases associated with intense demand on the bone marrow for cell production. Thalassemia major, osteopetrosis, and idiopathic myelofibrosis are examples of this rare cause of splenomegaly.
Hypersplenism
Hypersplenism is a clinical syndrome in which cytopenias result from excessive splenic function and splenic hypertrophy. The pathologic action of the spleen, that is, the reduction of circulating blood elements, has been attributed to four possible mechanisms: excessive splenic phagocytic activity, splenic antibody formation that causes hematopoietic cell destruction, overactivity of splenic function, and sequestration. [62] In patients with cirrhosis, abnormalities of cytokine production may contribute to the cytopenias noted. [42]
As the spleen enlarges, it can sequester erythrocytes, leukocytes, and platelets, resulting in cytopenias. Severe reductions in cell counts are unusual and should prompt a search for alternative etiologies.
Venous obstruction is the most common cause of hypersplenism. Any increase in portal pressure is reflected in the splenic venous sinuses. This impairs blood flow out of the cords and results in the sequestration of blood cells and hypersplenism. Hypersplenism in children is most frequently caused by portal hypertension. Extrahepatic venous obstruction from portal vein thrombosis is the most common cause of increased portal pressures. In extrahepatic venous obstruction, hepatic function is normal. Intrahepatic venous obstruction is usually due to cirrhosis.
Portal hypertension usually increases flow through minor collateral vessels between the portal circulation and the systemic circulation. Portal hypertension can result in recognizable dilatation of the superficial abdominal veins and esophageal varices. Patients with these varices may present with sudden and catastrophic GI hemorrhage.
Splenic sequestration
Splenic sequestration crisis is a specific form of acute hypersplenism in young children with sickle cell anemia. [62]
Children less than 6 years old can develop rapid splenic sequestration and splenomegaly with the consumption of large volumes of erythrocytes. They present with sudden weakness, dyspnea, and left-sided abdominal pain in addition to splenomegaly.
Splenic sequestration is an emergency. Rapid death from hypovolemic shock can result.
Treatment consists of fluids and erythrocyte transfusions. To prevent recurrences, splenectomy may be indicated. In most patients with sickle cell disease, the spleen eventually involutes, making sequestration no longer possible.
