Aetiology

Categorisation of splenomegaly according to aetiology is outlined below. Splenomegaly of indeterminate aetiology is termed idiopathic. A non-haematologist clinician may initiate an assessment of splenomegaly and even determine its aetiology, but there should be a low threshold for referral to a haematologist.

Hepatic

Alcohol-induced liver disease causes portal hypertension with resultant retrograde pressure into the spleen and further splenomegaly.[6] Chronic exposure of hepatocytes to ethyl alcohol causes Mallory bodies to form within and leads to cell destruction. Fibrosis occurs within the liver parenchyma that then bridges from portal triad to portal triad. Eventually, extensive irreversible scarring occurs.

Many other liver diseases can also lead to cirrhosis. The underlying mechanisms of liver injury may differ, but the end result is the same: cirrhosis. Examples include primary biliary cholangitis, primary sclerosing cholangitis, viral hepatitis (B or C), non-alcoholic steatotic liver disease, and hereditary haemochromatosis.

In portal hypertension, the spleen enlarges due to increased retrograde pressure through the portal and then the splenic vein. The enlarged spleen clears all the cellular elements of the blood more rapidly than normal, and thus affected patients have varying degrees of leukopenia, anaemia, and thrombocytopenia. Patients can also develop varices where the portal and systemic circulations merge, especially in the distal oesophagus and the haemorrhoidal veins, which may present as oesophageal variceal rupture or haemorrhoidal bleeding. The umbilical veins are also affected but this does not lead to severe clinical consequences.

Neoplastic disease

Neoplastic aetiologies include myeloproliferative neoplasms (essential thrombocythaemia, polycythaemia vera, and primary myelofibrosis); leukaemias (acute lymphoblastic leukaemia, acute myeloid leukaemia, chronic lymphocytic leukaemia, chronic myeloid leukaemia, and hairy cell leukaemia); Hodgkin/non-Hodgkin lymphomas; primary splenic tumours; and metastatic disease.[7]​ An international standard (WHO Classification of Tumours) is available for differential diagnosis of the leukaemias and lymphomas.[8]​ Updated guidance is available from the National Comprehensive Cancer Network (NCCN).[9]

Benign lesions may also lead to splenomegaly. Splenic benign lesions include splenic hamartoma, littoral cell angioma (lesions that are benign growths of endothelial cells; may recur in other organs over time), haemangioma, and cysts.

Vascular occlusive

The veins draining the spleen towards the liver can become occluded by clots, leading to splenomegaly.

  • Splenic vein thrombosis can occur as a consequence of acute pancreatitis, because the splenic vein courses just superior and posterior to this organ. The onset of splenomegaly can be rapid and painful.

  • Portal vein thrombosis may be seen in myeloproliferative diseases (especially in young women with polycythaemia vera). Portal vein thrombosis may also occur in paroxysmal nocturnal haemoglobinuria (PNH), a clonal disorder in which erythrocytes are especially sensitive to lysis by complement, and hypercoagulable states, such as antiphospholipid antibody syndrome, or as an adverse effect of oral contraceptives. Collateral vessels may form around the portal vein, and re-establishment of blood flow through the portal vein may occur over time (cavernous transformation of the portal vein). Splenomegaly may be mild or severe. In patients with underlying myeloproliferative disorder with hypercoagulability leading to the portal vein thrombosis, there can be synergistic reasons for the splenomegaly.

  • Budd-Chiari syndrome is caused by thromboses in small vessels within the liver, with tracking of thrombosis towards the main hepatic veins. It can occur after high-dose chemotherapy (as a consequence of preparatory chemotherapy at the time of bone marrow transplant), in PNH, and in myeloproliferative disorders.

Immunological/inflammatory

Amyloidosis[10]

  • Describes the extracellular tissue deposition of fibrils composed of low molecular weight subunits of a variety of proteins. Major forms of amyloidosis (i.e., build up of amyloid) include AL (light chain) amyloid, AA, and transthyretin. These proteins can deposit anywhere, but typically target the soft tissues, heart, liver, and spleen. Splenomegaly may be mild, moderate, or severe, and can lead or contribute to cytopenias.

Autoimmune haemolytic anaemia

  • Direct antiglobulin tests reveal the presence of immunoglobulin on the surface of red cells (warm-type), which leads to clearance of these red cells by the reticuloendothelial system. Red cells become spherocytes, which are more prone to destruction. Splenomegaly can result in either warm- or cold-type haemolysis (associated with complement on the surface of red cells) because the splenic red pulp is so active in clearing these cells that it expands. Generally, this type of splenomegaly is mild.

Haemophagocytic lymphohistiocytosis (HLH)​

  • HLH can be primary or secondary.

  • Primary HLH usually presents in childhood. It is caused by genetic mutations that impair the cytotoxic function of natural killer and cytotoxic T cells. Genetic mutations associated with HLH include PRF1, RAB27A, STX11, STXBP2, UNC13D, LYST, AP3B1, SH2D1A, XIAP, NLRC4, CDC42, the Epstein-Barr virus susceptibility diseases, and XLP.[11][12]

  • Secondary HLH can be seen in association with autoimmune conditions, immunodeficiency, infection, or malignancy; however, in some cases an associated illness is not identified.[13][14]​

  • Several criteria have been developed to identify patients with syndromes that may represent HLH, including HLH-2004, and the HScore.[15][16][17]​ However, both lack sensitivity and specificity, therefore no single set of criteria is sufficient to diagnose a HLH across all populations.[15]

  • ​A EULAR/ACR (European Alliance of Associations for Rheumatology/American College of Rheumatology) task force recommends that clinical and laboratory abnormalities together should be used to recognise potentially life-threatening HLH.​[15]

Rheumatological disorders

  • Rheumatological syndromes such as rheumatoid arthritis can cause splenomegaly as a result of expansion of the white pulp. This is due to a systemic expansion of immune cells. The degree of splenomegaly is usually mild to moderate.

  • Felty syndrome is a triad of rheumatoid arthritis, splenomegaly, and neutropenia. Neutropenia is mediated by an antibody response or, in some cases, by excessive large granular lymphocytes in the spleen or the systemic circulation.

  • Splenomegaly in systemic lupus erythematosus occurs by a similar mechanism to that in rheumatoid arthritis and generally is mild to moderate.

Sarcoidosis

  • A disease of unknown origin and mechanism, characterised by non-caseating granulomas, found mostly in the lungs and lymph nodes. The spleen can become quite enlarged in sarcoidosis, leading to symptoms of pain and inanition. Cytopenias can occur and may be exacerbated by the marrow being filled with non-caseating granulomas, decreasing marrow output of leukocytes, red blood cells, and platelets.

Lysosomal storage disorders

Gaucher's disease

  • The prototypical example of lysosomal storage disease-associated splenomegaly.[18] It is a common genetic disease, particularly among those of Ashkenazi Jewish descent.[19]​ Due to a deficiency of glucocerebrosidase, cells of the reticuloendothelial system accumulate glucocerebroside, which is a breakdown product of the metabolism of fatty acids. The cells become hypertrophic and cannot be removed from the spleen or liver. Hepatosplenomegaly can be severe. Cytopenias and bone pain (crises) are common presenting features.[19]​ Bone imaging reveals distinctive changes, such as the 'Erlenmeyer flask' sign in the distal femurs. Bone density is compromised.

Niemann-Pick disease

  • Caused by an abnormality, or a deficiency, of the sphingomyelinase gene.[20] Includes three types: type A is seen in infants and causes neuronal disorders; type B has a later onset of presentation and is non-neuronopathic; and type C, the most common form, is neuronopathic, showing a later onset and abnormal cholesterol transport. Type C disease affects Ashkenazi Jews in a disproportionate manner.

Infectious

Malaria

  • A major health problem in anopheles mosquito-affected parts of the world. It is most commonly caused by four protozoan parasites: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae.[21]

  • Transmission to humans occurs through the bite of the anopheles mosquito. The parasite has various life-cycle stages but primarily infects the red blood cells, causing lysis. The spleen enlarges partly through the overactivity of the red pulp in clearing these lysed red cells.[22]

  • Hyper-reactive malarial splenomegaly (HMS) is caused by an inappropriate immune response to chronic malarial parasite exposure. It is one of the leading causes of massive splenomegaly in malaria-endemic regions.[23]

Epstein-Barr virus (EBV)

  • Causes infectious mononucleosis. Infection manifests as fever, pharyngitis, posterior cervical adenopathy, and splenomegaly. Splenomegaly is usually mild but can be substantial under unusual circumstances. Generally, once the infection is cleared, the spleen reverts to normal size. Chronic EBV infections can occur in immunocompromised patients and can lead to generalised adenopathy and more prominent hepatosplenomegaly. EBV may be responsible for a complication of solid organ transplant recipients, an entity called post-transplant lymphoproliferative disease, in which splenomegaly may be a feature.

Dengue

  • Characterised by fever, malaise, headache, asthenia, and less commonly, bleeding, plasma leakage and organ impairment (e.g., hepatosplenomegaly).[24]

  • Approximately 1 in 10 people with severe dengue have secondary HLH, which has a high mortality rate.[25] Patients with dengue-associated HLH have fever, thrombocytopenia, splenomegaly, anaemia, and hepatomegaly, and raised serum ferritin.[26]

Hepatitis viruses

  • Chronic ongoing infection of the liver by hepatitis B or C viruses can lead to cirrhosis and resultant splenomegaly.

Endocarditis

  • Caused by many different types of bacteria and other organisms. May cause splenomegaly because the entire immune system is expanded in an attempt to clear the organisms from the circulation. Additionally, the spleen can become a seeding ground for the invading organism, and splenic abscesses can appear. Splenic abscesses can become quite large, with liquefaction necrosis within, leading to splenomegaly.

Splenic abscesses secondary to sepsis

  • Splenic abscesses can occur as a consequence of seeding from septicaemia unrelated to endocarditis. Bacteria or fungi can be the culprits. Splenomegaly can be mild to moderate.

Inherent red blood cell abnormalities

Cytoskeletal defects

  • Can lead to abnormal deformability of red blood cells, which get trapped in the red pulp of the spleen, causing splenomegaly.[27] Spectrin abnormalities are the most common type of cytoskeletal defect and result in hereditary spherocytosis. Hereditary elliptocytosis is another example of a cytoskeletal defect.

Haemoglobinopathies

  • Can be divided into thalassaemias and structural defects (amino acid substitutions) in alpha- or beta-globin.[28]

  • In homozygous sickle cell anaemia, repeated infarctions in the spleen lead to a self-destructive process by which the spleen is reduced to a small fibrotic nubbin. However, in some sickle cell variants, such as sickle C (HbSC) disease, the spleen can become enlarged. In children, there can be sudden enlargement and pooling of red cells within the spleen, known as sequestration crisis. Hypotension and cardiovascular collapse can occur.

  • Thalassaemias result from an improper amount of alpha- or beta-globin being produced. Clinically, thalassaemias are divided into three categories.

    • Thalassaemia major: severe anaemia with anisocytosis and poikilocytosis, with severe microcytosis. Liver and spleen can be massively enlarged.

    • Thalassaemia intermedia: less severe thalassaemia. Spleen is usually mildly enlarged.

    • Thalassaemia minor: hypochromic microcytic anaemia may be present. Spleen can be normal sized or slightly enlarged.

Trauma

Spleen can be ruptured, with tears in the splenic capsule and intraperitoneal bleeding necessitating emergency splenectomy. Rarely, trauma can lead to bleeding within the splenic capsule, and a subcapsular haematoma may result.

Drug-related

Granulocyte colony-stimulating factor treatment can cause splenomegaly.[29] In very rare cases, splenic rupture may result. High-dose chemotherapy can lead to Budd-Chiari syndrome. Prior or current treatment with oral contraceptives raises the possibility of portal vein thrombosis.

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