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| | __NOTOC__ |
| {{Infobox_Disease | | {{Infobox_Disease |
| | Name = Hereditary elliptocytosis | | | Name = Hereditary elliptocytosis |
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| | ICDO = | | | ICDO = |
| | OMIM = | | | OMIM = |
| | MedlinePlus = | | | MedlinePlus = 000563 |
| | MeshID = | | | MeshID = |
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| {{SI}} | | {{Hereditary elliptocytosis}} |
| {{CMG}}
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| {{EH}}
| | '''For patient information click [[Hereditary elliptocytosis (patient information)|here]]''' |
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| ==Overview==
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| '''Hereditary elliptocytosis''' is a blood disorder in which a large proportion of the sufferer's [[erythrocytes]] (i.e. red blood cells) are [[ellipse|elliptical]] rather than bi-[[concave]] disc-shaped. It is also known as ovalocytosis. The disorder predisposes to [[haemolytic anaemia]].
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| ==Historical perspective==
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| Elliptocytosis was first described in 1904, and was first recognised as a [[heredity|hereditary]] condition in 1932. More recently it has become clear that there is much genetic [[heterogeneity]] amongst sufferers, and the severity of the condition is highly variable.
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| ==Aetiology==
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| 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. 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, and that those of African and Mediterranean descent are of higher risk. Some subtypes of hereditary elliptocytosis are significantly more prevalent in regions where [[malaria]] is [[Endemic (epidemiology)|endemic]]. For example, in equatorial Africa its incidence approaches 160 per 10,000, and in Malayan natives its incidence is over 15% (1500-2000 per 10,000). Being an almost wholly [[autosomal dominant]] disorder, there is no predilection towards either sex in hereditary elliptocytosis. The most important exception to this rule of autosomal dominant inheritance is for a subtype of hereditary elliptocytosis called [[hereditary pyropoikilocytosis]] (HPP). This condition is [[autosomal recessive]].
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| [[Image:Autosomal Dominant Pedigree Chart.svg|thumb|left|140px|Figure 1 - A pedigree showing the typical inheritance pattern of an [[autosomal dominant]] trait.]]
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| There are a number of different subtypes of hereditary elliptocytosis. 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. The following categorisation of the disorder demonstrates its heterogeneity (in approximate order from least severe to most severe)<ref>{{cite journal| author = Coetzer T, Lawler J, Prchal JT and Palek J| year=1987 |month=September |title =Molecular Determinants of Clinical Expression of Hereditary Elliptocytosis and Pyropoikilocytosis| journal = [[Blood (journal)|Blood]]| volume=70| issue=3| pages=491-588| url=http://www.bloodjournal.org/cgi/reprint/70/3/766.pdf| format=PDF| accessdate=2006-10-31}}</ref>:
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| *'''Common hereditary elliptocytosis'''
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| **With [[asymptomatic]] carrier status - ''the individual has no symptoms of disease and diagnosis is only able to be made on [[blood film]]''
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| **With mild disease - ''the individual has no symptoms and a mild and compensated haemolytic anaemia''
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| **With sporadic [[haemolysis]] - ''the individual has a predilection towards haemolysis in the presence of particular [[comorbidities]], including [[infection]]s, and [[Cyanocobalamin|vitamin B{{ssub|12}}]] deficiency''
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| **With [[neonate|neonatal]] [[poikilocytosis]] - ''during the first year of life'' only ''the individual has a symptomatic haemolytic anaemia with poikilocytosis''
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| **With [[chronic]] haemolysis - ''the individual has a moderate to severe symptomatic haemolytic anaemia (this subtype has variable [[penetrance]] in some [[Pedigree chart|pedigrees]])''
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| **With [[Zygosity|homozygosity]] or compound [[Zygosity|heterozygosity]] - ''depending on the exact mutations involved, the individual may lie anywhere in the spectrum between having a mild haemolytic anaemia and having a life-threatening haemolytic anaemia with symptoms mimicking those of HPP (see below)''
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| **With [[pyropoikilocytosis]] (HPP) - ''the individual is typically of African descent and has a life-threateningly severe haemolytic anaemia with micropoikilocytosis (small and misshapen erythrocytes) that is compounded by a marked instability of erythrocytes in even mildly elevated temperatures (pyropoikilocytosis is often found in burns victims and is the term is commonly used in reference to such people)
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| *'''Spherocytic elliptocytosis''' (also called '''hereditary haemolytic ovalocytosis''') - ''the individual is typically of European descent and both elliptocytes and spherocytes are simultaneously present in their blood''
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| *'''South-east Asian ovalocytosis''' (SAO) (also called '''stomatocytic elliptocytosis''') - ''the individual is of South-East Asian descent (typically Malaysian, Indonesian, Melanesian, New Guinean or Filipino, has a mild haemolytic anaemia, and has resistance to [[malaria]]''
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| ==Pathophysiology==
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| ===Common hereditary elliptocytosis===
| | {{SK}} Elliptocytosis, hereditary |
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| A number of genes have been linked to common hereditary elliptocytosis. These mutations have a common end result; they destabilise the [[cytoskeleton|cytoskeletal]] scaffold of cells. This stability is especially important in erythrocytes as they are constantly under [[shear stress|shear forces]] which deform them. 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 which are deformed as a result of passing through a capillary are forever rendered elliptical. These elliptocytotic 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).
| | ==[[Hereditary elliptocytosis overview|Overview]]== |
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| [[Image:Cytoskeleton (Elliptocytosis).JPG|thumb|left|450px|Figure 2 - A schematic diagram representing the relationships between cytoskeletal molecules as relevant to hereditary elliptocytosis.]] | | ==[[Hereditary elliptocytosis historical perspective|Historical Perspective]]== |
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| The most common genetic defects (present in two-thirds of all cases of hereditary elliptocytosis) are in genes for the [[polypeptide]]s α-spectrin or β-spectrin. These two polypeptides combine with one another ''in vivo'' to form an αβ [[dimer|heterodimer]]. These αβ heterodimers then combine together to form [[spectrin]] [[tetramer]]s. These spectrin tetramers are among the basic structural subunits of the cytoskeleton of all cells in the body. Although there is much interindividual variability, it is generally true that 'α'-spectrin mutations result in an inability of α-spectrin to interact properly with β-spectrin to form a heterodimer. In contrast, it is generally true that 'β'-spectrin mutations lead to αβ heterodimers being incapable of combining to form spectrin tetramers<ref>{{cite journal| author = McMullin MF| year=1999| month=April| title=The molecular basis of disorders of the red cell membrane| journal=Journal of Clinical Pathology| volume=52| issue=4| pages=245-248| url=http://www.pubmedcentral.gov/picrender.fcgi?artid=501324&blobtype=pdf| format=PDF| accessdate=2006-11-02}}</ref>. The end result is a weakness in the cytoskeleton of the cell. Individuals with a single mutation in one of the spectrin genes are usually asymptomatic, but those who are homozygotes or are compound heterozygotes (i.e. they are heterozygous for two different elliptocytosis-causing mutations) have sufficient [[cell membrane]] instability to have a clinically significant [[haemolytic anaemia]].
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| Less common than spectrin mutations are [[protein 4.1]] mutations. Spectrin tetramers must bind to [[actin]] in order to create a proper cytoskeleton scaffold, and protein 4.1 is an important protein involved in the stabilisation of the link between spectrin and actin. Similarly to the spectrin mutations, protein 4.1 mutations cause a mild haemolytic anaemia in the heterozygous state, and a severe haemolytic disease in the homozygous state. Erythrocytes of individuals who are homozygous for this mutation type show not only a destabilised cytoskeleton but also disorder of molecules within the cell membrane itself, which is evidence that protein 4.1 plays some part in maintaining the normal organisation of the cell membrane.
| | ==[[Hereditary elliptocytosis classification|Classification]]== |
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| The third group of mutations which lead to elliptocytosis are those which cause [[glycophorin C]] deficiencies. There are three phenotypes caused by abnormal glycophorin C, these are named Gerbich, Yus and Leach (see [[glycophorin C]] for more information). Only the rarest of the three, the Leach phenotype, causes elliptocytosis. Glycophorin C has the function of holding protein 4.1 to the cell membrane. It is thought that elliptocytosis in glycophorin C deficiency is actually the consequence of a protein 4.1 deficit, as glycophorin C deficient individuals also have reduced intracellular protein 4.1 (probably due to the reduced number of binding sites for protein 4.1 in the absence of glycoprotein C). ''[[Plasmodium falciparum]]'' (the [[pathogen]] responsible for malaria) has a surface protein called erythrocyte-binding antigen 140, which is now known to bind to glycophorin C. This suggests that ''plasmodium falciparum'' is less able to bind to the erythrocytes of those with the Leach phenotype, suggesting these individuals have a relative resistance to malaria. Clinically, this has not yet been shown.
| | ==[[Hereditary elliptocytosis pathophysiology|Pathophysiology]]== |
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| Multiplication of mutations tends to infer more serious disease. For instance, in HPP, the most common [[genotype]] results from receiving 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 which causes the affected individual's cells to preferentially produce the defective α-spectrin rather than normal α-spectrin.
| | ==[[Hereditary elliptocytosis differential diagnosis|Differentiating Hereditary elliptocytosis from other Diseases]]== |
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| ===Spherocytic elliptocytosis=== | | ==[[Hereditary elliptocytosis epidemiology and demographics|Epidemiology and Demographics]]== |
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| The molecular defect associated with spherocytic elliptocytosis has yet to be elucidated. As with common hereditary elliptocytosis, multiple gene defects are probably capable of causing this phenotype. Mutations in the genes coding for β-spectrin, glycophorin C and [[protein 4.2]] have all been implicated in spherocytic elliptocytosis. Except for protein 4.2 linked disease (which is autosomal recessive), spherocytic elliptocytosis is an autosomal dominant condition.
| | ==[[Hereditary elliptocytosis risk factors|Risk Factors]]== |
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| ===Southeast Asian ovalocytosis=== | | ==[[Hereditary elliptocytosis screening|Screening]]== |
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| The primary defect in SAO differs significantly from other forms of elliptocytosis in that it is a defect in the gene coding for a protein that is not directly involved in the cytoskeleton scaffolding of the cell. Rather, the defect lies in a protein known as the [[band 3 protein]], which lies in the cell membrane itself. The band 3 protein normally binds to another membrane-bound protein called [[ankyrin]], but in SAO this bond is stronger than normal. Other abnormalities include tighter tethering of the band 3 protein to the cell membrane, increased [[tyrosine]] [[phosphorylation]] of the band 3 protein, reduced [[sulfate]] [[anion]] transport through the cell membrane, and more rapid [[Adenosine triphosphate|ATP]] consumption. These (and probably other) consequences of the SAO mutations lead to the following erythrocyte abnormalities<ref>{{cite journal| author = Liu S, Palek J, Yi SJ, Nichols PE, Derick LH, Chiou S, Amato D, Corbett JD, Cho MR and Golan DE| year=1995| month=July| date=1 July 1995| title=Molecular Basis of Altered Red Blood Cell Membrane Properties in Southeast Asian Ovalocytosis: Role of the Mutant Band 3 Protein in Band 3 Oligomerization and Retention by the Membrane Skeleton| journal=[[Blood (journal)|Blood]]| volume=86| issue=1| pages=349-358| url=http://www.bloodjournal.org/cgi/reprint/86/1/349.pdf| format=PDF| accessdate=2006-10-31}}</ref>:
| | ==[[Hereditary elliptocytosis natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| *a greater robustness of cells to a variety of external forces, including:
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| **a reduction in cellular sensitivity to [[osmosis|osmotic]] pressures
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| **a reduction in fragility related to temperature change
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| **greater general rigidity of the cell membrane
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| **loss of sensitivity to substances which cause [[spicule|spiculation]] of cells
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| *reduced anion exchange
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| *partial [[intracellular]] depletion of ATP
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| *a reduction in expression of multiple [[antigens]]
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| These changes are thought to give rise to the scientifically and clinically interesting phenomenon that those with SAO exhibit - a marked ''in vivo'' resistance to infection by the causative pathogen of [[malaria]], ''[[Plasmodium falciparum]]''. Unlike those with the Leach phenotype of common hereditary elliptocytosis (see above), there is a clinically significant reduction in both disease severity and prevalence of malaria in those with SAO. Because of this, the 35% incidence rate of SAO along the north coast of Madang Province in Papua New Guinea, where malaria in endemic, is a good example of [[natural selection]]<ref>{{cite journal| author = Mgone CS, Koki G, Paniu MM, Kono J, Bhatia KK, Genton B, Alexander ND and Alpers MP| year=1996 |month=May-June |title=Occurrence of the erythrocyte band 3 (AE1) gene deletion in relation to malaria endemicity in Papua New Guinea| journal = Transactions of the Royal Society of Tropical Medicine and Hygiene| volume=90| issue=3| pages=228-231| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8758056&dopt=Abstract| format=| accessdate=2006-10-31}}</ref>.
| | ==Diagnosis== |
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| [[Image:Malaria Enters Erythrocyte.JPG|thumb|left|340px|Figure 3 - A representation of the steps involved in the entry of ''Plasmodium falciparum'' into an erythrocyte.]] | | [[Hereditary elliptocytosis diagnostic study of choice|Diagnostic Study of Choice]] | [[Hereditary elliptocytosis history and symptoms|History and Symptoms ]] | [[ Hereditary elliptocytosis physical examination|Physical Examination]] | [[Hereditary elliptocytosis laboratory findings|Laboratory Findings]] | [[Hereditary elliptocytosis electrocardiogram|Electrocardiogram]] | [[Hereditary elliptocytosis chest x ray|Chest X Ray]] | [[Hereditary elliptocytosis CT|CT]] | [[Hereditary elliptocytosis MRI|MRI]] | [[Hereditary elliptocytosis ultrasound|Ultrasound]] | [[Hereditary elliptocytosis other imaging findings|Other Imaging Findings]] | [[Hereditary elliptocytosis other diagnostic studies|Other Diagnostic Studies]] |
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| The reasons behind the resistance to malaria become clear when given an explanation the way in which ''Plasmodium falciparum'' invades its host. This parasite is an [[obligate intracellular parasite]], which must enter the cells of the host it is invading. The band 3 proteins aggregate on the cell membrane at the site of entry, forming a circular [[orifice]] that the parasite squeezes through. These band 3 proteins act as [[Receptor (biochemistry)|receptors]] for the parasite. Normally a process much like [[endocytosis]] occurs, and the parasite is able to isolate itself from the intracellular proteins that are toxic to it while still being inside an erythrocyte (see figure 2). The increased rigidity of the erythrocyte membrane in SAO is thought to reduce the capacity of the band 3 proteins to cluster together, thereby making it more difficult for the malaria parasite to properly attaching to and enter the cell. The reduced free ATP within the cell has been postulated as a further mechanism behind which SAO creates a hostile environment for ''Plasmodium falciparum''.
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| ==Treatment== | | ==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.
| | [[Hereditary elliptocytosis medical therapy|Medical Therapy]] | [[Hereditary elliptocytosis surgery |Surgery]] | [[Hereditary elliptocytosis primary prevention|Primary Prevention]] | [[Hereditary elliptocytosis secondary prevention|Secondary Prevention]] | [[Hereditary elliptocytosis cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Hereditary elliptocytosis future or investigational therapies|Future or Investigational Therapies]] |
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| [[Folate]] helps to reduce the extent of haemolysis in those with significant haemolysis due to hereditary elliptocytosis. | | ==Case Studies== |
| | [[Hereditary elliptocytosis case study one|Case #1]] |
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| Because the [[spleen]] is the bodily organ which breaks down old and worn-out blood cells, those individuals with more severe forms of hereditary elliptocytosis can have a [[splenomegaly]] which causes a worsening of the signs and symptoms of their anaemia. These can include:
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| *Vague, poorly localised abdominal pain
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| *Fatigue and [[dyspnoea]]
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| *Growth failure
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| *Leg ulcers
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| *[[Gallstones]].
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| 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 [[neonate]]s 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.
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| 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.
| | {{Hematology}} |
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| ==Prognosis==
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| Those with hereditary elliptocytosis have a good [[prognosis]], only those with very severe disease have a shortened [[life expectancy]].
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| ==References==
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| {{reflist|2}} | |
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| ==External link==
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| * [http://www.nlm.nih.gov/medlineplus/ency/article/000563.htm MedlinePlus Entry]
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| {{Hematology}}
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| {{SIB}}
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| [[sr:Елиптоцитоза]] | | [[sr:Елиптоцитоза]] |
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