Thalassaemia

Thalassaemia

November 6, 2019 2 By Bertrand Dibbert


I’m Chuen Wen from SGH Hematology. Today I’ll be talking about thalassaemia. Thalassaemia is a very broad and complex disorder. This talk is going to give broad overview of thalassaemia focusing especially on adult population in this region, particularly Singapore. Normally individuals have one beta globin gene on each copy of chromosome 11. More than 200 mutations affecting these beta globin genes and their regulatory sequences has been identified, resulting in thalassaemia of variable clinical outcomes. In beta thalassaemia trait, one of the beta globin genes is carrying a thalassaemia mutation. And these individuals are clinically asymptomatic with only mild anemia and variable microcytosis. Carrying two defective beta globin genes results in a wide spectrum of clinical manifestation, including thalassaemia intermedia with mild to modulate anemia and thalassaemia major with severe anemia that is transfusion-dependent. There are also other hemoglobin variants such as HbE, which may interact with beta thalassaemia mutations to produce thalassaemia intermedia or major. There are two alpha globin genes on each chromosome 16. Clinical syndrome of alpha thalassaemia is determined by the number of functional alpha genes present. In silent alpha thalassaemia, one alpha gene is deleted. People with this condition are asymptomatic, but minority may have reduced MCV or MCH. In alpha thalassaemia trait, two genes are deleted. These are asymptomatic carriers with their hemoglobin either normal or minimally reduced. MCV and MCH are reduced. Patients with HbH disease have three alpha genes deletion. Clinical features are variable. They may have moderate anemia with reduced MCV, MCH, hepatosplenomegaly. And jaundice may also occur. Hb Bart’s hydrops fetalis is an important cause of stillbirth in Southeast Asia. Fetus is either stillborn or dies soon after birth. Alpha thalassaemia may also arise from non-deletional mutations of the alpha globin gene. One common example in Southeast Asia is Hb Constant Spring. Thalassaemia is a major public health problem in Southeast Asia, and hence the importance of this screening. The population at risk can be screened for beta thalassaemia trait by performing full blood count, Hb electrophoresis, and other techniques to quantify HbA2, which should be increased in beta thalassaemia trait. It may be difficult to diagnose alpha thalassaemia trait with these tests. And DNA analysis may be needed. Screening can be conducted at antenatal clinics or prior to planning for a child. When heterozygous carrier mothers are identified, their partners are tested. If the partners are also carriers for the similar related type of thalassaemia, the couple can be offered the option of prenatal diagnosis for severe form of thalassaemia. Some methods of prenatal diagnosis includes fetal DNA analysis on amniotic fluid cells taken by amniocentesis in second trimester or direct analysis of fetal DNA obtained by chorionic villus sampling done at 9 to 13 weeks of gestation. Symptoms of anemia and timing of the symptoms are important clues to the severity of thalassaemia. In severe form of alpha thalassaemia, symptoms and signs including hepatosplenomegaly occur in utero or at birth. And for beta thalassaemia major these occur few months after birth. Full blood count and peripheral blood film would show microcytic and hypochromic anemia. It is important to distinguish it from iron deficiency anemia, which in turn may also occur concurrently with thalassaemia traits. Iron studies can help to detect iron deficiency. Separation of the hemoglobin fractions can be done with Hb electrophoresis or High Performance Liquid Chromatography, HPLC. In addition, HPLC can also quantify the Hb fractions. Staining of the red cells for HbH inclusion bodies may be helpful in suggesting a diagnosis of alpha thalassaemia. But this is often not detectable in alpha thalassaemia traits. In normal individual, they’re mainly HbA with small percentage of HbA2 and HbF. In beta thalassaemia major, there is no or very low level of HbA and persistently high HbF level. Beta thalassaemia intermedia may have the same results, but the HbA level can be higher. And HbF level can be lower than in the beta thalassaemia major patient. In beta thalassaemia trait, HbA2 fraction is slightly raised, usually more than 4%. In HbH disease, there’s increased Hb Bart in neonatal period detected in about 20% to 40% of the patient. And there are variable amounts of HbH detected later in life. The diagnosis of alpha thalassaemia trait and silent alpha thalassaemia often only can be confirmed by DNA analysis as the amount of HbH is often minimal and not detectable. In beta thalassaemia, there is absent or decreased production of beta chain. Alpha chain production is unaffected, and hence leading to an excess of alpha chains. These alpha chains, in the absence of their partner beta chains, are unstable and precipitate in red cell precursors to interfere with normal red cell maturation. There’s intramedullary destruction of red cells precursors, and hence ineffective erythropoiesis. The mature red cells that enter the circulation have alpha chain inclusion that interfere with their passage in the circulation, especially in the spleen. The spleen hypertrophies and results in splenomegaly. On top of that, the degradation products of excess alpha chains produce much negative effects on the red cell membrane proteins and lipids resulting in rigid red cells with a shortened lifespan. Both the ineffective erythropoiesis and hemolysis results in anemia. And this in turn stimulates erythropoietin production that results in expansion of the bone marrow and skeletal abnormality. The anemia is corrected with blood transfusion with its own complications. The anemia associated with thalassaemia may be severe and is accompanied by ineffective erythropoiesis with bone expansion and extramedullary hematopoiesis in the liver, spleen, and other sites including paravertebral masses. Transfusion, the mainstay of treatment, has its own related complications. And these include transfusion transmitted infection, mainly hepatitis B, C, and HIV, and iron overload. Iron deposition in the heart, liver, and multiple endocrine glands including pituitary, thyroid, parathyroid, and pancreas resulting in severe damage to these organs. In beta thalassaemia, there is absent or decreased production of beta chain. Alpha chain production is an effective, and hence leading to an excess of alpha chains. These alpha chains, in the absence of their partner beta chains, are unstable and precipitate in red cell precursors to interfere with normal red cell maturation. There’s intramedullary destruction of red cells precursors, and hence ineffective erythropoiesis. The mature red cells that enter the circulation have alpha chain inclusion that interfere with their passage in the circulation, especially in the spleen. The spleen hypertrophies and results in splenomegaly. On top of that, the degradation products of excess alpha chains produce much negative effects on the red cell membrane proteins and lipids, resulting in rigid red cell with a shortened the lifespan. Both the ineffective erythropoiesis and hemolysis results in anemia. And this in turn stimulates erythropoietin production that results in expansion of the bone marrow and skeletal abnormality. The anemia is corrected with blood transfusion with its own complications. Several methods can be used to monitor iron overload. Serum ferritin can easily be performed, and it broadly relates to the body iron. However, its prediction of iron loading can be unreliable. And there are conditions that would increase the ferritin level. Patients with ferritin levels of less than 2,500 microgram per liter or preferably less than 1,000 microgram per liter is associated with lower risk of cardiac disease and death from iron overload. Liver ion concentration can be used to monitor iron loading. Liver iron concentration can be measured by liver biopsy and MRI scan, Ferriscan. SQUID, or Superconducting Quantum Interference Device, can be used as well. But it is not universally available. For monitoring liver iron concentration, the aim is for a level less than 7 milligram per gram of dry weight. Cardiac iron is reflected by heart function test and can be measured by a MRI technique called T2* with the aim of cardiac T2* of more than 20 milliseconds. Cardiac T2* can detect myocardial iron loading before ejection fraction worsens. There are three types of iron chelators available currently, namely deferoxamine, deferiprone, and deferasirox. The different types of chelators have their own advantages and side effects as shown in the table. Generally, chelation should be initiated after the first 10 to 20 transfusion of ferritin level above 1,000 microgram per liter for the thalassaemia major patients. Sometimes combination of deferoxamine and deferiprone are given for patients with severe iron loading, especially of the heart. Thank you.