improved neutrophil function.73

Hereditary Spherocytosis

Hereditary spherocytosis, also known as congenital hemolytic jaundice or familial hemolytic anemia, is

an autosomal dominant disease that is the most common of the congenital hemolytic anemias affecting

1 in 5,000 individuals.74 There are a variety of genetic defects in this syndrome that primarily affect

spectrin and ankyrin that alter the binding of the cytoskeleton to the erythrocyte cellular membrane

causing decreased cellular plasticity with membrane loss.75 The normal shape of the erythrocyte is

changed from the biconcave disc into a sphere and the decreased membrane-to-volume cell ratio causes

a lack of deformability that impacts the passage of erythrocytes through channels of the splenic red

pulp. Because of this delay in cell transit, there is ATP deprivation resulting in increased cellular

destruction. The condition is more frequent in Caucasians and in African Americans and is usually noted

in the childhood or adolescent ages. Since it is an autosomal dominant inheritance, patients may be

screened and diagnosed at quite an early age.

The diagnosis is primarily made by evaluation of the red cell smear showing a large number of

spherocytes. Spherocytes may also appear during autoimmune hemolytic anemias but in hereditary

spherocytosis the Coombs test is negative and an osmotic fragility test may be performed which is

diagnostic. Also, contributing to the diagnosis is a positive family history.

Patients with hereditary spherocytosis have mild to moderate anemia, splenomegaly, and jaundice.

The patients may have intermittent flares of disease that cause significant increased rates of hemolysis

causing jaundice. Between 30% and 60% of patients have been reported to have pigmented gallstones

due to the breakdown of hemoglobin.74

The treatment for hereditary spherocytosis is splenectomy that is indicated in virtually all patients.76

This treatment does not remove the spherocytes but it relieves all symptoms.77 The major question

involving management of these patients is the timing of splenectomy. Because of the increased

incidence of overwhelming postsplenectomy sepsis in very young children, it is usually recommended

that patients wait until after the age of at least 4 if not 6 years prior to splenectomy. For younger

patients who are very symptomatic and require splenectomy, partial splenectomies have been reported

to be beneficial in relieving the abdominal symptoms as well as the anemia and may be a useful

alternative procedure until patients reach an age in which total splenectomy is safer.78 Patients with

partial splenectomies had regrowth of tissue but with short term did not have recurrent anemia.69

Patients should be assessed at the time of scheduling a splenectomy for the presence of gallstones and a

laparoscopic cholecystectomy should be performed if stones are identified.

Hereditary Elliptocytosis

Hereditary elliptocytosis is a disease that is related to hereditary spherocytosis although not as severe.

For patients who are symptomatic, virtually all of the same comments regarding pathophysiology and

treatment can be made about hereditary elliptocytosis as for hereditary spherocytosis. This disease is

also inherited in an autosomal dominant pattern and the defect is felt to be present in spectrin. The

predominant abnormality changes spectrin such that it exists as a dimer instead of tetramer that is the

normal structure. This change leads to an alteration in membrane plasticity that creates cells that are

more elliptically shaped instead of a biconcave disc.

The signs and symptoms caused in this disease are much more mild than hereditary spherocytosis in

that only 10% of patients have clinical manifestations of anemia, splenomegaly, and in some cases

jaundice. The treatment recommendation for symptomatic patients is splenectomy again, which may be

performed with laparoscopic techniques and also cholecystectomy if gallstones are present.

Hereditary Nonspherocytic Hemolytic Anemia

There is a heterogeneous group of rare hemolytic anemias caused by inherited defects primarily

enzymes involved in glycolysis. It is felt that these genetic defects may decrease cellular energy

production leading to increased red cell destruction as these cells pass through the relatively hypoxic

environment of the red pulp of the spleen. The most common subtypes in this group of hemolytic

anemias are pyruvate kinase deficiency and glucose 6-phosphate dehydrogenase (G6PD) deficiency.

Patients present with anemia, jaundice, increased reticulocytes, and possibly cholelithiasis. The

diagnosis can be facilitated in that the shape of the cell does not show typically spherocytes and there is

normal osmotic fragility.

The primary treatment for these diseases is blood transfusion. In G6PD deficiency, splenectomy is not

2002

felt to be beneficial whereas it may reverse some of the symptoms associated with pyruvate kinase

deficiency.

Thalassemia

Thalassemia is an autosomal dominant disease with a variety of structural defects in one of the globin

chains. The disease is categorized as these are alpha, beta, gamma, or delta thalassemia, depending on

which of the globin chains is defective. The vast majority of patients in North America have beta

thalassemia. Thalassemia major, otherwise known as Mediterranean anemia or Cooley anemia, is a

homozygous expression of this genetic defect. Thalassemia minor is a heterozygous expression and these

patients are only mildly symptomatic and are carriers for the more severe form of the disease.

The pathophysiology of thalassemia major or beta thalassemia is the lack of production of normal

beta-chain hemoglobin leading to a surplus of alpha-chain hemoglobin in adult patients. These excess

globin chains precipitate in the cytoplasm and attach to the inner surfaces of cytoplasmic membrane

leading to poor passage of these cells through the splenic sinusoids. This intracellular inclusion then

leads to increased destruction and over time causes significant splenomegaly due to this increased

clearance of red cells.

The diagnosis is made by identifying microcytic hypochromic anemia with target cells and an increase

in reticulocytes on the peripheral smear. Protein electrophoresis will show very low levels of

hemoglobin A with predominant amounts of the fetal hemoglobin or hemoglobin F. The clinical

symptom of alpha-thalassemia major is severe anemia within the first year of life. Decreased growth

rate, enlargement of the head, splenomegaly, and hepatomegaly are the typical clinical findings.79

The primary treatment for thalassemia major is frequent transfusions combined with iron chelation

therapy. Some patients may develop significant splenomegaly due to overload or hypertrophy from

excess trapping of red cells.80 Patients may be referred for splenectomy for symptomatic splenomegaly

or for patients with massive and frequent transfusion requirements. One report suggested that episodes

of transfusion are decreased from 18 per year down to 4 per year after splenectomy. In general, if there

are symptoms of massive splenomegaly, these will be resolved with splenectomy as well. As with other

hematologic disorders in children, there has been a recent trend toward partial splenectomy particularly

in children younger than 4 to 5 years.81 This will result in symptomatic improvement in between 1 and

2 years with recurrent disease due to hypertrophy of the residual splenic remnant.82

Although splenectomy may be beneficial in terms of the transfusion requirements and local

symptoms, the typical mode of death with this disease is myocardial failure due to hemosiderin

accumulation. Splenectomy does not alter this cardiac problem to any great extent. In fact, recent data

suggest that splenectomy in thalassemia patients increases vascular complications.

Sickle Cell Anemia

Sickle cell anemia is a hereditary hemolytic anemia that is due to a genetic alteration of a single amino

acid substitution in the beta chain. This results in a change from glutamic acid to valine in the sixth

amino acid position of the beta chain of hemoglobin molecule. Because of this substitution, patients who

are homozygous for sickle cell defect have a characteristic stiffening or sickling of the red blood cells

when they become hypoxic.83 This change in red cell shape leads to blockage in hypoxic areas such as

the red pulp of the spleen. There can occasionally be sequestration crises in which a portion of the blood

volume gets actively trapped or sequestered to the spleen during the sickle cell crisis. This pattern of

red cell shape change in relatively hypoxic areas can lead to tissue infarction with bone pain, hematuria,

abdominal pain, and priapism.

The incidence of this disease, which almost exclusively occurs in the black population, is

approximately 0.5% for homozygous disease, with approximately 8% of African Americans being

carriers for the sickle cell trait. Patients who have a combination of a sickle cell allele as well as a beta

thalassemia allele manifest a similar disease process.

The clinical signs of the disease usually present during the second 6 months of life as in early infancy

the patient is asymptomatic due to the presence of fetal hemoglobin. The patients may have acute crises

with abdominal pain and bone pain in conjunction with significant anemia. During acute crises of

splenic sequestration, there may be massive enlargement of the spleen with an urgent decompressive

splenectomy required. Patients who do not need splenectomy for splenic sequestration may be followed

as this disease goes through a natural progression of ischemic necrosis of large areas of the spleen with

eventual hyposplenism with a shrunken organ by early adolescence. Splenectomy is reserved for the

very young patients who have massive splenomegaly in sequestration crises early in life.

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Wiskott–Aldrich Syndrome

Wiskott–Aldrich syndrome is an X-linked disease characterized by thrombocytopenia, combined B- and

T-cell deficiency, eczema, and a propensity to develop other malignancies. The genetic defect in this

disease is felt to be related to an abnormal adhesion molecule affecting immune cell interaction as well

as platelet adhesion. Thrombocytopenia is the major problem with this rare disease and most patients

present with manifestations of poor clotting, bloody diarrhea, epistaxis, and petechiae at a young age.

The platelet counts typically range between 20,000 and 40,000 and the platelets that are present are

dysfunctional being small sized, 25% to 50% of normal platelet volume. In this disease, the spleen

sequesters platelets and partially degrades them releasing “microplatelets” back into the circulation.84

Splenectomy in the Wiskott–Aldrich syndrome was initially avoided as there was a very problematic

postoperative course characterized by severe and fatal infections due to the underlying

immunodeficiency combined with the potential for overwhelming postsplenectomy infection. However,

splenectomy does increase the number, size, and function of platelets and can lead to amelioration of

the bleeding problems in very symptomatic patients.84 The combination of splenectomy with antibiotic

suppression particularly in younger patients may be beneficial. The optimal treatment of Wiskott–

Aldrich syndrome is an human leukocyte antigen (HLA) match sibling bone marrow transplantation.85

However, splenectomy with antibiotics results in better survival than unmatched bone marrow

transplantation. Patients who do not undergo bone marrow transplantation or splenectomy typically do

not survive past the age of 5 years. The pathology of spleens removed for Wiskott–Aldrich syndrome

shows a near complete depletion of white pump supporting the clinical immune deficiency seen in this

syndrome.86

Hypersplenisim

7 Hypersplenism is a physical enlargement of the spleen that can be broadly categorized as the

neoplastic disorders, hematopoietic disorders of the bone marrow, and metabolic or storage disorders.

In neoplastic disorders, the spleen is infiltrative and large typically by leukemic or lymphoma cells. This

often happens in the mid or late course of a person’s disease but can be associated with isolated

splenomegaly in which the splenectomy is performed not only to treat hypersplenism, but also to make

the definitive diagnosis (see Diagnostic Splenectomy section below). Hypersplenism can be associated

with diseases of hematopoiesis related to myeloid metaplasia in which the bone marrow is infiltrated

with fibrotic material and the spleen becomes a site of secondary non–bone marrow hematopoiesis.

Enlargement can lead to symptoms of hypersplenism due to the massive size of the spleen and often the

benefits of extramedullary hematopoiesis are outweighed by the sites of circulating blood cell

destruction in this enlarged spleen. Secondary hyperplenism can also occur when there is deposition of

lipid within the spleen such as in Gaucher disease leading to enlargement that can cause pancytopenia.

Each of these categories of secondary hypersplenism is associated with pancytopenia and mass effect of

the spleen causing early satiety and weight loss. These disorders typically lead to spleen size more than

1,500 g and can produce spleens that essentially fill the entire left side of the abdomen.

Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the most common of all chronic leukemias. It predominantly

affects males more than females with 2:1 predominance and has a peak incidence in the sixth decade of

life or older. This indolent disease presents with fatigue, lymphadenopathy, hepatosplenomegaly, and

eventually anemia and thrombocytopenia. The disease progression may occur over a 5- to 10-year

period.

2004