Leukemia (Blood Cancer)

 Beta thalassemia is a genetic disorder where there’s a deficiency in the production of the β-globin chains of hemoglobin, which is the oxygen-carrying protein in red blood cells - or RBCs for short. Beta thalassemia is most commonly seen in Mediterranean, African, and South East Asian populations.

Normally, hemoglobin is made up of four globin chains, each bound to a heme group. There are four major globin chain types - alpha (α), beta (β), gamma (γ), and delta (δ). These four globin chains combine in different ways to give rise to different kinds of hemoglobin. First, there’s hemoglobin F (or HbF), where F stands for fetal hemoglobin, and it’s made up of two α-globin and two γ-globin chains. Hemoglobin A (or HbA), the major adult hemoglobin form, is made up of two α-globin and two β-globin chains. Finally, hemoglobin A2 (or HbA2) accounts for a small fraction of adult hemoglobin in the blood, and it’s made up of two α-globin and two δ-globin chains. With beta-thalassemia, there’s either a partial or complete β-globin chain deficiency, due to a point mutation, which is when a single nucleotide in DNA is replaced by another nucleotide, in the beta-globin gene present on chromosome 11. And most often, these mutations occur in two regions of the gene called the promoter sequences and splice sites, which affect the way the mRNA is read. The result is either a reduced or completely absent beta globin chain synthesis.

And since this is an autosomal recessive disease, two mutated copies of the gene, one from each parent, are needed to develop the disease. If the person has just one mutated gene that codes for either reduced production or absent production of beta-globin chains, then they have beta-thalassemia minor. If the person has two mutated genes that code for reduced beta globin chain synthesis, then they’re said to have beta-thalassemia intermedia. If the person has two β0 mutations then no beta globin chains are produced, and they’re said to have beta-thalassemia major. When there’s a β-globin chain deficiency, free α-chains accumulate within red blood cells, and they clump together to form intracellular inclusions, which damage the red blood cells, and cell membrane. This causes hemolysis, or red blood cell breakdown in the bone marrow; or extra-vascular hemolysis when red blood cells are destroyed by macrophages in the spleen. Hemolysis causes hemoglobin to spill out directly into the plasma, where heme is recycled into iron and unconjugated bilirubin. Over time, the excess unconjugated bilirubin leads to jaundice, and excess iron deposits lead to secondary hemochromatosis.

At the same time, hemolysis leads to hypoxia, because there are fewer red blood cells to carry oxygen to organs and tissues. And a consequence of hypoxia is that it signals the bone marrow, and extra-medullary tissues like the liver and spleen, to increase red blood cell production, which may cause bone marrow containing bones, like those in the skull and face, as well as the liver and spleen, to enlarge. Now, beta-thalassemia minor is usually asymptomatic. On the other hand, with beta-thalassemia major, symptoms do not develop until the first 3 to 6 months of life. That’s because during the first 3 to 6 months of life, fetal hemoglobin is still produced, and that process uses up some of the free α-chains. Common beta-thalassemia major signs and symptoms include symptoms of anemia like pallor, shortness of breath, and easy fatigability; jaundice, swollen abdomen due to an enlarged liver and spleen, hepatosplenomegaly; and growth retardation.

Complications due to hemochromatosis include arrhythmias, pericarditis, cirrhosis, hypothyroidism, and diabetes mellitus. Other beta-thalassemia major findings may include enlarged forehead and cheekbones, which are called chipmunk facies. On a skull X-ray, the skull bones show a radiolucent bone marrow with fine, hair-like projections that look a bit like how the hair on your arms stands up when you get goosebumps, so it’s called a ‘hair-on-end’ appearance. Alternatively, this is also called a crew-cut appearance, named after a type of haircut. Diagnosis of beta-thalassemia usually begins with a routine blood test that shows a low hemoglobin level, decreased mean corpuscular volume or MCV, and a high red blood cell distribution width, or RDW, which indicates that red blood cells come in a lot of different sizes. However, the RDW is often normal with beta-thalassemia minor. The peripheral blood smears show microcytic, or small, and hypochromic, or pale, red blood cells. There are also target cells, which are small red blood cells that look like bullseyes due to scrunching up of the excess cell membrane.

Lab work may also show high serum iron, high ferritin, and high transferrin saturation level. Finally, the diagnosis is confirmed with hemoglobin electrophoresis, which shows low amounts of HbA, but an increase in HbF and HbA2 levels, which are formed when excess α-chains start binding to γ- and δ-chains. In beta-thalassemia minor, there’s usually an increased HbA2 level greater than 3.5% on gel electrophoresis. Beta thalassemia minor usually doesn’t require any treatment. Depending on hemoglobin levels, treatment of anemia in beta-thalassemia major and sometimes, intermedia, includes periodic blood transfusions. But, keep in mind that regular blood transfusions add up to the iron overload, which can worsen hemochromatosis. To prevent this, iron chelating agents like deferoxamine are given, which trap some of the excess iron and sweep it away through feces or urine. Finally, a splenectomy can be done when splenomegaly causes excess hemolysis.

All right, as a quick recap… Beta thalassemia is an autosomal recessive disorder caused by a mutation in the beta-globin gene present on chromosome 11, which results in a reduced (β+), or completely absent (β0) beta-globin chain synthesis. There are three types- beta-thalassemia minor, intermedia, and major. Beta-thalassemia major causes chipmunk facies, ‘hair-on-end’ appearance on skull X-ray, hepatosplenomegaly, jaundice, and secondary hemochromatosis.

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