Iron deficiency Anemia Describe the normal maturation stages of RBC's stem cell proerythroblast erythroblast nucleated rbc

reticulocyte rbc What are the morphological characteristics of normal RBC? Anucleate biconcave discs Disc with central pallor Size 8 m diameter Describe the pathways for hemoglobin synthesis Hemoglobin synthesis involves 2 biosynthetic pathways Heme Heme consists of 4 pyrrole groups joined into large ring with ferrous iron incorporated into center. Globin chains Globin chains contain approximately 150 amino acids Two globin dimers form hemoglobin Most important hemoglobin is hemoglobin A comprising 95% of the hemoglobin normal red cell. Errors in globin synthesis result in hempglobinopathies or Thalassemias. What is the normal red cell turnover? A normal life-span of RBC's is about 120 days Aging RBC's are removed by mononuclear phagocytic engulfment in spleen Heme and globin chains are separated Heme is divided into iron (which is recycled) and porphyrin rings (eliminated as bilirubin) Globin is dismantled into amino acids How is erythropoiesis controlled? less than 1% of RBC's are replaced every day. Normal levels of Hg levels are maintained through a feedback mechanism involving erythropoietin A sensing mechanism responds to the tissue oxygen content within the kidney and results in the release of erythropoietin. What are the main functions of RBC's? Carry oxygen to the tissue Transport of oxygen is influenced by pH, 2-3-DPG level and valence of iron. Return to lungs carrying carbon dioxide What are the steps involved in evaluation of a patient with anemia? Distinction between hypo and hyperproliferative anemia

Use of red cell size to further narrow down the possibilities Review of the blood smear How do you distinction between hypo and hyperproliferative anemia? Reticulocyte count helps to categorize the anemia into hypo-or hyper-proliferative type. Normal 0.5-1.5% What are the characteristics of hypoprolifearative anemia? Decreased reticulocytes Bone marrow unable to produce requisite number of RBC's Lack of essential substance iron, B12, folate Invasion of marrow by a disease process as in Leukemia Aplastic anemia What are the characteristics of hyperprolifearative anemia? Hyperproliferative: Increased reticulocytes Cause of anemia outside marrow Hemolytic anemia Hemorrhage Post anemia treatment Decreased survival of rbc's Marrow normal and responds adequately by increasing the output What are the morphological characteristics of Reticulocytes Larger Continuing capacity to synthesize hemoglobin RNA-containing red cells are usually grayish on Wright's stain and contrast well with mature, orthochromic or pink red cells, providing a clue to the presence of a reticulocyte response. Cytoplasm may be slightly bluish-pink due to residual RNA (polychromasia) Reticulocyte usually the first stage RBC"s released from marrow into peripheral blood What are the ways by which one can express retic response? There are three ways to express retic response Retic count Corrected retic count Absolute retic count What is retic count? Retic count: Measures the per cent of newly released erythrocytes in the circulating blood Reticulocytes are counted as the number of NMB-reactive cells per 1,000 red cells and expressed as percent reticulocytes (absolute number per 100 red cells). What is corrected reticulocyte count Anemia increases the apparent retic count by decreasing the denominator

Corrected reticulocyte count = %reticulocyte X (Patient's Hct/Expected normal Hct of 45) Less than 2% = hypoproliferative type. This means that anemia is due to underproduction of red cells by the bone marrow. What is absolute Reticulocyte count? The absolute reticulocyte count can also distinguish between hypo/hyperproliferative anemia. If the absolute reticulocyte count is 100,000 mm3 or higher, the anemia is hyperproliferative type (i.e. hemolytic anemia or anemia of acute blood loss). If it is less than 100,000 mm3 the anemia is hypoproliferative (iron, B12, or folic deficiency, anemia of chronic disorder etc.). What is MCV, MCH, MCHC? MCV (mean corpuscular volume) divides the anemia into micro, normo, and macrocytic types. 80-100 cu m = Normocytic <80 cu m = microcytic anemia >100 cu m = macrocytic anemia Each of these categories suggest a particular differential diagnosis. MCH (mean corpuscular hemoglobin) and MCHC (mean corpuscular hemoglobin concentration) do not provide additional information. What is RDW? RDW (red cell distribution width) measures anisocytosis (heterogeneity) RDW is abnormal in a majority (more than 90%) of cases of iron deficiency. It is however normal in thalassemias and anemia of chronic disorder. Thus a patient who has low MCV and high RDW is very likely to have iron deficiency anemia. On the other hand if the RDW is normal, the low MCV may suggest a thalassemic syndrome or an anemia or chronic disorder. What is the differential for microcytic hypo chromic anemia? Iron deficiency anemia Thalassemia Sideroblastic anemia Chronic disease Rheumatoid arthritis Renal failure etc Is microcytic represents abnormal hemoglobin synthesis or a maturation defect? Microcytic : Abnormal hemoglobin synthesis Macrocytic: A maturation defect (B12, Folate deficiency) What is the hematologic consequence to iron deficiency ? There is disturbance of proliferation and maturation of erythroblasts due to deficient heme synthesis Hemoglobin decreases and the red cells become small (microcytic) with reduced hemoglobin concentration (hypo chromic)

What are the symptoms of iron deficiency anemia? gradual onset asymptomatic for long time fatigue, tired decreased exercise tolerance angina in patients with CAD short of breath edema les Pica What are the physical findings of iron deficiency anemia? ability to detect early anemia by inspection of conjunctiva is poor pallor smooth tongue brittle nails koilonychia high output state tachycardia bounding water hammer pulse venous hum flow murmurs List conditions that can give rise to microcytic anemia? What are the distinguishing features with regard to retic count and RDW? Iron deficiency Retic count decreased, RDW is high Thalassemia Retic count elevated, RDW is normal Chronic disease Retic count decreased, RDW is normal How can we confirm iron deficiency ? Serum Iron Total Iron-binding capacity Saturation Ferritin Bone marrow iron Discuss the value of serum iron? Serum Iron measures Transferrin-associated ferric ion Normal Range: 12.7 to 35.9 mol/L (60 to 180 g/dl) Decreased serum iron levels may precede changes in red cell morphology or in red cell indices All transport iron in the plasma is bound in the ferric form to the specific iron-binding protein, transferrin. Serum iron refers to this transferrin-bound iron. Serum iron concentration is increased in the sideroblastic anemia's and in some cases of thalassemia. Discuss the value of Total Iron-binding capacity Total Iron-binding capacity Normal Range: 45.2 to 77.7 mol/L (250 to 410 g/dl) TIBC, the concentration iron necessary to saturate the iron-binding sites of transferrin, is a measure of transferrin concentration.

Transferrin carries 2 iron atoms per molecule Transferrin is normally 30% bound to iron TIBC reflects a measurement of serum Transferrin Measured by saturating all available binding sites Discuss the value of Transferrin . How do you calculate saturation of transferrin? Transferrin Normal range170-370 mg/dl Saturation of transferrin is calculated by the following formula % Transferrin Saturation = Serum Iron (mol/L) X 100 Normal mean transferrin saturation is approximately 30%. Normal range 20% to 50% Compare and contrast iron deficiency anemia to anemia of chronic disease with reference to serum iron, TIBC and saturation of transferrin? Iron deficiency anemia Serum Iron Low TIBC Increased Saturation of Transferrin Reduced often <16% Chronic disease Serum Iron normal TIBC Decreased or normal Saturation of Transferrin Reduced >16% A normal plasma iron level and iron-binding capacity do not rule out the diagnosis of iron deficiency when the hemoglobin level of the blood is above 90 g/L (9 g/dl) (females) and 110 g/L (11g/dl) (males). Discuss the value of Ferritin Ferritin is protein that carries iron. Its exact function is not known. Ferritin values however reflect the total iron stores of the body very well. Low ferritin values are diagnostic of iron deficiency. Most sensitive for iron deficiency anemia Since ferritin is an acute phase reactant high values do not necessarily rule out iron deficiency. Very high values (about 1,000) may indicate presence of hemochromatosis. normal : 32-100 ng/ml What are the characteristics of anemia of chronic disorder? She should not have anemia of chronic disorder. There are no apparent chronic disorders. (Chronic infection, Rheumatoid arthritis, Chronic renal failure, Malignancy) Iron studies in ferritin values, along with RDW suggest iron deficiency anemia. In anemia of chronic disorder, Fe utilization is poor, red cell survival is shorter. This anemia is mediated through various cytokines, especially TNF, IL-1. What is the sequence of changes in lab assessment in iron deficiency anemia? Iron stores in marrow are depleted Serum ferritin falls TIBC increases Plasma iron falls

Transferrin desaturation Hemoglobin decreases Total red cell count falls microcytic hypochromic red cells List tissues /cells require Iron for normal development? RBC's: Anemia Iron containing enzymes Depletion results in changes in Nails and mucous membranes. Ridges and spoon shaped nails Mal-absorption Esophageal web What are the normal resource for iron in diet? Liver and red meats Apricots, peaches, prunes apples, grapes Eggs Spinach Vitamins and many food items (Cereal) are fortified with iron. What is the daily requirement of iron for a normal adult? The daily requirement in a adult male is 1mg. In woman it is 1.5 to 2mg. per day because of menstrual loss. Pregnancy requires an additional intake of .9 to 1 gm of iron. Therefore, during pregnancy iron supplements are necessary. What is the daily requirement of iron for erythropoesis? 25 mgm of iron is needed for daily production of red cells If the hematopoesis requires 25 mgm and GI tract absorption is only 1-2 mgm a day , what is the source for iron? Most of the iron is recycled iron from dying red cells List common causes of iron deficiency anemia. Most important cause is chronic blood loss Menstruating women: Excessive menstrual flow. 2 mgm of iron per day. Multiple pregnancies close to each other. About 500-1000 mg of iron lost per pregnancy. Males and Post menopausal women GI tract blood loss Cancer colon Ankylostoma duodenale (Underdeveloped countries, the leading cause) Hemorrhoids Nutritional deficiency (Not in USA) clay or starch pica Frequent blood donations Malabsorption (Sprue, gastrectomy) Rare causes Hereditary hemorrhagic telengiectasia (Nose bleeds, GI bleeds)

Hemoglobinuria What are the clinical modes of presentation of iron deficiency anemia? Asymptomatic : Detected on incidental evaluation Fatigue, tired and poor exercise tolerance Dysphagia Angina Congestive heart failure What is your therapeutic strategy for treatment of iron deficiency anemia? Identify the source of blood loss and plan to take care of it Provide iron supplement Patient should be put on iron supplements In pregnancy for the duration of pregnancy plus 6 to 12 months afterwards. Prolonged duration of therapy (6-12 months) even after normalization of hemoglobin is to restore iron stores in bone marrow. How soon can you expect a therapeutic response to iron supplement with Ferrous sulfate 325 mg po tid? Symptomatic improvement in few days Reticulocyte response in 2 weeks (<10%) rise in hemoglobin 1 gm per two weeks About 8 weeks to near normal hemoglobin Where is iron absorbed? Iron absorption Iron is absorbed in duodenum and proximal jejunum. Hydrochloric acid produced by the stomach is helpful in iron absorption, as it reduces ferric to ferrous form. What are the problems associated with iron therapy? GI distress. Start with low dose and gradually increase Black stools: Without an advanced warning patient might think it is malena. Antacid use to be discontinued: Impairs absorption What is the role for enteric coated preparations to diminish gastric irritation? Iron is absorbed from duodenum Slow release enteric coated tablets bypass duodenum Do not use them What is the role for parenteral iron? Indicated when the bleeding rate exceeds our ability to replace it as in Hereditary hemorrhagic telengiectasis GI distress is intolerable In patients with gastrectomy rapid transit can bypass duodenum, lack of acid What is the role for Blood transfusion in iron deficiency anemia? You do not need blood transfusions even in severe chronically anemic patients.

Patients adapt to chronic anemia extremely well and Iron replacement therapy can correct the problem gradually. You can do harm from transfusion by throwing them into heart failure, for already they have a high output state In extreme cases you can do exchange transfusion with packed red blood cells