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Zinc Deficiency in Humans PDF
Zinc Deficiency in Humans PDF
1
2 Zinc Deficiency in Human Health
Table 1 Etiology of zinc deficiency in human populations Table 2 Typical zinc contents of common food items (from
Clinical and Behavioral Effects of Zinc macular degeneration; and (xxvii)apathy and irritability.
Deficiency Abnormal levels of zinc have been found in the eyes of
people with cataracts, cataracts or glaucoma, and zinc has
As a consequence of the large number of zinc-dependent been found useful in treating myopia (nearsightedness).
metabolic functions, the clinical morbidities associated Zinc is important to male sex organ function and repro-
with zinc deficiency are considerable. The crosstalk ductive fluids and since oysters have the highest zinc
between the metabolic cycles of zinc and other essential content of any food, there may be more to the old sayings
micronutries allows zinc deficiency to achieve a domino about oysters and romance. Zinc deficiency has also been
effect that affects most organ systems in adverse manner. linked to pectus excavatum (or pectus deformities),
It is not surprising that some people associate zinc defi- Marfan syndrome, Ehlers-Danlos syndrome (EDS) and
ciency with chronic fatigue syndrome. Important clinical Mitral valve prolapse syndrome. In chronic zinc defi-
manifestations of zinc efficiency are listed in Table 3. The ciency, smoking tobacco can result in the metabolic
spectrum of clinical effects depends on the dose, age, stage demand for zinc being met partially with toxic cadmium
of development, deficiencies of related metals and other from cigarette smoke, eventually resulting in lung disease.
micronutrients, and individual susceptibility and may It is clear from the above that there are no defining
include: (i) primary T-cell lymphocyte immune system symptoms of human zinc deficiency since many of these
dysfunction (leading to failure to terminate incipient symptoms are general and are associated with other med-
malignancies, viral and fungal infections); (ii) frequent ical conditions. Some of these effects are discussed in
opportunistic infections (due to inability to protect cell detail below.
membranes from viruses, toxins, complement, and
venoms); (iii) respiratory and skin allergies, (iv) asthma;
(v) chronic diarrhea; (vi) abnormal neurosensory changes, Reproduction
(vii) poor appetite (particularly in the young and aged); Zinc deficiency affects reproduction adversely in both
(viii) mental lethargy, (ix) fertility problems (including males and females since all the hormones and a wide
hypogonads, failure of sexual maturity, benign prostatitis range of enzymes involved in reproduction are sensitive
in men, and menstrual cramping and bloating in women), to zinc stress. In particular, zinc is essential for the
(x) birth defects; (xi) growth failure (dwarfism) and synthesis and secretion of luteinizing hormones and
growth retardation; (xi) premature aging; (xii) vision pro- follicle-stimulating hormone, gonadal differentiation,
blems; (xiii) loss of taste; (xiv) joint pain; (xv) essential and fertilization. Zinc fingers exercise significant controls
hypertension; (xvi) angina pectoris; (xvii) ischemia of on the biological effects of estrogens and androgens
effort; (xviii) delayed wound healing; (xix) scleroderma; elements of the DNA that turn on the genes active
(xx) systemic scleroderma (including lethal pulmonary in protein synthesis during early pregnancy. Zinc is
hypertension); (xxi) loss of hair color; (xxii) anemia; involved in the formation of prostaglandins required
(xxiii) striae (stretch marks); (xxiv) night blindness; for maintenance of pregnancy and also important at
(xxv) acne; and (xxvi) defective connective tissue and parturition to initiate the uterine contractions for
Decreased thymocyte count in thymus Increased CD4þ cell count in AIDS patients
Decreased peripheral T-cell count Clinical benefits in common colds
Decreased proliferative T-cell response to mitogens Clinical benefits rheumatoid arthritis
Reduced cytotoxic T-cell activity Increased lymphocyte blast transformation
Decreased T helper cell function Effects of Zinc Supplementation
Decreased macrophage function Increased thymocyte count in thymus
Lowered neutrophil functions Impaired immune function restored
Decreased antibody production Increased proliferative T-cell response to mitogens
Reduced placental transfer of antibodies from mother to fetus Increased CD4þ cell count
Imbalance in functions of Th-1 and Th-2 cells Improved neutrophil functions
Altered CD4/CD8 ratio Increased production of anti-viral interferon- (IFN-)
Increased blood glucocorticoids concentration Increased production of cytokines such as interleukin-1
(IL-1), IL-2, IL-3, IL-4, IL-6, INF-
, INF- and TNF-
Impaired leucocyte functions (chemotaxis, phagocytosis and Increased lymphocyte receptor expression
bacterial killing)
Block activation of protease, an essential protein-splitting enzyme
of HIV
Zinc Deficiency in Human Health 5
expulsion of the fetus. Another way that zinc can influ- weights and reduced pregnancy complications. Zinc defi-
ence pregnancy is through the impact on insulin-like ciency in the mother can jeopardize a child’s health in two
growth factors known to be potent stimulators of cell ways. On the one hand, it increases the rate of pregnancy
proliferation and tissue differentiation. and the risks of delivery complications, low birth weight
The concentration of zinc in the male genital organs and other adverse birth outcomes. On the other hand,
and human semen is extremely high relative to those of maternal zinc deficiency can lead to adverse post-natal
other body fluids and tissues. The zinc is secreted pri- development and latent effects which can persist through-
marily by the prostate, and one can infer that low zinc out lifetime.
status can have a significant impact on proper functioning Neonates with zinc deficiency show higher rates of
of this organ. High levels of zinc found in maturing congenital valvular defects, gastrointestinal tract atresia,
spermatozoa are believed to exercise some influence on increased congenital malformations (such as wry-neck,
oxygen consumption by the spermatozoa, chromatin sta- hernia, varus, valgus footstep, etc) and life-threatening
bilization and acrosin activity. Clinical studies show that conditions including respiratory disorders, convulsive
zinc deficiency negatively affects the formation and syndrome and edematic syndrome and lower rate of phy-
maturation of spermatozoa, testicular growth, and testi- sical development. Infants with zinc deficiency general
cular steroidogenesis. Zinc supplementation has been have higher disease morbidity marked by conditions such
shown to be beneficial to infertility in female and improve as rickets, anemia, dystrophy, atopic dermatitis, various
sperm count, motility and morphology in subfertile men types of allergic reactions, alimentary disorders such as
with idiopathic asthenozoospermia and/or oligozoosper- hypotrophy and paratrophy and increased susceptibility
mia. Besides infertility, zinc deficiency can contribute to to infectious diseases. Meta-analysis of the results from
the pathogenesis of other male reproductive dysfunction randomized controlled trials of women receiving zinc
such as hipogonadism and feminization. The mechanisms supplements during pregnancy in developing countries
for the effects are not fully understood. provide a strong evidence that significant benefits can be
derived from maternal Zn supplementation in relation to
neonatal morbidity and infant infections.
Pregnancy and Prenatal Development
A critical role for zinc in the development of the
The conceptus requires zinc for normal growth and central nervous system (CNS) is biologically plausible
development and is therefore at heightened risk when because (i) zinc-dependent enzymes are involved brain
the supply of zinc is suboptimal. Maternal zinc deficiency growth; (ii) zinc is involved in the production of neuro-
can disrupt the normal function of trophoblast, the transmitters, (iii) zinc-dependent neurotransmitters are
embryonic-derived component of the placenta responsi- involved in brain memory function, (iv) zinc finger
ble for implantation, production and secretion of proteins play a role in the brain structure and
hormones, establishment of the maternal-fetal barrier neurotransmission, (v) high concentrations of zinc in the
and the mediation of metabolic exchanges across this synaptic vesicles of the ‘‘zinc containing’’ neurons in the
barrier. The trophoblast is important for establishing forebrain serve as a moderator of neuronal excitability.
and maintaining the fetoplacental unit and trophoblastic Clinical evidence for the impairment of the central ner-
dysfunction has been linked to improper fetal develop- vous system (CNS) by zinc deficiency are two-fold: (a)
ment and poor pregnancy outcomes including CNS dysfunction is a prominent clinical feature in most
spontaneous abortion, prolonged gestation, difficult cases of acrodermatitis enteropathica, a genetic defect
labor, low birth weight, and more complications during associated with zinc deficiency syndrome, and (b) marked
delivery. Malformations associated with zinc deficiency improvement in immune function is achieved with zinc
include abnormalities in brain and eye functions, audio- therapy. The treatment of acrodermatitis enteropathica
metric performance, cleft lip and palate, and with zinc is rapidly attended by an increase in hedonic
abnormalities of the heart, lung and urogenital systems. tone, alertness, motivation and responsiveness along with
Fetuses in zinc-deficient mothers often show growth rapid decreases in nervousness, irritability and restless-
retardation, and a high frequency of skeletal abnormal- ness. The impairment of cognitive processes in infants
ities. Biochemical and functional abnormalities can be by zinc deficiency is well documented in the scientific
displayed in the lung and pancreatic systems. Evidence literature, but a consensus has not yet been reach.
that zinc deficiency is a teratogenic risk in humans Zinc has been used successfully to treat children with
include (i) women with acrodermatitis enteropathica attention deficit hyperactivity disorder (ADHD), a high-
tend to have complicated pregnancies if they do not incidence condition characterized by short attention
receive zinc supplements; (ii) low plasma zinc levels span, impulsivity, overactivity and inability to socialize.
have been associated with increased risk of malformations Furthermore, many authors have reported significant
and low birth weight; and (iii) several studies show that beneficial effects of zinc supplementation on the cognitive
zinc supplementation is associated with increased birth functions of children from poor developing countries.
6 Zinc Deficiency in Human Health
In addition to effects on the child’s cognition, zinc defi- adapt to the stress of suboptimal zinc. Zinc deficiency
ciency also impairs the acquirement of motor skills, affects the balance between the Th-1 and Th-2 cells, a
locomotive development, speech, and ability to orient critical factor in cell-mediated immunity.
himself or herself. These effects of zinc deficiency are Zinc has been used successfully to restore immune
remarkably similar to those commonly associated with function in the zinc-specific malabsorption syndrome
childhood lead poisoning. Since zinc deficiency is much known as acrodermatitis enteropathica as well as other
more prevalent in childhood populations, one must won- morbidities. Some immunological dysfunction in the
der whether this condition is being misclassified for lead elderly such as decreased interferon- (IFN- ) produc-
poisoning in many (if not most) epidemiological studies. tion can be corrected with zinc. Impaired immune
Maternal zinc deficiency during early pregnancy can response to diphtheria vaccination in hemodialysis
influence the development of epigenetic marks at the Avy patients has been linked to zinc deficiency and is correct-
locus in the early embryo thereby influencing all tissue able with zinc therapy. The subject of zinc and
development and possibly the germ line. Subsequent immunodeficiency has been extensively reviewed in a
incomplete erasure of the epigenetic alterations at Avy number of publications. Hypozincuria is a clinical mani-
induced by zinc deficiency represents a plausible festation of HIV-AIDS and zinc therapy has been shown
mechanism by which adaptive evolution may occur in to increase the CD4þ cell count and reduce the incidence
animals. It is increasingly evident that epigenetic altera- of bacteria infections in HIV-infected patients. Zinc salts
tions at metastable epiallelles may be the mechanistic link are increasingly gaining favor as non-prescription drug
between early nutrition and zinc deficiency and chronic for reducing the duration and severity of common colds.
disease susceptibility in adults. Zinc deficiency can be
considered an important contributory factor to the
Growth
‘‘Barker Effect’’ which posits that exposures in the womb
and postnatal environment can predispose one to the The first recognized clinical presentations of zinc defi-
heightened risk of certain autoimmune diseases such as ciency and the essential role of zinc in human nutrition
asthma, diabetes, hypertension and coronary heart disease were growth retardation (the zinc-deficient dwarfs of the
later in life. In this sense, the effects of maternal exposure Middle East) and hypogonadism; impairment of physical
to zinc deficiency on birth defects may be more profound growth remains one of the most studied clinical features
than is generally realized. of poor zinc status. Tens of clinical trials designed to
assess the effects of zinc supplementation on physical
growth have been conducted in many countries. A
Immune Function
meta-analysis of 25 of the prospective intervention stu-
Zinc is essential to most cell systems involved in the dies showed that zinc supplementation had a highly
immune function and its deficiency can diminish immu- significant effect on linear growth and body weight of
nocompetence and resistance to infections (Table 3). Zinc children. Since zinc has no pharmacological effect on
poor status impairs the activity of natural killer cells, growth, the improvements on growth rates must stem
some neutrophil functions and phagocytosis by macro- from a correction of pre-existing zinc deficiency. In addi-
phages. Zinc is critically important for the maturation and tion to impaired growth of children, zinc deficiency can
functioning of T cells since it is an essential co-factor for retard intrauterine growth and the importance of ade-
the thymulin, a thymus hormone. Zinc deficiency reduces quate maternal zinc nutriture for normal fetal growth
the proliferation and cytokine secretion in mitogen-acti- and development has been documented in a number
vated leukocytes. Thus, thymic atrophy and lymphopenia studies.
are well-known hallmarks of zinc deficiency in humans. Zinc can mediate growth through its influence on the
Zinc is an essential constituent of HIV proteins required synthesis and secretion of growth hormones and activity
for viral replication. The nucleocapsid protein p7 of HIV- of insulin-like growth factors. Zinc is involved in DNA
1 contains two retrovirus type ‘‘zinc finger’’ domains and RNA syntheses which moderate critical metabolic
which are necessary for multiple phases of viral replica- pathways involved in growth such as cell transcription
tion. Both the ‘‘zinc-finger’’ domains of HIV- 49 and gag- and replication; synthesis of collagen, osteocalcin, soma-
precursor proteins containing such ‘zinc-fingers’ have tomedin-c, insulin and alkaline phosphatase; and
become attractive targets for antiviral therapeutics. differentiation of chodrocytes, osteoblasts, and fibroblasts.
Cytokines are necessary for adequate development and Zinc is intimately linked to bone growth through its
function of a range of cells involved in immune responses, mediating influence on a number of hormones involved in
and reported changes in the production of cytokines such bone metabolism and the cross-talk with the calcium
as interleukin-1 (IL-1), IL-2, IL-3, IL-4, IL-6, interferon- metabolic pathways. It plays a role in collagen cross-
(INF-), INF-
, and tumor necrosis factor- (TNF-) linking and stimulates bone formation and mineralizatin
presumably reflect the attempt of cells of the genome to while reducing bone resorption. Furthermore, zinc
Zinc Deficiency in Human Health 7
concentration in the bone is elevated relative to those of There is a compelling body of data from clinical trials
other tissues hence zinc has been considered to be an that zinc supplementation, either alone or with oral rehy-
essential component of calcified matrix. dration solutions (ORSs), can significantly reduce the
The mediating effect of zinc on appetite may lead to duration and severity of both acute and persistent diar-
growth impairment. Zinc deficiency has been implicated rhea and dysentery in children (see review by Hoque and
in the pathogenesis of anorexia nervosa. Animal studies Binder, 2006). The beneficial effects of zinc supplementa-
show that zinc deficiency can reduce total food intake by tion on recovery from diarrhea are reported to be greater
up to 50% and when the anorexic animals were force-fed, in stunted children, a condition likely related to zinc
they became seriously sick and some even died. The deficiency. Zinc can be effective because it corrects an
symptoms were reversed with zinc repletion. In human underlying zinc deficiency that may be contributing, in
populations, at least 5 trials have shown that zinc therapy some manner, to the child’s diarrhea or dysentery.
improved weight gain in anorexia. A 1994 randomized, Wilson’s disease is a hereditary disorder associated
double-blind, placebo-controlled trial showed that zinc with copper overload in the body. Classic treatment
(14 mg per day) doubled the rate of body mass increase in involves ‘‘decoppering’’ with penicillamine or other che-
the treatment of anorexia nervosa. A study of zinc levels lating agents. In recent years, zinc therapy has replaced
in five tissue and fluid samples collected from fifteen chelating agents as first-line therapy for Wilson’s disease.
anorexic patients to those from fifteen controls showed a The zinc induces the expression of metallothioneins
statistically significant reduction in zinc content in whole which are highly effective detoxification proteins able to
blood, blood serum, plasma, urine and washed scalp hair chelate free copper ions in the blood not bound to cer-
in anorexic patients compared to controls. Subsequent uloplasmin. The metallothionein-bound copper is stored
zinc supplementation resulted in increased zinc levels in temporarily in the mucosa of the gut and subsequently
all anorexic patients, attended by a subjective improve- excreted via the stool. The reversal of copper poisoning
ment in appetite. The molecular mechanisms involved in by normalization of free copper concentration in blood
zinc suppression of appetite are poorly understood and with zinc therapy does link Wilson’s disease, in one way
recent studies have implicated zinc’s influence on gene or the other, to zinc deficiency or metabolic zinc
expression of appetite-related peptides including neuro- imbalance.
peptide-Y (NPY), melanin-containing hormone, ghrelin, Zinc metabolism and homeostasis have been impli-
calcitonin gene-related products and serotonin. In addi- cated in many processes related to brain aging and the
tion to anorexia and weight loss, other reported effects onset and development of age-related neurodegenerative
linked to zinc deficiency include taste impairment, sali- disorders. A number of recent studies have suggested that
vary secretion disorders and loss of smell all of which can zinc deficiency accompanies many cases of Parkinson
predispose an individual to greatly reduced appetite. disease (PD) which can be correlated with vision pro-
Anorexia nervosa is a poorly understood disorder of blems, olfactory loss and taste loss. Studies of brain tissue
unclear aetiology, associated with high morbidity and from PD patients have reported significantly lower levels
mortality, for which most conventional therapies are of zinc in the cerebrospinal fluid. The role of zinc in
often to be very unsatisfactory. It has recently been pathogenesis of PD is highly speculative, and some people
recommended that zinc supplementation should be tried have proposed that that a dyshomeostasis of zinc ions is
first for any patient with anorexia nervosa, particularly present in PD rather than zinc deficiency per se.
since such therapy cannot cause the patient any harm. Zinc oxide (calamine) was used for treatment of
wounds by ancient Egyptians and today a wide array of
zincated creams, emollients, dressings and bandages are
Other Clinical Effects
commercially available for treating wounds even though
Dermatological effects resulting from severe zinc defi- we still do not know how zinc enhances wound healing or
ciency and in patients suffering from acrodermatitis to what extent the zinc is absorbed. In contrast to topical
enteropathica include erythematous scaling eruptions in applications, zinc deficiency is now recognized to have
the naso-labial and retro-auricular folds, with the derma- adverse effect on the wound healing process and to pro-
titis extending to the trunk and becoming exudative upon long the time for tissue repair. Normal wound healing has
continued zinc deficiency, and bullous pustular dermatitis three phases (i) inflammation, (ii) cellular proliferation
of the extremities and the oral, anal and genital areas, and (iii) remodeling, all of which can involve zinc-depen-
combined with paronychia and generalized alopecia dent anabolic, endocrine and immune processes. It is
(acrodermatitis enteropathica). therefore not surprising that a large number of the studies
Diarrhea is a prominent clinical feature in most cases in animal models and humans have reported that zinc
of acrodermatitis enteropathica, a zinc-deficiency syn- deficiency is associated with increased risk for chronic
drome. Diarrhea with severe zinc deficiency has been wound and delayed wound healing. At the same time,
reported in children in many developing countries. studies of burn patients have reported low plasma zinc
8 Zinc Deficiency in Human Health
levels and increased urinary excretion of zinc which can Ho E (2004) Zinc deficiency: DNA damage and cancer risk. Journal of
Nutritional Biochemistry 15: 572–578
create a vicious cycle of zinc deficiency. Hoogenraad TU (2005) Paradigm shift in treatment of Wilson’s disease:
Sickle cell disease (SCD) is caused by a single muta- zinc therapy now treatment of choice. Brain & Development
tion in the adult -globin gene which drastically reduces 28: 141–146
Hoque KM and Binder HJ (2006) Zinc in the treatment of acute diarrhea:
the solubility of deoxygenated hemoglobin leading to current status and assessment. Gastroenterology 130: 2201–2205
chronic hemolytic anemia. Growth retardation, delayed Leonard MB, Zemel BS, Kawchak DA, Ohene-Frempong K and
sexual maturation, hyperammonaemia, abnormal dark Stallings VA (1998) Plasma zinc status, growth and maturation in
children with sickle cell disease. Journal of Pediatrics 132: 467–471
adaptation and cell-mediated immune disorder are pre- McAleer MF and Tuan RS (2004) Cytotoxicant-induced trophoblast
sentations of sickle cell anemia that have been related to dysfunction and abnormal pregnancy outcomes: role of zinc and
zinc deficiency. Other studies have found that decreased metallothionein. Birth Defects Research 72: 361–370
Mocchegiani E, Bertoni-Freddari C, Marcellini F and Malavolta M (2005)
plasma zinc is common in children with SCD along with Brain, aging and neurodegeneration: role of zinc ion availability.
decreased linear growth, skeletal growth, muscle mass, Progress in Neurobiology 75: 367–390
and sexual and skeletal maturation. Some trials with Nriagu JO, editor (1980) Zinc in the Environment, Part 2: Health Effects.
Wiley, New York
zinc supplementation have demonstrated significant Oteiza PI and Mackenzie GG (2005) Zinc, oxidant-triggered cell
improvements in secondary sexual characteristics, rever- signaling and human health. Molecular Aspects of Medicine
sal of dark adaptation abnormality and normalization of 26: 245–255
Ozata M, Mergen M, Oktenli C, Aydin A, Sanisoglu SY, Bolu E,
plasma ammonia levels. Other reported beneficial effects Yilmaz MI, Sayal A, Isimer A and Ozdemir IC (2002) Increased
of zinc therapy for SCD patients include increased zinc oxidative stress and hypozincemia in male obesity. Clinical
plasma, erythrocyte and neutraphil levels and enhanced Biochemistry 35: 727–631
Prasad AS (1985) Clinical, endocrinological and biochemical effects of
activities of zinc-dependent enzymes. Interestingly, a zinc deficiency. Clinics in Endocrinology and Metabolism
novel therapeutic approach to sickle cell disease employs 14: 567–585
engineered zinc-finger protein transcription factors Salguiro MJ, Zubillaga MB, Lysionek AE, Sarabia MI, Caro R, De Paoli T,
Hager A, Weilli R and Boccio J (2000) Zinc as an essential
designed to activate and regulate the expression of the micronutrient: a review. Nutrition Research 20: 737–755
-globin gene. Salguiro MJ, Zubillaga MB, Lysionek AE, Caro RA, Weilli R and
Boccio JR (2002) The role of zinc in the growth and development of
children. Nutrition 18: 510–519
See also: 00001 Scherz H and Kirchhoff E (2006) Trace elements in foods: zinc contents
of raw foods – a comparison of data originating from different
geographic regions of the world. Journal of Food Composition and
Analysis 19: 420–433
Further Reading Scheplyagina LA (2005) Impact of the mother’s zinc deficiency on the
woman’s and newborn’s health status. Journal of Trace Elements in
ATSDR (1993). Toxicological Profile for Zinc. US Department of Health & Medicine and Biology 19: 29–35
Human Services, Agency for Toxic Substances and Disease Walker CF and Black RE (2004) Zinc and the risks for infectious disease.
Registry, Atlanta, Georgia Annual Review of Nutrition 24: 255–275
Bozalioglu S, Ozkan Y, Turan M and Simsek B (2005) Prevalence of zinc Wellinghausen N, Kirchner H and Rink L (1997) Immunobiology of
deficieny and immune response in short-term hemodialysis. Journal zinc. Trends in Immunology (formerly Immunology Today)
of Trace Elements in Medicine and Biology 18: 243–249 18: 519–521
Fraker PJ and King LE (1994) Reprogramming of the immune system
during zinc deficiency. Annual Reviews of Nutrition 24: 277–298
Gray M (2003) Does oral zinc supplementation promote healing of
chronic wound? Journal of Wound, Ostomy and Continence Nursing
30: 295–299 Web-based Resources
Hambidge M (2000) Human zinc deficiency. Journal of Nutrition
130: 1344S–1349S
Hambidge M (2003) Biomarkers of trace mineral intake and status. Office of Dietary Supplements, National Institutes of Health,
Journal of Nutrition 133: 948S–955S Bethesda, Maryland 20892 USA Web: http://ods.od.nih.gov