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=== Cellular Implications ===
=== Cellular Implications ===
The primary defect in hereditary spherocytosis is a deficiency of membrane surface area. Decreased surface area may be produced by two different mechanisms: 1) Defects of spectrin, ankyrin (most commonly), or protein 4.2 lead to reduced density of the membrane skeleton, destabilizing the overlying lipid bilayer and releasing [[band 3]]-containing [[microvesicles]]. 2) Defects of [[band 3]] lead to band 3 deficiency and loss of its lipid-stabilizing effect. This results in the loss of band 3-free microvesicles. Both pathways result in membrane loss, decreased surface area, and formation of spherocytes with decreased deformability.{{cn|date=September 2021}}
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 [[Pulmonary alveolus|alveoli]] of the lungs and throughout circulation. Decreased surface area may be produced by two different mechanisms:

# Defects of Spectrin, Ankyrin (most commonly), 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 (as seen above).
# 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.{{cn|date=September 2021}}


=== Cardiovascular and Organ Sequelae ===
=== Cardiovascular and Organ Sequelae ===

Revision as of 19:43, 23 March 2022

This article is about the hereditary hematologic manifestation of spherocytic disorders. For details that pertain to the mechanical state of spherocytic cells, see Spherocytosis.
Hereditary spherocytosis
Other namesMinkowski–Chauffard syndrome
Peripheral blood smear from patient with hereditary spherocytosis
SpecialtyHematology

Hereditary spherocytosis (HS) is a congenital hemolytic disorder, wherein a genetic mutation coding for a structural membrane protein phenotype leads to a spherical shaping of erythrocytic cellular morphology. As erythrocytes are sphere-shaped (spherocytosis), rather than the normal biconcave disk-shaped, their morphology interferes with these cells' abilities to be flexible during circulation throughout the entirety of the body - arteries, arterioles, capillaries, venules, veins, and organs. This difference in shape also makes the red blood cells more prone to rupture[1] under osmotic and/or mechanical stress. Cells with these dysfunctional proteins are degraded in the spleen, which leads to a shortage of erythrocytes resulting 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 (symptom-free carrier), to moderate (anemic, jaundiced, and with splenomegaly), to severe (hemolytic crisis, in-utero hydrops fetalis), because HS is caused by genetic mutations in a multitude of structural membrane proteins and exhibits incomplete penetrance in its expression.[citation needed]

Early symptoms include anemia, jaundice, splenomegaly, and fatigue.[2] 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 (unconjugated or indirect bilirubin) accumulating within the gallbladder. Also, patients who are heterozygous for a hemochromatosis gene may exhibit iron overload, despite the hemochromatosis genes being recessive.[3][4]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 normal hemoglobin, reticulocyte and bilirubin levels. The resultant asplenic patient is susceptible to encapsulated bacterial infection, and prevented with vaccination. If other symptoms, such as abdominal pain persist, the removal of the gallbladder may be warranted for symptomatic cholelithiasis.[citation needed]

Epidemiology

Hereditary spherocytosis is the heritable hemolytic disorder, affecting 1 in 2,000 people of Northern European ancestry.[5] According to Harrison's Principles of Internal Medicine, the frequency is at least 1 in 5,000 within the United States of America.[6] While HS is most commonly (though not exclusively) 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:

Hereditary spherocytosis can be an autosomal recessive or autosomal dominant trait.[9] The autosomal recessive inheritance pattern accounts for close to 25% of the clinical cases. The autosomal dominant inheritance patter 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.[citation needed]

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 (alpha and beta), ankyrin,[7] band 3 protein, protein 4.2,[8] and other red blood cell membrane proteins:[6]

Hereditary Spherocytosis Type Genotypic Etiology Phenotypic Expression
OMIM* Gene Locus Erythrocyte Membrane Protein Affected
HS-1 182900 ANK1 8p11.2 Ankyrin
HS-2 182870 SPTB 14q22-q23 Spectrin (Beta)*
HS-3 270970 SPTA 1q21 Spectrin (Alpha-1)*
HS-4 612653 SLC4A1 17q21-q22 Band-3 Protein
HS-5 612690 EPB42 15q15 Protein-4.2

*Online Mendelian Inheritance in Man (OMIM). The Alpha-1 refers the Alpha-1 Subunit of the Spectrin protein. The Beta refers the Beta Subunit of the Spectrin protein.

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.[citation needed]

Erythrocyte Membrane Protein Protein Function Compromised Process Effect Pathogenesis of HS Likelihood Mechanical Effect

(In Order)

Spectrin (Alpha-1) Alpha-1 subunit Actin Association Failure in plasma membrane tethering to actin cytoskeleton.
HS Alpha-1 deficiency.
Caption: The deficiency of Alpha-1 subunits in Spectrin protein network (top). The resulting failed or weakened tethering of Spectrin interior to the plasma membrane to the greater actin cytoskeleton (bottom).
Caption: The deficiency of Alpha-1 subunits in Spectrin protein network (top). The resulting failed or weakened tethering of Spectrin interior to the plasma membrane to the greater actin cytoskeleton (bottom). 		Most Common
  1. Erythrocytic plasma membrane loss.
  2. Formation of spherocytes.
  3. Decreased surface area.
  4. Decreased plasma membrane compliance.
  5. Fragility
  6. Hemolysis
Micrograph of a spherocyte (center).
Spectrin (Beta) Hydrophobic interactions and electrostatic attraction to ankyrin and actin Failure in plasma membrane tethering to actin cytoskeleton.
HS Beta deficiency.
Caption: The deficiency of Beta subunits in Spectrin protein network (top). The resulting failed or weakened tethering of Spectrin interior to the plasma membrane to the greater actin cytoskeleton (bottom).
Caption: The deficiency of Beta subunits in Spectrin protein network (top). The resulting failed or weakened tethering of Spectrin interior to the plasma membrane to the greater actin cytoskeleton (bottom).
Ankyrin Hydrophobic interactions and electrostatic attraction to Beta subunit Failure to mediate anchorage of integral plasma membrane proteins to spectrin.
HS Ankyrin deficiency.
Caption: The deficiency of Ankyrin that normally associates with plasma membrane proteins (top). The resulting failed or weakened anchorage of Spectin to interior plasma membrane, and subsequently weakened association between the greater actin cytoskeleton and the plasma membrane (bottom).
Caption: The deficiency of Ankyrin that normally associates with plasma membrane proteins (top). The resulting failed or weakened anchorage of Spectin to interior plasma membrane, and subsequently weakened association between the greater actin cytoskeleton and the plasma membrane (bottom). 		Common
Band-3 Failure to mediate the exchange of chloride (Cl−) with bicarbonate (HCO3−) across plasma membranes. Deficiency causes reduced lipid-stabilization at the plasma membrane.
HS Band-3 deficiency.
Caption: The deficiency of Band-3 Protein (top). The resulting destabilized plasma membrane without integral Band-3 Protein for association with Protein-4.2 and subsequently Ankyrin (bottom).
Caption: The deficiency of Band-3 Protein (top). The resulting destabilized plasma membrane without integral Band-3 Protein for association with Protein-4.2 and subsequently Ankyrin (bottom). 		Less Common
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.
HS Protein-4.2 deficiency.
Caption: The deficiency of Protein-4.2 (top). 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 (bottom).
Caption: The deficiency of Protein-4.2 (top). 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 (bottom). 		Least Common

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:

  1. Defects of Spectrin, Ankyrin (most commonly), 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 (as seen above).
  2. 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.[citation needed]

Cardiovascular and Organ Sequelae

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 red blood cells need to be flexible in order to pass through. In hereditary spherocytosis, red blood cells fail to pass through and get phagocytosed, causing extravascular hemolysis.[10]

Clinical Presentation

Diagnostics

In a peripheral blood smear, the red blood cells will appear abnormally small and lack the central pale area that is present in normal red blood cells. These changes are also seen in non-hereditary spherocytosis, but they are typically more pronounced in hereditary spherocytosis. The number of immature red blood cells (reticulocyte count) will be elevated.[2] An increase in the mean corpuscular hemoglobin concentration is also consistent with hereditary spherocytosis.[citation needed]

Other protein deficiencies cause hereditary elliptocytosis, pyropoikilocytosis or stomatocytosis.[citation needed]

In longstanding cases and in patients who have taken iron supplementation or received numerous blood transfusions, iron overload may be a significant problem. This is a potential cause of heart muscle damage 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.[11] In this test, the spherocytes will rupture in liquid solutions less concentrated than the inside of the red blood cell. This is due to increased permeability of the spherocyte membrane to salt and water, which enters the concentrated inner environment of the RBC and leads to its rupture.[12] Although the osmotic fragility test is widely considered the gold standard for diagnosing hereditary spherocytosis, it misses as many as 25% of cases. Flow cytometric analysis of eosin-5′-maleimide-labeled intact red blood cells and the acidified glycerol lysis test are two additional options to aid diagnosis.[13]

Treatment

Although research is ongoing, at this point there is no cure for the genetic defect that causes hereditary spherocytosis.[6] Current management focuses on interventions that limit the severity of the disease. Treatment options include:

  • Splenectomy: As in non-hereditary spherocytosis, acute symptoms of anemia and hyperbilirubinemia indicate treatment with blood transfusions or exchanges and chronic symptoms of anemia and an enlarged spleen indicate dietary supplementation of folic acid and splenectomy,[14] the surgical removal of the spleen. Splenectomy is indicated for moderate to severe cases, but not mild cases.[2] To decrease the risk of sepsis, post-splenectomy spherocytosis patients require immunization against the influenza virus, encapsulated bacteria such as Streptococcus pneumoniae and meningococcus, and prophylactic antibiotic treatment. However, the use of prophylactic antibiotics, such as penicillin, remains controversial.[6]
  • Partial splenectomy: Since the spleen is important for protecting against encapsulated organisms, sepsis caused by encapsulated organisms is a possible complication of splenectomy.[2] The option of partial splenectomy may be considered in the interest of preserving immune function. Research on outcomes is currently limited,[2] but favorable.[15]
  • Surgical removal of the gallbladder may be necessary.[6]

Complications

Common Complications

  • Hemolytic crisis, with more pronounced jaundice due to accelerated hemolysis (may be precipitated by infection).
  • Aplastic crisis with dramatic fall in hemoglobin 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 B19.
  • Folate deficiency caused by increased bone marrow requirement.
  • Pigmented gallstones occur in approximately half of untreated patients. Increased hemolysis of red blood cells leads to increased bilirubin levels, because bilirubin is a breakdown product of heme. The high levels of bilirubin must be excreted into the bile by the liver, which may cause the formation of a pigmented gallstone, which is composed of calcium bilirubinate. Since these stones contain high levels of calcium carbonates and phosphate, they are radiopaque and are visible on x-ray.
  • Leg ulcer.
  • Abnormally low hemoglobin A1C levels. Hemoglobin A1C (glycated hemoglobin) is a test for determining the average blood glucose levels over an extended period of time, and is often used to evaluate glucose control in diabetics. The hemoglobin A1C levels are abnormally low because the life span of the red blood cells is decreased, providing less time for the non-enzymatic glycosylation of hemoglobin. Thus, even with high overall blood sugar, the A1C will be lower than expected.

Forschung

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.[citation needed]

See also

References

  1. ^ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease. St. Louis, Mo: Elsevier Saunders. p. 625. ISBN 0-7216-0187-1.
  2. ^ a b c d e Bolton-Maggs, P. H. B.; Stevens, R. F.; Dodd, N. J.; Lamont, G.; Tittensor, P.; King, M. -J.; General Haematology Task Force of the British Committee for Standards in Haematology (2004). "Guidelines for the diagnosis and management of hereditary spherocytosis". British Journal of Haematology. 126 (4): 455–474. doi:10.1111/j.1365-2141.2004.05052.x. PMID 15287938.
  3. ^ J L Rasmussen; D A Odelson; F L Macrina (1987-08-01). "Complete nucleotide sequence of insertion element IS4351 from Bacteroides fragilis. - UKPMC Article - UK PubMed Central". UKPMC Article. Archived from the original on 2012-12-23. Retrieved 2012-07-03.
  4. ^ Paula Bolton-Maggs (September 2011). "Guidelines for the Diagnosis and Management of Hereditary Spherocytosis" (PDF). The British Committee for Standards in Haematology. Retrieved 2 July 2012.
  5. ^ "Hereditary spherocytosis: MedlinePlus Genetics".
  6. ^ a b c d e f Anthony S. Fauci; Eugene Braunwald; Dennis L. Kasper; Stephen L. Hauser; Dan L. Longo; J. Larry Jameson; Joseph Loscalzo (2008). Harrison's principles of internal medicine (17th ed.). New York: McGraw-Hill Medical. pp. Chapter 106. ISBN 978-0071466332.
  7. ^ a b c Gallagher PG, Forget BG (December 1998). "Hematologically important mutations: spectrin and ankyrin variants in hereditary spherocytosis". Blood Cells Mol. Dis. 24 (4): 539–43. doi:10.1006/bcmd.1998.0217. PMID 9887280.
  8. ^ a b c Perrotta S, Gallagher PG, Mohandas N (October 2008). "Hereditary spherocytosis". Lancet. 372 (9647): 1411–26. doi:10.1016/S0140-6736(08)61588-3. PMID 18940465. S2CID 10926437.
  9. ^ Eber S, Lux SE (April 2004). "Hereditary spherocytosis--defects in proteins that connect the membrane skeleton to the lipid bilayer". Semin. Hematol. 41 (2): 118–41. doi:10.1053/j.seminhematol.2004.01.002. PMID 15071790.
  10. ^ Chapter 12, page 425 in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson (2007). Robbins Basic Pathology. Philadelphia: Saunders. ISBN 978-1-4160-2973-1. 8th edition.
  11. ^ Won DI, Suh JS (March 2009). "Flow cytometric detection of erythrocyte osmotic fragility". Cytometry Part B. 76 (2): 135–41. doi:10.1002/cyto.b.20448. PMID 18727072. S2CID 7339411.
  12. ^ Goljan. Rapid Review Pathology. 2010. Page 213.
  13. ^ Bianchi, P.; Fermo, E.; Vercellati, C.; Marcello, A. P.; Porretti, L.; Cortelezzi, A.; Barcellini, W.; Zanella, A. (2011). "Diagnostic power of laboratory tests for hereditary spherocytosis: A comparison study in 150 patients grouped according to molecular and clinical characteristics". Haematologica. 97 (4): 516–523. doi:10.3324/haematol.2011.052845. PMC 3347664. PMID 22058213.
  14. ^ Bolton-Maggs PH, Stevens RF, Dodd NJ, Lamont G, Tittensor P, King MJ (August 2004). "Guidelines for the diagnosis and management of hereditary spherocytosis". Br. J. Haematol. 126 (4): 455–74. doi:10.1111/j.1365-2141.2004.05052.x. PMID 15287938.
  15. ^ Buesing, K. L.; Tracy, E. T.; Kiernan, C.; Pastor, A. C.; Cassidy, L. D.; Scott, J. P.; Ware, R. E.; Davidoff, A. M.; Rescorla, F. J.; Langer, J. C.; Rice, H. E.; Oldham, K. T. (2011). "Partial splenectomy for hereditary spherocytosis: A multi-institutional review". Journal of Pediatric Surgery. 46 (1): 178–183. doi:10.1016/j.jpedsurg.2010.09.090. PMID 21238662.
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