Zinc deficiency
BMJ 2003; 326 doi: https://doi.org/10.1136/bmj.326.7386.409 (Published 22 February 2003) Cite this as: BMJ 2003;326:409
All rapid responses
The discovery that SARS is caused by a coronavirus, related to a
group of viruses causing the common cold, may be of considerable
significance in relation to evidence that zinc ions provide a natural
protective mechanism against viruses - especially those causing
respiratory tract infections. Over the past 30 years, researchers have
demonstrated the critical role of zinc in diverse physiological processes,
such as growth and development, maintenance and priming of the immune
system, and tissue repair.
Direct antiviral effects of zinc ions have been demonstrated against
rhinoviruses responsible for the common cold (1,2,3,4,5) and the role of
zinc in the respiratory epithelium has recently come under scrutiny(6).
Zinc has also been shown to directly decrease the incidence of respiratory
infections in young children from developing countries (7) probably by
mechanisms that involve restoration of T-cell immunity lost as a result of
deficiency of this mineral.
Zinc deficiency has been described as worldwide public health problem
and it is not confined to developing countries. Even in the USA moderate
to severe zinc deficiency can occur throughout the population. The causes
of zinc deficiency are multiple. They include:-
Food grown in soils that are low in zinc,
Superphosphate fertilizers that reduce zinc uptake by plants.
Eating foods that are low in zinc. (Very few foods are
naturally zinc-rich)
Poor absorption of zinc from the stomach and intestines.
Food contaminants and additives further reducing intestinal
zinc absorption.
Excessive zinc loss through body fluids such as sweat and
semen.
Poor body storage of zinc.
Strategies to overcome zinc deficiency are now being considered in
many developing countries and these include zinc supplementation and food
fortification. But now here is a problem! Zinc tablets and fortified
foods both aim to deliver the zinc through gastrointestinal absorption,
which can be very inefficient. Plant phytates and the presence of other
essential minerals such as iron and calcium can all reduce zinc uptake
from the gut. A better route for zinc absorption is the mouth and throat.
The development of zinc lozenges that release zinc ions in the buccal
cavity can have great benefits for both local actions to combat
respiratory tract viruses and to facilitate general zinc repletion.
Although zinc lozenges are available, most products fail to achieve
their goals because the amount of zinc they contain is too low or because
the formulation contains substances such as Vitamin C that trap the zinc
ions. The reason that these unsatisfactory lozenges exist is one of taste
as the ability to produce a pleasant-tasting zinc lozenge with sufficient
dose has eluded most manufacturers. By contrast, our research in South
Africa and the UK has focussed specifically on development of maximum
strength 15mg zinc lozenges (Zinc Advance) that have an excellent and
taste profile. Even young children enjoy sucking them.
Zinc ions when released in the vicinity of the oral mucous membranes
can protect cells from attack by viruses such as rhinoviruses. It is
believed that zinc ions attach to cell surface receptors thereby blocking
viral attachment and uncoating (8) Whilst there is not yet any evidence
that attachment of the coronavirus causing SARS can be blocked by zinc
ions, they are thought to help repair microscopic holes punched in cell
membranes by viruses(9) .
I believe there could be considerable benefit from the widespread use
of maximum strength zinc lozenges as a precautionary measure during the
SARS pandemic. Moreover, the extensive use of such lozenges would raise
the general level of immune status in the community with several important
potential consequences:-
1. An increase the general resistance to viral infections.
2. Possible reduction in the mortality rate from infections such as SARS
3. Reduction in the number of other viral infections that cause fevers
thereby reducing the burden on an over-stretched health-care profession.
Perhaps the work, which has led to the availability of effective zinc
lozenges since 2000 in the UK, could be of benefit
at this time.
G.F.Rowland BSc, PhD
ZinCare International Ltd
For further information please contact:
Hannah Smith,
Press Office,
Zeon Healthcare Limited,
PO Box 32,
Bourton-on-the-Water,
Cheltenham GL54 2WD
Email: pressoffice@zeonhealthcare.com
References
1. Geist F. C., Bateman J. A., Hayden F. G. In vitro activity of zinc
salts against human rhinoviruses. Antimicrob. Agents Chemother.
1987;31:622-624
2. Korant B. D., Butterworth B. E. Inhibition by zinc of rhinovirus
protein cleavage: interaction of zinc with capsid polypeptides. J. Virol.
1976;18:298-306
3. Al-Nakib W., Higgins P. G., Barrow I., Batstone G., Tyrrell D. A.
Prophylaxis and treatment of rhinovirus colds with zinc gluconate
lozenges. J. Antimicrob. Chemother. 1987;20:893-901
4. Mossad S. B., Macknin M. L., Medendorp S. V., Mason P. Zinc
gluconate lozenges for treating the common cold: a randomized, double-
blind, placebo-controlled study. Ann. Intern. Med. 1996;125:81-88
5. Prasad AS, Fitzgerald JT, Bao B, Beck FW&Chandrasekar
PH.Duration of symptoms and plasma cytokine levels in patients with the
common cold treated with zinc acetate. A randomized, double-blind, placebo
-controlled trial.Ann. Intern. Med. 2000; 133: 245-52
6. Truong-Tran Ai Q, Joanne Carter, Richard Ruffin and Peter D
Zalewski New insights into the role of zinc in the respiratory epithelium.
Immunology and Cell Biology 2001; 79:170 - 178.
7. Sazawal S, Black RE, Jalla S, Mazumdar S, Sinha A&Bhan MK.
Zinc supplementation reduces the incidence of acute lower respiratory
infections in infants and preschool children: a double-blind, controlled
trial.Pediatrics 1998; 102: 1-5.
8. Novick SG, Godfrey JC, Pollack RL&Wilder HR.Zinc-induced
suppression of inflammation in the respiratory tract, caused by infection
with human rhinovirus and other irritants.Med. Hypotheses 1997; 49: 347-
57.
9. Pasternak C. A. A novel form of host defense: membrane protection
by Ca2+ and Zn2+. Biosci. Rep. 1987;7:81-91
Competing interests:
The author is a founder and share-holder of ZinCare International Ltd
Competing interests: No competing interests
Dear Sir,
I read your article in BMJ with great interest. I wish to
draw your attention to the following lines: Firstly, the levels of RDA for
zinc have not been defined todate and there is little of research in the
area of zinc nutrition that is currently going on in a country like India,
where the problem of zinc deficiency seems to be huge in the form of
hidden hunger.
Secondly, Noel W.Solomons data and a few other
papers(1,2,3) talk much about the interactions between iron and zinc at
the site of absorption. I personally feel that these interactions be
considered in the wake of highly prevalent iron deficiency and zinc
deficiency (which is ofcourse going unrecognized in many parts of India).
Thirdly, RDA for both iron and zinc should be recaculated based upon the
interactions and the current literature(Compartmental modelling of the
pools of iron and zinc in the human body).Fourthly, to define the best
indicator of zinc status in children and adults seems to be very big task.
None of the indicators like serum zinc, hair zinc, activities of alkaline
phosphatase, ribonuclease, nucleoside phosphorylase, carbonic anhydrase
seem to correlate with each other. These points have to be borne in mind
before planning a strategy to implement zinc supplementation in India.
B.SREEDHAR, SCIENTIST 'B', DEPARTMENT OF BIOCHEMISTRY, ARMED FORCES
MEDICAL COLLEGE, PUNE - 411 040.
Competing interests:
None declared
Competing interests: No competing interests
Dear Editor,
We read the recent editorial on zinc deficiency (1), with great interest.
We would like to suggest that the neglect of the consequences of zinc
deficiency may also be true of investigations into prostate cancer. The
peripheral zone of human prostate gland, where prostate cancer most
commonly arises, accumulates and secretes high levels of citric acid (2).
Normal prostate and benign prostatic hyperplasia are also found to
accumulate the highest levels of zinc in the body. This is a result of the
unique metabolic capabilities of prostate epithelial cells. In prostate
cancer the ability to accumulate zinc and citric acid is diminished. These
and other correlations between zinc and citrate in the prostate have been
indicative of an important role of zinc in the regulation of citrate
metabolism in normal and malignant prostate epithelial cells. In the
prostate epithelial cells intramitochondrial accumulation of high levels
of zinc inhibits mitochondrial aconitase, which in turn truncates Kreb’s
cycle and markedly decreases the cellular energy (ATP) production normally
coupled to citrate oxidation. This prevents metabolism of citric acid in
the prostate epithelial cells leading to its accumulation and subsequent
secretion(3,4). The evidence for decreased citric acid and zinc in
prostate cancer and its occurrence early in prostate cancer before
histological changes forms the basis of a new concept for the role of zinc
and citrate-related energy metabolism in prostate malignancy(2). It has
also been found that testosterone and prolactin regulate zinc accumulation
in prostate epithelial cells(5). This unique interaction between prostate,
zinc and citric acid suggests zinc as a novel candidate in preventive,
diagnostic and therapeutic strategies against prostate cancer.
Reference:
1.Prasad AS. Zinc deficiency: Has been known of for 40 years but ignored
by global health organisations.Editorial]BMJ.2003. 326(7386):409-410
2.Costello LC, Franklin RB. Novel role of zinc in the regulation of
prostate citrate metabolism and its implications in prostate cancer.
Prostate.1998. 35(4):285-296.1 Review.
3.Costello LC, Franklin RB. The intermediary metabolism of the prostate: a
key to understanding the pathogenesis and progression of prostate
malignancy.
Oncology. 2000.59(4):269-282.
4.Feng P, Liang JY, Li TL, Guan ZX, Franklin R, Costello. Zinc induces
mitochondria apoptogenesis in prostate cells. Mol Urol. 2000.4(1):31-36.
5.Costello LC, Franklin RB. Testosterone and prolactin regulation of
metabolic genes and citrate metabolism of prostate epithelial cells. Horm
Metab Res. 2002.34(8):417-424.
Competing interests:
None declared
Competing interests: No competing interests
Dear Editor,
We were pleased to see Prasad’s editorial(1). It was timely
considering that the BMJ alone has published at least four randomised
trials of zinc supplementation in developing countries within the last two
years (2-5) and more being published in other journals. We agree that
there is overwhelming evidence from developing countries to justify the
wide spread provision of zinc supplementation as a public health measure.
This evidence is convincingly robust when it comes to zinc’s effect in
reducing the rates of diarrhoea and pneumonia, the two leading causes of
death in many developing countries(2,4-6); but not that clear for
malaria(3) and growth retardation(8). Evidence of effectiveness is
required in the latter two conditions.
The international community have been slow in the adoption and
implementation of this evidence-based intervention. However, we believe,
the World Health Report 2002 (published last October) was a move in the
right direction when it introduced zinc supplementation as cost-effective
intervention for high mortality developing countries. Zinc
supplementation would be an excellent example of an intervention for the
WHO Health Evidence Network (HEN) to pool and disseminate the available
evidence to policy makers.
Yours Sincerely,
Arash Rashidian
Health Services Research Scholar
Jane Noyes
MRC Research Fellow
Department of Health Sciences, University of York
1. Prasad AS. Zinc deficiency has been known for 40 years but ignored
by global health organisations. BMJ 2003; 326:409-410
2. Rahman MM, Vermund SH, Wahed MA, Fuchs GJ, Baqui AH, and Alvarez
JO. Simultaneous zinc and vitamin A supplementation in Bangladeshi
children: randomised double blind controlled trial BMJ 2001; 323: 314-318.
3. Müller O, Becher H, van Zweeden AB, Ye Y, Diallo DA, Konate AT and
et al. Effect of zinc supplementation on malaria and other causes of
morbidity in west African children: randomised double blind placebo
controlled trial. BMJ 2001; 322: 1567-1570.
4. Bhandari N, Bahl R, Taneja S, Strand T, Mølbak K, Ulvik RJ, and et
al. Effect of routine zinc supplementation on pneumonia in children aged 6
months to 3 years: randomised controlled trial in an urban slum. BMJ 2002;
324: 1358-1361.
5. Baqui AH, Black RE, El Arifeen S, Yunus M, Chakraborty J, Ahmed S,
and Vaughan JP. Effect of zinc supplementation started during diarrhoea on
morbidity and mortality in Bangladeshi children: community randomised
trial. BMJ 2002; 325: 1059-1063
6. Bhutta ZA, Black RE, Brown KH, Gardner JM, Gore S, Hidayat A, and
et al. Prevention of diarrhea and pneumonia by zinc supplementation in
children in developing countries: Pooled analysis of randomized controlled
trials. Journal of Pediatrics 1999; 35: 689-697.
7. Dijkhuizen MA, Wieringa FT, West CE, Martuti S, Muhilal. Effects
of Iron and Zinc Supplementation in Indonesian Infants on Micronutrient
Status and Growth
Journal of Nutrition 2001; 131: 2860 – 2865.
8. The World Health Report 2002: reducing risks, promoting healthy
life. Geneva: World Health Organisation 2002.
Competing interests:
None declared
Competing interests: No competing interests
I know little about zinc defficiency but could not fail to notice
that the author is one of the contributors in 9 of the 14 references that
include a named person.
Competing interests:
None declared
Competing interests: No competing interests
EDITOR – Ananda Prasad deserves to be congratulated for his
excellent, seminal work on zinc deficiency. He wonders why the problems
caused by widespread zinc deficiency have been ignored by global health
organisations for 40 years.1 Why is there so little interest in
preventing infections, infertility, foetal abnormalities, growth
retardation and cognitive impairment?
Could the discovery in 1966, that oral contraceptive and (therefore HRT)
oestrogens and progestogens lower serum zinc levels and raise copper
levels, have something to do with this ostracism? 2
As zinc helps to regulate immunity and reproduction, it would seem
important to prevent deficiencies and many diseases including autoimmune
diseases and cancers. I have been assessing the zinc status of my patients
since the 1970s and most of them have been zinc deficient when first
tested if they are not already taking supplements. Of 150 women consulting
for preconception care, usually following infertility or recurrent
miscarriages, 95% were zinc deficient in their sweat, 85% were magnesium
deficient, and 91% had used oral contraceptives. Our 1988 finding of zinc
deficiency in dyslexic children in the UK has also been ignored.3 Zinc and
magnesium deficiencies are more severe in headache and migraine patients
of both sexes 4 and also in women with osteoporosis, especially if they
are taking HRT.5
The problem of essential nutrient deficiency is prevalent world wide,
not just in developing countries. Ananda Prasad’s discoveries are of
fundamental importance for many aspects of human health.
Ellen C G Grant
physician and medical gynaecologist
20 Coombe Ridings, Kingston-upon-Thames, Surrey, KT2 7JU
ellencggrant@onetel.net.uk
1 Prasad AS. Zinc deficiency. BMJ 2003;326:409-10.
2 Grant ECG, Howard JM, Davies S et al. Zinc deficiency in dyslexia;
concentrations of zinc and other minerals in sweat and hair. BMJ
1988;296:608-9.
3 Halsted JA, Hackly BM,Smith JC. Plasma-zinc and copper in pregnancy
and after oral contraception. Lancet 1968 i:278-83.
4 Grant ECG. The Pill, hormone replacement therapy, vascular and mood
over-reactivity, and mineral imbalance. J Nutr Environ Med1998;8:105-16.
5 McLaren-Howard J, Grant ECG, Davies S. Hormone replacement therapy and
osteoporosis: bone enzymes and nutrient imbalances. J Nutr Environ Med
1998;8:129-38.
Competing interests:
None declared
Competing interests: No competing interests
Professor Prasad obviously feels passionate about zinc deficiency and
claims that World Health Organization (WHO) should include zinc deficiency
in its top priorities.[1] WHO well recognizes the global public health
issues related to micronutrient deficiencies of iodine, vitamin A and
iron.[2] Global health is defined as ‘health problems, issues, and
concerns that transcend national boundaries, may be influenced by
circumstances or experiences in other countries, and are best addressed by
cooperative actions and solutions.’[3] Unfortunately Professor Prasad has
not provided any significant evidence to support the probable global
health nature of zinc deficiency and hence his claim to prioritise zinc
deficiency remains largely unsubstantiated.
References-
1. Prasad AS. Zinc deficiency. BMJ 2003; 326: 409-10.
2. http://www.who.int/nut/#mic
3. http://www.globalhealth.gov/faq.shtml
Competing interests:
None declared
Competing interests: No competing interests
The editorial by Prasad on zinc deficiency is very timely and
appropriate ( 1). Undoubtedly zinc deficiency can cause growth
retardation,increased susceptibility to infection and nutritional
anaemia.We agree with Dr Prasad that WHO should awake to the call and
should make recommendations for inclusion of zinc intake in their
publications. Fortunately most pharmaceutial companies have realised the
importance of zinc in diet and have made iron formulations with zinc as
Fefol one of the popular brands of iron is now available as Fefol-Z
containing zinc(2). During pregnancy it should routinely be given with
iron for better results. It has also a role in young children with
diarrhoea with supplementation along with other measures (3). Zinc should
be used more often in day to day clinical practice along with vitamin
A,iron and proteins .
References:
1. Prasad AS. Zinc deficiency has been known for 40 years but ignored by
global health organisations. BMJ 2003;326:409-410.
2. Malik S.(eds). Haematinics .In Indian Drug Review. Mediworld
Publications,New Delhi 2002;6: 548-562.
3. Sajawal S,Black RE,Bhan MK,Bhandari N,Sinha A,Jalla S.Zinc
supplementation in young children with acute diarrhea in India.N Engl J
Med 1995; 338:839-844.
Competing interests:
None declared
Competing interests: No competing interests
Editor,
Prasad describes the history of the study of zinc deficiency as starting in 1961.
There is a family of traditional healers in Andhra Pradesh in India which has been treating Indian childhood cirrhosis with Zinc Oxide for several generations. Indian childhood cirrhosis is thought to be a condition of chronic copper overload where excess hepatic copper leads to cirrhosis in young children. As to how these traditional healers struck upon Zinc as an intervention to reduce the copper load is puzzling.
It is thought that a combination of genetic defects and use of corroded copper and brass vessels to heat and store milk led to Indian Childhood Cirrhosis being endemic in some parts of the country.
The lesson is that there are times when we can learn from traditional healers.
1. Prasad AS. Zinc deficiency Has been known of for 40 years but ignored by global health organisations. BMJ 2003;326:409-410 ( 22 February )
Competing interests:
None declared
Competing interests: No competing interests
Zinc deficiency, transglutaminase and autoimmune diseases
EDITOR - We would like to add another facet to Prasad´s thought-
provoking editorial on zinc deficiency (1). Already in mid 1970´s it was
found that zinc at physiological concentrations inhibits a family of
calcium-dependent thiol-enzymes, the transglutaminases, by competing with
calcium for a crucial binding site on the enzyme (2). Indeed, it was
proposed that zinc is the physiological moderator of transglutaminase
activity (3). After the report by Dieterich et al. in 1997 (4), showing
that tissue transglutaminase is the autoantigen of EMA, coeliac disease
(CD) has become a model for understanding the pathogenesis of autoimmune
disorders. Our recent study (5) shows that zinc at physiological levels
inhibits the calcium-amplified binding of IgA antibodies in sera from CD-
patients to tissue transglutaminase.
We propose that low intestinal zinc concentrations, induced by an
inflammation or infection, allow calcium to activate tissue
transglutaminase in the lamina propria or in macrophages attracted to the
site of inflammation. The activated enzyme catalyses the hydrolysis of
specific glutamine residues to glutamic acid in food gliadins. The
modified gliadin residues fit to the HLA DQ2/DQ8 receptors and the immune
reaction leads to a release of interferon-gamma that initiates the
destruction of the intestinal villi. Hypozincaemia caused by malabsorption
due to the villous atrophy aggravates the disease.
Furthermore, there are obvious reasons to believe that the
pathogenesis of dermatitis herpetiformis resembles that of CD, although
with another, epidermal, transglutaminase involved (6). Indeed, it has
been shown that the zinc content in epidermis from patients with this
dermatitis is lower than in normal subjects (7).
Moreover, children with CD run an increased risk of developing IDDM.
Interestingly, a Swedish case-control study (8) showed that a low
groundwater concentration of zinc is associated with later development of
childhood onset diabetes.
Indeed, in all areas of the world - not only in the developing
countries - zinc has a potential for improving public health.
1. Prasad AS. Zinc deficiency. BMJ 2003:326:409-10
2. Credo CG, Stenberg P, Tong YS, Lorand L. Inhibition of
fibrinoligase and transglutaminase by zinc ions. Fed. Proc. 1976:35(7)
3. Stenberg P. The effect of metal ions on transamidating enzymes.
Fed. Int. Pharm. 1976:418
4. Dieterich W, Laag E, Schopper H et al. Identification of tissue
transglutaminase as the autoantigen of celiac disease. Nat. Med.
1997:3:797-801
5. Roth EB, Sjöberg K, Stenberg P. Biochemical and immuno-
pathological aspects of tissue transglutaminase in coeliac disease.
Autoimmunity 2003:36:221-226
6. Sardy M, Karpati S, Merkl B, Paulsson M, Smyth N. Epidermal
transglutaminase is the autoantigen of dermatitis herpetiformis. J. Exp.
Med. 2002:195:747-57
7. Michaelsson G, Ljunghall K. Patients with dermatitis
herpetiformis, acne, psoriasis and Darier´s disease have low epidermal
zinc concentrations. Acta Derm. Venereol. 1990:70:304-308
8. Haglund B, Ryckenberg K, Selinus O, Dahlquist G. Evidence of a
relationship between childhood-onset type 1 diabetes and low groundwater
concentration of zinc. Diabetes Care 1996:19:873-5
Competing interests:
None declared
Competing interests: No competing interests