Hemoglobinopathies Dr mukhtar jama nour, MBBS Amoud University for health and science institute 5/31/2014Dr mukhtar jama nour,MBBS1 5/31/2014Dr mukhtar jama nour,MBBS2 hemoglobinopathies These diseases are caused by dysfunction of the genes encoding the globin chains of the haemoglobin molecule. Normal haemoglobin is comprised of two alpha and two non-alpha globin chains. Alpha globin chains are produced throughout life, so severe mutations may cause intrauterine death.5/31/2014Dr mukhtar jama nour,MBBS3 Production of non-alpha chains varies with age; fetal haemoglobin (HbF-/) has two gamma chains, while the predominant adult haemoglobin (HbA-/) has two beta chains. Thus, disorders affecting the beta chains do not present until after 6 months of age. A constant small amount of haemoglobin A2 (HbA2-/, usually < 2%) is made from birth. 5/31/2014Dr mukhtar jama nour,MBBS4 The geographical distribution of the common haemoglobinopathies is shown in Figure 24.24. The haemoglobinopathies can be classified into qualitative or quantitative abnormalities.5/31/2014Dr mukhtar jama nour,MBBS5 Geographical distribution of hemoglinopathies 5/31/2014Dr mukhtar jama nour,MBBS6 Qualitative abnormalities-abnormal haemoglobins In qualitative abnormalities (called the abnormal haemoglobins), there is a functionally important alteration in the amino acid structure of the polypeptide chains of the globin chains. Several hundred such variants are known; they were originally designated by letters of the alphabet, e.g. S, C, D or E, but are now described by names usually taken from the town or district in which they were first described. 5/31/2014Dr mukhtar jama nour,MBBS7 The best-known example is haemoglobin S, found in sickle-cell anaemia. Mutations around the haem-binding pocket cause the haem ring to fall out of the structure and produce an unstable haemoglobin. These substitutions often change the charge of the globin chains, producing different electrophoretic mobility, and this forms the basis for the diagnostic use of haemoglobin electrophoresis to identify haemoglobinopathies5/31/2014Dr mukhtar jama nour,MBBS8 Quantitative abnormalities-thalassaemias In quantitative abnormalities(the thalassaemias) there are mutations causing a reduced rate of production of one or other of the globin chains, altering the ratio of alpha to non-alpha chains. In alpha-thalassaemia excess beta chains are present, whilst in beta-thalassaemia excess alpha chains are present. The excess chains precipitate, causing red cell membrane damage and reduced red cell survival 5/31/2014Dr mukhtar jama nour,MBBS9 Sickle-cell anaemia Sickle-cell disease results from a single glutamic acid to valine substitution at position 6 of the beta globin polypeptide chain. It is inherited as an autosomal recessive trait . Homozygotes only produce abnormal beta chains that make haemoglobin S (HbS, termed SS), and this results in the clinical syndrome of sickle-cell disease. Heterozygotes produce a mixture of normal and abnormal beta chains that make normal HbA and HbS (termed AS), and this results in the clinically asymptomatic sickle-cell trait.5/31/2014Dr mukhtar jama nour,MBBS10 Sickle cell disease 5/31/2014Dr mukhtar jama nour,MBBS11 Epidemiology The heterozygote frequency is over 20% in tropical Africa . Individuals with sickle-cell trait are relatively resistant to the lethal effects of falciparum malaria in early childhood; the high prevalence in equatorial Africa can be explained by the selective survival advantage it confers in areas where falciparum malaria is endemic. However, homozygous patients with sickle-cell anaemia do not have correspondingly greater resistance to falciparum malaria 5/31/2014Dr mukhtar jama nour,MBBS12 Pathogenesis When haemoglobin S is deoxygenated, the molecules of haemoglobin polymerise to form pseudocrystalline structures known as 'tactoids'. These distort the red cell membrane and produce characteristic sickle-shaped cells . The polymerisation is reversible when reoxygenation occurs. The distortion of the red cell membrane, however, may become permanent and the red cell 'irreversibly sickled'.5/31/2014Dr mukhtar jama nour,MBBS13 The greater the concentration of sickle-cell haemoglobin in the individual cell, the more easily tactoids are formed, but this process may be enhanced or retarded by the presence of other haemoglobins. Thus, the abnormal haemoglobin C variant participates in the polymerisation more readily than haemoglobin A, whereas haemoglobin F strongly inhibits polymerisation 5/31/2014Dr mukhtar jama nour,MBBS14 Clinical features Sickling is precipitated by hypoxia, acidosis, dehydration and infection. Irreversibly sickled cells have a shortened survival and plug vessels in the microcirculation. This results in a number of acute syndromes, termed 'crises', and chronic organ damage. Vaso-occlusive crisis. Plugging of small vessels in the bone produces acute severe bone pain. This affects areas of active marrow: the hands and feet in children (so-called dactylitis) or the femora, humeri, ribs, pelvis and vertebrae in adults. Patients usually have a systemic response with tachycardia, sweating and a fever. This is the most common crisis. 5/31/2014Dr mukhtar jama nour,MBBS15 Dactylitis in 6months old patient 5/31/2014Dr mukhtar jama nour,MBBS16 Sickle chest syndrome. This may follow on from a vaso-occlusive crisis and is the most common cause of death in adult sickle disease. Bone marrow infarction results in fat emboli to the lungs which cause further sickling and infarction, leading to ventilatory failure if not treated. 5/31/2014Dr mukhtar jama nour,MBBS17 Sequestration crisis. Thrombosis of the venous outflow from an organ causes loss of function and acute painful enlargement. In children the spleen is the most common site. Massive splenic enlargement may result in severe anaemia, circulatory collapse and death. Recurrent sickling in the spleen in childhood results in infarction and adults may have no functional spleen. In adults the liver may undergo sequestration with severe pain due to capsular stretching. 5/31/2014Dr mukhtar jama nour,MBBS18 Aplastic crisis. Infection of adult sicklers with human parvovirus 19 results in a severe but self-limiting red cell aplasia. This produces a very low haemoglobin which may cause heart failure. Unlike in all other sickle crises, the reticulocyte count is low 5/31/2014Dr mukhtar jama nour,MBBS19 Investigations Patients with sickle-cell disease have a compensated anaemia, usually around 6-8 mg/dL. The blood film shows sickle cells, target cells and features of hyposplenism. A reticulocytosis is present.5/31/2014Dr mukhtar jama nour,MBBS20 diagnosis The definitive diagnosis requires haemoglobin electrophoresis to demonstrate the absence of HbA, 2-20% HbF and the predominance of HbS. Both parents of the affected individual will have sickle-cell trait. 5/31/2014Dr mukhtar jama nour,MBBS21 5/31/2014Dr mukhtar jama nour,MBBS22 management All patients with sickle-cell disease should receive prophylaxis with daily folic acid, and penicillin V to protect against pneumococcal infection which may be lethal in the presence of hyposplenism. These patients should be vaccinated against pneumococcus and, where vaccine is available, Haemophilus influenzae B and hepatitis B. 5/31/2014Dr mukhtar jama nour,MBBS23 Vaso-occlusive crises are managed by aggressive rehydration, oxygen therapy, adequate analgesia (which often requires opiates) and antibiotics.A regular transfusion programme to suppress HbS production and maintain the HbS level below 30% may be indicated in patients with recurrent severe complications such as cerebrovascular accidents in children or chest syndromes in adults. Exchange transfusion, in which a patient is simultaneously venesected and transfused to replace HbS with HbA, may be used in life-threatening crises or to prepare patients for surgery.5/31/2014Dr mukhtar jama nour,MBBS24 A high HbF level inhibits polymerisation of HbS and reduces sickling. Patients with sickle-cell disease and high HbF levels have a mild clinical course with few crises. Some agents are able to increase synthesis of HbF and this has been used to reduce the frequency of severe crises. The oral cytotoxic agent hydroxycarbamide has been shown to have clinical benefit with acceptable side-effects in children and adults who have recurrent severe crises. Relatively few allogeneic stem-cell transplants from HLA-matched siblings can be performed. 5/31/2014Dr mukhtar jama nour,MBBS25 Prognosis In Africa few children with sickle-cell anaemia survive to adult life without medical attention. Even with standard medical care, approximately 15% die by the age of 20 years and 50% by the age of 40 years. Other abnormal haemoglobins Another beta chain haemoglobinopathy, haemoglobin C (HbC) disease, is clinically silent but associated with microcytosis and target cells on the blood film. 5/31/2014Dr mukhtar jama nour,MBBS26 Thalassaemias Thalassemia is an inherited impairment of haemoglobin production, in which there is partial or complete failure to synthesize a specific type of globin chain. In alpha-thalassaemia, disruption of one or both alleles on chromosome 16 may occur, with production of some or no alpha globin chains. In beta-Thalassaemia, defective production usually results from disabling point mutations causing no (0) or reduced (-) beta chain production. 5/31/2014Dr mukhtar jama nour,MBBS27 Beta-thalassaemia Failure to synthesize beta chains (beta-thalassaemia) is the most common type of thalassemia, most prevalent in the Mediterranean area. Heterozygotes have Thalassemia minor, a condition in which there is usually mild anaemia and little or no clinical disability, which may be detected only when iron therapy for a mild microcytic anaemia fails. Homozygotes (Thalassemia major) either are unable to synthesize haemoglobin A or at best produce very little; after the first 4-6 months of life they develop profound hypochromic anaemia. Intermediate grades of severity occur. 5/31/2014Dr mukhtar jama nour,MBBS28 Diagnostic features of beta-thalassaemia ( thalasemia major) Beta-thalassaemia major (homozygotes) Profound hypochromic anaemia Evidence of severe red cell dysplasia Erythroblastosis Absence or gross reduction of the amount of haemoglobin A Raised levels of haemoglobin F Evidence that both parents have thalassaemia minor 5/31/2014Dr mukhtar jama nour,MBBS29 Beta-thalassaemia minor (heterozygotes) Mild anaemia Microcytic hypochromic erythrocytes (not iron-deficient) Some target cells Punctate basophilia Raised haemoglobin A2 fraction Evidence that one parent has thalassaemia minor 5/31/2014Dr mukhtar jama nour,MBBS30 Treatment of beta-thalassaemia major Erythropoietic failure Allogeneic bone marrow transplantation from human leucocyte antigen (HLA)-compatible siblingTransfusion to maintain Hb > 100 g/LFolic acid 5 mg dailyIron chelation therapySplenomegaly causing mechanical problems, excessive transfusion needs Splenectomy. 5/31/2014Dr mukhtar jama nour,MBBS31 5/31/2014Dr mukhtar jama nour,MBBS32