4 hemoglobin disorder


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4 hemoglobin disorder

  2. 2. IRON-DEFICIENCY ANEMIA Iron-deficiency anemia (or iron-deficiency anaemia) is a common anemia (low red blood cell level) caused by insufficient dietary intake and absorption of iron, and/or iron loss from intestinal bleeding. Anemia occurs when a person's blood contains insufficient red blood cells. This could result if:  The body does not make enough red blood cells  Bleeding causes loss of red blood cells more quickly than they can be replaced
  3. 3. Iron deficiency anemia: Other name: microcytic hypochromic anemia Most commonest form of anemia in underdeveloped country High incidence of iron deficiency anemia occurs in women during the reproductive life   Etiology/cause: Iron deficiency anemia may result from: •Inadequate iron intake •Impaired absorption of iron •Loss of blood/chronic blood loss •An increase physiological demand for iron  
  4. 4. 1.In adult males and post-menopausal women (pathological blood loss) Hookworm infestation Bleeding peptic ulcer Cancer of stomach Bleeding piles Colon cancer 2.In female in reproductive period of life Menstruation (excessive menstrual bleeding) Frequent pregnancy Lactation 3.Infant and children Dietary deficient in proportion to body requirement
  5. 5. Megaloblastic anemia: Megaloblastic anemia is characterized by formation of morphologically abnormal nucleated red cell precussor called megaloblasts in the bone marrow due to megaloblastic erythropoiesis Cause: 1. Deficiency of VitB12 2. Deficiency of folic acid
  6. 6. Cause of VitB12 deficiency 1. Inadequate intake of VitB12 (nutritional deficiency): it occurs among strict vegetarian 2. Decrease absorption: a.Gastric cause: Due to deficiency of intrinsic factor I. Gastric atrophy: Occurs as in Addisonian pernicious anemia II.After gastrectomy b. Intestinal cause I.Tropical sprue II.Celiac disease II.Lesion of small intestine 3.Drugs: (Rare) Paraminosalicyclic acid Metformin
  7. 7. Cause of folic acid deficiency: 1.Inadequate intake (nutritional deficiency): Common in poor, pregnant women 2.Increased requirement: During Pregnancy Puerperium Carcinoma (malignancy) Leukemia 3.Impaired absorption Tropical sprue Celiac disease 4.Hepatic cirrhosis 5.Drugs: Drugs like folate antagonist Phenytoin Trimethprim
  8. 8. Cardinal manifestation of 1.VitB12 deficiency: Macrocytic (megaloblastic) anemia Glossitis Subacute combined degeneration of spinal cord and peripheral neuropathy 2.Folic acid deficiency: Macrocytic (megaloblastic) anemia Glossitis Peripheral neuropathy (occasional) (subacute combined degeneration of spinal cord does not occur)
  9. 9. Pernicious anemia Addisonian pernicious anemia is a VitB12 deficiency megaloblastic anemia   Pathogenesis: Pernicious anemia occurs due to failure of secretion of intrinsic factor (IF) by the stomach due to permanent gastric atrophy Deficiency/absence of intrinsic factor ↓ VitB12 present in food is not absorbed ↓ VitB12 deficiency ↓ C/F of megaloblastic anemia
  10. 10. Aplastic anemia Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. The condition, as the name indicates, involves both aplasia and anemia. Typically, anemia refers to low red blood cell counts, but aplastic anemia patients have lower counts of all three blood cell types: red blood cells, white blood cells, and platelets, termed pancytopenia.  Classification: 1.Primary or idiopathic aplastic anemia: Cause unknown 2.Secondary aplastic anemia: Cause: Drugs: Which cause bone marrow depression Cytotoxic drugs Phenylbutazone Chloramphenicol Chemicals: Hairdye, benzene, DDT Ionizing radiation: Radiotherapy, diagnostic radiology Viral hepatitis 3.Other types of aplastic anemia a. Fanconi’s anemia: A familial aplastic anemia b.Pure red cell aplasia  
  11. 11. Clinical feature: Clinical feature is aplastic anemia comprises the features of anemia, neutropenia, thrombocytopenia Anaemia Thrombocytopenia: Bleeding manifestations Cerebral hemorrhage is cause of death Neutropenia: Infection Pneumonia and septicemia is cause of death
  12. 12. Pancytopenia: Pancytopenia is the state where all three formed elements of blood are reduced i.e. there is anemia, leukopenia, thrombocytopenia   Cause: Aplastic anemia Cytotoxic agents Radiotherapy Overwhelming infection Bone marrow infiltration: in disease like lymphoma, metastatic carcinoma of bone, multiple myeloma Hyperspleenism Megaloblastic anemia
  13. 13. Hemolytic anemia: Hemolytic anemia result from an increase in the rate of red cell destruction Normal life span of red cell is 120 days In hemolytic anemia life span may be shortened to 2-3 days in extreme cases Classification: Hemolytic anemia are classified on the basis of factors that causes hemolysis 1.Intracorpuscular cause: if the factors that cause hemolysis are inside the red cell 2.Extracorpuscular cause : if the factors that cause hemolysis are outside the red cell
  14. 14. Intracorpuscular defect: When the factors causing hemolysis of red cell is inside the cell A.Hereditary 1.Due to defect in membrane Hereditary spherocytosis Hereditary elliptocytosis 2. Due to defect in hemoglobin synthesis Thalassemia: Due to reduced synthesis of alpha or beta chain of globin Haemoglobinopathies: Due to synthesis of structurally abnormal globin, HbS, HbC, HbD 3.Due to deficiency of enzyme in red cell Deficiency of glucose-6-phosphate dehydrogenase enzyme Deficiency of enzyme of Embden-Meyerhoff pathway (pyruvate kinase) B.Acquired: Membrane defect. E.g. paroxysmal nocturnal hemoglobunuria (PNH )
  15. 15. Extracorpuscular defect: When the factor causing hemolysis of red cell is outside the cell 1. Immune dependent: a.Autoimmune hemolytic anemia b.Hemolytic disease of new born (erythroblastosis foetalis) c.Incompatible blood transfusion d.Drug induce hemolytic anemia 2.Non-immune dependent a.Mechanical hemolytic anemia Cardiac hemolytic anemia: Prosthesis value Microangpathic hemolytic anemia March hemoglobuinuria b. Infection e.g. malarial parasite c. Sever burn, shake, and spider bite d. Drug and chemical e.g. lead poisoning
  16. 16. Disorders of hemoglobin   Hemoglobin disorders are genetically determined disorders Thalassaemias: These occur due to reduction in the rate of synthesis of one or more types of polypeptide chain of hemoglobin Haemoglobinopathies: These are disorders in which structurally abnormal hemoglobin are produced
  17. 17. Thalassaemias: These are inherited disorder in which there is inadequate production of α chains or β chains (polypeptide) of hemoglobin Types A. β-thalassaemia: There is inadequate production of β-chain and thereby reduction of Hb A Classification of β thalassaemia: 1.On extend of reduction of β chain synthesis a.β° thalassaemia: There is complete absence of β-chain synthesis b.β + thalassasemia: There is incomplete reduction of β-chain synthesis 2.On the basis of clinical manifestation: a.β thalassasemia major: There is total suppression of β chain synthesis It is homozygous state It is usually a severe disease Death may occur during childhood b.β thalassasemia minor: Suppression of β chain synthesis is much less severe It is a heterozygous state It is mild or asymptomatic condition c.β thalassasemia intermedia:
  18. 18. Clinical feature of thalassasemia Mongoloid facies Hepatomegaly Splenomegaly Slow growth in childhood Anemia Recurrent infection Skin pigmentation
  19. 19. Β. α thalassasemia: There is defective synthesis of α chain with reduction in amount of HbA, HbA 2, and HbF   Types of α thalassasemia 1.α thalassasemia trait: It is asymptomatic 2.Hemoglobin-Bart’s Hydrop foetalis In fetus an excess production of γ chain is produced (absence of α chain) γ 4 called Hb-Bart’s Affected infants are either born dead or die within few hours of birth Gross edema, ascites, and hepatosplenomegaly are present 3.Hemoglobin-H disease: In adult an excess production of β chain occurs (absence of α chain) form β 4 called Hb-H. There is moderate to severe anemia
  20. 20. Hemoglobinopathies: These are condition associated with abnormal hemoglobin The common abnormal hemoglobin HbS: (tropical Africa)-------- α2 β2 6 glu--------val HbE: (south east Asia)------ α2 β2 26 glu--------lys HbC: (tropical Africa) ------ α2 β2 6 glu-------- lys HbD Punjab: (India)--------- α2 β2 121 glu--------gln   Glu: glutamic acid, val: valine, lys: lysine, gln:glutamine
  22. 22. DEFINITION Sickle Cell Disease:  A genetic hemoglobinopathy  Results in deformation, increased rigidity, and destruction of RBCs  Vasocclusive and pro-inflammatory disease process  Chronic multiorgan system disease  Severe morbidity and early mortality
  23. 23. What is Sickle Cell Anemia (SCA)?  First described in Chicago in 1910 by James Herrick as an inherited condition that results in a decrease in the ability of red blood cells to carry oxygen throughout the body    Sickle red blood cells become hard and irregularly shaped (resembling a sickle) Become clogged in the small blood vessels and therefore do not deliver oxygen to the tissues. Lack of tissue oxygenation can cause excruciating pain, damage to body organs and even death.
  24. 24. DEFINITION  Autosomal recessive genetic disease: β-globin gene (chromosome 11q) mutation GAGGTG at 6th codon  Glutamic Acid  Valine at the 6th amino acid along the β-globin chain   α2β2 = normal hemoglobin  α2βS = heterozygote = Sickle trait  α2S2 = homozygous recessive = Sickle cell disease
  25. 25. HISTORY OF SICKLE CELL DISEASE Known by many African tribes for centuries  Earliest historical report -- 1670 in Ghana  African cultures often named illness to describe the sounds of moaning made by the victims   Tribal names:  Ahututua – Twi tribe  Chwecheechwe – Ga tribe  Nuidudui – Ewe tribe  “Obanje” – “Children who come and go”
  26. 26. PATHOPHYSIOLOGY       Inheritance of mutated hemoglobin β-globin chain Mutation GAG  GTG at 6th codon Glutamic acid  Valine at 6th AA α2βS = heterozygote = Sickle trait α2S2 = homozygote recessive = Sickle cell disease Additional variants:  Hgb S - β+ thalassemia  Hgb S - β0 thalassemia  Hgb S - α thalassemia  Hgb SC  Hgb SD  Hgb SE  Hgb S-HPFH (Hereditary Persistance of Fetal Hgb)
  27. 27. PATHOPHYSIOLOG Y Sickling Mechanism 1. 2. 3. 4. 5. Deoxygenation HgbS  protein conformational change Hydrophobic Valine exposed at molecular surface Val6 of B2 chain of 1st Hgb S chain forms hydrophobic bond with Phe85 and Leu88 of a 2nd Hgb S B1 chain Pairing Hgb S monomers polymerize to form Hgb S chains Hgb S polymers precipitate in RBCs as long, rigid fibers
  28. 28. PATHOPHYSIOLOGY  HgbS fibers are rigid  Hgb S fibers deform RBC membranes  Membrane disruption exposes transmembrane proteins and lipids that are pro-inflammatory  Progressive sickling makes cells dense and inflexible
  29. 29. Hallmarks of Sickle Cell Pathophysiology Sickle Cell Formation  Microvascular vasoocclusion  Chronic Inflammation  Multiorgan System Disease 
  30. 30. PATHOPHYSIOLOGY Factors that Promote Hgb S polymerization:  Low pO2 / Hypoxia  Prolonged “Delay Time” – time RBC spends in microcirculation  Low pH  High Hgb S concentration  Genotype-dependent  Cellular “Dehydration”  Volume depletion (total body)  Sickling  Activation K+ / Cl- cotransporter and Gardos Ca2+- activated K+ efflux channels  ion and water efflux  Low Hgb F concentration  α2γS: gamma globin chains bind Hgb S chains and inhibit Hgb S polymerization, thus countering sickling process
  31. 31. Pathophysiology
  32. 32. Sickle cell anemia: (Summary) In sickle cell anemia RBC contains Hb S •Sickle cell anemia is present in 0.3-1% of West Africans and American blacks •When Hb S is exposed to low concentration of oxygen it precipitates into long crystal inside red blood cell. This crystal elongates the cell and gives it the appearance of being sickle rather than a biconcave disc . •The precipitated hemoglobin also damages the red cell membrane , so that the cell becomes highly fragile Sickle of red cells is initially reversible when oxygenation occurs but later become permanent irreversibly sickle due to membrane damage •Red cell will begin to sickle at an oxygen tension of 50-60 mmHg, which is usually found in microcirculation but it the flow is rapid, they resume normal shape when they are swept back to area of circulation where the oxygen tension is higher •But if the flow rate is slow and the cells are delayed in areas where oxygen tension is low, the cell sickle and this sickle cell greatly increase blood viscosity with further slowing of circulation
  33. 33. Effect:  These sickle cells cause great increase in blood viscosity and block small blood vessels impairing flow and causing ischaemia and infarction of tissue  Repeated sickling-unsickling of red cell cause loss of fragment of red cell membrane, which cause red cell to be fragile, so easy hemolysis occurs leading to anemia
  34. 34. Effect of anemia A. In anemia viscosity of blood decrease (due to decrease in red cells)   Decrease viscosity ↓ Decrease the resistance to blood flow in peripheral vessels ↓ Increase quantity of blood flow to tissue ↓ This increases quantity of blood is returning to heart from these tissues  
  35. 35. B.Anemia cause hypoxia to tissue Decrease amount of oxygen transported by blood to tissue ↓ Hypoxia ↓ Dilates peripheral blood tissue ↓ Increase flow of blood to tissue ↓ Increase venous return (blood to heart)   Thus these two effects cause ↓ Increase venous return to heart ↓ Increase cardiac output ↓ i.e. increase workload on the heart
  36. 36. Polycythemia: Increase in number of red cells above normal range per unit volume of blood   Classification: 1. True or absolute polycythemia 2. Relative polycythemia
  37. 37. 1.True or absolute polycythemia: There is an increase in total red cell volume Types A.Polycythemia Vera (erythremia): When there is pathological proliferation of red cell without erythropoietin stimulus, then it is called polycythemia vera Red cell count may be 7-8 million and hematocrit 60-70% Causes: Bone marrow tumor X-ray radiation Here WBC and platelet production also increase B.Secondary polycythemia (erythrocytosis): When the polycythemia occurs in response to increase erythropoietin production. Cause of increase erythropoietin production I .Secondary to hypoxia High altitude Congenital heart disease Chronic pulmonary disease like emphysema, pulmonary fibrosis II.Other factors that cause increase erythropoietin production Non-neoplastic kidney disease: Renal cyst Tumors: Kidney, liver Ovarian tumor C.Benign familial polycythemia
  38. 38. 2.Relative polycythemia: Here total red cell volume is within normal range. But there is increase in RBC conc or increase hematocrit due to hemoconcentration (loss of plasma portion) Cause: Dehydration Redistribution of body fluid Adrenal insufficiency: Increase loss of electrolyte—increase loss of fluid
  39. 39. Effect of polycythemia 1.On circulatory system a. Due to increase in viscosity of blood in polycythemia ↓ Blood flow through blood vessels is sluggish ↓ Decrease venous return to heart b.On the other hand, polycythemia increases volume of blood ↓ Increase venous return So actually cardiac output in polycythemia is not far from normal because these two factors more or less neutralize each other 2.On arterial blood pressure: Arterial pressure is normal in most people with polycythemia although in about 1/3 of them pressure increase   Cause: Because blood pressure regulating mechanism can maintain it up to certain limits
  40. 40. 3.On skin color: Color of skin depends to great extent on quantity of blood in subpapillary venous plexus In polycythemia vera, quantity of blood in this plexus is greatly increased Because the blood passes sluggishly through skin capillaries before entering the venous plexus, a larger than normal quantity of Hb is deoxygenated before the blood enters the plexus. The blue color of deoxygenated Hb masks the red color of oxygenated Hb. Therefore person with polycythemia vera ordinarily has a ruddy complexion with a bluish (cyanotic) tint to skin Polycythemia vera Increased red cells, increase WBC, increased platelets Increased only red cells Erythropoietin concentration in blood is normal   Secondary polycythemia Erythropoietin concentration in blood is increased
  41. 41. Jaundice: Jaundice is defined as yellow discoloration of skin, mucous membrane and sclera due to increase bilirubin concentration in the body fluid above normal Serum bilirubin: Normal: 0.3-1 mg/dl (5-17 umol/l) Classification of jaundice: 1.Latent jaundice: Clinically, there is no jaundice but serum bilirubin is more than normal but less then 3 mg/dl 2.Clinical jaundice: Jaundice is clinically seen as yellow coloration of skin, mucous membrane, and skin when bilirubin exceeds 3 mg/dl (50 umol/l)
  42. 42. Types of jaundice: 1. Hemolytic or prehepatic 2. Hepatocellular or hepatic 3. Obstructive or cholestatic or posthepatic   Site where jaundice can be seen: 1.Sclera or eye 2.Mucous membrane of mouth 3.Skin 4.Crease of palm and sole
  43. 43. Jaundice may develop due to any one of the following conditions 1.When there is excess production of bilirubin 2.When there is decrease uptake of bilirubin by liver cell 3.Impaired conjugation of bilirubin in hepatocytes 4.Impaired excretion of conjugated bilirubin through bile canaliculi
  44. 44. 1.Hemolytic jaundice: Hemolytic jaundice occurs due to increased breakdown of red cells which lead to increase in production of bilirubin Cause: Hemolytic anemia Ineffective erythropoiesis: E.g. thalassaemia, pernicious anemia   Jaundice is usually mild as normal liver can excrete 6 times the bilirubin that is normally formed Bilirubin is mainly unconjugated bilirubin   2.Hepatocellular jaundice/Hepatic jaundice: This type of jaundice develops due to failure of liver to transport bilirubin into bile as a result of liver cell damage Cause: Viral hepatitis Drugs Chronic alcoholic hepatitis Cirrhosis In Hepatocellular jaundice both unconjugated and conjugated bilirubin increase
  45. 45. 3.Obstructive or cholestatic jaundice/posthepatic jaundice: It occurs due to obstruction of bile flow obstructive may be intrahepatic or extrahepatic A.Intrahepatic obstruction: Cause: Viral hepatitis Drugs Alcoholic hepatitis Cirrhosis Pregnancy B.Extrahepatic obstruction: Obstruction in biliary tract. The obstruction may be in lumen, in wall, or outside the wall In the lumen: Gallstone, worm In the wall: Cholingitis, tumor, atresia, stricture Outside the wall: Carcinoma of head of pancreas, subhepatic abscess, enlarged lymph node The bilirubin in serum is conjugated
  46. 46. Unconjugated Conjugated Water insoluble Water soluble Lipid soluble Lipid insoluble Present in blood of normal healthy person Absent in blood of normal healthy individual Cannot pass in urine as it is not water soluble Can pass in urine as it is water soluble Vanden Bergh reaction indirect positive Vanden Bergh reaction direct positive
  47. 47. THANK YOU!!