IRON DEFICIENCY

ANEMIA
AND OTHER
HYPOPROLIFERATIVE
ANEMIAS
Shaina B. Ventura M.D.
■ The World Health Organization (WHO) defines
Anemia as a hemoglobin level
– Men: <130 g/L (13 g/dL)
– Women: <120 g/L (12 g/dL)
■ Erythropoeitin – hormone is the physiologic regulator of red cell
production in the bone marrow
– Produced and released by peritubular capillary lining cells
within the kidney and small amount of EPO is produced by
hepatocytes.
■ The fundamental stimulus for EPO production is the availability of
O2 for tissue metabolic needs.
■ Key to EPO gene regulation is hypoxia-inducible factor (HIF)-1α.
Categorized Anemia as
■ Hypoproliferative Anemia – Low Reticulocyte count;
Underproduction of RBC
– MCV – Mean corpuscular volume
■ Microcytic <80
■ Macrocytic >100
■ Normocytic 80-100
■ Hyperproliferative Anemia – Elevated Reticulocyte count;
Increased RBC loss/destruction
– Mostly from bleeding or hemolysis
Hypoproliferative anemias
■ Anemias associated with normocytic, normochromic red cells and
an inappropriately low reticulocyte response (reticulocyte index
<2–2.5)
■ Early Iron deficiency
■ Acute and chronic inflammation
■ Renal disease
■ Hypometabolic states
■ Anemia from marrow damage
■ Hypoproliferative anemias are the most common of
anemias
– Iron deficiency anemia - is the most common of
hypoproliferative anemias
– Anemia of inflammation - the second most
common form
 IRON METABOLISM
Iron Absorption
■ The absorption of most dietary iron occurs in
the duodenum and proximal jejunum and
depends heavily on the physical state of the
iron atom.
■ At physiological pH, iron exists in the oxidized,
ferric (Fe3+) state.
■ To be absorbed, iron must be in the ferrous
(Fe2+) state or bound by a protein such as
heme.
Iron Absorption
■ The low pH of gastric acid in the proximal
duodenum allows a ferric reductase enzyme,
duodenal cytochrome B (Dcytb), on the brush
border of the enterocytes to convert the insoluble
ferric (Fe3+) to absorbable ferrous (Fe2+) ions.

■ Once ferric iron is reduced to ferrous iron in the

intestinal lumen, a protein on the apical
membrane of enterocytes called divalent metal
cation transporter 1 (DMT1) transports iron across
the apical membrane and into the cell.
Iron Absorption
■ Hepcidin
– the Iron regulatory hormone
hepcidin, synthesized in the
hepatocytes of the liver.
– Inhibit ferroportin, transporter of
iron release in circulation thus
decrease plasma iron
concentrations.
Iron Absorption
■ Iron may be stored as ferritin or
transported through the cell to be
released at the basolateral surface
to plasma transferrin through the
membrane-embedded iron exporter,
ferroportin.
Iron Absorption
■ The function of ferroportin is
negatively regulated by hepcidin,
the principal iron regulatory
hormone.
■ In the process of release, iron
interacts with another ferroxidase,
hephaestin, which oxidizes the iron
to the ferric form for transferrin
binding
■ Hephaestin – converts Fe2+ to
Fe3+  transported by Tranferrin
■ The Duodenal pH-dependent process of iron absorption is
inhibited or enhanced by certain dietary compounds.
– Inhibitors of Iron absorption:
■ Phytate plant based diets – inhibit absorption
■ Calcium – inhibit uptake into enterocytes
– Enhancers of Iron absorption:
■ Ascorbic acid (vitamin C) - forms a chelate with ferric (Fe3+) iron in
the low pH of the stomach which persists and remains soluble in
the alkaline environment of the duodenum.
■ The iron-transferrin complex circulates in the plasma  interacts with specific
transferrin receptors on the surface of marrow erythroid cells.

■ Although transferrin receptors are found on cells in many tissues within the body

■ Developing erythroblast - The cell having the greatest number of receptors

(300,000–400,000/cell)
■ Tranferrin-Iron complex + Trasferrin receptor  internalized via clathrincoated pits
and transported to an acidic endosome  At low pH  Iron Released
■ The iron  heme synthesis
■ transferrin-receptor complex  is recycled to the surface of the cell, where the bulk
of the transferrin is released back into circulation  transferrin receptor re-anchors
into the cell membrane.
■ At this point a certain amount of the transferrin receptor protein may be released
into circulation and can be measured as “soluble transferrin receptor protein”
■ Within the erythroid cell, iron in excess of the amount needed for hemoglobin synthesis
binds to a storage protein, apoferritin, forming ferritin
■ 1 milliliter of red cells = 1 mg of elemental iron,
■ Adult male will need to absorb at least 1 mg/d of elemental iron daily to meet
needs.
■ Adult females in the childbearing years will need to absorb an average of 1.4 mg/d.
■ If the delivery of iron to the stimulated marrow is suboptimal, the marrow’s
proliferative response is blunted, and hemoglobin synthesis is impaired.
■ The result is a hypoproliferative marrow accompanied by microcytic, hypochromic
anemia.
NUTRITIONAL IRON BALANCE

■ The balance of iron in humans is tightly controlled and designed to conserve iron for
reutilization.
■ There is no regulated excretory pathway
■ for iron, and the only mechanisms by which iron is lost are blood loss
■ And the loss of epithelial cells from the skin, gut, and genitourinary tract.
IRON-DEFICIENCY ANEMIA

■ Iron deficiency is one of the most prevalent forms of

malnutrition.
■ Globally, 50% of anemia is attributable to iron
deficiency and accounts for approximately nearly a
million deaths annually worldwide.
■ In the Philippines:
– Iron-deficiency anemia (IDA)
is considered the most
common form of anemia in
the Philippine population

– The highest prevalence of infants 6-11 months

anemia in the country were 14% pregnant women

observed in infants aged 6– 10% 35% elderly male

elderly female
11 months (40.1%), pregnant lactating women
women (24.6%), elderly 20%
males (23.0%), elderly 21%
females (19.1%), and
lactating women (16.7%)

Published online 2019 Jun 7 Zinc and Iron Nutrition Status in the Philippines Population and Local Soils
LABORATORY IRON STUDIES
■ Serum Iron
■ Total Iron-Binding Capacity
■ Serum Ferritin
■ Evaluation of Bone Marrow Iron Stores
■ Red Cell Protoporphyrin Levels
■ Serum Transferrin Receptor Protein
Serum Iron and
Total Iron-Binding Capacity
■ Serum iron level - amount of circulating iron bound to Transferrin
– Normal range: 50–150 μg/dL
■ TIBC - an indirect measure of the circulating transferrin
– Normal range: 300–360 μg/dL.
■ Transferrin Saturation:
Transferrin Saturation = Serum Iron × 100 ÷ TIBC

25–50% - normal range:

<20% Iron-deficiency states
>50% Iron overload
 Serum Ferritin
■ Storage form of Iron
■ Level correlates with total body iron stores
■ Most convenient laboratory test to estimate iron stores
– Adult Male average 100ug/L
– Adult Female 30ug/L
■ As iron stores are depleted, the serum ferritin falls to <15 μg/L. - levels
are diagnostic of absent body iron stores
 Bone Marrow Iron Stores
■ Estimates RE iron stores from the iron stain of a bone marrow aspirate or biopsy
■ Also provides information about the effective delivery of iron to developing
erythroblasts.
■ Marrow smear is stained for iron
– 20–40% of developing erythroblasts (sideroblasts) have visible ferritin granules
in their cytoplasm
■ This represents iron in excess of that needed for hemoglobin synthesis.
– In states in which release of iron from storage sites is blocked, RE iron will be
detectable, and there will be few or no sideroblasts
Red Cell Protoporphyrin Levels

■ Protoporphyrin is an intermediate in the pathway to heme synthesis.

■ Protoporphyrin accumulates within the red cell when heme synthesis is impaired,
– This reflects an inadequate iron supply to erythroid precursors to support
hemoglobin synthesis.
– Normal values are <30 μg/dL of red cells.
– Iron deficiency, values >100 μg/dL are seen.
■ Absolute of relative iron deficiency and lead poisoning - are the most common
causes of increased red cell protoporphyrin levels.
Transferrin Receptor Protein

■ Serum levels of TRP reflect the total erythroid marrow mass from release from
transferrin receptor protein enriched erythroid cells,
■ Elevated in absolute iron deficiency.
■ Normal values are 4–9 μg/L determined by immunoassay.
 3 STAGES OF IRON DEFICIENCY
■ Stage 1: NEGATIVE IRON BALANCE
■ Stage 2: IRON DEFICIENT ERYTHROPOEISIS
■ Stage 3: IRON DEFICIENCY ANEMIA
 1st Stage: NEGATIVE IRON BALANCE
– When demands for iron exceed the body’s ability to absorb iron
from the diet
■ The iron deficit must be compensated by mobilization of iron
from RE storage sites.
– This stage results from a number of physiologic mechanisms
■ Blood loss
■ Pregnancy (in which the demands for red cell production by the
fetus outstrip the mother’s ability to provide iron)
■ Rapid growth spurts in the adolescent
■ Inadequate dietary iron intake
■ During this period, iron stores are decreased
– Low serum ferritin level
– Low stainable iron on bone marrow aspirations.
■ As long as iron stores are present and can be mobilized, the
serum iron, total iron-binding capacity (TIBC), and red cell
protoporphyrin levels remain within normal limits.
■ At this stage, red cell morphology and indices are normal.
 2 nd
Stage: IRON DEFICIENT
ERYTHROPOEISIS
■ Iron stores become depleted
– serum iron begins to decrease
– TIBC increases
– Red cell protoporphyrin levels increase
■ Marrow iron stores are absent when the serum ferritin level is <15 μg/L.
■ If Serum iron remains within the normal range, hemoglobin synthesis is unaffected
despite the dwindling iron stores.
■ Once the transferrin saturation falls to 15–20%, hemoglobin synthesis becomes
impaired.
3rd Stage: IRON DEFICIENCY ANEMIA

■ Evaluation of the peripheral blood smear reveals the first

appearance of microcytic cells,
■ hypochromic reticulocytes in circulation.
■ Gradually, the hemoglobin begins to fall, reflecting iron-
deficiency anemia.
■ The transferrin saturation at this point is <10–15%
■ With more severe anemia (hemoglobin 7–8 g/dL),
hypochromia and microcytosis become prominent
■ Appearance of target cells and misshapen red cells
(poikilocytes) on the blood smear as cigar- or pencil-shaped
forms
■ Erythroid marrow becomes increasingly ineffective.
■3 STAGES OF IRON DEFICIENCY
CAUSES OF IRON DEFICIENCY
 CLINICAL PRESENTATION OF IRON
DEFICIENCY
■ Cardinal rule is that the appearance of iron deficiency
in an adult male or post-menopausal female means
gastrointestinal blood loss until proven otherwise
■ Common signs of anemia—fatigue, pallor, and
reduced exercise capacity
■ Signs of advanced tissue iron
– Cheilosis (fissures at the corners of the mouth)
– koilonychia (spooning of the fingernails)
■ .
Iron-Deficiency Anemia
TREATMENT
■ RED CELL TRANSFUSION
– Indications
■ Symptoms of anemia
■ Cardiovascular instability
■ Continued and excessive blood loss.
 ORAL IRON THERAPY
■ 200 mg of elemental iron per day, usually as three or four iron tablets
– (1 tablet containing 50–65 mg elemental iron)
– Should result in the absorption of iron up to 50 mg/d.
– Some preparations combined designed to enhance iron absorption, such as
ascorbic acid.
– Taken on an empty stomach,
– Complications:
■ Gastrointestinal distress in 15-20% of patients
■ Abdominal pain, nausea, vomiting, constipation
■ Typically, the reticulocyte count should begin to increase within 4–7 days after
initiation of therapy and peak at 1–1. weeks.
■ Iron tolerance test - determine the patient’s ability to absorb iron
– 2 iron tablets are given on an empty stomach
■ serum iron is measured serially over the subsequent 2–3 h.
■ Normal absorption  increase in the serum iron of at least 100 μg/dL.
– If iron deficiency persists despite adequate treatment, it may be
necessary to switch to parenteral iron therapy
 PARENTERAL IRON THERAPY
■ Indications:
– Intolerance to oral iron
– In need of Iron correction in such cases as acute
persistent gastrointestinal or menstrual blood loss.
■ Parenteral iron is used in two ways:
– 1. Total dose of iron administered as required to correct
the hemoglobin deficit
■ Provides least 500 mg of iron stores;
– 2. Administer in repeated small doses of parenteral iron
over a protracted period.
■ Commonly used in dialysis centers
■ 100 mg of elemental iron to be given weekly for 10 weeks
to augment the response to recombinant EPO therapy.
■ The amount of iron needed by an individual patient is calculated by the
following formula:
– Body weight (kg) × 2.3 × (15 – patient’s hemoglobin, g/dL) + 500 or
1000 mg (for stores).

■ Complications of IV Iron preparations

– Anaphylaxis
– Arthralgias
– Skin rash
– Low-grade fever.
OTHER HYPOPROLIFERATIVE ANEMIAS
■ Chronic inflammation
■ Renal disease
■ Endocrine and nutritional deficiencies
(hypometabolic states)
■ Marrow damage
■ANEMIA OF ACUTE AND CHRONIC
INFLAMMATION/INFECTION (AI)
■ Associated with the release of proinflammatory cytokines
■ is one of the most common forms of anemia seen clinically
– low serum Iron
– Increased red cell protoporphyrin
– Hypoproliferative marrow,
– Transferrin saturation in the range of 15–20%
– Normal or increased serum ferritin.
■ANEMIA OF ACUTE AND CHRONIC
INFLAMMATION/INFECTION (AI)
■ Serum ferritin
– Increase threefold over basal levels in the face of inflammation
– These changes are due to the effects of inflammatory cytokines and
hepcidin, the key iron regulatory hormone, acting at several levels of
erythropoiesis
■ Interleukin 1 (IL-1)
– directly decreases EPO production in response to anemia.
– IL-1, acting through accessory cell release of interferon γ (IFN-γ),
suppresses the response of the erythroid marrow to EPO
■ IFN-β by marrow stromal cells
– suppresses the response to EPO.
■ Hepcidin
– increased in inflammation via an IL-6 mediated pathway
– and acts to suppress iron absorption and iron release from
storage sites.
■ Acute infection
– produce a decrease in hemoglobin levels of 2–3 g/dL
within 1 or 2 days;
– largely related to the hemolysis of red cells near the end
of their natural life span.
■ANEMIA OF CHRONIC KIDNEY DISEASE
(CKD)
■ Associated with a moderate to severe hypoproliferative anemia
■ The anemia is primarily due to a failure of EPO production by the diseased kidney
and a reduction in red cell survival
■ Red cells are typically normocytic and normochromic, and reticulocytes are
decreased.
■ Patients with the hemolytic-uremic syndrome increase erythropoiesis in response to
the hemolysis, despite renal failure
■ Usually normal serum iron, TIBC, and ferritin levels
■ Chronic hemodialysis develop iron deficiency from blood loss through
the dialysis procedure. Iron must be replenished in these patients to
ensure an adequate response to EPO therapy
■ANEMIA IN HYPOMETABOLIC STATES

■ The release of EPO from the kidney is sensitive to the need for O2, not
just O2 levels.
– EPO production is triggered at lower levels of blood O2 content in
disease states (such as hypothyroidism and starvation) where
metabolic activity, and thus O2 demand, is decreased
1. Endocrine Deficiency States
■ Testosterone and anabolic steroids augment erythropoiesis;
castration and estrogen administration to males decrease
erythropoiesis.

■ Hyperparathyroidism may be due to decreased EPO

production as a consequence of the renal effects of
hypercalcemia or to impaired proliferation of erythroid
progenitors
2. Protein Starvation
■ Decreased dietary intake of protein may lead to mild to moderate
hypoproliferative anemia; this form of anemia may be prevalent in the
elderly
■ In marasmus, where patients are both protein- and calorie-deficient, the
release of EPO is impaired in proportion to the reduction in metabolic
rate.
TREATMENT
Hypoproliferative Anemias
■ Many patients with hypoproliferative anemias experience recovery of normal
hemoglobin levels when the underlying disease is appropriately treated.
■ For those in whom such reversals are not possible— such as patients with end-stage
kidney disease, cancer, and chronic inflammatory diseases—symptomatic anemia
requires treatment.
■ The two major forms of treatment are transfusions and EPO.
TRANSFUSIONS

■ Indications:
– patients with serious underlying cardiovascular or pulmonary
disease cannot tolerate hemoglobin levels above 7–8 g/dL
 ERYTHROPOIETIN
■ EPO is particularly useful in anemias in which endogenous EPO levels are
inappropriately low, such as CKD or AI
■ In patients with CKD, the usual dose of EPO is 50–150 U/kg three times a week
intravenously
■ Hemoglobin levels of 10–12 g/dL are usually reached within 4–6 weeks if iron
levels are adequate; 90% of these patients respond.
■ A decrease in hemoglobin level occurring in the face of EPO therapy usually signifies
the development of an infection or iron depletion
■ chemotherapy-induced anemia in cancer patients
– Higher dose up to 300 U/kg three times a week, and only ∼60% of
patients respond.
END.

■ Reference:
– HARISSONS PRINCIPLES OF INTERNAL MEDICINE 20TH EDITION