Thalassaemia Integrative 3 PDF

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Sulaimani College of Medicine - University of Sulaimani

Dr Sana Dlawar Jalal

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thalassemia blood disorders genetic disorders medical presentation

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This document details a presentation on thalassaemia, focusing on the different types, their genetics, clinical features, and prevention strategies. It includes diagrams, charts, and tables to illustrate the concepts, making it a comprehensive medical overview.

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Dr Sana Dlawar Jalal MBChB, FRCPath-haematology Professor in haematopathology Sulaimani College of Medicine –University of Sulaimani Learning Outcome • After this session, you should be able to : -Understand the structure and function of Hb. -Describe the pathophysiology of thalassemia. - Understa...

Dr Sana Dlawar Jalal MBChB, FRCPath-haematology Professor in haematopathology Sulaimani College of Medicine –University of Sulaimani Learning Outcome • After this session, you should be able to : -Understand the structure and function of Hb. -Describe the pathophysiology of thalassemia. - Understand the three different phenotypes of thalassemia . -Understand and explain the genetic mutations underlying thalassemia. -Describe the laboratory diagnosis of thalassemia . -Understand the importance preventive program . Hemoglobin Structure Types of normal Hemoglobins • All Normal Haemoglobins consists of two pairs of globin chains, at the centre of each is one heme group. • Hb A ( Adult Hb) : α2 β2 (~96%). • HbF (Fetal Hb) : α2 γ2 (0.1-<2.0%). • Hb A2 (minor Adult Hb) : α2 δ2(1.8-3.5%). Normal forms of Hb in the embryo and fetus Hb Globin chains Period when mainly present Gower 1 ς2ε2 Early embryo Gower 2 α2ε2 embryo Portland 1 ς2β2 embryo I Hemoglobinopathies I Disorders of globin synthesis rather than hem synthesis. Qualitative Disorders -Abnormal hemoglobins are formed when the sequence of globin chain amino acids is altered. There is usually only a single amino acid substitution in one of the globin (polypeptide) chains. Quantitative Disorders -Thalassemia result from a lack of production of globin chains to maintain adequate Hb levels. β- Thalassaemia • β-Thalassaemias are inherited defects in the rate of synthesis of β-globin chains of Hb, which are widely distributed throughout the world, with considerable frequencies in certain areas particularly the Mediterranean and Middle Eastern countries, including Kurdistan and Iraq. Iraq Global Distribution of Hb- Disorders Genetics of β thalassemia • There is one β- globin gene on each chromosome 11 in human genome. • This form of thalassaemia is mostly caused by point mutations involving various points in and around the beta globin gene. • The inheritance of this disorder is autosomal recessive, so that heterozygous are usually symptomless, while homozygotes are severely or moderately affected. • β0 denotes absent β chain synthesis, while β+ means reduced synthesis of β chain . Chromosomal location of globin genes 11p15.5 16p13.3 Beta cluster Alpha cluster Recessively Inherited Diseases Clinically β thalassaemia could be classified into : • β Thalassemia Major : Severe clinical manifestations presenting before the age of 2 years, usually transfusion dependent. Due usually to homozygosity to β thalassemia gene defect (β0 β0, β+ β+, β0 β+) . • β Thalassemia minor : Mild or no clinical manifestations, usually does not require specific management. Due usually to heterozygosity to β thalassemia gene defect(β0β or β+ β) . • β Thalassemia Intermedia : Moderate manifestations, intermediate between major and minor. Simplified diagram of types of Beta thal. Genetic defect & relevance of Beta chain Normal β chain production production Normal β gene + β thal. Gene defect reduced β chain production βo thal. Gene defect No β chain production Courtesy of professor Nasir Al Allawi Chr 11 β Chr 11 Chr 11 Chr 11 Chr 11 Chr 11 Defective β gene β Normal beta genes Normal β gene β β Heterozygous to beta thalassemia genetic defect Thalassamia Minor Homozygous to beta thalassemia genetic defect Thalassamia Major β β Courtesy of professor Nasir Al Allawi Pathophysiology of β thalassemia major Courtesy of professor Nasir Al Allawi α gene α chains Hb A tetramer (α2 β2) (normal) β gene (defect) β chains I Excess α chains in RBC precursors Disturb RBC metabolism & toxic to RBC membranes Red cell damage Leave marrow and destroyed in RES γ Chains (Hb F,α2γ2) δChains Destroyed in marrow (HbA2, α2δ2) Hypochromic RBC Compensatory mechanisms Erythoid hyperplasia Extramedullary erythropoiesis Hepato-splenomegaly M potpen Clinical features of β thalassaemia Major • First diagnosis between age of 6 months and 2 years. • Presentation usually with pallor, poor feeding, failure to thrive , abdominal swelling (due to hepato-splenomegaly) and sometimes Jaundice. - Deformities in the skull due to bone marrow expansion (Bossing , and mongoloid facies; hair-on-end appearance on skull X-ray). - Increased frequency of infections. Bossing of the skull Blood Picture in βThalassaemia Major thegiraffe Finn • • Complete Blood Picture (CBP) Moderate to sever hypochromic anisopoikylocytosis. • HCT is evidently reduced. • MCV and MCH are both reduced. • Leucocytes : Maybe normal or increased. • Platelets : may be normal or increased. • Reticulocytes : usually range 2-8%. • • Hb electrophoresis: increased Hb F very high. Hb A2 is variable. Ferritin ???? ma high A A if B Imitation microcytic anemia, with marked Blood film in βThalassaemia Major Prognosis of β -Thalassaemia Major • If no Transfusions, death usually occurs in the first few years of life. • If iron overload is allowed to occur then death in 2nd or early third decade, most commonly due to progressive cardiac damage due to iron deposition, with heart failure or arrhythmias, often precipitated by infections. • However, if measures to prevent iron overload by iron chelation are instituted early on, with the transfusion, Iron overload consequences maybe limited, although delayed puberty and stunted growth may still be encountered, but otherwise patients may develop normally. old ITH Blood picture of β-Thalassemia Minor • Hb is usually reduced 1-2 g/dl less than normal for age and sex. • MCH and MCV are reduced. • RBC count is > 5 x 1012/L in 85% of cases. • Reticulocyte count is slightly increased or normal. • Blood film : slight hypochromia, anisocytosis, poikiocytosis, microcytosis, tear drop cells and target cells. 1 Normal Blood Film in β thal minor Thalassemia Major Normal blood film Thalassemia minor Normal blood film Diagnostic tests in β-Thal Minor: • Increase in Hb A2 : Normal range of Hb A2 is 1.8-3.5%, in Beta thalassemia minor it is increased to 4-7% . • Increased Hb A2 is considered diagnostic of Beta thalassemia minor. is it e Peytondeficit • S. Transferrin saturation(S.Iron/TIBC) is usually normal or upper normal. Alpha thalassaemias • Much less common in our country than Beta thalassemia, and of much less clinical significance. GHEE • Due to reduced or absent synthesis of alpha (α) globin chains of hemoglobin. • (Alpha (α) chains are constituents of all three normal Hb A, A2 and F). Clinical Phenotypes of Alpha thalassaemia (relevant to number of alpha genes remaining): No alpha genes α o α o Incompatible with life One Alpha gene α+ αo Courtesy of professor Nasir Al Allawi Thalassaemia intermedia phenotype No alpha chains 1. Hb Barts Hydropes Fetalis Markedly reduced alpha chain production 2. Hb H disease Two alpha genes α + α + Moderately reduced Alpha chains 3. α Thalassemia minor Three Alpha genes Normal α+ α genes Minimally reduced Alpha chains 4. Silent α thal. carrier state Courtesy of professor Nasir Al Allawi Hemoglobin H disease • Common in Southeast Asia, less so in Mediterranean countries. Sporadic in Iraq. • The only clinical phenotype of alpha thalassemia of clinical significance. • Due to deletion of three of the four normal alpha genes. So, only one functional alpha gene is left with associated marked reduction in alpha chain production. Clinical Features • • • • Very variable, variable pallor. Variable degrees of splenomegaly. Sometimes Jaundice. Most unusual to see severe thalassemic skeletal changes or growth retardation. • Usually survive to adult life. • Anemia aggravated by infections, oxidant drugs. CBP Sever hypochromic anemia with marked aniso-poikylocytosis. • Electrophoresis : ~ Shows Hb A with 5-40% Hb H. • On modification of the retics stain : characteristic Hb H inclusions could be seen in RBCs( Golf ball appearance). Alpha thalassemia minor • Due to deletion of two alpha genes, leaving only two alpha genes, so only moderate reduction of alpha chain production. • Clinical and blood picture, the same as beta thalassemia minor. • Hb electrophoresis shows Hb A, with normal or reduced Hb A2 and normal Hb F. minor IB iffery go word iron Thalassaemia Intermedia Clinical Features TI has an extraordinarily wide clinical spectrum, unlike TM, which presents with severe anaemia requiring frequent blood transfusions Mild TI Completely asymptomatic until adulthood Severe TI Presentation between 2 and 6 years Retarded growth and development Cappellini N, et al, eds. Thalassaemia International Federation; 2010. Thalassaemia Prevention First step - Premarital Screen : to identify couples at risk of bearing affected children, depending on red cells indices, followed by the estimation of HbA2 and HbF levels, in addition to sickling test. Second Step - Genetic Counseling: to allow the couples at risk to take an informed decision. Third step - Prenatal Diagnosis : to detect any affected fetus in early gestation in couples at risk and allow the partners the choice of termination. Thank you

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