Content

Introduction

The word thalassemia refers to a group of hereditary diseases that involve a protein present in the blood, called hemoglobin, which has the task of carrying oxygen to all the tissues of the body.

People with thalassemia produce less hemoglobin and red blood cells and, as a result, develop anemia which causes ailments such as fatigue, paleness and shortness of breath.

Thalassemia mainly affects the populations of the Mediterranean area, South Asia, Southeast Asia and the Middle East. In Italy there are about three million healthy carriers, mainly concentrated in Sardinia, Sicily, in the southern regions but also in the Po and Veneto delta, there are an estimated 7,000 people affected by the severe form of the disease.

Thalassemias can be divided into two main groups: alpha and beta thalassemias.

In Italy and in the Mediterranean area, the most common form is beta-thalassemia.

The most severe form of the disease is major beta-thalassemia, also known as Mediterranean anemia or Cooley's disease.

Other types are beta-thalassemia intermedia, alpha-thalassemia major or hydrops fetalis, and hemoglobin H disease.

You may be a healthy carrier of thalassemia, also known as thalassemia minor, microcythemia, or a thalassemia trait. Healthy carriers do not have major health problems but, if their partner is also a healthy carrier, they risk having children affected by the severe form of thalassemia.

Thalassemia is recognized as a rare disease by the National Health Service (SSN) and therefore is exempt from a ticket.

It belongs to the group of hereditary anemias and has the RDG010 exemption code as specified in Annex 1 of the Ministerial Decree 279/2001.
On the website of the National Center for Rare Diseases of the Istituto Superiore di Sanità (ISS) you can find the link to the diagnosis and treatment centers of the various regions and the link to the "list of the numerous associations that deal with thalassemia in Italy.

Symptoms

Thalassemia can cause a variety of problems, many of which can be controlled by undergoing specific treatments.

Children who have the most severe form of thalassemia, the beta-thalassemia majorthey usually show their first complaints (symptoms) a few months after birth.

Less serious forms, on the other hand, may not show evident signs of their presence during infancy or even up to adulthood.

Healthy carriers of the disease generally do not have ailments.

Major health problems related to the disease include:

Anemia

Almost all people with thalassemia major or other severe forms of the disease develop anemia which, in severe cases, can be life-threatening.

When you are anemic, the levels of hemoglobin (a protein that carries oxygen throughout the body) in the blood are low and the following disorders (symptoms) are generally felt:

  • tiredness, and a general lack of energy (fatigue)
  • shortness of breath
  • pounding and irregular heartbeat (palpitations)
  • pallor of the face
  • yellowing of the skin and eyes (jaundice)

In the most serious cases the patient is forced to periodic and frequent blood transfusions for the whole course of life.

Excess of iron levels in the body

Most people with thalassemia major or other severe forms will also be at risk of developing a series of disorders (symptoms) caused by the "accumulation of iron in the body from the repeated blood transfusions to which it has had to undergo. Iron, in fact, is contained in the" hemoglobin present in " internal red blood cells.
An excess of iron in the body can cause:

  • heart problems, which include situations involving the heart muscle (cardiomyopathy), irregular heartbeat and heart failure
  • enlarged liver and liver cirrhosis
  • delayed sexual development (puberty)
  • low levels of estrogen (female hormone) or testosterone (male hormone)
  • diabetes
  • insufficient functioning of the thyroid gland (hypothyroidism) and parathyroid glands (hypoparathyroidism)

The only way to avoid the accumulation of iron is to carry out a drug treatment called chelation therapy able to bind iron and eliminate it before it is deposited in the various organs.

In addition to the accumulation of iron, other disorders can also occur in severe forms of thalassemia. These include:

  • growth retardation in infancy
  • biliary stonesi (hard, stone-like formations in the gallbladder) that can cause inflammation of the gallbladder (cholecystitis), abdominal pain (abdominal colic) and yellow skin and moss (jaundice)
  • unusual bone growth, such as an enlarged skull bone (forehead, cheekbones)
  • weak, brittle bones (osteoporosis)
  • reduced fertility, some people with thalassemia may need specific treatment

Causes

The causes of thalassemia are exclusively genetic: the only way to contract the disease is to inherit from one's parents one or more defective genes responsible for the production of hemoglobin; it is not contagious and cannot be caused by any other factor.

How thalassemia is inherited

Genes are elementary units present in the chromosomes found inside cells. They contain the hereditary information necessary for living organisms for the production of proteins and ribonucleic acid (RNA) and determine the characteristics of each individual such as, for example, eye and hair color.

In people with thalassemia there is a defect in the genes involved in the production of hemoglobin, a globe-shaped protein located inside red blood cells containing an iron molecule that binds with oxygen and allows it to be transported throughout the world. body.

In people with the thalassemia major, or other severe forms of thalassemia, little or no hemoglobin is produced and this can lead to anemia which, if severe and not corrected with regular blood transfusions, is incompatible with life.

Each individual inherits half of their genetic makeup from their mother and half from their father. In order for a baby to be born with the severe form of thalassemia, the beta-thalassemia major or Cooley's disease, you need to inherit a copy of the defective gene from both parents and this can only happen if both are porters of the defective gene, i.e. if they have thalassemia minor, also called microcythemia or thalassemia trait.

If only one of the parents is a healthy carrier it is not possible for a child to be born with severe thalassemia.
In case both parents are healthy carriers of beta-thalassemia there is:

  • 25% chance (1 in 4) that each of their children does not inherit faulty genes and does not have thalassemia, nor can they pass it on
  • 50% chance (1 in 2) that each of their children will inherit only one copy of the defective gene from one of their parents and are therefore a subject healthy carrier
  • 25% chance (1 in 4) that each of their children will inherit copies of the defective gene from both parents and thus be born with severe thalassemia (beta-thalassemia major)

In addition to beta-thalassemia major there is an "other form of disease, the alpha thalassemia, which is inherited in a more complex way since it affects four potentially defective genes, instead of two.
The children of parents porters healthy people with alpha-thalassemia they could be born sick only if they inherit three or four copies of the defective gene; if, on the other hand, they inherited one or two copies they would be healthy carriers.

The risk of developing thalassemia around the world

Thalassemia mainly affects people originating from:

  • Mediterranean basin (including Italy, Greece, Turkey, Cyprus and Morocco)
  • India, Pakistan and Bangladesh
  • Middle East
  • China and Southeast Asia

A simple blood test is enough to reveal the condition healthy carriers. The test is done regularly during pregnancy and after birth, but can be done at any time.

Diagnosis

The ascertainment (diagnosis) of the presence of the disease is carried out by means of a specific blood test to be performed, preferably, at a specialized center for this type of analysis.

The blood test can be carried out at any time in life, from infancy to adulthood, to find out if you are sick or healthy carriers of beta-thalassemia and, therefore, at risk of having a child with severe form of the disease.

Antenatal diagnosis

Although very high levels of prevention have been achieved in Italy to prevent the birth of new children with thalassemia major, it still happens that the disease is ascertained (diagnosed) during pregnancy or immediately after birth in the newborn.

During pregnancy, an "at risk" couple can carry out investigations (diagnosis) using molecular tests to find out if the baby will be born sick or healthy. The main prenatal tests are amniocentesis and CVS.

Post-natal diagnosis

In the newborn the disease can be discovered through the analysis of the fetal blood contained in the umbilical cord, or through a small blood sample from the heel of the foot.

The condition of healthy carrier of thalassemia, or microcythemia, is ascertained (diagnosis) by means of a specific blood test to be performed at a specialized center. There are two types of analysis to be carried out:

  • first level test, if one of the following conditions exists:
    • have a known healthy carrier family member
    • have a microcytosis (red blood cells of less than normal volume) not due to a lack of iron
    • be a couple of childbearing age who intend to plan a pregnancy regardless of the haematological parameters
    • be a teenager or an adult who wants to know if they are a healthy carrier of the thalassemia tract
  • second level test, if in the results of the first level analyzes are highlighted alterations with respect to the norm that suggest a serious or minor form of thalassemia

Exemptions

Thalassemia is recognized as a rare disease by the National Health Service and, therefore, is exempt from a ticket. It belongs to the group of hereditary anemias and has the RDG010 exemption code as specified in Annex 1 of the Ministerial Decree 279/2001.
On the website of the National Center for Rare Diseases of the Istituto Superiore di Sanità, you can find the link to the diagnosis and treatment centers of the various regions and the link to the "list of the numerous associations that deal with thalassemia in Italy.

The conditions of exemptions for the execution of the first and second level tests fall within those foreseen by the national legislation: to find out more, you can consult the website of the Ministry of Health.

Screening

In Italy there is no health control program (screening) to detect thalassemia at a national level.Only in regions with the highest percentage of healthy carriers such as Sicily, for example, is screening free for all pregnant women, or of childbearing age, and for family members of the sick.

Therapy

Current treatment of beta-thalassemia major or other severe forms mainly includes:

  • blood transfusions
  • removal of excess iron
  • instrumental monitoring of excess iron
  • bone marrow or stem cell transplant
  • treatment of complications of the disease

Compared to the past, the removal of the spleen is less frequently used.
Gene therapy is still in an experimental stage.

Blood transfusions

In most people with thalassemia major or other severe forms, it is necessary to have regular blood transfusions (transfer of blood to the patient through a needle cannula inserted into a vein in the arm) to treat the anemia. Usually, transfusions are done in the hospital and take a few hours each time . The frequency with which they must be carried out depends on the type of thalassemia you are suffering from. If it is the most severe form, the beta-thalassemia major, blood transfusion may be required once a month, in less severe types, only occasionally.
Very frequent transfusions can cause iron accumulation in the body and require specific medicines for its elimination. Those who do not undergo transfusions, when necessary, will have changes in the bones and facial features, enlarged liver and spleen and an increase in the volume of the heart.

Elimination of excess iron

The cure for removing excess iron caused by regular blood transfusions is known as chelation therapy and should be started after about 10 transfusions. This is very important as too high iron levels in the body can damage organs.

Medicines used in chelation therapy are known as chelating agents. Those currently available are:

  • desferoxamine (DFO), the drug is administered subcutaneously with a very slow infusion (12 hours) and must be repeated five or six times a week
  • deferiprone (DFP), can be taken in tablet or liquid form, three times a day; it is sometimes used in conjunction with DFO to reduce the number of infusions
  • deferasirox (DFX), soluble tablets to be taken once a day

Each drug has its advantages and disadvantages and doctors will evaluate and recommend the best one on a case-by-case basis.

Instrumental monitoring of excess iron

There are several analyzes to reliably measure the amount of iron in the body:

  • LIC, test that measures the iron concentration in the liver. It is performed by means of a liver biopsy (removal of a very small amount of liver tissue) and for this it requires the consent of the patients and / or their parents.
  • SQUID, a new non-invasive method used to accurately evaluate the excess of iron. It is based on the paramagnetic properties of iron to measure its concentration in the body. Unfortunately, it is a very expensive, technologically demanding technique and is only available in some centers in Italy. However, arrangements can be made with SQUID centers to carry out the investigation should the treating physician deem it necessary
  • MRI, nuclear magnetic resonance imaging is a non-invasive method and more easily available on the national territory, compared to the SQUID technique, to measure the accumulation of iron in the liver. The iron concentrations (T2 *) obtained with this method are very reliable. MRI has also been shown to be a useful tool for assessing iron overload in the heart

Bone marrow or stem cell transplant

The only definitive cure (therapy) against Mediterranean anemia is a bone marrow transplant. It consists in the administration of stem cells, taken from the bone marrow of a compatible donor, which will replace the defective ones of the patient. This therapy is limited by the availability of a compatible donor and by a number of other factors such as, for example, the patient's overall health and the absence of severe liver damage.
Stem cells are produced in the bone marrow (the spongy tissue found in bones) and have the ability to transform into different types of blood cells.

In stem cell transplantation, cells from a healthy donor are transferred to the patient through a cannula connected to a needle placed in a vein (drip). When they arrive in the patient's body, the transfused stem cells begin to produce healthy red blood cells that replace the defective ones.

Stem cell transplantation is an intensive treatment that involves a series of risks such as, for example, the rejection of the transplanted cells by the immune system of the diseased organism or the aggression against the cells of the diseased organism by the transplanted cells ( graft versus host disease). These are very dangerous situations because they lead to the destruction of cells.

To determine whether this type of intervention in patients with severe types of thalassemia is appropriate, the long-term benefits of a stem cell transplant must be weighed against the possible risks involved. The richest and most readily available source of totipotent stem cells (ie capable of giving rise to all the cells of the organism) resides in the blood of the umbilical cord.These cells, when compatible, can be collected and used in place of the bone marrow, with an excellent probability of healing (98%), a reduced incidence of rejection and an absent mortality.

Treatment of complications of the disease

Thalassemia can cause a number of other problems that may need to be managed, through:

  • hormone therapy, useful in cases of delayed puberty (sexual maturation) and for the treatment of low hormonal levels
  • vaccinations and antibiotics, to prevent and treat infections
  • thyroid hormones, in case of problems with the thyroid gland (hypothyroidism)
  • bisphosphonates, drugs to help strengthen bones in cases of fragility (osteoporosis)
  • surgery removal of the gallbladder to eliminate gallstones

Children and adults with severe forms of thalassemia can be supported by a team of different health professionals who work together in specialized centers for the treatment of the disease.
In Italy, thalassemias are considered rare diseases and clinical centers have been identified for their prevention, surveillance, diagnosis and therapy.

New therapeutic strategies

In recent years, considerable progress has been made in the experimentation of alternative therapies to bone marrow transplantation. Gene therapy is now a potential treatment option when a compatible donor is missing. The new generation lentiviral vectors are more efficient, safer and with no evidence of damage to the genetic material (genotoxicity). In various parts of the world, several clinical trials are underway with encouraging results, especially with respect to the level of production of normal hemoglobin, the improvement of biological parameters, the lower demand for transfusions and the better quality of life.Long-term studies will be needed to definitively confirm the safety of lentiviral vector-based gene therapy.

Prevention

Thalassemia major or Mediterranean anemia or Cooley's disease, is a serious disease that lasts for a lifetime and is frequent especially in some Italian regions.

This is why it is important to prevent it through specific analyzes capable of identifying the presence of the thalassemia tract among young people and among couples of childbearing age. It often happens that healthy carriers of the disease having no disorders do not know they are and therefore risk having a sick child.

If both parents are healthy carriers of microcythemia, in fact, at each pregnancy the probability of having a sick child is 25% (25 probability out of 100) regardless of whether they have already had healthy children.

For an optimal prevention strategy, it is important to identify young people with microcitemics as early as adolescence. In this way, being aware of their condition, they could choose not to become pregnant with a microcitemic partner, avoiding having a sick child.

Being informed is also beneficial in the event that an at-risk couple, unaware of their condition as a healthy carrier, decides to have children. Being aware of it will allow them to face every chosen path with awareness.

For the purposes of prevention, it is important that the examination for microcythemia is carried out at a specialized center capable of performing DNA analysis and providing a certain diagnosis and specific genetic counseling.

Living with

There are many things you can do to stay as healthy as possible if you have thalassemia.

A healthy lifestyle

To avoid developing some of the disorders related to thalassemia, it is important to:

  • follow a healthy and balanced diet. A special diet is not normally required, although sometimes it may be advised to take supplements, such as folic acid, calcium or vitamin D. Patients who have to undergo transfusions continuously over time (chronically), on the other hand, must follow a diet low in iron as they tend to accumulate it. On food labels the percentage of iron contained in them is generally listed, reading it carefully allows you to avoid those with the highest quantities
  • engage in regular physical activity. After receiving the positive opinion of your doctor, perform a movement in which the weight of the body rests on the bones (walking, dancing, etc.) helps to strengthen them and reduce the risk of osteoporosis
  • avoid smoking and drinking excessive amounts of alcohol. This can help keep your bones and heart healthy
  • protect yourself from infections. Wash your hands with soap and water regularly, avoid close contact with sick people whenever possible, and make sure you have all vaccinations

Also, you should take all medications prescribed by your doctor and undergo all required checkups.

Pregnancy and contraception

Women with the thalassemia major or other serious forms of the disease can bring a pregnancy to term while giving birth to a healthy child but it is important that they consult their gynecologist first because:

  • the partner could be a bearer healthy of thalassemia and in this case genetic counseling is useful to discuss the possible consequences
  • some people with thalassemia may need fertility drugs
  • during pregnancy there is an increased risk that certain diseases may occur such as heart problems in the mother and growth problems in the baby
  • more careful monitoring and changes to existing therapies may be required during pregnancy

If you are not planning to become pregnant, it is advisable to use a reliable form of contraception.

Precautions in case of surgical interventions

If you have to undergo surgery under general anesthesia, it is important both to inform the surgeon that you are thalassemic and to tell the doctors where you are being treated that you will have to undergo surgery. In fact, general anesthesia can cause problems including an increased likelihood of thrombotic events. To reduce the risk of complications, careful monitoring during surgery and a blood transfusion before or after surgery may be necessary. .

When to see your doctor

Thalassemia can cause a number of serious disorders (symptoms) that can arise even suddenly and require medical attention or hospitalization.
Particular attention must be paid to:

  • high temperature (fever) from 38 ° C (100.4F) and up
  • chills
  • diarrhea and vomiting
  • fast heartbeat
  • rapid breathing
  • dizziness or fainting
  • sudden pain or swelling of the belly (abdominal)
  • worsening of yellowing of the skin or eyes (jaundice)
  • weakness of the limbs
  • pounding and irregular heartbeat (palpitations)
  • drowsiness
  • seizures (fits)

If any of the described ailments (symptoms) occur, you should contact the attending physician immediately. If this is not possible, it is advisable to go to the nearest emergency room or call an ambulance. Finally, it is necessary to warn the medical staff that you have thalassemia.

On the website of the National Center for Rare Diseases of the Istituto Superiore di Sanità you can find the link to the diagnosis and treatment centers of the various regions and the link to the list of the numerous associations that deal with thalassemia in Italy.

Be a healthy carrier of thalassemia

A healthy carrier is defined as an individual who has only one defective gene for the synthesis of hemoglobin and, therefore, minimal alterations that do not cause obvious symptoms. This situation is also called thalassemia minor. Often, the healthy carrier does not know that they are defective because they do not have any visible alteration and becomes aware of it following a simple blood test at a specialized center. In these people the red blood cells are in greater number than normal but are a little smaller (hence the name of microcythemia) and However, the healthy gene allows more than enough red blood cells and hemoglobin to be produced to lead a normal life.

THE healthy carriers they will never develop severe thalassemia, but they can produce babies with thalassemia and may sometimes have mild anemia.

Geographical spread of healthy carriers

Anyone can be a carrier of thalassemia, but it is much more common in people from certain geographic areas such as:

  • Mediterranean basin (including Italy, Greece and Cyprus)
  • India, Pakistan and Bangladesh
  • Middle East
  • China and Southeast Asia

A simple blood test is sufficient to reveal if you are a carrier, if you think you are among the population at risk.

Analysis to discover that they are healthy carriers

Anyone can ask to undergo a test to find out if they are a healthy carrier of thalassemia at any time in their life. It can be particularly useful if:

  • in your family there are people with thalassemia (family history of thalassemia)
  • you are sexually active and want to find out if you are at risk of having a child with thalassemia
  • you know that your partner is a healthy carrier and you want to check that you are not in the same condition as this would increase the risk of having sick children

Having children

THE healthy carriers, are at risk of giving birth to thalassemia babies only if the partner is also a healthy carrier or have thalassemia.

Therefore, if you are planning to have a child, it is recommended that your partner undergo tests to verify that they are not also a healthy carrier.

In the event that both parents are healthy carriers of the beta-thalassemia tract (beta form of thalassemia) for each pregnancy there is:

  • 25% chance (1 in 4) that the child does not inherit faulty genes and does not have thalassemia, nor can he pass it on
  • 50% chance (1 in 2) that the child will inherit only one copy of the defective gene from one of the parents and is therefore healthy carrier
  • 25% chance (1 in 4) that the child will inherit the copies of the defective gene from both parents and thus be born with severe thalassemia (beta-thalassemia major)

If both partners are healthy carriers, before trying to become pregnant it is important that they inform their doctor and consult a geneticist who can explain the risks to the unborn child and the possible actions to be taken.

Possible health problems

The healthy carrier of thalassemia will never develop severe thalassemia. You will be able to live a normal life without experiencing significant health problems.

However, you may have mild anemia, with low levels of hemoglobin (the substance that carries oxygen around the body) in your blood. As a result, he may feel tired (fatigue) and appear pale in color. Anemia can only be found by undergoing a blood test, but if you find that you are affected, you should not take iron supplements on your own unless tests reveal that it is a form caused by the lack of it (iron deficiency anemia).Again, the doctor will have to prescribe the treatment because taking iron supplements if there is already enough of it in the body could be harmful.

Carriers of other blood diseases

Individuals with thalassemia are also at risk of giving birth to a child with a blood disorder if their partner carries a different type of disorder always involving a "hemoglobin abnormality":

  • hemoglobin C (HbC)
  • hemoglobin D (HbD)
  • hemoglobin E (HbE)
  • hemoglobin lepore
  • sickle cell anemia

Bibliography

Atzeni MM, Masala A. Homozygous β-thalassemia

Cao A, Galanello R. Beta-thalassemia. Genetics in Medicine. 2010; 12: 61-76

Galanello R, Origa R. Beta-thalassemia. Orphanet Journal of Rare Diseases. 2010; 21: 5-11 

Ivaldi G, Barberio G. Recommendations for the first level diagnosis of hemoglobinopathies of the Italian Society of Thalassemia and Hemoglobinopathies-SITE. Scientific series S.I.T.E. 2012, 1

Society for the Study of Thalassemia and Hemoglobinopathies and of the Italian Foundation "Leonardo Giambrone". Guidelines for Intermediate Beta-Thalassemia. 2003

Ministry of Health, Istituto Superiore di Sanità (ISS), Center for the evaluation of the effectiveness of health care (CeVEAS). Guideline 20: Physiological Pregnancy. 2011

Old JM, Traeger-Synodinos J, Galanello R et al. Prevention of Thalassemias and other Haemoglobin Disorders. Thalassaemia International Federation: Cyprus, 2005

Ryan K, Bain BJ, Worthington D, James J, Plews D, Mason A. et al. Significant haemoglobinopathies: guidelines for screening and diagnosis. British Journal of Hematology. 2010; 149: 35-49

Steinberg MH, Forget BG, Higgs DR, Weatherall DJ. Disorders of Hemoglobin: genetics, pathophysiology and clinical management, 2nd ed. Cambrige University Press, 2009

Magrin E, Miccio A, Cavazzana M. Lentiviral and genome-editing strategies for the treatment of β-hemoglobinopathies. Blood. 2019; 134: 1203-1213

In-depth link

Associations that deal with thalassemia in Italy and to which you can contact for detailed information on how to keep the disease under control

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