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The Science and Practice of Micronutrient Supplementations in Nutritional

Anemia: An Evidence-Based Review

Article  in  Journal of Parenteral and Enteral Nutrition · May 2014

DOI: 10.1177/0148607114533726 · Source: PubMed

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PENXXX10.1177/0148607114533726Journal of Parenteral and Enteral NutritionChan and Mike

Tutorial
Journal of Parenteral and Enteral
Nutrition
The Science and Practice of Micronutrient Volume 38 Number 6
August 2014 656­–672
Supplementations in Nutritional Anemia: An © 2014 American Society

Evidence-Based Review for Parenteral and Enteral Nutrition

DOI: 10.1177/0148607114533726
jpen.sagepub.com
hosted at
online.sagepub.com

Lingtak-Neander Chan, PharmD, BCNSP, CNSC1; and

Leigh Ann Mike, PharmD, BCPS, CGP1

Abstract
Nutritional anemia is the most common type of anemia, affecting millions of people in all age groups worldwide. While inadequate access
to food and nutrients can lead to anemia, patients with certain health status or medical conditions are also at increased risk of developing
nutritional anemia. Iron, cobalamin, and folate are the most recognized micronutrients that are vital for the generation of erythrocytes.
Iron deficiency is associated with insufficient production of hemoglobin. Deficiency of cobalamin or folate leads to impaired synthesis
of deoxyribonucleic acid, proteins, and cell division. Recent research has demonstrated that the status of copper and zinc in the body can
significantly affect iron absorption and utilization. With an increasing number of patients undergoing bariatric surgical procedures, more
cases of anemia associated with copper and zinc deficiencies have also emerged. The intestinal absorption of these 5 critical micronutrients
are highly regulated and mediated by specific apical transport mechanisms in the enterocytes. Health conditions that persistently alter the
histology of the upper intestinal architecture, expression, or function of these substrate-specific transporters, or the normal digestion and
flow of these key micronutrients, can lead to nutritional anemia. The focus of this article is to review the science of intestinal micronutrient
absorption, discuss the clinical assessment of micronutrient deficiencies in relation to anemia, and suggest an effective treatment plan and
monitoring strategies using an evidence-based approach. (JPEN J Parenter Enteral Nutr. 2014;38:656-672)

Keywords
adult, life cycle; geriatrics, life cycle; minerals/trace elements; nutrition, vitamins; nutrition, anemia; iron; copper; cobalamin; folate; zinc

Anemia is a medical condition indicative of poor nutrition sta- women.5 But in smaller studies focusing on the more vulnera-
tus or poor health. It is characterized by the reduction of hemo- ble populations, prevalence as high as 55% has been reported.6
globin concentration, which is the most reliable diagnostic The causes of anemia are usually multifactorial. They can
criterion at the population level. Although the lower limit of be generally grouped into 4 main categories: (1) increased loss
normal hemoglobin concentration remains a debated topic and of blood volume or red cells (eg, acute or chronic bleeding),
likely varies among different races and ethnicities, the World (2) increased destruction of red cells (eg, hemolytic anemia),
Health Organization (WHO) standard is still the most widely (3) increased demand or decreased production/differentiation
adopted definition of anemia (Table 1).1-3 Anemia is a signifi- of red cells (eg, bone marrow failure, insufficient supply of
cant global health problem that affects a quarter of the popula- nutrients involved in erythropoiesis, erythropoietin defi-
tion worldwide. Epidemiological data show that the prevalence ciency), and (4) miscellaneous causes (eg, anemia of chronic
of anemia is the highest among preschool-age children and disease, cancer) (Table 2). These causes are not mutually
pregnant women, although the condition essentially affects all exclusive, and a person can have multiple causes leading to
age groups.4 Since anemia is a dynamic medical condition
affected by many factors, the incidence is higher in the vulner-
able populations, such as malnourished individuals, young From the 1University of Washington, Seattle, Washington, USA.
children, pregnant women, older adults (especially residents in Financial disclosure: None declared.
nursing homes or assisted living facilities), and patients with
Received for publication January 2, 2014; accepted for publication April
kidney diseases, uncontrolled chronic illness, extensive surger- 3, 2014.
ies in the gastrointestinal (GI) tract, or cancer. The prevalence
This article originally appeared online on May 20, 2014.
of anemia also increases with age after the fifth decade of life
in both sexes. In the United States, the exact prevalence of ane- Corresponding Author:
mia in the entire population has not been formally evaluated. Lingtak-Neander Chan, PharmD, BCNSP, CNSC, Associate Professor,
School of Pharmacy, Interdisciplinary Faculty, Graduate Program in
According to National Health and Nutrition Examination
Nutritional Sciences, School of Public Health, University of Washington,
Survey III (NHANES III), among community-dwelling adults 1959 NE Pacific St, HSC H-361B, Box 357630, Seattle, WA 98195, USA.
65 years or older, the prevalence is 11% in men and 10.2% in Email: neander@u.washington.edu

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Chan and Mike 657

Table 1.  Cutoff of Hemoglobin Concentrations in Defining Table 3.  Overview of the Involvement of Iron, Cobalamin,
Anemia According to WHO Recommendations. Copper, Folate, and Zinc in Erythropoiesis.

Hemoglobin Micronutrient Major Physiological Roles in Erythropoiesis

Age Group Concentration, g/dL
Iron Key component of the oxygen-carrying protein
Children aged 6–59 mo <11.0 hemoglobin
Children aged 5–11 y <11.5 Cobalamin Cofactor for amino acid synthesis and
Children aged 12–14 y <12.0 tricarboxylic acid cycle; facilitates maturation
Adult males (>15 y) <13.0 and differentiation of the erythroid lineage
Adult females, nonpregnant (>15 y) <12.0 Folate Key component of 1-carbon transfer system for
Adult females, pregnant <11.0 DNA and protein synthesis and cell division
Copper Key regulator for iron transport from the
These thresholds are set at the fifth percentile of the hemoglobin intestine (eg, hephaestin) and release from cells
concentration of a normal population of the same sex and age group (as into the circulation (eg, ceruloplasmin)
measured as venous blood at sea level). Data from the World Health Zinc Cofactor for protein synthesis and regulator for
Organization (WHO; http://www.who.int/vmnis/indicators/haemoglobin.
cell differentiation
pdf).

Table 2.  Summary of Major Categories and Causes of Anemia. to become erythroblasts, reticulocytes, and eventually the enu-
cleated erythrocytes that carry oxygen throughout the body.7
Category Examples of Cause Iron is an essential nutrient substrate in this process since it is
Increased loss of blood •• Acute hemorrhage the key component of the oxygen-carrying hemoglobin as well
volume or red cells •• Gastrointestinal bleed as a number of electron-transferring enzymes in the respiratory
chain; however, a few other micronutrients also play important
Increased destruction •• Autoimmune hemolytic reaction roles. Cobalamin and folate are needed for DNA synthesis, cell
of red cells •• Drug-induced hemolysis division, and the proliferation of the progenitor cells. Zinc is not
Decreased production/ •• Bone marrow failure only vital for protein and DNA synthesis but is also a key com-
differentiation of red •• Disruption of the supply of “raw ponent of a zinc-finger factor, GATA-1, that functions as a regu-
cells materials” involved in erythropoiesis lator of the differentiation and development of erythroid cell
•• Erythropoietin deficiency lineage.8-10 Copper is a cofactor for cytochrome c oxidase, an
(eg, end-stage kidney disease) important component of the mitochondrial electron transport
chain.11 In addition, ceruloplasmin, a plasma protein, and hepha-
Miscellaneous causes •• Anemia of chronic disease
estin, a membrane protein, are 2 cuproproteins with ferroxidase
•• Cancer
activity that closely regulate the intestinal absorption and release
Note that these causes are not mutually exclusive. of iron into the systemic circulation (Table 3 and Figure 1).12-14
Deficiencies in selenium and riboflavin have also been linked to
the development of anemia, although the exact mechanisms
anemia. Statistics from the WHO show that as many as 50% of remain unclear and the optimal strategy in assessing and replac-
the documented cases of anemia worldwide, especially those ing these nutrients has not been investigated.15-19 The diagnosis
in developing countries, are related to iron deficiency.3,4 This and clinical evaluation of anemia have been extensively
finding is consistent with the data from NHANES III, which reviewed elsewhere.20-22 The purposes of this tutorial are
show that nutrient deficiencies are the most common cause of to (1) discuss the science of micronutrient deficiencies—
anemia in the United States. Specifically, deficiencies in iron, specifically iron, cobalamin, folate, copper, and zinc—in rela-
folate, and cobalamin account for one-third of all documented tion to anemia; (2) translate the scientific knowledge into prac-
anemia cases in older adults.5 With the continued growth of the tice in assessing nutritional anemia; and (3) discuss the effective
aging population, the increased number of patients receiving treatment strategies based on the available evidence.
interventions that can impair nutrient absorption or homeosta-
sis, such as bariatric surgery, cancer therapy, and treatment for
human immunodeficiency virus infection, the incidence of Iron
nutritional anemia is expected to rise.
Erythropoiesis involves the supply of hematopoietic stem
Homeostasis and Daily Turnover
cells from the bone marrow, the presence of stem cell factor Approximately 3–5 g of iron are stored in the human body under
interleukin-3 (IL-3), granulocyte-macrophage colony-stimulat- normal physiology. About 60% of the total body iron is in the
ing factor (GM-CSF), and the production and release of eryth- form of hemoglobin in the circulating erythrocytes, and 15% is
ropoietin (EPO) from the renal cortex to facilitate the found in muscle fiber as myoglobin. The remaining amount is
differentiation of stem cells into proerythroblasts, which mature stored in the hepatic parenchymal tissues (about 1000 mg), the

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658 Journal of Parenteral and Enteral Nutrition 38(6)

ZINC
Cell differenaon
COPPER
Pluripotent Hematopoiec Proerythroblasts Oral absorpon
stem cells stem cells of iron
Cell proliferaon
and differenaon Hemoglobin IRON
Synthesis
COBALAMIN
FOLATE
Erythroblasts

Circulang
Reculocytes
erythrocytes

Figure 1.  Summary of the key roles of iron, cobalamin, folate, copper, and zinc in erythropoiesis. Iron is the essential micronutrient for
the synthesis of hemoglobin, the oxygen-carrying unit of erythrocytes. Copper plays a pivotal role in regulating the intestinal absorption
and systemic release of iron from diets and supplements. Zinc regulates protein and DNA synthesis and promotes the differentiation
of the pluripotent stem cells into proerythroblasts. Cobalamin and folate are key cofactors in regulating DNA synthesis, cell division,
and proliferation of the progenitor cells. (Illustration adapted from Lankhorst CE, Wish JB. Anemia in renal disease: diagnosis and
management. Blood Rev. 2010;24(1):39-47, with permission from Elsevier.)

Table 4.  Summary of the Primary Site of Micronutrient Absorption From the GI Tract, the Major Transport Proteins Involved, and the
Known Factors That May Significantly Affect Their Functions.

Micronutrient Primary Site of Absorption Known Apical Transporter of Significance Remarks

Nonheme iron Duodenum DMT1 (aka SLC11A2) Also has affinity for lead, cobalt,
manganese, copper, and zinc
Heme iron Duodenum and proximal jejunum Unknown; SLC46A1 (aka HCP1 or PCFT)  
plays a small role
Cobalamin Terminal ileum Cubilin-amnionless (aka intrinsic factor  
receptor)
Folate Duodenum and proximal jejunum SLC19A1 (minor) SLC46A1 enhanced by vitamin D
  SLC46A1 (major) but inhibited by alcohol
Copper Most of the small intestine CTR1 (major)  
  DMT1 (minor)  
Zinc Duodenum and jejunum ZIP4 (aka SLC39A4)  

reticuloendothelial system (approximately 600 mg), and as
plasma transferrin (3 mg).23,24 Although the normal daily iron
turnover for erythropoiesis alone is about 20–30 mg, most iron is
recycled and reincorporated into new cells. The net daily iron
loss in the absence of active bleeding is between 1 and 2 mg
through desquamation, menstrual blood loss, and turnover of
epithelial tissues. Thus, only about 1–2 mg of dietary iron will be
absorbed when the body is not in a net iron deficit to maintain
normal homeostasis.23
Absorption of Iron From the GI Tract
The duodenum is the primary site where iron, especially non-
heme iron, is absorbed via a highly regulated transcellular
process (Table 4). When given in a large amount, passive
uptake of nonheme iron via the paracellular route also occurs.
This route also appears saturable. Thus, increasing the oral
dose of iron does not translate to a proportional increase in the
amount absorbed.24-26 Data suggest that iron uptake also takes
place in the colon, although the relative absorption efficiency
is only about one-tenth of that from the duodenum.24
While both heme (primarily from myoglobin and hemoglo-
bin from meat) and nonheme iron (primarily from nonanimal
sources) can be absorbed from the small intestine, their
absorption processes are facilitated by different epithelial car-
rier proteins and regulated by different mechanisms. Heme
iron has higher oral bioavailability or fractional absorption
(15%–35%) than does nonheme iron (2%–20%).25 Even when

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Chan and Mike 659

Table 5.  Summary of Assessment Approaches for the Key Micronutrients That Affect Hematopoiesis.

Micronutrient Deficiency Specific Laboratory Findings Remarks

Iron ↓ Serum iron ● Ferritin would ↑ in the presence of inflammation; not a reliable test
↓ TSAT or ↑ TIBC in critically ill patients, patients with an active infection, or those
↓ Ferritin with acute inflammatory responses
↓ MCV ● MCV may appear within the normal range if there is concurrent
↑ sTfR deficiency in cobalamin and/or folate
↑ Zinc protoporphyrin

Cobalamin ↑ MMA ● Homocyst(e)ine concentration can be ↑ in the presence of renal

↑ Serum homocyst(e)ine dysfunction
↑ MCV ●  MCV may appear normal in the presence of iron deficiency

Folate ↓ Erythrocyte folate ● Serum folate is transiently elevated for up to 5 hours after a meal;
↓ Serum folate (fasting) measure during fasting if possible
↑ MCV ●  MCV may appear normal in the presence of iron deficiency

Copper ↓ Plasma copper ● Inflammation can ↑ both plasma copper concentration and
↓ Ceruloplasmin ceruloplasmin concentration

Zinc ↓ 24-Hour urine zinc excretion ● Inflammation ↓ plasma zinc concentration; do not check plasma
↓ Plasma/serum zinc (only in the zinc in critically ill patients. Consider checking C-reactive protein
absence of inflammation) before checking plasma zinc

MCV, mean corpuscular volume; MMA, methylmalonic acid; sTfR, soluble transferrin receptor; TIBC, total iron binding capacity; TSAT, transferrin
saturation.

iron-deficiency anemia is present, studies showed that the
increase in fractional iron absorption from diet is very modest
(up to 20%).27,28 On the other hand, the bioavailability of iron
sulfate from iron supplements can approach 60% in severe
cases of iron-deficiency anemia.29 Therefore, when the body’s
demand of iron is high, such as in the case of pregnancy, or
there is increased blood cell production in response to anemia,
dietary intervention alone is ineffective, and iron supplements
should be used to reach therapeutic goal. Intravenous (IV)
iron administration bypasses the complex intestinal regulation
and will lead to a substantial increase in the total iron pool in
the body and therefore is the preferred approach in treating
severe anemia or providing iron to patients with severe malab-
sorptive disorders or intestinal failure.25
Assessment of Iron Status
The hallmark of pure iron-deficiency anemia includes the pres-
ence of low hemoglobin with decreased mean corpuscular vol-
ume (MCV). MCV may not be significantly reduced if folate
or cobalamin is also deficient. Iron studies show a reduction in
serum iron, serum ferritin, and transferrin saturation (TSAT)
and an increase in total iron binding capacity (TIBC).
Unfortunately, these tests can be influenced by a number of
medical conditions, such as inflammation and infections.
Therefore, assessment of anemia made with these test results
should be supported by relevant clinical suspicions or findings.
For example, ferritin as a surrogate marker of iron status can be
masked by the presence of inflammation since ferritin is a
positive acute-phase reactant. The process of iron mobilization
from the liver and other depots for the synthesis of proteins
such as anti-inflammatory cytokines causes a transient increase
in serum ferritin.30 Serum soluble transferrin receptor (sTfR)
concentration reflects the cellular need for iron or rate of eryth-
ropoiesis and is less affected by inflammation than is ferritin. It
is increased in iron-deficiency anemia and may be used to
assist in evaluating iron status. Assessment approaches for the
clinical status of different micronutrients are summarized in
Table 5.
Goal of Therapy and Replacement Strategy
In addition to managing the underlying cause(s) of iron defi-
ciency, the goal of treatment should be directed at restoring
hemoglobin concentrations and replenishing iron stores.31
After initiating supplemental iron, serum reticulocyte count
should increase within a few days. Since iron utilization by the
bone marrow typically peaks in 2 weeks, a clinically detectable
increase in hemoglobin concentration should be evident within
2–3 weeks if the patient is responsive to therapy.32 In the
absence of continued blood loss and defects in other erythro-
poietic elements (eg, deficiency of cobalamin, copper, or EPO
production), it can be expected that hemoglobin can increase
by 1–2 g/dL in the first 2 weeks and then 0.7–1 g/dL per week
thereafter until the normal range is attained, as long as ade-
quate iron supply is provided. Repletion of iron stores (eg,
normalization of ferritin) will take longer. Therefore, the dura-
tion of treatment should be at least 3 months, even if normal

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660 Journal of Parenteral and Enteral Nutrition 38(6)
Table 6.  Examples of the Commonly Used Oral Iron Supplements.
Salt Form Elemental Iron, % (w/w)
Ferrous calcium citrate 9.5
Ferrous gluconate 12
Ferric ammonium citratea 18
Ferrous bisglycinate 20
Ferrous sulfate heptahydrate 20
Ferrous sulfate monohydrate, dried 30
Ferrous fumarate 33
Carbonyl iron (vaporized elemental iron) 98
Polysaccharide complexa 100
Heme iron polypeptide 100
a
Uses ferric ion instead of ferrous ion.
hemoglobin concentration is achieved 2–3 weeks after therapy
is initiated. It may take more than 32 weeks in at-risk patients
to fully restore serum ferritin concentration despite early nor-
malization of hemoglobin concentration.33 Once hemoglobin
concentration is normalized, it is advisable to monitor hemo-
globin concentration and red cell indices every 3–4 months for
up to 1 year. Iron profiles should be rechecked in high-risk
patients.31 In some patients, chronic iron supplementation may
be needed to maintain a normal iron pool. Iron dosing should
be based on the amount of elemental iron contained within
each product.
Iron supplementation can be given orally (enterally) or intra-
venously. In addition, iron dextran can also be administered
intramuscularly. Since the body does not have a specific mecha-
nism to eliminate iron, parenteral iron therapy with inadequate
monitoring can result in iron overload. Together with the addi-
tional costs of parenteral administration, IV iron therapy should
be reserved for patients in whom oral iron therapy is ineffective,
such as those having chronic malabsorptive disorders, severe
upper GI tract complications (eg, villous atrophy, fistulae for-
mation), significant resection of the duodenum and proximal
jejunum, or intolerance to oral therapy despite trying different
formulations. Otherwise, oral iron supplementation is the pre-
ferred approach in treating iron deficiency. Unlike dietary iron,
which exists as ferric salt, most oral iron supplements are for-
mulated as ferrous salt, making them a direct substrate for the
DMT1 transporter. The amount of elemental iron varies,
depending on the salt form of the product (Table 6).
One of the most common regimens in replacing iron defi-
ciency is ferrous sulfate, 325 mg thrice daily. This regimen is
based on the assumption that the maximal daily rate of hemo-
globin regeneration is 0.25 g of hemoglobin/100 mL of blood.
Assuming that the total blood volume of an adult is about 5 L
in the absence of acute blood loss, the total amount of hemo-
globin regenerated is approximately 12.5 g/d. Since the aver-
age iron content in hemoglobin is 0.34 g/100 g of hemoglobin
or 3.4 mg of iron/g of hemoglobin, the total amount of daily
iron needed would be 3.4 × 12.5 = 42.5 mg.34 And assuming
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Available Formulations
Tablets
Tablets
Capsules
Capsules, tablets
Oral solution, tablets, enteric-coated tablets, film-coated tablets
Capsules, tablets, extended-release tablets
Tablets, chewable tablets
Tablets, chewable tables, oral suspension
Capsules, oral solution, film-coated tablets
Capsules
the oral bioavailability of iron is 20%, the total daily amount to
be administered would be 212.5 mg. Thus, 3 tablets of iron
sulfate 325 mg provide the comparable amount of elemental
iron (iron sulfate contains 20% elemental iron, or 65 mg per
325 mg salt). Clearly, this regimen contains many assumptions
and does not consider the increased fractional iron absorption
that occurs when more severe iron deficiency is present.
Therefore, the clinical response to this regimen varies among
individuals. Some of the biggest challenges with this regimen
include nonadherence and a very high incidence of side effects,
which include nausea, GI upset, constipation, and vomiting.
The GI-related side effects are proportionate to the amount
of elemental iron present in the GI tract lumen. Reducing the
dose of elemental iron improves GI tolerance and patient adher-
ence. Thus, ferrous sulfate 200 mg twice daily is usually better
tolerated by most patients than 325 mg thrice daily and is rec-
ommended by the current British guidelines.31 In a large-scale
interventional trial sponsored by the WHO comparing the effi-
cacy and safety of 240 mg/d of elemental iron (equivalent to
4 ferrous sulfate 325-mg tablets) vs 120 mg/d, the higher dose
regimen was not associated with a greater increase in hemoglo-
bin concentration but a significantly increased incidence of
GI-related side effects.35 These findings appear to support the
kinetic data showing a lack of a linear dose-response relation-
ship for the oral absorption of elemental iron.25 Higher doses
are not necessarily associated with quicker and better erythro-
poietic response and are poorly tolerated. In women with mild
iron-deficiency anemia without any evidence of malabsorptive
disorder, supplementation with 27 mg/d of elemental iron is an
effective approach in both normalizing hemoglobin and restor-
ing iron stores.36 A recent systematic review showed that as
little as 10 mg/d of elemental iron supplement is effective in
improving hemoglobin concentration.33
Iron regimens that require taking the supplement multiple
times daily can be costly and inconvenient to the patient and
are associated with increased potential for nonadherence.
Based on the kinetics and homeostasis of iron, the efficacy of
intermittent dosing has been evaluated in a number of clinical
Chan and Mike 661
trials. A recent meta-analysis showed that intermittent iron
supplementation with 60 mg of elemental iron once a week is
effective in increasing the concentrations of hemoglobin and
ferritin and preventing anemia in menstruating women.37
Intermittent dosing with at least 200 mg of ferrous fumarate
(equivalent to 66 mg of elemental iron) weekly is also effective
in improving hemoglobin concentration, although the duration
of treatment needs to be extended to at least 6 months.38
Therefore, intermittent dosing may be a feasible alternative
approach in supplementing iron in patients with mild anemia
or who are at risk of developing iron-deficiency anemia.
Iron absorption is enhanced when administered on an
empty stomach; however, this also worsens GI-related side
effects. Concurrent food intake, especially with high phytates
(eg, whole grains, legumes, nuts) or polyphenols (eg, tea, cof-
fee), reduces ferrous ion absorption by up to 50%.39,40
Concurrent acid-reducing drugs and zinc can reduce the effi-
ciency of DMT1-mediated ferrous transport and diminish fer-
rous ion absorption. Calcium may also impair the absorption
of both heme and nonheme iron, although the mechanism is
not fully understood. Coadministration of iron with ascorbic
acid or other acidic beverages is often recommended and is
believed to improve iron absorption by maintaining an acidic
luminal pH. The more recent findings that DMT1 functions
well at pH 6.0 suggest that this theory may have limited clini-
cal significance. The value of adding ascorbic acid likely
improves the absorption of food-based iron but not iron sup-
plements by enhancing the function of the brush-border ferri-
reductase (Dcytb) in the duodenum that converts ferric to
ferrous iron and serves as an antioxidant to prevent ferrous
iron from being oxidized to ferric iron.41,42 Recent research
suggest that concurrent vitamin A intake may improve iron
status; however, it is unclear whether the effect is on increas-
ing intestinal iron absorption or intracellular release of
iron.43,44 Finally, research data from a rat model suggest that a
high protein diet (40% total calories) may increase iron
absorption by 60% based on stable isotope studies. The mech-
anism appears to involve upregulation of intestinal expression
of the epithelial carrier proteins. The clinical significance of
this requires further investigation.45
Iron supplements cause dose-related GI side effects such as
nausea, vomiting, constipation, diarrhea, dark-colored stools,
and/or abdominal distress.46 Splitting the total daily amount in
divided doses may reduce these symptoms. Taking with food
may also reduce GI side effects but at the expense of reducing
iron absorption. Enteric-coated or delayed-release iron prepa-
rations may cause fewer GI side effects likely due to the
decreased amount of elemental iron presented to the upper GI
tract. Many clinicians discourage the use of these products for
fear that the net amount of elemental iron being absorbed may
be lower than that from the immediate-release formulations or
oral liquid. Nevertheless, since the bioavailability of iron is not
directly proportional to the amount, the clinical significance
may be limited. More important, better clinical responses may
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be attained if patients’ adherence is improved with these prod-
ucts. A longer course of therapy may be necessary with these
products to fully restore iron pools in the body.
Newer oral iron products contain both nonheme iron and
heme iron. The absorption of these combination products may
be better than the nonheme salt alone. They also seem to have
fewer GI-related side effects and are well tolerated. But the
pharmacokinetic and clinical outcomes data are limited, and
the cost of the products is substantially higher. Finally, oral fer-
rous supplements can precipitate drug-nutrient interactions
(eg, ciprofloxacin) and impair the absorption of other micronu-
trients (eg, copper).
A growing body of literature suggests that the conventional
approach in the United States of using 325 mg of ferrous sulfate
(or 65 mg of elemental iron) thrice daily is not better than using
lower doses in improving hemoglobin concentration.31,33 In
fact, large doses of elemental iron may aggravate an inflamma-
tory response in patients with Crohn’s disease, possibly through
increased oxidative stress.47 A study in octogenarians showed
that a single daily dose of 50 mg of elemental iron (as ferrous
gluconate liquid) was as effective as 150 mg (given as a 500-mg
ferrous calcium citrate tablet [9.52% elemental iron or 48 mg of
elemental iron], 3 times daily) in increasing the concentrations
of hemoglobin and ferritin. The incidence of GI-related adverse
events was significantly higher in the patients receiving 150 mg
of elemental iron. The incidence of nausea/vomiting, constipa-
tion, and black stools was almost twice as common in the
patients receiving the higher doses, which also led to a higher
dropout rate.48 Therefore, there is a need to reassess the conven-
tional approach of iron dosing. Studies of higher quality
strongly suggest that the daily doses of oral elemental iron can
be much lower in most cases of iron-deficiency anemia. We
suggest a starting dose of 30–65 mg of elemental iron (equiva-
lent to about 1 tablet of ferrous gluconate, 325 mg, to 1 tablet of
ferrous sulfate, 325 mg) once daily for most patients and moni-
tor for clinical responses and adverse events.
For parenteral iron therapy, several products can be consid-
ered. Each product has a slightly different pharmacokinetic pro-
file and different dosing recommendations. Some parenteral
iron products are labeled only for use in patients with chronic
kidney disease or who are receiving hemodialysis, while others
are labeled for use in patients who have an unsatisfactory
response to oral iron or who cannot tolerate oral iron. Iron dex-
tran has the higher retention rate and longest duration of effect
but may cause an anaphylactoid reaction. A test dose of iron
dextran is required prior to the first administration. Infusion of
parenteral iron can also cause hypersensitivity reactions.
Patients should be observed for signs and symptoms of hyper-
sensitivity during and after infusion. All parenteral iron prod-
ucts except ferric carboxymaltose can cause hypotension during
infusion. Ferric carboxymaltose can cause hypertension.
Observe patients for blood pressure changes during the infusion
of parenteral iron products. The dosing information and safety
issues for these products are summarized in Table 7.
 Table 7.  Summary of Commercially Available Intravenous Iron Products.

662
Trade Elemental
Salt Form Namea Iron, mg/mL Labeled Uses Recommended Doses Remarks

Iron dextran INFeD 50 Treatment of patients with documented ● Dose is based on the following formula: ● Risk for anaphylactic-type reactions
  iron deficiency in whom oral Dose (mL) = 0.0442 (desired Hb − observed ● A test dose is required prior to first
  administration is unsatisfactory or Hb) × LBW + (0.26 × LBW) administration
impossible ● A total dose as a single infusion is
possible
  ● Individual doses of 100 mg or less may be ● Can also be administered
given on a daily basis until the calculated total intramuscularly
amount required has been reached
Iron sucrose Venofer 20 Treatment of iron-deficiency anemia ●  On hemodialysis: 100 mg ● Observe for hypersensitivity
  in adult patients with chronic kidney ●  Not on dialysis: 200 mg reactions and hypotension during
  disease ● Peritoneal dialysis: 300 mg on 2 occasions, 14 infusion
days apart, followed by 400 mg 14 days later   
Ferric gluconate Ferrlecit 12.5 Treatment of iron-deficiency anemia in ● 125 mg each dose ● Observe for hypersensitivity
  adult patients and in pediatric patients ● Most patients require a cumulative dose of reactions and hypotension during
age 6 years and older with chronic 1000 mg administered over 8 dialysis sessions infusion
kidney disease receiving hemodialysis ● Contains benzyl alcohol as
who are receiving supplemental EPO preservative
therapy
Ferumoxytol Feraheme 30 Treatment of iron-deficiency anemia ● 510-mg IV injection followed by a second ● Observe for hypersensitivity
in adult patients with chronic kidney 510-mg IV injection 3–8 days later reactions and hypotension during
disease infusion
  ● Can alter magnetic resonance
imaging studies
Ferric Injectafer 50 Treatment of iron-deficiency anemia in ● <50 kg: 15 mg/kg on day 1; repeat after at ● Observe for hypersensitivity
carboxymaltose adult patients: least 7 days reactions and hypertension during
● Who have intolerance to oral ● ≥50 kg: 750 mg on day 1; repeat after at least infusion
  iron or have had unsatisfactory 7 days; maximum 1500 mg per course ● May be repeated if iron deficiency
response to oral iron; who have recurs
non-dialysis-dependent chronic
kidney disease
Ferric Monofer 100 Treatment of iron-deficiency anemia in ● Cumulative dose is based on the following ● Not available in the United States
carboxymaltose the following conditions: formula: ● Observe for hypersensitivity
● When oral iron preparations are Iron dose (mg iron) = body weight (kg) × reactions and hypotension during

Downloaded from pen.sagepub.com at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 23, 2015
ineffective or cannot be used
● Where there is a clinical need to
  deliver iron rapidly
 
(target Hg – actual Hg) infusion
(g/dL) × 2.4(C) + iron for iron stores (mg iron)
● Bolus doses: 500 mg up to thrice weekly until
cumulative dose has been administered
● Infusion: doses up to 20 mg/kg as a single  
dose or as weekly infusions until cumulative
dose has been administered

EPO, erythropoietin; Hb, hemoglobin; LBW, lean body weight; IV, intravenous.
a
INFeD (Watson Pharma, Inc, Morristown, NJ); Ferrlecit (sanofi-aventis U.S. LLC, Bridgewater, NJ); Venofer (Fresenius Medical Care, Waltham, MA); Feraheme (AMAG Pharmaceuticals, Inc, Waltham, MA); Injectafer
(American Regent, Inc, Shirley, NY); and Monofer (Pharmacosmos A/S, Holbaek, Denmark).
Chan and Mike 663
Cobalamin
Homeostasis and Daily Turnover
Cobalamin is a cobalt-containing intracellular cofactor
essential for the maintenance of neurological functions and
cell division. It exists in 2 active forms in vivo: (1) as 5′-deoxyad-
enosylcobalamin in the mitochondria to facilitate tricarboxylic
acid cycle by functioning as the cofactor of L-methylmalonyl-
CoA mutase, which promotes the conversion from
L-methylmalonyl-CoA to succinyl-Co, and (2) as methylcobala-
min primarily in the cytosol that becomes the cofactor for methi-
onine synthase to promote the methylation of homocysteine
(Hcy) to methionine, which serves as the precursor of a major
methyl group donor for most methylation reactions involving
DNA and protein synthesis.49,50 Research conducted in Western
countries indicates the daily cobalamin turnover is between 1.4
and 5.1 mcg with an average loss of 0.13% of the total body
cobalamin pool. The total body cobalamin store based on studies
(including from autopsies) ranged from 780–11,100 mcg, with
the average between 2500 and 3900 mcg.51 These data suggest
that even in the absence of cobalamin intake, a well-nourished
individual typically has well over 12 months of cobalamin
reserves. Patients who are under high metabolic stress or with
severe malnutrition may develop cobalamin deficiency sooner.
Absorption From the GI Tract
Food-based cobalamin is typically bound to proteins. The lib-
eration of food-bound cobalamin into the GI lumen requires
the presence of digestive enzymes, gastric acid, and pepsin.
The absorption of food-bound cobalamin begins in the stom-
ach, continues in the intestinal lumen, and occurs most effi-
ciently in the terminal ileum, where the gastric intrinsic factor
(IF)–cobalamin complex is taken up by the mucosal brush-
border IF receptor, cubilin. The IF-cobalamin-cubilin complex
becomes internalized, and cobalamin is released inside the
ileal epithelial cells. The detailed molecular mechanism and
regulation of this process have been reviewed elsewhere.52,53
The mean bioavailability of cobalamin varies highly even
among healthy individuals, ranging from 20% to just over
60%.51 In older adults, the bioavailability can be decreased to
as low as about 2%, likely due to the GI physiological changes
associated with aging.54 About 1%–2% of the free luminal
cobalamin that reaches the ileal mucosa may be absorbed
across the mucosal barrier by simple diffusion without the aid
of IF.55 This is an important characteristic since it provides the
basis that even patients lacking IF will absorb an adequate
amount of cobalamin as long as the dose is approximately 100
times the recommended daily intake.
Cobalamin supplements are typically formulated as free
crystalline cobalamin that is not bound to protein. Their oral
bioavailability is relatively high at 60%–70% for most indi-
viduals with an intact GI tract. However, because IF-mediated
absorption is a saturable process, the oral bioavailability of
cobalamin decreases with higher doses. For example, the oral
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bioavailability of a single 2-mcg dose is about 46% (translates
to 0.9 mcg absorbed), whereas the bioavailability of a single
50-mcg dose is only about 3% (translates to 1.5 mcg actually
absorbed). Therefore, similar to oral iron supplementation, the
net increase in cobalamin absorption does not parallel the
increase in dose administered.56,57 Mathematically, even if the
bioavailability of a single cobalamin dose of 500 mcg is only
1.2%, the net amount absorbed should still be sufficient to
replenish the daily turnover amount (up to 4 mcg) in most
patients.
Assessment of Cobalamin Status
The hallmark of cobalamin-deficiency anemia includes the
presence of low hemoglobin with increased MCV. Similar to
the case of iron-deficiency anemia, these tests are nonspecific.
Concurrent iron deficiency may decrease MCV and “mask” the
appearance of hypocobalaminemia in the red cell index.
Therefore, other risk factors and diet history must be part of the
clinical assessment. The sensitivity of serum cobalamin con-
centration is low except in extremely deficient states, and most
laboratories have a very wide reference range (200–900 pg/
mL). Furthermore, a lack of agreement among samples assayed
by different laboratories or methods has been reporterd.49 On
the other hand, accurate detection of cobalamin deficiency is
possible via the assessment of parameters in the metabolic path-
ways of Hcy and methylmalonic acid (MMA). Savage et al58
and Lindenbaum et al59 reported that more than 98% of the
patients with cobalamin deficiency (including those with neuro-
logical symptoms without anemia) had increases in the total
Hcy and MMA concentrations. MMA is a more specific marker
than Hcy in patients with renal impairment since serum total
Hcy concentration is elevated with decreased renal function.
MMA and serum cobalamin concentration can also be used
together to help determine treatment progress. A detailed cri-
tique and comparison of the diagnostic strategy and laboratory
assessments of cobalamin status has been published else-
where.60 Subclinical cobalamin deficiency, characterized by
low serum cobalamin concentration and/or elevated MMA or
Hcy that is responsive to cobalamin therapy without clinical
symptoms, is fairly common in the geriatric population. It is
unclear at this point whether chronic supplementation of cobal-
amin is necessary.61
Goal of Therapy and Replacement Strategy
The goal of therapy in cobalamin deficiency should include
the improvement of clinical symptoms, normalization of labo-
ratory tests, preferably both MMA and serum cobalamin con-
centration, and repletion of cobalamin stores. It may take
additional months after the normalization of cobalamin status
to improve some of the clinical symptoms, especially neuro-
logical symptoms.
Hydroxocobalamin and aqueocobalamin are the 2 natural-
occurring cobalamin derivatives. They are converted to either
664 Journal of Parenteral and Enteral Nutrition 38(6)
methylcobalamin or 5′-deoxyadenosylcobalamin in mamma-
lian cells. Cyanocobalamin is the synthetic form most com-
monly used in cobalamin supplements and fortified foods in
the United States. It contains a cyanide group, which is
cleaved and metabolized to the 2 active forms intracellularly.
Limited kinetic data suggest that hydroxocobalamin is
slightly more potent and better retained by the body than is
cyanocobalamin.55
Cobalamin supplements are available as an oral tablet, cap-
sule, liquid, nasal spray, and injectable solution. Recently, cobal-
amin sublingual tablets have gained attention. Unfortunately, the
idea of “sublingual vitamin B12” is a myth based on misinter-
pretation of data. There exists no physiological evidence that
cobalamin can be rapidly and efficiently absorbed under the
tongue. Most commercially available “sublingual” vitamin B12
products are either chewable or orally disintegrating tablets and
may not offer any additional clinical benefits over conventional
oral tablets but come with a higher cost to the patients.62-64
Oral cyanocobalamin is an effective treatment approach for
cobalamin deficiency as long as a significant portion of the ileum,
including the terminal ileum, is present and functional. Evidence
suggests that the initial daily dose of cyanocobalamin should be
between 250 and 2000 mcg for at least 1 week, although more
clinical experience supports an initial treatment duration for 1–3
months.65-67 This is followed by the maintenance period with at
least 125 mcg/d until symptoms are resolved. In patients with
Roux-en-Y gastric bypass surgery, pernicious anemia, or lack of
IF, cyanocobalamin maintenance doses of at least 350 mcg/d or
higher should be used.66,68 In patients who also have neurological
symptoms, the effectiveness of oral therapy has not been studied
extensively and parenteral therapy is preferred.
Parenteral cyanocobalamin and hydroxocobalamin have
also been used in the treatment of cobalamin deficiency. The
typical doses range from 100 mcg/mo to 1000 mcg/d for 1
week. Maintenance regimen can be given at 1000 mcg intra-
muscularly every 4–6 weeks. Since the retention rate of intra-
muscularly administered cyanocobalamin is inversely
proportional to the dose, giving the smaller dose (eg, 500 mcg)
at a more frequent interval is likely more effective than admin-
istering higher doses every 1–2 months (Table 8). Alternatively,
hydroxocobalamin can be used instead, since the retention rate
is >70% for a 1000-mcg intramuscular dose.55 For patients with
malabsorptive disorder, gastrectomy, or Roux-en-Y gastric
bypass, cyanocobalamin nasal spray is also a good option. The
initial regimen is 1 spray (500 mcg) administered in 1 nostril
once weekly. New steady-state serum cobalamin concentration
should be achieved after 4 doses (1 month of therapy).69
Folate
Homeostasis
Folates refer to a family of B vitamins structurally including
a pteridine ring attached to para-aminobenzoate with a
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Table 8.  Comparison of Dose and Retention Rate of
Cyanocobalamin After Oral and Intramuscular Therapy.
Percentage of Dose Retention After
Administration
Dose, mcg Intramuscular Injection Oral
1 100 56
10  97 16
25  95  
50  85 3
100  55   
500  30 2
1,000  15 1.3
polyglutamyl tail. The fully reduced form, tetrahydrofolate, is
an essential cofactor involved in the 1-carbon transfer system
to enable the biosynthesis of key compounds such as purine
nucleotide, thymidylate, and methionine, which are vital in the
synthesis of DNA, lipids, histones, and amino acids.70 From
the erythropoietic perspective, folate (and cobalamin) sustains
the rate of de novo synthesis of DNA for the erythroid progeni-
tor cells. There is also evidence suggesting that increased DNA
damage and apoptosis of the hematopoietic stem cells may
occur when folate or cobalamin deficiency is present.71 Liver
serves as the primary folate pool for the body, where approxi-
mately 50% of the total body folate reserve is stored. Red
blood cells and muscles also serve as folate depots. The hepatic
folate reserve increases with age and peaks between 11 and 30
years. Older adults have a lower folate reserve. The estimated
total body folate pool is about 20 mg based on tissues analyzed
from autopsies.72 The average daily turnover rate is about 1%
under normal physiology.73 Therefore, the estimated net daily
requirement is about 200 mcg. Since the oral bioavailability of
folate is not 100%, a higher amount must be consumed to meet
daily needs. In patients with increased metabolic demands,
higher daily folate turnover is expected.
Absorption From the GI Tract
Dietary folates exist primarily in the reduced form as 5-methyl-
tetrahydrofolate and formyltetrahydrofolate polyglutamate. The
bioavailability is about 50%. However, food-based folates are
chemically labile and undergo degradation with cooking and
food processing. The actual amount absorbed may vary depend-
ing on the meal. Folic acid, on the other hand, is a synthetic
monoglutamate form of folate used almost exclusively in food
fortification as well as in dietary/pharmaceutical supplements. It
is readily converted to the natural forms after ingestion. The oral
bioavailability of folic acid is 85% when taken with food (either
as a food fortificant or as a supplement) or 100% when taken on
an empty stomach.74 Folate absorption in the small intestine is
mediated by specific carrier transporters.75
Chan and Mike 665
Assessment of Folate Status
Similar to cobalamin, deficiency in folate causes low hemo-
globin with a nonspecific increase in MCV. Historically, folate
status has been assessed with folate concentration in the serum
or red blood cells. Serum folate concentration predominantly
reflects recent dietary intake and may change significantly
after a meal or a folic acid supplement. Pharmacokinetic data
show that 800 mcg of folic acid either as a prenatal vitamin or
a folic acid oral capsule increases the serum folate concentra-
tion by up to 4.5-fold and does not return to baseline level for
8 hours.76,77 A similar trend is also seen with folic acid–forti-
fied beverages.78 Therefore, if a serum folate concentration is
used to determine folate status, the blood sample should be
drawn during fasting, or at least 8 hours after any vitamin
supplement that contains folic acid or food product fortified
with folic acid. On the other hand, because folate is taken up
only by the developing erythrocyte in the bone marrow and
not by the circulating mature erythrocyte during its 120-day
life span, red cell folate concentration is an accurate reflection
of folate store.77,79
Goal of Therapy and Replacement Strategy
The goal of therapy should including correcting anemia and
replenishing folate storage as reflected by normal red cell folate
concentration. Before starting folic acid supplementation, cobal-
amin status should be evaluated since the treatment of folate
deficiency could mask the symptoms of untreated cobalamin
deficiency. Most published data focus on the prevention of ane-
mia during pregnancy. Well-designed controlled trials aimed to
determine the dose and duration of folic acid supplementation in
nonpregnant women are lacking. Available data suggest that
daily oral folic acid doses of 5–10 mg appear to be well tolerated
in nonpregnant individuals.80 The duration of treatment should
be at least 3–4 months. In most patients, folate-deficiency ane-
mia can be prevented by optimizing dietary intake since folic
acid is fortified in many food products. Patients with malabsorp-
tive disorders or increased demand for folate may require daily
supplementation of folic acid to prevent recurrent anemia; how-
ever, the most effective dose is unclear in nonpregnant individu-
als. Daily doses between 500 and 800 mcg may be a reasonable
initial approach. Titrate the doses based on dietary intake and
follow up red cell folate concentration. In patients whose dietary
folate intake is suboptimal, a weekly supplementation of folic
acid 500 mcg can be effective in preventing anemia.81
Copper
Homeostasis
Anemia associated with hypocupremia has been reported in
animals between 1930 and 1945.82-84 Cases of hypocupremia
have also been reported in patients with tropical sprue and
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megaloblastic anemia.85 But since protein calorie malnutrition
and hypoferremia were always present in these cases, it was
thought that copper deficiency alone was unlikely the cause of
anemia, especially since anemia consistently improved after
iron supplementation. Isolated cases of hypocupremia with
anemia and neutropenia continued to be reported in the litera-
ture thereafter. But the occurrence was rare and the mechanism
remained unclear for decades. With the surge of the number of
bariatric surgical procedures performed worldwide, an increas-
ing number of cases of copper-responsive anemia have been
published in the past decade and reignited the interest in under-
standing the role of copper in the pathogenesis and manage-
ment of anemia.86-88 It is now clear that copper is a vital
enzymatic cofactor in humans. Cuproproteins are involved in
important physiological functions. Two of the most direct
functions by cuproproteins on erythropoiesis include the regu-
lation of intestinal iron absorption by hephaestin and iron
release from the storage site by ceruloplasmin.89,90 The total
body copper pool is estimated to be 50–120 mg in adults.91
Approximately one-third of the total body copper is found in
the liver. The daily turnover is estimated to be approximately 1
mg through fecal loss. Therefore, total body store can be
depleted in several months if intake is insufficient.
Absorption From the GI Tract
The oral bioavailability of copper varies from 12%–70%
depending on the body copper status as well as the total amount
present in the GI tract. The average bioavailability based on
normal diets is between 30% and 40%.92,93 Copper binds to
food and complexes with mucosal secretions in the GI tract and
requires acid to be liberated for optimal absorption. Citrus
products and other chelating agents can improve copper
absorption by keeping copper from forming inabsorbable com-
plexes.94 Copper absorption takes place in the stomach and the
entire small intestine. But the most efficient absorption process
occurs in the ileum.
Once inside the enterocyte, cuprous ions are bound to vari-
ous copper chaperones for distribution to different organelles
and cellular compartments. In response to hypoferremia or
hypocupremia, copper is released into the systemic circulation
from the enterocyte. During the absorption process, copper
surplus is stored transiently in the enterocytes by binding to
metallothionein.91,94 If not needed by the body, the excess cop-
per will be lost through desquamation of the intestinal epithe-
lial cells under normal physiology, and copper overload can be
prevented. If copper is administered intravenously, this protec-
tive mechanism is bypassed, and the risk of copper toxicities is
increased over time.
The interrelationships between zinc and copper intake, spe-
cifically copper deficiency–associated anemia induced by
excessive zinc intake, were reported in rodents as early as
1964.83 Oral elemental zinc intake at 50 mg/d or higher induces
the metallothionein protein in enterocytes, which causes a
666 Journal of Parenteral and Enteral Nutrition 38(6)
“copper trap” that binds a large amount of dietary copper. This
can lead to a significant reduction in oral copper absorption.91
Cases of hypocupremia from chronic high intake of zinc have
been reported.95 There is also some evidence suggesting zinc
may interfere with copper transport through CTR1 and DMT1.
Copper absorption may also be impaired by high-dose supple-
mentation with iron or ascorbic acid. A high protein diet
increases copper absorption.96
Assessment of Copper Status
A patient with copper deficiency may have symptoms that affect
multiple organ systems. From the hematological perspective,
nonspecific anemia may be present by itself or with leukopenia
and pancytopenia.86,97,98 Previous studies and our ongoing
research suggest that approximately 60%–70% of symptomatic
copper deficiency presents with anemia, and more than 50% are
normocytic anemia. It is therefore important to identify other
concurrent causes of anemia, including other micronutrient defi-
ciencies. Risk factors for copper deficiency, which should be
suggested by diet history, GI tract surgery, or other precipitating
factors such as a large amount of zinc supplementation, should
also be identified.
Although serum or plasma copper concentration can be mea-
sured, it is not a reliable marker of copper status by itself as it
increases in the presence of an inflammatory response (ie, positive
acute-phase reactant).99-102 In the plasma, copper is highly bound
(~95%) to ceruloplasmin (also known as ferroxidase I), a blue
protein containing several copper atoms per molecule. In effect,
ceruloplasmin reflects total body copper status, and copper defi-
ciency decreases ceruloplasmin concentrations. Although some
interindividual variation is present, ceruloplasmin is still a reliable
indicator of copper status because of its large and relatively stable
binding capacity with plasma copper. Therefore, when evaluating
copper status in the body, ceruloplasmin concentration should be
assessed together with plasma copper concentration. Red cell cop-
per concentration may be less prone to the acute-phase response,
but its validity has not been established.103
Goal of Therapy and Replacement Strategy
The goals of therapy for copper deficiency are to treat the underly-
ing causes, reverse anemia and other related symptoms, and
restore copper status of the body. The amount of elemental copper
in different salt forms is summarized in Table 9. Many commer-
cially available copper supplements have their copper content
listed as elemental copper. The treatment experience for copper
deficiency is very limited. A meta-analysis of the published case
reports suggests that for noncritically ill patients, an initial treat-
ment regimen of oral elemental copper 2 mg/d (equivalent to 8 mg
of copper sulfate) up to 4 mg 3 times a day for 3 weeks reverses
hypocupremia within 2–3 weeks. For symptomatic critically ill
patients or for those who have severe malabsorptive disorders
such as short bowel syndrome or high ostomy output, IV
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Table 9.  Examples of Available Copper and Zinc Supplements
and the Respective Amount of Elemental Minerals.
Salt Form Elemental Mineral, % (w/w)
Copper gluconate 14
Cupric sulfate pentahydrate 25.5
Copper chloride 37
Zinc gluconate trihydrate 13
Zinc gluconate 14.3
Zinc sulfate 23
Zinc acetate 30
Zinc picolinate 35
Zinc chloride 48
Zinc oxide 81
If a product is labeled according to the amount of elemental mineral,
there is no need to calculate the elemental amount based on the salt form.
Refer to manufacturer’s package insert for product-specific information.
elemental copper should be given. Reported doses range from 1–4
mg/d as a short IV infusion for up to 6 days and then transition to
the oral elemental copper regimen as described above if possible.
Monitoring should also include serum copper and ceruloplasmin
concentrations to ensure repletion is successful, which is typically
achieved in 1 week but may take up to 3 months.86-88,104-107
Zinc
Homeostasis
Anemia caused by zinc deficiency alone is rare. But since zinc
plays an important role in protein synthesis and enzyme func-
tion, zinc deficiency may impair the homeostasis of iron and
copper. This can either result in anemia or poor response to ther-
apy with iron and copper supplementation. Zinc is the most
abundant trace element in the body other than iron. It is an essen-
tial nutrient that is a constituent of, or a cofactor to, more than
300 enzymes. These zinc metalloenzymes participate in the
metabolism of carbohydrates, proteins, lipids, and nucleic
acids.108-111 The normal adult body contains 1.5–2.5 g of zinc.
Zinc is extensively distributed in the body with 95% of the body
pool distributed intracellularly. In the blood, 85% of zinc is in
erythrocytes, although the zinc content in each leukocyte is at
least several folds higher than that of an erythrocyte.112,113 Zinc
undergoes substantial enteropancreatic recirculation. It is also
lost through sweat, hair and nail growth, and skin shedding.
Under normal physiology, the net loss is about 2–3 mg/d.
Absorption From the GI Tract
The intestinal transport of zinc has been reviewed recently.114-116
In brief, zinc ions are liberated from food-bound proteins at neu-
tral pH in the GI lumen and transported via both saturable and
passive transport processes. The transport process is the most
Chan and Mike 667
efficient in the duodenum and the jejunum. Diet and supple-
ments are the only source of zinc for humans. Body zinc stores,
the amount of zinc in diet, and the presence of phytate affect the
oral bioavailability of zinc. The absorption kinetics is similar to
that with cobalamin in that even though the net amount absorbed
would increase with larger intake, the fractional zinc absorption
would decrease.108 Dietary zinc is largely bound to proteins and
released gastric acid and pancreatic enzymes for absorption in
the distal jejunum and ileum. Ionic zinc found in zinc supple-
ments can be absorbed in the duodenum since it is already in free
form and does not need to be liberated from proteins.
Assessment of Zinc Status
Since 98% of the total body zinc is present in tissues and end
organs, plasma zinc concentration tends to be maintained by
continuous shifting from intracellular sources. Plasma zinc is a
reliable biomarker to evaluate the dose-dependent changes of
zinc status in response to dietary changes or supplementation in
a patient who is relatively healthy and clinically stable. It is a
poor indicator of total body zinc store.108 More important, zinc
is a negative acute-phase reactant, and its serum concentration
is inversely related to serum C-reactive protein concentra-
tion.117-119 Conversely, serum zinc concentrations may be nor-
mal during starvation or wasting syndromes due to release of
zinc from tissues and cells. Therefore, the sensitivity and speci-
ficity of serum/plasma zinc concentration alone in assessing
zinc status are poor in patients who are sick or clinically unsta-
ble. Measuring the rate of zinc turnover in the plasma through
the use of 24-hour zinc loss in body fluids (eg, urine and stool)
provides better assessment of total body zinc status.120,121
However, the feasibility of this approach can be limited in the
outpatient setting, and the accuracy in critically ill patients is
questionable since renal failure is often present.
Goal of Therapy and Replacement Strategy
The goal of therapy in zinc deficiency should be directed to restor-
ing total zinc store rather than normalizing plasma zinc concentra-
tion. Serial plasma zinc concentrations can be used before and after
initiating zinc supplements to evaluate the response to therapy.
Zinc supplements are available in various salt and dosage forms.
The amount of elemental zinc varies depending on the salt form
used and is summarized in Table 9. Similar to folic acid supple-
mentation, plasma zinc concentration increases dramatically
shortly after taking a zinc supplement and returns to baseline
within approximately 5 hours.122 Therefore, to avoid falsely ele-
vated zinc concentration, plasma zinc concentration should be
checked at least 5 hours after consuming zinc-containing supple-
ments or vitamin product. Zinc supplementation regimens vary,
and the best regimen in the management of anemia has not been
validated. Given the Recommended Daily Allowance is around 10
mg and the upper limit is 40 mg, any doses providing elemental
zinc within this range would be a reasonable starting regimen in the
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management of anemia. Dosing providing more than 50 mg of
elemental zinc increases the risk of copper malabsorption, and con-
current copper supplementation is recommended if higher doses of
zinc are used.91 Zinc absorption can be impaired by concurrent iron
administration, especially if the iron/zinc ratio is over 3:1.123
Translating the Science and Evidence to
Clinical Practice
Considerations in Product Selection When
Supplementing Micronutrients
The nonparenteral route is the preferred initial choice for all
patients unless documented malabsorptive disorders or villous
atrophy is present that severely impairs intestinal absorption.
Oral regimens are preferred over parenteral regimens because
not only are oral supplements effective in most patients, but
they are also more accessible and affordable as maintenance
therapy. More important, when the body’s micronutrient status
has improved, intestinal transport and absorption would be
downregulated under normal physiology and less mineral
would be absorbed. This is an important intrinsic regulatory
mechanism by the body to prevent systemic toxicity. Parenteral
regimens bypass this highly regulated intestinal absorption pro-
cess and lead to a significant increase in the total amount of
micronutrients in the body after each administration. Since the
daily amount eliminated from the body is very small for iron,
copper, and zinc, the risk of toxicity goes up with repeated par-
enteral administration. Some clinicians have been advocating
the use of IV iron as the first line of iron supplementation for
patients with inflammatory bowel disease and bariatric surgery
because of the much higher bioavailability over oral products.
IV administration is also less likely to cause GI disturbances,
which can lead to low adherence. A meta-analysis showed that
in patients with inflammatory bowel disease, although the mean
changes in hemoglobin and ferritin concentrations with IV iron
therapy are higher than with oral therapy, the net difference in
hemoglobin may not be clinically significant (0.68 g/dL).124
When supplementing iron, copper, and zinc, the doses of the
micronutrient should be based on the amount of elemental min-
erals (Table 10). This information should be communicated
with the patient to facilitate proper product selection when mak-
ing purchases. Since mineral and vitamin supplements are regu-
lated under the Dietary Supplement and Health Education Act
(DSHEA), these products do not need to undergo extensive
clinical testing to ensure certain pharmaceutical standards are
met. Therefore, product safety and consistency can be a con-
cern. Advising patients to purchase more reliable brands, such
as those undergoing routine voluntary testing by independent
laboratories or have received verification by the U.S.
Pharmacopeial Convention (USP), may address the safety con-
cern and help provide more consistent clinical responses.
Patients with celiac disease should be advised to purchase only
gluten-free supplements. All parenteral products, on the other
668 Journal of Parenteral and Enteral Nutrition 38(6)

Table 10.  Summary of Oral Bioavailability of Micronutrients and the Recommended Range of Doses for Initial Supplementation for
Their Deficiency.

Oral Bioavailability
Recommended Range of Oral
a
Micronutrients RDA for Adults Diet Supplements Doses for Initial Supplementation
Iron Male Nonheme: ~10% 20%–60%a 30–65 mg of elemental iron daily
    ≥19 years: 8 mg/d Heme: 15%–35%   on empty stomach if tolerated
  Female   for at least 3 months and until
    19–50 years: 18 mg/d   iron store is replenished
    ≥51 years: 8 mg/d  
    Pregnant: 27 mg/d  
    Breastfeeding: 9 mg/d  
Cobalamin Male: 2.4 mcg 20%–65% 1.3%–55% 500–1000 mcg cobalamin daily
  Female: 2.4 mcg   orally for 1 month
  Pregnant: 2.6 mcg  
  Breastfeeding: 2.8 mcg  
Folate Male: 400 mcg DFE 50% 85% with food 500 mcg folic acid daily orally for
  Female: 400 mcg 100% on empty at last 3 months
  Pregnant: 600 mcg stomach
  Breastfeeding: 500 mcg
Copper Male: 0.9 mg 12%–70% (average Presumably similar to 2 mg elemental copper daily to
  Female: 0.9 mg 30%–40%) dietary copper twice daily for 2–3 weeks
  Pregnant: 1.0 mg
  Breastfeeding: 1.3 mg  
Zinc Male: 11 mg 20%–92% depending Similar to food 10–20 mg elemental zinc
  Female: 8 mg on body zinc status   daily; doses higher than 50
  Pregnant: 11 mg and types of diet   mg daily should add copper
  Breastfeeding: 12 mg   supplementation

DFE, dietary folate equivalent.

a
Recommended Daily Allowance (RDA) values can be accessed through the U.S. Department of Agriculture website: http://iom.edu/Activities/Nutrition/
SummaryDRIs/~/media/Files/Activity%20Files/Nutrition/DRIs/RDA%20and%20AIs_Vitamin%20and%20Elements.pdf.

hand, are prescription drugs with more reliable product consis-
tency. Their safety and efficacy must be supported by data from
clinical trials for their intended indications prior to receiving the
approval of the U.S. Food and Drug Administration.
Future Challenges
The prevalence of anemia remains stable despite the availabil-
ity of fortified food and vitamin/mineral supplements, mostly
because the dynamic of this medical condition has been evolv-
ing. In many parts of the industrialized world, the precipitating
cause of nutritional anemia has mostly shifted from malnutri-
tion due to an insufficient food supply to secondary anemia due
to aging, GI tract surgery, drug therapy (eg, treatment for can-
cer, viral hepatitis), and some other iatrogenic causes. Despite
being a common and well-recognized medical condition, well-
controlled high-quality research aimed to assess and treat nutri-
tional anemia is scarce. Newer understanding of the
coregulations among iron, copper, zinc, and other B vitamins,
as well as the impact of inflammatory responses on the expres-
sion and function of various transport proteins, may further
challenge the conventional approach in treating anemia,
especially in the at-risk populations such as bariatric surgery
recipients, geriatric patients, and patients with inflammatory
bowel disease and celiac disease.
Summary
Anemia is a dynamic medical condition that is usually revers-
ible and preventable. Micronutrient status of the body plays an
important role in the prevention and optimization of the treat-
ment response for anemia. The 5 micronutrients of particular
importance are iron, cobalamin, folate, copper, and zinc.
Although lack of access to nutritionally balanced food is still a
common cause of anemia in general, in the Western world,
especially in the United States, the increased incidence of ane-
mia is also attributed to the aging population and the number of
recipients of proximal GI tract surgical procedures, including
bariatric surgery. In addition to dietary changes, the anatomical
and physiological changes to the GI tract associated with these
conditions may alter the intestinal transport and regulation of
micronutrient absorption. Reduction of gastric acid release
appears to cause a direct negative effect in reducing folate trans-
port and decreasing the amount of iron and copper being

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Chan and Mike 669
liberated from food. Bypassing the duodenum and proximal
jejunum has a more significant impact in reducing the absorp-
tion of iron, folate, and possibly copper.
Oral micronutrient supplementation is affordable, effective,
and generally well tolerated and should be the first-line man-
agement approach. Supplements for micronutrients are avail-
able in different formulations and salt forms. The decision on
which salt form, formulation, and dose to use should be indi-
vidualized based on the patient’s clinical condition, treatment
response, side effects, affordability, and adherence. In most
cases, the management goals for nutritional anemia should
include both normalizing hemoglobin concentration and
restoring the body reserve of the micronutrients.
Glossary
Hematocrit: The percentage of red blood cells in a blood sam-
ple. Also referred to as packed RBC volume.
Heme iron: Sources of iron bound within the iron-carrying
proteins, such as hemoglobin and myoglobin. The most
common sources of heme iron are red meat, poultry, and
fish. Heme iron is not the primary source of dietary iron but
is generally better absorbed than nonheme iron.
Hemoglobin: The oxygen-carrying part of red blood cells
(RBCs). The amount of hemoglobin in the blood is typi-
cally expressed in g/dL of blood (grams of hemoglobin per
deciliter).
Mean cell volume or mean corpuscular volume (MCV):
Assessment of the size of the RBCs that indicates whether
RBCs are smaller than usual (microcytic) or larger than nor-
mal (macrocytic). The average MCV is 90 ± 8 femtoliter
(fL). A low MCV is not specific to iron deficiency. Low val-
ues are encountered in thalassaemia (2 or 3 gene deletions for
α-thalassemia or β-thalassemia, including heterozygotes) and
in about 50% of people with anemia due to inflammation.
Nonheme iron: Also referred to as inorganic iron, found
mostly in plant foods, such as lentils and beans, or in iron-
fortified foods. Nonheme iron is not bound to protein.
Instead, it exists in ferric or ferrous form. Nonheme iron is
the most abundant source of dietary iron.
Serum ferritin: A measure of the amount of iron in body
stores if there is no concurrent infection; higher concentra-
tions reflect the size of the iron store; when the concentra-
tion is low (<12–15 ng/mL), then iron stores are depleted.
When infection is present, the concentration of ferritin may
increase even if iron stores are low; this means that it can be
difficult to interpret the concentration of ferritin in situa-
tions in which infectious diseases are common.
Soluble serum transferrin receptor (sTfR): Derived mostly
from developing RBCs and reflects the intensity of erythro-
poiesis and the demand for iron; the concentration rises in
iron-deficiency anemia, and it is a marker of the severity of
iron insufficiency only when iron stores have been
exhausted, provided that there are no other causes of
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abnormal erythropoiesis. The concentration of sTfR is also
increased in hemolytic anemia and thalassemia. Clinical
studies indicate that sTfR is less affected by inflammation
than is serum ferritin.
Transferrin saturation (TSAT): Transferrin, the principal
plasma protein for transport of iron, binds iron strongly at
physiologic pH. Transferrin is generally 20%–45% satu-
rated with iron. TSAT is usually reported as percent satura-
tion (100 × serum iron/TIBC).
Zinc protoporphyrin: A surrogate marker that reflects a
shortage in the supply of iron in the last stages of making
hemoglobin so that zinc is inserted into the protoporphyrin
molecule in the place of iron. Zinc protoporphyrin can be
detected in RBCs by fluorimetry and is a measure of the
severity of iron deficiency.
Normal physiology: Protoporphyrin + Fe++ à Fe++
protoporphyrin + globin → hemoglobin
When there is a lack of iron then zinc replaces iron in a
very small but measurable proportion of molecules,
Altered Response: Protoporphyrin + Zn++ à zinc pro-
toporphyrin + globin → ZPP-globin
Free erythrocyte protoporphyrin (FEP) is the compound left
over after the zinc moiety has been removed using strong
acids during the extraction and chemical measurement
process.
Further Reading
1. Butler CC, Vidal-Alaball J, Cannings-John R, et al. Oral vitamin B12 ver-
sus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic
review of randomized controlled trials. Fam Pract. 2006;23:279-285.
2. Chen M, Krishnamurthy A, Mohamed AR, Green R. Hematological dis-
orders following gastric bypass surgery: emerging concepts of the inter-
play between nutritional deficiency and inflammation. Biomed Res Int.
2013;2013:205467.
3. Chung M, Balk EM, Ip S, et al. Reporting of Systematic Reviews of
Micronutrients and Health: A Critical Appraisal. Nutrition Research
Series, vol 3. Rockville, MD: Agency for Healthcare Research and Quality;
2009. Technical Reviews, No. 17.3.
4. Knovich MA, Il’yasova D, Ivanova A, Molnár I. The association between
serum copper and anaemia in the adult Second National Health and Nutrition
Examination Survey (NHANES II) population. Br J Nutr. 2008;99:
1226-1229.
5. Lee TW, Kolber MR, Fedorak RN, van Zanten SV. Iron replacement ther-
apy in inflammatory bowel disease patients with iron deficiency anemia:
a systematic review and meta-analysis. J Crohns Colitis. 2012;6:267-275.
6. Ruz M, Carrasco F, Rojas P, et al. Heme- and nonheme-iron absorption and
iron status 12 mo after sleeve gastrectomy and Roux-en-Y gastric bypass in
morbidly obese women. Am J Clin Nutr. 2012;96:810-817.
7. Stabler, SP. Vitamin B12 deficiency. N Engl J Med. 2013;368:149-160.
8. Zhao N, Zhang AS, Enns CA. Iron regulation by hepcidin. J Clin Invest.
2013;123:2337-2343.
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