AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Hereditary spherocytosis (HS) is a familial hemolytic disorder with marked heterogeneity of clinical features, ranging from an asymptomatic condition to fulminant hemolytic anemia. The morphologic hallmark of HS is the microspherocyte, which is caused by loss of membrane surface area, and an abnormal osmotic fragility in vitro. Investigation of HS has afforded important insights into the structure and function of cell membranes and into the role of the spleen in maintaining red blood cell (RBC) integrity. An intrinsic genetic defect causes defects in membrane proteins.

The major complications are aplastic or megaloblastic crisis, hemolytic crisis, cholecystitis and cholelithiasis, and severe neonatal hemolysis.

Pathophysiology

Hemolysis in HS results from the interplay of an intact spleen and an intrinsic membrane protein defect that leads to abnormal RBC morphology.

HS erythrocytes are caused by membrane protein defects resulting in cytoskeleton instability. Spectrin deficiency leads to loss of erythrocyte surface area, which produces spherical RBCs. Spherocytic RBCs are culled rapidly from the circulation by the spleen. Patients with HS develop splenomegaly. Biochemical spectrin deficiency and the degree of spectrin deficiency are reported to correlate with the extent of spherocytosis, the degree of abnormality on osmotic fragility test results, and the severity of hemolysis. Hemolysis primarily is confined to the spleen and, therefore, is extravascular. Spectrin deficiency is the result of impaired synthesis, whereas in other instances, it is caused by quantitative or qualitative deficiencies of other proteins that integrate spectrin into the cell membrane. In the absence of these binding proteins, free spectrin is degraded, leading to spectrin deficiency.

Four abnormalities in red cell membrane proteins have been identified and include (1) spectrin deficiency alone, (2) combined spectrin and ankyrin deficiency, (3) band 3 deficiency, and (4) protein 4.2 defects. Spectrin deficiency is the most common defect. Each is associated with a variety of mutations that result in different protein abnormalities and varied clinical expression. Most cases of HS are heterozygous because homozygous states are lethal.

Spectrin deficiency

Mutations of alpha-spectrin are associated with recessive forms of HS, whereas mutations of beta-spectrin occur in families with autosomal dominant forms of HS. Synthesis of alpha-spectrin is 3-fold greater than that of beta-spectrin. The excess alpha chains normally are degraded. Heterozygotes for alpha-spectrin defects produce sufficient normal alpha-spectrin to balance normal beta-spectrin production. Defects of beta-spectrin are more likely to be expressed in the heterozygous state because synthesis of beta-spectrin is the rate-limiting factor. Red cell membranes isolated from individuals with autosomal recessive HS have only 40-50% of the normal amount of spectrin (relative to band protein 3), whereas red cell spectrin levels range from 60-80% of normal in the autosomal dominant form of HS.

Identification of an alpha-spectrin mutation involves a point mutation at codon (969), resulting in an amino acid substitution (alanine [Ala]/aspartic acid [Asp]) at the corresponding site of alpha-spectrin in 50% of patients with severe recessive HS. Mutations involving the alpha-spectrin beta-spectrin gene also occur, each resulting in spectrin deficiency. The first identified point mutation leads to a defective binding of spectrin to protein 4.1. Several other beta-spectrin mutations have been identified. Some of these mutations result in impaired beta-spectrin synthesis. Others produce unstable beta-spectrins or abnormal beta-spectrins that do not bind to ankyrin and undergo proteolytic degradation.

Ankyrin defects

HS is described in patients with translocation of chromosome 8 or deletion of the short arm of chromosome 8 where the ankyrin gene is located, and patients with HS and deletion of chromosome 8 are shown to have a decrease in red cell ankyrin content. Ankyrin is the principal binding site for spectrin on the red cell membrane. Studies of cytoskeletal protein assembly in reticulocytes indicate that ankyrin deficiency leads to decreased incorporation of spectrin. In HS caused by ankyrin deficiency, a proportional decrease in spectrin content occurs, although spectrin synthesis is normal. Of particular interest, 75-80% of patients with autosomal dominant HS have combined spectrin and ankyrin deficiency and the 2 proteins are diminished equally.

Band 3 deficiency

Band 3 deficiency has been recognized in 10-20% of patients with mild-to-moderate autosomal dominant HS. These patients also have a proportionate decrease in protein 4.2 content on the membrane. In some people with HS who are deficient in band 3, the deficiency is considerably greater in older RBCs. This suggests that band 3 protein is unstable.

Protein 4.2 (pallidin) deficiency

Hereditary hemolytic anemia has been described in patients with a complete deficiency of protein 4.2. Spherocytes, elliptocytes, or sphero-ovalocytes have characterized RBC morphology. Deficiency of protein 4.2 in HS is relatively common in Japan. One that appears to be common in the Japanese population (protein 4.2 Nippon) is associated in the homozygous state with a red cell morphology described as spherocytic, ovalocytic, and elliptocytic. Another mutant protein 4.2 (protein 4.2 Lisboa) is caused by a deletion that results in a complete absence of protein 4.2. This is associated with a typical HS phenotype.

Frequency

United States

HS is the most common of the hereditary hemolytic anemias among people of Northern European descent. In the United States, the incidence of the disorder is approximately 1 case in 5000 people. However, this figure probably is an underestimate. Given that the incidence of HS in the United States is 1 case in 5000 people and that approximately 25% of all HS is autosomal recessive, calculations indicate that the HS silent carrier state might exist in 1.4% of the population.

• HS usually is transmitted as an autosomal dominant trait, and the identification of the disorder in multiple generations of affected families is the rule. Homozygosity for this dominantly transmitted HS gene has not been identified. This suggests that the homozygous state is incompatible with life. Twenty-five percent of all newly diagnosed patients do not demonstrate a dominant inheritance pattern. Parents of these patients do not have clinical or hematological abnormalities. New mutations have been implicated that may explain some of these sporadic cases.
• An autosomal recessive mode of inheritance also occurs. This is supported by the descriptions of families in which apparently healthy parents have had more than one affected child. This recessive pattern may account for 20-25% of all HS cases. It manifests only in individuals who are homozygous or compound heterozygous and often is associated with severe hemolytic anemia.

International

The disease is encountered worldwide, but its incidence and prevalence in other groups are not established clearly.

Mortality/Morbidity

• Anemia or hyperbilirubinemia may be of such magnitude as to require exchange transfusion in the neonatal period. Anemia usually is mild to moderate; however, sometimes it is very severe and sometimes it is not present. Splenomegaly is the rule, and palpable spleens have been detected in more than 75% of affected subjects. Severe hemolytic anemia requires red cell transfusions.
• In chronic congenital hemolytic anemia (ie, HS), long periods of asymptomatic disease depend on a fragile equilibrium in which the excessive destruction of cells is balanced by accelerated erythropoiesis. Disruption of this equilibrium can lead to rapid and dramatic falls in blood hemoglobin levels, producing an aplastic crisis. Most, if not all, aplastic crises are caused by infection with type B19 human parvovirus (HPV). In some cases, an abrupt increase in the rate of red cell destruction may occur, possibly because of increased splenic activity (hemolytic crisis). Another type of crisis develops because of complicating folate deficiency (megaloblastic crisis), to which patients with chronic hemolysis appear to be particularly prone. The onset of megaloblastic crises tends to be more gradual than that of aplastic or hemolytic crises and is unrelated to complicating infections.
• In patients with mild HS, cholelithiasis may be the first sign of an underlying red cell disorder. Cholelithiasis is common in HS. Gallstones of the pigment type (caused by bilirubin) may be found in very young children, but the incidence of gallstones increases markedly with age. A history of family members with cholelithiasis in the second or third decade of life is a clue to the possible presence of HS.

Race

• HS is the most common hereditary hemolytic anemia among people of Northern European descent. Its incidence and prevalence in other ethnic groups are not clearly established.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Anemia, jaundice, and splenomegaly are the clinical features of HS. However, signs and symptoms are highly variable. Anemia or hyperbilirubinemia may be of such magnitude as to require exchange transfusion in the neonatal period. The disorder also may escape clinical recognition altogether. Anemia usually is mild to moderate; however, sometimes it is very severe and sometimes it is not present.

• Children diagnosed early in life usually have a severe form of HS, thus resulting in their early presentation.
• Jaundice is likely to be most prominent in newborns. Approximately 30-50% of adults with HS had a history of jaundice during the first week of life. The magnitude of hyperbilirubinemia may be such that exchange transfusion is required. Beyond the neonatal period, jaundice rarely is intense. Icterus is intermittent and is associated with fatigue, cold exposure, emotional distress, or pregnancy. An increase in scleral icterus and a darker urine color commonly are observed in children with nonspecific viral infections.
• Usually, laboratory evidence of ongoing hemolysis exists. Splenomegaly is the rule, and palpable spleens have been detected in more than 75% of affected subjects. The liver is normal in size and function.
• A family history of HS is present, or the patient may report a history of a family member having had a splenectomy or cholecystectomy before the fourth decade of life.
• The signs and symptoms are those associated with all chronic hemolytic states, such as mild pallor, intermittent jaundice, and splenomegaly.
• Adults who remain undiagnosed usually have a very mild form, and they live with the HS remaining undetected until challenged by an environmental stressor.

Physical

• Moderate HS is the most common form. Moderate HS accounts for 60-75% of all HS cases. In most cases, the pattern of transmission is autosomal dominant, although recessive inheritance also is observed. It is associated with mild-to-moderate anemia, modest splenomegaly, and intermittent jaundice.
• Mild HS occurs in 20-30% of cases of autosomal dominant HS. Anemia generally is not present because the bone marrow is able to fully compensate for the persistent destruction of red cells. Little or no splenomegaly occurs. These patients usually are asymptomatic. They often are not diagnosed until later in life. They are identified as a result of hemolytic or aplastic episodes triggered by infection. The condition is identified only through family surveys.
• Severe HS occurs in approximately 5% of all patients with HS. Severe hemolytic anemia that requires red cell transfusions and an incomplete response to splenectomy characterize severe HS. The pattern of inheritance is recessive. The parents of a patient who is affected have no signs of HS or have only a mild increase in the reticulocyte count, a few spherocytes on peripheral blood smear, a minimally abnormal incubated osmotic fragility test result, or an abnormal spectrin content detected when using sensitive techniques.
• Other important clues are jaundice and upper right abdominal pain indicative of gallbladder disease. This is especially important if a family history positive for gallbladder disease is present.
• Any patient who presents with profound and sudden anemia and reticulocytopenia with the aforementioned physical findings also should have HS in the differential diagnosis.

Causes

An intrinsic genetic defect causes defects in membrane proteins. Hemolysis in HS results from the interplay of an intact spleen and an intrinsic membrane protein defect that leads to abnormal RBC morphology.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The classic laboratory features of HS include minimal or no anemia, reticulocytosis, an increased mean corpuscular hemoglobin concentration (MCHC), spherocytes on the peripheral blood smear, hyperbilirubinemia, and abnormal results on the osmotic fragility test.
• • RBC morphology is distinctive yet not diagnostic.
  • Anisocytosis is prominent, and the smaller cells are spherocytes.
  • Unlike the spherocytes associated with immune hemolytic disease and thermal injury, HS spherocytes are fairly uniform in size and density. Spherocytes are characterized by a lack of central pallor, decreased mean corpuscular diameter, and increased density.
  • Other biochemical changes of hemolysis also are present, including increased lactate dehydrogenase (LDH), increased unconjugated bilirubin, and decreased serum haptoglobin. RBC indices demonstrate an increase in MCHC.
• An increased MCHC obtained from an electronic cell counter is a characteristic feature of red cells in HS. MCHC values greater than the upper limit of normal (35-36%) are common. This increased MCHC is a result of mild cellular dehydration. The mean cell volume (MCV) in patients with HS actually is low. This relatively low MCV may reflect membrane loss and cell dehydration.
• The most sensitive test to help detect HS is the incubated osmotic fragility test performed after incubating RBCs for 18-24 hours under sterile conditions at 37°C.
• • Hemolysis of HS cells may be complete at a solute concentration that causes little or no lysis of normal cells.
  • Not uncommonly, some individuals with HS have a normal fresh osmotic fragility test result.
  • Osmotic fragility after prolonged incubation at 37°C usually is abnormal.
• Other laboratory tests used to diagnose HS include the autohemolysis test and the glycerol lysis test. These rarely are used and offer no advantage over the osmotic fragility test.
• Further characterizing the specific membrane lesion by looking for abnormalities in spectrin, ankyrin, pallidin, or band 3 is possible. However, these studies are not routine and are available only in select research laboratories.
• The initial workup if hemolysis is suggested should include the following:
• • Reticulocyte count
  • Lactate dehydrogenase
  • Fractionated bilirubin
  • Haptoglobin
  • Peripheral smear: Howell-Jolly bodies may be present, indicating remnant splenic tissue if the patient has had their spleen removed. Findings also may include megalocytosis.
  • Vitamin B-12 and folate: This should be measured to determine the nutritional stores during recovery from an aplastic crisis.
  • Herpes simplex virus, HPV type 19, and infectious mononucleosis: Testing for these may help identify an infectious etiology for the aplastic crisis.
• If the diagnosis is being made late in life, patients must have an evaluation of their total iron body stores, especially if the patient has a history of frequent blood transfusions. Liver dysfunction or cardiac problems may be present in patients with severe iron overload. This evaluation includes tests for iron stores and serum ferritin levels.

Imaging Studies

• If the patient presents with signs and symptoms of hemolysis in addition to right upper abdominal quadrant pain, fever, and leukocytosis, an ultrasound of the biliary tree should be performed to help exclude cholecystitis or cholelithiasis.

Procedures

• If an aplastic crisis is suggested, further evaluation of WBCs and platelets should be pursued. This may require a bone marrow biopsy and aspirate to rule out aplasia or megaloblastosis. Obtaining bone marrow aspirate for testing rarely is necessary except in cases of aplastic or megaloblastic crisis. Test results help evaluate marrow function and the development of the lineage.

Histologic Findings

Anemia, reticulocytosis, and spherocytosis on peripheral blood smear examination provide strong hints to suggest the diagnosis of HS. Spherocytic RBCs are not specific to HS. Autoimmune hemolytic anemia also may produce spherocytosis, which usually can be excluded by negative findings on a direct antiglobulin test.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

For practical purposes, the treatment of HS involves presplenectomy care, splenectomy, and postsplenectomy complications.

• Neonates with severe hyperbilirubinemia caused by HS are at risk for kernicterus, and these infants should be treated with phototherapy and/or exchange transfusion as clinically indicated.
  • Aplastic crises occasionally can cause the hemoglobin level to fall because of ongoing destruction of spherocytes that is not balanced by new RBC production. Red cell transfusions often are necessary.
  • Folic acid is required to sustain erythropoiesis. Patients with HS are instructed to take supplementary folic acid (1 mg/d) for life in order to prevent a megaloblastic crisis. During the first 6 years of life, if patients have compensated anemia, are growing well, and can keep up with their peers in most activities, limiting folic acid supplementation to 1 mg/d is prudent.
  • Subsequently, depending on the severity of the disease, splenectomy usually is curative, but not always. Some splenectomies fail because of accessory spleen, accidental autotransplantation of splenic tissue into the peritoneum during surgery, another hemolytic disorder, or splenosis. Failure to observe Howell-Jolly bodies may indicate the presence of functional splenic activity.
• Indications for splenectomy are not always clear.
• • Little doubt exists that patients with more severe anemia and symptoms and complications of HS should undergo splenectomy. Similarly, splenectomy can be deferred safely in patients with mild uncomplicated HS (hemoglobin level >11 g/dL).
  • No good studies have been performed that provide a basis for clinical judgments in patients with moderate asymptomatic HS (hemoglobin level 8-11 g/dL).
• Splenectomy usually is curative, except in the unusual autosomal recessive variant of HS.
• • Red cell survival is improved significantly but is not absolutely normal. The MCV usually falls, but the MCHC does not change significantly. Postsplenectomy blood changes include an increased hemoglobin level, decreased reticulocyte count, and the appearance of Howell-Jolly inclusion bodies and target cells. Leukocytosis and thrombocytosis are expected corollaries of splenectomy.
  • Fatal sepsis caused by capsulated organisms (eg, Streptococcus pneumoniae, Haemophilus influenzae) is a recognized complication in children who have had a splenectomy. The estimated rate of mortality from sepsis is approximately 200 times greater than that expected in the general population. Although most septic episodes have been observed in children whose spleens were removed in the first years of life, older children and adults also are susceptible.
  • A simultaneous cholecystectomy in patients with bilirubin stones may eliminate future complications and the need for a second operative procedure.
• Bilirubin gallstones are found in approximately 50% of patients with HS and frequently are present in patients with very mild disease. Therefore, periodic ultrasonic evaluation of the gallbladder should be performed. If surveillance ultrasound examination findings reveal gallstones, performing a prophylactic laparoscopic cholecystectomy seems reasonable. This procedure helps prevent significant biliary tract disease and, in some patients with mild HS, helps avoid the need for splenectomy.
• Children who are candidates for splenectomy include those with severe HS requiring red cell transfusions and those with moderate HS who manifest growth failure or other signs and symptoms of anemia. Splenectomy for children with HS should be performed when the child is older than 6 years.
• Another interesting approach has been the use of partial splenectomy to retain splenic immunologic function while at the same time reducing the rate of hemolysis.

Surgical Care

Generally, the treatment of HS involves presplenectomy care, splenectomy, and postsplenectomy complications. See Medical Care. A trend toward partial splenectomies exists in the pediatric population, which appears to control hemolysis and, at the same time, preserve splenic function.

Consultations

• Surgeon
• • Those patients with recurring episodes of severe hemolysis should be evaluated by a surgeon for possible splenectomy because splenectomy provides the greatest chance for control and possible cure of their disease.
  • Another reason for consulting a surgeon is for the complications of gallstone formation and for the prevention of formation in those patients with continued hemolysis.
• Hematologist
• • If the diagnosis is unclear after routine testing or the patient has severe episodes of hemolysis, consultation with a hematologist is warranted because the patient may have a variant of HS or more than one hemolytic disease.
  • A hematologist also may provide treatment advice directed at iron over load issues for patients who have an extensive transfusion history or for those who have been receiving prolonged oral iron supplementation.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Vitamins

These agents are essential for normal DNA synthesis.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Evaluation for splenectomy by a surgeon should take place. Consideration of a partial splenectomy can be sought if access to a surgeon experienced in this procedure is possible.

Further Outpatient Care

• After splenectomy, RBC survival improves dramatically, enabling most patients with HS to maintain a normal hemoglobin level.
• Ideally, splenectomy should not be performed until a child is older than 6 years because of the increased incidence of postsplenectomy infections with encapsulated organisms such as S pneumoniae and H influenzae in young children.

In/Out Patient Meds

• Lifelong folic acid supplementation is recommended for these patients secondary to low levels of chronic hemolysis. This is especially true for those who have not undergone splenectomy.

Complications

• Often, the patient has had multiple RBC transfusions. This occurs because of multiple hemolytic episodes or an inaccurate diagnosis. Iron overload can become a serious problem, resulting in liver dysfunction. Another cause of iron overload is the addition of oral iron supplementation for the anemia. If a patient presents with mild liver dysfunction, iron store studies should be performed.

Prognosis

• After splenectomy, RBC survival improves dramatically, enabling most patients with HS to maintain a normal hemoglobin level.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Occasionally, patients with HS are incorrectly diagnosed with Gilbert disease.
• Vaccination against pneumococcal organisms and H influenzae must be administered to patients prior to splenectomy and, indeed, probably to all patients with severe HS.
• If a partial splenectomy is performed, splenic function is preserved and vaccinations may be delayed until after surgery; however, the long-term data is not well established.

Special Concerns

• After splenectomy, all patients should have yearly immunizations updated as needed, especially those covering encapsulated organisms.
• All patients should be placed on supplemental folic acid replacement because of chronic hemolysis.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Agre P, Asimos A, Casella JF, McMillan C. Inheritance pattern and clinical response to splenectomy as a reflection of erythrocyte spectrin deficiency in hereditary spherocytosis. N Engl J Med. Dec 18 1986;315(25):1579-83. [Medline].
• Costa FF, Agre P, Watkins PC, et al. Linkage of dominant hereditary spherocytosis to the gene for the erythrocyte membrane-skeleton protein ankyrin. N Engl J Med. Oct 11 1990;323(15):1046-50. [Medline].
• Gallagher PG. Hematologically important mutations: ankyrin variants in hereditary spherocytosis. Blood Cells Mol Dis. Nov-Dec 2005;35(3):345-7.
• Glader BE, Naumovski L. Hereditary red blood cell disorders. In: Emery AE, Rimoin, DL, eds. Principles and Practice of Medical Genetics. New York, NY:. Churchill Livingstone;1996.
• Hassoun H, Palek J. Hereditary spherocytosis: a review of the clinical and molecular aspects of the disease. Blood Rev. Sep 1996;10(3):129-47. [Medline].
• Hassoun H, Vassiliadis JN, Murray J, et al. Hereditary spherocytosis with spectrin deficiency due to an unstable truncated beta spectrin. Blood. Mar 15 1996;87(6):2538-45. [Medline].
• Korones D, Pearson HA. Normal erythrocyte osmotic fragility in hereditary spherocytosis. J Pediatr. Feb 1989;114(2):264-6. [Medline].
• Lee RD, Glader JN, Lukens JN. In: Lee GR, Foerster J, Lukens J, Paraskevas F, Greer JP, Rodgers GM, eds. Wintrobe's Clinical Hematology. 10th ed. Baltimore, Md: Lippincott Williams & Wilkins; 1999:. 1132-42.
• Nakashima K, Beutler E. Erythrocyte cellular and membrane deformability in hereditary spherocytosis. Blood. Mar 1979;53(3):481-5. [Medline].
• Peters LL, Lux SE. Ankyrins: structure and function in normal cells and hereditary spherocytes. Semin Hematol. Apr 1993;30(2):85-118. [Medline].
• Rice HE, Oldham KT, Hillery CA, et al. Clinical and hematologic benefits of partial splenectomy for congenital hemolytic anemias in children. Ann Surg. Feb 2003;237(2):281-8.
• Sackey K. Hemolytic anemia: Part 2. Pediatr Rev. Jun 1999;20(6):204-8. [Medline].
• Sackey K. Hemolytic anemia: Part 1. Pediatr Rev. May 1999;20(5):152-8; quiz 159. [Medline].
• Savvides P, Shalev O, John KM, Lux SE. Combined spectrin and ankyrin deficiency is common in autosomal dominant hereditary spherocytosis. Blood. Nov 15 1993;82(10):2953-60. [Medline].
• Stoehr GA, Stauffer UG, Eber SW. Near-total splenectomy: a new technique for the management of hereditary spherocytosis. Ann Surg. Jan 2005;241(1):40-7.

Article Last Updated: Jun 14, 2006