What is Thalassemia? 

Thalassemia is a form of chronic anemia of genetic (hereditary) origin, that is, passed from parents to children. It is not transmitted by blood, air, water, physical or sexual contact and is not caused by a deficiency in food, lack of vitamins or mineral salts. 

Thalassemia is part of a group of blood disorders (hemoglobinopathies) characterized by a genetic defect that results in decreased production of one of the two types of chains that make up the hemoglobin molecule. Depending on the genes involved, the defect is identified as either a-thalassemia (alpha chain defect) or b-thalassemia (beta chain defect). 

Although there are other types of thalassemia, the most common in Brazil and in the world is beta-thalassemia, which, depending on its severity, is divided into three main groups: thalassemia minor, thalassemia major and thalassemia intermedia.

Thalassemia minor, or thalassemia trait, is not considered a disease, but rather a genetic trait. Its bearer usually does not present any symptoms, leading a totally normal life, working, practicing sports, etc. In most cases, the only obvious change is the skin color, which is whiter than normal. 

Thalassemia intermedia occurs when the thalassemia gene is mutated and encompasses a much broader clinical picture than thalassemia major. The severity of thalassemia intermedia is extremely variable, and transfusions are generally not required, as is the case with thalassemia major.

What is the origin of the name? 

The word thalassemia derives from the combination of the Greek terms thalassa (sea) and emas (blood). With this word, doctors wanted to describe a hematological disease (relating to blood) whose origin is in countries bordering the Mediterranean Sea, such as Greece and Italy. Therefore, thalassemia is also known as Mediterranean anemia. 

Other names used are Cooley's anemia (after Thomas Cooley, the American pediatrician who, together with the physician Perl Lee, first described the disease in 1927) and microcythemia (erythrocytes, or small red blood cells or red blood cells).

Anemia vs Thalassemia 

Anemia is a generic group of diseases that affect hemoglobin or red blood cells, but the popular use of this term is usually made to refer to the most common types of this disease, which are often caused by nutritional deficiencies. An example is the case of iron deficiency anemia, which manifests itself when iron levels are below normal. 

Thalassemias are a type of anemia. They are classified as hereditary hemoglobinopathies resulting from mutations in globin genes (alpha or beta in the vast majority of cases). Such genetic alterations promote reduction or even absence in the synthesis of one or more globin chains (which form hemoglobin). 

As a result, there is an imbalance in the production of these chains, with the main consequence of this deficit being ineffective erythropoiesis, which is when red blood cells do not complete their development. 

Those who suffer from this hereditary problem do not have a correct production of hemoglobin - it is worth emphasizing that this is not a contagious disease, nor is it caused by poor diet or lack of vitamins and mineral salts.

Iron overload complications 

Iron overload is common in Mediterranean anemia, caused by ineffective erythropoiesis, which increases intestinal iron uptake. 

Excess iron reserves can cause toxicity in the liver, heart and other organs, as there may be deposition of the mineral in these organs. This situation can be avoided with iron chelation from childhood. 

The overload can still cause endocrine and metabolic abnormalities, such as hypogonadism, hypothyroidism, insulin resistance and diabetes, and impaired growth. 

In the heart, it can generate heart failure and arrhythmias. 

In the lung, it can generate pulmonary hypertension and pulmonary abnormalities, such as restrictive and obstructive defects of the small airways, hyperinflation, decreased maximum oxygen consumption and abnormal anaerobic thresholds. 

In addition, the thromboembolic risks in these patients are much higher, due to a hypercoagulable state. Other common changes are leg ulcers and an increased risk of cancer.

Hemoglobin S-beta-Thalassemia disease

Because both the hemoglobin (Hb) S genes (the abnormal hemoglobin responsible for sickle cell disease) and the beta thalassemia genes are more frequent in people of African or South East Asian origin, inheritance of both defects is relatively common. Because of mutations or deletions in the beta globin gene, hemoglobin beta polypeptide chains are produced less frequently in beta thalassemia, which affects hemoglobin A production.

Beta globin mutations can result in either a partial loss of function (beta + allele) or a total loss of function (beta 0 allele). As a result, the S-beta thalassemia symptoms vary depending on whether the patient possesses the beta+ or beta 0 genotype. Those with beta+ produce varying amounts of beta globin (and thus have varying amounts of Hb A). Those with beta 0 do not produce beta globin and thus do not have Hb A. 

Clinical symptoms vary according to Hb A concentration. Thus, Hb-S-beta 0 thalassemia manifests similarly to sickle cell disease (Hb SS), while Hb S–beta+ thalassemia causes symptoms of moderate anemia and some signs and symptoms. symptoms of sickle cell anemia, which are generally less frequent and less severe than those of pure sickle cell disease. Mild to moderate microcytic anemia often appears along with a few sickled RBCs on the stained blood smear. 

Diagnosis requires quantitative hemoglobin testing. Electrophoresis consistently shows a higher than 50% concentration of Hb S. The level of Hb A is decreased in Hb-S-beta + or absent in Hb-S-beta 0. The increase in Hb F is variable. 

Treatment, if needed (eg. symptomatic anemia, painful flare-ups, end-stage organ disease), is the same as treatment for sickle cell disease.

Types of Thalassemia 

A class of inherited microcytic hemolytic anemias known as thalassemias is characterized by faulty hemoglobin production.

Alpha thalassemia is particularly common among people from Africa, the Mediterranean region and Southeast Asia. Beta thalassemia is more common among people from the Mediterranean region, the Middle East, Southeast Asia and India. Anemia, hemolysis, splenomegaly, bone marrow hyperplasia, and, in the event of multiple transfusions, iron overload, all produce signs and symptoms.

Diagnosis is based on quantitative analysis of hemoglobin.Transfusion, splenectomy, chelation, and stem cell transplantation are among the possible treatments for severe types.

Among inherited hemoglobinopathies, thalassemia is one of the most prevalent abnormalities of hemoglobin production. Alpha and beta are the names of the two pairs of chains that make up the hemoglobin molecule in a healthy adult (hemoglobin A). Adults' normal blood also contains 1.4% of fetal hemoglobin (fetal hemoglobin F), which has gamma chains instead of beta chains, and 2.5% of hemoglobin A2, which is made of alpha and delta chains. When the production of at least one globin polypeptide chain (beta, alpha, gamma, or delta) is decreased, it results in thalassemia, which causes an unbalanced synthesis of hemoglobin.

01. Thalassemia Alpha 

The production of alpha globin depends on 4 functioning alpha genes that are on chromosomes 16, with two genes on each chromosome. People with alpha thalassemia have mutations on chromosome 16 and are classified according to the number of mutated alpha genes. There are four genetic possibilities for a person to have this type of thalassemia.

SILENT CARRIER (α-/α) – In this type of alteration, the individual is the carrier of a defective gene, inherited from one of the parents, without showing symptoms or requiring treatment. That is, the silent carrier is not considered sick and does not need treatment. 

TRAIT ALPHA THALASSEMIA (α-/α- or –/αα) – This type of alpha thalassemia occurs when two genes are defective, the blood count shows some mild changes, and the carrier may have pale skin and, as an adult, feel a little of tiredness. 

HEMOGLOBIN H DISEASE (α-/–) – Considered among the most serious cases, where the person inherits three altered genes from the parents, the individual can manifest the hemoglobin H disease (which has a function similar to that of normal hemoglobin, but is more unstable and its lifespan is shorter, so the red blood cells will have a shorter duration in the body), resulting in anemia and the need for treatment.

FETAL HYDROPSY (–/–) – There are cases in which the mutation affects all four genes, which causes the body's complete inability to produce alpha chains, making normal hemoglobin production impossible. The disease developed is incompatible with life and leads the fetus to death while still in the womb. But fortunately, this is rare.

02. Beta Thalassemia 

Beta thalassemia encompasses three clinical presentations, as the genetic alteration that occurred on chromosome 11: beta thalassemia minor/beta thalassemic trait (mild anemia), inter-semi beta splints medium (mild to severe anemia, may require blood transfusions) blood sporadically) and beta thalassemia major (severe anemia, requiring blood transfusions every 2–4 weeks since the first months of life). 

The treatment of transfusion-dependent thalassemias is based on based on three “pillars”: transfusion of phenotyped red blood cells and iron chelation and effect, and patient adherence to treatment. 

Genetic mutations for beta thalassemia come from the countries in the Mediterranean, Middle East, India, Central Asia, Southern China, the Far East, North Africa, and arrived in Brazil by through immigration movements, mainly with the Italians us and greeks.

Subtypes of Beta Thalassemia  

• MINOR THALASSEMIA (or thalassemia trait)

carriers only have a genetic inheritance of thalassemia, acquired from the father or mother. They have mild anemia, without the need for treatment. 

But being aware that you have this type of thalassemia is very important, since there is a 25% chance that a child, daughter of a father and mother with minor thalassemia, will be born with major thalassemia, the most serious type of the disease, which requires lifelong treatment.

General discussions over Minor Thalassemia 

•Minor thalassemia may present with symptoms. Although the carrier has a genetic alteration that causes red blood cells to be smaller than normal, they function normally. This happens because the body creates an adaptation mechanism, causing patients to produce greater amounts of red blood cells. Thus, if symptoms such as tiredness, dizziness, body aches arise, it is important to seek a doctor to find out what has been causing it. 

•Taking iron and folic acid is allowed. It is possible that a person with thalassemia minor needs to take these two supplements. But it's important to be careful. Iron is only indicated if tests show that there is iron deficiency in the body. 

However, if it is used without recommendation and for long periods, it can lead to iron overload causing damage to organs such as the liver and glands. 

Folic acid, on the other hand, does not cause any harm if taken without real need. However, it is only indicated if the patient states that he consumes few raw green leaves, that is, salads. Ideally, a plate of these leaves should be consumed 4 times a week.

•Donating blood and organs is prohibited. It depends. Minor thalassemia does not affect the functioning of the organs, so people with this genetic condition can opt for this type of donation. Being a voluntary blood donor is also possible, as long as the hemoglobin is equal to or greater than 13 g/dl for men, and 12.5 g/dl for women. 

•Pregnant women need to take iron. Pregnant non-thalassemic women often also need to take it. It is normal that during pregnancy there is a drop in hematocrit and hemoglobin. The difference is that more frequent monitoring of hematimetric indices is recommended, which may be monthly in pregnant women with thalassemia minor. In addition, of course, always keeping in touch with the obstetrician to have information on the development of the fetus and what is the best type of delivery, normal or cesarean section. 

In the vast majority of cases, the pregnancy proceeds as if it were a woman without the thalassemia trait and rarely poses any danger to the fetus.

•Minor thalassemia needs treatment. What often happens is the indication of the use of folic acid, since by presenting a greater production of red blood cells, the body of these people also has an increased consumption of acid. The important thing is to always be in contact with the doctor so as not to carry out treatments that are not recommended. 

•Thalassemia minor relationship – doctor's office. There is no rule about how often you should go to the doctor, but it is recommended to go at least once a year for a check-up. 

Women should pay attention to their menstrual period to check for increased blood loss, and if so, go to the doctor as soon as possible. In the case of children, up to 12 years old, it is important to have a closer follow-up to ensure that the child has adequate vitamin levels and grows up healthy. Always remembering that it is extremely important to follow the expert's indications. 

•Children with thalassemia and growth. Children with thalassemia minor are the same as children without the trait, as long as they eat properly and do not have other illnesses. They are expected to grow in the normal ranges of the general population. 

•Good quality of life for thalassemia minor. A normal quality of life is expected. There are no restrictions for people with this type of thalassemia. Of course, for high-performance activities, such as marathons and long swimming competitions, patients with thalassemia minor may not achieve the same performance, but they are not prevented from doing so.

• THALASSEMIA INTERMEDIATE 

As the name suggests, this type is somewhere between thalassemia minor (not at all serious) and thalassemia major (more severe), and is caused by a mutation that may have been inherited from either the father or the mother, not both. 

For this reason, in some cases the bearer may present a milder anemia, and in others more severe.

• THALASSEMIA MAJOR

This is the most serious type of beta thalassemia, as its carriers have severe anemia. In this case the correct treatment can avoid several health complications. 

WHAT DEFINES THALASSEMIA MINOR FROM THALASSEMIA MAJOR?

While in thalassemia minor, patients have mild anemia and do not need treatment, in thalassemia major the production of hemoglobin fails, resulting in red blood cells (red blood cells) that are more fragile and of shorter duration, and reduced capacity to carry oxygen throughout the body. To get an idea, a child with thalassemia major without treatment maintains hemoglobin levels in the blood below 7 g/dL, while a child without the disease has a hemoglobin value above 11-12 g/dL. 

TREATMENT IS ESSENTIAL! 

Without treatment with transfusions, the person does not reach adulthood. With proper transfusion and drug treatment to remove excess iron from the body caused by repeated blood transfusions, a person can lead a normal life.

Causes of Thalassemia  

Thalassemia is a disease caused by genetic alterations that interfere with the formation of globin chains, which are structures that form hemoglobin and are linked to iron, promoting oxygen uptake. 

Globin chains can be alpha, beta, gamma, delta, epsilon and zeta, undergoing changes throughout the person's development. After birth, throughout the child's development, it is possible to observe a higher prevalence of alpha and beta chains, so that adults have 4 globin chains: 2 alpha and 2 beta. 

However, due to genetic alterations, it is possible that there is an alteration in the synthesis process of these chains, giving rise to different types of anemia, which can be more or less severe.

Symptoms of Thalassemia

The main symptoms of thalassemia are: 

•Fever that starts low and gradually increases, eventually reaching 104.9 F. (40.5 C) 

•Headache 

•Weakness and exhaustion 

•Muscle pain 

•Sweat 

•The cough is dry 

•Loss of appetite and weight loss

•Stomach ache 

•Constipation or diarrhea 

•Eruption stomach bloating

•Tiredness 

•Pallor and/or yellowish skin

•Delay in growth

•Bone changes 

•Abdominal enlargement

•Swelling of the spleen.

Thalassemia risk factors 

Here are the chances of one being prone to Thalassemia – 

•work or visit places where thalassemia fever iscommon. 

•As a clinical microbiologist, you will deal with Salmonella typhi bacteria. 

•Having close contact with someone who has or has recently had thalassemia fever. 

•Drink sewage-tainted water that contains Salmonella typhi.

Prevention of Thalassemia 

With access to clean water, sanitary conditions, and competent medical care, thalassemic fever can be avoided and managed. Unfortunately, in many underdeveloped countries, achieving these goals can be difficult. As a result, vaccinations are the most effective strategy for preventing thalassemia disease. If you live or plan to travel to places where thalassemia is a serious threat, you should get vaccinated.

Vaccines 

There are two available vaccinations. 

• One is administered as a solitary injection at least a week before departure. 

• One is taken orally as four capsules every day and one capsule every other day.

Neither vaccine is guaranteed to be 100% effective. Both require booster vaccinations. 

How to diagnose Thalassemia? 

The diagnosis is made based on personal and family history and laboratory test results.

Seek family history of dysfunction, determining severity, and other hemoglobinopathies. 

The absence of a family history, however, does not exclude the diagnosis, since both parents can be asymptomatic. 

Look for age of onset of symptoms (the older, the greater the severity), the severity of the symptoms, and a suggestive physical examination. 

Laboratory tests 

The initial test is a complete blood count with blood smear review and iron studies. 

Hemoglobin analysis, genetic testing and bone marrow evaluation can also be done. 

Findings include: microcytic anemia, red blood cell inclusions, high reticulocyte count, signs of hemolysis (high LDH and indirect bilirubin, low haptoglobin, and negative Coombs test), and normal white blood cell and platelet counts. 

Regarding iron, normally the serum iron level and transferrin saturation are increased, whereas serum ferritin is usually normal. 

Hemoglobin analysis (electrophoresis) and genetic testing are needed to confirm.

Differential diagnosis 

The main differential diagnosis of thalassemia is iron deficiency, chronic deficiency anemia, inflammatory anemia, liver diseases and other hereditary anemias.

Treatment 

Treatment depends on the severity of the thalassemia. Minor thalassemia does not require specific treatment.

Blood transfusions and folic acid supplements are two treatment options for thalassemia intermedia. The body need the nutrient folic acid to produce red blood cells.

In addition to folic acid supplementation and blood transfusions, patients with severe (or greater) thalassemia need to be given drugs that are used with chemotherapy to help the body produce normal hemoglobin.

If the patient has had repeated blood transfusions, it is possible that there is too much iron. This can damage organs, especially the liver. Therefore, it is important to avoid vitamin supplements that contain iron and to avoid taking too much vitamin C, which can increase the amount of iron you absorb from food. 

Less common treatments for thalassemia gravis include: 

•transplanting bone marrow or blood stem cells

•Spleen removal surgery in situations of severe splenomegaly, in which the organ enlarges dramatically.

Possible complications  

The following are the primary thalassemia complications: 

• Iron overload: Thalassemia patients may have too much iron in their body as a result of their condition or from receiving repeated blood transfusions. The endocrine system, liver, and heart can all suffer harm from too much iron.

• Infections: Infection risk is higher in thalassemia patients. This is especially true if the person has had their spleen removed. 

• Bone deformities: Thalassemia can enlarge the bones by causing the bone marrow to grow, which can lead to aberrant bone structure, particularly in the face and skull. Additionally, bone marrow enlargement thins and renders bones fragile, raising the risk of fractured bones. 

• Spleen enlargement (splenomegaly): The spleen assists the body in removing damaged or old blood cells. Large amounts of red blood cells are frequently destroyed along with thalassemia, making the spleen work harder than usual.This causes an enlarged spleen called splenomegaly. This can make anemia symptoms worse and reduce the lifespan of the red blood cells in the transfused blood. If the spleen grows too large, it may need to be removed. 

• Slower growth rates: A child's growth may be slowed down by anemia.

Puberty of children may delayed because of thalassemia. 

• Heart problems: Conditions such as congestive heart failure and abnormal heart rhythms (arrhythmias) may be associated with thalassemia gravis.