Hereditary elliptocytosis, also known as ovalocytosis, is an inherited blood disorder in which an abnormally large number of the person's
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.
Presentation
RBCs are elleptical in shape rather than normal biconcave shape.
Most cases are asymptomatic with abnormalities in their peripheral blood film.
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):
These mutations have a common 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).
EL2 and EL3: The most common genetic defects (present in two-thirds of all cases of hereditary elliptocytosis) are in genes for the
polypeptides α-spectrin or β-spectrin. These two polypeptides combine with one another in vivo to form an αβ
heterodimer. These αβ heterodimers then combine to form
spectrintetramers. 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.[1] In both cases 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.[citation needed]
EL1: Less common than spectrin mutations are
band 4.1 mutations. Spectrin tetramers must bind to
actin in order to create a proper cytoskeleton scaffold, and band 4.1 is an important protein involved in the stabilisation of the link between spectrin and actin. Similarly to the spectrin mutations, band 4.1 mutations cause a mild haemolytic anaemia in the heterozygous state, and a severe haemolytic disease in the homozygous state.[citation needed]
Another group of mutations that lead to elliptocytosis are those that 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 band 4.1 to the cell membrane. It is thought that elliptocytosis in glycophorin C deficiency is actually the consequence of a band 4.1 deficit, as glycophorin C deficient individuals also have reduced intracellular band 4.1 (probably due to the reduced number of binding sites for band 4.1 in the absence of glycoprotein C).[citation needed]
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.[2]
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. This risk is relative to the severity of the disease.[citation needed]
Folate helps to reduce the extent of haemolysis in those with significant haemolysis due to hereditary elliptocytosis.[citation needed]
Because the
spleen breaks down old and worn-out blood cells, those individuals with more severe forms of hereditary elliptocytosis can have
splenomegaly. Symptoms of splenomegaly can include:[citation needed]
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.[citation needed]
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.[4] 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 United States,[5] 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,[6] and in
Malayan natives its incidence is 1500-2000 per 10,000.[7] 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.[8]
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.[citation needed]
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:[9]
Common hereditary elliptocytosis (in approximate order from least severe to most severe)
With
asymptomatic carrier status - individuals have no symptoms of disease and diagnosis is only able to be made on
blood film
With mild disease - individuals have no symptoms, with a mild and compensated haemolytic anaemia
With
neonatalpoikilocytosis - individuals have a symptomatic haemolytic anaemia with poikilocytosis that resolves in the first year of life
With
chronic haemolysis - individual has a moderate to severe symptomatic haemolytic anaemia (this subtype has variable
penetrance in some
pedigrees)
With
homozygosity or compound
heterozygosity - depending on the exact mutations involved, individuals 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)
With
pyropoikilocytosis (HPP) - individuals are typically of African descent and have 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)
South-east Asian ovalocytosis (SAO) (also called stomatocytic elliptocytosis) - individuals are of South-East Asian descent (typically
Malaysian,
Indonesian,
Melanesian,
New Guinean or
Filipino, have a mild haemolytic anaemia, and has increased resistance to
malaria
Spherocytic elliptocytosis (also called hereditary haemolytic ovalocytosis) - individuals are of European descent and elliptocytes and spherocytes are simultaneously present in their blood
History
Elliptocytosis was first described in 1904,[10] and was first recognised as a
hereditary condition in 1932.[11] More recently it has become clear that the severity of the condition is highly variable,[12] and there is much genetic
variability amongst those affected.[13]