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Thalassemia Types

The several types of thalassemia may be divided into two groups: Alpha and Beta

The several types of thalassemia may be divided into two large groups: α-thalassemia (alphathalassemia) and β-thalassemia (beta-thalassemia), with subtypes in each one of them. The difference case by case lies in the genetic form of pronouncement of the disease: that is, in the amount and characteristic of the mutation which occurs in the chromosome 11 or 16. To have a notion of the possibilities, there is some one thousand mutations already described in the medicine involving the genes which lead to thalassemia – the most frequent ones are from the group of beta-thalassemias. In Brazil, it is estimated that about three million people have the disease gene – 90% of them have the slighter versioncarrier state condition (minor thalassemia) of the beta-thalassemias, the minor thalassemia.


Alpha

People with alphathalassemia have one or more mutations in the chromosome 16 – genetic defect which affects production of the two chains α (alpha) of globin that, jointly with the two chains beta, comprise the hemoglobin. This condition may provoke both decrease of the chains alpha and their total scarcity.

The individual may only inherit the problem from one of the parents and become a bearer of the defective gene or genes which lead to alphathalassemia, without presenting the anemia symptoms or requiring treatment. In some people with thalassemia, in whom the genetic mutation is light and affects quality of only a small amount of hemoglobins, one can observe a minor anemia, which usually only concerns and deserves medical monitoring in specific situations, which are usually aggravated such as surgeries, pregnancy and in the senior age.

Another possibility is that the person with thalassemia develops the so-called hemoglobin disease H (HbH), when decrease of the alpha chains is aggravated. Since the beta chains continue to be produced, the remainders start to be connected between themselves, originating a new type of hemoglobin, the H (HbH). Such molecule has the same function of a normal adult hemoglobin, which is oxygenating the cells, tissues and organs. The fact is that, since it is more unstable, the average life of the HbH is lower, and the status will soon develop to anemia, from moderate to severe, with all consequences for the organism – such as fatigue, bone deformation and increase of the liver – if it is not treated. (See details on these complications in the link on MAJOR thalassemia). For the patients with the hemoglobin H disease, the recommendation is the periodical treatment with blood transfusion, in a specialized center, in addition to medical monitoring and general check-up on an annual basis.

On the other hand, when the mutations in the chromosome 16 lead to full incapacity of the organism to produce the alpha chains, the production of normal hemoglobin – which is comprised of two alpha globin chains and two of beta – does not occur as well. The status, known as fetal hydropsy, is rare and, since it does not have the presence of the molecule responsible for taking oxygen to the cells, tissues and organs, causes death of the baby in formation yet in the uterus.



Beta

The beta-thalassemias are the most frequent in Brazil and around the world, and people with this type of thalassemia have one or more mutations in the chromosome 11. The genetic defect affects production of the two β (beta) chains, which, jointly with the two alpha chains, form the hemoglobin. This condition may cause decrease of the beta chains and its full scarcity in the organism. There is a variety of subtypes of beta-thalassemia, caused by about one thousand mutations already described in the medicine, but they are usually classified in three basic forms: minor (or thalassemic trace), intermediate and major thalassemia.

Also known as minor thalassemia or just thalassemic trace?. The person has only the genetic inheritance of the disease – transmitted by the father or mother –, but is not sick. In most cases, the person does not present symptoms or presents a discrete anemia, throughout life, which does not impair the organism and does not require treatment.

Treatment: No more specific care is required for the anemia, but the person with minor thalassemia needs to pay attention when the organism goes through a stress situation that may aggravate the status – such as surgeries, severe diseases and, in case of women, the period of pregnancy. Sometimes, for short periods, the recommendation by the experts to these people is restricted to usage of folic acid, an important fuel to encourage the organism to increase production of red blood cells, that is, the blood components which carry in their inside the hemoglobins.

Another important guideline is finding the origin of all chronic anemias, even the minor ones. Some people don't know they have the minor thalassemia gene and, sometimes, even due to indication of a physician less experienced in hematologic diseases, are usually and mistakenly submitted to the treatment indicated for iron-deficiency anemia – the most common one, caused by absence of iron.

Expert Tip – there are simple exams – and offered free of charge by the single health system (SUS) – which show the metabolism of this mineral in the organism (ferric iron, saturation of transferrin, ferritin) and that may discard the diagnosis of anemia due to lack of iron.

Attention: Although a person may normally live with minor thalassemia, without the need to treatment, there is a good reason to want to know the diagnosis: there is a chance of 25% of a child, from father and mother, both with the gene of this light form of the disease, to be born with major thalassemia, the more severe pronouncement and requiring treatment as soon as possible – preferably in the first months of life – to avoid complications. If the parents know the existence of the thalassemic traces, they will be more attentive after the birth, they will seek specialized help and may take in advance the precautions required to ensure a long life of quality to their children.

Also known as Mediterranean anemia or Cooley anemia, the major thalassemia is the most studied since it is the most severe pronouncement of the disease. Without appropriate treatment, the person with thalassemia, who inherits the genetic defect both from the father and the mother, develops a severe anemia that may lead the organic and toxic changes, complications to health and even death.

The severity of an anemic status is assessed by the amount of hemoglobin in the blood. In the person with major thalassemia, the levels of this protein are usually kept below eight grams per deciliter, generally between 6 and 7g/dl, when in a healthy adult the normal is for them to be between 11 and 16 g/dl.

What is caused in the organism: Decrease or lack of beta globin chains affects formation of the hemoglobins, originating minor red blood cells, more fragile (they die fast) and with lower capacity of transporting oxygen by the organism. This is the usual condition to cause the chronic anemia, with its classic symptoms of paleness, fatigue, feeling of weakness and sleepiness. But there is an aggravating factor: in order to form a normal hemoglobin, two beta globin chains need to be connected to two alpha chains. In the absence of the beta chains, therefore, the alpha ones are accumulated and deposited in the circulating red blood cells, destroying them. This process known as hemolysis aggravates the anemic process, in addition to promoting release of higher levels of bilirubin in the bloodstream. In turn, this substance which is part of the hemoglobin metabolism and is also responsible for the jaundice in the newborns, may leave the person with major thalassemia with the eyes and the skin yellowish.

Treatment: During the whole life, the person with major thalassemia should be submitted to blood transfusion every 15, 20 or 30 days, depending on the medical recommendation. The procedure controls the severe anemia and, if it is initiated in the first months of life, removes the risks of the complications that may affect the well being or reduce the life expectation of the person, such as bone deformities, increase of the spleen and liver, cardiac insufficiency, among others. Another essential intervention which is usually made after the 10th transfusion is introduction of the chelating therapy or chelation. Made with usage of specific medications, it serves to eliminate from the organism the excess iron, a remainder resulting from greater capacity the intestine of the person with thalassemia has to absorb the iron from the food ingested and also from the periodical transfusions, which put in the bloodstream a concentration of red blood cells carried from this mineral.

The sum BLOOD TRANSFUSION + CHELATING THERAPY is equal to NORMAL LIFE AND WITH QUALITY for who needs to live with major thalassemia.

More complications, if the treatment is postponed: To correct the chronic severe anemia, the own organism recurs to some defense mechanisms which end up creating other health problems to the patient.

The bone marrow, for example, responsible for producing the blood components, including the red blood cells, increases up to 30 times its natural size to be able to produce more and compensate for the low levels of these cells in the organism. With that, the bone formation is also affected. The bones grow more than usual and may cause deformities in the skull and face, especially, in the upper dental arch, as well as distortions of the ribs and vertebras. They also get thinner and more fragile, which makes the growth stage of the children difficult, in addition to extending the risks of fractures and osteoporosis. If the person goes through transfusion on a regular basis the levels of hemoglobin are kept, thus avoiding bone deformities)

  • The spleen and the liver, in turn, also increase their size, because they will "exercise more" by assuming one more task: helping the bone marrow to produce blood. In the intrauterine life, these two organs produce the blood cells of the baby up to the 32nd week of pregnancy, period in which the bone marrow is not mature enough yet to assume such function. After that, they start to exercise other core "activities" for the good functioning of the organism. Such as in major thalassemia the body feels there is always lack of hemoglobin, the spleen and the liver go back to operation --- a reaction the physicians call extramolecular eritropoyesis (that is, when production of the red blood cells occurs out of the normal place).
  • The heart also tries to compensate for the decrease of the capacity by the hemoglobins to take the oxygen up to the cells, tissues and organs and, because of that, it starts to beat faster in the attempt to accelerate the blood circulation and, consequently, the access to this vital "ingredient". Such extra effort causes tachycardia and increase of the heart, which later may cause a cardiac insufficiency. In order to avoid it, it is necessary to keep the hemoglobin level.
  • Since the nature is wise, in the presence of an anemia, the gastrointestinal system starts to absorb a larger amount of iron from the food being ingested. It also occurs in the organism of the person with major thalassemia, but in this case the natural defense mechanism disturbs more than it helps. This is because, since anemia in the person with thalassemia occurs due to lack of hemoglobin and not iron, the extra absorption of this mineral ends up provoking an overload which is too prejudicial to health. The remainders of iron are deposited in vital organs – pancreas, intestine, heart – and cause reactions which unbalance the organism and may originate diseases (diabetes, cardiopathies) and lead to death.

As the own name suggests, this type of thalassemia is in the middle, because there are people with thalassemia who present quite differentiated levels of the disease, which sometimes are similar to minor, or to major. In some cases, the person with intermediate thalassemia has a light anemia, but differently of people who have the thalassemic trace, he/she may someday require blood transfusion. There are also people who have changes to the exams suggesting major thalassemia, but, by keeping the hemoglobin levels between 8g/dl and 10g/dl, who live without the periodical transfusions.

Difference: Two important features may mitigate the similarities and help confirming the diagnosis. The intermediate thalassemia is caused by a genetic mutation that may have been inherited by the father or the mother – and not by both, such as in the major one (Not true). In addition, even if discrete chronic anemia discards the blood transfusions, the person with intermediate thalassemia will not have the privilege of living well, without treatment (such as the case of people with the minor one) and will need to recur to the chelating therapy at some point in adult life.

Treatment: In some cases, even causing such a light anemia as that which occurs with people with only the thalassemic trace, the genetic mutation that leads to intermediate thalassemia really causes the person with thalassemia to develop the disease and, because of that, the organism reacts. Not by chance, individuals with minor thalassemia will never need the blood transfusion or the chelating therapy, while people with thalassemia will certainly recur to these procedures at some point of life.

Some studies have shown that, although it is more discrete and silent than in people with major thalassemia, people who live with the intermediate thalassemia also usually develop the same complications of the more severe form of the disease. As a result, the transfusion regime is recommended during some periods – for example, in the childhood, if the children have difficulty to grow and present risk of bone deformities – or in some cases, when the spleen or the liver starts to increase too much (due to or when there is a trend of the person with thalassemia to develop the diseases following thalassemia, such as diabetes and cardiopathies. As to the chelating therapy, even without the help of the blood transfusion, only the fact of the intestine absorbing greater amount of iron from the food causes this person with thalassemia to accumulate the mineral throughout the life and requires to eliminate it in the adult phase – usually after the 20 years of age, (many patients with thalassemia intermedia need to be chelated before the age of 20 year).

The intermediate thalassemia may present a light anemia status as the case of the minor one, but the case should be the same given to people with major thalassemia, such as monitoring of the hemoglobin levels and iron in the organism. The treatment is individual and will depend on the clinical status and history of each person with thalassemia. The older the person with intermediate thalassemia, even if he/she has never made blood transfusions, the greater will be the chance to need the chelating therapy.

  • Bone changes: An overactive bone marrow – result of the efforts made by the organism to produce more red blood cells and compensate for anemia – causes the bones to become deformed, fragile and thinner, interrupting their growth and leaving the patients more vulnerable to fractures. However, severe bone problems may be solved by a regular blood transfusion therapy.

    Osteoporosis: The patients are encouraged to practice physical exercises and increase calcium on their diet to avoid a severe bone disease, the osteoporosis. Calcium and vitamin D capsules may offer additional benefits. The cigar should also be avoided. Some physicians have shown benefic effects of usage of biophosphonates, administered by oral route or intravenous; however, its role in the fight against osteoporosis still needs to be confirmed.
  • Overactivity or expansion of the bone marrow and folic acid: since the bone marrow of people with intermediate thalassemia works hard to fight anemia of the body through production of more red blood cells, the patients need extra amounts of certain vitamins mainly of folic acid. An insufficient amount of folic acid may aggravate the anemia in people with intermediate thalassemia. The folic acid is naturally found in food such as meat and vegetables. However, an additional amount (generally a tablet per day) supplies the needs of the patients.
  • Bladder stone: People with intermediate thalassemia develop bladder stone (cholelithiasis) more frequently than normal. The stones in the bladder are produced from byproducts (pigments from the bile) which are released during degradation of the red blood cells and are accumulated in an organ next to the liver, called gall bladder, where they may cause obstruction and originate abdominal pain. The presence of stones in the bladder may be confirmed through an ultrasound. In some cases in which abdominal pain lasts the gall bladder needs to be removed.
  • Ulcers in the legs: People with intermediate thalassemia, mainly those not so young, usually have ulcers in the regions of the ankle, as a result of unsatisfactory circulation and oxygen in some parts of the body. These ulcers tend to be persistent and with a really hard treatment. However, regular blood transfusions to increase the hemoglobin levels and thus improve provision of oxygen to the tissues, as well as other simple measures (such as keeping legs and feet high above the heart level for 1 to 2 hours during the day, sleeping with the lower edge of the bed slightly elevated and protect the ankles upon usage of socks) may provide some relief. Some medications, such as zinc sulphate tablets, may also be useful in some cases, as well as the hydroxyurea – individually or in combination with other agents capable of increasing fetal hemoglobin, such as erythropoietin and the butyrates. (not proven)
  • Renal complications: Other medical problems reported in people with intermediate thalassemia are renal injuries that may be the result of excess uric acid in the blood. The uric acid is the most important residual product comprised as a result of an overactive bone marrow. The drug Alopurinol may help reduce the amount of uric acid produced.
  • Thrombophilia: there may be an increased risk of thrombosis, which occurs when thrombocytes or platelets are accumulated in the blood vessels and form clots (platelet aggregates) which prevent the normal blood flow, thus reducing oxygenation of the cells and tissues. A regular count of the number of platelets allows for the physician to establish the need for prescribing anti-platelet drugs, if the count is high, or blood thinners, if there is a surgery scheduled or occurrence of thrombosis.
  • Extramedular erythropoiesis: Production of red blood cells in the outer portion of the bone marrow. Differently from the patients with major thalassemia, receiving regular blood transfusions since the early age, which suppress the excessive activity of the bone marrow, the patients with intermediate thalassemia do not receive such regular transfusions and therefore continue to produce high levels of red blood cells, including out of the bone marrow – mainly in the thorax and in the para-spinal region. X-rays may disclose the tissue forming blood developing in masses in such regions.

    Production of red blood cells in the para-spinal region may cause neurologic complications when an extra pressure starts to be exercised around the dorsal spine. It may generally be identified through x-rays or more sensitive methods, such as the magnetic resonances. Repeating, such conditions may be generally controlled through a blood transfusion therapy, which will suppress the extra formation of blood and, consequently, reduce the masses formed. When more severe neurologic conditions occur more active therapeutic measures may be needed, such as radiotherapy. (hydroxyurea has also been used with good results).
  • Cardiac and endocrine complications: The chronic anemia may cause cardiac problems and both the heart and liver may be injured by an overload of iron. Both conditions may be controlled as described for the major thalassemia. (cardiac diseases in thalassemia intermedia is usually not related to iron overload).



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