Hereditary Elliptocytosis

Introduction to hereditary elliptic polycythemia Hereditary ellipsoidosis is a hereditary disease characterized by an increase in oval cells in peripheral blood to more than 25%. Normal people may have a small number of elliptical red blood cells in the peripheral blood, but no more than 15%, and in patients with hereditary neutropenia, the cells are at least 25%, more often more than 75%, and even more Up to 90%. The ratio of the transverse diameter to the longitudinal diameter of the elliptical red blood cells does not exceed 0.78. Patients with hereditary ellipsoid hyperplasia have hemolysis, and only 10% to 15% of patients with hemolytic anemia occur clinically. basic knowledge The proportion of illness: 0.002% Susceptible people: no special people Mode of infection: non-infectious Complications: hemolytic anemia, jaundice, splenomegaly, gallstones

Causes of hereditary elliptic polycythemia

Cause:

Ordinary HE is mostly autosomal dominant, a few is autosomal recessive, and SAO and HPP are autosomal genetic diseases.

Pathogenesis:

1. Molecular lesions The primary lesion of HE is an abnormality of the membrane skeleton, mainly involving the protein in the horizontal direction of the membrane skeleton, namely: membrane contractile protein-membrane protein-4.1 protein-membrane contractile protein, in normal cell membrane, membrane contraction More than 90% of the protein is present in tetramer form ( chain and chain form a dimer, two dimers form a tetramer by docking), and the dimer does not exceed 5%. In the cell membrane of HE patients, the membrane The content of contractile protein is mostly normal, but the structure is abnormal, can not be connected to each other, mainly in the form of dimer (normal people only account for 5% to 8%), can not form tetramers, and the stability of membrane skeleton lacking tetramer is reduced. The content of dimer in the membrane is directly related to the instability of the membrane. According to the reason that the membrane shrinkage protein cannot form a tetramer, the membrane protein abnormality can be divided into:

1 membrane contractile protein (including alpha chain and beta chain) is abnormal;

24.1 protein abnormality;

3 blood glycoprotein C (or D) is abnormal, 70% to 80% of HE has one or more of the above membrane proteins abnormalities.

(1) Membrane contractile protein: Membrane contractile protein abnormality is caused by the simultaneous deficiency of chain, chain or both chains. chain abnormality is the most common. More than 20 mutations have been found, and chain mutation mainly occurs at N-terminal I. One of the 106 amino acids in the region causes a change in the hydrolysis site of trypsin. This fragment becomes smaller, affecting the docking point between the dimers, and cannot form a tetramer. For example, the I/74 mutation leads to . The amino acid of the N-terminal part of the chain is hydrolyzed to form an incomplete chain with a molecular weight of 74 kD (normal MW: 80 kD), and the I/65 mutation forms an chain with a molecular weight of 65 kD. These incomplete chains and chains can form a dimer. However, they cannot be docked to form tetramers. Such abnormalities are caused by genetic mutations. Recently, the II region of the alpha chain may also be abnormal, and 20% to 30% of asymptomatic HE is caused by such mutations. In other words, the chain abnormality determines the dimer docking ability, that is, the ratio of dimer to tetramer, and the content of dimer in the membrane is positively correlated with the clinical severe disease. From this point of view, I/74 is the heaviest. I/50 or I/40 second, I/65 again, whether the alpha chain abnormality appears clinically The shape also depends on the total amount of membrane contracting protein in the membrane skeleton and the proportion of abnormal membrane contracting protein. In common type HE, the total amount of membrane contracting protein is normal; the content of dimer is low, and the abnormal membrane shrinkage protein accounts for the total amount of membrane contracting protein. 25% to 50%; in HPP, the total amount of membrane contractile protein is reduced (can be reduced by 30%), the content of dimer is high, almost all membrane contractile proteins are abnormal, and the decrease of membrane contractile protein content in HPP may be due to alpha chain synthesis. The reduced or alpha chain is degraded prior to binding to the beta strand.

Another form of -chain abnormality is the LELY mutation (low-expression allele of the -chain gene), and the -LLY mutation forms an -chain with a molecular weight of only 40 kD, lacking the ability to bind to the -chain, and its main defect is the -chain gene. The 45th intron has an abnormality that affects mRNA splicing, skipping some of the 46th exon, so that this segment cannot be expressed, and this is exactly the key segment that is paired with the chain. This alpha chain is ineffective. However, there is generally no clinical manifestation, because the formation of normal chain far exceeds the chain, even if some of the chain is ineffective, it has no effect, but if other mutations of the chain gene are combined, there may be other obvious elliptic erythrocyte lesions. In some people, LELY carriers can be as high as 36% to 51%.

The abnormality of the C-terminus of the -chain can also affect the formation of tetramers. The point mutation of the -strand is rarely meaningful in heterozygotes, but in homozygotes, it can cause obvious atypical cells. In addition, -chain anomalies can affect anchors. Protein binding.

(2) Zone 4.1 protein abnormality: 20% to 40% of HE is caused by 4.1 protein deficiency, and a small part is 4.1 protein dysfunction. The normal function of 4.1 protein is to strengthen the binding of membrane contractile protein to actin. Its abnormality can affect the stability of the membrane skeleton. In heterozygotes, the 4.1 protein is reduced by about half. The clinical manifestation is normal HE or spheroidal HE with mild hemolysis. In homozygotes, 4.1 protein can be completely deficient. In the case of HPP with marked hemolysis, the extent of 4.1 protein deficiency is associated with decreased cell deformability and increased mechanical fragility.

(3) abnormal blood group glycoprotein C: blood type glycoprotein C and D (D is a variant of C) caused by HE is very rare, the clinical is generally common type HE, the symptoms are light, the osmotic fragility is slightly increased, actually it is light Degree of recessive spherical HE, peripheral blood elliptic cells are rare or even lacking, red blood cells lacking blood type glycoprotein C often have a lack of protein P55, and 4.1 protein content is also reduced, lack of blood type glycoprotein A or B red blood cell morphology and function All are normal.

(4) Others: Oral cell HE (Southeast Asian oval erythrocytosis) is mainly associated with zone 3 protein abnormalities. It has been found that 27 nucleotides are absent in the DNA encoding the 3 protein, resulting in a zone 3 protein. The 400th to 408th amino acids at the junction of the cytoplasmic and transmembrane regions are lost.

Changes in HE membrane proteins have been reported in different countries. Miraglia et al. (1994) reported that among the 61 HEs in 28 families in Italy, 18 (29%) had 4.1 protein partial deficiency and 31 (51%) had membrane contractile protein dimerization. 12 cases (20%) showed no abnormalities, 4.1 protein deficiency was milder, and membrane contractile protein dimers increased in severity, severity was related to dimer amount and membrane contractile protein content; Among the 16 cases of HE reported in Japan (1994), 13 cases were partially deficient in 4.1 protein, and the mutation of -chain of membrane contractile protein was rare, but 2 of the 7 cases reported globally were in Japan.

2. Mechanism of ellipsoidal red blood cell formation The mechanism of HE forming elliptical red blood cells is unclear. Normal red blood cells can form elliptical cells during aging. HE red blood cells can only form oval, nucleated red blood cells and erythrocytes after they are released from the bone marrow into the blood circulation. The reticulocyte morphology is normal. Normal red blood cells can also have an elliptical shape when they pass through capillaries or under shear force. Once they disappear through capillaries or external forces, they can return to normal morphology. Experiments prove that this mechanical effect If the duration is too long, the deformed red blood cells cannot return to the normal shape. This suggests that when the red blood cells are subjected to external force, the membrane skeleton protein may gradually reconnect, causing the cell morphology to change, but it can be restored, and the erythrocyte membrane protein of HE patients is presumed. There is a defect in the horizontal connection. Therefore, under the action of a certain shear force, the membrane skeleton protein reconnects and becomes an elliptical cell after the microcirculation, but the external force cannot be restored after normal removal, and the stability of the membrane skeleton is weakened. , has been confirmed: definitely related to membrane skeleton protein abnormalities Cells easily broken by an external force, and therefore, the more severe the disease, and shaped cells were disrupted cells the more.

According to HE analysis of 113 families in 61 families, Lecomte et al. pointed out that the degree of hemolysis is related to the proportion of membrane contractile protein dimer. More than 40% to 50% often have severe hemolysis, requiring splenectomy; How much depends on the mutation site, as well as the content of the membrane-shrinking protein in the membrane. The increase in membrane mechanical brittleness is related to the increase in the content of dimers that do not form tetramers, while the erythrocyte deformability is related to the amount of membrane-shrinking protein. As for the relationship with the morphology of red blood cells, it seems that the alpha "I/65" mutant has the largest number of elliptical red blood cells.

In each type of HE, most of the elliptical red blood cells are destroyed in the spleen and a small part is destroyed in the liver and bone marrow, which may explain that splenectomy can reduce hemolysis.

Hereditary elliptic polycythemia prevention

No anemia or only mild anemia, generally do not require treatment. If hemolysis is severe, spleen-cutting hereditary elliptic polycythemia can restore hemoglobin and reticulocytes to near normal. However, the abnormal shape of red blood cells became more obvious after splenectomy. Since some of the infants and children's HE can be relieved or relieved by themselves, the splenectomy should be considered after the age of 3, and it is better to have the spleen, preferably after 5 years of age. Asymptomatic or only mild anemia has little effect on health and does not require treatment. If there is more obvious hemolytic anemia, splenectomy should be done. The characteristics of oval red blood cells still exist after splenectomy, but hemolysis can be stopped or reduced, hemoglobin can return to normal, and complications caused by chronic chronic hemolysis, such as cholelithiasis, can be prevented.

Hereditary elliptic polycythemia complications Complications hemolytic anemia jaundice spleen gallstone

Hemolytic hemolytic anemia, jaundice, splenomegaly, can be complicated by gallstones and pure red blood cell aplastic anemia in the process of chronic hemolytic anemia.

Hereditary elliptic polycythemia symptoms common symptoms erythrocytosis hemolytic anemia red blood cell malformation

The most important feature of HE is that the oval blood cells in the peripheral blood are more than 25%, but its clinical symptoms and hematological changes are very different in different types of HE. Because there is not enough correlation between clinical manifestations and molecular lesions, Clinical classification can only be performed based on clinical performance and laboratory tests.

Ordinary (or light) HE is the most common, especially in African populations, which is dominantly inherited, heterozygous carriers are asymptomatic, no anemia, no splenomegaly, and the reticulocytes are slightly elevated, but rarely more than 3%. Peripheral blood plate oval erythrocyte increase, often more than 40%, molecular lesions are mostly membrane contraction protein defects, followed by 4.1 protein defects, very few blood group glycoprotein C deficiency, 10% to 15% of common type HE heterozygotes can simultaneously There is a membrane contraction protein "LELY" inherited, so there is obvious hemolysis, elliptical red blood cells and broken red blood cells correspondingly increased, homozygous common type HE is seriously ill, showing the following type (HPP).

Hereditary heat-induced polymorphism (HPP) is rare, is a recessive inheritance, membrane contraction protein itself is severely deficient in the connection, moderate to severe hemolytic anemia, visible broken red blood cells, deformed red blood cells, red blood cells are sensitive to heat (45 to 46 ° C is broken, normal red blood cells should be 49 ° C), severe membrane shrinkage protein is also reduced, splenectomy can reduce but can not completely correct anemia.

Spherical elliptic polycythemia is a rare somatic dominant disease with dual characteristics of HS and HE. It is mainly found in Europe. It has mild to moderate anemia. It can be seen in round oval cells and a little in blood. Spherical red blood cells, increased osmotic fragility, unlike other types of HE where hemolysis occurs, there is hemolysis but there are generally no abnormal cells and red blood cell fragments in the blood film. Splenectomy is effective, and some patients are due to a shortage of C-terminal ends of the membrane contractile protein chain. Molecular lesions in other patients are unknown.

Southeast Asia oval erythrocytosis is a somatic dominant disease, which can be as high as 30% among indigenous people in Melanesia, Indonesia, Malaysia, Philippines, etc., but rare in other areas, this disease is heterozygous (pure The morphological characteristics of blood cells in which zygotes cannot survive are that some red blood cells have a rod shape that crosses the central light-stained area to two. The membrane of this cell is particularly hard, which is due to the variation of the zone 3 protein (the inner segment of the plasma and the inner segment of the membrane The lack of 9 amino acids) caused by aggregation in the membrane, the Plasmodium can not invade this hard cell, the strange is that the cell deformability is poor, but only mild hemolysis, generally no anemia.

Examination of hereditary elliptic polycythemia

1. Red blood cell morphology: The shape of mature red blood cells in the peripheral blood is elliptical, oval, rod-shaped or sausage-shaped. The ratio of the transverse diameter to the longitudinal diameter of the cells is less than 0.78, and the number is greater than 25%. In addition, in the spherical cellular HE, there are still Small spherical red blood cells and small oval cells; in HPP, a large number of abnormal cells can be seen; in oral cellular HE, there are many cell membranes with stiff cell membranes, with rod-shaped segments in the center of the cells, and reticulocytes and nucleated red blood cells in normal morphology.

2. Brittleness test: Erythrocyte osmotic fragility is mostly normal in normal type HE, and is increased in patients with spheroidal HE, HPP and severe HE. The degree of increase is related to the ratio of spherical cells and atypical cells. The red blood cell autolysis test is in HPP and The globular cellular HE increased, and the addition of glucose or ATP was only partially corrected. Under the action of mechanical shear force, the erythrocyte membranes of common HE and HPP were prone to rupture (poor membrane stability, increased mechanical fragility), while oral cellular HE The red blood cells are stable, and the red blood cell deformability of each type of HE is reduced.

3. Thermal instability test: normal red blood cells rupture and membrane contraction protein degeneration at 49-50 °C, while HPP erythrocytes appear at 45-46 °C, but the thermal instability test is not specific, membrane contraction protein Other HEs caused by chain defects are sometimes positive, while a few typical HPPs are negative.

4. Analysis of erythrocyte membrane protein, the following abnormalities can be found by analyzing the erythrocyte membrane protein by SDS-PAGE:

14.1 protein deficiency or migration abnormalities;

2 membrane contractile protein deficiency (mainly seen in HPP);

3 Membrane protein chain or chain with abnormal molecular weight, SDS-PAGE combined with other methods can quantitatively analyze membrane protein components.

5. Low-ionic strength non-denaturing gel electrophoresis analysis of membrane contractile protein: The ratio of dimer and tetramer membrane contractile protein in erythrocyte membrane skeleton can be found by this method. Normal human, 90%-95% of membrane contractile protein is Tetramer, while in HE, the dimer content increases.

6. Analysis of trypsin hydrolyzed fragments of membrane contractile proteins: HE-expressed membrane contractile proteins were analyzed by planar gel electrophoresis after trypsin hydrolysis, and hydrolyzed fragments with abnormal size and migration speed were found.

7. Molecular biological methods: molecular biological methods can be used to directly detect membrane proteins with mutations.

Diagnosis and diagnosis of hereditary elliptic polycythemia

diagnosis

According to clinical manifestations, red blood cell morphology and family survey, the vast majority of HE can be clearly diagnosed, the vast majority of HE peripheral blood oval red blood cells are greater than 25%, generally up to 60% to 90%, rod cells can exceed 10%, Oval red blood cells can also be found in some normal people, but the number is rarely more than 15%, generally less than 5%, and rod cells are rare.

Differential diagnosis

Oval red blood cells can also be found in other blood system diseases such as: iron deficiency, myelofibrosis, myeloid anemia, myelodysplastic syndrome, megaloblastic anemia, thalassemia, pyruvate kinase deficiency, etc., but the above diseases except ellipse Outside of the red blood cells, there are many other special shaped cells and clinical signs. It is not possible to identify HE and the above diseases according to the number of oval red blood cells. The most reliable basis is family survey.

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