Disease name:
Introduction:
Thalassemia is also known as maritime anemia. Is a group of hereditary small cell hemolytic anemia. A common feature is that one or more of the globin peptide chains in hemoglobin are reduced or not synthesized due to defects in the globin gene. Lead to changes in the composition of hemoglobin, the clinical symptoms of this group of diseases vary in severity, mostly manifested as chronic progressive hemolytic anemia.
Cause:
[Etiology and pathogenesis]
The disease is caused by a deletion or point mutation of the globin gene. There are four kinds of peptide chains constituting globin, namely α, β, γ, δ chains, which are respectively encoded by their corresponding genes. Deletions or point mutations of these genes can cause synthesis obstacles of various peptide chains, resulting in components of hemoglobin. change. Thalassemia is usually divided into four types: α, β, δβ, and δ, among which β and α thalassemia are more common.
1. Beta thalassemia The human beta globin gene cluster is located at 11p15.5. The occurrence of beta thalassemia (referred to as beta thalassemia) is mainly due to point mutations in genes, and a few are gene deletions. Gene deletion and some point mutations can completely inhibit the production of β-chain, called β0 thalassemia; some point mutations inhibit the production of β-chain, which is called β+ thalassemia.
There are more mutations in the β-thalassaemia gene, and more than 100 mutation points have been discovered so far, and 28 have been found in China. There are 6 common mutations: 1 β41-42 (-TCTT), accounting for about 45%; 2 IVS-II654 (C → T), accounting for about 24%; 3β17 (A → T); about 14%; 4TATA Box - 28 (A → T), about 9%; 5 β71-72 (+A), about 2%; 6 β26 (G → A), that is, HbE26, about 2%.
Heavy beta thalassemia is homozygous for β0 or β+ thalassemia or double heterozygous for β0 and β+ thalassemia, because β-strand formation is completely or almost completely inhibited, so that HbA synthesis with β-chain is reduced or disappeared, and redundant The α chain is combined with the γ chain to become HbF( a2 γ2), which significantly increases HbF. Due to the high oxygen affinity of HbF, the patient's tissue is hypoxic. Excess a-chain is deposited in the red blood cells and red blood cells, and the a-chain inclusion bodies are attached to the red blood cell membrane to make them stiff, and are mostly destroyed in the bone marrow, resulting in "ineffective hematopoiesis". Some of the red blood cells containing inclusion bodies mature and are released into the peripheral blood, but they are easily destroyed when they pass through the microcirculation; this inclusion body also affects the permeability of the red blood cell membrane, resulting in shortened life of red blood cells. For the above reasons, the child is clinically chronic hemolytic anemia. Anemia and hypoxia stimulate the secretion of erythropoietin, which causes the bone marrow to increase hematopoiesis, thus causing bone changes. Anemia increases the absorption of iron by the intestines, and repeated blood transfusions during the treatment process cause iron to be stored in large quantities in the tissue, resulting in hemosiderosis.
Light thalassemia is a heterozygous state of β0 or β+ thalassemia, and the synthesis of β-strand is only slightly reduced, so its pathophysiological changes are extremely mild. Intermediate beta thalassemia is a double heterozygote of some β+ thalassemia and homozygous for some thalassemia variants, or a double heterozygous state of two different variant globin-producing anemias, the pathophysiological changes Between heavy and light.
2. alpha thalassemia human a globin gene cluster is located at 16Pter-p13.3. There are 2 a-bead genes in each chromosome, and a pair of chromosomes have 4 a-globin genes. Most a thalassemia (abbreviated as a thalassemia) is due to the deletion of the a-globin gene, and a small number is caused by gene point mutations. If only one gene on a chromosome is missing or defective, the synthetic part of the alpha chain is inhibited, called a+ thalassemia; if two a genes on each chromosome are missing or defective, it is called a0 thalassemia.
Heavy alpha thalassemia is a homozygous state of a0 thalassemia, and its four a-globin genes are all deleted or defective, so that no a-chain is formed at all, and thus the synthesis of HhA, HbA2 and HbF containing a-chain is reduced. A large number of gamma-chain synthesis gamma 4 (Hb Bart's) occurs in the fetal phase. Hb Bart's has a very high affinity for oxygen, causing tissue hypoxia and causing fetal edema syndrome. The intermediate type and alpha thalassemia are heterozygous states of α0 and a + thalassemia, which are caused by deletion or defect of three a-globin genes. The patient can only synthesize a small amount of α chain, and the excess β chain is synthesized HbH (β4). ). HbH has a high affinity for oxygen and is an unstable hemoglobin. It is easy to denature and precipitate in red blood cells to form inclusion bodies, which causes the erythrocyte membrane to be stiff and shorten the life of red blood cells.
Light alpha thalassemia is a+ homosexual homozygous or a0 thalassemia heterozygous state. It has only 2 a-globin gene deletions or defects, so there is a considerable amount of a-chain synthesis, and the pathophysiological changes are slight. The static a thalassemia is a heterozygous heterosexual state, which has only one alpha gene deletion or defect, the synthesis of the a chain is slightly reduced, and the pathophysiological changes are very slight.
symptom:
Clinical manifestation and diagnosis
Most of the disease occurs when the baby is sick, showing anemia, weakness, and abdomen ablation. Developmental delay, etc., heavy and long-growing dysplasia, often died before the age of adulthood. Light and intermediate patients can generally live to adulthood and can participate in labor. If you pay attention to diet and diet, you can reduce complications and improve symptoms. Insufficient endowment and weak kidney are the main reasons. The kidney is a congenital one, and the kidney is not full. Then biochemical passive. "Children's labor, get the mother's womb." It can be seen that 'Tonzi Labor' is closely related to parents. Kidney essence does not charge at the same time also affects the function and growth of the spleen and stomach of the day after tomorrow. The appearance of jaundice, accumulation, etc., has resulted in this false and misleading certificate.
Hemoglobin quantification is a method of routine clinical diagnosis. The increase in HbA2 is the basis for the diagnosis of mild beta thalassemia. The HbF of severe beta thalassemia usually increases, sometimes to 90%; the increase in HbA2 is usually above 3%. In alpha thalassemia syndrome, the percentage of HbA2 and F is generally normal, and its diagnosis often depends on other causes of exclusion of small cell anemia. HbH disease can be diagnosed when hemoglobin electrophoresis shows rapid movement of HbH or Bart fragments. Recombinant DNA profiling techniques (especially using polymerase chain reaction methods) are important in prenatal diagnosis and genetic counseling.
In the severe beta thalassemia, X-ray examination of the bone showed a characteristic of chronic bone marrow hyperactivity. The cortical layers of the skull and long bones become thinner and the bone marrow cavity becomes wider. The space of the skull stenosis is obvious, and the trabecular trabeculae have a "sun ray"-like radiation pattern. Osteoporosis may occur in long bones. Cones and skulls may be in the form of particles or frosted glass. The finger (toe) bone loses its normal shape and is rectangular or even convex on both sides.
(a) beta thalassemia
According to the severity of the disease, it is divided into the following three types.
1. Heavy, also known as Cooley anemia. The child is asymptomatic at birth, and begins to develop from 3 to 12 months. It is chronic progressive anemia, pale, liver and spleen, stunted, often with mild jaundice, and the symptoms become increasingly obvious with age. Due to the compensatory proliferation of bone marrow, the bones become larger and the medullary cavity is widened, first in the metacarpal bone, and later in the long bones and ribs. After 1 year old, the skull changes obviously, and the head becomes enlarged, the frontal bulge, the sacral height, and the nasal bridge collapse. The distance between the two eyes widens to form a special face of thalassemia. Children often have bronchitis or pneumonia. When concurrent with hemosiderosis, due to excessive iron deposition in the heart muscle and other organs such as liver, pancreas, pituitary gland, etc., the corresponding symptoms of the organ damage, the most serious of which is heart failure, it is The result of myocardial damage caused by anemia and iron deposition is one of the important causes of death in children. If the disease is not treated, it will die more than 5 years old.
Laboratory examination: peripheral blood is small cell hypochromic anemia, red blood cell size varies, central light-stained area is enlarged, abnormal shape, target shape, debris red blood cells and nucleated red blood cells, spotted red blood cells, polychromatic red blood cells, Hao - Zhou's body, etc.; reticulocytes are normal or increased. Bone marrow is markedly active in the red blood cell system, with medium and late red blood cells accounting for the majority, and mature red blood cells are the same as peripheral blood. Red blood cell osmotic fragility is significantly reduced. The HbF content is significantly increased, mostly >0.40, which is an important basis for the diagnosis of heavy β thalassemia. The X-ray of the skull shows that the inner and outer plates of the skull are thinned, the barriers are widened, and vertical short-like spurs appear between the cortical bones.
2. Mild patients have asymptomatic or mild anemia, and the spleen is not large or slightly enlarged. The course of the disease is good and can survive to the old age. The disease is easily overlooked and was found in a family survey of severe patients.
Laboratory examination: mature red blood cells have mild morphological changes, red blood cell penetration is better than normal or reduced, hemoglobin electrophoresis shows increased HbA2 content (0.035 ~ 0.060), which is the characteristics of this type. The HbF content is normal.
3. The intermediate type has more symptoms than the young one. The clinical manifestation is between light and heavy, moderate anemia, mild or moderate spleen, jaundice may be optional, and bone changes are lighter.
Laboratory examination: changes in peripheral blood and bone marrow, such as heavy, red blood cell osmotic fragility, HbF content of about 0.40 ~ 0.80, HbA2 content is normal or increased.
(b) a thalassemia
1. The static patient is asymptomatic. The morphology of red blood cells is normal. The Hb Bart's content in cord blood at birth is 0.01-0.02, but disappears after 3 months.
2. Light patients are asymptomatic. The morphology of red blood cells is slightly changed, such as different sizes, central light staining, and abnormal shape; red osmotic osmotic fragility is reduced; denatured globin is positive; HbA2 and HbF are normal or slightly lower. The umbilical cord blood Hb Bart's content in children is 0.034 ~ 0.140, completely disappeared at 6 months after birth.
3. The intermediate type is also called hemoglobin H disease. The clinical manifestations of this type vary greatly, and the time of anemia and the severity of anemia are different. Most of them gradually develop anemia, fatigue, liver spleen and mild jaundice after infancy; older patients may have a special face similar to heavy beta thalassemia. Combined with respiratory infections or taking oxidative drugs, anti-malarial drugs, etc. can induce acute hemolysis and aggravate anemia, and even hemolytic crisis.
Laboratory examination: changes in peripheral blood and bone marrow are similar to heavy beta thalassemia; red blood cell osmotic fragility is reduced; denatured globin bodies are positive; HbA2 and HbF levels are normal. At birth, the blood contains about 0.25Hb Bart's and a small amount of HbH; with age, HbH gradually replaces Hb Bart's, which is about 0.024 to 0.44. The inclusion body formation test was positive.
4. Heavy, also known as Hb Bart's fetal edema syndrome. The fetus often died after 30 to 40 weeks of abortion, stillbirth or half an hour after delivery. The fetus is severely anemia, jaundice, edema, hepatosplenomegaly, ascites, and pleural effusion. The placenta is large and crisp.
Laboratory examination: Morphological changes of mature red blood cells in peripheral blood such as heavy β thalassemia, nucleated red blood cells and reticulocytes were significantly increased. Almost all hemoglobin is Hb Bart's or a small amount of HbH, no HbA, HbA2 and HbF.
diagnosis:
According to clinical features and laboratory tests, combined with a positive family history, a diagnosis can generally be made. When there are conditions, genetic diagnosis can be made. The disease must be identified with the following diseases.
1. Iron deficiency anemia The clinical manifestations of mild thalassemia and morphological changes of red blood cells are similar to those of iron deficiency anemia, so they are easily misdiagnosed. However, iron deficiency anemia often has iron deficiency causes, serum ferritin content is reduced, red blood cells in the bone marrow are reduced, red blood cells are free of leaves, and iron treatment is effective.
2. Infectious hepatitis or cirrhosis is mild due to HbH disease, accompanied by hepatosplenomegaly and jaundice. In a few cases, liver function damage may occur, so it is easily misdiagnosed as jaundice hepatitis or cirrhosis. However, it can be identified by medical history inquiry, family survey, red blood cell morphology observation, and hemoglobin electrophoresis.
complication:
1. Excess iron accumulation: Long-term blood transfusion can cause iron deposits and excessive iron accumulation can cause damage to multiple organs. The main affected are the heart, liver, pancreas and various endocrine organs. Patients with heart failure, cirrhosis, liver function decline, diabetes, and short stature and hypoplasia due to multiple endocrine disorders.
2. Reactions caused by blood transfusion: Adverse reactions caused by common blood transfusions include fever, chills and rashes. More severe reactions such as acute hemolysis, tracheal contraction, and decreased blood pressure are rare, but they must not be ignored.
3. Diseases transmitted by blood transfusion: mainly transmitted by blood transfusion is a viral disease. Although multiple preventive measures have reduced the chance of infection during the whole process of blood transfusion, there are occasional cases of hepatitis C and hepatitis B due to blood transfusion. As for the spread of HIV, it can be said that it is extremely rare. Of the above three viruses, only hepatitis B can be prevented by an effective vaccine.
4. Spleen enlargement: Under the stimulation of long-term anemia and hemolysis, many people with severe and moderate anemia will have problems with spleen enlargement. Excessive spleen will exacerbate anemia and require patients to receive a greater amount of blood transfusions leading to more severe iron accumulation. Timely removal of a large spleen can often improve the situation.
5. Formation of gallstones: Long-term hemolysis makes thalassemia patients more likely to suffer from gallstones than the average person. Patients with gallstones may often develop symptoms of upper right abdominal pain, skin, yellowing of the eyes, and brown urine.
6. Side effects of iron removal: It is worth mentioning that iron medicine sometimes affects vision, hearing and bone growth. Therefore, the injection amount of iron-removing drugs should be determined according to the amount of iron accumulation. Do not increase or decrease the amount of iron.
treatment:
Light thalassaemia requires no special treatment. Intermediate and severe thalassemia should be treated by one or more of the following methods.
1. General treatment pay attention to rest and nutrition, and actively prevent infection. Appropriate supplementation of folic acid and vitamin E.
2. Blood transfusion and de-iron therapy This method is still one of the important treatment methods.
A small infusion of red blood cell infusion is only applicable to intermediate alpha and beta thalassemia and is not recommended for heavy beta thalassemia. For severe β-thalassaemia, moderate and high-volume blood transfusion should be given from the early stage to make the child grow and develop close to normal and prevent bone lesions. The method comprises the following steps: firstly infusion of concentrated red blood cells, so that the hemoglobin content of the child reaches 120-150 g/L; then infusion of concentrated red blood cells 10-15 ml/kg every 2 to 4 weeks, so that the hemoglobin content is maintained at 90-105 g/L. the above. However, this method is prone to lead hemosiderosis, so it should be treated with iron sputum mixture at the same time.
3. Iron sputum mixture is commonly usedDeferoxamine(deferoxamine), which can increase iron excretion from urine and feces, but does not prevent the absorption of iron from the gastrointestinal tract. Iron load assessment is usually performed after regular infusion of red blood cells for 1 year or 10 to 20 units. If iron overload (eg SF >1000 μg/L) is applied, the iron sputum mixture is applied. Deferoxamine daily 25~50mg/kg, 1 subcutaneous injection for 12 hours per night, or intravenous infusion of isotonic glucose for 8 to 12 hours; 5 to 7 days per week, long-term application. Or add a slow infusion of red blood cell suspension. Deferoxamine has little side effects, occasionally allergic reactions, long-term horns can cause cataracts and long bone development disorders, too much dose can cause vision and hearing loss. The combination of vitamin C and chelating agents enhances the action of deferoxamine from iron in the urine at a dose of 200 rng/day.
4. Splenectomy and splenectomy have better curative effect on blood red and white β-thalassaemia, and poor effect on heavy β-thalassaemia. Splenectomy can cause weakened immune function, and should be performed after 5 to 6 years of age and strictly control the indications.
5. Hematopoietic Stem Cell Transplantation Allogeneic hematopoietic stem cell transplantation is currently a method that can cure severe beta thalassemia. If there is a HLA-matched hematopoietic stem cell donor, it should be the preferred method for treating severe beta thalassemia.
6. Gene activation therapy The application of chemical drugs can increase the expression of γ gene or reduce the expression of α gene to improve the shape of β thalassemia.Hydroxyurea5-Azacytidine (5-AZC), cytarabine, malilan, isoniazid, etc. are currently being explored.
prevention:
1. Carry out crowd census and genetic counseling, and make pre-marital guidance to avoid marriage between the carriers of thalassaemia genes, which is of great significance for the prevention of this disease. Using genetic analysis for prenatal diagnosis, it can diagnose the severe β and alpha thalassemia fetus in early pregnancy and stop the pregnancy in time to avoid the occurrence of fetal edema syndrome and the birth of severe β thalassemia patients. An effective method.
2. Mediterranean-type anemia belts have the same appearance and growth as normal people.
3. The supplement of vitamins is the same as ordinary people, and is given when the doctor thinks it is necessary. Because the appearance is not easy to detect the disease, iron is often given to the blood, should pay attention.
4. Pre-marital check-up: The married person should check whether it is a Mediterranean-type anemia-bearing person, and if so, pay special attention to prenatal examination.
5. Prenatal examination: If both husband and wife are carriers, the fetal examination should be taken after the 12th week of pregnancy. If it is determined to be a Mediterranean-type anemia, the fetus can be aborted to avoid the burden of future care.
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