Thalassemia is classified according to the amino acid chain involved, mainly alpha thalassemia (alpha chain involvement) and beta thalassemia (beta chain involvement). It can also be classified as mild or severe thalassemia according to one or two gene defects. α-thalassemia is mostly seen in blacks (25% of blacks have at least one gene defect), and β-thalassemia is mostly seen in Mediterranean regions or Southeast Asia. It has been reported in all provinces south of the Yangtze River in China, with a higher incidence in Guangdong, Guangxi, Hainan, Sichuan, Chongqing and other provinces, and is less common in the north. If a couple is a carrier of homozygous thalassemia, each pregnancy has a 1/4 chance of having a normal child, 1/2 chance of being a carrier, and another 1/4 chance of being a patient with thalassemia major, therefore, it is a very important disease in terms of genetic counseling and prenatal diagnosis.
Three types of thalassemia.
(1) Heavy: anemia, progressive worsening of hepatosplenomegaly, jaundice, and dysplasia appearing in the first few days of life, with specific manifestations such as a large head, widened eye spacing, saddle nose, prominent forehead, and prominent cheeks, which are typified by a breech head, and fractures of the long bones are possible. The skeletal changes are caused by hyperhematopoietic bone marrow, widening of the bone marrow and thinning of the cortex. In a few patients, thoracic masses occur between the ribs and spine, and gallstone disease and lower limb ulcers may also be seen. Common complications include acute pericarditis, secondary hypersplenism, and secondary hemochromatosis.
(2) Intermediate type: mild to moderate anemia, most patients can survive into adulthood.
(3) Mild: mild anemia or asymptomatic, usually found during family history investigation.
Etiology and pathogenesis
The disease is due to deletion or point mutation of the pearlin gene. There are 4 types of peptide chains that make up the pearl protein, namely α, β, γ and δ chains, which are encoded by their corresponding genes. The deletion or point mutation of these genes can cause the impaired synthesis of various peptide chains, resulting in the alteration of hemoglobin components. Usually, thalassemia is divided into 4 types, such as α, β, δβ and δ, among which β and α thalassemia are more common.
1, β-thalassemia: The human β-luciferin gene cluster is located at 11p15, 5. β-thalassemia (referred to as β-thalassemia) occurs mainly due to point mutations of genes, and a few are gene deletions. Gene deletions and some point mutations can lead to complete suppression of β chain production, called β0 thalassemia; some point mutations lead to partial suppression of β chain production, called β+ thalassemia.
There are more mutations in the β-depleted gene, and more than 100 mutation points have been found so far, 28 of which have been found in China. There are six common mutations: ① β41-42 (-TCTT ), accounting for about 45%; ② IVS-Ⅱ654 ( C → T ), accounting for about 24%; ③ β17 ( A → T ); accounting for about 14%; ④ TATA box- 28 ( A → T ), accounting for about 9%; ⑤ β71-72 ( +A ), accounting for about 2%; ⑥ β26 ( G → A ), i.e. HbE26, accounting for about 2%.
Heavy β-depletion is a pure heterozygote of β0 or β+ depletion or a double heterozygote of β0 and β+ depletion, because the β-chain production is completely or almost completely inhibited, so that the synthesis of HbA containing β-chain is reduced or disappeared, while the excess α-chain combines with γ-chain and becomes HbF( a2 γ2), which makes HbF increase significantly. Due to the high oxygen affinity of HbF, it causes hypoxia in patient tissues. The excess α chains are deposited in young erythrocytes and erythrocytes, forming α chain inclusion bodies attached to the erythrocyte membrane and stiffening them, which are mostly destroyed in the bone marrow and lead to “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; these inclusion bodies also affect the permeability of the red blood cell membrane, resulting in a shortened life span of the red blood cells. For these reasons, the children present clinically with chronic hemolytic anemia. Anemia and hypoxia stimulate increased secretion of erythropoietin, which induces increased hematopoiesis in the bone marrow, thus causing skeletal changes. Anemia increases iron absorption from the intestine and, together with repeated blood transfusions during treatment, results in massive iron storage in the tissues, leading to iron-containing hemoglobin deposition.
Mild-type geodystrophy is a heterozygous state of β0 or β+ geodystrophy in which the synthesis of β chains is only mildly reduced, so its pathophysiological changes are extremely mild. Intermediate β-thalassemia is a double heterozygous state of some β+-thalassemia and pure heterozygous state of some variants of β-thalassemia, or double heterozygous state of two different variants of dyscrasia, and its pathophysiological changes are between heavy and light.
2. α-thalassemia: The human α-zucin gene cluster is located at 16Pter -p13, 3. There are 2 α-zucin genes on each chromosome, and a total of 4 α-zucin genes on a pair of chromosomes. Most alpha thalassemia (referred to as alpha thalassemia) is due to deletion of the alpha globin gene, and a few are caused by point mutations. If only one alpha gene on one chromosome is missing or defective, the synthesis of the alpha chain is partially inhibited, and it is called alpha+ thalassemia; if two alpha genes on each chromosome are missing or defective, it is called alpha0 thalassemia.
Severe α-dysplasia is a pure state of α0-dysplasia, in which all 4 α-jugin genes are missing or defective, resulting in the complete absence of α-chain production, and thus the synthesis of HhA, HbA2 and HbF, which contain α-chains, is reduced. A large amount of γ-chain synthesis γ4 (Hb Bart’s) occurs during fetal life, and the affinity of Hb Bart’s for oxygen is extremely high, causing tissue hypoxia and fetal edema syndrome. Intermediate and α-dysplasia is a heterozygous state of α0 and α+-dysplasia, which is caused by the deletion or defect of three α-juicein genes, and the patient can only synthesize a small amount of α chains, and the excess β chains are synthesized into HbH (β4). HbH has a high affinity for oxygen and is an unstable hemoglobin, which is easily denatured and precipitated in the erythrocytes to form inclusion bodies, causing the erythrocyte membrane to stiffen and shorten the life span of erythrocytes.
Mild type α-dysplasia is α+-dysplasia pure or α0-dysplasia heterozygous state, it only has 2 α-luciferin genes missing or defective, so there is a considerable amount of α-chain synthesis, and the pathophysiological changes are mild. It has only one alpha gene deletion or defect, and the synthesis of alpha chain is slightly reduced, and the pathophysiological changes are very mild.
Clinical manifestations and laboratory tests
(I) β-thalassemia
According to the different severity of the disease, it is divided into the following 3 types.
1. Heavy: also known as Cooley’s anemia. The child is asymptomatic at birth, and the onset of the disease begins at 3 to 12 months of age, with chronic progressive anemia, pallor, large liver and spleen, dysplasia, and often mild xanthogranuloma, with symptoms becoming more pronounced with age. Due to compensatory bone marrow hyperplasia, the bones become larger and the marrow cavity is widened, first in the metacarpals and later in the long bones and ribs; after the age of 1 year, the skull changes significantly, showing a larger skull, a bulging forehead, high cheekbones, a collapsed nasal bridge, and a wider distance between the eyes, resulting in a special face of thalassemia. Children with thalassemia are often affected by bronchitis or pneumonia. When the disease is complicated by ferritinosis, the excessive iron deposited in the myocardium and other organs such as liver, pancreas and pituitary gland causes the corresponding symptoms of damage to these organs, the most serious of which is heart failure, which is the result of myocardial damage caused by anemia and iron deposition, and is one of the important causes of death in children. If the disease is not treated, most of them die before the age of 5 years.
Laboratory tests: peripheral blood picture shows small cell hypochromic anemia with variable size of erythrocytes, enlarged central lightly stained area, anomalous, target-shaped, fragmented erythrocytes and nucleated erythrocytes, dot-colored erythrocytes, multi-staining erythrocytes, and Howe’s vesicles; reticulocytes are normal or elevated. The bone marrow picture showed a markedly active proliferation of the erythroid system, with a predominance of intermediate and late juvenile erythrocytes, and the mature erythrocyte changes were the same as in peripheral blood. The HbF content is significantly increased, mostly >0.40, which is an important basis for the diagnosis of severe β-depletion. Cranial X-ray shows thinning of the inner and outer plates of the skull, widening of the plate barrier, and vertical short hair-like bone spurs between the bone cortex.
2. Light: The patient is asymptomatic or mildly anemic, and the spleen is not large or mildly enlarged. The disease has a good course and can survive to old age. The disease is easily overlooked and is mostly detected during family investigations in heavy patients.
Laboratory tests: Mature erythrocytes have mild morphological changes, erythrocyte osmotic fragility is normal or reduced, hemoglobin electrophoresis shows increased HbA2 content (0,035-0,060), which is the characteristic of this type, and HbF content is normal.
3. Intermediate type: symptoms appear mostly in young children, and its clinical manifestations are between light and heavy, with moderate anemia, mild or moderately large spleen, with or without xanthogranuloma, and mild skeletal changes.
Laboratory tests: changes in peripheral blood and bone marrow picture, such as heavy, decreased erythrocyte permeability fragility, HbF level of about 0.40-0.80, HbA2 level is normal or increased.
(II) Alpha thalassemia
1.Static type: The patient is asymptomatic. The erythrocyte morphology is normal, and the Hb Bart’s content in the cord blood at birth is 0.01~0.02, but it disappears after 3 months.
2. Light type: Patients are asymptomatic. There are mild changes in the morphology of red blood cells, such as unequal size, central light staining, and heterogeneity; the permeability fragility of red button cells is reduced; the denatured pearl protein vesicles are positive; the content of HbA2 and HbF is normal or slightly low. The Hb Bart’s level of umbilical cord blood is 0,034~0,140, which disappears completely at 6 months after birth.
3. Intermediate type: Also known as hemoglobin H disease. The clinical manifestations of this type vary greatly, and the time of appearance of anemia and the severity of anemia vary. Most of them gradually develop anemia, fatigue and weakness, hepatosplenomegaly, and mild xanthogranuloma after infancy; older patients may develop a special face similar to that of heavy β-teratopia. Acute hemolysis can be induced by combined respiratory tract infection or oxidizing drugs or antimalarial drugs, which can aggravate the anemia and even cause hemolytic crisis.
Laboratory tests: peripheral blood picture and bone marrow picture are similar to those of severe β-teratopia; erythrocyte osmotic fragility is reduced; degenerate beadlets are positive; HbA2 and HbF levels are normal. The blood contains about 0.25 Hb Bart’s and a small amount of HbH at birth; with age, HbH gradually replaces Hb Bart’s, and its content is about 0.024-0.44. Inclusion body production test is positive.
4, Heavy: also known as Hb Bart’s fetal edema syndrome. The fetus is often aborted at 30-40 weeks, stillborn or dies within half an hour after delivery, and the fetus is severely anemic, xanthogranuloma, edema, hepatosplenomegaly, ascites and pleural fluid. The placenta is large and brittle.
Laboratory tests: The morphology of peripheral blood is altered as in severe β-depletion, with a marked increase in nucleated and reticulocytes. The hemoglobin is almost exclusively Hb Bart’s or with a small amount of HbH, without HbA, HbA2 and HbF.
Diagnosis and differential diagnosis
The diagnosis can generally be made based on clinical features and laboratory tests, combined with a positive family history. When available, genetic diagnosis can be made. The disease must be differentiated from the following diseases.
1. Iron deficiency anemia: The clinical manifestations and morphological changes of red blood cells in thalassemia minor are similar to those of iron deficiency anemia, so it is easy to be misdiagnosed. However, iron deficiency anemia is often differentiated by the presence of iron deficiency triggers, reduced serum ferritin content, reduced extracellular iron granulocytes, elevated erythrocyte free protophylin, and effective iron therapy.
2, infectious hepatitis or cirrhosis: because HbH disease is less anemic, but also accompanied by hepatosplenomegaly, xanthogranuloma, a few cases can also have liver function damage, so it is easy to be misdiagnosed as xanthogranulomatous hepatitis or cirrhosis. However, it can be differentiated by medical history questioning, family investigation and observation of red blood cell morphology and hemoglobin electrophoresis examination.
Treatment
No special treatment is needed for mild forms of thalassemia. Intermediate and severe cases should be treated by one or more of the following methods.
1. General treatment: pay attention to rest and nutrition, and actively prevent infection. Take appropriate folic acid and vitamin E supplements.
2. Blood transfusion and iron removal therapy: This method is still one of the important treatment methods at present.
Red blood cell transfusion: The small amount transfusion method is only applicable to intermediate α and β geodynia, and is not advocated for heavy β geodynia. For heavy β-depletion, medium and high volume transfusion should be given from early stage in order to make the child’s growth and development close to normal and prevent bone lesions. The method is: first, repeated transfusion of concentrated red blood cells to make the child’s hemoglobin level reach 120-150g/L; then, 10-15ml/kg of concentrated red blood cells should be transfused every 2-4 weeks to maintain the hemoglobin level above 90-105g/L. However, this method can easily lead to iron-containing hemoglobinosis, so iron chelating agent should be given at the same time.
3, iron chelating agent: commonly used deferoxamine ( deferoxamine ), can increase iron excretion from the urine and feces, but can not prevent the absorption of iron in the gastrointestinal tract. The iron load is usually assessed after 1 year or 10-20 units of regular infusion of red blood cells, and iron chelating agents are started if there is iron overload (e.g. SF >1000μg/L). Desferrioxamine 25-50 mg/kg daily, once a night for 12 hours continuously subcutaneously or added to isotonic glucose solution for 8-12 hours; 5-7 days a week for long-term application. Or add to red blood cell suspension for slow infusion. Desferrioxamine side effects are not significant, occasionally allergic reactions, long-term make angle even can cause cataract and long bone development disorder, too large a dose can cause vision and hearing loss. Vitamin C combined with chelation can enhance the effect of desferrioxamine from urinary iron excretion, the dose is 200rng/day. Agaricus is a traditional blood tonic formula in China, and ferrous lactate is a good bivalent iron tonic preparation, and many blood tonic products on the market use them as a separate formula. Iron edge tablets, however, use ferrous lactate, gum and zinc protein all as efficacious ingredients, which can better prevent and improve anemia and enhance human immunity by combining the three effects of iron supplementation, blood production plus nutrition.