Iron deficiency Anemia
Describe the normal maturation stages of RBC's
The answer
stem cell
proerythroblast
erythroblast
nucleated rbc
reticulocyte
rbc
What are the morphological characteristics of normal RBC?
The answer
Anucleate biconcave discs
Disc with central pallor
Size 8 µm diameter
Describe the pathways for hemoglobin synthesis
The answer
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?
The answer
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?
The answer
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?
The answer
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?
The answer
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?
The answer
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?
The answer
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?
The answer
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
The answer
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?
The answer
There are three ways to express retic response
Retic count
Corrected retic count
Absolute retic count
What is retic count?
The answer
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
The answer
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 answer
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?
The answer
MCV (mean corpuscular volume) divides the anemia into micro, normo, and macrocytic types.
80-100 cu µm = Normocytic
<80 cu µm = microcytic anemia
<100 cu µm = 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?
The answer
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?
The answer
Iron deficiency anemia
Thalassemia
Sideroblastic anemia
Chronic disease
Rheumatoid arthritis
Renal failure etc
Is microcytic represents abnormal hemoglobin synthesis or a maturation defect?
The answer
Microcytic : Abnormal hemoglobin synthesis
Macrocytic: A maturation defect (B12, Folate deficiency)
What is the hematologic consequence to iron deficiency ?
The answer
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?
The answer
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?
The answer
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?
The answer
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 ?
The answer
Serum Iron
Total Iron-binding capacity
Saturation
Ferritin
Bone marrow iron
Discuss the value of serum iron?
The answer
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.
Discuss the value of Total Iron-binding capacity
The answer
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
Discuss the value of Transferrin . How do you calculate saturation of transferrin?
The answer
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?
The answer
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
The answer
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?
The answer
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?
The answer
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?
The answer
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?
The answer
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 answer
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?
The answer
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?
The answer
Most of the iron is recycled iron from dying red cells
List common causes of iron deficiency anemia.
The answer
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?
The answer
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?
The answer
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?
The answer
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?
The answer
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?
The answer
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?
The answer
Iron is absorbed from duodenum
Slow release enteric coated tablets bypass duodenum
Do not use them
What is the role for parenteral iron?
The answer
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?
The answer
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