thalassemia
Introduction
Introduction to globin-producing anemia A globin-forming anemia (also known as thalassemia) 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. basic knowledge The proportion of illness: the incidence rate is about 0.003%-0.005% Susceptible people: no specific population Mode of infection: non-infectious Complications: hemochromatosis diabetes
Cause
The cause of globin-forming anemia
Genetic factors (86%)
A normal person inherits two -globin genes (/) from both parents, and synthesizes sufficient -globin chains. If one or more defective genes are inherited from the parents, -globin-producing anemia is caused. The severity of clinical manifestations depends on the number of abnormal alpha genes. A normal person inherits a normal -globin gene from both parents and synthesizes a normal amount of -globin chain. If the abnormal gene is inherited from the parent, the disease is caused, and an abnormal gene is inherited from the parent and inherited from the other parent. A normal beta gene, the patient is heterozygous, that is, -globin-producing anemia, about half of the -chain synthesis, and the condition is reduced. If both parents inherit an abnormal gene, the patient is homozygous, that is, 0 beads. Protein-producing anemia, with little or no beta-chain formation, is a serious condition.
Pathogenesis
1. Alpha globin-producing anemia: Most of the genetic abnormalities causing the disease are gene deletions, and the number of alpha gene deletions is parallel to the degree of -globin chain deficiency and clinical manifestations, but a few patients have no alpha gene deletion. It is due to point mutation or several base deletion of gene, which affects RNA processing, mRNA translation or instability of -globin chain which leads to synthesis, and finally causes -globin chain deficiency. When -globin chain is lacking, it is not enough. The -globin chain is paired with -chain to form HbA, and the remaining -chain forms HbH(4), while -oxygen is too high, it is not suitable for transporting oxygen, and it is unstable, precipitates, forms inclusion bodies, causes hemolysis, when When the chain is completely absent, no HbF (22) is formed in the fetal period, only Hb Barts (4), and 4 has a very high affinity, and can not release enough oxygen to the tissue, so that the fetus is deprived of oxygen and died.
Fetal edema syndrome: the parents of the fetus are heterozygous for the normal gene and 0 gene, that is, both parents are (--/), the fetus unfortunately inherits the 0 gene of both parents, that is, the four genes are missing, no The formation of -chain, the normal fetal HbF (22) is absent, and the chain self-polymerizes to form Hb Barts (4). Hb Barts has high oxygen affinity, and emits less oxygen to the tissue, leading to fetal asphyxia. Most of the fetuses in this disease are pregnant. 30 to 40 weeks to become a stillbirth and abortion, or death a few hours after premature birth.
Hemoglobin H disease: one of the parents of the patient is 0 globin-producing anemia trait (--/), and the other is -globin-producing anemia trait (/-), and the patient inherits abnormal from both parents. The gene (-/-) causes hemoglobin H disease. The patient can only produce a small amount of -globin chain, and the / chain synthesis ratio is about 0.3 (normal ratio should be 1.0). Since the chain is insufficient, there is no chain. The paired -strands self-polymerize into 4 tetramers, that is, HbH. HbH not only has high oxygen affinity, but also releases less oxygen to tissues, and is unstable, and easily precipitates in red blood cells to form HbH inclusion bodies, which causes red blood cells to be destroyed in the spleen.
2. Beta globin-producing anemia: The molecular pathology of this disease is quite complicated. It is known that more than 50 kinds of gene mutations can cause this disease. These gene mutations can be roughly divided into five categories:
1 gene fragment deletion, resulting in the lack of -chain synthesis;
2 transcriptional mutations, single-base point mutations occur in the transcriptional regulatory region of the beta gene, reducing the transcription of the beta gene, resulting in insufficient synthesis of the beta strand;
3 processing mutations, that is, point mutations occur in the region that affects the formation of mRNA processing, resulting in the lack or deficiency of -chain synthesis;
4 termination of the mutation mutation, point mutation occurs in the translation termination code, the formation of abnormal mRNA, resulting in the lack of -chain synthesis;
5 frameshift mutation, deletion or insertion of one or several (non-3 or 3 multiple) bases, causing frame shift of the gene base arrangement, resulting in the lack of -chain synthesis, due to insufficient or missing -chain The chain that fails to pair with the chain is unstable, precipitation occurs, and chain inclusion bodies are formed in the red blood cells, causing the red blood cells to be destroyed in the bone marrow or the spleen, and the HbA (22) of the disease is reduced and HbF (22) HbA2 (22) increased, the mechanism of HbF increase may be due to the longer lifespan of HbF red blood cells (called F cells). The mechanism of HbA2 increase is that HbA is relatively decreased, and the second is that gene mutation causes adjacent gene expression. Increased sake.
Prevention
Globin-producing anemia prevention
In terms of mating, medical advice should be provided to patients to prevent homozygous 0 globin-producing anemia in the next generation. In both couples, heterozygous -globin-producing anemia, coping with fetal prenatal genetic diagnosis, avoiding homozygous 0 Birth of children with globin-producing anemia.
In view of the lack of root therapy and poor prognosis in this disease, positive family history should be advocated for premarital examination and fetal prenatal genetic diagnosis to avoid the birth of children with homozygous -globin-producing anemia.
Complication
Plaque protein-forming anemia complication Complications, hemochromatosis, diabetes
Giant spleen can cause functional sputum and then cause secondary infection and hemorrhage. It is easy to cause infection to become a common cause of death. Severe anemia requires long-term repeated blood transfusion, which will inevitably cause secondary hemochromatosis, leading to myocardial damage and sexual dysfunction, hypothyroidism, adrenal gland. Insufficient function, endocrine dysfunction such as diabetes, myocardial damage is another common cause of death.
Symptom
Symptoms of globin-producing anemia, common symptoms, cortical thinning, chronic anemia, hepatosplenomegaly, weakness, secondary infection
1. alpha globulin-producing anemia
Anemia can be born at birth, clinical manifestations of mild to moderate chronic anemia, accompanied by jaundice, hepatosplenomegaly, secondary infection, taking oxidant drugs can increase the instability of HbH and promote hemolysis, combined pregnancy can aggravate anemia The development of the patient is generally unaffected and the bone changes are not obvious.
2. Homozygous (0) globulin-producing anemia
The child was born at normal time. After several months of birth, HbF was gradually replaced by HbA (22). The child developed anemia, which was progressively aggravated. There may be fever, anorexia, diarrhea, jaundice, liver and spleen gradually growing. At the age of 4, the performance growth retardation, mental wilting, facial expressionless, weak and weak, bone marrow hematopoietic compensatory hyperplasia caused the bone marrow cavity to widen the cortical bone, resulting in the forehead, top bulge, skull enlargement, cheek Uplift, nose bridge collapse, maxillary and teeth protrusion, forming a special face, patients with chronic ulcers of the lower extremities, the sooner the onset, the heavier the symptoms.
3. Heterozygous () globin-producing anemia
These patients are also known as static or micro-beta-globin-producing anemia, because most patients have no anemia or other symptoms, and many of them are found in censuses, family surveys or other diseases. Red blood cells, red blood cell osmotic fragility is mildly reduced, HbA2 is mildly increased, and a small number of patients may have anemia, especially when combined with pregnancy or secondary infection, it is mild to moderate anemia, jaundice may occur, mild splenomegaly hemolytic anemia Inclusion of red blood cells, hemoglobin electrophoresis appears HbH band, can be diagnosed affirmatively, if the ratio of globin chain synthesis can be determined, it is confirmed that the / chain synthesis ratio is 0.3-0.6, instead of the normal ratio of 1.0, it can be further diagnosed. The -globin gene probe hybridization technique can accurately detect the gene abnormality (--/-), and make a gene diagnosis. The family survey can find that the parents of the patient are and 0 globin-producing anemia traits.
Examine
Examination of globin-producing anemia
1. alpha globulin-producing anemia
(1) Peripheral blood: Most of the anemia is mild to moderate (Hb 50-100g/L), red blood cells are hypochromic, visible red blood cells are visible, stained with tar tar blue, and HbH inclusions in red blood cells are gray-blue round Granular.
(2) Determination of the half-life of red blood cells by the 51C gamma labeling method showed that the red blood cell life was significantly shortened.
(3) A slight increase in serum bilirubin: indirect bilirubin.
(4) Bone marrow shows marked red hyperplasia: HbH inclusion bodies in red blood cells can be seen after staining.
(5) Hemoglobin electrophoresis analysis HbH accounted for 5% to 40%, HbA2 was reduced to 1% to 2%, HbF (including trace: Hb Basts) <3%, and the rest was HbA.
2. Homozygous (0) globulin globulin anemia
(1) Peripheral blood: Most of the anemia is severe (Hb<50g/L), the red blood cell size is uneven, and it is hypochromic. The target red blood cells, basophilic red blood cells and abnormal red blood cells can be seen.
(2) Red blood cell osmotic fragility is significantly reduced: When the sodium chloride concentration is reduced to 0.14%, hemolysis is not complete, and there are nucleated red blood cells, teardrop-shaped red blood cells and alpha-chain inclusion body red blood cells, and white blood cell and platelet counts are generally normal.
(3) After the red blood cells in the peripheral red blood cells and bone marrow were stained with methyl violet or tar tar blue, -chain inclusion bodies with granular or rough irregularity were observed.
(4) The bone marrow image is proliferating and active: the red line is significantly increased, and the iron staining shows that the hemosiderin particles such as iron granules increase.
(5) serum indirect bilirubin, free hemoglobin often increased: urinary urinary biliary and urobilin increased.
(6) Red blood cell half-life measurement showed a significant shortened life.
Hemoglobin electrophoresis or alkali denaturing experiments see a significant increase in HbF, mostly accounting for 60% to 90% of hemoglobin, a few less than 30%, HbA2 can be normal, reduced or slightly increased, HbA deficiency (homozygous) or a small amount (double heterozygous The ratio of synthesis of the chain to the chain is from 0 to 0.3.
3. Heterozygous () globin-producing anemia
Anemia is hypochromic, red blood cell size varies, basophilic dot cells increase, target red blood cells are different, red blood cell osmotic fragility is reduced, bone marrow shows erythroid hyperplasia, iron staining shows iron granules increase, red blood cell half-life The measurement shows that the life is normal or slightly shortened. The radioactive iron kinetics study can find that the plasma iron conversion rate is high, while the radioactive iron in the circulating blood red blood cell combination is low, indicating that there is no red blood cell formation in the bone marrow, and hemoglobin electrophoresis shows that HbA2 is increased (3%~ 8%), HbF is normal or slightly elevated, generally not more than 5%.
Homozygous (0) globulin produces anemia, X-ray examination shows osteoporosis, thinning of cortical bone, widening of bone marrow cavity, clear trabecular streak of radiation erect hair, and pathological fracture.
Diagnosis
Diagnosis and identification of globin-producing anemia
diagnosis
1. alpha globin-producing anemia
According to chronic hemolytic anemia, red blood cell inclusions, hemoglobin electrophoresis, HbH band can be diagnosed. If the globin chain synthesis ratio can be determined, it is confirmed that the / chain synthesis ratio is 0.3 to 0.6, and the normal ratio is 1.0, which can be further confirmed. In recent years, alpha-globin gene probe hybridization technology can accurately detect alpha gene abnormality (--/-) and make gene diagnosis. Family surveys revealed that the parents of the patients were and 0 globin-producing anemia traits.
2. Homozygous (0) globin-producing anemia
According to juvenile onset, severe hemolytic anemia, dysplasia, hepatosplenomegaly, specific bone X-ray signs, hemoglobin electrophoresis showed HbF>30% characteristics, clinical diagnosis is not difficult, family survey, and chain synthesis ratio determination and gene The analysis can be further confirmed. Currently, polymerase chain reaction combined with oligonucleotide probe hybridization method, or polymerase chain reaction combined with restriction endonuclease digestion method for gene analysis and prenatal gene diagnosis.
3. Heterozygous () globin-producing anemia
One of the parents of the patient is -globin-producing anemia. The patient has no clinical symptoms or mild anemia, the red blood cell size is uneven or there is target red blood cells, the osmotic fragility is reduced, the HbA2 is increased and the HbF is normal or slightly increased, which is consistent with the above performance. Can be diagnosed as heterozygous () globin-producing anemia, should pay special attention to the identification of this disease and simple iron deficiency anemia, / synthesis ratio determination can further confirm the diagnosis, using PCR binding oligonucleotide probe Dot blot hybridization, or PCR combined with restriction endonuclease digestion, can be used for genetic diagnosis and prenatal genetic diagnosis.
Generally not confused with other diseases.
