GASTROENTEROLOGY 2009;137:S7–S12
Zinc: An Essential Trace Element for Parenteral Nutrition
KHURSHEED JEEJEEBHOY
Department of Medicine, St. Michael’s Hospital, Toronto, Ontario, Canada
Zinc is an essential trace element for human nutrition
that is an integral part of many enzyme systems,
including DNA polymerase complex. Zinc deficiency
has been associated with stunting of growth and sex-
ual immaturity. In children, deficiency causes a fatal
condition called acrodermatitis enteropathica. The
same syndrome has been observed in patients on total
parenteral nutrition (TPN) who do not receive zinc.
In TPN the requirements have been estimated by
balance studies to be 3 mg/d in patients without
gastrointestinal losses and a mean of 12 mg/d in
patients with diarrhea and fistula losses.
P atients relying on parenteral nutrition (PN) receive
most of their nutrients in the form of amino acids,
glucose, and lipid. However, for the optimal utilization of
these nutrients, other substances called micronutrients
are necessary. These substances are required in minute
quantities, which are disproportionately low as compared
with their influence on metabolism and health. These
micronutrients are of 2 types, trace elements and vita-
mins. Trace elements are inorganic elements, whereas
vitamins are complex organic molecules. Trace elements
are essential elements which are an integral part of met-
abolically active organic complexes such as enzymes. Cot-
zias defined an essential trace element as one with the
following characteristics:
1. Present in healthy tissues of all living things.
2. Constant tissue concentration.
3. Withdrawal leads to reproducible functional abnor-
malities
4. Addition of the element prevents abnormalities
5. The biochemical change is prevented or cured with the
clinical abnormality.
Using the Cotzias criteria, 7 elements—iron, zinc, copper,
chromium, selenium, iodine, and cobalt (in vitamin
B12)—are necessary for human health. In this monograph,
one of these elements, namely zinc and its requirement in
oral and PN are presented.
Background
Zinc as an essential nutrient was first recognized
for the growth of plant life in the 1860s; however, the
demonstration of zinc deficiency as a cause of clinical
disease was first shown in swine as causing parakerato-
sis.1 In humans, a rare genetic disorder called acroderma-
titis enteropathica resulted in skin parakeratosis and
diarrhea in infants fed cows’ milk but not human milk.
Studies by Moynahan2 showed that a specific peptide
existed in cow but not human milk, which chelated zinc.
The genetic disorder was the lack of an enzyme that
hydrolyzed the peptide and released the zinc. Feeding
zinc cured the syndrome in these infants who otherwise
died. On the other hand, in otherwise normal persons,
dietary zinc deficiency does not occur, mainly because
zinc is widely distributed in food. Therefore, it was not
clear if there was a mandatory requirement for zinc in
humans. In 1961, Prasad et al3 described a syndrome of
hypogonadism, anemia, and stunting in humans who
were geophagic. Supplementation with zinc restored
growth and sexual maturation, demonstrating the essen-
tiality for dietary zinc in humans.3
The use of PN created a unique situation in which it
was possible to feed individuals with purified diets spe-
cifically deficient in trace elements such as zinc. In addi-
tion, for the first time it was possible to create a demand
for nutrients by inducing anabolism. The anabolic state
is necessary to demonstrate a requirement for a nutrient
because clinical deficiency only occurs if there is a need
for the nutrient caused by anabolism, but no intake for
the specific nutrient. Kay and Tasman–Jones4 described 4
patients on PN who developed a syndrome comparable to
acrodermatitis enteropathica with marked reduction of
plasma zinc and corrected specifically by feeding/infus-
ing zinc. This paper demonstrated that zinc was essential
for patients receiving PN.
Distribution of Zinc
Zinc is a widely distributed element in foodstuffs
(shellfish, liver, milk, and wheat bran). In the human
body, zinc is widely distributed in many tissues, blood
cells, bone, and teeth.5,6 However, zinc at these sites is
firmly bound to protein, and during deficiency and
refeeding the concentrations of zinc in tissues (with the
exception of blood, milk, hair, and liver) do not change
significantly.7 Endogenous stores of zinc are mobilized in
the fasting state, but do not meet metabolic needs during
Abbreviations used in this paper: NPO, Nil Per Os; PN, parenteral
nutrition; TPN, total parenteral nutrition.
© 2009 by the AGA Institute
0016-5085/09/$36.00
doi:10.1053/j.gastro.2009.08.014
S8 KHURSHEED JEEJEEBHOY
anabolism, because the net movement of zinc is into
tissues and circulating zinc is reduced.
Although 86% is in skeletal muscle, there are certain
areas where zinc concentration is especially high and may
represent functional importance. They are the prostate,
hippocampus, pancreas, and kidney cortex. Zinc has been
identified as a part of about 120 enzymes.8 Among them
are carbonic anhydrase, carboxypeptidase, alkaline phos-
phatase, oxidoreductases, transferases, ligases, hydro-
lases, lyases, and isomerases. Although the syndrome of
zinc deficiency cannot be identified with the dearth of
any 1 enzyme, zinc deficiency does have a pronounced
effect on nucleic acid metabolism, thus influencing pro-
tein and amino acid metabolism.
Metabolic Functions
Zinc is an integral constituent of DNA polymer-
ase, reverse transcriptase, RNA polymerase, tRNA syn-
thetase, and the protein chain elongation factor.5 Thus,
zinc deficiency can alter protein synthesis at a number of
different points, and it is not surprising that in the
absence of zinc growth arrest occurs.9 Furthermore, zinc
deficiency is teratogenic as determined by animal studies
and observations in patients with untreated acroderma-
titis enteropathica.10 This finding suggests that zinc de-
ficiency may affect gene expression. In experimental stud-
ies in unicellular organisms, it has been shown that zinc
deficiency changes the nature of RNA polymerase and the
base composition of mRNA. The translated peptides con-
tain a preponderance of arginine-rich peptides that can
bind to anions such as phosphate groups in nucleic acids
and alter their action. Such an alteration could affect the
synthesis of histones, proteins that are known to reduce
the activity of DNA as a template.5
These experimental findings about zinc and nucleic
acids are interesting in view of the clinical observation
that a number of functions dependent on protein syn-
thesis are suppressed by zinc deficiency. These include
growth,6 cellular immunity,11,12 fertility,6 hair growth,
wound healing,13 and plasma protein levels. Thus, it is
obvious that zinc deficiency leads to profound disturbances
of protein synthesis. In addition, in volunteer studies, ex-
perimental mild zinc deficiency reduced thymulin levels and
the CD4/CD8 ratio.14
Control of Body Zinc
Absorption
Zinc absorption has a significant effect on body
zinc. Zinc is absorbed by a process that involves binding
to a surface receptor, followed by uptake into the entero-
cyte.15 The process is saturable and the efficiency of
absorption decreases at high zinc intakes. From the en-
terocyte, some zinc is removed by albumin or an alpha-2
macroglobulin and carried to the liver, the remainder
being bound to a metallothionein,16 the proportion
GASTROENTEROLOGY Vol. 137, No. 5
bound depending on the metallothionein content of the
enterocyte. Because zinc is not transferred to plasma
when so bound, this binding action inhibits absorption.
Subsequently, such bound zinc returns to the bowel
lumen when the enterocyte is shed. When body zinc is
high, there is a stimulation of metallothionein synthesis,
thus inhibiting absorption. In addition, absorption is
influenced by the following factors:
1. Binding to a ligand secreted by the pancreas enhances
absorption.
2. Luminal amino acids bind zinc and prevent its precipi-
tation by substances such as phosphates and phytates.
3. Pregnancy, corticosteroids, and endotoxin all enhance
absorption.
4. Phytates, phosphates, iron, copper, lead, and calcium
inhibit absorption.
Excretion
Zinc is excreted mainly in the feces, with a smaller
amount in the urine.17 The fecal losses rise with increased
intake, because they consist mainly of unabsorbed zinc
shed with enterocytes. In contrast, urinary excretion is
not influenced by intake. Significant losses may occur in
sweat in the tropics, but such losses diminish with defi-
ciency.18
Abnormal Losses
Wolman et al19 showed that diarrhea and stomal
and fistula losses were the major sites of enhanced ab-
normal losses of zinc from endogenous sources in pa-
tients kept nil per os (NPO). Increased losses also oc-
curred in urine in hypercatabolic individuals. Amino acid
infusions also increase urinary zinc losses. In the kidney,
zinc infusions enhance distal reabsorption of zinc, and
amino acid infusion increases proximal secretion.20
Metabolism of Zinc
As noted, zinc reaching the circulation is bound
to albumin and an alpha-2 macroglobulin.21 From the
circulation it is taken up by the liver and other tissues.
Infection results in increased uptake of zinc by the liver.22
Enhanced uptake of zinc into the liver reduces plasma
concentrations, and so circulating zinc concentrations
may be reduced by factors other than deficiency.23–25
Assessment of Zinc Status and Requirements
There is no reliable way of assessing zinc status.
Plasma zinc levels are normally regulated to between 80
and 120 ␮g/l or 12–18 ␮mol/l. Although circulating zinc
levels fall in the deficient state, there are other causes of
low circulating zinc levels that make this measurement
unreliable. Hair zinc levels are low when there is low-
grade chronic deficiency, but in acute deficiency hair does
not grow, and with profound deficiency hair loss occurs
and the remaining hair may have normal zinc concentra-
November Supplement 2009
tions.26 It has recently been shown that leukocyte zinc
levels are a reliable indicator of zinc deficiency, but this is
not an easy measurement to perform.27 Currently, the
best way of assessing zinc status and requirements is
through multiple clinical parameters. Abnormal gastro-
intestinal losses, hypercatabolism, or amino acid infu-
sions raise the need for zinc supplementation. The clin-
ical syndrome of acrodermatitis enteropathica confirms
the need for zinc supplementation. This syndrome con-
sists of scaly, red, desquamating lesions involving the
nasolabial folds and hands. In severe cases it extends to
the trunk, resulting in extensive exfoliation and second-
ary skin infection. There is often loss of hair.
Zinc Requirements
The relationship of intake to absorption is asymp-
tomatic and the fraction of intake absorbed falls as the
amount taken rises. The endogenous losses also rises
with increased intake. The point at which absorbed and
losses are equal is used to estimate dietary zinc require-
ments. On this basis, the requirements in adults is be-
tween 8 and 11 mg/d. Zinc intake during pregnancy and
lactation are estimated to be 12–13 mg/d. In patients
receiving PN, zinc requirements were estimated by per-
forming metabolic balance of intake versus losses in
stool, urine, and drainage during a randomly assigned
intake in the infusate. Using this technique Wolman et
al19 found that about 2.5 mg/d was required for balance
in patients without diarrhea. Requirements increased
with increased catabolism and gastrointestinal losses by
12 mg/L of small intestinal fluid and 17 mg/L of stool
measured in the NPO state.
In patients with burns, it has been shown that infusing
about 36 mg/d of zinc in patients with burns increased
skin levels of zinc and reduced infectious complications.
In addition to replacing losses, infants need zinc for
growth. This is especially true of preterm infants, because
two thirds of the infant’s zinc is transferred from the
mother during the last 10 –12 weeks of normal gestation.
It has been estimated that 0.50 – 0.75 mg of zinc is taken
up per day during the last 3 weeks of gestation and the
first 3 weeks of postnatal life in babies gaining 1.5 kg,
making the requirements about 300 –500 ␮g/kg per
day.28 During PN, James and MacMahon29 found that
infants required 300 ␮g/kg per day to maintain balance.
In older children, 50 ␮g/kg per day maintained normal
serum levels and for growth it is recommended that 100
␮g/kg per day be given as a safe intake.30 In addition,
supplementation is required for abnormal gastrointesti-
nal losses, but these have not been determined experi-
mentally.
Recommendations for PN
In stable patients without abnormal gastrointes-
tinal losses, between 3 and 4 mg/d meets requirements.
ZINC S9
In patients with diarrhea while NPO and gastrointestinal
losses from fistulae, stomas, and diarrhea, 12 mg of zinc
should be added per liter of losses. In patients with
burns, large amounts of zinc supplements has been
shown to reduce the rate of infection. Up to 36 mg/d has
been added and shown to benefit without toxicity.
Recommendations
● Zinc is an essential trace element and must be added
to all PN mixtures.
● In patients without gastrointestinal losses, 3– 4 mg
should be given daily.
● In patients with fistula, diarrhea, and intestinal
drainage, 12 mg of zinc should be added for each
liter of loss.
● In patients with burns, addition of about 36 mg/d of
zinc may reduce infectious complications.
Research Priorities
● Methods to evaluate zinc status.
● Zinc requirements in critically ill patients. Does ad-
ditional zinc reduce infectious complications?
● Benefits and risks of long-term zinc infusions in
patients on home PN.
Question and Answer Session
DR HOWARD: Let me take the chairman’s privilege
of asking the first question. Your important balance
studies were done as you described with the short bowel
patients NPO. But if you’re trying to avoid the hepatic
complications of PN, you really encourage them to eat.
Because we don’t know whether food zinc leads to net
absorption or net loss in short bowel patients, do you
think we need to repeat those balance studies and include
the enteral component or do you think we can look
separately at absorption and losses of zinc and other
divalent cations? So my question is, do we need to repeat
those balance studies with the subjects eating?
DR JEEJEEBHOY: That’s an interesting question. We
had patients of all types. Some of them had fistula losses
and short bowel. We demonstrated increased GI zinc
losses in people who had diarrheal disease. If they are
absorbing some zinc by mouth, obviously their require-
ments may drop. Because people have very different
lengths of bowel, I think a study like this would be
almost impossible to do. But what is the risk of giving
them extra zinc, you can see that tolerance is enormous,
so I think that we should err on the side of giving more
zinc than giving less zinc, because there’s no evidence of
toxicity unless you give huge amounts.
DR SHULMAN: The 24-hour urinary collections could
be helpful to assess zinc status. What are your thoughts on
that?
S10 KHURSHEED JEEJEEBHOY
DR JEEJEEBHOY: I think the 24-hour urine tells you
more about the catabolism and anabolism of zinc rather
than whether the person is deficient or not, it depends on
when in their course you collect it. It could tell you if the
patient is likely to become zinc deficient if they are losing
a lot of zinc in their urine. If you want to get a handle on
zinc status, it involves looking at the clinical picture—are
they catabolic or are they in the repair phase? You can
add a 24-hour urine; you can add metallothionein and
zinc plasma levels. But the whole picture has to be put
together to come to some conclusion as to what to do.
DR SHENKIN: I might follow up on Lyn’s question
about how much extra zinc. If zinc is taken orally, how
much of this is absorbed in patients who have short
bowel and are on long-term PN? I wonder if we can
expand the question a little bit more. Is there any toxicity
to chronic long-term overprovision of zinc because that is
what you’re recommending? As you’ve pointed out, the
body has its own natural defense mechanism for block-
ing zinc absorption and increasing zinc excretion when
you over provide zinc enterally. But when you give zinc
parenterally, we bypass the absorption brake and if you
give a lot of zinc parenterally, let’s say we move toward
your higher intakes and the patients at the same time are
eating and maybe absorbing some enterally, have the
studies been done which would show that this is safe? I
make the point especially in the light of the paper which
Lyn and I published recently, on the tissue concentra-
tions of patients who lived long-term on PN and who
were following the recommendations that you suggested.
Many of these patients had very high liver zinc concen-
trations, and therefore were accumulating zinc, which
could be harmful. I’m wondering before we just jump
and say this is fine, this is safe, should we be a little more
cautious?
DR JEEJEEBHOY: The risks of toxicity are extremely
small, as far as zinc is concerned. In tissues, 90% as I
mentioned is either in muscle, or in the liver (17%). In
regard to toxicity, I would like to turn the question
around and ask, if there’s accumulation in tissue, in what
way would it cause toxicity? What is the evidence that
there’s any toxicity? In contrast, there is good evidence
that severe zinc deficiency is associated with death. So I
think that we are over doing this toxicity issue with
regard to zinc. Patients on PN who have had these zinc
amounts for years and years have in fact done extremely
well.
DR BUCHMAN: Khursh, in a patient with systemic
inflammation, for example pancreatitis or Crohn’s dis-
ease, who also has fistula losses or diarrhea and may be
third-spacing fluid, how does one interpret the plasma
zinc concentrations?
DR JEEJEEBHOY: I don’t think you can use the
plasma zinc with any degree of accuracy in such a situa-
tion. If you measured the metallothionein levels, you
would find them to be high because it is an acute phase
GASTROENTEROLOGY Vol. 137, No. 5
reactant. Also, you’ve got albumin losses and cytokine
effects, you’ve got so many interactions I’m not sure you
can come to any interpretation of plasma zinc levels.
DR SHIKE: I think we need to make a distinction
between the hospitalized patient who gets PN for a few
days to a few weeks, and the long-term home patient. It
is in the long-term home PN patients that we have
potential for encountering trace element toxicity. These
home patients tend to be more stable on the whole and
therefore assessment parameters maybe a little more rel-
evant.
DR JEEJEEBHOY: I agree with you in the sense that
if you have a home patient who is not otherwise sick and
the problem is stable short bowel syndrome, measure-
ments of levels maybe more meaningful. But again, many
long-term patients have low albumin levels and other
abnormal parameters. The point I’m trying to make is
that in the present state of the art, you have to use a total
gestalt. You have to look at the whole picture and then
come to a decision as to what you want to do. It’s more
the art of medicine than science. A big problem with
home PN patients is that you have patients with different
degrees of short bowel and the issue comes up how are
you going to assess their absorption of a particular ele-
ment? Maybe we should ask the question can we recog-
nize zinc toxicity. We do know high levels have effects on
the kidneys and on the lungs. Perhaps we should be
screening patients for these toxic effects?
DR BERGER: Home PN patients are 1 group of pa-
tients where there are legitimate concerns about accumu-
lation, and potential toxicity. I myself am an intensive
care doctor where the PN requirements are for a period of
1–2 months, also in the critically ill there may be justifi-
cation for pharmacologic amounts of certain nutrients. I
think we must make separate recommendations for sta-
ble home PN patients and for critically ill patients.
DR BUCHMAN: In terms of the use of zinc in criti-
cally ill patients, what kind of outcomes should we be
evaluating? There are data to indicate zinc supplements
can prevent some viral infections. Is there a role for extra
zinc in the treatment or prevention of bacterial infec-
tions? For example in burn patients?
DR JEEJEEBHOY: I think this is an area for impor-
tant research. To my mind there are 2 areas where zinc
might be important in infection. One is of course its
anti-infective or immune-stimulating properties. The
other is that zinc affects insulin secretion rates. It’s been
shown that bloodstream glucose control is one of the
more important things in critically ill patients. These 2
areas could be profitably studied in patients in intensive
care units.
DR COMPHER: Dr Jeejeebhoy, I’m intrigued by your
comments about the immune effects of zinc, and aware
that in the home PN population the most common
complication is catheter-related bloodstream infections.
We know with infection, serum zinc levels are hard to
November Supplement 2009
interpret. We don’t have a good explanation for why
some patients go through 20 years with no infections,
and other patients have many infections. If we wanted to
evaluate a role of zinc status, in describing the risk of
bloodstream infection, how should we go about that?
DR JEEJEEBHOY: You need to identify these patients
with recurrent infections and in a multicenter, random-
ized trial determine whether they improve if they are
given zinc.
DR CHAMBRIER (Lyons, France): I’m concerned
about the long-term PN patient. Initially we gave 12
mg/d of zinc and all patients had a high zinc plasma so
now we give only 10 mg/d of zinc.
DR JEEJEEBHOY: I’ve not said that all patients
should receive 12 mg/d. What I’ve said is that if the
patient has 1 liter of constant losses from a fistula, then
12 mg should be added to their basic requirement of 3– 4
mg/d.
DR CHAMBRIER: But every patient has ⬎1 liter of
high bowel losses.
DR JEEJEEBHOY: We are talking about the NPO
state. They shouldn’t be eating anything and still put out
1 liter. There’s a big difference. You have to stop them
eating. What you’re describing is really the postprandial
patient. It doesn’t apply to this bowel loss.
DR CHAMBRIER: Thank you very much.
MS. SABINO (St. Francis Hospital, Hartford, CT):
Can you comment on whether there are excess losses of
zinc in head injury patients in acute care settings. How
much would you supplement these patients? Also, I un-
derstand medications like propofol increase zinc losses.
Are there other medications that deplete zinc?
DR JEEJEEBHOY: I’ve seen those studies. The prob-
lem is that propofol is often used in patients in the ICU
who are catabolic. These patients, as I mentioned, are
breaking down muscle and excreting endogenous zinc.
With a head injury, you have hypercatabolism. I’m not
aware of any systematic studies that have measured how
much zinc is lost in these catabolic individuals and how
they can be effectively supplemented. I think this is an
area for research. One would have to look at the urinary
zinc losses and estimate what the total losses are. There
are huge reserves that people have of zinc, so if you have
losses for 3 or 4 days, it doesn’t mean too much. On the
other hand, if you have continued losses for a month or
so then appropriate supplementation could be impor-
tant.
DR SEIDNER: Khursh, we haven’t discussed your
point on research into methods of evaluating zinc status
after we begin to replete these patients. In my practice, I
measure 24-hour urines to see if calcium and magnesium
status is adequate. Has that ever been done for zinc in
patients on home PN?
DR JEEJEEBHOY: I’m not aware of any systematic
studies of losses being done in the way you are talking
about, but the trouble is that urine losses of zinc are not
ZINC S11
like magnesium losses. Magnesium losses are very depen-
dent on the magnesium status of the patient. If you
become magnesium deficient, the urine magnesium al-
most gets wiped out, and it’s a very good index. Unfor-
tunately, with zinc, what happens is any kind of catabo-
lism of any sort is associated with increased losses. Low
insulin levels, insulin resistance, and infections—all these
things increase zinc losses. So I think it’s going to be
extremely difficult to use 24-hour urine zinc as an index
without major qualifications.
DR SEIDNER: So how are we going to monitor zinc
status?
DR JEEJEEBHOY: At the moment, I’m not aware of
any way of readily assessing zinc status.
MS. BEGANY (Children’s Hospital, Philadelphia,
PA): I’m just wondering if you could comment on zinc’s
relationship with copper and the potential when using
the higher dosing of zinc of seeing negative effects on
copper.
DR JEEJEEBHOY: Essentially, you’re talking about
the oral interaction of zinc and copper. When you have
high oral zinc levels, you induce metallothionein, which
binds oral copper, taking it out of the body. I’m not
aware that parenteral zinc particularly effects copper sta-
tus.
DR ZALOGA (Baxter, Deerfield, IL): Just to go back
to the propofol question for a moment. Propofol is
available from a number of companies. One of the com-
panies uses EDTA as a preservative and there’s Intensive
Care Medicine publications that looked at urinary excre-
tion of zinc. It’s quite considerable, it can go up 10-fold
when you use the EDTA containing propofol. The label
for that product has a warning on zinc deficiency. Other
propofol products use sodium metabisulfite as a preser-
vative and then zinc losses are not as high.
DR HOWARD: Dr Shenkin, you want to get in 1 last
hit?
DR SHENKIN: Yes, I want to come back to 2 inter-
related points, one to do with the effects of infection on
zinc, and the other how to monitor improvements in zinc
status. In regard to the first point, I think measuring
metallothionein is not possible in most clinical settings.
Many of us instead use C-reactive protein (CRP) in ex-
actly the same way as metallothionein. CRP is much
cheaper and everybody can measure it, and in fact when
CRP goes up, metallothionein goes up, and as infection
settles, metallothionein comes down and CRP comes
down, and zinc concentration ought to rise. If it doesn’t,
then maybe that’s an indication that zinc status is not
adequate. This deserves research confirmation I think.
I’m aware of 2 conflicting animal studies in relation to
zinc supplementation and infection, one of which when
zinc was given, the febrile response of rabbits was en-
hanced. If there was zinc depletion the febrile response
was less. In another study, I think also in rabbits, and
currently in press, giving zinc reduced the proinflamma-
S12 KHURSHEED JEEJEEBHOY
tory cytokine response. Now, these seem to be totally
conflicting studies, one suggesting increased cytokine
response to zinc, the other suggesting a reduced cytokine
response. I think as far as trying to get a handle on does
zinc cause damage, does it encourage inflammation, does
it suppress inflammation, focusing on these cytokine
responses might well be helpful.
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Received May 22, 2009. Accepted August 12, 2009.
Reprint requests
Address requests for reprints to: Khursheed Jeejeebhoy, MD,
FRCP(c), PhD, Professor Emeritus, University of Toronto, S-4646
Dufferin Street, Toronto, Ontario, Canada M3H 5S4. E-mail:
khushjeejeebhoy@compuserve.com.
Conflicts of interest
The author discloses no conflicts.