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== Classification ==
== [[hereditary spherocytosis classification|Classification]] ==
* Hereditary Spherocytosis classified on basis of underlying defect in protein and also on the basis of severity of hemolysis.
* Hereditary Spherocytosis classified on basis of underlying defect in protein and also on the basis of severity of hemolysis.
* Classification of hereditary spherocytosis on the basis of clinical severity.<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>{{cite web |url=http://www.ncbi.nlm.nih.gov/books/NBK1116/ |title=GeneReviews® - NCBI Bookshelf |format= |work= |accessdate=}}
* Classification of hereditary spherocytosis on the basis of clinical severity.<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>{{cite web |url=http://www.ncbi.nlm.nih.gov/books/NBK1116/ |title=GeneReviews® - NCBI Bookshelf |format= |work= |accessdate=}}

Revision as of 15:41, 28 November 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Zahir Ali Shaikh, MD[2]

Overview

Hereditary spherocytosis is a genetically-transmitted form of spherocytosis, an auto-hemolytic anemia characterized by the production of red blood cells that are sphere-shaped rather than donut-shaped, and therefore more prone to hemolysis.

Historical Perspective

  • Hereditary spherocytosis was first described in 1871.[1]
  • It is the commonest cause of inherited chronic hemolysis in the northern europe and north america.[2]

Classification

  • Hereditary Spherocytosis classified on basis of underlying defect in protein and also on the basis of severity of hemolysis.
  • Classification of hereditary spherocytosis on the basis of clinical severity.[3]"GeneReviews® - NCBI Bookshelf".
Locus Gene Protein Inheritance Severity Comment
SPH1 ANK1 Ankyrin-1 AD/AR mild-moderate/moderately severe-severe often transfusion dependant
SPH2 SPTB Spectrin beta chain,erythrocytic AD/AR mild-moderate/severe 1 fatal infantile case described
SPH3 SPTA1 Spectrin alpha chain,erythrocytic1 AR severe transfusion dependant
SPH4 SLC4A1 Band3(anion transport protein) AD mild-moderate certain SLC4A1 variants cause disease only when biallelic
SPH5 EPB42 Protein 4.2 AR mild-moderate 1 moderately severe case described
Classification Mild Moderate Severe
Hemoglobin (g/dl) 110-150 80-120 60-80
Reticulocyte count (%) 3-6 >6 >10
Bilirubin (ug/l) 17-34 >34 >51
Splenectomy usually not required indicated during school age, usually before puberty necessary - delay until 6 years of age if possible

Pathophysiology

  • The defects in hereditary spherocytosis lie in the cell membrane.[3]
  • The proteins essential for integrity of membrane structure lie immediately under the lipid bilayer, horizental aplha & beta spectrin molecules form heterodimers with linkage to vertical elements- ankyrin, proteins 4.1 & 4.2 and band 3 (a transmembrane protein).
  • Different genes code for each of these proteins, therefore hereditary spherocytosis is a hetrogenous disorder which can result from a defect in any one of these proteins.
  • The destabilization of membrane leads to both abnormal morphology and reduced red cell life span.
  • The shorter the life span of red blood cells, the worse the clinical effects.
  • Genetic defect and clinical severity tend to be fairly constant within a given family,but between family varies from mild asymptomatic hemolysis to severe continuous anemia with jaundice.

Causes

  • Hereditary spherocytosis is caused by a variety of genetic mutations.[4][5]
  • There are 05 genes associated with hereditary spherocytosis including, alpha spectrin (SPTA1), beta spectrin (SPTB), ankyrin (ANK1), band3 (SLC4A1) and protein 4.2 (EPB42).
  • Mutations in one or more of hereditary spherocytosis related genes can cause membrane protein deficiency leading to hereditary spherocytosis.
Molecular and Genetic Characteristics of 5 Erythrocyte Membrane Protein Genes
Gene Chromosome Location Membrane Protein Prevalent Mutations Heredity Associated Disease
ANK1 8p11.2 Ankyrin-1 frameshift, nonsense, splicing, novel mutations autosomal dominant, autosomal recessive hereditary spherocytosis
SLC4A1 17q21 Band3 missense,frameshift,polymorphism autosomal dominant hereditary spherocytosis,distal renal tubular acisosis
SPTA1 1q22-q23 alpha spectrin SpaLEPRA allele, splicing, frameshift autosomal recessive hereditary spherocytosis, hereditary eliptocytosis, hereditary pyropoikilocytosis
SPTB 14q23-q24.1 beta spectrin splicing, frameshift, nonsense, novel mutations autosomal dominant hereditary spherocytosis, hereditary eliptocytosis, hereditary pyropoikilocytosis
EBP42 15q15-q21 protein 4.2 missense, nonsense autosomal recessive hereditary spherocytosis

Differentiating Hereditary Spherocytosis from Other Diseases

  • Hereditary spherocytosis presents with hemolysis, therefore should be differentiated from following diseases.[6][5]
    • Autoimmune hemolysis
    • Thermal injury
    • Clostridial septicemia
    • Wilson disease
    • Hemoglobinopathies
    • Hereditary stomatocytosis
    • Congenital dyserythrpoietic anemia type II

Epidemiology and Demographics

  • Hereditary spherocytosis is reported worldwide in all racial and ethnic groups.[7]
  • It is the most common inherited anemia in the northern European ancestry and north america.[8]
  • The reported incidence of hereditary spherocytosis is 1 in 2000 births.[9]
  • It is less commonly seen in african american and southeast asian people.[5]

Risk Factors

  • A positive family history is an important risk factor for hereditary spherocytosis, as it is an inherited condition.[10]
  • There are no other risk factors have been clearly identified for this condition.

Screening

  • The screening test used for hereditary spherocytosis is automated mean cell hemoglobin concentration (MCHC).[11]
  • Erythrocyte distribution width when raised is also useful as a powerful screening test.[12]
  • The combination of these two tests (MCHC & erythrocyte distribution width) is an excellent predictor for the diagnosis of hereditary spherocytosis.[13]

Natural History, Complications, and Prognosis

Natural History

  • The clinical course of hereditary spherocytosis is variable depending upon the severity of disease.[14]
  • During infancy, hemoglobin level falls rapidly after 20 days of birth leading to transient & severe anemia, causing inappropriate erythrocyte response and splenic filtering function.[15]
  • About 20-30% of patients have mild disease with compensated hemolysis.
  • About 60-70% of patients have moderate disease, presenting in childhood but can present at any age.
  • About 3-5% of patients have severe hereditary disease with life threatening anemia, requiring regular transfusions to maintain a hemoglobin concentration of greater than 60g/L.
  • Without regular transfusions or splenectomy or both, patients may develop kernicterus, severe hemolytic anemia, gallstones, growth retardation, delayed sexual maturation, extramedullary hematopoiesis with hepatosplenomegaly and bony changes (thalassemic facies).[5]

Complications

  • The complications of hereditary spherocytosis include:[16][17][18]
    • hemolytic anemia
    • jaundice
    • kernicterus
    • cholelithiasis
    • hemolytic, aplastic and megaloblastic crises
    • growth failure
    • leg ulcers
    • skeletal abnormalities resulting from bone marrow expansion
    • multiple myeloma
    • leukemia

Prognosis

  • The prognosis of patients with hereditary spherocytosis is usually good with early diagnosis, regular followup and management.[19]
  • Patients with hereditary spherocytosis may remain undiagnosed for years if their hemolysis is mild.

Diagnosis

Diagnostic Criteria

  • The diagnosis of hereditary spherocytosis can be based on the physical examination, complete red cell count, recticulocyte count, medical history and specific tests, preferentially, the EMA (eosin-5-maleimide binding) test and AGLT (acidified glycerol lysis time).[18][20]
  • The diagnosis can be made at any age, including the neonatal period from day of birth.[21]
  • The diagnostic guidelines of hereditary spherocytosis from the British Committee for Standards in hematology do not recommend any additional tests for patients with classical clinical features and laboratory data.
  • The eosin-5-maleimide (EMA) binding test has high sensitivity (92–93%) and specificity (99%) for hereditary spherocytosis, although a positive test can also be obtained in patients affected by related conditions, such as congenital dyserythropoietic anemia type II (CDA II)
  • Other tests, such as the osmotic fragility (OF) test, acidified glycerol lysis test (AGLT) and the pink test, exhibit lower sensitivity compared to the EMA test (68%, 61% and 91%, respectively).[22]
  • Ektacytometry is a highly sensitive test of membrane deformability.


Simple Diagnostic Criteria to evoke the Diagnosis of Hereditary Spherocytosis
Clinical Parameters pallor, splenomegaly, inconstant jaundice
Biological paraneters & erythrocyte indices dec Hb, inc MCHC, inc %hyperdense cells, inc reticulocytes
Blood smear Spherocytes (may be absent)
Signs of hemolysis inc free bilirubin, dec haptoglobin, inc reticulocytes
Erythrocyte coombs test negative
Specific Biological Examinations for the Diagnosis of Hereditary Spherocytosis
Tests Principle/feasibility Sensitivity/Specificity
Osmotic resistance hemolysis test/routime examination 66%/low
Pink test hemolysis test/simple test time-out test <3 hours 96%/79-94%
AGLT Hemolysis test time of test >3 hours 81%/95%
Ektacytometry in osmolar gradient study of deformity of RBCs single laboratory in France test execution time:24 hours reference exam
Flow cytometry labeling of RBCs with eosin 5 maleimide/not available on routine basis test run time >48 h Being evaluated

History and Symptoms

  • Hereditary spherocytosis is a familial hemolytic disorder with marked heterogeneity.[23][24][25]
  • Clinical features range from asymptomatic to fulminant hemolytic anemia.[26]
  • Symptoms and history of hereditary spherocytosis include;
    • hemolysis
    • anemia
    • jaundice
    • weakness
    • irritability
    • shortness of breath
    • pallor
    • thrombocytopenia
    • pyelonephritis
    • hyperbilirubinemia

Physical Examination

  • The physical examination findings in hereditary spherocytosis include;[5]
    • scleral icterus
    • jaundice
    • splenomegaly

Laboratory Findings

Initial testing

  • CBC and RBC indices - The mean cell hemoglobin concentration (MCHC) and red cell distribution width (RDW) are both raised in hereditary spherocytosis.[27]
  • Blood smear review – shows the spherocytes and increased reticulocytes.
  • Coombs testing – used when hemolysis is present, to differentiate hereditary spherocytosis from autoimmune hemolytic anemia (AIHA). Coombs test is negative in hereditary spherocytosis.

Confirmatory tests

    • EMA (eosin 5 maleimide binding assay) test[28][29]
    • Osmotic fragility test
    • Acidified glycerol lysis test
    • Cryohemolysis
    • Plasma membrane protein electrophoresis

Imaging Findings:

  • There are no particular other imaging findings associated with HS.

Other Diagnostic Studies:

    • There are no other diagnostic tests available for the hereditary spherocytosis.

Treatment

Medical Therapy

  • There is no specific medical therapy for hereditary spherocytosis. As the diagnosis of hereditary spherocytosis is made, surveillance is needed to help detect and manage any complications.[30]
  • A routine annual review is usually sufficient to detect any complications such as parvovirus infection or abdominal pain which may necessitate the investigation for gallstones.
  • Folate supplementation is not always required, but is used as a routine for children with severe hemolysis and in pregnancy, regardless of severity of hereditary spherocytosis.[31]

Surgery

  • Splenectomy is very effective in reducing hemolysis, leading to significant prolongation of the red cell life span.[32][33]
  • Patients should be selected for splenectomy on the basis of their clinical symptoms and presence of complications such as gallstones, not simply on the basis of diagnosis alone.
  • Following splenectomy, the clinical manifestations and complications (anemia & gallstones) are much reduced in severe hereditary spherocytosis and abolished in milder cases, but at the risk of increased life threatening sepsis from encapsulated organisms, particularly streptococcus pneumoniae.[30][34]
  • Children or young adults with mild hereditary spherocytosis who also has gallstones are likely to benefit from combined splenectomy and cholecystectomy in terms of life expectancy.[30]

Prevention

  • The administration of vaccines (pneumococcal, haemophilus influenzae type b, meningococcal group C and influenza) is indicated 2 to 3 weeks before splenectomy.[35]
  • Postsplenectomy patients should also be given 1mg of folic acid daily for preventing secondary folic acid deficiency and oral penicillin (penicillin V) for preventing secondary infection until reaching adulthood.

Case Studies

Case #1

Related Chapters

Template:Otheruses4

External links

References

  1. ↑ Sayeeda Huq, Mark A. C. Pietroni, Hafizur Rahman & Mohammad Tariqul Alam (2010). "Hereditary spherocytosis". Journal of health, population, and nutrition. 28 (1): 107–109. PMID 20214092. Unknown parameter |month= ignored (help)
  2. ↑ Sayeeda Huq, Mark A. C. Pietroni, Hafizur Rahman & Mohammad Tariqul Alam (2010). "Hereditary spherocytosis". Journal of health, population, and nutrition. 28 (1): 107–109. PMID 20214092. Unknown parameter |month= ignored (help)
  3. ↑ 3.0 3.1 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.
  4. ↑ He, Ben-Jin; Liao, Lin; Deng, Zeng-Fu; Tao, Yi-Feng; Xu, Yu-Chan; Lin, Fa-Quan (2018). "Molecular Genetic Mechanisms of Hereditary Spherocytosis: Current Perspectives". Acta Haematologica. 139 (1): 60–66. doi:10.1159/000486229. ISSN 0001-5792.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 Perrotta, Silverio; Gallagher, Patrick G; Mohandas, Narla (2008). "Hereditary spherocytosis". The Lancet. 372 (9647): 1411–1426. doi:10.1016/S0140-6736(08)61588-3. ISSN 0140-6736.
  6. ↑ Robert D. Christensen, Hassan M. Yaish & Patrick G. Gallagher (2015). "A pediatrician's practical guide to diagnosing and treating hereditary spherocytosis in neonates". Pediatrics. 135 (6): 1107–1114. doi:10.1542/peds.2014-3516. PMID 26009624. Unknown parameter |month= ignored (help)
  7. ↑ Silverio Perrotta, Patrick G. Gallagher & Narla Mohandas (2008). "Hereditary spherocytosis". Lancet (London, England). 372 (9647): 1411–1426. doi:10.1016/S0140-6736(08)61588-3. PMID 18940465. Unknown parameter |month= ignored (help)
  8. ↑ Sayeeda Huq, Mark A. C. Pietroni, Hafizur Rahman & Mohammad Tariqul Alam (2010). "Hereditary spherocytosis". Journal of health, population, and nutrition. 28 (1): 107–109. PMID 20214092. Unknown parameter |month= ignored (help)
  9. ↑ Sayeeda Huq, Mark A. C. Pietroni, Hafizur Rahman & Mohammad Tariqul Alam (2010). "Hereditary spherocytosis". Journal of health, population, and nutrition. 28 (1): 107–109. PMID 20214092. Unknown parameter |month= ignored (help)
  10. ↑ Sayeeda Huq, Mark A. C. Pietroni, Hafizur Rahman & Mohammad Tariqul Alam (2010). "Hereditary spherocytosis". Journal of health, population, and nutrition. 28 (1): 107–109. PMID 20214092. Unknown parameter |month= ignored (help)
  11. ↑ L. A. Michaels, A. R. Cohen, H. Zhao, R. I. Raphael & C. S. Manno (1997). "Screening for hereditary spherocytosis by use of automated erythrocyte indexes". The Journal of pediatrics. 130 (6): 957–960. PMID 9202619. Unknown parameter |month= ignored (help)
  12. ↑ Silvia Eandi Eberle, Gabriela Sciuccati, Mariana Bonduel, Lilian Diaz, Raquel Staciuk & Aurora Feliu Torres (2007). "[Erythrocyte indexes in hereditary spherocytosis]". Medicina. 67 (6 Pt 2): 698–700. PMID 18422060.
  13. ↑ Michaels, Lisa A.; Cohen, Alan R.; Zhao, Huaqing; Raphael, Robert I.; Manno, Catherine S. (1997). "Screening for hereditary spherocytosis by use of automated erythrocyte indexes". The Journal of Pediatrics. 130 (6): 957–960. doi:10.1016/S0022-3476(97)70283-X. ISSN 0022-3476.
  14. ↑ Olga Ciepiela (2018). "Old and new insights into the diagnosis of hereditary spherocytosis". Annals of translational medicine. 6 (17): 339. doi:10.21037/atm.2018.07.35. PMID 30306078. Unknown parameter |month= ignored (help)
  15. ↑ F. Delhommeau, T. Cynober, P. O. Schischmanoff, P. Rohrlich, J. Delaunay, N. Mohandas & G. Tchernia (2000). "Natural history of hereditary spherocytosis during the first year of life". Blood. 95 (2): 393–397. PMID 10627440. Unknown parameter |month= ignored (help)
  16. ↑ Sayeeda Huq, Mark A. C. Pietroni, Hafizur Rahman & Mohammad Tariqul Alam (2010). "Hereditary spherocytosis". Journal of health, population, and nutrition. 28 (1): 107–109. PMID 20214092. Unknown parameter |month= ignored (help)
  17. ↑ Friedman, Ellen Wolkin; Williams, Jeannine C.; van Hook, Lucille (1988). "Hereditary spherocytosis in the elderly". The American Journal of Medicine. 84 (3): 513–516. doi:10.1016/0002-9343(88)90275-6. ISSN 0002-9343.
  18. ↑ 18.0 18.1 Guitton, C.; Garçon, L.; Cynober, T.; Gauthier, F.; Tchernia, G.; Delaunay, J.; Leblanc, T.; Thuret, I.; Bader-Meunier, B. (2008). "Sphérocytose héréditaire : recommandations pour le diagnostic et la prise en charge chez l'enfant". Archives de Pédiatrie. 15 (9): 1464–1473. doi:10.1016/j.arcped.2008.04.023. ISSN 0929-693X.
  19. ↑ Yuki Tateno, Ryoji Suzuki & Yukihiro Kitamura (2016). "Previously undiagnosed hereditary spherocytosis in a patient with jaundice and pyelonephritis: a case report". Journal of medical case reports. 10 (1): 337. doi:10.1186/s13256-016-1144-8. PMID 27906107. Unknown parameter |month= ignored (help)
  20. ↑ Sayeeda Huq, Mark A. C. Pietroni, Hafizur Rahman & Mohammad Tariqul Alam (2010). "Hereditary spherocytosis". Journal of health, population, and nutrition. 28 (1): 107–109. PMID 20214092. Unknown parameter |month= ignored (help)
  21. ↑ Yuki Tateno, Ryoji Suzuki & Yukihiro Kitamura (2016). "Previously undiagnosed hereditary spherocytosis in a patient with jaundice and pyelonephritis: a case report". Journal of medical case reports. 10 (1): 337. doi:10.1186/s13256-016-1144-8. PMID 27906107. Unknown parameter |month= ignored (help)
  22. ↑ Immacolata Andolfo, Roberta Russo, Antonella Gambale & Achille Iolascon (2016). "New insights on hereditary erythrocyte membrane defects". Haematologica. 101 (11): 1284–1294. doi:10.3324/haematol.2016.142463. PMID 27756835. Unknown parameter |month= ignored (help)
  23. ↑ Yuki Tateno, Ryoji Suzuki & Yukihiro Kitamura (2016). "Previously undiagnosed hereditary spherocytosis in a patient with jaundice and pyelonephritis: a case report". Journal of medical case reports. 10 (1): 337. doi:10.1186/s13256-016-1144-8. PMID 27906107. Unknown parameter |month= ignored (help)
  24. ↑ Maria Christina Lopes Araujo Oliveira, Rachel Aparecida Ferreira Fernandes, Carolina Lins Rodrigues, Daniela Aguiar Ribeiro, Maria Fernanda Giovanardi & Marcos Borato Viana (2012). "Clinical course of 63 children with hereditary spherocytosis: a retrospective study". Revista brasileira de hematologia e hemoterapia. 34 (1): 9–13. doi:10.5581/1516-8484.20120006. PMID 23049376.
  25. ↑ Immacolata Andolfo, Roberta Russo, Antonella Gambale & Achille Iolascon (2016). "New insights on hereditary erythrocyte membrane defects". Haematologica. 101 (11): 1284–1294. doi:10.3324/haematol.2016.142463. PMID 27756835. Unknown parameter |month= ignored (help)
  26. ↑ Sayeeda Huq, Mark A. C. Pietroni, Hafizur Rahman & Mohammad Tariqul Alam (2010). "Hereditary spherocytosis". Journal of health, population, and nutrition. 28 (1): 107–109. PMID 20214092. Unknown parameter |month= ignored (help)
  27. ↑ Farias, Mariela Granero (2017). "Advances in laboratory diagnosis of hereditary spherocytosis". Clinical Chemistry and Laboratory Medicine (CCLM). 55 (7). doi:10.1515/cclm-2016-0738. ISSN 1437-4331.
  28. ↑ Olga Ciepiela (2018). "Old and new insights into the diagnosis of hereditary spherocytosis". Annals of translational medicine. 6 (17): 339. doi:10.21037/atm.2018.07.35. PMID 30306078. Unknown parameter |month= ignored (help)
  29. ↑ Paola Bianchi, Elisa Fermo, Cristina Vercellati, Anna P. Marcello, Laura Porretti, Agostino Cortelezzi, Wilma Barcellini & Alberto Zanella (2012). "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. PMID 22058213. Unknown parameter |month= ignored (help)
  30. ↑ 30.0 30.1 30.2 Bolton-Maggs, P. H. B.; Stevens, R. F.; Dodd, N. J.; Lamont, G.; Tittensor, P.; King, M.-J. (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. ISSN 0007-1048.
  31. ↑ P. H. B. Bolton-Maggs (2004). "Hereditary spherocytosis; new guidelines". Archives of disease in childhood. 89 (9): 809–812. doi:10.1136/adc.2003.034587. PMID 15321852. Unknown parameter |month= ignored (help)
  32. ↑ P. H. B. Bolton-Maggs, R. F. Stevens, N. J. Dodd, G. Lamont, P. Tittensor & M.-J. King (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. Unknown parameter |month= ignored (help)
  33. ↑ Casale, Maddalena; Perrotta, Silverio (2014). "Splenectomy for hereditary spherocytosis: complete, partial or not at all?". Expert Review of Hematology. 4 (6): 627–635. doi:10.1586/ehm.11.51. ISSN 1747-4086.
  34. ↑ Sayeeda Huq, Mark A. C. Pietroni, Hafizur Rahman & Mohammad Tariqul Alam (2010). "Hereditary spherocytosis". Journal of health, population, and nutrition. 28 (1): 107–109. PMID 20214092. Unknown parameter |month= ignored (help)
  35. ↑ Sayeeda Huq, Mark A. C. Pietroni, Hafizur Rahman & Mohammad Tariqul Alam (2010). "Hereditary spherocytosis". Journal of health, population, and nutrition. 28 (1): 107–109. PMID 20214092. Unknown parameter |month= ignored (help)

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