The spleen has intrigued physicians and philosophers since ancient times1 and has been assigned mysterious powers, but its association with destruction of blood cells was not elucidated until the turn of the 20th century. The exaggerated and unfounded worry about somatic complaints often reflected by the sense of pain in the spleen (left hypochondrium) led to the term hypochondriac. In 1899, Chauffard proposed that increased splenic activity causes hemolysis.2 This proposal provided the impetus for therapeutic splenectomy, which was performed first in 1910 by Sutherland and Burghard3 in a patient with splenic anemia (hereditary spherocytosis) and subsequently by Kaznelson4 in a patient with essential thrombocytopenia (immune thrombocytopenic purpura) in 1916.
Hypersplenism is defined as blood cytopenias in the setting of splenomegaly. This is usually accompanied by hyperplasia of the affected cell precursors in the marrow. There can be a disproportional decrease in the blood platelets, white cells, and red cells, with thrombocytopenia and leukopenia being disproportionate to the anemia as a result of hypersplenism. Splenomegaly can occur as a result of elevated splenic venous pressures and vascular congestion, histiophagocytic hyperplasia, other cellular infiltration, or because of the inability of physically abnormal red cells, such as sickle cells in infants and children (prior to infarction atrophy), or antibody-coated cells, such as in autoimmune hemolytic anemia, to navigate the circulation or avoid engulfment by the mononuclear phagocyte population of the normal spleen.5 The blood cytopenias are not generally corrected by relief of portal hypertension.6,7
The embryonic spleen appears in the first trimester of gestation as a multiply lobulated condensation of highly vascular mesenchymal cell aggregates interposed in the arterial circulation in the dorsal mesogastrium. The full scope of the molecular basis of splenic organogenesis is not known. The HOX11 and WT1 genes are essential for its formation, and defects in their expression result in hyposplenia or asplenia.8,9,10
The lymphoid compartment, the white pulp, begins its development early in the second trimester of gestation, when mature T cells, principally CD4+ lymphocytes, form a continuous layer along the length of the vessels (periarteriolar sheaths). CD8+ cells reside in splenic cords and a specialized subset of γδT cells home to the pulp (Chap. 6). Immunoglobulin (Ig) D+ and IgG+ B lymphocytes form localized deposits, the primary lymph follicles. Secondary follicles arise later in life, after exposure to immunologic stimuli, and have a distinctive structure that includes a germinal center, a mantle zone, and a marginal zone containing IgM+ and IgG+ B lymphocytes.11,12
STRUCTURE AND FUNCTIONAL ORGANIZATION
The normal adult spleen weighs 135 ± 30 g and has a blood flow that is approximately 5 percent of the cardiac output. In addition to serving as a filter, the spleen plays a role in innate and adaptive immunity and protection against microbes. The spleen is composed of white pulp, a marginal zone, and red pulp. The spleen’s principal structure is organized around an arborizing array of arterioles that branch and narrow until they terminate in either (1) the stroma of cords, forming the open circulation, or (2) the sinusoids, forming the closed circulation of the spleen (Chap. 6). The cordal elements include histiocytes, antigen-presenting cells, pericytes, fibroblasts, and other cells necessary to maintain the discontinuous basal lamina that separates cords from sinusoid lumen.13 Lymphatic tissue is inconspicuous and found in T-cell–rich zones in the periarteriolar lymphoid sheaths.
The arterial vascular tree, which is lined by conventional CD31+ and CD34+ endothelial cells, branches into arterioles that terminate abruptly in caps of cordal macrophages. Blood cells must pass clusters of macrophages to enter the sinusoids.13 The sinusoids, the origin of the venous circulation, are lined by specialized cells having combined phagocytic and endothelial activities and a distinctive CD31+, CD34−, CD68+, CD8+ phenotype. A principal function of the spleen is to serve as a filter, removing aged or defective red cells and foreign particles by macrophages. This function is facilitated by diverting part of the splenic blood supply into the red pulp, where the blood slowly percolates through the nonendothelialized mesh studded with macrophages. Abnormal or senescent red cells and pathogens undergo phagocytosis by the macrophages. The blood then reenters the circulation through narrow slits, measuring 1 to 3 μm, in the endothelium of the venous sinuses. The bulk of the blood is rapidly channeled through vessels that link the arterioles with the venous sinuses. This blood is not filtered or modified.14
Approximately one-third of platelets are normally sequestered in the spleen.15 In many animals, such as dogs and horses, the red pulp is a reservoir for red cells, and splenic contraction provides the red cell volume with a functionally important boost.16 In humans, however, the splenic capsule is poorly contractile, and the spleen does not store red cells to any significant degree.17 Although margination of neutrophils occurs in the spleen, it is unclear to what degree it occurs in that site.18 Granulocyte colony-stimulating factor (G-CSF) administered to cirrhotic patients caused a rise in the blood neutrophil count; thereafter, indium scans of the spleen were performed, which did not show significant uptake by white cells.19
The slow transit of blood through the red pulp permits macrophages to recognize and destroy antibody- or complement-coated red cells and microorganisms, and to ingest poorly deformable red cells or particles retained mechanically by the narrow exit slits in the venous sinuses. The white pulp plays a major role in adaptive immunity. The spleen is involved in the phagocytosis of encapsulated bacteria including Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis.
Filtration and elimination of defective cells occur notably in hereditary abnormalities of the red cell membranes, such as spherocytosis, elliptocytosis, or stomatocytosis, or with antibody-coated red cells, neutrophils, or platelets. In these circumstances, cytopenias of varying severity may ensue. The spleen not only removes antibody-coated cells, but also produces antibodies, especially antiplatelet antibodies.20 Thus, the benefits of splenectomy in immune thrombocytopenic purpura is a result of both the decreased production of antiplatelet antibodies as well as decreased clearance by macrophages of antibody-coated platelets through the Fc recognition function of its large macrophage population.
Splenomegaly increases the proportion of blood channeled through the red pulp.13,21 Spleen enlargement may result from expansion of the red pulp compartment with increased blood flow; extramedullary hematopoiesis, notable in primary myelofibrosis; hyperplasia or neoplasia involving the white pulp, such as in infectious mononucleosis or lymphoma; or histiophagocytic hyperplasia.
The increased size of the filtering bed is more pronounced when the splenomegaly is caused by congestion as in portal hypertension than when it is caused by cellular infiltration as in leukemias, extramedullary hematopoiesis, or amyloidosis. Even in space-occupying disorders such as Gaucher disease and primary myelofibrosis, splenomegaly may be associated with hypersplenic sequestration of normal cells.
Splenomegaly increases the vascular surface area and thereby the marginated neutrophil pool.18,19 Platelets are especially likely to be sequestered in an enlarged spleen. However, sequestered white cells and platelets survive in the spleen and may be available when increased demand requires neutrophils or platelets, although their release may be slow.22
Some patients with anemia and splenomegaly have a relative erythropoietin deficiency.23 In one study of cirrhotic patients, 30 percent had a blunted erythropoietin response to anemia.24 Dilution of red cells in an expanded plasma volume is another commonly cited cause of a decreased blood hemoglobin concentration,25 although some studies do not demonstrate hemodilution.26 Iron deficiency associated with chronic blood loss, folic acid and vitamin B12 deficiency, and increased red cell destruction are frequently investigated, although rarely found in patients with liver disease.27 Red cells are destroyed prematurely in the red pulp in the setting of splenomegaly, but only rarely does this explain the anemia.28
Varying amounts of erythrophagocytosis are present, reflecting the normal culling of senescent red cells. Erythrophagocytosis increases as a result of hemolytic anemia and viral infections, and in alloimmunized transfusion recipients. Macrophages within the sinusoids contain red cell fragments. When the process is pronounced, the littoral cells become cuboidal and stand out on the basement membrane (“hobnails”). Sickle cell disease and red cell membrane disorders such as hereditary spherocytosis lead to sequestration of the poorly deformed red cells in the cords but little extrasinusoidal erythrophagocytosis is seen, in contrast to immune hemolytic anemia where macrophage erythrophagocytosis is prominent.13
The increased blood flow from an enlarged spleen expands the splenic and portal veins. A significant increase in portal venous pressure may occur when hepatic vessel compliance is decreased, as in cirrhosis or myelofibrosis. This process initiates a vicious cycle in which portal hypertension contributes to splenomegaly, organ enlargement leads to increased arterial blood flow, which, in turn, increases portal pressure.
Table 56–1 lists causes of splenomegaly, and Table 56–2 lists causes of massive splenic enlargement.
Table 56–1.Classification and Most Common Causes of Splenomegaly ||Download (.pdf) Table 56–1. Classification and Most Common Causes of Splenomegaly
a. Right-sided congestive heart failure
b. Budd-Chiari syndrome (inferior vena cava and hepatic vein thrombosis)
c. Cirrhosis with portal hypertension
d. Portal or splenic vein thrombosis
a. Viral infection
i. Acute HIV infection/chronic Infection
ii. Acute mononucleosis
iii. Dengue fever
iv. Rubella (rare except newborns)
v. Cytomegalovirus (rare except newborns)
vi. Herpes simplex (rare except newborns)
b. Bacterial infection
i. Subacute bacterial endocarditis
vii. Secondary syphilis
viii. Relapsing fever
xi. Rickettsial diseases (scrub typhus, Rocky Mountain spotted fever, Q fever)
xiii. Splenic abscess (most common organisms are Enterobacteriaceae, Staphylococcus aureus, Streptococcus group D, and anaerobic organisms as part of mixed flora infections)
c. Fungal infection
iii. Systemic candidiasis; hepatosplenic candidiasis
d. Parasitic infection
viii. Trypanosomiasis (cruzi, brucei)
ix. Toxoplasmosis (rare except newborns)
xii. Visceral larva migrans (Toxocara infection)
i. Systemic lupus erythematosus
ii. Felty syndrome
iii. Juvenile rheumatoid arthritis
iv. Autoimmune lymphoproliferative syndrome (ALP syndrome)
v. Hemophagocytic syndrome
vi. Common variable immunodeficiency
vii. Splenomegaly caused by granulocyte colony-stimulating factor administration
viii. Anti-D immunoglobulin administration (RhoGAM)
3. Secondary to hemolysis
a. Thalassemia major
b. Pyruvate kinase deficiency
c. Hereditary spherocytosis
d. Autoimmune hemolytic anemia (uncommon)
e. Sickle cell disease in early childhood (splenic sequestration)
i. Splenic hematoma (splenic cysts are usually a late complication of a hematoma)
ii. Littoral cell angioma
iii. Disorders of sphingolipid metabolism
1. Gaucher disease
2. Niemann-Pick disease
v. Amyloidosis (light chain amyloid [AL] and amyloid A protein [AA])
vi. Multicentric Castleman disease
viii. Hypereosinophilic syndrome
b. Extramedullary hematopoiesis
i. Primary myelofibrosis
ii. Osteopetrosis (childhood)
iii. Thalassemia major
1. Chronic lymphocytic leukemia (especially prolymphocytic variant)
2. Chronic myeloid leukemia
3. Polycythemia vera
4. Hairy cell leukemia
5. Heavy chain disease
6. Hepatosplenic lymphoma
7. Acute leukemia (acute lymphoblastic leukemia/acute myeloid leukemia)
8. Hodgkin lymphoma
1. Metastatic carcinoma (rare)
3. Wilms tumor
6. Malignant fibrous histiocytoma
7. Kaposi sarcoma
10. Hemangioendothelial sarcoma
Table 56–2.Causes of Massive Splenomegaly ||Download (.pdf) Table 56–2. Causes of Massive Splenomegaly
Chronic myeloid leukemia
Hairy cell leukemia
Chronic lymphocytic leukemia (especially prolymphocytic variant)
Leishmaniasis (kala azar)
Slight to moderate enlargement of the spleen usually does not produce local symptoms. Even massive splenomegaly can be well tolerated if it develops gradually. However, not infrequently, the patient complains of a sagging feeling or other types of abdominal discomfort, early satiety from gastric encroachment, and trouble sleeping on one side. Pleuritic pain in the left upper quadrant or referred to the left shoulder may accompany splenic infarcts, which may be recurrent.
In children with sickle cell anemia or patients with malaria, the spleen may become acutely enlarged and painful as a result of a sudden increase in red cell pooling and sequestration. These sequestration crises are characterized by sudden aggravation of the anemia. Splenic rupture is uncommon but can occur spontaneously with most causes of splenic enlargement or after blunt trauma. Rupture related to the splenic enlargement in infectious mononucleosis is a classic example.
The volume of an enlarged spleen is difficult to assess by palpation and percussion. Children and thin patients with low diaphragms may have a palpable spleen tip without splenomegaly.29 Generally, a palpable spleen signifies splenomegaly and is measured by the number of centimeters the spleen extends below the left costal margin. Splenic size is most accurately measured with abdominal ultrasound (Fig. 56–1) or computed tomographic scans (Fig. 56–2). Magnetic resonance imaging is used primarily to identify cysts, abscesses, and infarcts.30
A three-way composite of abdominal computerized tomography. A. Normal spleen size. B. Enlarged spleen. C. Massively enlarged spleen at the level of mid-kidney. Normally the spleen would either not be visualized or only a small lower pole would be evident at the level of the mid-kidney. (White arrow in each of the three images marks edge of splenic silhouette.) (Used with permission of Deborah Rubens, MD, The University of Rochester Medical Center.)
A two-way composite of ultrasonography examination for spleen size. A. Image of echo indicating normal spleen size with cranial to caudal longitudinal dimension of 10.3 cm. B. Image of echo indicating enlarged spleen with cranial to caudal longitudinal dimension of 16.2 cm. (White arrow in each image marks edge of splenic silhouette.) The normal spleen is usually less than 13 cm in length but the examiner has to consider other dimensions in assessing spleen size (volume). (Used with permission of Deborah Rubens, MD, The University of Rochester Medical Center.)
A wandering spleen (splenoptosis) is an uncommon phenomenon in which the spleen hangs by a long pedicle of mesentery. The condition may present in three ways: (1) an asymptomatic mass in the pelvis, (2) intermittent abdominal pain with or without gastrointestinal symptoms, or, less often, (3) an acute abdomen resulting from torsion. The diagnosis of splenoptosis may be made coincidentally on an imaging study.31 The condition may be accompanied by signs of hypersplenism, hyposplenism, and often, when developing slowly, is initially mistaken for a pelvic or lower abdominal tumor.
The characteristic features of hypersplenism are splenomegaly, blood cytopenias, and absence of other causes of cytopenias (e.g., anemia caused by bleeding). The blood cell morphology usually is normal, although a few spherocytes may result from metabolic conditioning of red cells during repeated slow transits through the expanded red pulp. Tests, such as epinephrine mobilization, were used in the past to try to distinguish sequestration from ineffective cellular production, but results are difficult to interpret as epinephrine also releases platelets and neutrophils from marginal pools.32
Thrombocytopenia is a common finding in patients with hepatic cirrhosis, portal hypertension, and splenomegaly. In a retrospective study, 64 percent of patients with nonalcoholic cirrhosis had thrombocytopenia.33 Other studies have found that approximately one-third of patients with cirrhosis develop severe thrombocytopenia or neutropenia.34,35 Decompensated liver disease and history of alcohol consumption are independent risk factors for hypersplenism,36 but why some patients develop marked blood cytopenias is not clear, although folate deficiency is a factor in some instances. The presence of thrombocytopenia or leukopenia in patients with chronic liver disease is associated with increased mortality.37
Ultrasound-guided fine-needle biopsy of the spleen can be useful in circumstances in which the spleen holds the tissue required for diagnosis, such as splenic lymphoma. However, fine-needle aspiration is rarely a definitive diagnostic tool but can indicate monoclonality of splenic lymphocytes, which is helpful and forces further diagnostic evaluation. Aspiration cytology and core biopsy can be obtained with relative safety in experienced hands using image-guided fine needles.38
The response to transfusion of blood products, especially platelets, may be significantly impaired in patients with massive splenomegaly.39
THERAPY, COURSE, AND PROGNOSIS
Splenectomy is indicated as an emergency procedure after abdominal trauma and partial rupture of the spleen. It also may be indicated when splenic size or infarcts causes sustained left upper abdominal pain or discomfort. Splenectomy has been used for the treatment of functionally significant blood cytopenias.39 In such circumstances, case reports have described dramatic restoration of blood counts to normal levels within days to weeks after splenectomy; however, the only controlled trial evaluating relief of cytopenias showed no improvement.6 Orthotopic liver transplant corrects the cytopenias in the majority of patients with cirrhosis.40
Hereditary spherocytosis, immune thrombocytopenic purpura, and immune hemolytic anemia are the most common indications for splenectomy. Splenectomy exerts its effect in autoimmune cytopenias by improving cell survival and also by decreasing autoantibody production. In thalassemia major, an improvement in the anemia is well described after splenectomy. In such cases, splenectomy may improve the response to transfusion. Some children with sickle cell anemia may benefit from splenectomy if repeated sequestration crises with abdominal pain occur before autosplenectomy renders the spleen atrophic.41
Splenectomy in patients with a massive spleen size (>1500 g), especially in primary myelofibrosis, is accompanied by higher morbidity and mortality than is removal of the spleen for immune blood cytopenia.42 Possible postoperative complications include extensive adhesions with collateral blood vessels, hepatic or portal vein thrombosis, injury to the tail of the pancreas, operative site infections, and subdiaphragmatic abscesses.
Laparoscopic splenectomy performed by experienced surgeons for suitable hematologic conditions can result in less abdominal trauma and pain, shorter hospital stays, and smaller abdominal scars.43 An advantage of open splenectomy in hematologic conditions such as the treatment of immune thrombocytopenic purpura is the increased ease of searching assiduously for accessory spleens.
Partial splenectomy has been explored because it may minimize the risks of immediate postsplenectomy thrombocytosis and overwhelming sepsis that may result from a complete absence of splenic function.44 However, the degree of thrombocytosis after splenectomy wanes to some degree with time postsplenectomy. Reduction of the splenic volume has been performed with ligation of some of the splenic arteries or the intraarterial infusion of Gelfoam particles causing embolization.45,46,47,48 These procedures induce large splenic infarcts and reduce the functional splenic mass. Arterial embolization can be performed percutaneously or intravascularly, but the patients must be observed closely for a number of days to weeks to detect signs of intraabdominal rupture of the splenic infarcts. The long-term results of embolization have been encouraging.46,47,48 Treatment with partial arterial embolization for recurrent thrombocytopenia in children temporarily improved the platelet count in approximately 70 percent of patients.49
Splenic radiation for treatment of an enlarged spleen is used sparingly. The procedure may be associated with severe cytopenias and especially thrombocytopenia (abscopal effect). It can be used in patients with an absolute contraindication to splenectomy who might benefit symptomatically from reduction of a massively enlarged spleen.50
Thrombopoietin synthesis and secretion are impaired in liver failure and this is corrected after liver transplantation.51,52 However, thrombocytopenia may not be corrected after liver transplant if the splenomegaly persists.
Thrombopoietin Receptor Agonists
After thrombopoietin was cloned53,54 several thrombopoietin mimetic drugs have been developed and tested. A phase II study reported that the oral thrombopoietin-receptor agonist (TPO-RA) eltrombopag increases platelet counts in patients with thrombocytopenia as a result of hepatitis C virus–related cirrhosis.55 A phase III study done in cirrhotic patients who received eltrombopag for 2 weeks prior to elective procedures had to be terminated prematurely because of the increased incidence of portal vein thrombosis in the treatment group compared to the placebo group. Although 72 percent of the eltrombopag patients avoided platelet transfusions compared to 19 percent of the placebo group patients, there was no significant difference in the incidence of major bleeding.56 A small study using the TPO-RA romiplostim administered subcutaneously in cirrhotic patients demonstrated the usefulness of the drug in reducing platelet transfusions in preparation for an elective surgical procedure.57
Erythropoietin and Granulocyte Colony-Stimulating Factor
There are minimal data to support the use of erythropoietic or myeloid growth factors in patients with splenomegaly and blood cytopenias. Patients with cirrhosis who have inappropriately low serum erythropoietin levels may benefit from treatment with exogenous erythropoietin; however, it may increase spleen size. Two reports documented the use of erythropoietin before and after liver transplantation to amplify marrow erythropoiesis in patients who refused blood transfusions for religious reasons.58,59 These reports demonstrated that liver transplantation in the setting of advanced cirrhosis can be successfully undertaken without the use of blood products.
A rise in the neutrophil count after G-CSF administration was described in patients with cirrhosis and leukopenia. The mean absolute neutrophil count increased from 1300 ± 200/μL to 4100 ± 200/μL following subcutaneous administration of G-CSF for 7 days.19 However, the clinical benefit of such treatment is not clear.