The document discusses microcytic anemia and its causes, primarily focusing on iron deficiency anemia, which results from impaired hemoglobin synthesis and can occur due to various factors like nutritional deficiencies, inflammation, or blood loss. Key mechanisms related to iron absorption and regulation, such as the roles of hepcidin and ferroportin, are explained, along with diagnostic markers and treatment principles. The document also highlights the prevalence of iron deficiency anemia in different populations and emphasizes the importance of dietary sources and supplementation in management.

1. Microcytic Anemia I
Microcytosis = Impaired (↓) Hemoglobin Synthesis
Abdul-Kader Souid9/26/2018
1
Hypochromic microcytic red cells
Arrow points to a small lymphocyte as a reference for size.
Arrowhead points to a small a red blood cell.
(3) Chronic inflammation (↑hepcidin)
(4) Sideroblastic anemia (↓heme)(1) Iron deficiency anemia
(2) Thalassemia trait
The hemoglobin consists of 2α
(red subunits) & 2β (blue
subunits), each containing an
iron-containing heme group
(green) to which O2 binds.
O2
2+

2. Iron Deficiency Anemia
(‘hypochromic microcytic anemia’)
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Normal Iron deficiency anemia showing
hypochromic (pale) red cells, some
small (microcytic) red cells, ↑size
variation (anisocytosis, ↑RDW)

3. Microcytosis (MCV <80 fL)
Microcytosis =↓hemoglobin synthesis (↓iron, ↓globin, or ↓protoporphyrin):
• Iron deficiency (iron-limiting erythropoiesis; nutritional vs. blood loss)
• Thalassemia trait (↓a or b globin synthesis)
• Inflammation (↓Fe bioavailability due to ↑hepcidin [blocks Fe absorption])
• ↓Protoporphyrin (hereditary sidroblastic anemia)
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Must know

4. Intestinal Iron Absorption
 Heme can be taken up by endocytosis (heme carrier
protein 1, HCP1) and Fe2+ is liberated in the
lysosome into the enterocyte.
 Fe3+ is reduced to Fe2+ by duodenal ferrireductase
cytochrome b (dcytb) and transported via the
divalent metal-ion transporter-1 (DMT-1) into the
enterocyte. Vitamin C also reduces Fe3+ to Fe2+.
 Enterocyte Fe2 is exported into
the blood by ferroportin or
stored as ferritin.
 Hepcidin blocks ferroportin.
 Fe2 in blood is carried by transferrin (Fe2Tf).
Must Know:
Ferroportin → Releases Fe2+ from enterocytes and macrophages into the blood.
Hepcidin binds to ferroportin → Retains Fe2+ inside enterocytes and macrophages.
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HO, heme oxygenase
Fe2Tf, diferric transferrin
Blocked by hepcidin

5. Hepcidin ↓ Iron Bioavailability
• Hepcidin is a 25-amino-acid protein.
• It prevents the release of iron from enterocytes and macrophages by
binding to ferroportin.
– Once hepcidin is bound to ferroportin, the ferroportin undergoes proteolysis.
– With membrane ferroportin depleted, Fe cannot be transported into the blood.
• Inflammation → ↑hepcidin → iron-deficiency anemia
• Hypoxia → ↓hepcidin → ↑Fe bioavailability → polycythemia
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Must Know

6. 9/26/2018 6
• Ferritin is a measure of stored iron.
• Serum iron is a measure of circulating iron bound to
transferrin.
• Total iron binding capacity (TIBC) is a measure of
transferrin capacity to bind iron.
• Percent transferrin saturation = serum iron ÷ TIBC.
Serum Iron Studies
serum
iron
UIBC
TIBC
Must watch video:
https://www.youtube.com/watch?v=YczPj71BFPY
Serum
ferritin
Serum
iron
Total iron
binding capacity
(TIBC)
Per cent
transferrin
saturation
Iron deficiency Low Low High Low
Inflammation High Low Low Normal

7. Evolution of Iron Deficiency
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Prussian blue staining of marrow
iron stores. Iron stores can be
graded on a scale of 0 to 4+.
A: a marrow with excess iron stores
(>4+); B: normal stores (2–3+); C:
minimal stores (1+); D: absent iron
stores (0).
Serum Iron

8. Iron Deficiency Anemia: Summary
• Microcytic anemia with  RDW and reticulocytopenia
•  Ferritin
•  Serum iron
•  TIBC (total iron binding capacity)
•  Transferrin saturation
•  ZPP (zinc protoporphyrin)
•  sTfR (serum transferrin receptor)
Must Know
Plasma ferritin <12 µg/L is indicative of absent iron stores.

9. Iron Deficiency Anemia
Prevalence
• Adult males <1%
• Adult females 20%
Mechanisms of iron deficiency
• ↑ Need for iron: Infants during their rapid growth, premature infants, growth
spurt during puberty, pregnancy, lactation, etc.
• ↓ Iron intake (nutritional iron deficiency due to poor diet): Prolonged
breastfeeding, iron-poor diet (vegetables and milk have low iron bioavailability).
• ↑ Loss: Menorrhagia, GI bleeding (bleeding ulcer, colorectal cancer [fecal
occult blood], infants on whole milk (milk-induced colitis), non-steroidal anti-
inflammatory drug (NSAID)-induced gastritis, hereditary hemorrhagic
telangiectasia (HHT).
• ↓ Absorption (relatively rare): Gastric or duodenal resection, coeliac disease, etc.
Notes: Iron absorption from meat is better than that from plants. Phytates (cereals,
nuts, legumes) inhibit iron absorption. Vitamin C promotes Fe absorption.
Must Know

10. Who gets Fe-deficiency and why?
• Malabsorption
– Stomach (resection; cancer; H. pylori; gastritis)
– Duodenum (coeliac disease, resection)
• Blood loss
– Hiatus hernia, gastritis, peptic ulcer, H. pylori, esophageal varices, tumors,
NSAID, telangiectasias, menstrual periods, hookworm, Ancylostoma
caninum, nose bleeding.
• Fe absorption from meat is better than from plants.
– Phytates (cereals, nuts, legumes) inhibit absorption of non-hem Fe.
– Vitamin C promotes hem Fe absorption.
Pica

11. Patient 1
• An 18-month-old boy presents with pallor and irritability.
For the last 6 months, his diet was whole milk.
• Hemoglobin = 50 g/L, RBC = 2 x1012/L, reticulocyte
count = 14 x109/L, MCV = 59 fL, and RDW = 21%.
• Problem list: Microcytic anemia with increased RDW and
reticulocytopenia, consistent with milk-induced iron deficiency.
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Normal Iron deficiency
anemia

12. Principles of Treatment
1. Treating the primary cause of iron deficiency
– Diet history
– Identify the site of blood loss (e.g., menorrhagia, stool occult blood,
endoscopy, colonoscopy, video capsule endoscopy)
2. Iron-rich food ± iron supplementation
– Ferrous sulfate (FeSO4), 325 mg once to three times per day:
• 120 to 180 mg elemental Fe/day (adults)
• 2-6 mg/kg elemental Fe/day (children)
• Treat 3 months after correction of anemia.

13. Required Reading
• Harrison’s Online – Chapter 103 (Iron Deficiency)
• Petry N, Olofin I, Hurrell RF, et al. The proportion of anemia associated with
iron deficiency in low, medium, and high human development index countries:
a systematic analysis of national surveys. Nutrients. 2016;8(11). pii: E693.
• Amin SB, Orlando M, Wang H. Latent iron deficiency in utero is associated
with abnormal auditory neural myelination in ≥ 35 weeks gestational age
infants. J Pediatr. 2013;163:1267-71.
• De-Regil LM, Jefferds ME, Sylvetsky AC, Dowswell T. Intermittent iron
supplementation for improving nutrition and development in children under 12
years of age. Cochrane Database Syst Rev. 2011;12:CD009085.
• Zimmermann MB, Hurrell RF. Nutritional iron deficiency. Lancet
2007;370:511–520.
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14. Optional Reading
Total iron binding capacity (TIBC) is a colorimetric assay that
uses two reagents sequentially. The first one is an acidic reagent
that contains an iron-binding dye. The acidic pH causes
transferrin to release all iron, which are captured by the iron-
binding dye along, producing a colored complex. The second one,
is a neutral reagent that raises the pH and restores transferrin’s
affinity for iron. The transferrin extracts iron from the dye-iron
complex and becomes 100% saturated. The decrease in
absorbance of the colored dye-iron complex is measured
spectrophotometrically at 660 nm and is directly proportional to
the TIBC of the serum sample
(http://www.randox.com/brochures/reagents/LT116.pdf).
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