HISTORY

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.

DEFINITION

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

ONTOGENY

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.

PATHOPHYSIOLOGY

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.