The thalassemia syndrome is a diverse set of hereditary illnesses caused by a genetic defect in the globin manufacturing process. The adult hemoglobin HbA (α2 β2) exhibits reduced or non-existent α or β-globin chain production. Chromosome 16 has the genes for α-globin, while chromosome 11 has the genes for β-globin.
• Thalassemia syndromes are endemic in the Indian subcontinent, tropical Africa (and their American ancestors), the Middle East, Asia, and the Mediterranean region.
• Autosomal codominant diseases, or thalassemias,
Grouping
The two primary forms of thalassemia syndromes are distinguished by the type of globin chain deficiency.
• β-thalassemia syndromes: These are defined by a decrease in globin β-chain production. The most frequent type of thalassemia syndrome is β-thalassemia, found in India and worldwide.
• α-thalassemia syndromes: These syndromes are defined by a decrease in the synthesis of globin α-chains. These are primarily found in India and the nations of Southeast Asia.
Clinical manifestations range from severe anemia to carriers who are completely asymptomatic. The globin chain imbalance that causes thalassemia syndromes' clinical and hematological characteristics.
• Microcytic hypochromic red blood cells result from diminished one globin chain production.
• Relative excess of other globin chains (α in β-thalassemia and β in α-thalassemia) due to uneven production and accumulation of the free chain. Hemolytic anemia and inadequate erythropoiesis result from this.
b-THALASSEMIA
A genetic condition known as β-thalassemia is characterized by reduced synthesis of structurally normal β-globin chains, whereas α-chain synthesis remains unaffected. Because the causing mutations are heterogeneous, the anemia's clinical severity varies.
The Study of Molecular Pathology
The genes for β-globin are found on chromosome 11. Numerous varieties of β-globin gene mutations have been found at the molecular level in β-thalassemia. These mutations can alter a single nucleotide base or cause the partial or total loss of a gene. For instance, a point mutation is most frequently observed when a single nucleotide base is substituted with a different base. Additional mutations consist of insertions or deletions.
The causal mutations are mostly divided into two groups based on the production of β-globin chains.
• Mutations with β0, which are characterized by the complete lack of β-globin production. For β0 -thalassemia, chain termination mutations are the most frequent cause.
• β+ mutations, which result in noticeably lessened or decreased (but still detectable) β-globin production. The most common cause of β+-thalassemia is splicing mutations.
β-thalassemia's pathophysiology
A. Implications of Faulty or Missing β-chains
• Anemia The following mechanisms generate it:
Diminished HbA synthesis: This results in "underhemoglobinized" microcytic, hypochromic RBCs with a subnormal ability for oxygen transport.
- Ineffective erythropoiesis: This disorder is characterized by the bone marrow's attempt to generate cells but its inability to deliver viable cells into the bloodstream. β-thalassemia major is linked to either decreased β-chain synthesis (β+) or its absence (β0). An imbalance in the synthesis of α- and β-globin leads to a reduced survival rate for red blood cells and their precursors. Since α-chain synthesis is normal, in developing normoblasts and red blood cells, these unstable free α-chains collect, precipitate, and form intracellular, insoluble inclusions.
- Extravascular hemolysis: α-chain inclusions are also present in RBCs that are discharged from the bone marrow. The α-chain inclusions lead to membrane damage in red blood cells. The aberrant progenitors, known as normoblasts, gave rise to the liberated red cells harboring inclusions in the α chain that escape
Hemolytic anemia is caused when the spleen destroys intramedullary apoptosis, which leads to extravascular hemolysis.
• Fetal hemoglobin (Hb F) production: Although γ-chain synthesis vanishes in Infants with thalassemia may continue to produce it after six months of age. Together, the Hb F (α2 γ2) is significantly elevated with α-chains; however, the amount varies. between 20 and 90%
B. Implications of Inefficient Erythropoiesis
• Modifications in the bone marrow: Severe hemolytic anemia causes the kidneys to produce more erythropoietin (EPO). EPO significantly increases erythroid hyperplasia in the bone marrow.
• Bone changes: The growing erythropoietic marrow drives the development of new bone on the exterior while eroding the bony cortex. This is particularly evident in the maxilla, facial bones, and skull vault. The X-ray of the skull shows the distinctive hair-on-end ("crew-cut") appearance caused by the creation of new bone. The thalassemic (Chipmunk) facies is a characteristic facies that develop with broad cheekbones, forehead (sometimes called frontal bossing), and upper jaw. Because of trabeculations, X-rays of the phalanges, metatarsals, and metacarpals show a mosaic pattern.
Extramedullary hematopoiesis: Extramedullary hematopoietic foci form in the liver and spleen, leading to hepatosplenomegaly since the bone marrow is unable to make up for the anemia.
• Cachexia: The majority of tissues experience hypoxia as a result of severe anemia, and these tissues compete with the metabolically active erythroid progenitors for the vital nutrients. Cachexia may result in people who are left untreated.
C. Iron Excess and Its Repercussions
• Iron excess causes include: - Enhanced duodenal absorption of dietary iron: The primary control mechanism for iron homeostasis is hepcidin, which is produced in the liver. Hepcidin regulates the uptake and storage of iron. Hepcidin levels in the blood are suppressed by ineffective erythropoiesis. A lower hepcidin level causes the body to absorb iron more readily.
Hemolysis. - Repeated transfusions (the standard course of therapy).
• Repercussions: Hemostasis and secondary iron overload result from a gradual iron overload. hemochromatosis. The parenchyma of organs is frequently harmed by excessive iron accumulation, most noteworthy in the pancreas, liver, and heart (significant cause of death).
β-Thalassemia Major β-thalassemia major also referred to as Mediterranean or Cooley's anemia, is characterized by homozygous β0/β0, β+/β+, or double heterozygous β0/β+. Southeast Asia, some sections of Africa, and Mediterranean countries are where it is most prevalent.
Clinical Characteristics
When hemoglobin production shifts from HbF to HbA, infants with thalassemia major are healthy at birth but experience moderate to severe anemia 6–9 months later. If treatment is not received, the clinical course is brief (primarily through repeated blood transfusions). Children that are untreated or not transfused experience growth retardation, which causes them to fail to thrive and pass away from anemia at the age of 4-5.
• In those who live longer, marrow hypercellularity results in marrow growth and broadening, which causes the traditional X-ray alterations. The face's swollen and deformed bones give rise to distinctive thalassemic facies.
• Liver and lymph nodes may also exhibit extramedullary hematopoiesis; splenomegaly: Spleen enlarges to 1500 g due to work hyperplasia and extramedullary hematopoiesis.
• While iron overload can cause hemosiderosis and secondary hemochromatosis, which primarily harm organs including the heart, liver, and pancreas, blood transfusions can still help treat anemia. Transplanting bone marrow is curative.
Results of the Lab
• Hemoglobin: In patients who have not received a transfusion, hemoglobin levels vary from 3 to 8 g/dL and anemia is mild to severe.
• RBC count: Compared to iron deficiency anemia, it is higher.
• Hematocrit: It is between 8 and 23%, and it is decreasing.
• Indexes of red cells:
- MCV: It significantly decreases between 45 and 70 feet.
MCHC: It is now between 22 and 30 g/dL.
MCH: It has been reduced to 20–28 pages.
- RDW: Unlike iron deficiency anemia, where it is elevated, red cell distribution width (RDW) is within normal bounds.
• Reticulocyte count: 5–15% of cells have an elevated count. However, given the poor erythropoiesis, the anemia severity is lower than anticipated.
• RBCs in a peripheral smear:
◆ Numerous target cells are present. They exhibit strong microcytic hypochromic anemia with moderate to marked variation in size (anisocytosis) and shape (poikilocytosis).
The target cell is an aberrantly shaped red blood cell.
Only the core and periphery of the red blood cell (RBC) seem hemoglobinized and target-like in this hemoglobin redistribution. It is apparent that normoblasts, or nucleated red cell precursors, exist in varied numbers.
They originate from extramedullary hematopoietic sites and are a result of "stress" erythropoiesis.
- Leukocytosis with a little left shift is present in WBCs.
- Platelets: Typical quantity
Bone marrow
• Cellularity: The bone marrow has a pronouncedly high cell count.
• M: E ratio: Depending on the severity of erythroid hyperplasia, it is reversed to 1:1 to 1:5.
• Erythropoiesis: There is a noticeable erythroid hyperplasia and it is normoblastic.
• There is normal myelopoiesis.
Normal is the megakaryopoiesis.
• There is a noticeable rise in bone marrow iron due to enhanced hemolysis and dietary absorption.
Biochemical results
• There is a rise in bilirubin, mostly unconjugated type.
• Urine's urobilinogen content rises, giving it a bright tint.
Serum haptoglobin levels are noticeably lower.
• Serum iron status: Significant increases have been observed in serum iron, serum ferritin, and transferrin saturation.
- An increase in iron levels results in a decrease in total iron binding capacity (TIBC).
Unique assessments
• There is an increase in HbF. In contrast to β+ thalassemia, the levels in β0 thalassemia are higher.
• Electrophoresis of hemoglobin
- In β+ thalassemia (β+/β+ or β0/β+ genotypes), exhibits bands of both HbA and HbF.
– Hb A is absent in βo thalassemia (β0 /β0 genotype) because no β-chains develop. Major hemoglobin is HbF, whereas HbA2 may be low or normal.
• One chromatographic method used as a confirmatory test is high-performance liquid chromatography (HPLC). In this, a matrix column is filled with a blood sample. Each type of hemoglobin is eluted at a different time and quantified after the mixture of hemoglobin is absorbed into the matrix.
• Calculating globin chain estimates: The typical α:β ratio is 1:1. If there is no β chain, this ratio changes to 5–30:1.
• Fetal hemoglobin resists alkali denaturation, but adult hemoglobin experiences denaturation, according to the alkali denaturation test for HbF. This test involves neutralizing and then alkalinizing a hemolysate, which denaturates adult hemoglobin and is precipitated by ammonium sulfate. Finally, the filtrate is obtained, and only Hb that is resistant to alkali is present. It is quantified and given as a proportion of the whole.
The acid elution slide test for F cells is a useful tool for examining how HbF is distributed among RBCs. Hemoglobins other than HbF are eluted from the RBCs using a citric acid—phosphate buffer (pH 3.3) on an air-dried peripheral blood smear. After staining, the distribution can be determined because only HbF is still present in the fixed RBCs. In healthy adults, 1–5% of RBCs have leftover Hb (F cells), and nearly all RBCs appear as ghosts. inherited perseverance
of fetal hemoglobin (HPFH) is a benign syndrome in which adults continue to produce considerable amounts of fetal hemoglobin (hemoglobin F). Most often in HPFH types, HbF is dispersed uniformly throughout RBCs (pan cellular distribution).
