Hypersplenism is a clinical syndrome characterized by splenomegaly, reductions in one or more peripheral blood cell lineages, and compensatory proliferation of hematopoietic cells in the bone marrow. Blood cell counts generally return to normal, and symptoms are alleviated following splenectomy. Hypersplenism is classified as either primary or secondary depending on whether the underlying cause is known.
Etiology
Primary hypersplenism is rare and of unknown cause. Secondary hypersplenism is more common and can result from the following categories of conditions:
Infectious Diseases
Conditions such as infectious mononucleosis, subacute infective endocarditis, viral hepatitis, brucellosis, schistosomiasis, kala-azar, and malaria.
Immune Disorders
Conditions such as Felty's syndrome and systemic lupus erythematosus (SLE).
Congestive Disorders
Conditions such as congestive heart failure, constrictive pericarditis, Budd-Chiari syndrome, liver cirrhosis, or portal and splenic vein thrombosis.
Hematological Disorders
Hemolytic anemias include hereditary spherocytosis, autoimmune hemolytic anemia, thalassemia, and sickle cell anemia.
Malignant hematologic disorders include acute and chronic leukemias, lymphomas, and amyloidosis.
Myeloproliferative neoplasms include polycythemia vera and primary myelofibrosis.
Splenic Diseases
Conditions such as splenic lymphoma, splenic cysts, and splenic hemangiomas.
Lipid Storage Disorders
Conditions such as Gaucher disease, Niemann-Pick disease, and glycogen storage diseases.
Other Causes
Conditions such as malignant tumors (e.g., angiosarcoma), drug-related factors, or extramedullary hematopoiesis.
Pathogenesis
The exact mechanisms by which hypersplenism causes reductions in blood cells are not fully understood but are thought to involve several factors:
Excess Phagocytosis
The spleen functions as a blood filter and is part of the mononuclear phagocyte system. Blood flows slowly through the red pulp, which is composed of a reticular filtration network formed by macrophages, and re-enters circulation via small interendothelial slits (0.2–0.5 μm) in the splenic venous sinuses. During this process, bacteria, foreign particles, or cells tagged with antibodies or complement are recognized and phagocytosed by macrophages. Additionally, aged, damaged, or less deformable cells are unable to pass through the slits, becoming sequestered and subsequently phagocytosed. When splenomegaly occurs for various reasons, more blood passes through the red pulp with a slower flow rate, enhancing the spleen’s filtering capacity. This leads to increased sequestration and destruction of both normal and abnormal blood cells, resulting in their reduction in circulation and stimulating compensatory hyperplasia of bone marrow hematopoietic cells.
Excessive Sequestration
The spleen does not normally store red blood cells but retains around one-third of platelets and a small fraction of white blood cells, primarily lymphocytes. When the spleen becomes significantly enlarged, 50–90% of platelets, 30% of red blood cells, and an even higher proportion of lymphocytes may be sequestrated, leading to reductions in circulating blood cells.
Hemodynamic Abnormalities
Splenomegaly is often accompanied by an increase in plasma volume and splenic blood flow, which can overload the splenic vein and elevate portal venous pressure. This, in turn, may exacerbate splenomegaly, increase splenic blood flow further, and form a vicious cycle.
Abnormal Autoantibodies
The spleen participates in antigen processing and antibody production. When splenomegaly occurs, mononuclear macrophages in the spleen may synthesize excessive autoantibodies, such as anti-red cell antibodies and anti-platelet antibodies.
Immune-Neuroendocrine Network
The spleen is an integral component of the body’s “immune-neuroendocrine” regulatory network. In hypersplenism or splenomegaly, this regulatory function becomes disrupted, resulting in the overproduction of factors such as blood cell inhibitory substances by the spleen. These factors may cause blood cells to be trapped within the spleen and accelerate their destruction.
In clinical practice, splenomegaly and pancytopenia are likely the result of the combined action of these pathogenic mechanisms.
Clinical Manifestations
The majority of patients are found to have varying degrees of splenomegaly during physical examination. However, in some cases, the spleen is not palpable, and imaging studies are required to confirm the diagnosis. Mild to moderate splenomegaly is often asymptomatic, while significant splenomegaly may lead to abdominal discomfort. Pain and a sensation of friction in the left hypochondriac region associated with respiration may suggest splenic infarction.
Pancytopenia is the hallmark manifestation of hypersplenism. The severity of blood cell reduction and associated symptoms do not correlate directly with the degree of splenomegaly. Mild reductions in blood cells typically present with no obvious clinical symptoms, while moderate to severe reductions may result in clinical manifestations such as anemia, infection, and bleeding. Secondary hypersplenism may also include symptoms of the underlying primary disease.
Laboratory and Imaging Studies
Peripheral Blood Findings
Blood tests may reveal reductions in one, two, or all three blood cell lineages, with cellular morphology remaining normal. In the early stages, leukopenia and/or thrombocytopenia are more pronounced, while pancytopenia is more frequently seen in advanced stages.
Bone Marrow Findings
Bone marrow examination typically shows hyperplasia or marked hyperplasia. The blood cell lineages that are reduced in the periphery generally exhibit significant proliferation in the bone marrow. Some patients may also show evidence of blood cell maturation abnormalities.
Imaging Studies
Imaging techniques such as ultrasound, CT, and MRI can confirm splenic size, providing critical information for diagnosing hypersplenism and its underlying cause. Additionally, the assessment of portal vein width can aid in diagnosing portal hypertension.
Radionuclide Studies
Radiolabeled red blood cells (e.g., using 51Cr) injected intravenously into the bloodstream can be used to measure their clearance rate from circulation and assess the splenic red cell sequestration index.
Diagnosis
The diagnostic criteria for hypersplenism include the following:
- Splenomegaly: In most patients, the spleen can be palpated during physical examination. In some cases where the spleen is not palpable or only barely palpable below the costal margin, confirmation via ultrasound, CT, or MRI is needed.
- Peripheral Blood Cytopenia: A reduction in one or multiple blood cell lineages.
- Proliferative Bone Marrow Findings: Bone marrow examination reveals active or markedly active proliferation, with mild blood cell maturation abnormalities in some patients.
- Improvement in Blood Counts After Splenectomy: Peripheral blood counts normalize or approach normal following splenectomy.
- Findings from Radionuclide Studies: After injecting 51Cr-labeled red blood cells or platelets, surface radioactivity over the spleen is found to be two to three times that over the liver.
The first four criteria are considered the most critical for diagnosis.
Differential Diagnosis
Hypersplenism needs to be differentiated from other conditions that cause splenomegaly and blood cell reductions.
Treatment
For secondary hypersplenism, management should focus on treating the underlying primary disease. If treatment of the primary condition proves challenging or if hypersplenism is severe and the primary disease permits, splenectomy may be considered. For primary hypersplenism, options include splenic radiotherapy, partial splenic embolization, or splenectomy.
Indications for splenectomy:
- Splenomegaly causing significant compressive symptoms that do not respond to conservative treatment.
- Severe hemolytic anemia.
- Marked thrombocytopenia leading to bleeding.
- Extreme neutropenia with a history of recurrent infections.
Common complications following splenectomy include thrombosis, embolism, and infections, necessitating careful consideration of surgical indications.