Iron deficiency Anemia
Anucleate biconcave discs
Disc with central pallor
Reticulocyte usually the first stage RBC"s released from marrow into peripheral blood
Cytoplasm may be slightly bluish-pink due to residual RNA (polychromasia)
Hemoglobin synthesis involves 2 biosynthetic pathways
Heme consists of 4 pyrrole groups joined into large ring with ferrous iron incorporated into center.
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.
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
Control of erythropoiesis
less than 1% of RBC's are replaced every day.
Normal levels of Hg levels are maintained through a feedback mechanism involving erythropoetin
A sensing mechanism responds to the tissue oxygen content within the kidney and results in the release of erythropoietin.
Main function of RBC's
Carry oxygen to the tissue
Return to lungs carrying carbon dioxide
Transport of oxygen is influenced by pH, 2-3-DPG level and valence of iron.
Steps 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 the blood smear
Reticulocyte count helps to categorize the anemia into hypo-or hyper-proliferative type.
Bone marrow unable to produce requisite number of RBC's
Lack of essential substance (iron, B12, folate) or invasion of marrow by a disease process as in leukemia , Aplastic anemia
Cause of anemia outside marrow
Post anemia treatment
Decreased survival of rbc's
Marrow normal and responds adequately by increasing the output
Reticulocytes are defined as immature red cells seen in the peripheral blood that contain at least two dots of reticulin material reactive with new methylene blue (NMB) in their cytoplasm.
More immature forms have multiple dots and small networks of skeins of bluish material. These remnants are residual ribosomal RNA used for hemoglobin synthesis in the developing erythrocyte.
The RNA is too finely distributed to form networks on Wright's stain; a supravital stain causes precipitation and aggregation of the RNA and creates the dots and skeins of reticulin.
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.
There are three ways to express retic response
Corrected retic count
Absolute retic count
Retic count: 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).
Inter-observer variation and uneven distribution of reticulocytes on the new methylene blue smear introduces a high analytic variation in reticulocyte counting; interlaboratory coefficients of variation in the 20% range are common, a degree of imprecision of which every clinician should be aware. Duplicate reticulocyte counts or 3-day average values may help to reduce the imprecision of the raw reticulocyte count.
Her reticulocyte count is 2.5%.
Corrected reticulocyte count = %reticulocyte X (Patient's Hct/Expected normal Hct of 40)
Our patient's Corrected reticulocyte count is 2.5 x 23 / 40. It is 1.2%.
Less than 2% = hypoproliferative type. This means that her anemia is due to underproduction of red cells by the bone marrow.
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.).
Normal MCV is 85-95fl
MCV divides the anemia in micro, normo, and macrocytic types.
Each of these categories suggest a particular differential diagnosis.
RDW (red cell distribution width) measures anisocytosis.
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.
MCH and MCHC do not provide additional information.
Differential for microcytic hypo chromic anemia.
Iron deficiency anemia
Chronic disease (Rheumatoid arthritis, Renal failure etc)
Microcytic : Abnormal hemoglobin synthesis
Macrocytic: A maturation defect (B12, Folate 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)
Retic count decreased
RDW is high
Retic count elevated
RDW is normal
Retic count decreased
RDW is normal
To confirm iron deficiency
Total Iron-binding capacity
Serum Iron measures Transferrin-associated ferric ion Normal Range: 12.7 to 35.9 µmol/L (60 to 180 µg/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.
Total Iron-binding capacity Normal Range: 45.2 to 77.7 µmol/L (250 to 410 µg/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
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%
Iron deficiency anemia
Serum Iron Low
Saturation of Transferrin Reduced often <16%
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).
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
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.
Tissues /cells require Iron for normal development
Iron containing enzymes
Depletion results in changes in Nails and mucous membranes.
Ridges and spoon shaped nails
Normal resource for iron in diet
Liver and red meats
Apricots, peaches, prunes apples, grapes
Vitamins and many food items (Cereal) are fortified with iron.
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.
Common causes of iron deficiency anemia.
Most important cause is chronic blood loss.
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
Ankylostoma duodenale (Underdeveloped countries)
Nutritional deficiency (Not in USA)
Malabsorption (Sprue, gatrectomy)
Hereditary hemorrhagic telengiectasia (Nose bleeds, GI bleeds)
Clinical sequelae to iron deficiency anemia
Asymptomatic until late
High output state
Congestive heart failure
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, along with vitamin supplement for the duration of her pregnancy plus 6 to 8 months afterwards.
Prolonged duration of therapy even after normalization of hemoglobin is to restore iron stores in bone marrow.
Ferrous sulfate 325 mg po tid
Reticulocyte response in 2 weeks (<10%)
About 8 weeks to near normal hemoglobin
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.
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
Role for Blood transfusion
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.