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27 thalassemias

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SMC, JSMU, MBBS, Blood module

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27 thalassemias

  1. 1. ENZYMES A protein with catalytic properties due to its power of specific activation © 2007 Paul Billiet ODWS
  2. 2. The Thalassemias
  3. 3. Objectives  By the end of this lecture the student should be able to:      Understand the normal stucture of Haemoglobin • Know the Diverse group of disorders which manifest as anemia of varying degrees. • Know the defective production of globin portion of hemoglobin molecule. • Know the Distribution of disease worldwide. • Describe the disease either homozygous or heterozygous defect. • Know the Defect results from abnormal rate of synthesis in one of the globin chains.
  4. 4. Hemoglobin Review • Each complex consists of : – Four polypeptide chains, non-covalently bound – Four heme complexes with iron bound – Four O2 binding sites
  5. 5. Globin Chains • Alpha Globin – 141 amino acids – Coded for on Chromosome 16 – Found in normal adult hemoglobin, A1 and A2 • Beta Globin – 146 amino acids – Coded for on Chromosome 11, found in Hgb A1 • Delta Globin – Found in Hemoglobin A2--small amounts in all adults • Gamma Globin – Found in Fetal Hemoglobin • Zeta Globin – Found in embryonic hemoglobin
  6. 6. Normal Haemoglobin • HbA - α2β2 • HbA2 - α2δ2 • HbF – α2γ2
  7. 7. Each goblin chain have separate genetic control α –thalassaemia affect α-chain synthesis β –thalassaemia affect β -chain synthesis
  8. 8. Thalassemia ►Diverse group of disorders which manifest  as anemia of varying degrees.  ►Result of defective production of globin  portion of hemoglobin molecule.  ►Distribution is worldwide.  ►May be either homozygous defect or  heterozygous defect.  ►Defect results from abnormal rate of  synthesis in one of the globin chains.     9
  9. 9. Thalassemia ►Results in overall decrease in amount of  hemoglobin produced and may induce  hemolysis.  ►Two major types of thalassemia:  – Alpha (α) - Caused by defect in rate of  synthesis of alpha chains.  – Beta (β) - Caused by defect in rate of  synthesis in beta chains.  ►May contribute protection against malaria.  10
  10. 10. Genetics of Thalassemia ►Adult hemoglobin composed two  alpha and two beta chains.  ►Alpha thalassemia usually caused by  gene deletion;   ►Beta thalassemia usually caused by  mutation.  ►Results in microcytic, hypochromic  anemias of varying severity.  11
  11. 11. GeneticTypes of Thalassaemia : There are two basic groups of thalassaemia.  Alpha ( α )Thalassaemia  Beta ( β )Thalassaemia
  12. 12. Demographics: Thalassemia • Found most frequently in the Mediterranean, Africa, Western and Southeast Asia, India and Burma.
  13. 13. Beta Thalassemia 14
  14. 14. β-Thalassaemia An absence or deficiency of β-chain synthesis of adult HbA β Chain synthesis Hb-A γ and δ chain Hb-A = α2β2
  15. 15. On the basis of synthetic ability β-genes are designated as • β gene – can synthesize normal amount of β-chain • β+ gene – can synthesize reduced amount of β-chain • β0 gene – cannot synthesize β-chain
  16. 16. Pathophysiology of β-Thalassaemia Various mutation in β-gene Complete or partial absence of β-chain Decreased adult HbA α-chain synthesis remain normal Free complementary α-chain – unstable and precipitate within normoblasts as insoluble inclusions Cell membrane damage & impaired DNA synthesis apoptosis i.e. ineffective erythropoeisis
  17. 17. 70-80% marrow normoblasts undergo apoptosis Inclusion bearing red cells undergo sequestration & destruction in spleen
  18. 18. Partial or lack of HbA synthesis ↓MCHC & MCH Hypochromia & microcytosis Norm al Thalassae mia
  19. 19. ↑Haemolysis ↑demands of phagocytic function  hyperplasia of phagocytes Hepatosplenomegaly To compensate anaemia extramedullary haemopoiesis in liver, spleen & brain Organomegaly
  20. 20. ↑Erythropoiesis marrow expansion & thinning of cortex of skull bone Thalassaemia facies
  21. 21. Classification & Terminology Beta Thalassemia • Normal β/β • Minor β/β0 β/β+ • Intermedia β0 /β+ β+ /β+ • Major β0 /β0 β+ /β+ β0 /β+
  22. 22. Classical Syndromes of Beta Thalassemia ►Silent carrier state – the mildest form of beta thalassemia. ►Beta thalassemia minor - heterozygous disorder resulting in mild hypochromic, microcytic hemolytic anemia. ►Beta thalassemia intermedia - Severity lies between the minor and major. ►Beta thalassemia major - homozygous disorder resulting in severe transfusion- dependent hemolytic anemia. 23
  23. 23. Silent Carrier State for β Thalassemia ►Are various heterogenous beta mutations that produce only small decrease in production of beta chains. ►Patients have nearly normal beta/alpha chain ratio and no hematologic abnormalities. ►Have normal levels of Hb A2. 24
  24. 24. Beta Thalassemia Minor ►Caused by heterogenous mutations that affect beta globin synthesis. ►Usually presents as mild, asymptomatic hemolytic anemia unless patient in under stress such as pregnancy, infection, or folic acid deficiency. ►Have one normal beta gene and one mutated beta gene. ►Hemoglobin level in 10-13 g/dL range with normal or slightly elevated RBC count. 25
  25. 25. Beta Thalassemia Minor ►Anemia usually hypochromic and microcytic with slight aniso and poik, including target cells and elliptocytes; May see basophilic stippling. ►Rarely see hepatomegaly or splenomegaly. ►Have high Hb A2 levels (3.5-8.0%) and normal to slightly elevated Hb F levels. ►Are different variations of this form depending upon which gene has mutated. ►Normally require no treatment. ►Make sure are not diagnosed with iron deficiency anemia. 26
  26. 26. Beta Thalassemia Intermedia ►Patients able to maintain minimum hemoglobin (7 g/dL or greater) without transfusions. ►Expression of disorder falls between thalassemia minor and thalassemia major. May be either heterozygous for mutations causing mild decrease in beta chain production, or may be homozygous causing a more serious reduction in beta chain production. ►See increase in both Hb A2 production and Hb F production. ►Peripheral blood smear picture similar to thalassemia minor. 27
  27. 27. Beta Thalassemia Intermedia ►Have varying symptoms of anemia, jaundice, splenomegaly and hepatomegaly. ►Have significant increase in bilirubin levels. ►Anemia usually becomes worse with infections, pregnancy, or folic acid deficiencies. ►May become transfusion dependent as adults. ►Tend to develop iron overloads as result of increased gastrointestinal absorption. ►Usually survive into adulthood. 28
  28. 28. Beta Thalassemia Major 1 of 3 ►Characterized by severe microcytic, hypochromic anemia. ►Detected early in childhood: – Infants fail to thrive. – Have pallor, variable degree of jaundice, abdominal enlargement, and hepatosplenomegaly. ►Hemoglobin level between 4 and 8 gm/dL. ►Severe anemia causes marked bone changes due to expansion of marrow space for increased erythropoiesis. ►See characteristic changes in skull, long bones, and hand bones. 29
  29. 29. Beta Thalassemia Major 2 of 3 ►Have protrusion upper teeth and Mongoloid facial features. ►Physical growth and development delayed. ►Peripheral blood shows markedly hypochromic, microcytic erythrocytes with extreme poikilocytosis, such as target cells, teardrop cells and elliptocytes. See marked basophilic stippling and numerous NRBCs. ►MCV in range of 50 to 60 fL. ►Low retic count seen (2-8%). ►Most of hemoglobin present is Hb F with slight increase in Hb A2. 30
  30. 30. Beta Thalassemia Major 3 of 3 ►Regular transfusions usually begin around one year of age and continue throughout life. ►Excessive number of transfusions results in tranfusional hemosiderosis; Without iron chelation, patient develops cardiac disease. ►Danger in continuous tranfusion therapy: – Development of iron overload. – Development of alloimmunization (developing antibodies to transfused RBCs). – Risk of transfusion-transmitted diseases. ►Bone marrow transplants may be future treatment, along with genetic engineering and new drug therapies. 31
  31. 31. Alpha Thalassemia 34
  32. 32. Classification & Terminology Alpha Thalassemia • Normal αα/αα • Silent carrier - α/αα • Minor -α/-α --/αα • Hb H disease --/-α • Barts hydrops fetalis --/--
  33. 33. Alpha Thalassemias • Result from gene deletions • One deletion—Silent carrier; no clinical significance • Two deletions—α Thal trait; mild hypochromic microcytic anemia • Three deletions—Hgb H; variable severity, but less severe than Beta Thal Major • Four deletions—Bart’s Hgb; Hydrops Fetalis; In Utero or early neonatal death
  34. 34. Alpha Thalassemia 2 of 2 ►Predominant cause of alpha thalassemias is large number of gene deletions in the alpha-globin gene. ►Are four clinical syndromes present in alpha thalassemia: – Silent Carrier State – Alpha Thalassemia Trait (Alpha Thalassemia Minor) – Hemoglobin H Disease – Bart's Hydrops Fetalis Syndrome 37
  35. 35. Silent Carrier State ►Deletion of one alpha gene, leaving three functional alpha genes. ►Alpha/Beta chain ratio nearly normal. ►No hematologic abnormalities present. 38
  36. 36. Alpha Thalassemia Trait (Alpha Thalassemia Minor) ►Also called Alpha Thalassemia Minor. ►Caused by two missing alpha genes. May be homozygous (-a/-a) or heterozygous (--/aa). ►Exhibits mild microcytic, hypochromic anemia. ►May be confused with iron deficiency anemia. ►Although some Bart's hemoglobin (γ4) present at birth, no Bart's hemoglobin present in adults. 39
  37. 37. Hemoglobin H Disease 1 of 2 ►Second most severe form alpha thalassemia. ►Usually caused by presence of only one gene producing alpha chains (--/-a). ►Results in accumulation of excess unpaired gamma or beta chains. Born with 10-40% Bart's hemoglobin (γ4). Gradually replaced with Hemoglobin H (β4). In adult, have about 30-50% Hb H. γ4 β4 40
  38. 38. Bart’s Hydrops Fetalis Syndrome ►Most severe form. Incompatible with life. Have no functioning alpha chain genes (--/--). ►Baby born with hydrops fetalis, which is edema and ascites caused by accumulation serous fluid in fetal tissues as result of severe anemia. Also see hepatosplenomegaly and cardiomegaly. ►Predominant hemoglobin is Hemoglobin Bart, along with Hemoglobin Portland and traces of Hemoglobin H. ►Hemoglobin Bart's has high oxygen affinity so cannot carry oxygen to tissues. Fetus dies in utero or shortly after birth. At birth, see severe hypochromic, microcytic anemia with numerous NRBCs. ►Pregnancies dangerous to mother. Increased risk of toxemia and severe postpartum hemorrhage. 41
  39. 39. Thanks

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