Beta-thalassemia

Definitions & Key takeaways

Thalassemia (British English: thalassaemia), also called Mediterranean anemia, is a form of inherited autosomal recessive blood disorder characterized by abnormal formation of hemoglobin. The abnormal hemoglobin formed results in improper oxygen transport and destruction of red blood cells. Thalassemia is caused by variant or missing genes that affect how the body makes hemoglobin, the protein in red blood cells that carries oxygen. People with thalassemia make less hemoglobin and have fewer circulating red blood cells than normal, which results in mild or severe microcytic anemia.

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Introduction0:00–0:22

Beta thalassemia is a genetic disorder where there's a deficiency in production of the betaglobin chains of hemoglobin, which are the oxygen carrying proteins in red blood cells or RBC S for short beta thalassemia is most commonly seen in Mediterranean, African and Southeast Asian populations.

Physiology0:22–1:08

Normally, hemoglobin is made up of four globin chains. Each bound to a heme group.
There are four major globin chain types, alpha beta gamma and delta. These four globin chains combine in different ways to give rise to the different kinds of hemoglobin.
First, there's hemoglobin F or HB F where F stands for fetal hemoglobin. And that's made up of two alpha globin and two gammaglobin chains, hemoglobin A or HVA.
The major adult hemoglobin form is made up of two alpha globin and two betaglobin chains. Finally, hemoglobin A two or HBA two accounts for a small fraction of adult hemoglobin in the blood and it's made up of two alpha globin and two delta globin chains with beta thalassemia.
There's either a partial or complete betaglobin chain deficiency due to a point mutation which is when a single nucleotide in DNA is replaced by another nucleotide in the betaglobin gene present on chromosome 11.

Causes1:08–2:09

And most often these mutations occur in two regions of the gene called the promoter sequences in splice sites, which affects the way the Mrna is read.
The result is either reduced or completely absent beta globin chain synthesis. And since this is an autosomal recessive disease, two mutated copies of this 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 beta zero mutations, then no betaglobin chains are produced. And they're said to have beta thalassemia major when there is a betaglobin chain deficiency, free alpha chains accumulate within red blood cells and they clump together to form intracellular inclusions which damage the red blood cells cell membrane.

Pathology2:09–3:12

This causes hemolysis or red blood cell breakdown in the bone marrow or extravascular hemolysis where 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.

Symptoms3:12–4:25

On the other hand, with beta thalassemia, major symptoms do not develop until the 1st 3 to 6 months of life. That's because during the 1st 3 to 6 months of life, fetal hemoglobin is still produced and that process uses up some of the free alpha chains.
Common beta thalassemia, major signs and symptoms include symptoms of anemia, like pallor shortness of breath and easy fatiguability, 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 chipmunk facies. On a skull X ray.
The skull bones show a radiolucent bone marrow with fine hair like projections that look a bit how the hair on your arms stand out when you get the goose bumps.
So it's called hair on end appearance. Alternatively, this is also called a crew cut appearance named after the 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 the red blood cells come in a lot of different sizes.

Diagnosis4:25–5:29

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 bulls eyes 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 HVA but an increase in HB F and HBA two levels which are formed when excess alpha chains start binding to gamma and delta chains.
In beta thalassemia minor, there's usually an increased HBA two level, greater than 3.5% on gel electrophoresis. Beta thalassemia does not always require treatment but when needed blood transfusions are given to correct low hemoglobin levels and associated symptoms based on the need for blood transfusion.

Treatment5:29–6:02

There are two clinically relevant categories of beta thalassemia. First, there's the transfusion dependent thalassemia category which refers to all the phenotypes that require recurrent blood transfusions for survival.
This category includes beta thalassemia major and sometimes intermediate beta thalassemia with severely reduced beta chain synthesis.
The second category is that of non transfusion dependent thalassemia which refers to thalassemias that do not require regular blood transfusions.

Review6:02–7:02

This category includes beta thalassemia minor and beta thalassemia intermedia with milder symptoms. Keep in mind that regular blood transfusions add up to the iron overload, which can worsen hemochromatosis to prevent this iron.
Key waiting 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. Beta thalassemia is an autosomal recessive disorder caused by a mutation in the betaglobin gene present on chromosome 11 which results in reduced or completely absent betaglobin chain synthesis.
There are three types, beta thalassemia, minor intermedia and major beta thalassemia. Major causes chipmunk facies, hair on end appearance on a skull X ray, hepatosplenomegaly, jaundice and secondary hemochromatosis.