Introduction

Thalassemia is an inherited (i.e. passed from parents to children through genes) blood disorder caused when the body doesn’t make enough of a protein called haemoglobin. Thalassemias are a heterogeneous group of single gene haemoglobinopathic disorders in which the production of normal haemoglobin is suppressed partially or completely because of defective synthesis of β- or α-globin chains. Normally, an individual inherits two alpha chains (ɑ2) and two beta chains (ß2) from each parent to form normal adult haemoglobin (HbA), which is represented as ɑ2ß2. Depending on the genetic defect which lies in transmission of ɑ chain or ß chain; thalassemias are classified as ɑ and ß thalassemia.

Each thalassemia may occur in heterozygous state (thalassemia minor) or homozygous state (thalassemia major). Synthesis of haemoglobin is grossly impaired when the individual is homozygous and severe anaemia develops. When the abnormality is heterozygous, there is little disability in the form of mild anaemia.

Types

1. Beta Thalassemia (more common)
   1. Major
   2. Minor ( more common)
2. Alpha Thalassemia (rare)

Clinical features

Children with thalassemia are usually normal at birth but soon develop symptoms of thalassemia.

1. Anaemia
2. Headaches
3. Fatigue
4. Shortness of breath
5. Jaundice
6. Enlargement of the spleen
7. They may not want to eat and they may vomit frequently after feedings.

How do I know if I have thalassemia?

People with moderate and severe forms of thalassemia usually find out about their condition in childhood, since they have symptoms of severe anemia early in life. People with less severe forms of thalassemia may only find out because they are having symptoms of anemia, or maybe because a doctor finds anemia on a routine blood test or a test done for another reason.

β-Thalassemia major (homozygous)

1. Also called Cooley’s anaemia,
2. Bossing of skull and prominence of malar eminences (mongoloid appearance) due to bone marrow hyperplasia
3. Retarded growth and development
4. Folate deficiency
5. Hepatosplenomegaly (enlarged liver and spleen)
6. Early and prominent splenomegaly (enlarged spleen)
7. Hemosiderosis leading to tissue dysfunction such as cardiac enlargement and cardiac failure
8. Skull X-ray shows hair on end appearance and widening of medullary spaces

β-Thalassemia minor (heterozygous)

1. Symptoms absent or minimal
2. Detected only when iron therapy fails to raise the haemoglobin in hypochromic anaemia

Effects of thalassemia on pregnancy

If you planing for a baby or expecting a baby and you or your partner are deemed to be in a high-risk group, you should be offered a blood test in early pregnancy (by 10th week of pregnancy). Both parents need to have a blood test. This test will assess the risk of inheritance of thalassaemia. Its effects on pregnancy, depends on the type of thalassaemia.

Effects of alpha-thalassaemia

• Alpha-thalassaemia minor cause anaemia in pregnancy (with two mutated genes).
• Alpha-thalassaemia HbH disease occur (with three mutated genes). It causes severe anaemia and requires blood transfusions.

Effects of beta-thalassaemia

• Beta-thalassaemia minor causes anaemia due to lack of iron.
• Beta-thalassaemia major makes it difficult to get pregnant without fertility treatment. If you conceive a baby, complications occur during pregnancy. Your blood transfusions or medications needs change as pregnancy progresses.

Diagnosis

Because of wide clinical variability, a definitive diagnosis is essential to properly manage the thalassemia patient. The initial evaluation starts with:

1. Haemoglobin red cell indices
2. Reticulocyte count
3. Peripheral blood film for type of anaemia (microcytic anaemia without iron deficiency usually indicates thalassemia)
4. Haemoglobin electrophoresis
5. Quantitative haemoglobin A2 and haemoglobin F evaluation (elevated foetal haemoglobin or A2 level with decreased (or absent) haemoglobin A1 are noted in β-thalassemia disorders)
6. Outside the neonatal period, α-thalassemia disorders may have normal haemoglobin electrophoresis and is often a diagnosis of exclusion.
7. Both α- and β-globin disorders require confirmatory studies including DNA testing.
8. Severe anaemia – thalassemia major
9. Mild anaemia – thalassemia minor
10. Investigations for Bilirubin levels (raised)
11. If both parents have thalassemia minor – thalassemia major
12. If one of the parents has thalassemia minor – thalassemia minor

Prevention of thalassaemia

As it is passed from parents to children, thus it gets very difficult to prevent. However either you or your spouse have any family history of thalassemia or have family members belonging to the places in the world where it is common, then you need to speak a genetic counselor to assess the level of your risk of passing thalassemia to your children.

Management of thalassemia

1. Regular red blood cell (RBC) transfusion - to prevent severe anaemia and suppress endogenous ineffective erythropoiesis.
2. Haemoglobin should be maintained between 8-10 g/dl.
3. Iron therapy is strongly contraindicated.
4. Folic acid supplements should be given.
5. Blood transfusions are also indicated for thalassemia intermedia patients who, despite maintaining haemoglobin more than 6 g/dL, develop dysmorphic skeletal features, growth failure, organ failure and significantly impaired quality of life.
6. Safe transfusion therapy involving expanded red blood cell antigen matched, leukodepleted, packed RBC transfusions at 2 to 5 week intervals - to maintain pre transfusion haemoglobin levels more than 9 g/dL.
7. Following transfusion, close observation for febrile, allergic and haemolytic reactions is required.
8. Early detection of alloimmunization by serial monitoring Coombs testing is recommended.

The treatment of thalassemia major has improved dramatically over the last 2 decades, leading to a sharp increase in survival rates and significant improvements in quality of life. Nonetheless, patients with thalassemia major may suffer medical problems from the disease itself or its therapy.

Complications

Hypersplenism

1. Hypersplenism can develop and results in increased anaemia or transfusion requirements.
2. If the number of RBC units transfused to maintain a desired level of haemoglobin increases, hypersplenism should be suspected. The detection of hypersplenism requires the haemoglobin and the number of units transfused to be monitored closely in all patients.
3. Splenectomy is considered in both the non transfused patient who develops worsening anaemia and the transfused patient with increasing transfusion requirements.
4. Splenectomy should be considered when the amount of blood required to maintain haemoglobin levels increases by 1.5 times or more than 225 mL/kg/year.
5. Splenectomy carries the risk of developing serious infections postoperatively, especially in the infant.
6. Thromboembolic events and pulmonary hypertension are also increased in splenectomized patients. These complications may be minimized by the routine use of aspirin or low-dose anticoagulants.

Iron overload

1. Iron overload is a major cause of morbidity for both transfused and non transfused thalassemia patients.
2. Early detection of iron overload, whether from red cell transfusions or increased gastrointestinal iron absorption, is essential to prevent organ damage.
3. Determination of serial serum ferritin levels
4. Direct measurement of hepatic iron by liver biopsy
5. New non-invasive techniques to determine the degree of iron overload - superconducting quantum interference device (SQUID)
6. Chronic transfusion therapy, elevated ferritin, and high hepatic iron are indications for chelation

Cardiac problems

1. Cardiac disease is the major cause of death in thalassemia patients and can be fatal in the second decade of life.
2. In the absence of effective iron chelation, patients often develop arrhythmia and congestive heart failure.
3. Reversal of iron overload is the most important factor in prevention and treatment.
4. Pulmonary hypertension is common in patients without iron-induced cardiomyopathy and may be secondary to anaemia, haemolysis, and thrombosis.
5. Improved transfusion therapy and nitric oxide modulating drugs may be very useful.

Endocrine dysfunction

1. Endocrine dysfunction caused by iron deposition results in hypothyroidism, hypoparathyroidism, diabetes, gonadal failure, growth failure, and osteoporosis.
2. Prevention, with annual endocrine screening, effective chelation, nutritional supplements, and exercise are required.
3. Treatment with specific hormone replacement therapy for endocrine deficiencies and bisphosphonates for osteoporosis are recommended.

Liver dysfunction

1. Liver toxicity can occur as a direct consequence of iron toxicity and/or from transfusion-acquired hepatitis.
2. Once hepatic dysfunction has been documented, rapid iron chelation and treatment of hepatitis is critical for preservation of liver function.
3. Hepatitis C can often be adequately treated with pegylated interferon and ribavirin.
4. Patients who have chronic hepatitis B or C should be monitored for development of hepatocellular carcinoma with alpha-fetoprotein and hepatic ultrasounds annually.

Infections

1. Infections are the second most common cause of death in thalassemia major.
2. Transmission of viral infections via blood transfusions is possible.
3. Bacterial infections including Streptococcus pneumoniae and Yersinia enterocolitica may be fatal. The latter is an iron-dependent bacterium, and infection often manifests with abdominal pain and fever.
4. Immunization for pneumococcus, Haemophilus influenzae, hepatitis (A, B), and influenza are indicated.
5. Following splenectomy, penicillin prophylaxis is required.

Management of iron overload

• Removal of iron in patients with iron overload due to repeated blood transfusions may be tried with desferrioxamine – an iron chelating agent (DESFERAL THERAPY)
• Standard dose is 25 to 40 mg/kg for children as an 8 to 12 hour slowly delivered subcutaneous infusion for 5 to 7 days per week- to keep serum ferritin less than 1000 μg/mL.
• Lower doses are given to young children less than 3 years of age.
• Ascorbic acid on the days of desferrioxamine infusion enhances iron excretion.
• High-dose short-term infusions increase toxicity without improved efficacy.
• Severe iron overload (ferritin >2500 μg/L or liver iron >15 mg/g dry weight) may be treated with continuous infusions of desferrioxamine at 50 mg/kg/day (maximum 6 g/day).
• Limiting iron intake helps to minimize hemosiderosis.
• Nutritional counselling to avoid iron rich diets and supplementation with tea is useful.
• Tea reduces iron absorption from food.

Iron chelation therapy with desferrioxamine therapy has increased patient survival and is the most effective therapy for the treatment of iron overload. However, desferal chelation in high doses can lead to toxicity and complications.

• Desferal toxicity monitoring requires annual hearing and ophthalmologic examinations.
• Deferiprone is for patients with contraindications to desferrioxamine.

Noncompliance is the major factor for ineffectiveness of therapy. Therefore, newer treatment therapies are being introduced like BONE MARROW TRANSPLANTATION (BMT) which can be introduced at an earlier age. Starting lifelong transfusions and chelation has a major impact on the patient and family. Compliance with the therapy is probably the most important factor in reducing the morbidity of chronic transfusion therapy. As with other chronic illnesses, thalassemia patients face considerable challenges, from financial hardship and absence from school and work to significant issues with self-esteem and assurance. All significantly affect the quality of life of the patients. Because of the genetic inheritance of thalassemia, prevention of disease involves identification of thalassemia carriers at risk and subsequent genetic counselling of affected couples and children.

References

1. Current Paediatric Therapy, Eighteenth Edition. Fredric D. Burg, Julie R. Ingelfinger, Richard A. Polin, Anne A. Gershon.
2. Special Care in Dentistry, Handbook of Oral HealthCare. Crispian Scully CBE, Pedro Diz Dios, Navdeep Kumar. Churchill Livingstone Elsevier. ISBN 13: 978 0 443 07151 5
3. Pediatric Secrets, Fourth Edition. Richard A. Polin, Mark F. Ditmar. Elsevier Mosby.
4. Textbook of Clinical Medicine. Second Edition. S.N. Chugh. Arya Publications. ISBN-81-7855-376-7