ArticlePDF Available

The Science and Practice of Micronutrient Supplementations in Nutritional Anemia: An Evidence-Based Review


Abstract and Figures

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.
Content may be subject to copyright.
Journal of Parenteral and Enteral
Volume 38 Number 6
August 2014 656 –672
© 2014 American Society
for Parenteral and Enteral Nutrition
DOI: 10.1177/0148607114533726
hosted at
Anemia is a medical condition indicative of poor nutrition sta-
tus or poor health. It is characterized by the reduction of hemo-
globin concentration, which is the most reliable diagnostic
criterion at the population level. Although the lower limit of
normal hemoglobin concentration remains a debated topic and
likely varies among different races and ethnicities, the World
Health Organization (WHO) standard is still the most widely
adopted definition of anemia (Table 1).1-3 Anemia is a signifi-
cant global health problem that affects a quarter of the popula-
tion worldwide. Epidemiological data show that the prevalence
of anemia is the highest among preschool-age children and
pregnant women, although the condition essentially affects all
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
children, pregnant women, older adults (especially residents in
nursing homes or assisted living facilities), and patients with
kidney diseases, uncontrolled chronic illness, extensive surger-
ies in the gastrointestinal (GI) tract, or cancer. The prevalence
of anemia also increases with age after the fifth decade of life
in both sexes. In the United States, the exact prevalence of ane-
mia in the entire population has not been formally evaluated.
According to National Health and Nutrition Examination
Survey III (NHANES III), among community-dwelling adults
65 years or older, the prevalence is 11% in men and 10.2% in
women.5 But in smaller studies focusing on the more vulnera-
ble populations, prevalence as high as 55% has been reported.6
The causes of anemia are usually multifactorial. They can
be generally grouped into 4 main categories: (1) increased loss
of blood volume or red cells (eg, acute or chronic bleeding),
(2) increased destruction of red cells (eg, hemolytic anemia),
(3) increased demand or decreased production/differentiation
of red cells (eg, bone marrow failure, insufficient supply of
nutrients involved in erythropoiesis, erythropoietin defi-
ciency), and (4) miscellaneous causes (eg, anemia of chronic
disease, cancer) (Table 2). These causes are not mutually
exclusive, and a person can have multiple causes leading to
533726PENXXX10.1177/0148607114533726Journal of Parenteral and Enteral NutritionChan and Mike
From the 1University of Washington, Seattle, Washington, USA.
Financial disclosure: None declared.
Received for publication January 2, 2014; accepted for publication April
3, 2014.
This article originally appeared online on May 20, 2014.
Corresponding Author:
Lingtak-Neander Chan, PharmD, BCNSP, CNSC, Associate Professor,
School of Pharmacy, Interdisciplinary Faculty, Graduate Program in
Nutritional Sciences, School of Public Health, University of Washington,
1959 NE Pacific St, HSC H-361B, Box 357630, Seattle, WA 98195, USA.
The Science and Practice of Micronutrient
Supplementations in Nutritional Anemia: An
Evidence-Based Review
Lingtak-Neander Chan, PharmD, BCNSP, CNSC1; and
Leigh Ann Mike, PharmD, BCPS, CGP1
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)
adult, life cycle; geriatrics, life cycle; minerals/trace elements; nutrition, vitamins; nutrition, anemia; iron; copper; cobalamin; folate; zinc
at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 23, 2015pen.sagepub.comDownloaded from
Chan and Mike 657
anemia. Statistics from the WHO show that as many as 50% of
the documented cases of anemia worldwide, especially those
in developing countries, are related to iron deficiency.3,4 This
finding is consistent with the data from NHANES III, which
show that nutrient deficiencies are the most common cause of
anemia in the United States. Specifically, deficiencies in iron,
folate, and cobalamin account for one-third of all documented
anemia cases in older adults.5 With the continued growth of the
aging population, the increased number of patients receiving
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
nutritional anemia is expected to rise.
Erythropoiesis involves the supply of hematopoietic stem
cells from the bone marrow, the presence of stem cell factor
interleukin-3 (IL-3), granulocyte-macrophage colony-stimulat-
ing factor (GM-CSF), and the production and release of eryth-
ropoietin (EPO) from the renal cortex to facilitate the
differentiation of stem cells into proerythroblasts, which mature
to become erythroblasts, reticulocytes, and eventually the enu-
cleated erythrocytes that carry oxygen throughout the body.7
Iron is an essential nutrient substrate in this process since it is
the key component of the oxygen-carrying hemoglobin as well
as a number of electron-transferring enzymes in the respiratory
chain; however, a few other micronutrients also play important
roles. Cobalamin and folate are needed for DNA synthesis, cell
division, and the proliferation of the progenitor cells. Zinc is not
only vital for protein and DNA synthesis but is also a key com-
ponent of a zinc-finger factor, GATA-1, that functions as a regu-
lator of the differentiation and development of erythroid cell
lineage.8-10 Copper is a cofactor for cytochrome c oxidase, an
important component of the mitochondrial electron transport
chain.11 In addition, ceruloplasmin, a plasma protein, and hepha-
estin, a membrane protein, are 2 cuproproteins with ferroxidase
activity that closely regulate the intestinal absorption and release
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
remain unclear and the optimal strategy in assessing and replac-
ing these nutrients has not been investigated.15-19 The diagnosis
and clinical evaluation of anemia have been extensively
reviewed elsewhere.20-22 The purposes of this tutorial are
to (1) discuss the science of micronutrient deficiencies—
specifically iron, cobalamin, folate, copper, and zinc—in rela-
tion to anemia; (2) translate the scientific knowledge into prac-
tice in assessing nutritional anemia; and (3) discuss the effective
treatment strategies based on the available evidence.
Homeostasis and Daily Turnover
Approximately 3–5 g of iron are stored in the human body under
normal physiology. About 60% of the total body iron is in the
form of hemoglobin in the circulating erythrocytes, and 15% is
found in muscle fiber as myoglobin. The remaining amount is
stored in the hepatic parenchymal tissues (about 1000 mg), the
Table 2. Summary of Major Categories and Causes of Anemia.
Category Examples of Cause
Increased loss of blood
volume or red cells
Acute hemorrhage
Gastrointestinal bleed
Increased destruction
of red cells
Autoimmune hemolytic reaction
Drug-induced hemolysis
Decreased production/
differentiation of red
Bone marrow failure
Disruption of the supply of “raw
materials” involved in erythropoiesis
Erythropoietin deficiency
(eg, end-stage kidney disease)
Miscellaneous causes Anemia of chronic disease
Note that these causes are not mutually exclusive.
Table 3. Overview of the Involvement of Iron, Cobalamin,
Copper, Folate, and Zinc in Erythropoiesis.
Micronutrient Major Physiological Roles in Erythropoiesis
Iron Key component of the oxygen-carrying protein
Cobalamin Cofactor for amino acid synthesis and
tricarboxylic acid cycle; facilitates maturation
and differentiation of the erythroid lineage
Folate Key component of 1-carbon transfer system for
DNA and protein synthesis and cell division
Copper Key regulator for iron transport from the
intestine (eg, hephaestin) and release from cells
into the circulation (eg, ceruloplasmin)
Zinc Cofactor for protein synthesis and regulator for
cell differentiation
Table 1. Cutoff of Hemoglobin Concentrations in Defining
Anemia According to WHO Recommendations.
Age Group
Concentration, g/dL
Children aged 6–59 mo <11.0
Children aged 5–11 y <11.5
Children aged 12–14 y <12.0
Adult males (>15 y) <13.0
Adult females, nonpregnant (>15 y) <12.0
Adult females, pregnant <11.0
These thresholds are set at the fifth percentile of the hemoglobin
concentration of a normal population of the same sex and age group (as
measured as venous blood at sea level). Data from the World Health
Organization (WHO;
at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 23, 2015pen.sagepub.comDownloaded from
658 Journal of Parenteral and Enteral Nutrition 38(6)
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
stem cells
stem cells
Cell differenaon
Oral absorpon
of iron
Cell proliferaon
and differenaon
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
Folate Duodenum and proximal jejunum SLC19A1 (minor)
SLC46A1 (major)
SLC46A1 enhanced by vitamin D
but inhibited by alcohol
Copper Most of the small intestine CTR1 (major)
DMT1 (minor)
Zinc Duodenum and jejunum ZIP4 (aka SLC39A4)
at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 23, 2015pen.sagepub.comDownloaded from
Chan and Mike 659
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
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
in critically ill patients, patients with an active infection, or those
with acute inflammatory responses
MCV MCV may appear within the normal range if there is concurrent
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
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;
measure during fasting if possible
Serum folate (fasting)
MCV MCV may appear normal in the presence of iron deficiency
Copper Plasma copper Inflammation can both plasma copper concentration and
ceruloplasmin concentration
Zinc 24-Hour urine zinc excretion Inflammation plasma zinc concentration; do not check plasma
zinc in critically ill patients. Consider checking C-reactive protein
before checking plasma zinc
Plasma/serum zinc (only in the
absence of inflammation)
MCV, mean corpuscular volume; MMA, methylmalonic acid; sTfR, soluble transferrin receptor; TIBC, total iron binding capacity; TSAT, transferrin
at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 23, 2015pen.sagepub.comDownloaded from
660 Journal of Parenteral and Enteral Nutrition 38(6)
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
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
Table 6. Examples of the Commonly Used Oral Iron Supplements.
Salt Form Elemental Iron, % (w/w) Available Formulations
Ferrous calcium citrate 9.5 Tablets
Ferrous gluconate 12 Tablets
Ferric ammonium citratea18 Capsules
Ferrous bisglycinate 20 Capsules, tablets
Ferrous sulfate heptahydrate 20 Oral solution, tablets, enteric-coated tablets, film-coated tablets
Ferrous sulfate monohydrate, dried 30 Capsules, tablets, extended-release tablets
Ferrous fumarate 33 Tablets, chewable tablets
Carbonyl iron (vaporized elemental iron) 98 Tablets, chewable tables, oral suspension
Polysaccharide complexa100 Capsules, oral solution, film-coated tablets
Heme iron polypeptide 100 Capsules
aUses ferric ion instead of ferrous ion.
at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 23, 2015pen.sagepub.comDownloaded from
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
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.
at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 23, 2015pen.sagepub.comDownloaded from
Table 7. Summary of Commercially Available Intravenous Iron Products.
Salt Form
Iron, mg/mL Labeled Uses Recommended Doses Remarks
Iron dextran
INFeD 50 Treatment of patients with documented
iron deficiency in whom oral
administration is unsatisfactory or
Dose is based on the following formula:
Dose (mL) = 0.0442 (desired Hb − observed
Hb) × LBW + (0.26 × LBW)
Risk for anaphylactic-type reactions
A test dose is required prior to first
A total dose as a single infusion is
Individual doses of 100 mg or less may be
given on a daily basis until the calculated total
amount required has been reached
Can also be administered
Iron sucrose
Venofer 20 Treatment of iron-deficiency anemia
in adult patients with chronic kidney
On hemodialysis: 100 mg
Not on dialysis: 200 mg
Peritoneal dialysis: 300 mg on 2 occasions, 14
days apart, followed by 400 mg 14 days later
Observe for hypersensitivity
reactions and hypotension during
Ferric gluconate
Ferrlecit 12.5 Treatment of iron-deficiency anemia in
adult patients and in pediatric patients
age 6 years and older with chronic
kidney disease receiving hemodialysis
who are receiving supplemental EPO
125 mg each dose
Most patients require a cumulative dose of
1000 mg administered over 8 dialysis sessions
Observe for hypersensitivity
reactions and hypotension during
Contains benzyl alcohol as
Ferumoxytol Feraheme 30 Treatment of iron-deficiency anemia
in adult patients with chronic kidney
510-mg IV injection followed by a second
510-mg IV injection 3–8 days later
Observe for hypersensitivity
reactions and hypotension during
Can alter magnetic resonance
imaging studies
Injectafer 50 Treatment of iron-deficiency anemia in
adult patients:
Who have intolerance to oral
iron or have had unsatisfactory
response to oral iron; who have
non-dialysis-dependent chronic
kidney disease
<50 kg: 15 mg/kg on day 1; repeat after at
least 7 days
50 kg: 750 mg on day 1; repeat after at least
7 days; maximum 1500 mg per course
Observe for hypersensitivity
reactions and hypertension during
May be repeated if iron deficiency
Monofer 100 Treatment of iron-deficiency anemia in
the following conditions:
When oral iron preparations are
ineffective or cannot be used
Where there is a clinical need to
deliver iron rapidly
Cumulative dose is based on the following
Iron dose (mg iron) = body weight (kg) ×
(target Hg – actual Hg)
(g/dL) × 2.4(C) + iron for iron stores (mg iron)
Not available in the United States
Observe for hypersensitivity
reactions and hypotension during
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.
aINFeD (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).
at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 23, 2015pen.sagepub.comDownloaded from
Chan and Mike 663
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
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
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
at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 23, 2015pen.sagepub.comDownloaded from
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
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
Folates refer to a family of B vitamins structurally including
a pteridine ring attached to para-aminobenzoate with a
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
Table 8. Comparison of Dose and Retention Rate of
Cyanocobalamin After Oral and Intramuscular Therapy.
Percentage of Dose Retention After
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
at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 23, 2015pen.sagepub.comDownloaded from
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
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
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
at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 23, 2015pen.sagepub.comDownloaded from
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
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
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
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.
at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 23, 2015pen.sagepub.comDownloaded from
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
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
at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 23, 2015pen.sagepub.comDownloaded from
668 Journal of Parenteral and Enteral Nutrition 38(6)
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.
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
Table 10. Summary of Oral Bioavailability of Micronutrients and the Recommended Range of Doses for Initial Supplementation for
Their Deficiency.
Micronutrients RDA for Adultsa
Oral Bioavailability Recommended Range of Oral
Doses for Initial SupplementationDiet Supplements
Iron Male Nonheme: ~10% 20%–60%a30–65 mg of elemental iron daily
on empty stomach if tolerated
for at least 3 months and until
iron store is replenished
19 years: 8 mg/d Heme: 15%–35%
19–50 years: 18 mg/d
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
orally for 1 month
Female: 2.4 mcg
Pregnant: 2.6 mcg
Breastfeeding: 2.8 mcg
Folate Male: 400 mcg DFE 50% 85% with food
100% on empty
500 mcg folic acid daily orally for
at last 3 months
Female: 400 mcg
Pregnant: 600 mcg
Breastfeeding: 500 mcg
Copper Male: 0.9 mg 12%–70% (average
Presumably similar to
dietary copper
2 mg elemental copper daily to
twice daily for 2–3 weeks
Female: 0.9 mg
Pregnant: 1.0 mg
Breastfeeding: 1.3 mg
Zinc Male: 11 mg 20%–92% depending
on body zinc status
and types of diet
Similar to food 10–20 mg elemental zinc
daily; doses higher than 50
mg daily should add copper
Female: 8 mg
Pregnant: 11 mg
Breastfeeding: 12 mg
DFE, dietary folate equivalent.
aRecommended Daily Allowance (RDA) values can be accessed through the U.S. Department of Agriculture website:
at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 23, 2015pen.sagepub.comDownloaded from
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.
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
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
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
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.
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:
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.
1. Beutler E, Waalen J. The definition of anemia: what is the lower limit
of normal of the blood hemoglobin concentration? Blood. 2006;107(5):
2. World Health Organization (WHO). Nutritional Anaemias. Geneva,
Switzerland: WHO; 1968. WHO Technical Report Series No. 405.
at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 23, 2015pen.sagepub.comDownloaded from
670 Journal of Parenteral and Enteral Nutrition 38(6)
3. World Health Organization. Haemoglobin concentrations for the diag-
nosis of anaemia and assessment of severity.
indicators/haemoglobin.pdf. Accessed April 28, 2014.
4. McLean E, Cogswell M, Egli I, Wojdyla D, de Benoist B, eds. Worldwide
Prevalence of Anaemia 1993-2005. WHO Global Database on Anaemia.
Geneva, Switzerland: World Health Organization; 2008.
5. Guralnik J, Eisenstaedt R, Ferrucci L, et al. Prevalence of anemia in per-
sons 65 years and older in the United States: evidence for a high rate of
unexplained anemia. Blood. 2004;104:2263-2268.
6. World Health Organization. Vitamin and Mineral Nutrition Information
System (VMNIS).
usa_ida.pdf. Accessed April 28, 2014.
7. Hodges VM, Rainey S, Lappin TR, Maxwell AP. Pathophysio-
logy of anemia and erythrocytosis. Crit Rev Oncol Hematol. 2007;64:
8. Zheng J, Kitajima K, Sakai E, et al. Differential effects of GATA-1
on proliferation and differentiation of erythroid lineage cells. Blood.
9. Cantor AB, Orkin SH. Transcriptional regulation of erythropoiesis: an
affair involving multiple partners. Oncogene. 2002;21(21):3368-3376.
10. Saleque S, Cameron S, Orkin SH. The zinc-finger proto-oncogene Gfi-1b
is essential for development of the erythroid and megakaryocytic lineages.
Genes Dev. 2002;16(3):301-306.
11. Bustos RI, Jensen EL, Ruiz LM, et al. Copper deficiency alters cell bio-
energetics and induces mitochondrial fusion through up-regulation of
MFN2 and OPA1 in erythropoietic cells. Biochem Biophys Res Commun.
12. Sarkar J, Seshadri V, Tripoulas NA, Ketterer ME, Fox PL. Role of
ceruloplasmin in macrophage iron efflux during hypoxia. J Biol Chem.
13. Anderson GJ, Frazer DM, McKie AT, Vulpe CD. The ceruloplasmin
homolog hephaestin and the control of intestinal iron absorption. Blood
Cells Mol Dis. 2002;29(3):367-375.
14. Petrak J, Vyoral D. Hephaestin—a ferroxidase of cellular iron export. Int
J Biochem Cell Biol. 2005;37(6):1173-1178.
15. Power HJ. Riboflavin (vitamin B-2) and health. Am J Clin Nutr.
16. Ajayi OA, Okike OC, Yusuf Y. Haematological response to supplements
of riboflavin and ascorbic acid in Nigerian young adults. Eur J Haematol.
17. Semba RD, Ferrucci L, Cappola AR, et al. Low serum selenium is
associated with anemia among older women living in the community:
the Women’s Health and Aging Studies I and II. Biol Trace Elem Res.
18. Semba RD, Ricks MO, Ferrucci L, Xue QL, Guralnik JM, Fried LP.
Low serum selenium is associated with anemia among older adults in the
United States. Eur J Clin Nutr. 2009;63(1):93-99.
19. Roy CN, Semba RD, Sun K, et al. Circulating selenium and carboxy-
methyl-lysine, an advanced glycation endproduct, are independent
predictors of anemia in older community-dwelling adults. Nutrition.
20. Koury MJ, Rhodes M. How to approach chronic anemia. Hematol Am Soc
Hematol Educ Prog. 2012;2012:183-190.
21. Pang WW, Schrier SL. Anemia in the elderly. Curr Opin Hematol.
22. Cullis J. Anaemia of chronic disease. Clin Med. 2013;13(2):193-196.
23. Andrews NC. Disorders of iron metabolism. N Engl J Med. 1999;341:
24. Blachier F, Vaugelade P, Robert V, et al. Comparative capacities of
the pig colon and duodenum for luminal iron absorption. Can J Physiol
Pharmacol. 2007;85(2):185-192.
25. Geisser P, Burckhardt S. The pharmacokinetics and pharmacodynamics of
iron preparation. Pharmaceutics. 2011;3:12-33.
26. von Drygalski A, Andris DA. Anemia after bariatric surgery: more than
just iron deficiency. Nutr Clin Pract. 2009;24(2):217-226.
27. Thankachan P, Walczyk T, Muthayya S, Kurpad AV, Hurrell RF. Iron
absorption in young Indian women: the interaction of iron status with
the influence of tea and ascorbic acid. Am J Clin Nutr. 2008;87(4):
28. Thankachan P, Kalasuramath S, Hill AL, Thomas T, Bhat K, Kurpad AV.
A mathematical model for the hemoglobin response to iron intake, based
on iron absorption measurements from habitually consumed Indian meals.
Eur J Clin Nutr. 2012;66:481-487.
29. Taylor P, Martínez-Torres C, Leets I, Ramirez J, Garcia-Casal MN,
Layrisse M. Relationships among iron absorption, percent saturation of
plasma transferrin and serum ferritin concentration in humans. J Nutr.
30. Thurnham DI. Interactions between nutrition and immune function: using
inflammation biomarkers to interpret micronutrient status. Proc Nutr Soc.
31. Goddard AF, James MW, McIntyre AS, Scott BB; British Society of
Gastroenterology. Guidelines for the management of iron deficiency anae-
mia. Gut. 2011;60(10):1309-1316.
32. Beshara S, Lundqvist H, Sundin J, et al. Pharmacokinetics and red cell
utilization of iron(III)-hydroxidesucrose complex in anaemic patients:
a study using positron emission tomography. Br J Haematol. 1999;104:
33. Casgrain A, Collings R, Harvey LJ, Hooper L, Fairweather-Tait SJ. Effect
of iron intake on iron status: a systematic review and meta-analysis of
randomized controlled trials. Am J Clin Nutr. 2012;96(4):768-780.
34. Bernhart FE, Skeggs L. The iron content of crystalline human hemoglo-
bin. J Biol Chem. 1943;147:19-22.
35. Charoenlarp P, Dhanamitta S, Kaewvichit R, et al. A WHO collaborative
study on iron supplementation in Burma and in Thailand. Am J Clin Nutr.
36. Fogelholm M, Suominen M, Rita H. Effects of low-dose iron supplemen-
tation in women with low serum ferritin concentration. Eur J Clin Nutr.
37. Fernández-Gaxiola AC, De-Regil LM. Intermittent iron supplementa-
tion for reducing anaemia and its associated impairments in menstruating
women. Cochrane Database Syst Rev. 2011;(12):CD009218.
38. Gilgen D, Mascie-Taylor CG. The effect of weekly iron supplementa-
tion on anaemia and on iron deficiency among female tea pluckers in
Bangladesh. J Hum Nutr Diet. 2001;14:185-190.
39. Petry N, Egli I, Zeder C, Walczyk T, Hurrell R. Polyphenols and phytic
acid contribute to the low iron bioavailability from common beans in
young women. J Nutr. 2010;140(11):1977-1982.
40. Hurrell R, Egli I. Iron bioavailability and dietary reference values. Am J
Clin Nutr. 2010;91(5):1461S-1467S.
41. Motoya T, Miyashita M, Kawachi A, Yamada K. Effects of ascorbic
acid on interactions between ciprofloxacin and ferrous sulphate, sodium
ferrous citrate or ferric pyrophosphate, in mice. J Pharm Pharmacol.
42. Troesch B, Egli I, Zeder C, Hurrell RF, Zimmermann MB. Fortification
iron as ferrous sulfate plus ascorbic acid is more rapidly absorbed than as
sodium iron EDTA but neither increases serum nontransferrin-bound iron
in women. J Nutr. 2011;141:822-827.
43. Mehdad A, Siqueira EM, Arruda SF. Effect of vitamin A deficiency on
iron bioavailability. Ann Nutr Metab. 2010;57:35-39.
44. Michelazzo FB, Oliveira JM, Stefanello J, Luzia LA, Rondó PH. The
influence of vitamin A supplementation on iron status. Nutrients. 2013;5:
45. Thomas CE, Gaffney-Stomberg E, Sun BH, O’Brien KO, Kerstetter JE,
Insogna KL. Increasing dietary protein acutely augments intestinal iron
transporter expression and significantly increases iron absorption in rats.
FASEB J. 2013;27:2476-2483.
at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 23, 2015pen.sagepub.comDownloaded from
Chan and Mike 671
46. Centers for Disease Control and Prevention. Recommendations to prevent
and control iron deficiency in the United States. MMWR Recomm Rep.
47. Gomollón F, Gisbert JP. Current management of iron deficiency anemia
in inflammatory bowel diseases: a practical guide. Drugs. 2013;73(16):
48. Rimon E, Kagansky N, Kagansky M, et al. Are we giving too much
iron? Low-dose iron therapy is effective in octogenarians. Am J Med.
49. Stabler SP. Vitamin B12 deficiency. N Engl J Med. 2013;368:149-160.
50. Scott JM. Folate and vitamin B12. Proc Nutr Soc. 1999;58:441-448.
51. Doets EL, In ‘t Veld PH, Szczecińska A, et al. Systematic review on
daily vitamin B12 losses and bioavailability for deriving recommenda-
tions on vitamin B12 intake with the factorial approach. Ann Nutr Metab.
52. Bose S, Kalra S, Yammani RR, Ahuja R, Seetharam B. Plasma mem-
brane delivery, endocytosis and turnover of transcobalamin receptor in
polarized human intestinal epithelial cells. J Physiol. 2007;581(pt 2):
53. Seetharam B, Yammani RR. Cobalamin transport proteins and their cell-
surface receptors. Expert Rev Mol Med. 2003;5(18):1-18.
54. Heyssel RM, Bozian RC, Darby WJ, Bell MC. Vitamin B12 turnover
in man: the assimilation of vitamin B12 from natural foodstuff by man
and estimates of minimal daily requirements. Am J Clin Nutr. 1966;18:
55. Carmel R. Cobalamin (vitamin B12). In: Ross AC, Caballero B, Cousins
RJ, Tucker KI, Ziegler TB, eds. Modern Nutrition in Health and
Disease. 11th ed. Philadelphia, PA: Lippincott Williams & Wilkins;
56. Berlin H, Berlin R, Brante G. Oral treatment of pernicious anemia with
high doses of vitamin B12 without intrinsic factor. Acta Med Scand.
57. Berlin R, Berlin H, Brante G, Pilbrant A. Vitamin B12 body stores dur-
ing oral and parenteral treatment of pernicious anaemia. Acta Med Scand.
58. Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum
methylmalonic acid and total homocysteine determinations for diagnosing
cobalamin and folate deficiencies. Am J Med. 1994;96:239-246.
59. Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders
cause by cobalamin deficiency in the absence of anemia or macrocytosis.
N Engl J Med. 1988;318:1720-1728.
60. Carmel R. Biomarkers of cobalamin (vitamin B-12) status in the epidemio-
logic setting: a critical overview of context, applications, and performance
characteristics of cobalamin, methylmalonic acid, and holotranscobalamin
II. Am J Clin Nutr. 2011;94(1):348S-358S.
61. Carmel R. Diagnosis and management of clinical and subclinical cobala-
min deficiencies: why controversies persist in the age of sensitive meta-
bolic testing. Biochimie. 2013;95:1047-1055.
62. Delpre G, Stark P, Niv Y. Sublingual therapy for cobalamin deficiency as
an alternative to oral and parenteral cobalamin supplementation. Lancet.
63. Bodamer OAF, Scaglia F. Sublingual therapy for cobalamin deficiency.
Lancet. 1999;354:1562.
64. Sharabi A, Cohen E, Sulkes J, Garty M. Replacement therapy for vitamin
B12 deficiency: comparison between the sublingual and oral route. Br J
Clin Pharmacol. 2003;56:635-638.
65. Solomon LR. Disorders of cobalamin (vitamin B12) metabolism: emerg-
ing concepts in pathophysiology, diagnosis and treatment. Blood Rev.
66. Andrès E, Dali-Youcef N, Vogel T, Serraj K, Zimmer J. Oral cobalamin
(vitamin B(12)) treatment: an update. Int J Lab Hematol. 2009;31(1):
67. Andrès E, Fothergill H, Mecili M. Efficacy of oral cobalamin (vitamin
B12) therapy. Expert Opin Pharmacother. 2010;11(2):249-256.
68. Rhode BM, Arseneau P, Cooper BA, Katz M, Gilfix BM, MacLean LD.
Vitamin B-12 deficiency after gastric surgery for obesity. Am J Clin Nutr.
69. Nascobal [package insert]. Spring Valley, NY: Par Pharmaceutical
Companies, Inc; 2011.
70. Zhao R, Matherly LH, Goldman ID. Membrane transporters and folate
homeostasis: intestinal absorption and transport into systemic compart-
ments and tissues. Expert Rev Mol Med. 2009;11:e4.
71. Koury MJ, Ponka P. New insights into erythropoiesis: the roles of folate,
vitamin B12, and iron. Annu Rev Nutr. 2004;24:105-131.
72. Hoppner K, Lampi B. Folate levels in human liver from autopsies in
Canada. Am J Clin Nutr. 1980;33:862-864.
73. Stites TE, Bailey LB, Scott KC, Toth JP, Fisher WP, Gregory JF III. Kinetic
modeling of folate metabolism through use of chronic administration of
deuterium-labeled folic acid in men. Am J Clin Nutr. 1997;65(1):53-60.
74. Institute of Medicine, National Academy of Sciences. Dietary Reference
Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin
B12, Pantothenic Acid, Biotin and Choline. Washington, DC: National
Academies Press; 1998.
75. Zhao R, Goldman ID. Folate and thiamine transporters mediated by
facilitative carriers (SLC19A1-3 and SLC46A1) and folate receptors. Mol
Aspects Med. 2013;34:373-385.
76. Maki KC, Ndife LI, Kelley KM, et al. Absorption of folic acid from
a softgel capsule compared to a standard tablet. J Acad Nutr Diet.
77. Bailey RL, Mills JL, Yetley EA, et al. Unmetabolized serum folic acid and
its relation to folic acid intake from diet and supplements in a nationally
representative sample of adults aged 60 years in the United States. Am J
Clin Nutr. 2010;92:383-389.
78. Carter B, Monsivais P, Drewnowski A. Absorption of folic acid and ascor-
bic acid from nutrient comparable beverages. J Food Sci. 2010;75(9):
79. Wu A, Chanarin I, Slavin G, Levi AJ. Folate deficiency in the alcoholic—
its relationship to clinical and haematological abnormalities, liver disease
and folate stores. Br J Haematol. 1975;29(3):469-478.
80. Butterworth CE Jr, Tamura T. Folic acid safety and toxicity: a brief
review. Am J Clin Nutr. 1989;50:353-358.
81. Joseph B, Ramesh N. Weekly dose of iron-folate supplementation with
vitamin-C in the workplace can prevent anaemia in women employees.
Pak J Med Sci. 2013;29(1):47-52.
82. Robscheit-Robbins FS, Whipple GH. Copper and cobalt-related hemoglo-
bin production in experimental anemia. J Exp Med. 1942;75(5):481-487.
83. Guggenheim K. The role of zinc, copper and calcium in the etiology of the
“meat anemia.” Blood. 1964:786-794.
84. Cartwright GE, Wintrobe MM. The question of copper deficiency in man.
Am J Clin Nutr. 1964;15:94-110.
85. Butterworth CE Jr, Gubler CJ, Cartwright GE, Wintrobe MM. Studies on
copper metabolism, XXVI: plasma copper in patients with tropical sprue.
Proc Soc Exper Biol Med. 1958;98:594.
86. Halfdanarson TR, Kumar N, Li CY, Phyliky RL, Hogan WJ.
Hematological manifestations of copper deficiency: a retrospective
review. Eur J Haematol. 2008;80(6):523-531.
87. Gletsu-Miller N, Broderius M, Frediani JK, et al. Incidence and preva-
lence of copper deficiency following roux-en-y gastric bypass surgery. Int
J Obes (Lond). 2012;36(3):328-335.
88. Griffith DP, Liff DA, Ziegler TR, Esper GJ, Winton EF. Acquired cop-
per deficiency: a potentially serious and preventable complication
following gastric bypass surgery. Obesity (Silver Spring). 2009;17(4):
89. Vulpe CD, Kuo YM, Murphy TL, et al. Hephaestin, a ceruloplasmin
homologue implicated in intestinal iron transport, is defective in the sla
mouse. Nat Genet. 1999;21(2):195-199.
90. Prohaska JR. Impact of copper limitation on expression and function of
multicopper oxidases (ferroxidases). Adv Nutr. 2011;2(2):89-95.
at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 23, 2015pen.sagepub.comDownloaded from
672 Journal of Parenteral and Enteral Nutrition 38(6)
91. Collins JF. Copper. In: Ross AC, Caballero B, Cousins RJ, Tucker KI,
Ziegler TB, eds. Modern Nutrition in Health and Disease. 11th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2014:206-216.
92. Wapnir RA. Copper absorption and bioavailability. Am J Clin Nutr.
93. Turnlund JR, Keyes WR, Anderson HL, Acord LL. Copper absorption
and retention in young men at three levels of dietary copper by use of the
stable isotope 65Cu. Am J Clin Nutr. 1989;49:870-878.
94. Crisponia G, Nurchia VM, Fanni D, Gerosa C, Nemolato S, Faa G.
Copper-related diseases: from chemistry to molecular pathology.
Coordination Chem Rev. 2010;254:876-889.
95. Rowin J, Lewis SL. Copper deficiency myeloneuropathy and pancytope-
nia secondary to overuse of zinc supplementation. J Neurol Neurosurg
Psychiatry. 2005;76(5):750-751.
96. Greger JL, Snedeker SM. Effect of dietary protein and phosphorus levels
on the utilization of zinc, copper and manganese by adult males. J Nutr.
97. Harvey LJ, McArdle HJ. Biomarkers of copper status: a brief update. Br
J Nutr. 2008;99(suppl 3):S10-S13.
98. Gabreyes AA, Abbasi HN, Forbes KP, McQuaker G, Duncan A, Morrison
I. Hypocupremia associated cytopenia and myelopathy: a national retro-
spective review. Eur J Haematol. 2013;90(1):1-9.
99. Bo S, Durazzo M, Gambino R, et al. Associations of dietary and serum
copper with inflammation, oxidative stress, and metabolic variables in
adults. J Nutr. 2008;138:305-310.
100. Malek F, Jiresova E, Dohnalova A, Koprivova H, Spacek R. Serum
copper as a marker of inflammation in prediction of short term out-
come in high risk patients with chronic heart failure. Int J Cardiol.
101. Mirastschijski U, Martin A, Jorgensen LN, Sampson B, Ågren MS. Zinc,
copper, and selenium tissue levels and their relation to subcutaneous
abscess, minor surgery, and wound healing in humans. Biol Trace Elem
Res. 2013;153(1-3):76-83.
102. Bui VQ, Stein AD, DiGirolamo AM, et al. Associations between serum
C-reactive protein and serum zinc, ferritin, and copper in Guatemalan
school children. Biol Trace Elem Res. 2012;148(2):154-160.
103. Oakes EJ, Lyon TD, Duncan A, Gray A, Talwar D, O’Reilly DS. Acute
inflammatory response does not affect erythrocyte concentrations of cop-
per, zinc and selenium. Clin Nutr. 2008;27(1):115-120.
104. Btaiche IF, Yeh AY, Wu IJ, Khalidi N. Neurological dysfunction and
pancytopenia secondary to acquired copper deficiency following duo-
denal switch: case report and review of the literature. Nutr Clin Pract.
105. Hayton BA, Broome HE, Lilenbaum RC. Copper deficiency-induced
anemia and neutropenia secondary to intestinal malabsorption. Am J
Hematol. 1995;48:45-47.
106. Schleper B, Stuerenburg HJ. Copper deficiency–associated myelopathy
in a 46-year-old woman. J Neurol. 2001;248(8):705-706.
107. Choi ER, Strum W. Hypocupremia-related myeloneuropathy following
gastrojejunal bypass surgery. Ann Nutr Metab. 2010;57:190-192.
108. King JC, Cousins RJ. Zinc. In: Ross AC, Caballero B, Cousins RJ, Tucker
KI, Ziegler TB, eds. Modern Nutrition in Health and Disease. 11th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2014:189-205.
109. King JC. Zinc: an essential but elusive nutrient. Am J Clin Nutr.
110. Chasapis CT, Loutsidou AC, Spiliopoulou CA, Stefanidou ME. Zinc and
human health: an update. Arch Toxicol. 2012;86(4):521-534.
111. Roohani N, Hurrell R, Kelishadi R, Schulin R. Zinc and its importance for
human health: an integrative review. J Res Med Sci. 2013;18(2):144-157.
112. Hinks LJ, Clayton BE, Lloyd RS. Zinc and copper concentrations in leu-
cocytes and erythrocytes in healthy adults and the effect of oral contra-
ceptives. J Clin Pathol. 1983;36(9):1016-1021.
113. Naber TH, van den Hamer CJ, van den Broek WJ, Roelofs H. Zinc
exchange by blood cells in nearly physiologic standard conditions. Biol
Trace Elem Res. 1994;46:29-50.
114. Lichten LA, Cousins RJ. Mammalian zinc transporters: nutritional and
physiologic regulation. Annu Rev Nutr. 2009;29:153-176.
115. Wang X, Zhou B. Dietary zinc absorption: a play of Zips and ZnTs in the
gut. IUBMB Life. 2010;62(3):176-182.
116. Cousins RJ. Gastrointestinal factors influencing zinc absorption and
homeostasis. Int J Vitam Nutr Res. 2010;80(4-5):243-248.
117. Ghayour-Mobarhan M, Taylor A, New SA, Lamb DJ, Ferns GA.
Determinants of serum copper, zinc and selenium in healthy subjects.
Ann Clin Biochem. 2005;42(pt 5):364-375.
118. Duggan C, MacLeod WB, Krebs NF, et al. Plasma zinc concentrations
are depressed during the acute phase response in children with falciparum
malaria. J Nutr. 2005;135(4):802-807.
119. Chan L-N, Sethi P, Mike LA, Lee JK, Farver KL, Reilly DF. Comparison
of clinical characteristics and outcomes in medically ill ICU (MICU)
patients according to serum zinc profile on admission [abstract]. JPEN J
Parenter Enteral Nutr. 2008;32(3):308.
120. Henderson LM, Brewer GJ, Dressman JB, et al. Use of zinc tolerance test
and 24-hour urinary zinc content to assess oral zinc absorption. J Am Coll
Nutr. 1996;15(1):79-83.
121. Sieniawska CE, Jung LC, Olufadi R, Walker V. Twenty-four-hour uri-
nary trace element excretion: reference intervals and interpretive issues.
Ann Clin Biochem. 2012;49(pt 4):341-351.
122. Meadows NJ, Grainger SL, Ruse W, Keeling PWN, Thompson RPH.
Oral iron and the bioavailability of zinc. BMJ. 1983;287:1013-1014.
123. Solomon NW, Jacob RA. Studies on the bioavailability of zinc in
humans: effect of heme and nonheme iron on the absorption of zinc. Am
J Clin Nutr. 1981;34:475-482.
124. Lee TW, Kolber MR, Fedorak RN, van Zanten SV. Iron replacement
therapy in inflammatory bowel disease patients with iron deficiency
anemia: a systematic review and meta-analysis. J Crohns Colitis.
at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 23, 2015pen.sagepub.comDownloaded from
... Adults suffering from nutritional disorders may exhibit severe organ dysfunction as well as atypical signs and symptoms of common health problems, which may be misdiagnosed or sub-optimally treated [23]. For example, insufficient intake of iron, vitamin B12, folate, as well as caloric and protein restriction, can cause nutritional anemia, which is manifested by low Hb concentration (<13.0 g/dL for male, <12.0 g/dL for female) [24]. In fact, the adult females are more susceptible to anemia than males due to the blood loss during menstrual cycle [25]. ...
... WHO defines anemia as having >13 g Hb/dL for men and >12 g Hb/dL for women [30]. Anemia is one of the most significant worldwide disorders affecting almost a third of the world population [24]. Due to menstruation, women of reproductive age are at a high risk of having anemia [34]. ...
Full-text available
Practicing restricted weight loss diet programs (WLDPs) without proper supervision can result in nutritional deficiency, which can lead to the development of several nutritional disorders. The current cross-sectional study aimed to investigate the impact of WLDPs practiced by university female students on the prevalence of micronutrient deficiencies, anemia, and organs dysfunction, and to assess the association of identified anomalies with dieting practices and dietary habits of university female students. A total of 185 (105 dieting and 80 non-dieting) volunteers’ female students at Al-Hussein Bin Talal University participated in this study. After the participants answered a questionnaire, blood samples were collected for hematological and biochemical analysis, and the body mass index (BMI) was determined. The results show that there were no significant differences between dieting and non-dieting groups in biochemical markers of kidney and liver functions as well as serum levels of copper, zinc, and folate. On the other hand, dieting participants exhibited significantly lower level of hemoglobin, serum ferritin, iron, and vitamin B12 than encounter group (p<0.05). Attempting WLDPs significantly increased the prevalence of anemia (46.7%), iron deficiency (57.1%), and iron deficiency anemia (IDA) (41.9%), comparing to non-dieting students (28.7%, 33.8%, and 15.0%, respectively) (p<0.005). Chi-square test showed that the development of anemia among dieting girls was significantly dependence of several factors including BMI category, source and duration of the diet programs, and skipping breakfast (p<0.05). In conclusion, young girls attempting WLDPs without professional guidance are more prone to the risk of nutrients deficiencies and the development nutritional disorders like IDA. An educational program should be employed to teach young females on when and how to adopt healthy WLDPs.
... To analyze the associations between hemoglobin and neuroimaging biomarkers, three models were tested for stepwise control of potential confounders. The first model did not include any covariates, the second model included age and sex as covariates, and the third model included all potential covariates (i.e., age, sex, education, APOE4 positivity, VRS, clinical diagnosis, BMI, annual income status, occupational complexity, smoking, alcohol intake, vitamin B 12 , folate, platelet level, serum creatinine, medication use within 4 weeks, and declined food intake over past 3 months) that might confound the relationship between hemoglobin level and brain changes (Ballard, 1997;Vellas et al., 1999;Borroni et al., 2002;Chan and Mike, 2014;Shi et al., 2018). In multiple linear regression analyses, the normality was checked using the Kolmogorov-Smirnov test for dependent variable(s). ...
Full-text available
Background: Despite known associations between low blood hemoglobin level and Alzheimer's disease (AD) or cognitive impairment, the underlying neuropathological links are poorly understood. We aimed to examine the relationships of blood hemoglobin levels with in vivo AD pathologies (i.e., cerebral beta-amyloid [Aβ] deposition, tau deposition, and AD-signature degeneration) and white matter hyperintensities (WMHs), which are a measure of cerebrovascular injury. We also investigated the association between hemoglobin level and cognitive performance, and then assessed whether such an association is mediated by brain pathologies. Methods: A total of 428 non-demented older adults underwent comprehensive clinical assessments, hemoglobin level measurement, and multimodal brain imaging, including Pittsburgh compound B-positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and magnetic resonance imaging. Episodic memory score and global cognition scores were also measured. Results: A lower hemoglobin level was significantly associated with reduced AD-signature cerebral glucose metabolism (AD-CM), but not Aβ deposition, tau deposition, or WMH volume. A lower hemoglobin level was also significantly associated with poorer episodic memory and global cognition scores, but such associations disappeared when AD-CM was controlled as a covariate, indicating that AD-CM has a moderating effect. Conclusion: The present findings suggest that low blood hemoglobin in older adults is associated with cognitive decline via reduced brain metabolism, which seems to be independent of those aspects of AD-specific protein pathologies and cerebrovascular injury that are reflected in PET and MRI measures.
Background: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) has been highlighted as a potential risk factor for cardiovascular disease in patients with chronic kidney disease (CKD). Methods: We assessed cross-sectionally the prevalence, associated factors, and treatment status of anemia and ESA hyporesponsiveness in 4460 non-dialysis-dependent CKD patients enrolled in a multicenter cohort in Japan. Anemia was defined as a hemoglobin (Hb) level of less than 11 g/dL or receiving ESA therapy. ESA hyporesponsiveness was defined by the erythropoietin-resistance index (ERI), which was the erythropoietin dose per week divided by body weight and Hb level (U/kg/week/g/dl). Results: Of the 4460 patients, 1050 (23.5%) had anemia. ESAs were administered to 626 patients, reaching a percentage of 57.5% of patients with stage G5 CKD. However, the ESA treatment rate was only 49.0% in patients with a hemoglobin level of < 11 g/dL. The proportion of patients receiving iron supplementation was lower than that of patients receiving ESAs regardless of CKD stage or hemoglobin level, and a significant proportion of patients did not receive iron supplementation, even those with iron deficiency. The ERI increased with CKD stage progression, and the multiple regression analysis showed that age, female sex, body mass index, cholesterol, glomerular filtration rate, and intact parathyroid hormone level were independent contributors. Conclusions: Our findings demonstrate that many Japanese patients with non-dialysis-dependent CKD receiving ESAs fail to maintain adequate hemoglobin levels. These results suggest the need for interventions for ESA hyporesponsiveness factors in addition to iron supplementation.
heme. Ketersediaan sumber zat besi yang terbatas menjadi salah satu penyebab tingginya prevalensi anemia pada santriwati di pondok pesantren.Tujuan: Mengetahui perbedaan asupan zat besi hem dan non hem, vitamin B12 dan folat, serta asupan enhancer dan inhibitor zat besi berdasarkan status anemia pada santriwati.Metode: Penelitian ini menggunakan desain cross-sectional dengan 58 santriwati berusia 15-19 tahun yang dipilih dengan metode purposive sampling. Subjek dibagi menjadi dua kelompok yaitu anemia dan non anemia. Data Penilaian asupan zat besi, hem, dan non hem menggunakan kuesioner IRONIC FFQ sedangkan asupan vitamin B12, folat, enhancer (protein, vitamin C, zinc) dan inhibitor (fitat, tanin, kalsium) menggunakan kuesioner SQFFQ. Pengukuran kadar Hb dengan metode cyanmethemoglobin. Analisis bivariat menggunakan uji Independent T-test dan Mann Whitney.Hasil: Sembilan puluh satu koma empat persen asupan zat besi subjek tergolong kurang. Asupan zat besi pada kelompok non anemia lebih besar dari kelompok anemia. Pada kelompok anemia rerata asupan hem sebesar 0,4 mg dan asupan non hem sebesar 5,58 mg. Sedangkan pada kelompok non anemia, rerata asupan hem sebesar 0,94 mg dan asupan non hem sebesar 9,04 mg. Terdapat perbedaan yang signifikan antara asupan zat besi total (p<0,001), besi hem (p<0,001) , besi non hem (p<0,001), serta asupan zinc, protein, vitamin B12 dan kalsium (p<0,05) berdasarkan status anemia.Simpulan: Terdapat perbedaan yang signifikan antara asupan zat besi hem, besi non hem, vitamin B12, protein, zinc dan kalsium berdasarkan status anemia.
Micronutrients (or microminerals) play vital roles in the health and nutrition of older people. Microminerals, or trace minerals, are termed as such due to the low levels present in the diet and similarly low levels in the body. Copper and zinc are two essential microminerals available in the diet; such microminerals or nutrients are required in small amounts of 1–100 mg/day. Trace mineral deficiencies result from use of parenteral nutrition, restrictive or popular diets, and metabolic abnormalities. Copper and zinc are essential elements involved in multiple body functions. Copper is found in food sources, such as legumes, nuts, seeds, organ meats, and whole grains. Total body copper is 100–200 mg, being higher in brain, liver, and kidneys; most of serum copper is bound to ceruloplasmin. Copper deficiency results from major burns, renal replacement therapy, parenteral nutrition, and gastric bypass procedures. Importantly, copper interacts with iron and zinc in the process of intestinal absorption; intake of each element and the body status may influence the absorption of the others. Zinc is a component of various enzyme systems; it is required for protein health, immune function, and wound healing. It is present in meat, sea food, grains, and vegetables. Zinc deficiency occurs from an inadequate diet, inadequate absorption, altered demand, or increased losses. Zinc replacement corrects deficiency in weeks; prolonged therapy may result in toxicity. There appears a relationship between the intake and levels of copper and zinc with respect to cardiovascular health and neurodegenerative diseases.
Despite what is known about risk factors, preventive treatment, and increased prevalence of fragility fractures in post-bariatric surgical patients, little is known about how patient perspectives of osteoporosis risk inform their commitment to bone health. The purpose of this study was to examine the lived experience of osteoporosis risk in people who have had bariatric surgery. Interpretive phenomenology was used to explore osteoporosis from the perspectives of patients who have had bariatric surgery. Eligibility criteria included female, age older than 18 years, and able to understand and speak English. This research provided an understanding of the risk of osteoporosis from the constructed realities and experiences of those who have had bariatric surgery. Participants in this study incorrectly felt they had little to no risk for osteoporosis after bariatric surgery. Patients need to be aware of an increased risk for osteoporosis leading to the potential for fragility fractures after bariatric surgery; nurses are well positioned to enhance osteoporosis prevention efforts in this population through pre- and postoperative education.
Nutritional assessment is an integral part of the clinical care of children with gastrointestinal (GI) disorders, as nutritional status can affect response to illness and outcome. Given the complex processes of growth and development in children, nutrition is of paramount importance. The comprehensive medical evaluation of children with GI disease must include an understanding of their growth patterns and changes in body composition as well as a grasp of the components of a nutritional assessment.
Full-text available
Vitamin B12 (B12; also known as cobalamin) is a B vitamin that has an important role in cellular metabolism, especially in DNA synthesis, methylation and mitochondrial metabolism. Clinical B12 deficiency with classic haematological and neurological manifestations is relatively uncommon. However, subclinical deficiency affects between 2.5% and 26% of the general population depending on the definition used, although the clinical relevance is unclear. B12 deficiency can affect individuals at all ages, but most particularly elderly individuals. Infants, children, adolescents and women of reproductive age are also at high risk of deficiency in populations where dietary intake of B12‑containing animal-derived foods is restricted. Deficiency is caused by either inadequate intake, inadequate bioavailability or malabsorption. Disruption of B12 transport in the blood, or impaired cellular uptake or metabolism causes an intracellular deficiency. Diagnostic biomarkers for B12 status include decreased levels of circulating total B12 and transcobalamin-bound B12, and abnormally increased levels of homocysteine and methylmalonic acid. However, the exact cut-offs to classify clinical and subclinical deficiency remain debated. Management depends on B12 supplementation, either via high-dose oral routes or via parenteral administration. This Primer describes the current knowledge surrounding B12 deficiency, and highlights improvements in diagnostic methods as well as shifting concepts about the prevalence, causes and manifestations of B12 deficiency.
Full-text available
: Plasma concentrations of some micronutrients are altered in the setting of acute infectious or inflammatory stress. Previous studies have provided conflicting evidence concerning the extent and direction of changes in plasma zinc concentrations during the acute phase response. We carried out an observational cohort study in 689 children enrolled in a randomized trial of zinc supplementation during acute falciparum malaria in order to evaluate the relation between plasma zinc concentration and the acute phase response. Plasma zinc was measured by atomic absorption spectrophotometry. On admission, 70% of all subjects had low plasma zinc (<9.2 micromol/L). Multivariate analysis of predictors of admission plasma zinc showed that admission C-reactive protein (CRP), parasite density, and study site were the most important predictors. Predictors of changes in plasma zinc from admission to 72 h included baseline CRP, change in CRP, treatment group, study site, and baseline zinc concentration. In children with acute malaria infection, baseline plasma zinc concentrations were very low and were inversely correlated with CRP (r = -0.24, P < 0.0001) and the degree of parasitemia (r = -0.19, P < 0.0001). Even when CRP and time were taken into account, zinc supplementation increased plasma zinc concentration from admission to 72 h. When available, plasma zinc concentrations should be interpreted with concurrent measures of the acute phase response such as CRP. In children whose age, diet, and/or nutritional status place them at risk of zinc deficiency, those with low plasma zinc levels should be supplemented with oral zinc and followed for clinical and/or biochemical response.
We present herein an approach to diagnosing the cause of chronic anemia based on a patient's history and complete blood cell count (CBC). Four patterns that are encountered frequently in CBCs associated with chronic anemias are considered: (1) anemia with abnormal platelet and/or leukocyte counts, (2) anemia with increased reticulocyte counts, (3) life-long history of chronic anemia, and (4) anemia with inappropriately low reticulocytes. The pathophysiologic bases for some chronic anemias with low reticulocyte production are reviewed in terms of the bone marrow (BM) events that reduce normal rates of erythropoiesis. These events include: apoptosis of erythroid progenitor and precursor cells by intrinsic and extrinsic factors, development of macrocytosis when erythroblast DNA replication is impaired, and development of microcytosis due to heme-regulated eIF2α kinase inhibition of protein synthesis in iron-deficient or thalassemic erythroblasts.
Riboflavin is unique among the water-soluble vitamins in that milk and dairy products make the greatest contribution to its intake in Western diets. Meat and fish are also good sources of riboflavin, and certain fruit and vegetables, especially dark-green vegetables, contain reasonably high concentrations. Biochemical signs of depletion arise within only a few days of dietary deprivation. Poor riboflavin status in Western countries seems to be of most concern for the elderly and adolescents, despite the diversity of riboflavin-rich foods available. However, discrepancies between dietary intake data and biochemical data suggest either that requirements are higher than hitherto thought or that biochemical thresholds for deficiency are inappropriate. This article reviews current evidence that diets low in riboflavin present specific health risks. There is reasonably good evidence that poor riboflavin status interferes with iron handling and contributes to the etiology of anemia when iron intakes are low. Various mechanisms for this have been proposed, including effects on the gastrointestinal tract that might compromise the handling of other nutrients. Riboflavin deficiency has been implicated as a risk factor for cancer, although this has not been satisfactorily established in humans. Current interest is focused on the role that riboflavin plays in determining circulating concentrations of homocysteine, a risk factor for cardiovascular disease. Other mechanisms have been proposed for a protective role of riboflavin in ischemia reperfusion injury; this requires further study. Riboflavin deficiency may exert some of its effects by reducing the metabolism of other B vitamins, notably folate and vitamin B-6.
Chronic kidney disease (CKD) is a multifaceted disease that has several associated complications. Anaemia is one of the most common complications that can develop early in the course of the disease process. It is associated with increased mortality, increased hospitalisation rates, and reduced quality of life. Lower levels of kidney function are associated with lower haemoglobin (Hb) levels and a higher prevalence and severity of anaemia.
Since its first discovery in an Iranian male in 1961, zinc deficiency in humans is now known to be an important malnutrition problem world-wide. It is more prevalent in areas of high cereal and low animal food consumption. The diet may not necessarily be low in zinc, but its bio-availability plays a major role in its absorption. Phytic acid is the main known inhibitor of zinc. Compared to adults, infants, children, adolescents, pregnant, and lactating women have increased requirements for zinc and thus, are at increased risk of zinc depletion. Zinc deficiency during growth periods results in growth failure. Epidermal, gastrointestinal, central nervous, immune, skeletal, and reproductive systems are the organs most affected clinically by zinc deficiency. Clinical diagnosis of marginal Zn deficiency in humans remains problematic. So far, blood plasma/serum zinc concentration, dietary intake, and stunting prevalence are the best known indicators of zinc deficiency. Four main intervention strategies for combating zinc deficiency include dietary modification/diversification, supplementation, fortification, and bio-fortification. The choice of each method depends on the availability of resources, technical feasibility, target group, and social acceptance. In this paper, we provide a review on zinc biochemical and physiological functions, metabolism including, absorption, excretion, and homeostasis, zinc bio-availability (inhibitors and enhancers), human requirement, groups at high-risk, consequences and causes of zinc deficiency, evaluation of zinc status, and prevention strategies of zinc deficiency.