Beta thalassemia is a genetic disorder where there’s a deficiency in 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 affects
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 a 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 cell’s
cell membrane. This causes hemolysis, or red blood cells breakdown in the bone marrow;
or extravascular 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 leads 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 extramedullary 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.
Ok, now, beta thalassemia minor is usually asymptomatic. On the other hand, with beta
thalassemia major, symptoms do not develop in 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 cheek bones,
which is called a 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 levels, 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 smear shows 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 a 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 causes chipmunk facies, ‘hair-on-end’
appearance on skull X-ray, hepatosplenomegaly, jaundice, and secondary hemochromatosis.