Mediterranean anemia: causes, symptoms and remedies

Mediterranean anemia, or beta-thalassemia, is an inherited blood disorder characterized by chronic anemia. In other words, those who are prone to this disorder have a chronically low erythrocyte count (total number of red blood cells in the blood) orhemoglobin concentration (average amount of oxygen contained in each blood cell).

The name derives from the Greek “thàlassa” (sea) and “haîma” (blood), and was chosen because of its diffusion among the populations settled in the Mediterranean basin.

To describe it for the first time (in 1925) was Thomas Benton Cooley, an American pediatrician specialized in hematology who found in a small group of boys of common Mediterranean origin (from Italy and Greece) a severe form of anemia, associated with an abnormal enlargement of the spleen (splenomegaly) and significant alterations of the skeletal structure. Since then, studies dedicated to the subject, in combination with epidemiological data collected through screening in various countries, have shown that this form of thalassemia is also widespread in North Africa, the Middle East and Southeast Asia.

The concentration of cases of Mediterranean anemia in Italy is mainly in the central-southern regions and in particular in Sardinia. At the base there is a mutation of the “beta” gene that inhibits the correct production of hemoglobin proteins, thus preventing the correct transport of oxygen. The cause is a hereditary genetic defect, that is, which is transmitted from mom or dad to children.

It’s not always the same

Mediterranean anemia can be of three different types.

The least severe form, which is called “thalassemic trait“, is characterized by the mutation of only one allele (or only one copy of the gene) of beta-globin: a slight anemia occurs, but in principle there are no disorders and you are healthy carriers. Also known as beta-thalassemia minor or heterozygous beta-thalassemia, this condition is the most common in Italy.

It is useful to know this situation because of the need to examine the partner and offer genetic advice.

There is also an intermediate form, also called non-transfusion dependent thalassemia, less serious, which, as the name implies, often does not require transfusions even if with age they may be required. Its effects affect mainly long bones, which are easily subject to fractures, and on the tissues of organs such as the spleen, liver and lymph nodes.

Finally, the most severe form of Mediterranean anemia, beta-thalassemia major or Cooley’s disease, also called transfusion-dependent thalassemia. In this case, both beta globin alleles are affected. The pathology manifests itself within the first two years of life, with symptoms such as fatigue, weakness and dyspnea, sometimes accompanied by jaundice, pallor, ulcers in the lower limbs, the presence of stones in the gallbladder (cholelithiasis), splenomegaly and thickening of the skull bones and cheekbones. In cases where iron overload occurs, heart failure and hepatic siderosis (which can impair organ function and cause cirrhosis) can also occur. The therapy is complex and consists of regular blood transfusions, removal of the spleen when necessary, pharmacological treatment of excess iron, bone marrow transplantation and gene therapy.

Diagnosis

The first step in diagnosing Mediterranean anemia is the interview. “In general, the presence of a form of microcytic anemia, that is, a smaller volume of red blood cells, for example less than 80 fl (femtoliters) in adults, and one or more healthy family carriers, are more than sufficient clues,” explains Silverio Perrotta, director of the Center for the Treatment of Thalassemias and Hemoglobinopathies of the Vanvitelli University of Naples.

The tests that are required to confirm the diagnosis of Mediterranean anemia are basically three:

• blood count to see the increased number of red blood cells, normal or slightly decreased haemoglobin and lower red blood cell volume (CVM);
• evaluation of sideremia, transferrin and ferritin that allows to exclude iron deficiency anemia;
• hemoglobin electrophoresis to assess the percentage of hemoglobin F and A2 (the latter increases in beta thalassemia).

“When the two partners are both carriers, it is possible, in case of pregnancy, to make prenatal diagnosis,” adds Silverio Perotta. “In this case, it is advisable to contact a Genetic Counselling Centre or a Thalassaemia Reference Centre since doctors and biologists specialising in the field work there.”

Among the main tasks that genetic counseling aims to do is first of all to inform the couple about the 25% risk of giving birth to a child with thalassemia, what form of thalassemia the unborn child could have and what are currently the complications of the disease, data on survival and therapeutic possibilities. Finally, the couple receives information on the possibility of carrying out prenatal diagnosis and how it is performed.

Treatment

Treatment depends on the type and severity of Mediterranean anemia. It must be said that compared to 20 years ago, the quality and expectancy of life have significantly improved thanks to early diagnosis and advances in treatment.

Transfusion therapy

It consists of blood transfusions to be carried out regularly according to a rhythm established by the doctor or, in the case of mild forms, at particular times of life such as during pregnancy or following haemolytic crises caused by infections. “The aim of transfusions is to correct the severe anaemia from which thalassaemic patients suffer and the increase in bone marrow activity,” explains Silverio Perotta. “With the correct transfusion regimen it is possible to suppress the erythropoietic activity that leads to the production of inefficient red blood cells. This helps prevent growth retardation, organ damage and bone deformities by allowing normal physical activities and a normal quality of life.”

Chelation therapy

The big side effect of blood transfusions is the accumulation of organ iron. It is a rather common event that can occur already after a dozen transfusions. The reference test for diagnosis is first the serum ferritin dosage, which is a storage iron index. However, it can give many false positives, since this value can also increase in case of infections and inflammations. “The organ diagnosis of iron overload is significantly improved with MRI of the liver and heart,” continues the specialist. “It is a non-invasive, repeatable, standardized technique that allows to monitor iron chelation therapy.”

Great strides have also been made with regard to treatment. For many years, especially before 2000, the only drug available to remove iron from the body was desferrioxamine: this substance was administered subcutaneously by slow infusion through a pump, for about 8-10 hours a day, 5 to 7 days a week. Today, two oral chelators are available, deferiprone, which is administered three times a day, and deferasirox, which is administered once a day orally and represents a great step forward for patients’ quality of life.

A new cure

There is much anticipation for an innovative drug that has received approval from US and European regulatory bodies and that will soon be approved in Italy. “Luspatercept has the ability to ‘engulf’ some of the substances that contribute to the premature death of red blood cells in the bone marrow,” says Silverio Perotta. “The drug is administered every three weeks subcutaneously and has made it possible to reduce the number of transfusions. In particular, it was seen in an experimental study that 70% of transfusion-dependent thalassemic patients reduced transfusion needs by a third and 10% even halved transfusions.

Bone marrow transplantation

It is the definitive cure in the case of the form of Mediterranean anemia called transfusion-dependent beta thalassemia. However, in order to carry out the transplant, it is essential to identify compatible donors. Usually it is a brother or sister, but it is also possible to activate a search among bone marrow donors. “The goal is to replace stem cells carrying defective genes for globin synthesis with normal stem cells,” continues Silverio Perotta. “The intervention consists in the removal of marrow from the donor and its infusion into the patient after having “eliminated” the cells of his marrow with the use of drugs”. The donor recovers within a week, while for the patient the time is longer. The most important complications of a bone marrow transplant are rejection, infections and the so-called graft-versus-host reaction. The success rate of a transplant is now in the order of 90%.

Gene therapy

The goal is to make thalassemia patients independent of transfusions. “To achieve this, a study was conducted on nine patients, three adults, three adolescents and three children under six years of age with a form of severe beta-thalassemia, who underwent gene therapy,” explains the specialist. “In practice, the patient’s cells were taken, modified in the laboratory with the transfer of the healthy gene and reinfused into the patient himself. The results of the study, supported by Telethon, opened up new perspectives of treatment. Three years later, there was a reduction in the number of transfusions for adults, while in three of the six youngest patients total independence was achieved. In recent years, other gene therapy protocols have been opened in both adults and children with transfusion-dependent thalassemia with excellent results.