Alpha and Beta Thalassemia – Minor and Major

Thalassemia is an inherited disease caused by a defect in hemoglobin.

Hemoglobin is a pigment found in red blood cells that binds to:

1. Oxygen
2. Carbon dioxide.

This binding allows red blood cells to transport oxygen to cells and carbon dioxide to lungs.

The hemoglobin contains 2 alpha and 2 beta chains that are connected to each other.

It is important for the proper function and survival of these cells that the number of alpha and beta globin chains in the red blood cells (erythrocytes) is the same.

The absence of alpha-hemoglobin chains causes an accumulation of beta-hemoglobin in the red blood cells and vice versa.

The result is the formation of precipitates (chain groups) that can damage the erythrocytes.

These aggregates oxidize and can cause:

• hemolysis (death of red blood cells) because they damage the cell membrane,
• Ineffective erythropoiesis (formation of red blood cells).

The severity of the disease depends on the imbalance of the number of globin chains.

Course and consequences of thalassaemia

The decrease in red blood cells causes anemia and the body tries to compensate for this by increasing iron absorption from food.

The spleen filters out the damaged erythrocytes and destroys them.

The consequences of thalassemia in the spleen are:

1. Overload
2. Splenomegaly (organ enlargement).

Over time, the enlarged spleen also retains white blood cells and platelets.

The consequences can be:

• Infections
• Bleedings.

Consequences of thalassaemia are:

• anoxia (lack of oxygen in the cells),
• Growth retardation in children and delayed puberty development.
• Gallstones, because the excessive production of bilirubin due to chronic hemolysis is the basic prerequisite for the formation of pigmentary gallstones (EVERSON G. T.: Gallbladder function in gallstone disease. Gastroenterol. Clin. North Am. 20 (1991), 85).
• bone changes and osteoporosis due to the increase and hyperactivity of the bone marrow (inside the bone),
• Bone marrow expansion contributes to the cortical part of the bone wearing out, resulting in bone regeneration: “brush skull”.

X-ray – brush skull as a result of thalassemia. [/caption]

Necessary blood transfusions lead to an accumulation of iron.

Iron is needed by the body, but an atom of free iron leads to the formation of free radicals that are toxic to the organism.

In the body, iron always binds to proteins: ferritin, transferrin, etc.

When these proteins are saturated with iron, this metal accumulates in the organs:

• liver (affected first), which can lead to chronic hepatitis and cirrhosis,
• heart (when the liver is already saturated), which leads to rhythm disturbances and heart failure,
• Glands, the consequences can be: hypogonadism, hypothyroidism, diabetes, hypoparathyroidism, Source: Borgna-Pignatti C – (Department of Clinical and Experimental Medicine, University of Ferrara and Division of Pediatrics, Arcispedale Sant’Anna, Via Savonarola 9, 44100, Ferrara, Italy)

Death occurs due to heart disease and not due to liver disease, because a small amount of iron is enough to alter the nerve conduction of the heart.

How is thalassaemia transmitted?

The cause of thalassaemia is always genetic: it is an autosomal recessive disease. One or both parents are healthy carriers of the disease.

The genes can pass on to their children.

Classification of thalassaemia

There are two types of globin chains: alpha and beta.

Alpha

• Healthy carrier
• Thalassemia feature
• HbH disease
• Hydrops fetalis – the most severe form of alpha-thalassemia, it leads to the death of the fetus or newborn.

Beta

• Minor, usually without symptoms,
• Intermedia
• Major.

Alpha-thalassemia

Alpha-thalassemia causes an excess of beta-globin, which leads to the formation of beta-globin tetramers (β4). This disease is called hemoglobin H disease.

The β4 tetramers are soluble, but can cause hemolysis in case of oxidation.

Hemoglobin-Constant-Spring disease is a severe form of this hemolytic disorder.

The most severe form of thalassemia is alpha thalassemia major, in which a fetus does not produce alphaglobin. This situation is incompatible with life.

The genes of alpha-globin are located on chromosome 16.

The alpha chain of hemoglobin consists of 4 spherical subunits.

Each subunit is encoded by a different gene in the chromosome.

The symptoms and complications of the disease depend on the number of missing or mutated genes:

1. A healthy carrier has no signs of the disease.
2. Two abnormal (or missing) genes produce alpha type thalassemia or minor thalassemia. This condition causes mild anemia.
3. If three genes are mutated or missing, the patient develops hemoglobin H disease (diagnosed by blood test). This form of thalassemia causes moderate or severe anemia.
4. If all genes are missing or have undergone a mutation, thalassemia is very severe and the child is stillborn or death occurs shortly after birth.

A child inherits four alpha globins (two from each parent).

The child of two people affected by thalassaemia (both with two missing or mutated genes) has:

• A 25% chance of developing the disease (3 or 4 abnormal genes),
• A 50% chance of being a healthy carrier,
• 25% of being healthy or having an abnormal gene.

If the father lacks two alpha-globin genes and the mother one alpha-globin gene, each child has a 25% chance of inheriting the following gene combinations:

• Four normal genes (no anemia),
• One missing gene and three normal genes (healthy carrier),
• Two “missing” genes and two normal genes (disease),
• Three missing genes and one normal gene (H-haemoglobinopathy),

Most people with alpha-thalassemia show only mild symptoms of the condition.

Beta-thalassemia

Beta-thalassemia causes an excess of alpha-globin forming alpha-globin tetramers (α4) instead of two pairs of alpha chains and two pairs of beta chains.

This insoluble formation accumulates in the erythroblast (immature red blood cell) and impairs:

• Erythropoiesis,
• cell maturation,
• The cell membrane.

The result is anemia and the formation of non-functioning red blood cells.

The beta chains are encoded by two different genes.

In case of absence or mutation:

• From only one gene, the anemia is only mildly pronounced or absent altogether,
• Of both genes, the symptoms are severe.

The beta-globin gene is located on chromosome 11.

A child inherits two beta-globin genes (one from each parent). If these genes are missing or altered, beta-thalassemia occurs. This means that the organism does not produce enough beta chains of hemoglobin.

1. Anyone who has only one modified gene is a healthy carrier, because it is a recessive gene. This condition is called beta-thalassemia minor and causes mild anemia.
2. When both genes are altered or absent, beta-thalassaemia intermedia or beta-thalassaemia major (also called Cooley’s anemia) develops.

The medial form causes a mild form of anemia. The major form causes severe anemia.

If each parent has an altered gene, each child has:

• A 25% chance of inheriting two normal genes (no anaemia),
• There is a 50% chance of inheriting an altered and a normal gene (beta-thalassemia minor), in which case the patient may have mild anaemia or have no symptoms at all in the case of minimal thalassemia.
• A 25% chance of inheriting two altered genes (beta-thalassemia major).

Difference between Thalassemia major and minor

There are two forms of beta-thalassemia: thalassemia minor (or benign anemia) and thalassemia major (known as Cooley’s anemia).

Thalassemia minor: the individual has an altered or missing gene (together with the gene of a normal beta chain). He is referred to as a heterozygous carrier of beta-thalassemiaemia.

People with thalassemia minor have mild anemia with a slight decrease in hemoglobin in the blood.

People with thalassaemia minor have normal iron levels in their blood. No treatment of thalassaemia minor is required.

Thalassaemia major (or Cooley’s anemia): Those with thalassaemia major have two altered genes of “beta-thalassemia” and no normal beta gene.

The affected person is a homozygous carrier of beta-thalassemiaemia.

This causes a deficiency in beta chain production.

Thalassaemia major is a serious disease.

The clinical picture of thalassaemia major was described in 1925 by the American pediatrician Thomas Cooley.

A child with thalassaemia major appears healthy at birth.

The predominant hemoglobin at birth is still fetal hemoglobin (HbF). HbF contains two alpha chains (such as adult hemoglobin HbA) and two gamma chains (as opposed to HbA).

Since the child does not have a beta chain, at birth it is protected from the effects of thalassaemia major.

Favism is a pathology caused by an enzyme deficiency: deficiency of glucose-6-phosphate dehydrogenase or G-6-PDH.

People suffering from this disease may experience anemia with jaundice because of the destruction of red blood cells when eating beans, peas and other vegetables.

This can also occur after taking some medications such as salicylates and sulfonamides.

Thalassemia in pregnancy

In general, pregnancy is possible and safe in women with β thalassemiaemia.

Today, women with thalassemia major or thalassemia intermedia can also have children. (Thalassaemia in pregnancy – Leung TY – Lao TT Best Pract res clin obstet gynaecol. 2012 Feb; 26 (1): 37-51).

The most important factors to be evaluated are measurements of cardiac function and iron exposure using magnetic resonance imaging.

Symptoms of thalassaemia

The symptoms of beta-thalassemia depend on the severity of the disease.

Healthy carriers do not show any symptoms.

Those affected by severe thalassaemia may experience the following symptoms from the first months of their lives:

• High-grade anemia,
• fatigue and weakness,
• Shortness
• Decreased growth,
• facial pallor (one of the first symptoms observed in newborns),
• dark urine,
• enlargement of the liver and spleen,
• Jaundice.

Anyone who does sports and has a hemoglobin value below 9 g / dl can have a significant drop in performance.

Among the consequences of Mediterranean anemia is the ban on blood donation if hemoglobin levels are lower than:

• 13,5 g/dl for men,
• 12.5 g/dl for women.

Diagnosis of Mediterranean anemia

The doctor diagnoses mild and severe thalassemia in childhood, because the symptoms appear already in the first two years of life.

Various blood tests are used to diagnose thalassemia:

A complete blood count includes:

• haemoglobin levels,
• Number and size of red blood cells.

People with thalassemia have fewer red blood cells and less hemoglobin than normal.

People with alpha/beta thalassemia may have smaller red blood cells.

An adult should have higher hemoglobin and hematocrit levels than:

1. Adult male – 13 g/dl haemoglobin and 39% haematocrit;
2. Adult woman – 12 g/dl haemoglobin and 36% haematocrit;
3. Pregnant woman – 11 g/dl haemoglobin and 33% haematocrit.

The number of reticulocytes (measuring the cells from which the erythrocytes are formed) can give an indication of whether the bone marrow produces a sufficient number of red blood cells.

Laboratory studies of iron levels indicate whether the cause of anemia is:

• Iron deficiency
• Thalassemia.

One should not confuse the ferritin levels with the iron content in the blood, because these are two different data.

In those affected by Mediterranean anemia, iron may be normal.

Indirect bilirubin (unconjugated) is higher in patients with thalassaemia.

If there is a family history of thalassaemia, a genetic test is used for diagnosis.

To diagnose prenatal Mediterranean anemia, a chorionic villus sampling of the fetus must be performed as early as the 10th week. In this way, one can find out whether the child will develop thalassemia.

How is thalassaemia treated?

The standard therapy consists of:

1. Blood transfusion
2. Iron expelling therapy (chelation).

In particularly severe cases, it is possible to perform:

1. removal of the spleen,
2. Bone marrow.

Blood transfusion involves transferring blood to the vein to restore normal levels of red blood cells and hemoglobin.

The transfusions are repeated:

• Every 4 months for moderate thalassaemia,
• Every 2-4 weeks with beta-thalassemia.

Iron chelation involves the removal of excess iron from the body.

Blood transfusions can cause overload with iron.

Patients receiving blood transfusions must undergo iron chelation therapy.

The pharmaceuticals used in iron chelation are:

1. deferoxamine, a solution for subcutaneous administration,
2. Deferasirox, a tablet taken orally.

Splenectomy (removal of the spleen) may be required in patients with hemoglobin H disease.

Bone marrow transplantation is the most effective method of treatment. Compatibility between donor and recipient exists when the donor has the same types of proteins (human leukocyte antigens HLA) as the recipient cells on the surface.

Sibling bone marrow transplantation is the best treatment option.

Most patients with thalassaemia lack a suitable donor.

The stem cells of the transplanted bone marrow begin to generate new blood cells.

Diet and diet for thalassemia

In thalassaemia major, foods high in iron should be restricted.

Increased absorption of iron in the intestine is characteristic of thalassemia.

A cup of black tea during the meal decreases iron absorption from food, especially in thalassemia intermedia (Alarcon, 1979).

However, there is no evidence that a low-iron diet would be helpful in thalassemia major; only foods that contain a lot of iron should be avoided, such as:

• Liver
• Chocolate
• Pulses
• Some vitamin cocktails.

One should pay attention to foods for children, such as breakfast cereal and multivitamins, as they contain a lot of iron.

Calcium

Many thalassemia factors cause calcium deficiency. Therefore, a diet rich in this mineral is recommended.

In order to avoid stone formation, dietary supplements should be avoided.

According to the blood group diet, thalassemia has developed mainly in the Mediterranean countries, because in these countries the inhabitants have always consumed a lot of gluten.

According to this theory, avoiding gluten-containing grains can reduce symptoms in most cases. Therefore, it should be avoided:

• Noodles
• Cracker
• Biscuits,
• Pizza
• Pastry
• Spelt
• Barley
• Oats
• Kamut,
• Sorghum.

What is the prognosis for thalassemia patients?

Patients with mild thalassemia have a good chance of survival if they undergo the necessary treatment (transfusions and iron chelation treatment).

Iron overload is the leading cause of death in thalassaemia patients, so iron chelation therapy is extremely important.

Bone marrow transplantation can definitely cure thalassemia.

Prevention of thalassaemia

Healthy carriers of beta-thalassaemia must be informed of the associated risks of reproduction with a partner with the same genetic modifications.

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