Chapter 93: Iron Deficiency Anemia
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Page 683- 689
Hypoproliferative Anemias
Recycling of Iron from senescent cells:
- Hypoproliferative anemia:
o most common anemia
- When erythropoiesis is stimulated
- Iron deficiency anemia
o Most common type of Hypoproliferative
anemia
- Anemias associated with:
o Normocytic and normochromic red cells
o Reticulocyte index <2-2.5
- Categories of Hypoproliferative anemias
o Early iron Deficiency (IDA) (before
hypochromic & microcytic RBC develops)
o Acute and chronic inflammation
(including malignancies)
o Renal disease
o Hypometabolic states
(protein malnutrition and endocrine diseases)
o Anemia from marrow damage
Iron Metabolism
- Free iron
o Highly toxic element
o Is able to generate free radicals such as
O2 or OH- Major role of iron
o Carry oxygen as part of hemoglobin and
myoglobin
o Critical element in iron-containing enzymes
(including cytochrome system)
The iron cycle in humans
- Transferrin
o Is the iron transport protein
o Carries 2 forms of Iron (monoferric and
diferric)
- As long as transferrin is maintained between:
20-60% and erythropoiesis is not increased
o Use of iron stores is NOT REQUIRED
- Transferrin-bound iron
o Normal Half- Clearance time: 60-90 minutes
o In IDA: Half- Clearance time: is 10-15
minutes
o Normal turn over: 6-8 times per day
o Clearance time is affected by: plasma iron
level and erythroid marrow activity.
There is an Increase in iron requirements
when pool of erythroid cells increases
Decrease of clearance time of iron from the
circulation
Formation of Iron-Transferrin complex
Iron-Transferrin complex circulates in the
plasma and binds with transferrin receptors
Once binding occurs, complex is internalized
via clathrin-coated pits and transported to
an acidic endosome
Iron is then released at an acidic pH
Iron is made available for heme synthesis
Transferrin-receptor complex: is recycled to
the surface of the cell and later released
back to the circulation
In the erythroid cell: excess iron is stored as
Ferritin
In the liver parenchymal cells: iron becomes
incorporated in heme-containing enzymes
and stored
Iron incorporated into hemoglobin (Hgb)
enters the circulation as new RBC
Iron that is part of red cell mass: not made
available until red cell dies
Once RBC becomes senescent: they are
recognized by the reticuloendothelial system
Red cell undergoes phagocytosis leading to
Hgb breakdown
Globin is returned to amino acid pool
Iron is presented back to circulating
transferrin
Stimulation of erythropoiesis
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- Normal plasma iron level
o 80-100 ug/dl
- Transferrin receptors
o Are located on the surface of merrow
erythroid cells
- Developing erythroblasts
o The cell with the greatest number of
receptors (300,000-400,000/cells)
- Apoferritin + Excess Iron=
Ferritin (storage form)
- Average lifespan of RBC: 120 days
o Reticuloendothelial system (RES)
recognizes senescent RBC and is
responsible for RBC phagocytosis
- 1 ml of RBC contains
o 1 mg of elemental iron
- Amount of iron required from the diet to replace
losses vary in sexes:
o Men: 10% of body iron content per year
o Women of child bearing age: 15% of body
iron content per year
- Dietary iron content
o 6 mg of elemental iron per 1000 calories
- Average iron intake and absorption
o Male: 15 mg/d with 6% absorption
o Female: 11 mg/d with 12% absorption
o Individual with IDA: 20% absorption in meat
containing diet
o Vegetarian diet: 5-10% absorption
- Substances in a vegetarian diet that reduces iron
absorption
o Phytates
o Phosphates
- During the last 2 trimesters of pregnancy:
o Daily iron requirements: increase to 5-6 mg
- Daily elemental iron needs
o Adult male: 1 mg
o Female in child bearing years: 1.4 mg/d
Hemolytic anemia
- Iron absorption takes place in the:
o Duodenum
o Proximal small intestine
- Absorption of iron is facilitated by:
o Acidic contents in stomach (maintains iron in
solution)
-
Ferroportin
o Is a membrane-embedded iron exporter
o Function is regulated by hepcidin
- Hepcidin
o Is the principal iron regulatory hormone
- Hephaestin:
o Is responsible for oxidizing the iron to the
ferric form for transferrin binding
- IF delivery of iron to stimulated marrow is
SUBOPTIMAL
o Marrow proliferative response: blunted
o Hemoglobin synthesis is impaired
o Resulting to: Hypoproliferative marrow
+Microcytic and Hypochromic anemia
Nutritional Iron Balance
- Routes of iron supplementation for the body:
o Absorption from food and medicinal iron
(PO)
o Red cell transfusion
o Ingestion of iron complexes
- Factors that influence iron absorption
o Erythroid hyperplasia: stimulates iron
absorption (even in normal or increased iron
stores and low hepcidin levels)
- In patients with high levels of ineffective
erythropoiesis
o There is excess absorption of dietary iron
o Molecular mechanism: production of
erythroferrone (ERFE) by developing
erythroblast
ERFE suppresses hepcidin
Increase absorption of dietary iron
Leading to: iron overload and tissue damage
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- In patients with acute iron toxicity: due to
ingestion of large number of iron tables
3. Iron Deficiency Anemia
- Defined as:
o Once transferrin saturation is
<10-15%
o In excessive intake of medicinal iron
Percentage of iron absorbed decreases BUT
absolute amount of iron goes up
Amount of iron absorbed exceeds transferrin
binding capacity of the plasma
Increase of free iron in blood stream
Leading to iron toxicity in critical organs such
as cardiac muscle cells.
- When iron stores are depleted (Serum
ferritin <15 ug/L)
o Serum Iron: falls
o TIBC: increases
o Red cell protoporphyrin: increases
Anemia
Iron Deficiency Anemia
- 50% of anemia is attributed to iron deficiency
- IDA
o Most prevalent form of malnutrition
Stages of Iron Deficiency
Three stages of progression to iron Deficiency
1. Negative Iron Balance
- Demands of iron exceed the body’s ability to
absorb iron
- Physiologic mechanism of this:
o Blood loss
o Pregnancy
o Rapid growth spurts in adolescent
o Inadequate dietary iron intake
- In severe prolonged IDA:
o Development of erythroid hyperplasia of
the marrow
Causes of Iron Deficiency
- Blood Loss of 10-20 ml of RBC per day
o Greater than the amount of iron that the
gut can absorb from a normal diet
- Iron stores or Ferritin levels
o Low
- Appearance of stainable iron on bone
o Low
- When Iron stores are still present:
o Serum iron: normal levels
o total iron-binding capacity (TIBC): normal
levels
o red cell protoporphyrin: normal levels
o Red cell morphology: normal
- As long as iron remains within normal limits: Hgb
synthesis is unaffected
2. Period of Iron- Deficient
Erythropoiesis
- Defined as:
o Once transferrin saturation is:
15-20%
- There is impairment of Hgb synthesis
- Peripheral blood smear (PBS): first
appearance of microcytic cells
- Presence of hypochromic reticulocytes
Clinical Presentation of Iron Deficiency
- IDA in adult male or post-menopausal
female women means:
o Gastrointestinal blood loss UNTIL
proven otherwise
- Usual signs of anemia
o Fatigue
o Pallor
o Reduced exercise capacity
- Signs of advanced tissue iron deficiency
o Cheilosis (fissure at the corners of the
mouth)
o Koilonychia (spooning of the fingernails)
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Laboratory Iron Studies
Serum Iron and Total Iron Binding Capacity
- Serum iron level
o Represents: amount of circulating iron bound to
transferrin
o Normal range: 50-150 ug/dL
o May have diurnal variation
- TIBC
o Indirect measure of the circulating transferrin
o Normal range: 300-360 ug/dL
- Transferrin saturation
o Normal value: 25-50%
o In IDA: <20%
o In Tissue iron overload: >50%
(disproportionate amount of iron bound to
transferrin being delivered to nonerythroid
tissues)
o Formula: Serum Iron x100 divided by TIBC
Serum Ferritin
- In the cells
o Iron is stored and complexed to proteins as
ferritin or hemosiderin
- Apoferritin
o Binds to free ferrous iron and stores it in ferric
form.
As ferritin accumulates within the cells of RES
Protein aggregates becomes hemosiderin
- In states of blockage of release of iron from
storage sites:
o RE iron will be detected
o Few or no Sideroblasts detected.
- In myelodysplastic syndrome
o Have mitochondrial dysfunction
o (+) Ring Sideroblast: represents
accumulation of iron in mitochondria
that appears in a necklace fashion
around the nucleus of the erythroblast.
Red Cell Protoporphyrin Levels
- Protoporphyrin
o An intermediate in the pathway to heme
synthesis
o Normal value: <30 ug/dL of RBC
o In IDA: >100 ug/dL
- Increased protoporphyrin within RBC is seen
in:
o Impairment of heme synthesis
- Most common causes that result in
Increased protoporphyrin within RBC
o absolute or relative iron deficiency
o Lead poisoning
- Increase protoporphyrin in RBC reflects:
o Inadequate iron supply to erythroid
precursors to support hemoglobin
synthesis
- Under steady state conditions
o Serum ferritin levels correlate with total body
iron stores
Serum Levels of Transferrin Receptor Protein
- Erythroid cells have highest number of
transferrin receptors in the body
- Serum ferritin:
o most convenient test to estimate iron stores
o Adult male normal level: 100 ug/L
o Adult female normal level: 30 ug/L
o Ferritin level <15 ug/L: diagnostic of absent
body iron stores
o Better indicator of iron overload compared
to marrow iron stain
- Serum Transferrin Receptor Protein (TRP)
o Reflects the total erythroid marrow
mass
o Normal values: 4-9 ug/L
Evaluation of Bone Marrow Iron Stores
- RE iron stores:
o Estimated by iron staining of bone marrow
aspirate or biopsy
- Marrow iron staining
o Provides information about the effective delivery
of iron to developing erythroblast
- Condition that has elevated serum TRP
o Absolute Iron Deficiency
Differential Diagnosis
- Differential diagnosis for hypochromic
microcytic anemia:
o IDA
o Thalassemia
o Anemia of Inflammation aka Anemia of
chronic disease
o Myelodysplastic Syndromes
o Sideroblasts: are 20-40% of developing
erythroblasts that have visible ferritin granules
o Ferritin granules: represent iron in excess
that is needed for hemoglobin synthesis
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Treatment of IDA
- Severity and cause of IDA: determines the approach to
patient
- Elderly with severe IDA and cardiovascular instability
o RBC transfusion
- Younger patients that can compensate for their anemia
o Iron replacement
- For unusual blood loss or malabsorption
o Do specific tests
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Red cell transfusion
- Reserved for individuals who have:
o Symptoms of anemia
o Cardiovascular instability
o Continued and excessive blood loss
- Corrects anemia acutely
- Transfused RBC provide iron source for
reutilization
- Iron Tolerance test
o Test done in the clinic to determine
patient’s ability to absorb iron
o Procedure: 2 Iron tablets are given on an
empty stomach and serum iron is
measured serially over 2-3 hours
o Normal absorption will result in: Increase in
the serum iron of at least 100 ug/dL
- If IDA persist despite adequate treatment
o May be necessary to switch to parenteral
therapy
Oral iron therapy
- Reserved for the following patients
o Established IDA
o Intact gastrointestinal tract
- Ascorbic acid
o Enhances iron absorption
- Daily dosing:
o 200 mg of elemental iron per day
o 200 mg of elemental iron per day, only
has iron absorption up to 50 mg/day
o About 3-4 iron tablets containing 50-65
mg elemental iron
o Should be taken on an empty stomach
- Patients who with gastric disease or prior
gastric surgery:
o Needs special treatment with iron solution
o These subsets of patients have reduced
retention capacity of the stomach that is
necessary to dissolve the shell of the iron
before iron release
Parenteral Iron therapy
- Given to patients:
o unable to tolerate oral therapy
o Needs are relatively acute
o Who need iron on an ongoing basis
o Due to persistent GI or menstrual blood
loss
- Erythropoietin (EPO) therapy
o Induces a large demand for iron that
cannot be met by physiologic release of
iron from RE source or oral iron absorption
o Needs adjunct Parenteral iron therapy
- Goal of therapy in IDA
o Repair the anemia
o Provide iron stores of at least 0.5-1
gram of iron
- Sustained treatment for IDA:
o Continuing for 6-12 months after
correction of anemia may be necessary to
provide the iron stores of 0.5-1 gram of
iron.
- Complications of oral iron therapy:
o Gastrointestinal distress: most
common & seen in 15-20% of patients
Abdominal pain, nausea, vomiting or constipation:
leads to non-compliance
- Response to iron therapy
o Reticulocyte count begins to increase within
4-7 days after initiation of therapy
o Reticulocyte count increase peaks at 1-1/2
weeks post initiation
- Parental Iron is used in two ways:
o Administer the total dose of iron required
to correct the hemoglobin deficit and
provide patient with at least 500 mg of
iron stores
o Give repeated small doses of parenteral
iron over a protracted period (in dialysis
centers)
- In dialysis centers:
o Give 100 mg of elemental iron to be
given weekly for 10 weeks to augment
the response of recombinant EPO
- Formula used to calculate the amount of
iron needed by patients
o Body weight (kg) x 2.3 x (15-patient’s
Hgb, g/dL) +500 or 1000 mg (for stores)
- Absence of response to iron therapy
o Due to poor absorption
o Non compliance
o Confounding diagnosis
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- Side effects:
o Anaphylaxis: much rarer in new formulations
o Arthralgias, skin rash and low-grade fever:
appears after several days after infusion of a
large dose of iron; dose related side effect
- To prevent side effects of giving large dose (>100
mg) of LMW iron dextran
o Dilute the iron preparation in 5% dextrose in
water or 0.9% NaCl solution
o Iron solution be infused over a 60-90 minute
period
o Give test dose of 25 mg of parenteral LMW iron
dextran
o If presence of chest pain, wheezing, a fall in BP:
stop iron transfusion
Other Hypoproliferative anemias
- Hypoproliferative anemias can be divided into 4
categories
o Chronic inflammation
o Renal Disease
o Endocrine and nutritional deficiencies
(hypometabolic states)
o Marrow damage
- Pathophysiology underlying the Hypoproliferative
anemias:
o Inadequate endogenous EPO production:
chronic inflammation, renal disease or
hypometabolism
o Inadequate response of erythroid marrow to
stimulation due to defective iron reutilization:
anemia of chronic inflammation
- When there is inadequate endogenous EPO
production
o Results in polychromatophilic “shift” reticulocyte
seen in the peripheral blood smear
Anemia of Acute and Chronic Inflammation/ Infection
(AI)
- Includes the following conditions:
o Inflammation
o Infection
o Tissue Injury
o Cancer- releases proinflammatory cytokines
- Serum ferritin values
o Most distinguishing feature: typically, serum
ferritin values increase threefold over basal
levels in the face of inflammation
- Changes seen in AI is due to:
o Inflammatory cytokines and hepcidin
o IL-1: decreases EPO production in
response to anemia
o TNF: suppresses the response of bone
marrow to EPO
o Hepcidin is increased and is made by
the liver via IL-6 mediated pathway
o Hepcidin: suppress iron absorption and
iron release from storage sites.
- With chronic inflammation: Primary disease
will determine the severity and
characteristics of anemia
o Cancer: normocytic and normochromic,
Hypoproliferative marrow
o Longstanding and active rheumatic
arthritis and TB: microcytic and
hypochromic anemia, Hypoproliferative
marrow
- With acute inflammation
o Have a decrease in Hgb level of 2-3 g/
dL within 1 or 2 days: due to hemolysis
o Fever and cytokines: exert pressure on
RBC limited capacity to maintain red
cell membrane hemolysis of RBC
- In patients with preexisting cardiac disease:
Moderate anemia Hgb 10-11 g/dl associated
with
o Angina
o Exercise intolerance
o Shortness of breath
Anemia of Chronic Disease (CKD)
- Associated with moderate to severe
hypoproliferative anemia
- Level of anemia correlates with the stage of
CKD
- Due to:
o the failure of EPO production by the
diseased kidney
o Reduction in red cell survival
- In patients with hemolytic-uremic
syndrome
o Have increased erythropoiesis in
response to hemolysis (despite renal
failure)
- In patients with polycystic kidney disease
o Have a smaller degree of EPO
deficiency for a given level of renal
failure
- In patients undergoing chronic
hemodialysis
o Iron must be replenished: to ensure
adequate response to EPO
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Anemia in Hypometabolic States
- Seen in patients with:
o Starvation states and protein deficiency
o Endocrine disorders that produce lower
metabolic rates (hypothyroidism)
- EPO production is triggered by: lower levels of
blood oxygen content in disease states
In Endocrine deficiency states
- Difference in levels of Hgb between men and
women is due to:
o Effects of androgen and estrogen on
erythropoiesis
- Factors that decrease erythropoiesis:
o Castration
o Estrogen administration to males
- Development of mild anemia is due:
o Nutritional deficiencies because iron and folic
absorption is affected in hypothyroid and
patients with deficiency in pituitary hormone
o Anemia is corrected when hormone deficiency
is corrected
- In Addison’s disease
o Anemia may be more severe
o Severity of anemia depends on: level of thyroid
and androgen hormone dysfunction
o Anemia may be masked by decreases in
plasma volume
o Once patients are given cortisol and volume
replacement: this leads to fall in Hgb
- In hyperparathyroidism, mild anemia is due to
o Decreased EPO production as a renal effect of
hypercalcemia
o Impaired proliferation of erythroid progenitors
Anemia in liver disease
- Have mild hypoproliferative anemia
- Peripheral blood smear shows: spur cells and
stomatocytes
o Spur cells and stomatocytes are from the
accumulation of excess cholesterol in the
membrane
o Accumulation of cholesterol in the
membrane is due to: deficiency of lecithincholesterol acyltransferase
- Red cell survival: shorted
o Production of EPO is inadequate to
compensate for this
- Associated nutritional deficiencies:
o Folate deficiency: inadequate intake
o Iron deficiency: due to blood loss and
inadequate intake
Anemia of aging
- Common in people over 65 years old
- Patients with unexplained anemia of aging DO
NOT HAVE
o Nutritional deficiency
o Renal dysfunction
- Older people have increased cytokines
(inflammation of aging)
o but not high enough to mimic anemia of
chronic inflammation
- Probable underlying pathophysiology of anemia
of aging
Decrease red cell survival in older people
EPO is in a normal range, which is
inappropriately low for the Hgb levels
In protein starvation
- Decreased dietary intake of protein
o Leads to: mild to moderate hypoproliferative
anemia (seen in elderly)
o Anemia is more severe in patients with greater
degree of starvation
- In Marasmus
o Patients have both protein and calorie
deficiency
o The degree of impaired release of EPO is
proportion to the reduction of metabolic rate
o Degree of anemia is masked by: volume
depletion
o Degree of anemia becomes apparent after:
refeeding
o Changes in RBC indices on refeeding should
prompt evaluation of iron, folate and B12
status
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Treatment for Hypoproliferative Anemia
- Reversal of hypoproliferative anemia is not possible
in the following diseases
o End stage kidney disease
o Cancer
o Chronic inflammatory diseases
Transfusion
- Threshold of transfusion is based on patient’s
symptoms
o NO cardiovascular or pulmonary disease: <7-8
mg/dl
o With physiologic compromise <10 g/dl
- 1 unit of PRBC
o Increases hemoglobin by 1 g/dL
- Darbepoetin alfa
o a longer preparation of EPOreduces
frequency of injection
o a molecularly modified EPO with
additional carbohydrate
o Half-life: 3-4 times longer than
recombinant human EPO
o Dosing: May be given weekly or every
other week
- Oral EPO mimetics
o Increases the biological half-life of active
hypoxia-induced factor (HIF)
o Shown to increase Hgb in patients with
CKD
- Associated with:
o Infectious risk
o Iron over load (in chronic transfusion)
Erythropoietin
- Given when endogenous EPO level is
inappropriately low (CKD or AI)
- Iron status should be evaluated
o Iron replacement should be given: to attain
optimal effects from EPO
- In CKD patients
o EPO is given: 50-150 U/kg three times a week
IV
o 90% of patients respond to EPO
o Hemoglobin levels of 10-12 g/dL are reached
within 4-6 weeks
- A decrease in Hgb level in the face of EPO therapy
means:
o Infection
o Iron depletion
- Factors that can compromise the response to EPO
o Aluminum toxicity
o Hyperparathyroidism
- During Infection:
o Stop EPO therapy
o Rely on transfusion to correct anemia UNTIL
infection is treated
- To correct chemotherapy- induced anemia in cancer
patients
o EPO: 300 U/kg three times a week
o Only 60% of patients responds to EPO
- Various risks associated with EPO administration
o Thromboembolic complication
o Tumor progression
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