Hereditary spherocytosis

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.

Symptoms
As in non-hereditary spherocytosis, 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).

Diagnosis
In a peripheral blood smear, the abnormally small red blood cells 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 transfusions, 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.

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 mutations. 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.

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 spherocytosis, acute symptoms of anemia and hyperbilirubinemia indicate treatment with blood transfusions 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.

Prevalence
It is the most common (1 in 2,000 of Northern European ancestry) disorder of the red cell membrane.