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3 hemoglobin 3 hemoglobin Presentation Transcript

  • HEMOGLOBIN 1
  • INTRODUCTION  The main function of red blood cell Transfer of O2 from lungs to tissue  Transfer of CO2 from tissue to lungs   To accomplish this function red cells has haemoglobin (Hb)  Each red cell has 640 million molecules of Hb 2
  • INTRODUCTION  Haemoglobin (Hb), protein constituting 1/3 of the red blood cells found in the cytoplasm of erythrocytes  Synthesis begins in proerythroblast 65% at erythroblast stage  35% at reticulocyte stage  3
  • STRUCTURE OF HEMOGLOBIN • • Hb is a spherical molecule consisting of 4 peptide subunits (globins) = quartenary structure Hb of adults (Hb A) is a tetramer consisting of 2 α- and 2 βglobins → each globin contains 1 heme group with a central Fe2+ ion (ferrous ion) 4
  • SYNTHESIS OF HAEMOGLOBIN (HB)  Haem & globin produced at two different sites in the cells Haem in mitochondria  Globin in polyribosomes   Well synchronized 5
  • Synthesis of Hb: Hemoglobin synthesis begins in proerythroblast and continues slightly even into the reticulocyte stage Steps: 2 succinyl-coA + 2 glycine = pyrrole 4 pyrrole= protoporphyrin lx Protoporphyrin lx + Fe++ (iron) = Heme 1 Heme molecule + 1 polypeptide = hemoglobin chain (hemoglobin subunit) 4 hemoglobin chain = hemoglobin molecule (4 hemoglobin subunit) There are several slight variations in different subunit hemoglobin chain depending on the aminoacid composition of polypeptide portion The different types of chain are designated alpha chain, beta chain, gamma chain, and delta chain 2 alpha chain + 2 beta chain = hemoglobin A • Each hemoglobin chain has 1 heme, so 4 hemoglobin chain in 1 hemoglobin molecule has 4 heme. • One heme has one iron so 1 hemoglobin molecule has 4 iron atoms • Each iron can bind with 1 molecule of oxygen ; so 1 molecule of Hb can transport 4 molecule of oxygen (8 oxygen atoms) 6
  • SYNTHESIS OF HAEMOGLOBIN 7
  • SYNTHESIS OF HAEM  Protoporphyrin ring with an iron atom in centre  The main site is mitochondria as it contains ALAS  Mature red cell does not contain mitochondria 8
  • STRUCTURE OF HAEM 9
  • SYNTHESIS OF GLOBIN 10
  • SYNTHESIS OF GLOBIN  Various types of globin combines with haem to form different haemoglobin  Eight functional globin chains, arranged in two clusters the β- cluster (β, γ, δ and ε globin “E” genes) on the short arm of chromosome 11  α- cluster (α and ζ globin “Z” genes) on the short arm of chromosome 16  11
  • Normal value Male: Range: 14-18gm/100ml of blood Average: 15.5 gm/100ml of blood Female: Range: 12-16.5 gm/100ml of blood Average: 14 gm/100ml of blood At birth: 23 gm/100ml of blood At first year: 10 gm/100ml of blood Molecular weight: 64,458 12
  • Hemoglobin consists of two parts a. Globin 96% b. Heme 4% Heme portion: Heme portion is synthesized mainly from acetic acid and glycine in the mitochondria Globin portion: Globin is composed of four large polypeptide chains. Globin is synthesized by ribosomes 13
  • Function of hemoglobin: •It is essential for transport of oxygen from lungs to the tissue and Carbondioxide from tissue to lungs •It is an important blood buffer and helps to maintain pH of blood •Various pigments of bile, stool, urine, etc are derived from it •It acts a reservoir for protein and iron 14
  • TRANSPORT OF O2 AND CO2 IN LUNGS 15
  • TRANSPORT OF O2 AND CO2 IN TISSUES 16
  • TYPES OF HEMOGLOBIN Adult Hb (Hb A) = 2 α and 2 β subunits HbA is the major form of Hb in adults and in children over 7 months. 1 HbA (2 α, 2 δ) is a minor form of Hb in adults. It forms only 2 – 3% of 2  a total Hb A. Fetal Hb (Hb F) = 2 α and 2 γ subunits - in fetus and newborn infants Hb F binds O2 at lower tension than Hb A → Hb F has a higher affinity to O2  After birth, Hb F is replaced by Hb A during the first few months of life. Hb S – in β-globin chain Glu is replaced by Val = an abnormal Hb typical for sickle cell anemia  17
  • Types of hemoglobin (variation) A)Physiological variation: Normally there are three different types of hemoglobin 1.Fetal hemoglobin (HbF): It contains 2α and 2γ polypeptide chain 2.Adult hemoglobin a.Hemoglobin A: It contains 2α and 2β polypeptide chain b.Hemoglobin A2 (HbA2): It contains 2α chain and 2β are replaced by 2δ chain     Hb A HbA2 HbF Adult 96% 3% 1% Neonate 30%   70% 18
  •   B)Pathological hemoglobin:(SEC-D) 1.Hb S: Contains 2α and 2β, but glutamic acid in 6th position is replaced by valine in (β-chain) 2.Hb E: Contains 2α and 2β, but glutamic acid in 26th position is replaced by lysine (in β-chain) 3.Hb C: Contains 2α and 2β, but glutamic acid in 6th position is replaced by lysine (in β-chain) 4.Hb D (Punjab): Contains 2α and 2β, but glutamic acid in 121st position  is replaced by glutamine (in β-chain) 19
  • DERIVATIVES OF HEMOGLOBIN  Oxyhemoglobin (oxyHb) = Hb with O2  Deoxyhemoglobin (deoxyHb) = Hb without O2  Methemoglobin (metHb) contains Fe3+ instead of Fe2+ in heme groups Carbonylhemoglobin (HbCO) – CO binds to Fe2+ in heme in case of CO poisoning or smoking. CO has 200x higher affinity to Fe 2+ than O2.  Carbaminohemoglobin (HbCO2) - CO2 is non-covalently bound to globin chain of Hb. HbCO2 transports CO2 in blood (about 23%).  Glycohemoglobin (HbA1c) is formed spontaneously by nonenzymatic reaction with Glc. People with DM have more HbA1c than normal (› 7%). Measurement of blood HbA1c is useful to get info about long-term 20 control of glycemia. 
  • Amount of oxygen that can be carried by Hb: Average Hb in Men: 16 gm/dl Women: 14 gm/dl Each gram of pure hemoglobin is capable of combining with 1.39 ml of oxygen Therefore In men: 100 ml of blood contains 16 gm of hemoglobin So 100 ml of blood contains 16 x 1.39 ml of oxygen = 21 ml of oxygen So in men: 100 ml of blood (16 gm Hb) can carry 21 ml of oxygen In female: 100 ml of blood contains 16 gm of hemoglobin So 100 ml of blood contains 14 x 1.39 ml of oxygen = 19 ml of oxygen So in women: 100 ml of blood (14 gm Hb) can carry 19 ml of oxygen 21
  • What would happen if hemoglobin were present freely in plasma? Normally, all of Hb is contained within RBC, only a minute amount (about 3 mg%) being present in the plasma. If Hb were freely present in plasma 1.It would increase viscosity of blood (thus rising BP) 2.It would increase colloidal osmotic pressure (thus affecting fluid exchange) 3.It would pass quickly through glomerular membrane and excreted out through urine. 22
  • Why RBC (Hb) is lower in female? 1.As because estrogen have an inhibitory effect on the secretion of erythropoietin, which is the major regulator of erythropoiesis. 2 .Testosterone is males have a stimulatory action on the secretion of erythropoietin Menstrual loss of blood in female is not the cause of lower level of RBC (Hb) Why RBC (Hb) is more in newborn? The newborn has been living in a state of relative hypoxia and hypoxia is a very potent stimulus for erythropoietin secretion. As age advances, Hb levels decrease and adult level are reached in a few year. 23
  • Fate of RBC Life span of RBC is 120 days. After 120 days RBC becomes fragile, so they become destroyed when they pass through tight spot of circulation or in reticuloendothelial cell of liver, spleen, lymph node, and bone marrow. After destruction (rupture) of RBC, Hb is released from them 1.Hemoglobin is phagocytised by RE cell and converted into heme and globin Hemoglobin Heme Globin 2.Globin is degraded into aminoacid. These aminoacids are liberated into plasma and are stored as aminoacid pool. 3.Heme is broken down into Fe (iron) and straight chain of 4-pyrrole ring (choleglobin) Heme Fe straight chain of 4-pyrrole ring Fe (iron) is bound to plasma protein “transferrin” and transported to the bone marrow for further production of Hb or store in liver or other tissue as ferritin and transferrin 24
  • 4. Straight chain of 4-pyrrole ring is converted to biliverdin straight chain of 4-pyrrole ring ↓ biliverdin ↓ biliverdin reductase bilirubin This bilirubin is released from RE cells into plasma 5. This bilirubin now binds with plasma protein “albumin” to form “unconjugated bilirubin” (water insoluble) This unconjugated bilirubin now enters into liver Here a. 80% conjugate with uridine diphosphate (UDP) glucoronide to form (mono- and dibilirubin glucoronide) b. 10% conjugate with sulphate and 10% with other This forms “conjugated bilirubin” (water soluble) Enzyme: Glucoronyl transferase 25
  • 6. Now this conjugated bilirubin is transported via bile duct into duodenum where they are converted into urobilinogen by intestinal bacteria. These urobilinogen a.Some of these urobilinogen are later converted to stercobilinogen and excreted through stool. When this stercobilinogen is exposed to external air. It is oxidized to stercobilin b.Some of these urobilinogen are reabsorbed by enterohepatic circulation. From it they reach the systemic circulation and finally into kidney. This urobilinogen is excreted through urine. When urobilinogen is exposed to air it is oxidized into urobilin. 26
  • Fate of RBC (Bilirubin metabolism) 27
  • The red cell absolute value 1)PCV (packed cell volume) or hematocrit (Hct): It is fraction of volume of blood occupied by RBC. Average: 45% 2)Mean corpuscular volume (MCV): The MCV is the average or mean volume of a single red blood cell expressed in cubic micrometer (cubic microns) Formula: Hct x 10 RBC count in million/mm3 = 45 x 10 = 90 um3 5 3 Range: 76-96 um /fl (femtoliter) 28
  • 3) MCH (Mean corpuscular hemoglobin): The MCH is the average hemoglobin content (weight of Hb) in a single RBC expressed in picogram (micro-microgram, uug) Formula: Hb in gram in 100 ml of blood x10 Red cell counts in million/mm3 15 x10 5 = 30 picogram (pg) Normal range: 27-32 pg 29
  • 4)MCHC (Mean corpuscular hemoglobin concentration): The MCHC represents the relationship between the red cell volume and its degree or percentage saturation with hemoglobin,that is how many parts or volumes of red cell are occupied by Hb. It represents the average concentration of Hb in the red cells The MCHC does not take into consideration the RBC counts, but represents the actual Hb conc in red cell only (i.e. not in whole blood) MCHC= Hb in gram/100 ml of blood x 100 Hct (PCV/100 ml of blood) 15 x 100 =33.3% 45 Normal range: 30-36 gm/dl 5) MCD (Mean corpuscular diameter) Range: 6.9-8 micrometer Average: 7.5 micrometer 30
  • Iron metabolism: Total body iron: 4-5 gm Distribution of iron in body 1. 65% in the form of Hb 2. 4% in the form of myoglobin in muscle 3. 1% in various heme compounds that promote intracellular oxidation (cytochrome, catalase, and peroxidase) 4. 0.1% in combination form with protein transferrin in blood plasma 5. 30% is stored mainly in R.E. system and liver cell as ferritin 31
  • Forms of iron A) Hemoglobin iron B) Plasma (transport) iron: Those bound with transferrin C) Tissue iron: a. Available iron: In the form of ferritin and hemosiderin b. Non-available iron: In the form of myoglobin. In enzymes of cellular respiration Iron present as a constituent of cell 32
  • Sources of iron: Meat, liver, egg yolk, peas, beans, lentils Daily requirement: Male: 0.5-1 mg Female during reproductive life (menstruating female): 1.5-2 mg Pregnant women: 1.5-2.5 mg Daily dietary requirement: Male: 5-10 mg Female: 15-20 mg Pregnant women = 20-30 mg Only 10% of dietary iron is absorbed from gut, so dietary requirement is greater than body requirement 33
  • Daily loss Male: 0.5-1 mg Menstruating female: 1.5-2 mg Absorption of iron: Iron absorption occurs mainly in duodenum and proximal jejunum. Form of absorption: Ferrous (Fe++) (Iron found in food is in ferric form, so all ferric iron must be converted to ferrous iron for absorption in GIT) Mechanism of absorption: Active transport (pinocytosis) 34
  • IRON METABOLISM •These transferrin carry the iron to the portions of the body where it is need •Transferrin: a.Carries the iron absorbed from GI tract to the tissue stores b.Transport iron from tissue stores to the marrow c.Transport iron from one storage site to another • When transferrin reaches the storage sites or the marrow, it attaches to cells and liberate it’s ferric ions which pass into the tissue cell where they are stored or utilized •The iron is loosely combined with apotransferrin, so iron can be released to any of tissue cells at any point in 35 the body
  • •Excess of iron in blood is deposited in all cells of body but especially in liver hepatocytes and RE cells of bone marrow In these cells, it combines mainly with protein, apoferritin to form ferritin (in cytoplasm) •Small quantities of iron are also stored as “hemosiderin” •Iron start to deposit as hemosiderin total quantity of iron in body is more than apoferritin storage pool can accommodate These ferritin and hemosiderin are called storage iron 36
  • Hemosiderin Ferritin Insoluble Soluble Formed when ferritin storage capacity finishes Form initially Cannot mobilized easily When iron quantity in body decreased it is mobilized easily Contain more iron than in ferritin Contains: apoferritin+iron Regulation of iron absorption: The absorption of iron is maximum when the requirement of iron in body is more and when the requirement is less absorption is also less 37
  • Anemia: Anemia may be defined as a reduction of hemoglobin concentration per unit volume of blood below normal in respect of age and sex of a person Site of observation of anemia Lower palpebral conjunctiva Dorsal surface of tongue Oral mucous membrane Skin of palm and sole Nail bed Sign and symptoms of anemia: Pallor of skin, conjunctiva, mucous membrane, nail bed Tachycardia Fatigue and weakness Headache Difficulty in breathing Anorexia 38
  • General causes of anemia: 1.Blood loss: Due to acute or chronic hemorrhage 2.Decreased production of RBC due to lack of some factors that are necessary for RBC production 3.Excessive destruction of blood cell in comparison to its production 4.Improper /inadequate function of bone marrow 39
  • Classification of anemia A)Aetiological classification: Classification according to cause 1. Anemia due to blood loss: a.Acute post hemorrhagic: It occurs due to any accident, which cause large amount of blood loss. Anemia is normocytic normochromic anemia b.Chronic post hemorrhagic: When small amount of blood is lost continuously from our body. E.g. in Hookworm infestation, chronic duodenal ulcer, bleed piles Anemia is initially normochromic normocytic but later changes to Hypochromic microcytic anemia. 40
  • 2.Anemia due to impaired red cell formation: a. Anemia due to disturbance of bone marrow function due to deficiency of factor necessary for erythropoiesis I. Iron deficiency anemia II. Megaloblastic anemia b.Anemia due to disturbance of bone marrow function not due to deficiency of factor required for erythropoiesis I. Anemia associated with chronic infection like renal failure, liver disease, disseminated malignancy II. Bone marrow infiltration III. Aplastic anemia IV. Anemia associated with myxedema and Hypopituitarism 3.Anemia caused by excessive red cell destruction: Hemolytic anemia 41
  • B Morphological classification: Based on characteristics of red cell as determined by blood examination (MCV, MCH, MCHC) 1. Normocytic normochromic anemia: Here MCV, MCH, MCHC are normal. E.g. aplastic anemia, acute post hemorrhagic anemia. 2. Microcytic hypochromic anemia: MCV: Decreased MCHC: Decreased MCH: Decreased E.g. iron deficiency anemia 3. Macrocytic anemia: MCV: Raised. E.g. megaloblastic anemia 42
  • Thank you!! 43