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Hereditary Spherocytosis: Review of the Genetic Disorder

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  • Ginamar Galvan

Abstract

This review is on the studies of several scientists whom completed research on the genetic disorder, spherocytosis. Based on several articles in the literature, it was learned that spherocytosis is an inherited anemia caused by the dysfunction of the cell’s cytoskeleton. These articles provide information of hereditary spherocytosis comprising of the disorder on the molecular level and how the patient’s diagnosis is concluded using laboratory testing. Patients can be found to be affected on a certain level ranging from mild to severe. They are then prescribed remedial medical attention pertaining to their level. The research showed that a form of response is to undergo a splenectomy which can ease a patient’s ailment, but has been found to not correct the life span of erythrocytes unlike speculation that it did.

Hereditary Spherocytosis: A Review on the Genetic Disorder

Introduction

Hereditary spherocytosis is an anemic disorder affecting the blood that causes erythrocytes to be produced as spheres while normal erythrocytes are shaped as concave disks. The spheroidal shape is caused by a loss of membrane surface relative to intracellular volume (Gallagher 2005). Spherocytosis is genetically based, meaning that it can be passed down from either parent who already encompasses the disorder. This disorder can be found in all racial classifications but is more prevalent in Caucasians (Oliveira et.al 2012). Spherocytosis in Northern Europe and North America have a 1 in 5000 births in reported incidences and is usually the cause of inherited chronic hemolysis (Huq et al., 2010 and Bolton-Maggs et al., 2004). In the reviewed literature, spherocytosis has been researched and discussed regarding various aspects of this disorder, including the functionality of erythrocytes and what occurs after diagnosis.

Cellular Level of Spherocytosis

In 1871, hereditary spherocytosis was first explained and the first splenectomy was also performed shortly after (Bolton-Maggs et al., 2004). Between family members, the expression of spherocytosis is somewhat similar but the degree of severity differs throughout. The cause of the irregular shape and lifespan of the erythrocytes is the defect of an element in the cytoskeleton which is made of proteins in which the vertical attachment of the proteins to the lipid bilayer membrane is affected and therefore it is weakened (Bolton-Maggs et al., 2004).

Other elements that influence the shape of the cell includes problems with spectrin, ankyrin, band 3 and/or protein 4.2 and the severity of the disorder is influenced by how many of these proteins are affected (Bolton-Maggs et al., 2004). Sodium dodecyl sulfate-polyacrylamide gel electrophorese is used as to determine whether or not these proteins have deficiencies. The defects in the genes of spherocytosis are present in five genes in chromosomes 1, 8, 14, 15 and 17 (Oliveira et al., 2012). Dysfunctions of these genes affect the membrane of the red blood cell which can threaten the cytoskeleton which is meant to maintain the form and elasticity of the cell. When the cytoskeleton is infringed upon, the red cell becomes abnormally shaped and does not live as long as a normal healthy cell (Oliveira et al., 2012). According to the article, “Guidelines for diagnosis and management of hereditary spherocytosis”, a hundred and seventy-four individuals were recruited from a hundred and twenty-three families and spectrin-deficient pro-bands were a larger cause than any other protein defect in patients when compared to parents who were seemingly regular.

Diagnosis of Spherocytosis

Hereditary spherocytosis is usually diagnosed when the patient is a child who has a varying extent of anemia, jaundice, and splenomegaly (Bolton-Maggs et al., 2004). Family history is also very important when diagnosing because in most cases seventy-five percent of patients will have a family history of the disorder (Gallagher 2010). There are different varieties at which hereditary spherocytosis affects people and treatments can sometimes require blood transfusions. Complications may develop which include severe anemia which may cause growth delay, deferred sexual maturation, tumors, and skin ulcers and many of these patients are transfusion dependent (Gallagher 2010).

The patients that participated in the clinical study at the Pediatric Hematology Center of Hospital das Clínicas, Universidade Federal de Minas Gerais in the journal, “Clinical course of 63 children with hereditary spherocytosis: a retrospective study”, were followed for about 19 years and had scheduled follow ups for every three months or in some cases more often if it was deemed necessary. They were diagnosed based upon their clinical history, physical examination and tests done in the laboratory and family histories were studied. Patients were classified as mild, moderate or severe depending on their hemoglobin concentration, bilirubin concentration and reticulocyte count and were also screened by ultrasonography to see if they had cholelithiasis. Splenectomy happened when there is an increase in the size of the organ and hemoglobin is decreased while reticulocyte count increased. Ones that needed a spleen sequestration were given immunizations and penicillin. When hemoglobin and reticulocyte count both decreased the patient was categorized to be in aplastic crisis.

Most patients have somewhat balanced hemolysis accompanied by slight to average anemia. Anemia can be asymptomatic except for some fatigue and jaundice occurs in patients about half of the time which is usually in association with viral infections (Gallagher 2010). When some patients’ erythrocytes are stressed, patients may notice symptoms because their body is compensating with amplified erythropoiesis for their hemolysis (Gallagher 2010).

In the journal, “Guidelines for diagnosis and management of hereditary spherocytosis”, several laboratory tests were used for diagnosis which includes osmotic fragility, acidified glycerol lysis test, osmotic gradient ektacytometry, and eosin-5-maleimide binding. Osmotic fragility is affected by elevated reticulocyte count while acidified glycerol lysis test detects autoimmune hemolytic anemia, hereditary persistence of fetal haemoglobin, pyruvate kinase and glucose-6-phosphate dehydrogenase deficiency as well as chronic renal failure. The osmotic gradient ektacytometry measures red cell deformability and the eosin-5-maleimide binding shows distinct histograms for red blood cells of spherocytosis. And in the journal, “Clinical course of 63 children with hereditary spherocytosis: a retrospective study”, the tests in the laboratory include the patient’s complete blood count, smear, reticulocyte count, concentration of bilirubin, positive osmotic fragility test and negative direct antiglobulin test. The osmotic fragility of the patients’ looked at the red blood cells in tubes that were washed in mixtures of increasing sodium chloride concentrations that were either put in incubation for 24 hours or not.

Treatment of Spherocytosis

There are ways to manage hereditary spherocytosis such as using folate therapy if the patient is severe, routine observation, frequent blood tests and in some cases splenectomy.

Splenectomy can improve anemia in most patients including even the most severe. The splenectomy can be performed laproscopically and is the more preferred method because it causes less discomfort after the surgery, quicker recovery time, shorter hospitalization, and decreased costs. Splenectomy complications can occur including infection, bleeding and pancreatitis (Gallagher 2010). This operation used to be considered routine in hereditary spherocytosis patients but now is being reconsidered concerning the complications that can arise. The patients that usually receive a splenectomy are diagnosed to be severe or are older patients whose vital organs are inhibited vascularly (Gallagher 2010). Moderate patients possess more options and may not need a splenectomy.

In “Clinical course of 63 children with hereditary spherocytosis: a retrospective study”, when patients were followed up, thirty-five patients needed transfusions and the need for them was more common in the severity group. Fourteen needed spleen sequestration, three had aplastic crisis, twenty-two had a splenectomy, seventeen developed cholelithiasis and ten had a cholecystectomy. Patients had different degrees of jaundice and anemia while most had some enlargement of the spleen. About 2/3 of the patients were anemic and seventy percent had splenomegaly. Patients that were classified as severe were younger and needed more blood transfusions than the other groups. A viral infection could lead to an overestimated severe classification because anemia level rises. All the patients were told and arranged to take folic acid.

Does Splenetomy return Red Cell life span to normal?

In some patients, anemia, reticulocytosis, and hyperbilirubinemia may disappear and cause some to infer that the patient no longer has problems with their red cell survival rate (Chapman 1968). Using a micro-hematocrit the hematocrit was determined, the reticulocytes were found in a methylene blue contained cover slip smear, and the red cell was counted by an electronic counter (Chapman 1968). The red cells that were being circulated were labeled with Diisopropyl fluorophosphates. DF32P were given to eleven patients that had a splenectomy two to twenty seven years before.

The mean cellular hemoglobin content and concentration were higher in males than females. The concentration was of a normal degree in the females and above normal in all but one of the males (Chapman 1968). Mean red blood cell life spans were determined by the disappearance of radioactivity from the circulating blood by calculating linear regression.

From the evidence the life span of the red blood cells seems to be somewhat dependent on age after their splenectomy. Patients that are within the same family do not show any consistency of the degree of spherocytosis expression. The red blood cell life span was averaged at about ninety-six days when normal life span is about one hundred twenty-three days (Chapman 1968). The range of life span between the patients ranged from seventy-six to one hundred eighteen days. From these results it is inferred that splenectomy does not repair red blood cell life span.

Conclusion

Hereditary spherocytosis is often identified in a patient’s childhood or early adult life, although, spherocytosis can be diagnosed at any age conditional to the entirety. This molecular disorder impacts their quality of life regarding aspects of treatment, finances, stress and recovery. As discoveries are made in this area of research, individuals will have a greater knowledge of spherocytosis and advancement in the treatment of this disorder including more options.

References

Bolton-Maggs, P. H. B., Stevens, R. F., Dodd, N. J., Lamont, G., Tittensor, P., & KIng, M. -. (2004). Guidelines for the diagnosis and management of hereditary spherocytosis.British Journal of Haematology, (126), 455-474. Retrieved from http://www.bloodmed.com/contentimage/guidelines/2121.pdf

Chapman, R. G. (1968). Red cell life span after splenectomy in hereditary spherocytosis.The Journal of Clinical Investigation,47(10), 2263–2267. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC297390/

Gallagher, P. (2005). Red Cell Membrane Disorders. Hematology 2005, 2005(1), 13-18. Retrieved , from http://asheducationbook.hematologylibrary.org/content/2005/1/13.long

Huq, S., Pietroni, M. A. C., Rahman, H., & Alam, M. T. (2010). Hereditary spherocytosis.J Health Popul Nutr.,28(1), 107-109. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2975852/

Oliveira, M. C. L. A., Fernandes, R. A. F., Rodrigues, C. L., Ribeiro, D. A., Giovanardi, M. F., & Viana, M. B. (2012). Clinical course of 63 children with hereditary spherocytosis: a retrospective study.Rev Bras Hematol Hemoter,34(1), 9-13. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459613/pdf/rbhh-34-009.pdf


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