Hereditary spherocytosis

Hereditary spherocytosis is a congenital hemolytic disorder wherein a genetic mutation coding for a structural membrane protein phenotype causes the red blood cells to be sphere-shaped, rather than the normal biconcave disk shape. This abnormal shape interferes with the cells' ability to flex during blood circulation, and also makes them more prone to rupture under osmotic stress, mechanical stress, or both. Cells with the dysfunctional proteins are degraded in the spleen, which leads to a shortage of erythrocytes and results in hemolytic anemia.
HS was first described in 1871, and is the most common cause of inherited hemolysis in populations of northern European descent, with an incidence of 1 in 5000 births. The clinical severity of HS varies from mild, to moderate, to severe, because HS is caused by genetic mutations in a multitude of structural membrane proteins and exhibits incomplete penetrance in its expression.
Early symptoms include anemia, jaundice, splenomegaly, and fatigue. Acute cases can threaten to cause hypoxia secondary to anemia and acute kernicterus through high blood levels of bilirubin, particularly in newborns. Most cases can be detected soon after birth. Testing for HS is available for the children of affected adults. Occasionally, the disease will go unnoticed until the child is about 4 or 5 years of age. A person may also be a carrier of the disease and show no signs or symptoms of the disease. Late complications may result in the development of pigmented gallstones, which is secondary to the detritus of the broken-down blood cells accumulating within the gallbladder. Also, patients who are heterozygous for a hemochromatosis gene may exhibit iron overload, despite the hemochromatosis genes being recessive. 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. On a blood smear, Howell-Jolly bodies may be seen within red blood cells. Primary treatment for patients with symptomatic HS has been total splenectomy, which eliminates the hemolytic process, allowing for normal hemoglobin, reticulocyte and bilirubin levels. The resultant asplenic patient is susceptible to encapsulated bacterial infections, the risk of which can be reduced with vaccination. If other symptoms such as abdominal pain persist, the removal of the gallbladder may be warranted for symptomatic cholelithiasis.

Epidemiology

Hereditary spherocytosis is the heritable hemolytic disorder, affecting 1 in 2,000 people of Northern European ancestry. According to Harrison's Principles of Internal Medicine, the frequency is at least 1 in 5,000 within the United States of America. While HS is most commonly found in Northern European and Japanese families, an estimated 25% of cases are due to spontaneous mutations.

Etiology

Hereditary spherocytosis is an erythrocytic disorder of that affects the following red cell membrane proteins in a congenital fashion:

Spectrin
Ankyrin
Band-3 protein
Protein-4.2
Lesser proteins of significance

Hereditary spherocytosis can be an autosomal recessive or autosomal dominant trait. The autosomal recessive inheritance pattern accounts for close to 25% of the clinical cases. The autosomal dominant inheritance pattern accounts for over 75% of the clinical cases. Many positive individuals will not present clinically, thus the etiologic data may be artificially skewed towards the more prominent dominant forms. These dominant forms tend to leave a family history that yields generational splenectomies and black gallstones cholelithiasis. Lastly, an estimated 25% of cases are due to spontaneous mutations.

Pathophysiology

Causative genetic mutations and phenotypic expressions

Hereditary spherocytosis is caused by a variety of molecular defects in the genes that code for the red blood cell proteins spectrin, ankyrin, band 3 protein, protein 4.2, and other red blood cell membrane proteins:
*Online Mendelian Inheritance in Man. The Alpha-1 refers the alpha-1 subunit of the spectrin protein. The Beta refers the beta subunit of the spectrin protein.
These genetic mutations are acted upon and executed by erythrocyte progenitor cells within the bone marrow, where red blood cells are normally produced in the non-pathological state.

Pathophysiology of mutated erythrocytic membrane proteins

These proteins are necessary to maintain the normal shape of a red blood cell, which is a biconcave disk. The integrating protein that is most commonly defective is spectrin which is responsible for incorporation and binding of spectrin to the greater actin cytoskeleton. This dysfunction of cytoskeletal instabilities ensue, and leave the plasma membrane of the cell less supported and/or weakened.

Erythrocyte Membrane Protein	Protein Function Compromised	Process Effect	Pathogenesis of HS	Likelihood	Mechanical Effect
Spectrin	Alpha-1 subunit actin association	Failure in plasma membrane tethering to actin cytoskeleton.	Caption: The deficiency of alpha-1* subunits in spectrin protein network. The resulting failed or weakened tethering of Spectrin interior to the plasma membrane to the greater actin cytoskeleton.*	Most Common	Erythrocytic plasma membrane loss. Formation of spherocytes. Decreased surface area. Decreased plasma membrane compliance. Fragility Hemolysis
Spectrin	Hydrophobic interactions and electrostatic attraction to ankyrin and actin	Failure in plasma membrane tethering to actin cytoskeleton.	Caption: The deficiency of Beta* subunits in spectrin protein network. The resulting failed or '*weakened tethering of Spectrin interior to the plasma membrane to the greater actin cytoskeleton.	Most Common	Erythrocytic plasma membrane loss. Formation of spherocytes. Decreased surface area. Decreased plasma membrane compliance. Fragility Hemolysis
Ankyrin	Hydrophobic interactions and electrostatic attraction to Beta subunit	Failure to mediate anchorage of integral plasma membrane proteins to spectrin.	Caption: The deficiency of ankyrin that normally associates with plasma membrane proteins. The resulting failed or weakened anchorage of spectrin to interior plasma membrane, and subsequently weakened association between the greater actin cytoskeleton and the plasma membrane.	Common	Erythrocytic plasma membrane loss. Formation of spherocytes. Decreased surface area. Decreased plasma membrane compliance. Fragility Hemolysis
Band-3	Failure to mediate the exchange of chloride with bicarbonate across plasma membranes.	Deficiency causes reduced lipid-stabilization at the plasma membrane.	Caption: The deficiency of band-3 protein. The resulting destabilized plasma membrane without integral band-3 protein for association with protein-4.2 and subsequently ankyrin.	Less Common	Erythrocytic plasma membrane loss. Formation of spherocytes. Decreased surface area. Decreased plasma membrane compliance. Fragility Hemolysis
Protein-4.2	Failure of ATP binding that regulates the association of band-3 with ankyrin.	Reduced density of plasma cell membrane skeleton, destabilizing the plasma lipid bilayer, thus releasing band-3 protein-containing microvesicles.	Caption: The deficiency of protein-4.2. The resulting inability of the greater actin cytoskeleton to associate with the plasma membrane via spectrin and ankyrin, and the subsequent loss of Band-3 Protein within microvesicles'.	Least Common	Erythrocytic plasma membrane loss. Formation of spherocytes. Decreased surface area. Decreased plasma membrane compliance. Fragility Hemolysis

Cellular implications

A secondary defect in hereditary spherocytosis is a deficiency of membrane surface area. The decrease in surface area leads to less efficient gas exchange of the erythrocyte at the alveoli of the lungs and throughout circulation. Decreased surface area may be produced by two different mechanisms:

Defects of spectrin, ankyrin, or PROTEIN 4.2 lead to reduced structural integrity of the plasma membrane, destabilizing the overlying lipid bilayer, and releasing band 3-containing microvesicles. Band-3 is important for gas exchange.
Defects of band 3 lead to band 3 deficiency and loss of its lipid-stabilizing effect within the plasma membrane lipid bilayer. This results in the release of band 3-free microvesicles.

Both pathways result in compromised plasma membrane integrity, decreased surface area, and formation of spherocytes with decreased mechanical compliance during circulation.

Cardiovascular and organ sequelae

Spherocytes have less plasma membrane compliance and fluidity, and this has implications throughout the entirety of circulation within the body, i.e. arteries, arterioles, capillaries, venules, veins, and organs. The lack of compliance and fluidity lead to a higher viscosity value for blood, which can have implications for both larger and smaller diameter vasculature. However, the most pronounced issues with the lack of compliance and fluidity declare themselves in the failure of the erythrocyte to deform itself when transiting arterioles, capillary beds, and venules. These vessels are smaller, and can become congested or blocked altogether. Studies have demonstrated that HS is related to deep vein thrombosis and arterial cardiovascular disease for this reason.
The spleen typically acts as a filter for blood, and targets pathogens and other damaged cells within circulation. Removing blood contaminants promotes entire-body homeostasis. The following facts about the spleen's role in normal body functioning are crucial to understanding the implications of HS on the overall health of the individual:

Removal of pathogens includes encapsulated bacteria, which reduces sepsis risk.
Removal of damaged erythrocytes reduces iron burden from heme via hepatosplenic recycling, which reduces sepsis risk.
Removal of damaged erythrocytes continues healthy signaling to bone marrow, where erythropoiesis replaces red blood cells lost to wear and tear.

In relation to the three facts above, the spleen misguidedly filters spherocytes – regardless of the age or functional status of the cell. The spleen is not dysfunctional itself when selecting spherocytes for destruction, as this is the regular function of the spleen both at an anatomic structure level, and at the molecular cellular level. At the anatomic level, the passage from the cords of Billroth into the sinusoids may be seen as a "bottleneck", where red blood cells need to be flexible in order to pass through. In HS, the erythrocytes fail to pass through fenestrations, and this is where resident splenic macrophages sample, or "bite", part of the stuck spherocytes' plasma membranes. The macrophages recognize that the spherocyte is not normal, and the macrophage is "programmed" to destroy irregularities filtered at the spleen from the blood. The resident splenic macrophages therefore phagocytose the spherocytes, causing extravascular hemolysis. This leads to both splenomegaly and anemia. Should this process continue unchecked chronically, inappropriate regulation of erythropoiesis leads to extramedullary hematopoiesis.