Hereditary spherocytosis pathophysiology: Difference between revisions

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==Overview==
==Overview==
There is intrinsic defects in erythrocyte membrane proteins that result in RBC cytoskeleton instability. Loss of erythrocyte surface area leads to the spherical shape of RBCs (spherocytes), which are culled rapidly from the circulation by the spleen. Hemolysis mainly confined to the spleen and, therefore, is extravascular. Splenomegaly commonly develops.
The [[Defect|defects]] in [[hereditary spherocytosis]] lie in the [[cell membrane]]. The [[Protein|proteins]] essential for integrity of [[cell membrane]] structure lie immediately under the [[lipid bilayer]], horizental [[Spectrin|alpha & beta spectrin molecules]] form [[Heterodimeric|heterodimers]] with linkage to vertical elements including [[ankyrin]], [[Protein|proteins]] 4.1 & 4.2 and [[band 3]] ([[transmembrane protein]]). The shorter the [[lifespan]] of [[Red blood cell|red blood cells]], the worse the [[clinical]] effects. [[Spectrin]] [[protein]] is a [[tetramer]] composed of alpha & beta [[Dimer|dimers]], its [[deficiency]] is most frequently seen in [[hereditary spherocytosis]]. [[Spectrin]] [[deficiency]] can result from impaired [[synthesis]] of [[spectrin]] or from [[qualitative]] or [[quantitative]] [[Defect|defects]] in other [[Protein|proteins]] that integrate [[Protein|proteins]] into [[Red blood cell|red blood cells]]. [[Ankyrin]] is the principal [[binding site]] for [[spectrin]] on [[Red blood cell|red blood]] [[cell membrane]], its [[deficiency]] leading to decreased incorporation of [[spectrin]], leading to proportional decrease in [[spectrin]] content as well despite normal [[synthesis]] of [[spectrin]]. [[Band 3]] [[deficiency]] is seen in 10-20% of [[Patient|patients]] with mild to moderate [[Autosomal dominant inheritance|autosomal dominant]] [[hereditary spherocytosis]] and is considerably greater in older [[Red blood cell|red blood cells]]. [[Protein 4.2|Protein 4.2 (Pallidin)]] [[deficiency]] leads to abnormal [[red blood cell]] [[morphology]] including [[Spherocytosis|spherocytes]], elliptocytes or sphero-ovalocytes, it is relatively common in japan. [[Red blood cell]] [[antibodies]] may also have a [[Pathogenesis|pathogenic]] role in [[red blood cell]] [[Opsonin|opsonization]] and removal by [[spleen]].


==Pathophysiology==
==Pathophysiology==
*The following four abnormalities in RBC membrane proteins have been identified in HS:
* The [[Defect|defects]] in [[hereditary spherocytosis]] lie in the [[cell membrane]].<ref name="Bolton-Maggs2004">{{cite journal|last1=Bolton-Maggs|first1=P H B|title=Hereditary spherocytosis; new guidelines|journal=Archives of Disease in Childhood|volume=89|issue=9|year=2004|pages=809–812|issn=0003-9888|doi=10.1136/adc.2003.034587}}</ref>
** Spectrin deficiency alone
* The [[Protein|proteins]] essential for integrity of [[cell membrane]] structure lie immediately under the [[lipid bilayer]], horizontal [[Spectrin|alpha and beta spectrin]] [[Molecule|molecules]] form [[Heterodimeric|heterodimers]] with linkage to vertical elements- [[ankyrin]], [[Protein 4.2|proteins 4.1 and 4.2]] and [[band 3]] (a [[transmembrane protein]]).
** Combined spectrin and ankyrin deficiency
* Different [[Gene|genes]] [[Genetic code|code]] for each of these [[Protein|proteins]], therefore [[hereditary spherocytosis]] is a heterogenous [[Disorder (medicine)|disorder]] that can result from a [[defect]] in any one of these [[Protein|proteins]].
** Band 3 deficiency
* The destabilization of [[membrane]] leads to both abnormal [[morphology]] and reduced [[Red blood cell|red cell]] [[life span]].
** Protein 4.2 defects
* The shorter the [[lifespan]] of [[Red blood cell|red blood cells]], the worse the [[clinical]] effects.
** '''Spectrin deficiency:''' The most frequent defect in HS is spectrin deficiency. The biochemical nature and the severity of spectrin deficiency correlate with the extent of spherocytosis, the degree of abnormality on osmotic fragility test results, and the severity of hemolysis. Spectrin deficiency can result from impaired synthesis of spectrin or from quantitative or qualitative deficiencies of other proteins that integrate spectrin into the red cell membrane. In the absence of those binding proteins, free spectrin is degraded, leading to spectrin deficiency. The spectrin protein is a tetramer made up of alpha-beta dimers. Mutations of alpha-spectrin are associated with recessive forms of HS, whereas mutations of beta-spectrin occur in autosomal dominant forms of HS.<sup> [5, 6]</sup> Synthesis of alpha-spectrin is threefold greater than that of beta-spectrin.  
* The [[Genetics|genetic]] [[defect]] and [[clinical]] severity tend to be fairly constant within a given [[family]], but between [[Family|families]] varies from mild [[asymptomatic]] [[hemolysis]] to severe continuous [[anemia]] with [[jaundice]].
** The excess alpha chains normally are degraded. Heterozygotes for alpha-spectrin defects produce sufficient normal alpha-spectrin to balance normal beta-spectrin production. Defects of beta-spectrin are more likely to be expressed in the heterozygous state because synthesis of beta-spectrin is the rate-limiting factor.  Red cell membranes isolated from individuals with autosomal recessive HS have only 40-50% of the normal amount of spectrin (relative to band protein 3). In the autosomal dominant form of HS, red cell spectrin levels range from 60-80% of normal. Approximately 50% of patients with severe recessive HS have a point mutation at codon (969) that results in an amino acid substitution (alanine [Ala]/aspartic acid [Asp]) at the corresponding site in the alpha-spectrin protein. This leads to a defective binding of spectrin to protein 4.1. Mutations involving the alpha-spectrin beta-spectrin gene also occur, each resulting in spectrin deficiency.  Several other beta-spectrin mutations have been identified. Some of these mutations result in impaired beta-spectrin synthesis. Others produce unstable beta-spectrins or abnormal beta-spectrins that do not bind to ankyrin and undergo proteolytic degradation. 
* The four [[Red blood cell|RBC]] [[membrane]] [[protein]] abnormalities recognized in [[hereditary spherocytosis]] include; [[spectrin]] [[deficiency]] alone, combined [[spectrin]] & [[ankyrin]] [[deficiency]], [[band 3]] [[deficiency]] and [[protein 4.2]] [[deficiency]].
** '''Ankyrin defects:''' HS is described in patients with translocation of chromosome 8 or deletion of the short arm of chromosome 8, where the ankyrin gene is located. Patients with HS and deletion of chromosome 8 have a decrease in red cell ankyrin content.  Ankyrin is the principal binding site for spectrin on the red cell membrane. Studies of cytoskeletal protein assembly in reticulocytes indicate that ankyrin deficiency leads to decreased incorporation of spectrin. In HS caused by ankyrin deficiency, a proportional decrease in spectrin content occurs, although spectrin synthesis is normal. Of particular interest, 75-80% of patients with autosomal dominant HS have combined spectrin and ankyrin deficiency and the two proteins are diminished equally.
* '''Spectrin deficiency'''
** '''Band 3 deficiency:''' Band 3 deficiency has been recognized in 10-20% of patients with mild-to-moderate autosomal dominant HS. These patients also have a proportionate decrease in protein 4.2 content on the erythrocyte membrane. In some individuals with HS who are deficient in band 3, the deficiency is considerably greater in older RBCs. This suggests that band 3 protein is unstable.
** [[Spectrin]] [[protein]] is a [[tetramer]] composed of alpha and beta [[Dimer|dimers]].<ref name="PerrottaDella Ragione2009">{{cite journal|last1=Perrotta|first1=S.|last2=Della Ragione|first2=F.|last3=Rossi|first3=F.|last4=Avvisati|first4=R. A.|last5=Di Pinto|first5=D.|last6=De Mieri|first6=G.|last7=Scianguetta|first7=S.|last8=Mancusi|first8=S.|last9=De Falco|first9=L.|last10=Marano|first10=V.|last11=Iolascon|first11=A.|title= -spectrinBari: a truncated  -chain responsible for dominant hereditary spherocytosis|journal=Haematologica|volume=94|issue=12|year=2009|pages=1753–1757|issn=0390-6078|doi=10.3324/haematol.2009.010124}}</ref><ref name="pmid19538529">{{cite journal| author=Maciag M, Płochocka D, Adamowicz-Salach A, Burzyńska B| title=Novel beta-spectrin mutations in hereditary spherocytosis associated with decreased levels of mRNA. | journal=Br J Haematol | year= 2009 | volume= 146 | issue= 3 | pages= 326-32 | pmid=19538529 | doi=10.1111/j.1365-2141.2009.07759.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19538529  }}</ref>
** '''Protein 4.2 (pallidin) deficiency:''' Hereditary hemolytic anemia has been described in patients with a complete deficiency of protein 4.2. RBC morphology in these cases is characterized by spherocytes, elliptocytes, or sphero-ovalocytes. Deficiency of protein 4.2 in HS is relatively common in Japan. One mutation that appears to be common in the Japanese population (resulting in protein 4.2 Nippon) is associated in the homozygous state with a red cell morphology described as spherocytic, ovalocytic, and elliptocytic. Another mutant protein 4.2 (protein 4.2 Lisboa) is caused by a deletion that results in a complete absence of protein 4.2. This is associated with a typical HS phenotype.
** The most frequent [[defect]] in [[hereditary spherocytosis]] is [[spectrin]] [[deficiency]].
** '''Aquaporin-1:''' In addition to abnormal levels of proteins affected by mutations, patients with HS may demonstrate aberrant distribution of other proteins in erythrocytes. Crisp et al found reduced expression of the water channel protein aquaporin-1 (AQP1) in the membranes of erythrocytes from patients with HS, compared with normal controls. The AQP1 content in erythrocyte membranes correlated with the clinical severity of HS.<sup> [7]</sup> 
** [[Mutation|Mutations]] of [[Spectrin|alpha spectrin]] are [[Association (statistics)|associated]] with [[Recessive|recessive forms]] of [[hereditary spherocytosis]] and [[Spectrin|beta spectrin]] [[Mutation|mutations]] occur in [[Dominant|autosomal dominant]] forms of [[hereditary spherocytosis]].
** '''Red blood cell antibodies:''' Using a mitogen-stimulated direct antiglobulin test, Zaninoni and colleagues found RBC antibodies in 61% of patients with HS. Patients with RBC-bound IgG of more than 250 ng/mL (the positive threshold of autoimmune hemolytic anemia) had increased numbers of spherocytes and mainly had spectrin deficiency. These researchers concluded that the more evident hemolytic pattern in patients with RBC autoantibodies suggests that these antibodies have a pathogenic role in RBC opsonization and removal by the spleen
** [[Spectrin]] [[deficiency]] can result from impaired synthesis of [[spectrin]] or from [[quantitative]] or [[qualitative]] [[Defect|defects]] in other [[Protein|proteins]] that integrate [[spectrin]] into the [[Cell membrane|red cell membrane]].  
** Approximately 50% of [[Patient|patients]] with severe [[Recessive gene|recessive]] [[hereditary spherocytosis]] have a [[point mutation]] at the [[Genetic code|codon (969)]] resulting in [[amino acid]] substitution ([[alanine]]/[[aspartic acid]]) at the corresponding site in [[Spectrin, alpha 1|apha spectrin]] [[protein]] leading to [[Defect|defective]] [[Binding (molecular)|binding]] of [[spectrin]] to [[Band 4.1|protein 4.1]].
* '''Akyrin deficiency'''
** [[Ankyrin]] is the principal [[binding site]] for [[spectrin]] on the [[red blood cell]] [[Cell membrane|membrane]].
** [[Ankyrin]] [[gene]] is located on [[Chromosome 8 (human)|chromosome 8]], therefore [[Chromosomal translocation|translocation]] of [[Chromosome 8 (human)|chromosome 8]] or [[Deletion (genetics)|deletion]] of [[Chromosome 8 (human)|short arm of chromosome 8]] can lead to [[hereditary spherocytosis]].
** [[Ankyrin]] [[deficiency]] leads to decreased incorporation of [[spectrin]], leading to a proportional decrease in [[spectrin]] content as well despite the normal synthesis of [[spectrin]].
* '''Band 3 deficiency'''
** [[Band 3]] [[deficiency]] is seen in 10-20% of [[Patient|patients]] with mild to moderate [[Dominance relationship|autosomal dominant]] [[hereditary spherocytosis]].
** [[Band 3]] [[deficiency]] is considerably greater in older [[Red blood cell|RBCs]] due to unstable nature of [[band 3]] [[protein]].
* '''Protein 4.2 (Pallidin) Deficiency'''
** [[Protein 4.2]] [[deficiency]] leads to abnormal [[Red blood cell|RBC]] [[morphology]] including [[Spherocytosis|spherocytes]], elliptocytes or sphero-ovalocytes.
** Its [[deficiency]] is relatively common in japan.
** A [[point mutation]] causing complete absence of [[protein 4.2]] is associated with typical [[hereditary spherocytosis]] [[phenotype]].
* '''Red Blood Cell Antibodies'''
** Zaninoni et all found [[Red blood cell|RBC]] [[antibodies]] in 61% of [[Patient|patients]] with [[hereditary spherocytosis]] using a [[mitogen]] stimulated [[Coombs test|direct antiglobulin test]].<ref name="pmid26259504">{{cite journal| author=Zaninoni A, Vercellati C, Imperiali FG, Marcello AP, Fattizzo B, Fermo E et al.| title=Detection of red blood cell antibodies in mitogen-stimulated cultures from patients with hereditary spherocytosis. | journal=Transfusion | year= 2015 | volume= 55 | issue= 12 | pages= 2930-8 | pmid=26259504 | doi=10.1111/trf.13257 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26259504  }}</ref>
** They concluded that the more evident [[Hemolysis|hemolytic pattern]] in [[Patient|patients]] with [[Red blood cell|RBC]] [[Autoantibody|autoantibodies]] suggests that these [[antibodies]] have a [[Pathogenesis|pathogenic role]] in [[Red blood cell|RBC]] [[Opsonin|opsonization]] and removal by [[spleen]].


==References==
==References==

Latest revision as of 22:02, 4 December 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

The defects in hereditary spherocytosis lie in the cell membrane. The proteins essential for integrity of cell membrane structure lie immediately under the lipid bilayer, horizental alpha & beta spectrin molecules form heterodimers with linkage to vertical elements including ankyrin, proteins 4.1 & 4.2 and band 3 (transmembrane protein). The shorter the lifespan of red blood cells, the worse the clinical effects. Spectrin protein is a tetramer composed of alpha & beta dimers, its deficiency is most frequently seen in hereditary spherocytosis. Spectrin deficiency can result from impaired synthesis of spectrin or from qualitative or quantitative defects in other proteins that integrate proteins into red blood cells. Ankyrin is the principal binding site for spectrin on red blood cell membrane, its deficiency leading to decreased incorporation of spectrin, leading to proportional decrease in spectrin content as well despite normal synthesis of spectrin. Band 3 deficiency is seen in 10-20% of patients with mild to moderate autosomal dominant hereditary spherocytosis and is considerably greater in older red blood cells. Protein 4.2 (Pallidin) deficiency leads to abnormal red blood cell morphology including spherocytes, elliptocytes or sphero-ovalocytes, it is relatively common in japan. Red blood cell antibodies may also have a pathogenic role in red blood cell opsonization and removal by spleen.

Pathophysiology

References

  1. Bolton-Maggs, P H B (2004). "Hereditary spherocytosis; new guidelines". Archives of Disease in Childhood. 89 (9): 809–812. doi:10.1136/adc.2003.034587. ISSN 0003-9888.
  2. Perrotta, S.; Della Ragione, F.; Rossi, F.; Avvisati, R. A.; Di Pinto, D.; De Mieri, G.; Scianguetta, S.; Mancusi, S.; De Falco, L.; Marano, V.; Iolascon, A. (2009). "-spectrinBari: a truncated  -chain responsible for dominant hereditary spherocytosis". Haematologica. 94 (12): 1753–1757. doi:10.3324/haematol.2009.010124. ISSN 0390-6078.
  3. Maciag M, Płochocka D, Adamowicz-Salach A, Burzyńska B (2009). "Novel beta-spectrin mutations in hereditary spherocytosis associated with decreased levels of mRNA". Br J Haematol. 146 (3): 326–32. doi:10.1111/j.1365-2141.2009.07759.x. PMID 19538529.
  4. Zaninoni A, Vercellati C, Imperiali FG, Marcello AP, Fattizzo B, Fermo E; et al. (2015). "Detection of red blood cell antibodies in mitogen-stimulated cultures from patients with hereditary spherocytosis". Transfusion. 55 (12): 2930–8. doi:10.1111/trf.13257. PMID 26259504.

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