Beta thalassaemia - Clinicals, Diagnosis, and Management

Hematology

Clinicals - History

Fact Explanation
Family history of thalassaemia Normal haemoglobin (Hb) is composed of 2 alpha chains 2 beta chains. Alfa chains are produced by genes on the chromosome 16 and beta globin chains are by chromosome 11. At birth 80% of the Hb are HbF (2 alfa and 2 gamma chains), in which gamma chains are gradually replaced by beta chains starting at the age of 6 months, and result in HbA. HbA is composed of 2 alfa and a beta chains. Beta thalassaemia results from either insufficient or no production of beta chains. It is an inherited disorder with an autosomal recessive inheritance due to the point mutations of the globin chains. Consanguinity increase the risk of thalassaemia as there is a high risk of meeting two recessive genes. Common presenting age of thalassaemia is 6-24 months of age. Family history of thalassaemia
Normal haemoglobin (Hb) is composed of 2 alpha chains 2 beta chains. Alfa chains are produced by genes on the chromosome 16 and beta globin chains are by chromosome 11. At birth 80% of the Hb are HbF (2 alfa and 2 gamma chains), in which gamma chains are gradually replaced by beta chains starting at the age of 6 months, and result in HbA. HbA is composed of 2 alfa and a beta chains. Beta thalassaemia results from either insufficient or no production of beta chains. It is an inherited disorder with an autosomal recessive inheritance due to the point mutations of the globin chains. Consanguinity increase the risk of thalassaemia as there is a high risk of meeting two recessive genes. Common presenting age of thalassaemia is 6-24 months of age.
Severity of the disease There are 3 types of beta thalassaemia: thalassaemia minor or the trait, intermedia and major. In thalassaemia minor, person may be asymptomatic and may be detected only by blood investigations or as iron deficiency anaemia responding to the iron treatment. Intermedia may or may not be associated with the need for blood transfusions. Thalassaemia major is the homozygous state with no production of beta globin chains, and is usually transfusion dependent. Hb A2 is not increased in homozygous β-thalassemia. Severity of the disease
There are 3 types of beta thalassaemia: thalassaemia minor or the trait, intermedia and major. In thalassaemia minor, person may be asymptomatic and may be detected only by blood investigations or as iron deficiency anaemia responding to the iron treatment. Intermedia may or may not be associated with the need for blood transfusions. Thalassaemia major is the homozygous state with no production of beta globin chains, and is usually transfusion dependent. Hb A2 is not increased in homozygous β-thalassemia.
Shortness of breath Anaemia cause low oxygenation of the blood, Hypoxia can be sensed by the carotid chemoreceptors and it will increase the depth of respiration. If the patient has heart failure anemia can worsen the symptoms.
Iron overload due to recurrent blood transfusions can also cause iron deposition in the cardiac tissue which is greatest in the ventricular walls with less in the atria and conduction system result in cardiac failure and exertional shortness of breath.
Shortness of breath
Anaemia cause low oxygenation of the blood, Hypoxia can be sensed by the carotid chemoreceptors and it will increase the depth of respiration. If the patient has heart failure anemia can worsen the symptoms.
Iron overload due to recurrent blood transfusions can also cause iron deposition in the cardiac tissue which is greatest in the ventricular walls with less in the atria and conduction system result in cardiac failure and exertional shortness of breath.
Lethargy, fatigue Due to the anaemia, the patient feels very tired during exercise. Body lacks sufficient oxygen and energy where person feels fatigue and lethargy. Lethargy, fatigue
Due to the anaemia, the patient feels very tired during exercise. Body lacks sufficient oxygen and energy where person feels fatigue and lethargy.
Recurrent infections Possible causes could be hypersplenism causing low white blood cell counts, splenectomy associated infections due to encapsulated organisms such as streptococcus, meningococcus and iron overload making the individual vulnerable for infections with Yersinia sp. Recurrent infections
Possible causes could be hypersplenism causing low white blood cell counts, splenectomy associated infections due to encapsulated organisms such as streptococcus, meningococcus and iron overload making the individual vulnerable for infections with Yersinia sp.
Bleeding manifestaions Hypersplenism causing low platelet count. Bleeding manifestaions
Hypersplenism causing low platelet count.
Polyuria and polydypsia Diabetes mellitus in thalassemia is due to impaired secretion of insulin secondary to chronic pancreatic iron overload and insulin resistance due to iron deposition within liver or skeletal muscle. Polyuria and polydypsia
Diabetes mellitus in thalassemia is due to impaired secretion of insulin secondary to chronic pancreatic iron overload and insulin resistance due to iron deposition within liver or skeletal muscle.
Right hypochondrial pain Hepatitis can be due to iron deposition in liver in recurrent blood transfusions. Right hypochondrial pain
Hepatitis can be due to iron deposition in liver in recurrent blood transfusions.
Excessive sleepiness and weight gainhildren Hypothyroidism is an endocrine problem occur due to the iron overload. Excessive sleepiness and weight gainhildren
Hypothyroidism is an endocrine problem occur due to the iron overload.
Poor school performance May be multifactorial. Chronic disease, recurrent hospital stays, missing the lessons, lethargy due to anaemia and psychological distress are the some o these factors. Poor school performance
May be multifactorial. Chronic disease, recurrent hospital stays, missing the lessons, lethargy due to anaemia and psychological distress are the some o these factors.
Subfertility Hypogonadotropic hypogonadism is common in these patients. Subfertility
Hypogonadotropic hypogonadism is common in these patients.
Failure to thrive in children Thalassemia will be clinically evident at the age of major 6 - 24 months. Affected infants are fail to thrive, feeding problems, diarrhea, irritability, recurrent bouts of fever may occur. Failure to thrive in children
Thalassemia will be clinically evident at the age of major 6 - 24 months. Affected infants are fail to thrive, feeding problems, diarrhea, irritability, recurrent bouts of fever may occur.
Facial-maxillary abnormalities Ineffective erythropoiesis can lead to bone marrow expansion with thinning if the skull bones, skull bossing, prominent malar eminence, depression of the bridge of the nose and mandibular hyperplasia. This can lead to faciomaxillary abnormalities. Facial-maxillary abnormalities
Ineffective erythropoiesis can lead to bone marrow expansion with thinning if the skull bones, skull bossing, prominent malar eminence, depression of the bridge of the nose and mandibular hyperplasia. This can lead to faciomaxillary abnormalities.

Clinicals - Examination

Fact Explanation
Thalassaemic facies When the disease is advancing,there is ineffective erythropoiesis can lead to bone marrow expansion with thinning if the skull bones, skull bossing, prominent malar eminence, depression of the bridge of the nose and mandibular hyperplasia. Thalassaemic facies
When the disease is advancing,there is ineffective erythropoiesis can lead to bone marrow expansion with thinning if the skull bones, skull bossing, prominent malar eminence, depression of the bridge of the nose and mandibular hyperplasia.
Pallor Due to the anaemia. Pallor
Due to the anaemia.
Jaundice Ineffective erythropoiesis causing red cell destruction and hyperbilirubinemia. Jaundice
Ineffective erythropoiesis causing red cell destruction and hyperbilirubinemia.
Splenomegaly Due to the extravascular haemolysis and extramedullary hematopoiesis. Splenomegaly
Due to the extravascular haemolysis and extramedullary hematopoiesis.
Hepatomegaly Due extramedullary hematopoiesis. Hepatomegaly
Due extramedullary hematopoiesis.
Features of cardiac failure: elevated jugular venous pressure, tender hepatomegally, peripheral oedema Iron overload due to recurrent blood transfusions can also cause cardiac failure. Features of cardiac failure: elevated jugular venous pressure, tender hepatomegally, peripheral oedema
Iron overload due to recurrent blood transfusions can also cause cardiac failure.
Dyspnea Anaemia leading to hypoxia or iron overload due to recurrent blood transfusion causing cardiac failure may be the aetiology for exertional dyspnea. Dyspnea
Anaemia leading to hypoxia or iron overload due to recurrent blood transfusion causing cardiac failure may be the aetiology for exertional dyspnea.
Murmers Due to the anaemia, they can have flow murmurs. Murmers
Due to the anaemia, they can have flow murmurs.
Injection sites Iron chelation therapy is given as subcutaneous injection. Injection sites
Iron chelation therapy is given as subcutaneous injection.
Growth failure Combination of factors such as chronic disease, loss of appetite, food restriction and recurrent hospital stays may be the cause. Growth failure
Combination of factors such as chronic disease, loss of appetite, food restriction and recurrent hospital stays may be the cause.
Delayed development of secondary sexual characteristics Iron overload can cause hypogonadism. Delayed development of secondary sexual characteristics
Iron overload can cause hypogonadism.

Investigations - Diagnosis

Fact Explanation
Full blood count Anaemia causes low haemoglobin, low pack cell volume and reduced red cell count. Mean corpuscular volume, mean corpuscular haemoglobin are all reduced as this is a microcytic hypochromic anaemia. Red cell distribution width is normal. Hypersplenism may cause reduction in all 3 cell lines. Full blood count
Anaemia causes low haemoglobin, low pack cell volume and reduced red cell count. Mean corpuscular volume, mean corpuscular haemoglobin are all reduced as this is a microcytic hypochromic anaemia. Red cell distribution width is normal. Hypersplenism may cause reduction in all 3 cell lines.
Blood picture Will show microcytic hypochromic anaemia with some target cells, anisocytosis, poikilocytosis (spiculated tear-drop and elongated cells)], and nucleated RBC (i.e., erythroblasts). Carriers usually have less RBC morphologic changes and erythroblasts are normally not seen. Blood picture
Will show microcytic hypochromic anaemia with some target cells, anisocytosis, poikilocytosis (spiculated tear-drop and elongated cells)], and nucleated RBC (i.e., erythroblasts). Carriers usually have less RBC morphologic changes and erythroblasts are normally not seen.
Haemoglobin electrophoresis In thalassaemia intermedia, HbA2 is elevated. Thalassaemia major has raised HbF with absent or reduced HbA. Normal concentration of HbA2 does not rule out beta thalassemia trait. Haemoglobin electrophoresis
In thalassaemia intermedia, HbA2 is elevated. Thalassaemia major has raised HbF with absent or reduced HbA. Normal concentration of HbA2 does not rule out beta thalassemia trait.
High Performance Liquid Chromatography (HPLC) Qualitative and quantitative Hb analysis is done by HPLC.
In beta thalassemia major, HbA is absent and HbF constitutes the 92-95% of the total Hb. In beta thalassemia intermedia and betathalassaemia minor, HbA levels are between 10 and 30% and HbF between 70-90%. HbA2 is variable is increased in beta thalassemia minor.

Hb electrophoresis and HPLC can detect other hemoglobinopathies (S, C, E, OArab, Lepore) that can be associated with beta-thalassemia.
High Performance Liquid Chromatography (HPLC)
Qualitative and quantitative Hb analysis is done by HPLC.
In beta thalassemia major, HbA is absent and HbF constitutes the 92-95% of the total Hb. In beta thalassemia intermedia and betathalassaemia minor, HbA levels are between 10 and 30% and HbF between 70-90%. HbA2 is variable is increased in beta thalassemia minor.

Hb electrophoresis and HPLC can detect other hemoglobinopathies (S, C, E, OArab, Lepore) that can be associated with beta-thalassemia.
Serum ferritin Can be used to screen for iron deficiency anemia. Serum ferritin
Can be used to screen for iron deficiency anemia.
PCR Mutations of the beta globin gene are detected by PCR-based procedures using reverse dot blot analysis or primer-specific amplification. PCR
Mutations of the beta globin gene are detected by PCR-based procedures using reverse dot blot analysis or primer-specific amplification.

Investigations - Management

Fact Explanation
Haemoglobin Transfusion is done according to blood haemoglobin level in order to maintain haemoglobin at around 9-10 g/dl. Haemoglobin
Transfusion is done according to blood haemoglobin level in order to maintain haemoglobin at around 9-10 g/dl.
Serum ferritin Needs to identify the time start the iron chelation therapy. But this can also be influenced by the other conditions such as inflammatory disorders, liver disease, malignancy. Serum ferritin
Needs to identify the time start the iron chelation therapy. But this can also be influenced by the other conditions such as inflammatory disorders, liver disease, malignancy.
Cardiac magnetic resonance imaging (MRI) There is a reduction in cardiac iron overload and improved cardiac function, seen on MRI after treatment with iron chelators. Cardiac magnetic resonance imaging (MRI)
There is a reduction in cardiac iron overload and improved cardiac function, seen on MRI after treatment with iron chelators.
Haemoglobin Transfusion is done according to blood Hb level. If the Hb is < 7 g/dl for more than two weeks, without any evidence of infection patients will need blood transfusion. Haemoglobin
Transfusion is done according to blood Hb level. If the Hb is < 7 g/dl for more than two weeks, without any evidence of infection patients will need blood transfusion.
Serum ferritin Recurrent transfusion can lead to iron overload. Serum ferritin
Recurrent transfusion can lead to iron overload.
Echocardiography Excess iron can be deposited in the myocardium causing impaired ventricular function. Echocardiography
Excess iron can be deposited in the myocardium causing impaired ventricular function.
Thyroid function tests Hypothyroidism is a known endocrine complication due to iron overload. Thyroid function tests
Hypothyroidism is a known endocrine complication due to iron overload.
Fasting blood sugar Diabetes mellitus is occurred due to impaired secretion of insulin secondary to chronic pancreatic iron overload and insulin resistance due to iron deposition within liver or skeletal muscle. Fasting blood sugar
Diabetes mellitus is occurred due to impaired secretion of insulin secondary to chronic pancreatic iron overload and insulin resistance due to iron deposition within liver or skeletal muscle.
Cardiac Magnetic Resonance Imaging-T2* measurement Used for non-invasive assessment of cardiac iron status. Cardiac Magnetic Resonance Imaging-T2* measurement
Used for non-invasive assessment of cardiac iron status.

Management - Supportive

Fact Explanation
Health education Educating the parents, or young child on the nature of the disease, symptoms of anaemia, complications of the disease, method of taking iron chelation therapy at home etc will improve the compliance for the treatment and improve the quality of life. Health education
Educating the parents, or young child on the nature of the disease, symptoms of anaemia, complications of the disease, method of taking iron chelation therapy at home etc will improve the compliance for the treatment and improve the quality of life.
Prevention of infections Needs to avoid crowded places especially after splenectomy. They need to be vaccinated for pneumococcal, meningococcal infections before the splenectomy. Prevention of infections
Needs to avoid crowded places especially after splenectomy. They need to be vaccinated for pneumococcal, meningococcal infections before the splenectomy.
Psychological support Child might be psychologically distressed due to the nature of the chronicity of disease, recurrent hospital stays, recurrent absenteeism from the school and peer bullying etc. So they need proper addressing of these issues. Psychological support
Child might be psychologically distressed due to the nature of the chronicity of disease, recurrent hospital stays, recurrent absenteeism from the school and peer bullying etc. So they need proper addressing of these issues.
Diet Drinking tea may reduce iron absorption. Iron rich food like liver, meat and green leaves are best avoided. Diet
Drinking tea may reduce iron absorption. Iron rich food like liver, meat and green leaves are best avoided.
Carrier detection If the both parents are carriers of the thalassaemia, or if the pregnant women presenting at an antenatal clinic with a MCH < 27 pg should be investigated further for beta thalassaemia trait. Chorionic villus sampling can be used to identify the homozygous fetus and do the termination of pregnancy where possible . Carrier detection
If the both parents are carriers of the thalassaemia, or if the pregnant women presenting at an antenatal clinic with a MCH < 27 pg should be investigated further for beta thalassaemia trait. Chorionic villus sampling can be used to identify the homozygous fetus and do the termination of pregnancy where possible .
Screening Screening is recommended for high risk groups. Providing national premarital screening and genetic counselling is important. Screening
Screening is recommended for high risk groups. Providing national premarital screening and genetic counselling is important.

Management - Specific

Fact Explanation
Blood transfusion Thalassaemia needs lifelong treatment to keep the haemoglobin at a normal range they need blood transfusion. Goals of transfusion therapy are to correction of anemia, suppression of the erythropoiesis and inhibition of gastrointestinal iron absorption. Usually the indication to start blood transfusion will be severe anemia (Hb < 7 g/dl for more than two weeks, excluding other contributory causes such as infections. After one transfusion, gradually haemoglobin levels will go down with the time, they again develop features of anaemia where they need another blood transfusion. These people need haemoglobin check ups at regular intervals and blood transfusion is done when the haemoglobin is 9-10g/dl and accepted post-transfusion level of Hb is 13 to 14 g/d. Infused should not exceed maximum rate of 5 ml/kg/hour in order to prevent volume overload. Annual requirement need to be calculated and splenectomy is needed when it is more than 180-200 ml/Kg. Blood transfusion
Thalassaemia needs lifelong treatment to keep the haemoglobin at a normal range they need blood transfusion. Goals of transfusion therapy are to correction of anemia, suppression of the erythropoiesis and inhibition of gastrointestinal iron absorption. Usually the indication to start blood transfusion will be severe anemia (Hb < 7 g/dl for more than two weeks, excluding other contributory causes such as infections. After one transfusion, gradually haemoglobin levels will go down with the time, they again develop features of anaemia where they need another blood transfusion. These people need haemoglobin check ups at regular intervals and blood transfusion is done when the haemoglobin is 9-10g/dl and accepted post-transfusion level of Hb is 13 to 14 g/d. Infused should not exceed maximum rate of 5 ml/kg/hour in order to prevent volume overload. Annual requirement need to be calculated and splenectomy is needed when it is more than 180-200 ml/Kg.
Vitamin C and folic acid In those who receiving iron chelation Vitamin C may improve iron excretion. Folic acid is needed for rapid cell division. Folic acid deficiency will lead to growth failure. Vitamin C and folic acid
In those who receiving iron chelation Vitamin C may improve iron excretion. Folic acid is needed for rapid cell division. Folic acid deficiency will lead to growth failure.
Iron chelation therapy Iron chelators are used to reduce tissue iron levels, prevent excessive organ iron accumulation and neutralize toxic labile iron pools. Iron chelation is started when the serum ferritin is rise above 1000 ng/ml or once they have had 10-20 transfusions. Deferoxamine and deferasirox are the 2 main types of chelators available. Deferoxamine is available as 24-hour intravenous infusion or subcutaneous 12-hour infusion. Sensorineural hypoacusia, ocular toxicity (night-blindness, blurred vision, decreased visual acuity, impairment of colour vision), retarded growth and skeletal changes, infections by Yersinia Enterocolitica, and other pathogens are the possible complications with desferrioxamine therapy.
Deferasirox is given once-daily, orally at a dose of 20 mg/kg/day. Gastrointestinal disturbances, skin rash and increases in serum creatinine are the possible complications.
There are studies done on newer chelators such as deferiprone and ICL670, which are orally active. Hydroxybenzyl-ethylenediamine-diacetic acid (HBED) and starch deferoxamine, are parenteral drugs that require less frequent administration than is currently deferoxamine. Deferiprone is the only orally active iron chelator available in practice. Agranulocytosis, nausea, vomiting, gastric discomfort, arthralgia, zinc deficiency, and fluctuating ALT levels are the possible side effects due to iron chelation with deferiprone.
Iron chelation therapy
Iron chelators are used to reduce tissue iron levels, prevent excessive organ iron accumulation and neutralize toxic labile iron pools. Iron chelation is started when the serum ferritin is rise above 1000 ng/ml or once they have had 10-20 transfusions. Deferoxamine and deferasirox are the 2 main types of chelators available. Deferoxamine is available as 24-hour intravenous infusion or subcutaneous 12-hour infusion. Sensorineural hypoacusia, ocular toxicity (night-blindness, blurred vision, decreased visual acuity, impairment of colour vision), retarded growth and skeletal changes, infections by Yersinia Enterocolitica, and other pathogens are the possible complications with desferrioxamine therapy.
Deferasirox is given once-daily, orally at a dose of 20 mg/kg/day. Gastrointestinal disturbances, skin rash and increases in serum creatinine are the possible complications.
There are studies done on newer chelators such as deferiprone and ICL670, which are orally active. Hydroxybenzyl-ethylenediamine-diacetic acid (HBED) and starch deferoxamine, are parenteral drugs that require less frequent administration than is currently deferoxamine. Deferiprone is the only orally active iron chelator available in practice. Agranulocytosis, nausea, vomiting, gastric discomfort, arthralgia, zinc deficiency, and fluctuating ALT levels are the possible side effects due to iron chelation with deferiprone.
Splenectomy Splenectomy helps to decrease transfusion requirements in people with thalassaemia. It is usually considered when the annual red cell requirement exceeds 180-200 ml/Kg of RBC and if there are other indications for splenectomy such as are symptoms of splenic enlargement, leukopenia and/or thrombocytopenia and increasing iron overload despite good chelation. Due to the risk of postsplenectomy sepsis surgery is usually delayed till 6-7 years of age. Post of penicillin prophylaxis is then started as they are vulnerable to infections with encapsulated organisms such as Pneumococcus species, Meningococcus species, and Haemophilus influenzae. Splenectomy
Splenectomy helps to decrease transfusion requirements in people with thalassaemia. It is usually considered when the annual red cell requirement exceeds 180-200 ml/Kg of RBC and if there are other indications for splenectomy such as are symptoms of splenic enlargement, leukopenia and/or thrombocytopenia and increasing iron overload despite good chelation. Due to the risk of postsplenectomy sepsis surgery is usually delayed till 6-7 years of age. Post of penicillin prophylaxis is then started as they are vulnerable to infections with encapsulated organisms such as Pneumococcus species, Meningococcus species, and Haemophilus influenzae.
Management of complications Hypothyroidism, hypogonadism, growth failure, diabetes mellitus and cardiac failure are the possible complications that need specific management. Cardiac disease is reversible on certain occasions with the help of patients with intensive iron chelation therapy. Thrombosis is a significant complication of thalassemia. Intramuscular depot-testosterone esters at a dose of 50-100 mg twice a month is given till the virilisation in patients with hypogonadism. Management of complications
Hypothyroidism, hypogonadism, growth failure, diabetes mellitus and cardiac failure are the possible complications that need specific management. Cardiac disease is reversible on certain occasions with the help of patients with intensive iron chelation therapy. Thrombosis is a significant complication of thalassemia. Intramuscular depot-testosterone esters at a dose of 50-100 mg twice a month is given till the virilisation in patients with hypogonadism.
Bone marrow transplantation Hematopoietic stem cell transplantation in childhood is the only curative therapy for beta thalassemia major. If there are any risk factors such as hepatomegaly, extent of liver fibrosis, severe iron accumulation they can be can be considered for stem cell transplantation from an HLA identical sibling. Bone marrow transplantation
Hematopoietic stem cell transplantation in childhood is the only curative therapy for beta thalassemia major. If there are any risk factors such as hepatomegaly, extent of liver fibrosis, severe iron accumulation they can be can be considered for stem cell transplantation from an HLA identical sibling.
Management of thalassemia intermedia Management of thalassemia intermedia is symptomatic. Hypersplenism causing worsening of anemia, retarded growth and mechanical disturbance from the large spleen are the indications for splenectomy in these patients. Management of thalassemia intermedia
Management of thalassemia intermedia is symptomatic. Hypersplenism causing worsening of anemia, retarded growth and mechanical disturbance from the large spleen are the indications for splenectomy in these patients.

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