ce April 2017

Continuing Education
L E S S O N

Learning Objectives
Upon successful completion of the
lesson, the pharmacist will be able to
do the following:
1. Understand the prevalence and
etiology of iron deficiency anemia
2. Understand and apply diagnostic
tools to detect iron deficiency
anemia
3. Identify symptoms and risk factors
Answer online at eCortex.ca

By Victor Wong, Bsc(Pharm), PharmD and Lucy Wang, MPharm

Approved for

Approved for 1 CE unit by the Canadian Council on Continuing Education in Pharmacy • CCCEP #1065-2016-1723-I-P • Not valid for CE credits after April 10, 2018

TOPIC

Iron Deficiency Anemia

1.0
CEU

The author, expert reviewers and EnsembleIQ have each declared that there is no real or potential conflict of
interest with the sponsor of this CE lesson.

world, being most prevalent among women

of reproductive age and growing children.
for iron deficiency anemia
Furthermore, iron deficiency anemia in
4. Apply evidence-based treatment the elderly significantly increases morbidity
options to manage iron deficiency and mortality, while anemia itself is found
anemia to be an independent risk factor for mortal-
5. Discuss the pharmacist’s role in ity in patients with chronic kidney disease
managing anemia and heart failure.(3)
The dangers of iron deficiency anemia
are not just present in the elderly or chroni-
Instructions cally ill, but in infants and adolescents as
1. After carefully reading this lesson, well. In growing children and adolescents,
study each question and select iron deficiency has been linked to irrevers-
the one answer you believe to ibly poor growth of both stature and brain
be correct. Answer online at function.(4–7)
eCortex.ca In pregnancy, iron deficiency anemia
2. To pass this lesson, a grade of at Background has been linked to premature delivery, low
least 75% (6 out of 8) is required. Anemia is defined as a “reduced concentra- birth weight, and an increased risk of peri-
If you pass, your CEU(s) will tion of hemoglobin in the blood.”(1) Hemo- natal infant mortality.(5)
be recorded with the relevant
globin is a vital protein in red blood cells From a socioeconomic perspective,
provincial authority(ies). (Note:
that helps to carry oxygen from the lungs iron deficiency anemia impairs work-
to tissues and organs throughout the body. place productivity and quality of life, with
some provinces require individual
Individuals with anemia have inadequate recent studies drawing strong correlations
pharmacists to notify them.)
levels of hemoglobin resulting in insuffi- between low iron and depression.(8)
cient distribution of oxygen and higher risk The prevalence and comorbidities of iron
of associated morbidity and mortality. Iron deficiency anemia warrants heightened
is an essential component of hemoglobin, awareness by pharmacists to identify symp-
necessary for growth, development and toms of the disease, recommend appro-
normal cellular functioning. Most of the priate therapy, monitor for therapeutic
Answer online at eCortex.ca 3 to 4 grams of elemental iron in the body efficacy, and monitor for undesirable side
is found in hemoglobin. Iron deficiency effects that may increase non-adherence

·ca
anemia is an insufficiency in hemoglobin and therapeutic failure.
secondary to low iron stores.(2)
F O N T: H E LV E T I C A N E U E 7 5 B O L D ( M O D I F I E D )

C YA N 5 0 , Y E L L O W 1 0 0
More than one quarter of the world’s Pathophysiology
M A G E N TA 1 0 0

C YA N 1 0 0 population is anemic, with one half of Iron deficiency anemia occurs when iron
that burden being iron deficiency anemia. intake can no longer adequately support
Currently, iron deficiency anemia is the iron expenditure or loss.(1) Iron homeosta-
most common nutritional disorder in the sis is particularly unique because the body

Supported by an educational grant from Aralez Pharmaceuticals Inc.

ce
CE2
Continuing Education
L E S S O N

has no mechanism to actively excrete

iron, with the balance of iron stores being
solely dependent on iron absorption.(1)
In most clinical settings, restricted
since iron stores may not be released
quickly enough to meet the increased
demands of erythropoiesis.(2)
April 2017
Iron Deficiency Anemia

Answer online at eCortex.ca

Finally, food and medications (e.g. PPIs

which impair absorption) may impair
the absorption of iron, particularly non-
heme iron salts.(10) Specifically, the con-
erythropoiesis is the most important CAUSES OF IRON DEFICIENCY tent of calcium in a meal reduces absorp-
cause of anemia secondary to reduced Iron loss due to natural desquamation tion of iron, and the content of phytate
availability of iron. There are two main of mucosal cells, including the natural in bran, oats and rye fiber, polyphenols
causes of iron-restricted erythropoiesis: shedding of GI lining, and excretion via in tea and some cereals, and soy protein
absolute iron deficiency, and functional urine and feces, accounts minimally to reduce the absorption of iron salts.(2,11–13)
iron deficiency.(2) the daily loss of iron (~1 g/day), and an Less commonly, individuals may have a
In absolute iron deficiency, iron stores additional 2 mg of iron is lost per day due genetic predisposition to low iron.(2)
in the bone marrow, liver and spleen are to menstruation.(1) In fact, the human
absent and thus unavailable for normal body is so efficient at preserving iron Presentation and Diagnosis
rates of erythropoiesis.(2) This results in the stores that the daily requirement for iron Iron deficiency commonly presents with
reduced production of hemoglobin. Abso- in a normal, healthy individual is 5 mg symptoms including fatigue, weakness,
lute iron deficiency is usually caused by for males, 15 mg for growing children, headache, tachycardia and decreased
poor intake of dietary iron, decreased iron and 15 mg for menstruating women.(1) immunity. Signs may include pallor,
absorption, and/or increased blood loss.(2) Hence, the body of a regular, healthy smooth tongue, angular cheilitis and
In functional iron deficiency, ane- individual is able to replenish iron stores koilonychia (a nail disease).(2) However,
mia occurs despite having normal or through dietary iron alone.(1,9) many individuals are asymptomatic or
increased body iron stores due to insuf- In contrast, abnormal decreases in may not identify that their symptoms
ficient iron available for erythroid pre- iron stores leading to iron deficiency are are secondary to anemia. As a result,
cursors.(2) This is most common during generally a result of blood loss, decreased anemia is insidious and often presents
situations of inflammation such as infec- iron absorption and ingestion, food and with symptoms related to exacerbation
tion, inflammation or malignancy.(2) In medications. of an underlying co-morbidity, such
these situations, iron is released back into Blood loss is the most common cause as increasing angina from coronary
circulation by macrophages, making iron of iron deficiency in developed countries artery disease, dyspnea in patients with
less available for red cell production.(2) and may be overt (visible by the patient congestive heart failure, or are discovered
Alternatively, individuals being treated or physician) or occult (not visible by during routine blood tests.(2) In children
with erythropoiesis-stimulating agents patient or physican, such as gastrointes- and infants, there may be symptoms of
may also have functional iron deficiency tinal bleeding).(2) Furthermore, drugs neurodevelopmental delay.(4,5,7,14)
that may increase gastrointestinal bleed- Studies on long-term anemic patients
F I G U R E 1 Iron input and output ing risk should be suspected in cases of have suggested cognitive and motor
from the body occult blood loss.(2) These include agents impairment specifically in language and
such as NSAIDS, anti-coagulants, anti- coordination.(4,5,7,14) It is still unknown if
Iron absorption platelets, and SSRIs. there can be reversal of these symptoms
1-2 mg Decreased ingestion of iron leading to with treatment.
deficiency is observed in individuals with
dietary restrictions, such as vegetarians and DIAGNOSIS
30 mg 30 mg vegans or other meat-restricted diets. Situ- An examination of a patient’s history and
Plasma
ations of malabsorption include gastritis, analysis of red blood indices are used
Celiac disease and gastric bypass surgery.(2) to make a diagnosis of iron deficiency

Tissues
FIGURE 2 Detailing the multiple signs and symptoms of anemia
Anorexia Nausea
Exertional Increased
Chest pain dyspnea pulse pressure,
Fatigue Gastrointestinal systolic ejection
Loss system murmur
1-2 mg Risk of life
threatening
Depression Central nervous system cardiac failure Cardiovascular Tachycardia
system palpitations

Impaired cognitive Cardiac

function Signs and symptoms enlargement
Bone marrow: Storage in of anemia hypertrophy
in red blood cell mononuclear
precursors 6 mg phagocytes Low skin
Vascular tempertaure
Immune system system
Impaired T-cell
Hemoglobin in and macrophage Genital tract
red blood cells function
24 mg 24 mg Pallor of skin, mucous
membranes, and
Loss of libido Menstrual problems conjunctiva
Adapted from Rang and Dale’s Pharmacology(1)
Adapted from Therapeutic Choices: Common Anemias(15)
Iron Deficiency Anemia

Answer online at eCortex.ca

TA B L E 1
Increased Requirements
• Growing infants and children
• Menstruating women
April 2017

Causes of iron deficiency anemia.

Decreased Intake
• Low socioeconomic status
• Vegetarian diet
ce Continuing Education
L E S S O N

TA B L E 2 Health Canada recommended

daily intake of elemental iron.
Recommended Dietary
Allowance (mg per day)
CE3

• Pregnancy • Lack of balanced diet or poor intake

• Lactation • Alcoholism Infants
• Multiparity • Elderly 0-6 months 0.27
• Parturition • High risk ethnic groups (First Nations, Indo-Canadians*)
7-12 months 11
Increased Loss Decreased Absorption
• Menorrhagia • Dietary factors (tannins, phytates in fiber, calcium in
Children
• GI bleeding milk, tea, coffee, carbonated drinks) 1-3 years 7
• Regular blood donors • Upper GI Pathology:
• Post-operative patients with significant blood loss - Chronic gastritis 4-8 years 10
• Hematuria - Gastric lymphoma
• Intestinal parasites (travel or immigration from an - Celiac disease Males
endemic area) - Crohn’s disease
• Intravascular hemolysis: hemoglobinuria • Medications that decrease gastric acidity or bind iron 9-13 years 8
• Extreme physical exercise (endurance athletes) • Gastrectomy or intestinal bypass
• Pathological (hemolytic anemias) • Duodenal pathology 14-18 years 11
• Chronic renal failure patients Greater than 18 years 8
Taken directly from British Columbia Ministry of Health guidelines for iron deficiency anemia.(11)
Females
anemia. There are different benefits and measure of the body’s iron stores. A vast 9-13 years 8
limitations to some of the commonly majority of iron deficiency anemia guide-
14-18 years 15
used lab values. lines around the globe recommend the
measurement of serum ferritin concen- 19-50 years 18
Hemoglobin Count trations as the primary diagnostic tool Greater than 50 years 8
Hemoglobin count is a measure of the for iron deficiency anemia.(8)
amount of hemoglobin in grams per liter Though guidelines around the world Pregnant 27
unit of blood. Since anemia is defined as a cite differing threshold values, a serum Breastfeeding
reduction in hemoglobin concentration, ferritin of below 30ug/L is generally
14 – 18 years 10
hemoglobin count is a direct, defining accepted as an indicator for true iron
measurement for the diagnosis of ane- deficiency.(15) The benefits to measuring 19 – 50 years 9
mia.(16) Current Canadian standards state serum ferritin include its universal acces- Taken directly from the CPhA monograph for oral iron
that a patient is anemic if their hemoglo- sibility and its high standardization and preparations.(22)
bin count is less than 135g/L in men and specificity, making it highly reliable.(16)
less than 120g/L in women.(15) The only drawback to measuring Treatment
Currently, hemoglobin count is not ferritin serum levels is false negatives Regardless of the presence or absence of
recommended as the sole diagnostic mea- due to the presence of inf lammatory symptoms, all patients with iron defi-
surement for the diagnosis of iron defi- disorders. (18,19) It is well documented ciency anemia should be treated because
ciency anemia due to its low specificity.(16) that ferritin levels rise in patients the risk of associated morbidity and pro-
Instead, hemoglobin count is only seen as with inf lammatory conditions. There- gression of anemia will continue until
a “red flag” to begin further investigation. fore, patients with active infections adequate iron stores are replenished.
or experiencing active inf lammation Current standard of care suggests a two-
Mean Corpuscular Volume could be anemic despite having ferritin part treatment protocol. The first step is
Mean corpuscular volume (MCV) is levels as high as 100µg/L. (19) To date, to find and alleviate the underlying cause
the average volume of red blood cells there is no universal conversion factor of anemia.(20) Once the underlying cause
expressed in femtoliters.(3) Superior to that accurately accounts for higher fer- of the iron loss has been established and
hemoglobin count in terms of specific- ritin levels in this patient population. (18) addressed, the second step is to replenish
ity, MCV is typically the second test that the patient’s iron stores via supplementa-
would be performed in the differential Transferrin Saturation tion.(20) Only patients with severely symp-
diagnosis of anemias.(16) Iron deficiency Transferrin saturation can be seen as an tomatic iron deficient anemia (e.g., symp-
anemia present with microcytic cells alternative or complementary measurement toms of myocardial ischemia) should be
(smaller than normal cells yielding low for the diagnosis of iron deficiency treated with red blood cell infusion.(21)
MCV values).(3) Patients with iron defi- anemia.(8) It is expressed as a ratio of
ciency anemia commonly have MCV val- plasma iron to total iron binding capacity. DIETARY IRON AND IRON HOMEOSTASIS
ues fall below 80 fl.(9) This is a relatively Though sub-optimal due to its large diurnal A typical western diet provides approxi-
late change in lab values and limits our variation and low specificity, transferrin mately 15-20 mg of iron.(1) It is encouraged
opportunity for early detection. saturation proves to be particularly useful that individuals consume enough dietary
in diagnosing iron deficiency anemia iron daily to replenish low iron stores.
Ferritin Concentration in patients with inflammatory disorders See Table 2 for Health Canada’s recom-
Ferritin is a form that iron takes when or infection.(16) Thresholds of transferrin mended daily allowance of elemental iron
being stored intracellularly.(13,17) There- saturation to determine iron deficiency in healthy individuals. Many food sources
fore, ferritin concentration is a direct range between 15-20%.(8) have good sources of iron.
ce
CE4
Continuing Education
L E S S O N

Dietary iron exists in two forms: heme

iron and non-heme iron. Heme iron is
derived from the hemoglobin and myo-
globin of animals and is obtained through
TA B L E 3
Food
Amount of iron found in common foods.

Breakfast cereals, fortified with 100% of the DV for iron, 1 serving

April 2017
Iron Deficiency Anemia

Answer online at eCortex.ca

Milligrams per serving

18
Percent DV*
100
meat products. The richest sources of Oysters, eastern, cooked with moist heat, 3 ounces 8 44
heme iron are found in lean meats and White beans, canned, 1 cup 8 44
seafood.(17) Heme iron is more efficiently Chocolate, dark, 45%–69% cacao solids, 3 ounces 7 39
absorbed (15-35%) than non-heme iron Beef liver, pan fried, 3 ounces 5 28
and thus contributes to greater than
40% of total absorbed iron in a non-veg- Lentils, boiled and drained, ½ cup 3 17
etarian diet.(24,25) Conversely, non-heme Spinach, boiled and drained, ½ cup 3 17
iron can be found from plant and ani- Tofu, firm, ½ cup 3 17
mal byproducts, such as milk, and much Kidney beans, canned, ½ cup 2 11
more difficult to absorb in the body
Sardines, Atlantic, canned in oil, drained solids with bone, 3 ounces 2 11
(2-20%).(26) Nuts, beans, vegetables and
fortified grain products contain the most Chickpeas, boiled and drained, ½ cup 2 11
non-heme iron. Tomatoes, canned, stewed, ½ cup 2 11
In general, more iron is absorbed when Beef, braised bottom round, trimmed to 1/8” fat, 3 ounces 2 11
iron stores are low, and less when stores Potato, baked, flesh and skin, 1 medium potato 2 11
are high.
Absorption mechanisms for heme iron Cashew nuts, oil roasted, 1 ounce (18 nuts) 2 11
vs. non-heme iron differ greatly. In order Green peas, boiled, ½ cup 1 6
to fully understand both the pathophysi- Chicken, roasted, meat and skin, 3 ounces 1 6
ology and treatment of iron deficiency Rice, white, long grain, enriched, parboiled, drained, ½ cup 1 6
anemia, we must first understand the
Bread, whole wheat, 1 slice 1 6
mechanisms responsible for iron absorp-
tion. The current up to date absorption Bread, white, 1 slice 1 6
mechanisms for non-heme and heme iron Raisins, seedless, ¼ cup 1 6
are depicted in figures 3 and 4, respec- Spaghetti, whole wheat, cooked, 1 cup 1 6
tively. It is recommended that the learner Tuna, Bluefin, fresh, cooked with dry heat, 3 ounces 1 6
reviews these pathways extensively in
order to grasp a full understanding of the Turkey, roasted, breast meat and skin, 3 ounces 1 6
risk and benefits of available iron prepara- Nuts, pistachio, dry roasted, 1 ounce (49 nuts) 1 6
tions, as discussed below. Broccoli, boiled and drained, ½ cup 1 6
Though the mechanism by which Egg, hard boiled, 1 large 1 6
heme-iron is absorbed into circulation is
Rice, brown, long or medium grain, cooked, 1 cup 1 6
still being studied, the bottom line is clear:
heme iron is absorbed more efficiently into Cheese, cheddar, 1.5 ounces 0 0
circulation via an alternate pathway com- Cantaloupe, diced, ½ cup 0 0
pared to non-heme iron.(13,17,26) Mushrooms, white, sliced and stir-fried, ½ cup 0 0
Cheese, cottage, 2% milk fat, ½ cup 0 0
IRON SUPPLEMENTS
Milk, 1 cup 0 0
Currently, there are several types of iron
preparations available on the market: Taken directly from the U.S. Department of Health and Human Services’ fact sheet on iron.(23)
* DV = Daily Value. The DV for adults and children 4 and above is 18 mg.
heme and non-heme oral iron products,
and IV iron. The choice between these
supplements depends upon the cost and into three daily doses.(15) Patients are to such as nausea, dyspepsia and constipa-
availability of the products, tolerability be treated until three months after they tion are most commonly seen with the
of the patient to the oral preparation, reach a hemoglobin count of greater use of oral iron salts. Some individuals
and any functional restrictions that the than 135 g/L for men and greater than may require additional management of
patient may have that may alter absorp- 120 g/L in women in order to replenish constipation using high-fiber diet or laxa-
tion of iron. iron stores.(29) tives. Though these adverse reactions are
The benefits of oral iron salts include typically dose related, the resulting conse-
Oral Iron Salts their accessibility, low cost, general effi- quence is a high rate of patient discontin-
The current mainstay of therapy comes cacy and safety.(21) In addition, having uation and non-adherence to therapy.(26)
in the form of oral iron salts.(15,19) Recom- been used for several decades in the treat- Up to 70 percent of patients who are pre-
mended iron salt preparations include fer- ment of iron deficiency anemia, safety scribed iron salts, especially ferrous sul-
rous gluconate, ferrous sulfate and ferrous and efficacy data pertaining to oral iron fate, report gastrointestinal side effects.(26)
fumarate. Of these three salts, their elemen- salts are well known and documented. Another major disadvantage of oral
tal iron contents are depicted in Table 4. Drawbacks of oral iron salt therapy iron salts is their low oral bioavailabil-
Current guidelines recommend 105- include low tolerability and absorp- ity. This unfavorable absorption profile
200 mg of elemental iron per day, divided tion.(9,15,16,19,30) Gastric adverse reactions is due to the fact that non-heme iron is
Iron Deficiency Anemia

Answer online at eCortex.ca

TA B L E 4
Iron Salt
Ferrous fumarate
April 2017

Content of elemental iron in common oral iron salt preparations.

Percent of Elemental Iron (%)
33
Salt Strength (mg)
300
ce
Elemental Iron Content (mg)
99
Continuing Education
L E S S O N

TA B L E 5 Estimated total dose of

absorbed iron needed for anemia
correction based on hemoglobin values.
Hemoglobin (g/dL) Absorbed iron total dose (mg)
CE5

Ferrous gluconate 11.6 300 36

Ferrous sulfate 20 300 60 Greater than 11 500
Ferrous sulfate, dried 30 300 90 9-11 1000
Taken directly from the CPhA monograph for oral iron preparations. Less than 9 1500
Note that these values were based on and taken from the
Non-heme iron is also best absorbed paper Individualized Treatment for Iron-deficiency Anemia
F I G U R E 3 Proposed absorption
as the ferrous salt in a mildly acidic in Adults done by Allenye et al. which are based on studies
mechanism for non-heme iron.13,17,27,28 medium. (11,30) Gastric acidity is helpful, done on elemental iron only.9
and medications that reduce acid such
Non-heme iron is ingested,
as antacids, histamine receptor block- Bovine Heme Iron
usually in ferric form ers, and proton pump inhibitors may Bovine heme iron is iron in the heme
impair iron salt absorption. (10) Though form, extracted from cows available on the
absorption can be increased with the Canadian market as an oral formulation
co-ingestion of ascorbic acid in the containing 11 mg tablets of heme iron.
Ferric iron enters
the duodenum absence of food, the estimated absorp- Due to its specialized absorption path-
tion efficiency remains approximately way, studies on healthy volunteers have
10-20%. (9) shown bovine heme iron to be better
absorbed than non-heme iron salts, (i.e.,
Duodenum cytochrome b Iron Polysaccharide Complex up to 20 times better than an equivalent
(DcytB), ferrous reductase,
and potentially ascorbic acid The iron polysaccharide complex (IPC) dose of ferrous fumerate.)(12,34, 27) In addi-
reduces ferric iron to ferrous iron is an iron supplement containing 150 mg tion, supplementation with bovine heme
of elemental iron formulated with a slow iron in regular blood donors was shown in
release profile to decrease incidents of GI early studies to have less intolerance issues
intolerance that are common with iron such as less constipation, nausea, cramping
Divalent ion transporter (DMT1)
on the microvillus membrane salts. The theory behind IPC is that the and reduced GI distress.(35) It should also be
transports ferrous iron from the majority of gastric intolerance caused by noted that, as opposed to iron salts which
intestinal lumen to the enterocyte. iron salts is a result of rapid iron release are better absorbed on an empty stomach,
in the GI tract. IPC, however, stores iron heme iron absorption is not affected by the
atoms in an inner core and slowly releases presence of food and therefore more conve-
Ferrous iron is
iron in a controlled fashion, much like nient to take since they can be consumed
in the enterocyte the endogenous ferritin protein.(31,32) One with or without meals.(12)
multi-center randomized controlled trial In comparison to IV iron therapy,
done by Ortiz et al. concluded that the which has long been considered the gold
oral iron(III) polymaltose complex was standard for iron supplementation in
at least equally efficacious when compared the highest risk anemic patient popula-
Ferrous iron
to ferrous sulfate, while offering a more tion of chronic kidney disease patients,
Ferrous iron
stored in transported into agreeable safety profile.(33) Therefore, the heme iron supplements have demon-
enterocyte circulation by benefits of IPC include decreased adverse strated equivalence in several studies.
as ferritin ferroportin 1 (FPN1) drug reactions as well as pill burden (one- In one study, heme iron supplements
which interacts with a-day dosing). (11 mg 3 times daily) were shown to
hephaestin to oxidize One major critique of IPC therapy is have similar efficacy to IV iron sucrose
ferrous iron back to that the long acting release profile of IPC (200 mg monthly) in maintaining hemo-
ferric form
is not compatible with the nature of iron globin in non-dialysis chronic kidney
absorption. Recall that iron absorption disease patients, with no differences in
is mainly achieved in the duodenum. adverse events over six months.(36) In
absorbed via a far more complex pathway Therefore, absorption of iron from IPC another open prospective study, heme
in comparison to heme iron.(13,17,26) is limited to the duration of time the for- iron supplements (21 mg or 36 mg per
Furthermore, iron salts are subject to mulation can stay within that absorp- day) were able to replace the use of IV
many food and drug interactions. They tion “sweet spot.”(15) This, of course, is iron and not only sustain response to
are easily chelated by surrounding ions limited by gastric emptying and passage, rHuEPO in the majority of hemodialy-
such as calcium, and by common foods which results in less iron present at the sis patients, but was able to significantly
such as phytates in bran, oats and rye duodenum villi for absorption. Conse- increase rHuEPO efficiency (p=0.04).(37)
fiber, soy proteins, polyphenols found quently, sustained-release capsules are A similar trial showed similar achieve-
in tea and some vegetables and cere- less efficient for oral absorption because ment in maintaining rHuEPO response
als.(11,13,30) As such, it is generally recom- they release iron too far distally in the while having a reduction in GI side effects
mended that iron salts be consumed on intestine, hence reducing the amount of and significant reduction of gas (p=0.3)
an empty stomach if tolerated to maxi- iron present for absorption at the duo- suggesting better patient compliance.(38)
mize absorption.(11,26,30) denal villi.(30) These studies indicate that oral heme iron
ce
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Continuing Education

FIGURE 4
L E S S O N

Proposed absorption mechanism for heme iron.(13,17,27,28)

Though it is well known

that heme iron is absorbed
Heme iron is ingested and
April 2017
Iron Deficiency Anemia

Answer online at eCortex.ca

iron is still the mainstay of iron replace-

ment therapy for patients with chronic
kidney disease undergoing dialysis or
conditions that result in iron malabsorp-
goes into the duodenum tion.(3,16) Doses vary between preparations
more efficiently than non-
heme iron, the mechanism but typically range between 100 mg to
by which this happens is 510 mg, once to thrice per week.(15)
still poorly understood. The Heme iron is uptaken into
depicted pathway is an up the enterocyte by receptor INDIVIDUALIZING TREATMENT
to date summary of the mediated endocytosis As noted earlier, the duration of iron
(likely via HCP1) at the luminal
hypothesis for heme iron brush border membrane replacement therapy typically continues
absorption. for three months after the patient has
reached a normal hemoglobin count. A
new study, however, done by Alleyne et al.
Heme iron is in the enterocyte suggests that patients who are intolerant
to the traditional therapy of 105-200 mg
of iron per day in divided doses should
follow a cycled therapeutic regimen.(9)
The premise of cycled dosing is based on
Intact heme
Heme iron is engulfed into the concept that decreasing daily iron
could possibly be
endosomes or lysosomes Heme iron is catabolized doses requires an increase in the dura-
transported directly
within 2-3 hours of heme into non-heme iron tion of therapy. Since iron intolerance is
across basolateral
uptake and subsequently and biliverdin at the
membrane by FLVCR mostly dose related, cycled therapy would
catabolized into non-heme endoplasmic reticulum
into circulation allow patients to choose a smaller daily
iron and biliverdin by by heme-oxygenase 1
where it binds to dose at the expense of increasing their
heme-oxygenase 2
hemopexin
duration of therapy with a set total dose
of iron as the target.(9) The research sug-
gests that patients should aim to complete
Non-heme iron possibly their iron replacement therapy in cycles
transported to cytoplasm of 500 mg of absorbed iron. Assuming a
via DMT1 10% absorption for iron salts, a total dose
of 5000 mg of elemental iron will yield
500 mg of absorbed iron, which is enough
to replenish iron stores in moderately defi-
Non-heme iron in the cytoplasm follows cient patients.(9) By this method, patients
the non-heme iron release pathway into who are intolerant can take a smaller
circulation to bind onto transferrin
dose of daily iron (e.g. 50 mg of iron per
day, yielding 5 mg of absorbed iron) for a
longer duration of therapy. By following
supplementation is a viable, efficient and therapy is contraindicated or ineffective. the above exampled regimen, the patient
safe iron delivery method for treatment IV iron may also be given to individuals would reach target hemoglobin levels by
of iron deficiency anemia equivalent to with severe and active blood loss, gastric approximately 100 days of therapy.
the traditional gold standard. surgery, coexisting inflammatory states By using this dosing method, patients
A drawback of bovine heme iron is its that interfere with iron homeostasis, or are not only more involved with their care,
animal protein origin, making it unsuit- malabsorption conditions like Celiac but can calculate the theoretical amount
able for patients with dietary restrictions disease which may limit absorption of they need to take of other iron prepara-
to animal products. Furthermore, a sec- oral iron.(3) There are currently several tions. Take, for instance, the example of
ondary drawback to bovine heme iron is different forms of parenteral iron on the heme iron. With the absorption of heme
it’s cost. Current retail value of bovine market including ferumoxytol, iron dex- iron ranging between 15-35%, assuming
heme iron is approximately $1.01 per tab- tran, iron sucrose and sodium ferric.(15) an absorption rate of 25%, the manufac-
let at Canadian pharmacies such as Shop- The main benefit of parenteral iron is ture recommended dosing of three 11 mg
pers Drug Mart®, making it the most the avoidance of the need for GI absorp- tablets per day will yield 8.25 mg of iron
expensive oral iron tablet formulation tion, making it 100% bioavailable. IV per day. Following this regimen, a mod-
on the market. Therefore, pharmacists iron allows administration of nearly full erately iron deficient patient will need to
must consider the patient’s own financial replacement doses in one or two infusions take three tablets per day for only 61 days
budget during product selection. rather than over the course of several to replenish their iron stores completely.
months with oral iron.(30) Drawbacks of An additional benefit to dosing with heme
PARENTERAL IRON parenteral iron include the possibility for iron would be less variation secondary to
Parenteral iron is typically appropriate anaphylactic reactions, although this risk dietary practices. Of course, one limitation
for patients who are unable to tolerate is exceedingly low. IV iron is also signifi- to this dosing “rule” is that the conclusions
gastrointestinal side effects of oral iron cantly more expensive than oral iron.(15) are tentative and extrapolated based on
supplementation, or where oral iron Though not commonly used, parenteral studies done with iron salts. Nevertheless,
Iron Deficiency Anemia

Answer online at eCortex.ca April 2017

with no clear “rule of thumb” for the dos-

ing of heme iron, this estimation will have
to suffice until further studies are done
in the field.
use, pharmacists should make use of
follow-ups to determine the existence of
adverse drug reactions secondary to the
initiation of the chosen drug therapy.
ce Continuing Education
L E S S O N

11. Guidelines and Protocols Advisory Committee. Iron Deficiency

- Investigation and Management. 2010.
12. Nam T, Shim JY, Kim B, Rah SY, Park K, Kim S-Y, et al. Clinical
Study on the Iron Absorption from Heme-Iron Polypeptide and
Nonheme-Iron *. Nutr Sci. 2006;9(4):295–300.
CE7

Pertaining to nutrition, pharmacists 13. Waldvogel-abramowski S, Waeber G, Gassner C, Buser A, Frey

BM, Favrat B, et al. Physiology of Iron Metabolism. Transfus
Role of the Pharmacist should be promoting adequate iron Med Hemotherapy. 2014;41:213–21.
In a community setting, pharmacists intake in the infant and pregnant popula- 14. Shafir T, Angulo-Barroso R, Calatroni A, Jimenez E, Lozoff
have the unique role of educator and tion. For mothers that choose to use for- B. Effects of iron deficiency in infancy on patterns of motor
development over time. Hum Mov Sci. 2006;25:821–38.
clinical advisor. With respect to iron mula, pharmacists should advise against 15. Lim W. Common Anemias. In: Association CP, editor.
deficiency anemia, a vast majority of using cow milk and instead advise care- Therapeutic Choices. 7th ed. Ottawa; 2014.
cases that are presented to the phar- givers to choose age appropriate and iron 16. Cook JD. Diagnosis and management of iron-deficiency anae-
mia. Best Pract Res Clin Haemotology. 2005;18(2):319–32.
macy involve patients who have already fortified formula. For pregnant women, 17. West AR, Oates PS. Mechanisms of heme iron absorption :
been diagnosed with iron deficiency pharmacists should be knowledgeable Current questions and controversies. World J Gastroenterol.
and are looking for a product to use. about nutritional iron needs during 2008;14(26):4101–10.
18. Thurnham DI, Mccabe LD, Haldar S, Wieringa FT, Northrop-
In this scenario, pharmacists should pregnancy and suggest frequent iron Clewes CA, Mccabe GP. Adjusting plasma ferritin concentra-
understand the advantages and disad- monitoring followed by the appropriate tions to remove the effects of subclinical inflammation in the
vantages of each form of iron therapy supplementation. assessment of iron deficiency: a meta-analysis. Am J Clin Nutr.
2010;92:546–55.
before selecting an appropriate product Finally, pharmacists are often 19. Nielsen OH, Coskun M, Weiss G. Iron replacement therapy:
for the patient. In brief, treatment with approached daily with queries about do we need new guidelines? Curr Opin Gastroenterol.
an iron salt is cost effective, accessible chronic fatigue or “low energy”. It is 2016;32(2):128–35.
20. Pettit K, Rowley J, Brown N. Iron deficiency. Paediatr Child
and well documented in literature per- important that pharmacists recognize Health (Oxford). Elsevier Ltd; 2011;21(8):339–43.
taining to efficacy, dosing, and adverse signs and symptoms of iron deficiency ane- 21. Camaschella C. Iron-Deficiency Anemia. N Engl J Med.
effects. Conversely, disadvantages of iron mia such as fatigue and refer appropriately. 2015;372(19):1832–43.
22. Canadian Pharmacist’s Association. Iron Preparations: Oral.
salts include gastric intolerance resulting CPhA Monogr. 2011;
in poor compliance, which incidentally Conclusion 23. National Institutes of Health - Office of Dietary Supplements.
is the number one reason for poor treat- Though iron deficiency anemia is com- Iron: Dietary Supplement Fact Sheet [Internet]. U.S.
Department of Health and Human Services. 2016 [cited 2016
ment response.(21,20) mon, it is in no way a silent bystander. Mar 25]. Available from: https://ods.od.nih.gov/factsheets/
Pertaining to other oral iron prepa- Due to the ease of treatment, it is easy Iron-HealthProfessional/#en17
rations, advantages of the polysaccha- for the healthcare practitioner to over- 24. Hurrell R, Egli I. Iron bioavailability and dietary reference
values. Am J Clin Nutr. 2010;91:1461–7.
ride iron complex formulation include look its significant impact on both qual- 25. Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G.
decreased adverse drug reactions and pill ity and duration of life. At present, there Hemostasis and Thrombosis. In: Hyde M, editor. Rang and
burden whereas its disadvantage lies in its are several available treatment options on Dale’s Pharmacology. 7th ed. London; 2012. p. 294–308.
26. Zimmermann MB, Hurrell RF. Nutritional iron deficiency.
release profile which compromises iron the market, making it the pharmacist’s Lancet. 2007;370:511–20.
absorption in the duodenum. In addi- role to educate and help choose the most 27. Shayeghi M, Latunde-dada GO, Oakhill JS, Laftah AH, Takeuchi
tion, other than being the only available appropriate treatment option for each K, Halliday N, et al. Identification of an Intestinal Heme
Transporter. Cell. 2005;122:789–801.
oral iron preparation that is comparable patient’s individual need. 28. Olivares M, Figueroa C, Pizarro F. Acute Copper and Ascorbic
to IV iron therapy, bovine heme iron Acid Supplementation Inhibits Non-heme Iron Absorption in
offers both a more agreeable drug safety References Humans. Biol Trace Elem Res. 2015;1–5.
1. Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G. 29. Short M, Domagalski J. Iron deficiency anemia Evaluation and
and absorption profile in comparison to management. Am Fam Physician. 2013;87(2):98–104.
Haemopoietic system and treatment of anaemia. In: Rang
iron salts. Drawbacks of treatment with and Dale’s Pharmacology. 2012. p. 309–17. 30. Killip S, Bennett JM, Chambers MD. Iron Deficiency Anemia.
bovine heme iron would include its high 2. Schrier SL, Mentzer WC, Tirnauer JS. Causes and diagnosis Am Fam Physician. 2007;75(5):671–8.
of iron deficiency anemia in the adult [Internet]. UpToDate. 31. Coe EM, Bowen LH, Speer JA, Bereman RD. Comparison of
cost and incompatibility in patients with Polysaccharide Iron Complexes Used as Iron Supplements.
2015 [cited 2016 Apr 20]. Available from: http://www.
dietary restrictions to beef. uptodate.com.myaccess.library.utoronto.ca/contents/ 292(1095):287–92.
Concerning parenteral iron, the most causes-and-diagnosis-of-iron-deficiency-anemia-in-the- 32. Coe EM, Bowen LH, Speer JA, Sayers DE, Bereman RD. The
Recharacterization of a Polysaccharide Iron Complex (Niferex).
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278(1995):269–78.
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3. Cook K, Inneck BA, Lyons WL. Anemias. In: Dipiro JT, Talbert
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high cost and potential for anaphylaxis Pharmacotherapy: A Pathophysiologic Approach. 8th ed. 2011.
anemia : a multicenter , randomized , controlled study Efficacy
often warrants serious consideration of 4. Gordon N. Iron deficiency and the intellect. Brain Dev.
and safety of oral iron ( III ) polymaltose complex versus ferrous
2003;25:3–8.
the risks versus benefits of using paren- 5. Harris RJ. Iron deficiency anaemia : does it really matter?
s. J Matern Neonatal Med ISSN. 2011;24(11):1347–52.
34. Seligman PA, Moore GM, Schleicher RB. Clinical Studies of HIP:
teral iron therapy. Paediatr Child Health (Oxford). 2007;17(4):143–6. An Oral Heme-Iron Product. Nutr Res. 2000;20(9):1279–86.
Using knowledge of all the above 6. Lozoff B, Clark KM, Jing Y, Armony-Sivan R, Angelilli ML, 35. Frykman E, Bystrom M, Jansson U, Edberg A, Hansen T. Side
Jacobson SW. Dose-Response Relationships between Iron
advantages and disadvantages, it is Deficiency with or without Anemia and Infant Social-Emotional
effects of iron supplements in blood donors: superior tolerance
the pharmacist’s role to use his or her of heme iron. J Labratory Clin Med. 1994;123(4):561–4.
Behavior. J Pediatr. 2008;152(5):696–702. 36. Nagaraju SP, Cohn A, Akbari A, Davis JL, Zimmerman DL. Heme
professional judgment when selecting 7. Lozoff B, Georgieff MK. Iron Deficiency and Brain Development. iron polypeptide for the treatment of iron deficiency anemia
iron replacement therapy for the patient. Semin Pediatr Neurol. 2006;158–65. in non-dialysis chronic kidney disease patients: a randomized
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To do so, the pharmacist must assess nosis and treatment of iron deficiency across indications: a 37. Nissenson AR, Berns JS, Sakiewicz P, Ghaddar S, Moore
the patient for any existing or previous systematic review. Am J Clin Nutr. 2015;102:1585–94. GM, Schleicher RB, et al. Clinical Evaluation of Heme Iron
iron use, paying particular interest to 9. Alleyne M, Horne MK, Miller JL. Individualized Treatment for Polypeptide: Sustaining a Response to rHuEPO in Hemodialysis
Iron-deficiency Anemia in Adults. Am J Med. 2008;121:943–8. Patients. Am J Kidney Dis. 2003;42(2):325–30.
any adverse reactions that might have 10. Heidelbaugh JJ. Proton pump inhibitors and risk of vitamin and 38. Ghaddar S, Moor GM. Evaluation of the Ability of Heme Iron
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selection and counseling on appropriate drug Saf. 2013;4(3):125–33. Dialysis Patients: A Prospective Clinical Evaluation. 2003.
ce
CE8

Questions
Continuing Education
L E S S O N

Answer online at eCortex.ca. Quick Search CCCEP #1065-2016-1723-I-P

April 2017
Iron Deficiency Anemia

Answer online at eCortex.ca

1. Which of the following b) Fatigue was effective in rHuEPO told her to “ask the pharmacist
statements is false: c) Decreased immunity response for an appropriate iron supple-
a) Blood loss is a significant d) Koilonychia d) Iron salts were superior ment.” Which of the following
contributor for iron deficiency e) Pallor to both heme and IV iron would you recommend for ID?
anemia supplementation a) Iron salts
b) Iron deficiency anemia is 4. Choose the statement b) Polysaccharide iron complex
commonly a congenital that ranks the percentage of 6. ID is a 33 year old female c) Heme iron
disease elemental iron in iron salts who is asking for an over-the- d) Parenteral iron
c) Vegetarians are at high risk from highest to lowest counter product for fatigue. e) None of the above; you need
of iron deficiency anemia a) Ferrous fumarate, dried You learn that ID has been to see her hemoglobin count
d) Iron deficiency anemia is ferrous sulfate, ferrous experiencing fatigue on and off before making a clinical
prevalent among women of sulfate, ferrous gluconate for the past 6 months and has decision
child bearing age b) Dried ferrous sulfate, ferrous difficulty concentrating at work.
e) Growing children and at gluconate, ferrous sulfate, In addition, ID has shared that 8. ID is started on ferrous
increased risk of iron defi- ferrous fumarate she typically feels fatigued sulfate, 1 tablet TID. You
ciency anemia c) Ferrous fumarate, ferrous during her menstrual period. follow up with her in 2 weeks
sulfate, dried ferrous sulfate, Which of the following would and discover she has been
2. Choose the statement ferrous gluconate you recommend? experiencing gastric upset
that ranks diagnostic for iron d) Ferrous gluconate, ferrous a) More sleep and counsel her since starting the tablets.
deficiency from least to most fumarate, ferrous sulfate, on sleep hygiene Upon further investigation, you
specific. dried ferrous sulfate b) An iron tablet as she could learn that she has already tried
a) Ferritin, MCV, hemoglobin e) Ferrous sulfate, ferrous possibly be low on iron taking her iron tablets at meals
count gluconate, ferrous fumarate, c) A b-complex OTC item adver- with no alleviation of symp-
b) MCV, ferritin, hemoglobin dried ferrous sulfate tised for “stress” toms. You also learn that ID
count d) Refer her to her family physi- is has no dietary or monetary
c) Hemoglobin count, ferritin 5. In studies on hemodialysis cian to get a full blood test restrictions. What would you
MCV patients comparing heme iron e) Tell her that fatigue is not recommend?
d) Hemoglobin count, MCV, supplementation to IV iron, a real medical problem and a) Stop the iron salts, start on a
ferritin researchers found: there is nothing you can offer polysaccharide iron complex
e) MCV, hemoglobin count, a) Heme iron was as equally b) Stop the iron salts, start on a
ferritin effective as IV iron in sup- 7. A few weeks later, ID comes heme iron preparation
porting rHuEPO response to your pharmacy with a pre- c) Switch to a different iron salt
3. Which of the following is b) IV iron was significantly scription for an “iron supple- d) Stop the iron salts, start on
NOT a sign or symptom of superior to heme iron in ment.” ID explains that she was parenteral iron
anemia? rHuEPO response diagnosed with iron deficiency e) Stop the iron salts and seek
a) Decreased blood pressure c) Neither supplementation anemia and that her physician the physician’s advice

Answer online at eCortex.ca

Faculty: Iron Deficiency Anemia

ABOUT THE AUTHORS REVIEWERS CONTINUING EDUCATION This lesson is published by EnsembleIQ, 2300
Victor Wong is pharmacist-owner of two All lessons are reviewed by pharmacists PROJECT MANAGER Yonge St., Suite 1510, Toronto, ON M4P 1E4.
Shoppers Drug Mart pharmacies, as well for accuracy, currency and relevance to Rosalind Stefanac, Toronto, Ont. If you have any questions, please contact
as a teaching associate at the University current pharmacy practice. [email protected].
of Toronto’s Faculty of Pharmacy. He CE DESIGNER No part of this CE lesson may be reproduced,
is a Chief Examiner at the Pharmacy This lesson is valid until April 10, 2018. Shawn Samson, TwoCreative.ca in whole or in part, without the written
Examining Board of Canada. Information about iron deficiency anemia permission of the publisher. ©2017
may change over the course of this time.
Lucy Wang received her Master of Pharmacy Readers are responsible for determining
degree in the UK and has an extensive the most current aspects of this topic.
research background in the field of nano-
technology. She is currently Ontario licenced
pharmacist practising at Shoppers Drug Mart.

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