Hereditary spherocytosis
Encyclopedia
Hereditary spherocytosis is a genetically-transmitted (autosomal dominant) form of spherocytosis
, an auto-hemolytic
anemia
characterized by the production of red blood cells that are sphere-shaped rather than bi-concave disk shaped (Donut-Shaped), and therefore more prone to hemolysis.
, the spleen's hemolysis results in observational symptoms of fatigue
, pallor
, and jaundice
.
The spleen
's hemolysis
results directly in varying degrees of anemia
and hyperbilirubinemia, which in turn result in symptoms of fatigue
, pallor
, and jaundice
.
Acute cases can threaten hypoxemia
through anemia
and acute kernicterus
through hyperbilirubinemia, particularly in newborns.Most cases can be detected soon after birth. An adult with this disease should be aware when they have children to have them tested, although if the child does it will probably be noticed soon after birth. Occasionally, the disease will not be noticed until the child is about 4 or 5 years of age.
Chronic symptoms include anemia
, increased blood viscosity, and splenomegaly
, a potentially life-threatening enlargement of the spleen
due to its increased activity. Furthermore, the detritus of the broken-down blood cells—unconjugated or indirect bilirubin
--accumulates in the gallbladder
, and can cause pigmented gallstones or "sludge" to develop. In chronic patients, an infection
or other illness can cause an increase in the destruction of red blood cells, resulting in the appearance of acute symptoms, a hemolytic crisis. Spherocytosis patients who are heterozygous for a hemochromatosis gene may suffer from iron overload despite the hemochromatosis genes being recessive (http://ukpmc.ac.uk/classic/articlerender.cgi?artid=1296185 and http://www.bcshguidelines.com/pdf/hereditaryspherocytosis.pdf page 10).
s lacking the central pallor as seen in non-hereditary spherocytosis is typically more marked in hereditary spherocytosis.
Other protein deficiencies cause hereditary elliptocytosis
, pyropoikilocytosis or stomatocytosis.
In longstanding cases and in patients who have taken iron
supplementation or received numerous blood transfusion
s, iron overload may be a significant problem, being a potential cause of cardiomyopathy
and liver disease
. Measuring iron stores is therefore considered part of the diagnostic approach to hereditary spherocytosis.
An osmotic fragility test can aid in the diagnosis. In this test, the spherocytes will rupture in mildly hypotonic solutions - this is due to increased permeability of the spherocyte membrane to salt and water.
s. A patient has a 50% chance of passing the mutation onto his/her offspring.
Hereditary spherocytosis is caused by a variety of molecular defects in the genes that code for spectrin
(alpha
and beta
), ankyrin
, band 3
protein, protein 4.2
, and other erythrocyte membrane proteins:
These proteins are necessary to maintain the normal shape of an erythrocyte, which is a biconcave disk. The integrating protein that is most commonly defective is ankyrin
which is responsible for incorporation and binding of spectrin, thus in its dysfunction cytoskeletal instabilities ensue. As the spleen normally targets abnormally shaped red cells (which are typically older), it also destroys spherocytes. In the spleen, the passage from the cords of Billroth
into the sinusoids may be seen as a bottleneck, where erythrocytes need to be flexible in order to pass through. In hereditary spherocytosis, erythrocytes fail to pass through and get phagocytosed, causing extravascular hemolysis.
, acute symptoms of anemia
and hyperbilirubinemia indicate treatment with blood transfusion
s or exchanges and chronic symptoms of anemia and splenomegaly
indicate dietary supplementation of folic acid and splenectomy
, the surgical removal of the spleen.
Experimental gene therapy
exists to treat hereditary spherocytosis in lab mice; however, this treatment has not yet been tried on humans due to all of the risks involved in human gene therapy.
To decrease the risk of sepsis
, post-splenectomy spherocytosis patients require immunization against the pneumococcus bacterium, influenza virus, and prophylactic antibiotic treatment when undergoing dental work or surgical procedures.
Spherocytosis
Spherocytosis is an auto-hemolytic anemia characterized by the production of red blood cells , or erythrocytes, that are sphere-shaped, rather than bi-concave disk shaped. Spherocytes are found in hereditary spherocytosis and autoimmune hemolytic anemia.It almost always refers to hereditary...
, an auto-hemolytic
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
characterized by the production of red blood cells that are sphere-shaped rather than bi-concave disk shaped (Donut-Shaped), and therefore more prone to hemolysis.
Symptoms
As in non-hereditary spherocytosisSpherocytosis
Spherocytosis is an auto-hemolytic anemia characterized by the production of red blood cells , or erythrocytes, that are sphere-shaped, rather than bi-concave disk shaped. Spherocytes are found in hereditary spherocytosis and autoimmune hemolytic anemia.It almost always refers to hereditary...
, the spleen's hemolysis results in observational symptoms of fatigue
Fatigue (physical)
Fatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...
, pallor
Pallor
Pallor is a reduced amount of oxyhaemoglobin in skin or mucous membrane, a pale color which can be caused by illness, emotional shock or stress, stimulant use, lack of exposure to sunlight, anaemia or genetics....
, and jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
.
The spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
's hemolysis
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
results directly in varying degrees of anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
and hyperbilirubinemia, which in turn result in symptoms of fatigue
Fatigue (physical)
Fatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...
, pallor
Pallor
Pallor is a reduced amount of oxyhaemoglobin in skin or mucous membrane, a pale color which can be caused by illness, emotional shock or stress, stimulant use, lack of exposure to sunlight, anaemia or genetics....
, and jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
.
Acute cases can threaten hypoxemia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
through anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
and acute kernicterus
Kernicterus
Kernicterus is damage to the brain centers of infants caused by increased levels of unconjugated bilirubin. This may be due to several underlying pathologic processes. Newborn babies are often polycythemic. When they break down the erythrocytes, one of the byproducts is bilirubin, which circulates...
through hyperbilirubinemia, particularly in newborns.Most cases can be detected soon after birth. An adult with this disease should be aware when they have children to have them tested, although if the child does it will probably be noticed soon after birth. Occasionally, the disease will not be noticed until the child is about 4 or 5 years of age.
Chronic symptoms include anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, increased blood viscosity, and splenomegaly
Splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
, a potentially life-threatening enlargement of the spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
due to its increased activity. Furthermore, the detritus of the broken-down blood cells—unconjugated or indirect bilirubin
Bilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
--accumulates in the gallbladder
Gallbladder
In vertebrates the gallbladder is a small organ that aids mainly in fat digestion and concentrates bile produced by the liver. In humans the loss of the gallbladder is usually easily tolerated....
, and can cause pigmented gallstones or "sludge" to develop. In chronic patients, an infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
or other illness can cause an increase in the destruction of red blood cells, resulting in the appearance of acute symptoms, a hemolytic crisis. Spherocytosis patients who are heterozygous for a hemochromatosis gene may suffer from iron overload despite the hemochromatosis genes being recessive (http://ukpmc.ac.uk/classic/articlerender.cgi?artid=1296185 and http://www.bcshguidelines.com/pdf/hereditaryspherocytosis.pdf page 10).
Diagnosis
In a peripheral blood smear, the abnormally small red blood cellRed blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s lacking the central pallor as seen in non-hereditary spherocytosis is typically more marked in hereditary spherocytosis.
Other protein deficiencies cause hereditary elliptocytosis
Hereditary elliptocytosis
Hereditary elliptocytosis, also known as ovalocytosis, is an inherited blood disorder in which an abnormally large number of the sufferer's erythrocytes are elliptical rather than the typical biconcave disc shape. It is one of many red-cell membrane defects. In its severe forms, this disorder...
, pyropoikilocytosis or stomatocytosis.
In longstanding cases and in patients who have taken iron
Iron
Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...
supplementation or received numerous blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
s, iron overload may be a significant problem, being a potential cause of cardiomyopathy
Cardiomyopathy
Cardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...
and liver disease
Liver disease
Liver disease is a broad term describing any single number of diseases affecting the liver.-Diseases:* Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons , autoimmunity or hereditary conditions...
. Measuring iron stores is therefore considered part of the diagnostic approach to hereditary spherocytosis.
An osmotic fragility test can aid in the diagnosis. In this test, the spherocytes will rupture in mildly hypotonic solutions - this is due to increased permeability of the spherocyte membrane to salt and water.
Pathophysiology
Hereditary spherocytosis is an autosomal dominant or recessive trait, most commonly (though not exclusively) found in Northern European and Japanese families, although an estimated 25% of cases are due to spontaneous mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s. A patient has a 50% chance of passing the mutation onto his/her offspring.
Hereditary spherocytosis is caused by a variety of molecular defects in the genes that code for spectrin
Spectrin
Spectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane of many cell types in pentagonal or hexagonal arrangements, forming a scaffolding and playing an important role in maintenance of plasma membrane integrity and cytoskeletal structure...
(alpha
SPTA1
Spectrin alpha chain, erythrocyte is a protein that in humans is encoded by the SPTA1 gene.-Interactions:Spectrin, alpha 1 has been shown to interact with Abl gene.-Further reading:...
and beta
SPTB
Spectrin beta chain, erythrocyte is a protein that in humans is encoded by the SPTB gene.-Further reading:...
), ankyrin
Ankyrin
Ankyrins are a family of adaptor proteins that mediate the attachment of integral membrane proteins to the spectrin-actin based membrane skeleton. Ankyrins have binding sites for the beta subunit of spectrin and at least 12 families of integral membrane proteins...
, band 3
Band 3
Anion Exchanger 1 or Band 3 is a phylogenetically preserved transport protein responsible for mediating the exchange of chloride for bicarbonate across a plasma membrane. Functionally similar members of the AE clade are AE2 and AE3.It is ubiquitous throughout the vertebrates...
protein, protein 4.2
Protein 4.2
Erythrocyte membrane protein band 4.2 is a protein that in humans is encoded by the EPB42 gene.Protein 4.2 is a cytoskeleton protein found in red blood cells.-External links:...
, and other erythrocyte membrane proteins:
| Type | OMIM | Gene | Locus |
|---|---|---|---|
| HS1 | ANK1 ANK1 Ankyrin 1, erythrocytic, also known as ANK1, is a protein which in humans is encoded by the ANK1 gene.-Tissue distribution:The protein encoded by this gene, Ankyrin 1, is the prototype of the ankyrin family, was first discovered in erythrocytes, but since has also been found in brain and... |
8p11.2 | |
| HS2 | SPTB SPTB Spectrin beta chain, erythrocyte is a protein that in humans is encoded by the SPTB gene.-Further reading:... |
14q22-q23 | |
| HS3 | SPTA SPTA SSTA may refer to*Scottish Primary Teachers' Association*Spectrin, alpha 1... |
1q21 | |
| HS4 | SLC4A1 | 17q21-q22 | |
| HS5 | EPB42 | 15q15 |
These proteins are necessary to maintain the normal shape of an erythrocyte, which is a biconcave disk. The integrating protein that is most commonly defective is ankyrin
Ankyrin
Ankyrins are a family of adaptor proteins that mediate the attachment of integral membrane proteins to the spectrin-actin based membrane skeleton. Ankyrins have binding sites for the beta subunit of spectrin and at least 12 families of integral membrane proteins...
which is responsible for incorporation and binding of spectrin, thus in its dysfunction cytoskeletal instabilities ensue. As the spleen normally targets abnormally shaped red cells (which are typically older), it also destroys spherocytes. In the spleen, the passage from the cords of Billroth
Cords of Billroth
The Cords of Billroth are found in the red pulp of the spleen between the sinusoids, consisting of fibrils and connective tissue cells with a large population of monocytes and macrophages...
into the sinusoids may be seen as a bottleneck, where erythrocytes need to be flexible in order to pass through. In hereditary spherocytosis, erythrocytes fail to pass through and get phagocytosed, causing extravascular hemolysis.
Complications
- Haemolytic crisis, with more pronounced jaundice due to accelerated haemolysis (may be precipitated by infection).
- Aplastic crisis with dramatic fall in haemoglobin level and (reticulocyte count)-decompensation, usually due to maturation arrest and often associated with megaloblastic changes; may be precipitated by infection, such as influenza, notably with parvovirus.
- Folate deficiency caused by increased bone marrow requirement.
- Pigment gall stone, in approximately half of untreated patients.
- Leg ulcer.
- Abnormally low results when testing mean blood glucose via Glycated hemoglobin.
Treatment
As in non-hereditary spherocytosisSpherocytosis
Spherocytosis is an auto-hemolytic anemia characterized by the production of red blood cells , or erythrocytes, that are sphere-shaped, rather than bi-concave disk shaped. Spherocytes are found in hereditary spherocytosis and autoimmune hemolytic anemia.It almost always refers to hereditary...
, acute symptoms of anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
and hyperbilirubinemia indicate treatment with blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
s or exchanges and chronic symptoms of anemia and splenomegaly
Splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
indicate dietary supplementation of folic acid and splenectomy
Splenectomy
A splenectomy is a surgical procedure that partially or completely removes the spleen.-Indications:The spleen, similar in structure to a large lymph node, acts as a blood filter. Current knowledge of its purpose includes the removal of old red blood cells and platelets, and the detection and fight...
, the surgical removal of the spleen.
Experimental gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
exists to treat hereditary spherocytosis in lab mice; however, this treatment has not yet been tried on humans due to all of the risks involved in human gene therapy.
To decrease the risk of sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
, post-splenectomy spherocytosis patients require immunization against the pneumococcus bacterium, influenza virus, and prophylactic antibiotic treatment when undergoing dental work or surgical procedures.