Thalassemia: Definition, Causes, Types, Symptoms, Diagnosis, Treatment and Prognosis

It is a hereditary hemoglobinopathy disease.

An error in protein, which interferes with the transport of oxygen in the body by hemoglobin (red blood pigment).

The name “Thalassemia” is Greek which means “Thalassa” for the sea and aima for the blood, discovered and described for the first time by an American doctor (Dr. Cooley).

Hemoglobin, the oxygen transport molecule , consists of a combination of four so-called globin chains.

Normally, each adult has two alpha chains and two beta chains. Thalassemia has many mutations in genetic defects that alter the structure of hemoglobin.

Each protein has a specific task. Hemoglobin binds to oxygen in the lungs and carries it to places where it is consumed, such as in the muscles.

Depending on whether the alpha or beta globin chain is defective, it is referred to as alpha or beta thalassemia.

For safety, the body has several replacement copies of these genes. However, if the mutated gene is obtained from both parents, the consequences and limitations for the affected person are also greater.

If a person still has sufficiently functional copies, that is, only one defective gene from the mother or father, this is called mild thalassemia or thalassemia minor.

In the case of thalassemia minor, affected people, apart from a borderline reduction in hemoglobin level, almost never experience symptoms and no treatment is necessary.

If the person has no or few copies of functional genes, if the error in hemoglobin is inherited by both parents, we speak of thalassemia major or thalassemia major.

Thalassemia intermedia is an intermediate form that does not always need treatment or only in certain stages of life.

Beta thalassemia is much more common than alpha thalassemia alpha.

Causes of thalassemia

With each act of breathing, the lungs fill with fresh oxygen, which has to be carried to every cell in the body.

This is the job of red blood cells (erythrocytes), which absorb oxygen and carry it through the veins to all corners of the body.

In order for them to conserve oxygen, they need a certain protein that contains iron, called hemoglobin.

For hemoglobin, there are building instructions in the body, from different genes.

In the case of thalassemia, these instructions are falsified in part, due to a genetic modification (mutation) that causes defective hemoglobin building blocks to form.

As a result, less functional hemoglobins can be built that carry less oxygen load to cells.

The broken components of hemoglobin are deposited in the red blood cells and change shape and are discarded in the spleen and there is a constant lack of functional red blood cells, resulting in anemia.

Types of thalassemia

Thalassemia occurs in various forms and degrees of severity. There is a general clinical classification due to the symptoms and the appearance of the disease as:

Thalassemia minor

Defect in the copy of a gene acquired only from one parent in a heterozygous way.

Symptoms of thalassemia minor are mild except for mild mycrocytic anemia (small red blood cells) and possibly a slightly enlarged spleen.

Thalassemia major

Defect in the copy of two genes acquired from both parents in a homozygous way).

Thalassemia major is the rarest but most serious form of thalassemia. Patients need blood transfusions regularly.

Thalassemia intermedia

It is a special form of homozygous thalassemia (two copies of the gene defect acquired from both parents), but mitigating additional changes in blood formation, for example, fetal hemoglobin production, for life.

Fetal hemoglobin normally occurs only in neonates and infants and is later replaced as the individual grows.

In the case of thalassemia intermedia, patients repeatedly need blood transfusions.

Alpha y beta thalassemias

Hemoglobin is made up of several building blocks. Depending on which of them is altered, there is an alpha or beta thalassemia.

Alpha thalassemia is more common in Asia and beta thalassemia is more common in Europe.

The severity of the disease depends on whether a patient produces only altered versions of a hemoglobin building block, or whether it also forms a functional version.

Beta thalassemia

For the hemoglobin beta-block, each person has two different building instructions, one in the genes they inherited from the father and one in the mother. These types of thalassemias are common in the Mediterranean region.

Beta thalassemia minor

In beta thalassemia minor, only one of the genes is adulterated.

This is a mild form of thalassemia that causes little or no symptoms. Other than mild myococytic anemia and possibly a slightly enlarged spleen, you have no symptoms.

Beta thalassemia major

Also called Cooley’s anemia. In this type of thalassemia, patients do not form normal beta-globin chains.

The most severe form of thalassemia is thalassemia major. Children should have blood transfusions as therapy from six months to twelve months of age. Children without transfusions are not able to survive in the medium term.

The reason that children do not need blood transfusions from birth is the initial production of so-called fetal hemoglobin (2 alpha and 2 γ chains), which do not require beta chains.

However, the production of γ chains decreases with each month of life, and the lack of beta chains becomes increasingly important and then manifests clinically.

Beta thalassemia intermedia

The special form of homozygous thalassemia, blood transfusions (link to therapy) is from the age of 1 year, occasionally necessary or only in special stages of life or complications such as when infections occur, in pregnancy or in some stages of growth.

Alpha thalassemia

In alpha thalassemias there are even four genes for alpha blocking of hemoglobin, two maternal and two paternal, which code for the alpha globin chain.

Therefore, there are different forms of alpha thalassemia with different presentations. Alpha thalassemias are common in Asia and Africa.

Thalassemia minimal alpha

If it is just a mutation, we talk about alpha thalassemia lows, which occur without symptoms.

Alpha thalassemia minor

When alpha thalassemia minor occurs, both genes are defective and it is also called intermediate. This brings mild or no symptoms and causes changes in values ​​when a blood test is done.

Alpha thalassemia intermedia

In alpha thalassemia intermedia, there are three faulty gene copies. It is called hemoglobin H disease).

This hemoglobin is made up of four beta-globin chains, and symptoms are mild to moderate, including anemia, enlarged liver and spleen (hepatosplenomegaly), folic acid deficiency, and gallstones.

Alpha thalassemia major

It is a special form of thalassemia major, where all the genes are defective. Embryos that fail in all four alpha genes are not viable, and affected children generally die during pregnancy, before birth.

Delta and gamma thalassemia are also present, but both are very rare
and generally mild.

Generally, the various genetic alterations are inherited from parents to their children, but they can also occur accidentally, shortly after fertilization of the egg.

Symptoms of Thalassemia

The two main forms of thalassemia are already evident in the first years of life.

Affected babies are very pale. The skin of those affected is usually slightly yellowish (jaundice). The color comes from breakdown products of hemoglobin.

Anemia causes dizziness and headache. Patients quickly get out of breath, feel tired. It is often difficult for them to concentrate.

Thalassemia patients tend to have a higher heart rate at rest, their heart beats unusually fast, in order to better distribute the existing blood in the body causing tachycardia.

An abnormally large stomach is also visible. Since normally, blood formation in the liver and spleen occurs after birth, the abnormal production of erythrocytes at this age affects these organs,

Decomposition products accumulate and an enlarged spleen occurs – splenomegaly, or an enlarged liver – hepatomegaly.

The body tries to make up for the lack of oxygen in the blood by forming more and more red blood cells in the bone marrow.

For this, the cavity widens in the bone in which the marrow is located and there is an increase in volume of the bones.

The bones become wider and more friable. Due to anemia (decrease in red blood cells), there is an excessive production of blood cells that do not work in the red bone marrow.

This is notable for particularly thick or wide unstable bones.

This structural change means that the bone can no longer fulfill its other functions, for example, the supporting function.
Causing less stable bones that can easily deform and break bone fractures).

Beta thalassemia major is usually more severe than alpha thalassemia major.

People who only have a minor thalassemia may run out of breath faster during exercise and be less efficient than completely healthy people. But you can also live without symptoms.

Growth retardation is observed as a consequence of iron overload after repeated transfusions.

Thalassemia diagnosis

Thalassemia major appears as early as the fourth or fifth month of life. By the third month of life, the hemoglobin level is usually low in children.

In healthy children it increases gradually, not so much in children with beta thalassemia major. These are unusually pale.

Additional evidence of thalassemia can be found in a child’s family history.

If a family member is diagnosed with thalassemia or if the patient has ancestry in a region where thalassemia is prevalent, the suspicion of the disease is confirmed.

At first glance, thalassemia looks like iron deficiency anemia in that they have very small red blood cells.

But there are notable differences: the level of iron in the blood serum decreases in iron deficiency in patients with thalassemia, it is normal, so laboratory tests are necessary.

A hemoglobin lab test finally tests whether a patient actually has thalassemia and, if so, what form. A diagnosis in utero (prenatal diagnosis) is possible.

Thalassemia treatment

The only chance for recovery in thalassemia major (to avoid the long-term consequences of frequent blood transfusions): stem cell or bone marrow transplantation with a sibling or donor.

This procedure is risky because the body’s own bone marrow must be destroyed and the immune system is paralyzed for weeks.

The success of the therapy is greater than 90 percent for sibling donors, and approximately 80 to 85 for external donors in transplantation before the age of 16 years.

Each child should receive a transplant if there is an identical donor sibling. To find out if a sibling donor fits must be determined in specialized laboratory investigations.

Patients with alpha thalassemia major can be treated quite well with blood transfusions, since they need less amounts of blood than patients with beta thalassemia major.

People with only a mild form of thalassemia, such as beta thalassemia minor or alpha thalassemia intermedia, usually do not require transfusions.

The doctor may indicate a treatment with the administration of folic acid and vitamin B12 to support blood formation.

In case of severe symptoms, symptoms that strongly limit the affected person in everyday life, daily ingestion or injection of drugs is unavoidable.

Effect of treatments

Blood transfusions

Through blood transfusion, the body gets enough red blood cells and stops with its own production.

This leads to a reduction or alleviation of all complaints (enlarged spleen and liver, fractures, etc.) and prevents them.

Iron overload after repeated transfusions.

In regular blood transfusions, the body always receives the associated iron, which is present in erythrocytes (red blood cells) and has no way to excrete excess iron.

Therefore, iron is deposited in the organs, which can lead to serious damage to organs such as the heart and hormone-forming organs.

This was the most common cause of death for those affected before the discovery of the chelators.

Therapies to reduce the effects

Iron removal therapy with iron chelators.

The side effects of blood transfusion are treated with chelators.

Chelators can bind excess iron and allow the body to excrete it mainly through the kidneys and then through the urine.

With this treatment, a normal life is possible, but it does not combat the cause of the disease. So far there are several chelators with different advantages and disadvantages on the market. On the choice of drug, the doctor decides after the individual case of patients.

Hormone Replacement Therapy

When excessive iron accumulation (iron poisoning) affects the hormone-forming organs, hormone replacement therapy (hormone replacement) is necessary to ensure growth in children or proper regulation of metabolic processes.

Types of iron chelators

Desferal

  • The active substance is desferioxamine.
  • In its mechanism of action it causes iron to be excreted through the intestine or kidney.
  • It must be given as injections or by infusion.
  • The therapy is relatively slow throughout the night.
  • It is not that common today as there are newer therapies that are simpler.
  • It is the best known and safest drug.

Exjade

  • The active substance is defarasirox.
  • It is administered once a day.
  • Its administration is oral, dissolved in water.
  • It can possibly lead to kidney disorders, but they are mostly reversible.
  • It is a relatively new but safe drug.

Ferriprox

  • The active substance is deferiprone.
  • It is used in cases of incompatibility with Desferal and Defarasirox.
  • It is administered three times a day.
  • Relatively good at removing iron from the heart muscle.
    Its presentation is in tablets.
  • One side effect is that it can cause joint pain.
  • Great care must be taken not to reduce white blood cells as it can lead to susceptibility to infection.
  • Necessary blood levels should be checked every 4 to 12 weeks.

In all patients with iron overload, 1 to 2 times a year, all organs in which iron deposits are present (heart) and in which they are attacked by drugs (kidney and liver) should be monitored.

The dose and frequency of drug intake are determined by the amount of iron stores in the organs and controlled in the laboratory by the level of ferritin.

Forecast

Just a few decades ago, without transfusions or medications, there was no survival to adulthood.

Today, all affected children reach adulthood through new therapies. Life expectancy is only limited thanks to modern therapies.