Hereditary elliptocytosis

Hereditary elliptocytosis

Peripheral blood smear showing an abundant number of elliptocytes
Classification and external resources
Specialty hematology
ICD-10 D58.1
ICD-9-CM 282.1
OMIM 611804
DiseasesDB 4172
MedlinePlus 000563
eMedicine ped/987 med/648
MeSH D004612

Hereditary elliptocytosis, also known as ovalocytosis, is an inherited blood disorder in which an abnormally large number of the patient's erythrocytes (i.e. red blood cells) are elliptical rather than the typical biconcave disc shape. Such morphologically distinctive erythrocytes are sometimes referred to as elliptocytes or ovalocytes. It is one of many red-cell membrane defects. In its severe forms, this disorder predisposes to haemolytic anaemia. Although pathological in humans, elliptocytosis is normal in camelids.

Historical perspective

Elliptocytosis was first described in 1904,[1] and was first recognised as a hereditary condition in 1932.[2] More recently it has become clear that the severity of the condition is highly variable,[3] and there is much genetic variability amongst those affected.[4]

Genetic prevalence

The incidence of hereditary elliptocytosis is hard to determine, as many sufferers of the milder forms of the disorder are asymptomatic and their condition never comes to medical attention.[5] Around 90% of those with this disorder are thought to fall into the asymptomatic population. It is estimated that its incidence is between 3 and 5 per 10,000 in the USA,[6] and that those of African and Mediterranean descent are of higher risk. Because it can confer resistance to malaria, some subtypes of hereditary elliptocytosis are significantly more prevalent in regions where malaria is endemic. For example, in equatorial Africa its incidence is estimated at 60-160 per 10,000,[7] and in Malayan natives its incidence is 1500-2000 per 10,000.[8] Almost all forms of hereditary elliptocytosis are autosomal dominant, and both sexes are therefore at equal risk of having the condition. The most important exception to this rule of autosomal dominance is for a subtype of hereditary elliptocytosis called hereditary pyropoikilocytosis (HPP), which is autosomal recessive.[9]

There are three major forms of hereditary elliptocytosis: common hereditary elliptocytosis, spherocytic elliptocytosis and southeast Asian ovalocytosis.

Common hereditary elliptocytosis is the most common form of elliptocytosis, and the form most extensively researched. Even when looking only at this form of elliptocytosis, there is a high degree of variability in the clinical severity of its subtypes. A clinically significant haemolytic anaemia occurs only in 5-10% of sufferers, with a strong bias towards those with more severe subtypes of the disorder.

Southeast Asian ovalocytosis and spherocytic elliptocytosis are less common subtypes predominantly affecting those of south-east Asian and European ethnic groups, respectively.

The following categorisation of the disorder demonstrates its heterogeneity:[10]

Pathophysiology

Common hereditary elliptocytosis

A number of genes have been linked to common hereditary elliptocytosis (many involve the same gene as forms of Hereditary spherocytosis, or HS):

Type OMIM Gene
EL1 or HS5 611804 EPB41
EL2 or HS3 130600 SPTA1
EL3 or HS2 182870 SPTB
EL4 or HS4 or SEO 109270 SLC4A1

These mutations have a common end result; they destabilise the cytoskeletal scaffold of cells. This stability is especially important in erythrocytes as they are constantly under the influence of deforming shear forces. As disc-shaped erythrocytes pass through capillaries, which can be 2-3 micrometres wide, they are forced to assume an elliptical shape in order to fit through. Normally, this deformation lasts only as long as a cell is present in a capillary, but in hereditary elliptocytosis the instability of the cytoskeleton means that erythrocytes deformed by passing through a capillary are forever rendered elliptical. These elliptical cells are taken up by the spleen and removed from circulation when they are younger than they would normally be, meaning that the erythrocytes of people with hereditary elliptocytosis have a shorter than average life-span (a normal person's erythrocytes average 120 days or more).

Figure 2 - A schematic diagram representing the relationships between cytoskeletal molecules as relevant to hereditary elliptocytosis.

Inheritance of multiple mutations tends to infer more serious disease. For instance, the most common genotype responsible for HPP occurs when the affected individual inherits an α-spectrin mutation from one parent (i.e. one parent has hereditary elliptocytosis) and the other parent passes on an as-yet-undefined defect that causes the affected individual's cells to preferentially produce the defective α-spectrin rather than normal α-spectrin.

Diagnosis

The diagnosis of hereditary elliptocytosis is usually made by coupling a family history of the condition with an appropriate clinical presentation and confirmation on a blood smear. In general it requires that at least 25% of erythrocytes in the specimen are abnormally elliptical in shape, though the observed percentage of elliptocytes can be 100%. This is in contrast to the rest of the population, in which it is common for up to 15% of erythrocytes to be elliptical.[12]

If some doubt remains regarding the diagnosis, definitive diagnosis can involve osmotic fragility testing, an autohaemolysis test, and direct protein assaying by gel electrophoresis.[13]

Treatment

The vast majority of those with hereditary elliptocytosis require no treatment whatsoever. They have a mildly increased risk of developing gallstones, which is treated surgically with a cholecystectomy if pain becomes problematic.

Folate helps to reduce the extent of haemolysis in those with significant haemolysis due to hereditary elliptocytosis.

Because the spleen breaks down old and worn-out blood cells, those individuals with more severe forms of hereditary elliptocytosis can have a splenomegaly, splenectomy can be performed in case that their situation may cause a worsening of the signs and symptoms of their anaemia. These can include:

Removal of the spleen (splenectomy) is effective in reducing the severity of these complications, but is associated with an increased risk of overwhelming bacterial septicaemia, and is only performed on those with significant complications. Because many neonates with severe elliptocytosis progress to have only a mild disease, and because this age group is particularly susceptible to pneumococcal infections, a splenectomy is only performed on those under 5 years old when it is absolutely necessary.

Because chronic haemolysis increases an individual's risk of gallstones, people with elliptocytosis have an increased risk of suffering from gallstones. This risk is relative to the severity of the disease, and those with symptomatic elliptocytosis should have regular abdominal ultrasounds to monitor the progression of their gall bladder disease.

Prognosis

Those with hereditary elliptocytosis have a good prognosis, only those with very severe disease have a shortened life expectancy.

See also

References

  1. ↑ Dresbach M (1904). "Elliptical human red corpuscles". Science 19 (481): 469–470. doi:10.1126/science.19.481.469. PMID 17730874.
  2. ↑ Hunter, WC (1932). "Further study of a white family showing elliptical erythrocytes". Ann Intern Med 6: 775–781. doi:10.7326/0003-4819-6-6-775.
  3. ↑ Gallagher, Pg (2005). "Red cell membrane disorders." (Free full text). Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program 2005 (1): 13–8. doi:10.1182/asheducation-2005.1.13. PMID 16304353.
  4. ↑ Tse, Wt; Lux, Se (January 1999). "Red blood cell membrane disorders.". British journal of haematology 104 (1): 2–13. doi:10.1111/j.1365-2141.1999.01130.x. ISSN 0007-1048. PMID 10027705.
  5. ↑ Kim, D (24 May 2006). "Elliptocytosis, Hereditary". Medscape. WebMD LLC. Retrieved 12 August 2013.
  6. ↑ Bannerman, Rm; Renwick, Jh (July 1962). "The hereditary elliptocytoses: clinical and linkage data.". Annals of Human Genetics 26 (1): 23–38. doi:10.1111/j.1469-1809.1962.tb01306.x. ISSN 0003-4800. PMID 13864689.
  7. ↑ Hoffman, R; Benz, E; Shattil, S; Furie, B; Cohen, H (2005). Hoffman Hematology: Basic Principles and Practice (4th ed.). Philadelphia: Churchill Livingstone. ISBN 0-443-06628-0.
  8. ↑ Cattani, Ja; Gibson, Fd; Alpers, Mp; Crane, Gg (1987). "Hereditary ovalocytosis and reduced susceptibility to malaria in Papua New Guinea." (Free full text). Transactions of the Royal Society of Tropical Medicine and Hygiene 81 (5): 705–9. doi:10.1016/0035-9203(87)90001-0. ISSN 0035-9203. PMID 3329776.
  9. ↑ Kutlar, A (22 October 2013). "Hereditary Pyropoikilocytosis". Medscape. WebMD LLC. Retrieved 29 January 2015.
  10. ↑ Coetzer T, Lawler J, Prchal JT, Palek J (1 September 1987). "Molecular determinants of clinical expression of hereditary elliptocytosis and pyropoikilocytosis". Blood 70 (3): 766–72. PMID 3620700.
  11. ↑ McMullin MF (1999). "The molecular basis of disorders of the red cell membrane". J. Clin. Pathol. 52 (4): 245–8. doi:10.1136/jcp.52.4.245. PMC 501324. PMID 10474512.
  12. ↑ Gerard M. Doherty (2010). Current Diagnosis & Treatment - Surgery (13th ed.). McGraw Hill Professional. pp. 204–5. ISBN 978-0-07-163515-8. Retrieved 5 May 2011.
  13. ↑ Robert S. Hillman; Kenneth A. Ault; Henry M. Rinder (2005). Hematology in clinical practice: a guide to diagnosis and management (4th ed.). McGraw-Hill Professional. p. 147. ISBN 978-0-07-144035-6. Retrieved 5 May 2011.

External links

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