Thalassemia is genetic, inherited form of anemia. This disease mainly affects individuals of Southeast Asian, Chinese, and Filipino ancestry and some people of African and Mediterranean ancestry; in its most severe form it results in the death of the fetus or newborn. Individuals with less severe cases have varying degrees of anemia. Affected individuals can't create hemoglobin properly, and they produce small, pale, short-lived red blood cells.

Hemoglobin proteins are composed of four polypeptides -- two "alpha chains" and two "beta chains". One of the two types of polypeptides making up the hemoglobin protein in the blood cells of people with thalassemia is defective or missing.

In alpha thalassemia, the alpha chains are defective or missing. In beta thalassemia, the more serious version of this disease, the beta chains are defective or missing.

There are three classifications of beta thalassemia. In order of increasing severity, they are thalassemia minor, thalassemia intermedia, and thalassemia major.

Thalassemia major is more commonly known as Cooley's anemia. Symptoms include slow growth, jaundice, an enlarged heart, liver, and spleen, and thinned bones. An enlarged skull, facial deformities, and tooth misalignment may also occur. Bone fractures can be common. Bone and tooth deformities occur because the body spurs the overgrowth of bone marrow (hyperplasia) to produce more blood cells in a futile attempt to compensate for the disease.

Untreated children die young, usually of heart failure or infections.

Thalassemia intermedia produces milder symptoms for the first two decades of life in most cases. In initial diagnoses, physicians sometimes mistake it for iron deficiency. Thalassemia minor may not produce any symptoms, though changes in the blood occur.

People suffering from any form of this disease are most often treated with transfusions of red blood cells. These frequent transfusions cause their bodies to accumulate too much iron, which can damage internal organs like the heart and kidneys. Ultimately, the excess iron will cause organ failure and death.

To prevent organ damage, patients are treated with a chelation medication called Desferal to remove excess iron. Desferal, which binds to the iron so that it can be removed by the kidneys, must be injected over a long period of time, and the treatment can be extremely painful. Scientists are seeking new chelation drugs that can be delivered more quickly and less painfully.

Part of the information in this writeup was found at www.thalassemia.org, http://www.emedicine.com/radio/topic686.htm and http://members.aol.com/neskander/ANEMIA.html. The rest is based on work I did for the science dictionary at http://biotech.icmb.utexas.edu/

The thalassaemias (Greek thalassa, meaning 'sea') are a group of haemolytic anaemias that affect people throughout the world, but are usually associated with those of Mediterranean descent. It is a genetic disease that results in the defective production of haemoglobin protein chains. These particular protein chains are also called 'globins', thus haemoglobin. The disease is classed according to which of the chains are affected.

Haemoglobin

As human beings develop from embryo to adult, the properties of haemoglobin (the oxygen-binding component of blood) also needs to change. Embryonic haemoglobin changes at around the 12th week of gestation to foetal haemoglobin (Hb F). This, in turn, is slowly replaced by the adult haemoglobins (Hb A and Hb A₂) over the first six months after birth.

Normal haemoglobin (Hb) of all types is made up of four globin-protein chains, which fold together to form a protein tetramer. This allows the binding of up to four molecules of O₂ and enables the blood to perform its function of supplying oxygen to respiring cells. Foetal haemoglobin is made up of two α globin chains and two γ globin chains, written as α₂γ₂. In an adult, 98% of haemoglobin is Hb A, which is made up of two α globin chains and two β globin chains, α₂β ₂. The other 2%, Hb A₂, is made up of two α globin chains and two δ globin chains, α₂δ₂. The genes coding for haemoglobin proteins can be found on chromosomes 11 (β,δ and γ chains) and 16 (α chain).

Thalassaemia

The thalassaemias are inherited haemolytic anaemias, and result in the increased destruction of red blood cells. The normal lifespan of a red cell is typically around 120 days; survival times are significantly shortened in those with a thalassaemia. However, this does not necessarily mean that a clinical anaemia will be seen in someone who does have a shortened red cell life, as the person's bone marrow will increase the amount of red cell production as a compensatory measure to maintain normal function. This is called a 'compensatory haemolytic disease'. If these compensatory measures are unable to compensate the increased loss of red cells, then the person will experience the symptoms of anaemia.

In thalassaemia, the cause of early red cell destruction is caused by the decreased rate of production of a certain globin chain (depending on the type of thalassaemia). Haemoglobin is formed from two pairs of globin chains, and so if there is a reduced availability of one of these chains, normal Hb synthesis is impaired. This leads to an excess of the normally produced globin within the red blood cell (e.g., in α thalassaemia, there would be an excess of β globin chains), which accumulate and form an unstable product which precipitates, leading to the destruction of the cell. This imbalance is the hallmark of all forms of thalassaemia.

The thalassaemias are classified according to which of the haemoglobin chains is being synthesised inefficiently, thus α thalassaemia and β thalassaemia. Whilst these share the name 'thalassaemia', they are separate diseases, and so I shall discuss each individually. For interest, there is also a δβ thalassaemia, but it is incredibly rare.

α thalassaemia

Aetiology and Epidemiology The α thalassaemias are seen most frequently in south-east Asia (Thailand, the Malay Peninsula and Indonesia) and west Africa, where the prevalence is usually around 20-30%. They are also seen in southern Europe and the Middle East, and sporadic cases have been reported in all racial groups.

Each chromosome 16 contains two closely linked genes that 'code' for α globins, and thus there are four α globin genes per cell. In patients with α thalassaemia, there has been a genetic deletion of one, two, three, or all four of these genes. The severity of the α thalassaemia is dependant on how many of the genes have been deleted in an individual.

Since a person can be missing any from one to four of the α globin chains, logically, there must be two versions of a defective chromosome 16. The first (α⁺ thalassaemia determinant) is missing one of the two α globin genes. The second (α⁰ thalassaemia determinant) is missing both. This means that there are six different possible genetic states:

1. normal + normal = normal (4 genes)
2. normal + α⁺ thalassaemia = heterozygous α⁺ thalassaemia (3 genes)
3. normal + α⁰ thalassaemia = heterozygous α⁰ thalassaemia (2 genes)
4. α⁺ thalassaemia + α⁺ thalassaemia = homozygous α⁺ thalassaemia (2 genes)
5. α⁺ thalassaemia + α⁰ thalassaemia = HbH disease (1 gene)
6. α⁰ thalassaemia + α⁰ thalassaemia = homozygous α⁰ thalassaemia, also called Hb Bart's hydrops fetalis syndrome (0 genes)

Both of the α thalassaemia determinants are found in south-east Asia and Mediterranean regions, meaning that these areas see the full spectrum of α thalassaemia disease. For instance, in northern Thailand, where both determinants are particularly common, 0.4% of all births are stillborn due to Hb Bart's hydrops fetalis syndrome, while 1% of the population has HbH disease. To contrast, in west Africa, the Middle East, India, and the Pacific Islands, the α⁰ thalassaemia determinant is very, very rare, and so HbH disease is also rare, with Hb Bart's hydrops fetalis syndrome being non-existent.

Signs and symptoms The main signs and symptoms of anaemia are below. The manifestation of these signs and symptoms vary according to the severity of the thalassaemia: α⁺ thalassaemia trait – this results in the deletion of only one gene, and patients are usually asymptomatic, though possibly slightly anaemic.

α⁰ thalassaemia trait – the deletion of two genes due to a heterozygous α⁰ thalassaemia is also asymptomatic. The patient, again, may have a slight anaemia, but this would usually only be detected in a routine blood test. This is also true for a homozygous α⁺ thalassaemia determinant, again where only two genes are missing.

Both of these traits are examples of compensatory haemolytic diseases.

Haemoglobin H disease – This is a chronic haemolytic anaemia due to the presence of both α⁺ and α⁰ thalassaemia determinants. The deletion of three α globin genes means that α globins are produced at a greatly lowered rate, and so there is an accumulation of β globins that combine to form the unstable β₄ tetramer called HbH. This haemoglobin tetramer precipitates in the red cells, forming rigid Heinz bodies that are visible in blood films. These Heinz bodies are removed from the red cell during its passage through the spleen, but this damages the red cell membrane, resulting in a reduction of the cell's lifespan.

There is a variable clinical picture for this disease; some patients are only mildly affected, living almost normal lives. However, most have a moderate to severe manifestation and will experience the usual symptoms of a clinical anaemia. They will usually have a haemoglobin level between 7 – 11g/dL, but it can be as low as 3-4g/dL. They will also have an enlarged spleen. A third of patients will experience skeletal abnormalities due to increased red cell production by the bone marrow.

Haemoglobin Bart's hydrops fetalis – This is the deletion of all four α globin genes due to homozygous α⁰ thalassaemia determinant. This means that no α globins are produced and so the remaining globin chain, γ globin, is forced to form the γ₄ tetramer called Hb Bart's. This condition is incompatible with life, and the baby is either stillborn sometime after the 25th week of gestation, or dies very shortly after birth.

β thalassaemia

Aetiology and Epidemiology β thalassaemia is most prevalent in the southern Europe / Mediterranean area, with around 10-30% of the population carrying the β thalassaemia trait. Other areas that are commonly affected are south east Asia (5% prevalence) and Africa (1.5% prevalence). It also occurs in the Middle East, India, Pakistan and southern China, and it is thought that this distribution is seen because the trait is in someway protective against Plasmodium falciparum in those who have heterozygous β thalassaemia.

Unlike α thalassaemia, β thalassaemia is caused by point mutations in the genetic code rather than by deletions. To date, over 200 different genetic defects have been found that result in the disease, and the prevalence of different particular genetic abnormalities vary across the different regions. These defects are mostly point mutations resulting in the addition, substitution or deletion of a single nucleotide. This means that a variable pattern of in the severity of the disease, as some mutations will cause more damage to the resulting β globin than others, with the less severe defects producing a vaguely serviceable protein, and more severe ones causing a complete loss of output of the β globin chain.

β thalassaemia is classified as to its severity using β⁺ thalassaemia for the less severe forms of the mutation (meaning there is still some output of β globin), and β⁰ thalassaemia to indicate that no functional β globin is being produced. There is only one β globin gene on chromosome 11, and so there are three possible genetic states:

1. normal gene + normal gene = normal
2. normal gene + β thalassaemia gene = heterozygous β thalassaemia
3. β thalassaemia gene + β thalassaemia = homozygous β thalassaemia

Thus, two heterozygous parents has a 25% chance of having a thalassaemia free child, 50% chance of producing a heterozygous child and 25% of producing a homozygous child with full-blown thalassaemia.

Signs and Symptoms The main signs and symptoms of anaemia are below. The manifestation of these signs and symptoms vary according to the severity of the thalassaemia: Heterozygous β thalassaemia – this is the carrier state for β thalassaemia, and is sometimes called β thalassaemia minor. It is an asymptomatic condition, and any anaemia due to the defective β globin synthesis will be either mild or absent.

Homozygous β⁺ thalassaemia – also called thalassaemia intermedia, this results in a moderate anaemia (haemoglobin concentration of 7-10g/dL) that usually present around the age of 1-2 years. Most patients with this condition are reasonably well and will only require blood transfusions when there is a concurrent illness. Clinical features include: skeletal deformity due to increased red cell production by bone marrow; enlarged spleen; recurrent leg ulcers; and haemosiderosis in adult life due to increased iron absorption.

Homozygous β⁰ thalassaemia – also called Cooley's anaemia and thalassaemia major. Children with this form of β thalassaemia will present relatively early in life, usually before the first birthday. This is because of the gradual replacement of the functional foetal haemoglobin over the first six months of life with the non-functional adult haemoglobin. Presenting signs and symptoms include:

• failure to thrive and recurrent bacterial infection
• severe anaemia (Hb 2.5-6.5g/dL) from 3-6mths
• mild jaundice
• extramedullary haemopoiesis that soon leads to hepatosplenomegaly (with an enlarged abdomen) and bone expansion. This gives rise to the classical thalassaemic facies with frontal and parietal bossing; enlargement of the maxillary bones, which can result in severe dental deformities and malocclusion of the teeth; and depression of the bridge of the nose. These classic features are only observed in patients from countries without a good blood transfusion service.

Signs and Symptoms of Anaemia

Symptoms of anaemia are usually seen once haemoglobin levels fall below 8g/dL, and include fatigue, breathlessness, headache, faintness, visual disturbances, anorexia, nausea, bowel disturbances, menstrual disturbances, loss of libido, chest pain (angina), pain in legs after a period of walking (intermittent claudication) and palpitations.

Investigations for the thalassaemias

Full Blood Count (FBC) - simple blood test to measure haemoglobin concentration, red cell and reticulocyte numbers and various other parameters of red blood cells, as well as a count of white blood cells and platelets.

Blood Film - examines the morphology of the blood cells. For thalassaemia, a peripheral blood smear will show microcytic, hypochromic red cells, similar to those seen in iron deficiency anaemia, as well as target cells. In α thalassaemia there will be Heinz bodies.

Haematinic assay - this quantifies the serum iron, serum ferritin, serum soluble transferrin receptor and total iron binding capacity (TIBC) of the blood to give an accurate picture of a patient's iron status. This is useful to distinguish thalassaemia from iron deficiency anaemia; in iron deficiency anaemia, the serum iron levels will be reduced, but they will be raised in thalassaemia.

X-rays – x-rays of the long bones will show expansion of the marrow and a thinned cortex. Skull x-rays will show a typical 'hair on end' appearance in β thalassaemia.

Electrophoresis – electrophoresis of a blood sample will separate out the different types of haemoglobin e.g., in homozygous β⁰ thalassaemia there'll be no HbA band.

Treatment for the thalassaemias

Treatment for all the thalassaemias except homozygous β⁰ thalassaemia is supportive rather than active. Iron supplementation is not given because patients do not have an iron deficiency, and any supplementation will cause an iron overload. However, folate supplementation is given in order to support the increased production of red blood cells by the bone marrow. It is unusual for patients to require blood transfusions unless they are experiencing another concurrent illness, in which case a transfusion may be given as a supportive measure. Some patients may require a splenectomy, the surgical removal of the spleen, if it enlarges sufficiently that they experience symptoms due to the enlargement, e.g., pooling of red cells, an increased plasma volume and secondary hypersplenism.

In homozygous β⁰ thalassaemia, treatment is regular blood transfusions every 4-6 weeks in an attempt to keep Hb levels above 10g/dL. At the same time, an iron chelating agent such as desferrioxamine needs to be given as an overnight subcutaneous infusion on 5-7 nights a week to prevent iron overload. Daily vitamin C is also given as is increases the urinary excretion of iron in response to desferrioxamine. Regular serum ferritin measurements should be made in order to assess iron overload. Long-term folate supplementation should be given to support the marrow's production of red cells. Bone marrow transplantation has been used in young patients with HLA-matched siblings with mixed success.

Prognosis

The prognosis for HbH and homozygous β⁺ thalassaemia is fairly positive. While there will always be an anaemia present, patients can live relatively normal lives under advice of their physicians. They will have an increased incidence of leg ulcers, gallstones and infections, and may in time need a splenectomy to treat an overly enlarged spleen. They may also have some skeletal abnormalities.

For homozygous β⁰ thalassaemia, the biggest problem is not the anaemia, which is severe but well treated by giving transfusions, but the dangers of iron overload. Iron absorption from the gut is increased and this, together with the regular blood transfusions that are needed and the body's inability to actively excrete iron, results in iron toxicity. An excess of iron in the body will lead to damage of the endocrine glands resulting in a failure of growth and a delay or failure of the development of secondary sexual characteristics; cirrhosis of the liver; damage to the pancreas resulting in diabetes mellitus; and damage to the heart leading to a fatal arrhythmia or congestive cardiac failure by the time the patient has reached adolescence. Unless the patient is given iron chelation therapy at the same time as being transfused, death will occur due to iron overload between the ages of 10 and 20 years. Assuming compliance on the part of the patient with the iron chelating therapy, normal growth and sexual development occurs. However, compliance is not always easy as it is an unpleasant and cumbersome regime to have to experience, with many unpleasant side-effects in itself.

References

• Hughes-Jones N C, Wickramasinghe S N, Hatton C, 2004, Lecture Notes On: Haematology, 7th edition, Blackwell Publishing, 27-50
• Kumar P, Clark M, 2002, Clinical Medicine, 5th edition, WB Saunders, 427-430
• Provan D, 2003, ABC of Clinical Haematology, 2nd edition, BMJ Books, 11-12