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Zinc Deficiency in Human Health
Jerome Nriagu, School of Public Health, University of Michigan
ª 2007 Elsevier B.V. All rights reserved.
Introduction
Etiology of Zinc Deficiency
Epidemiological Aspects of Zinc Deficiency
Clinical and Behavioral Effects of Zinc Deficiency
Further Reading
Introduction
especially in the developing countries, pulses and cereals
represent the major source of zinc. In the United States
and other developed countries, however, meat provides
40–60%, pulses about 20–40% and dairy products about
10–30% of the dietary zinc. It is interesting that recent
movement to dietary habits that eschew red meat (high in
zinc and iron) in favor of fish, poultry and diary products
may be a risk factor for both zinc and iron deficiency, as
would a purely vegetarian diet.
The bioavailability of zinc in most common foods
typically is in the range of 10–30%. Some non-digestible plant constituents such as phytates, dietary fibers
and lignin can bind zinc in ways that inhibit its absorption thereby engendering dietary zinc deficiency.
Calcium is also known to inhibit zinc adsorption and
often acts synergistically with phytate in inhibiting
zinc adsorption. Other factors known to affect zinc
absorption include high concentrations of ferrous iron
(especially in supplements) and pharmacological intakes
of folic acid.
Comprehensive reviews of conditioned zinc deficiency are available (see Further Reading list). Increased
urinary excretion of zinc has been reported in a number of
conditions including liver diseases, kidney diseases and
alcoholism and during treatment with some chelating
agents such as ethylenediamine tetraacetate (EDTA)
and penicillamine. Hypozincuria can accompany conditions associated with increased catabolism such as
surgery, burns, multiple injuries, major fractures, diabetes
mellitus, chronic bleeding from hookworm and other
intestinal parasites, stress and from excessive menstruation, protein deprivation and starvation. Excessive
sweating was associated with zinc deficiency in nutritional dwarfism. Intestinal malabsorption is a common
mechanism for zinc deficiency in people experiencing
gastrointestinal diseases with contributing factors being
protein-losing enteropathies, and sustained loss of intestinal secretions. Morphological alterations of the intestine
as an intervention strategy for obesity can lead to loss of
absorptive function and zinc deficiency.
Other physiological conditions may lead to increased
requirement for zinc, including pregnancy, lactation, dilutional effects of rapid growth (such as the catch-up growth
Zinc exposure is receiving increasing attention as a public
health problem because of the U-shaped dose-response
curve in which adverse health effects are associated with
the presence of either too little or too much zinc in the
vulnerable tissues or organs. The growing scientific interest and research have led to a paradigm shift in terms of
which arm of the U-curve should be of most concern to
public health. Attention was focused for years on zinc
toxicity because of the general belief that zinc deficiency
could not occur in humans because zinc was assumed to
be ubiquitous and plentiful in our diets. About 40 years
ago, zinc was recognized as an essential micronutrient for
human health by Dr. Ananda Prasad, a nutrition chemist
at Wayne State University in Detroit, Michigan. Since
then, various laboratory and clinical tests combined with
many zinc supplementation trials have led to the documentation of widespread incidence of zinc deficiency in
human populations. Today, zinc deficiency is recognized
as a nutritional problem worldwide, pandemic in both
developed and developing countries. The risk factors for
the silent epidemic of zinc deficiency are primarily environmental in origin.
Etiology of Zinc Deficiency
The causes of zinc deficiency fall under two main categories (i) nutritional causes such as consumption of food
items with either low zinc contents or unavailable forms
of zinc, and (ii) conditioned (secondary) deficiency
related to diseases and genetic malfunctions that impair
intestinal absorption and/or increase intestinal loss of
zinc. Various factors that may contribute to zinc deficiency are outline in Table 1.
The zinc contents of common food items from various
parts of the world vary widely (Table 2). Soils in some
parts of the world are depleted in zinc and consumption of
locally grown foods can result in endemic zinc deficiency
in some communities. Besides the geogenic factors, major
contributors to zinc deficiency include poverty, limited
food availability and food preferences. For most people
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
Factor
Driver/Moderator
Inadequate dietary intake
Geologically-induced in local diets
Low animal-protein intake
Low-income diets
Institutional and hospital diets
High fiber/phytate diets
Infant formulae
Old age
Gastrointestinal disorders
(steatorrhea)
Crohn’s disease
Wilson’s disease
Cystic fibrosis
Parasitic infections
Protein deficiency
Inflammatory bowel diseases
Cardiovascular diseases (?)
Burns
Surgery
Increased sweating
Alcoholism
Neoplastic diseases
(anorexia and starvation)
Diabetes
Collagen diseases (rheumatoid
arthritis; lupus)
Chronic bleeding from hookworm
and other intestinal parasites
Renal Diseases
Cirrhosis of the liver
Monorrhagia
Hemodialysis
Occupational exposure to silica
Oral contraceptive agents
Excessive menstruation
Excessive sex (male)
Pregnancy
Lactation
Rapid growth
Stress
Obesity
Tissue anabolism
Chelating drugs
Prolonged intravenous therapy
Total parenteral nutrition (TPN)
Acrodermatitis enteropathica
Sickle-cell disease
Down’s syndrome
Congenital hypoplasia
Typical Zinc
Content
(mg/100 g)
Food Item
<1
Chicken breast
Decreased bioavailability
Deceased absorption
Excessive losses
Increased requirements
Iatrogenic
Genetic defects
of premature infants), stress, obesity, trauma and rehabilitation after starvation. Poor zinc status has been associated
with a number of genetic diseases such as sickle-cell
anemia, thalassemia, and amyotrophic lateral sclerosis but
acrodermatitis enteropathica (Brandt Syndrome, DanboltCross Syndrome or Congenital Zinc Deficiency) is the
only inherited disease known in which the symptoms are
consistent with those of severe zinc deficiency. More
recently, genomic studies have identified a number of
Chicken liver
Tuna
Salmon
Other finfish
White rice
1–2
Vegetables: leaves,
stems and flowers
Dark chicken meats
Pork loin
Sword fish
Mushrooms
Whole milk
2–4
White wheat
flour/ white bread
Veal
Lamb
Pork
Turkey dark meat
Lobster
Clam
Crab
Skim milk
Yogurt
White bean
Chicken pea
4–10
Duck
Beef
Beef liver
Pig liver
> 10
Oyster
Peanut butter
crunch
Vegetables: roots
and tubers
Vegetables: fruits
Fruits
Tofu
Eggs
Cottage, Cheddar
and Blue cheese
Nuts (almond,
walnuts)
Eel
Shrimp
Beans (Navy, Black,
Pinto, etc)
Bran cereals
Nuts (cashews,
pecans, peanuts)
Bovine kidney
Pig kidney
Rye kernel
Barley kernel
Oat kernel
Buckwheat kernel
Peanuts, roasted
Lentil
Whole wheat flower
Corn meal
Some breakfast
cereals
Pork
Lamb
King crab
Some breakfast
cereals
Breakfast cereals
fortified with zinc
Beef chuck and
lean beef shank
specific gene polymorphisms which can up-regulate the
expression of proteins and metalloenzymes that may
induce conditioned zinc deficiency.
Epidemiological Aspects of Zinc
Deficiency
Early indications of abnormally low in infants compared
with adults and children in other age groups came from
analysis of their hair and plasma samples. Infants are
particularly at risk because zinc concentration in mother’s
mark decline sharply following delivery regardless of the
Zinc Deficiency in Human Health
Figure 1 Food and spices that contain elevated levels of zinc
(from Wikipedia, 2007)
maternal zinc intake or zinc status. Breastfeeding provides
optimal zinc level up to six months and the zinc intake
may become marginal after that. Because adaptive immunity is not fully functional, newborns are more susceptible
to diarrheal and respiratory diseases. Since zinc plays a
central role in immunity, the zinc deficiency serves to
heighten the risk of infections and diseases. Another
important factor that is believed to contribute to zinc
deficiency in the 5- to 6-month age group is the introduction of complementary foods and infant formulae low
in zinc. Other contributing factors include the dilutional
effect of rapid growth and specific growth factors in early
postnatal life that make it difficult to achieve a positive
zinc balance.
Compelling evidence for nutritional zinc deficiency
comes from the classic randomized controlled studies of
dietary zinc supplementation in young children during
the last 30 years which showed widespread occurrence of
growth-limiting zinc deficiency in otherwise healthy
infants and young children in many parts of the world.
There is also a compelling body of clinical data from
treatment trials that zinc is effective as prophylaxis and
3
in the treatment of acute diarrhea and lower respiratory
infections, thereby linking pre-existing zinc deficiency
status to these common childhood diseases.
Zinc deficiency is one of the most prevalent risk factor
for nutrient-related diseases, and is a leading contributor
to the global burden of anemia (as direct proximate cause
or by potentiating the role of iron in anemia). Young
children as well as pregnant and postpartum women are
at highest risk of zinc deficiency which may occur
throughout life span depending on dietary habits.
Populations in the developing countries consume limited
animal products (excellent source of many trace elements) and plants or cereal meals high in inhibitors and
are generally at increased risk of zinc deficiency. The
FAO national food balance data suggests that about half
of the world’s population is a risk for zinc deficiency but
the World Health Organization estimates that zinc deficiency affects one-third of the world’s population (about
two billion people) with the prevalence rates ranging
from 4 to 73% in various regions (WHO, 2002).
Although severe zinc deficiency is rare, the incidence of
mild to moderate deficiency is common throughout the
world. The worldwide prevalence rates for copper, cobalt,
manganese and cobalt deficiencies are currently unknown
and are believed to be quite high and represent potential
moderators of zinc deficiency.
It is estimated that about 800,000 deaths (about 1.5% of
all deaths) and about 20% of perinatal mortality worldwide can be attributed to zinc deficiency, a predisposing
risk factor for diarrhea and pneumonia, the two most
common causes of death in children less than five years
old. Infantile and early childhood zinc deficiency has been
associated with stunted growth and with learning, psychomotor and neurobehavioural problems. The loss of
healthy life years attributable to iron deficiency alone
amounts to 29 million disease adjusted life years
(DALYs), about 2.9% of global total, 18% of which occurs
in sub-Saharan Africa. Zinc deficiency is a risk factor for
many chronic diseases and is believed to be responsible
for about 10% of diarrheal diseases, 16% of lower respiratory tract infections and 18% of malarial attacks
worldwide (WHO, 2002).
The beneficial effects of zinc supplementation for
diarrhea prevention may be comparable to those achievable through clean water supply and quality sanitation.
For children under 5 years old, the public health benefit
of zinc supplementation in the prevention of acute
respiratory disease and malaria is believed to be much
higher (and considerably cheaper) than that of any currently available intervention strategy for either morbidity.
The maintenance of optimal zinc nutriture is probably
the most effective preventive measure that can be undertaken to reduce childhood morbidity and mortality in the
developing countries.
4 Zinc Deficiency in Human Health
Clinical and Behavioral Effects of Zinc
Deficiency
As a consequence of the large number of zinc-dependent
metabolic functions, the clinical morbidities associated
with zinc deficiency are considerable. The crosstalk
between the metabolic cycles of zinc and other essential
micronutries allows zinc deficiency to achieve a domino
effect that affects most organ systems in adverse manner.
It is not surprising that some people associate zinc deficiency with chronic fatigue syndrome. Important clinical
manifestations of zinc efficiency are listed in Table 3. The
spectrum of clinical effects depends on the dose, age, stage
of development, deficiencies of related metals and other
micronutrients, and individual susceptibility and may
include: (i) primary T-cell lymphocyte immune system
dysfunction (leading to failure to terminate incipient
malignancies, viral and fungal infections); (ii) frequent
opportunistic infections (due to inability to protect cell
membranes from viruses, toxins, complement, and
venoms); (iii) respiratory and skin allergies, (iv) asthma;
(v) chronic diarrhea; (vi) abnormal neurosensory changes,
(vii) poor appetite (particularly in the young and aged);
(viii) mental lethargy, (ix) fertility problems (including
hypogonads, failure of sexual maturity, benign prostatitis
in men, and menstrual cramping and bloating in women),
(x) birth defects; (xi) growth failure (dwarfism) and
growth retardation; (xi) premature aging; (xii) vision problems; (xiii) loss of taste; (xiv) joint pain; (xv) essential
hypertension; (xvi) angina pectoris; (xvii) ischemia of
effort; (xviii) delayed wound healing; (xix) scleroderma;
(xx) systemic scleroderma (including lethal pulmonary
hypertension); (xxi) loss of hair color; (xxii) anemia;
(xxiii) striae (stretch marks); (xxiv) night blindness;
(xxv) acne; and (xxvi) defective connective tissue and
macular degeneration; and (xxvii)apathy and irritability.
Abnormal levels of zinc have been found in the eyes of
people with cataracts, cataracts or glaucoma, and zinc has
been found useful in treating myopia (nearsightedness).
Zinc is important to male sex organ function and reproductive fluids and since oysters have the highest zinc
content of any food, there may be more to the old sayings
about oysters and romance. Zinc deficiency has also been
linked to pectus excavatum (or pectus deformities),
Marfan syndrome, Ehlers-Danlos syndrome (EDS) and
Mitral valve prolapse syndrome. In chronic zinc deficiency, smoking tobacco can result in the metabolic
demand for zinc being met partially with toxic cadmium
from cigarette smoke, eventually resulting in lung disease.
It is clear from the above that there are no defining
symptoms of human zinc deficiency since many of these
symptoms are general and are associated with other medical conditions. Some of these effects are discussed in
detail below.
Reproduction
Zinc deficiency affects reproduction adversely in both
males and females since all the hormones and a wide
range of enzymes involved in reproduction are sensitive
to zinc stress. In particular, zinc is essential for the
synthesis and secretion of luteinizing hormones and
follicle-stimulating hormone, gonadal differentiation,
and fertilization. Zinc fingers exercise significant controls
on the biological effects of estrogens and androgens
elements of the DNA that turn on the genes active
in protein synthesis during early pregnancy. Zinc is
involved in the formation of prostaglandins required
for maintenance of pregnancy and also important at
parturition to initiate the uterine contractions for
Table 3 Immunological effects and functions of zinc
Effects of Zinc Deficiency
Decreased incidence of opportunistic infections in AIDS patients
Decreased thymocyte count in thymus
Decreased peripheral T-cell count
Decreased proliferative T-cell response to mitogens
Reduced cytotoxic T-cell activity
Decreased T helper cell function
Decreased macrophage function
Lowered neutrophil functions
Decreased antibody production
Reduced placental transfer of antibodies from mother to fetus
Imbalance in functions of Th-1 and Th-2 cells
Altered CD4/CD8 ratio
Increased blood glucocorticoids concentration
Increased CD4þ cell count in AIDS patients
Clinical benefits in common colds
Clinical benefits rheumatoid arthritis
Increased lymphocyte blast transformation
Effects of Zinc Supplementation
Increased thymocyte count in thymus
Impaired immune function restored
Increased proliferative T-cell response to mitogens
Increased CD4þ cell count
Improved neutrophil functions
Increased production of anti-viral interferon- (IFN-)
Increased production of cytokines such as interleukin-1
(IL-1), IL-2, IL-3, IL-4, IL-6, INF-, INF- and TNF-
Increased lymphocyte receptor expression
Impaired leucocyte functions (chemotaxis, phagocytosis and
bacterial killing)
Block activation of protease, an essential protein-splitting enzyme
of HIV
Zinc Deficiency in Human Health
expulsion of the fetus. Another way that zinc can influence pregnancy is through the impact on insulin-like
growth factors known to be potent stimulators of cell
proliferation and tissue differentiation.
The concentration of zinc in the male genital organs
and human semen is extremely high relative to those of
other body fluids and tissues. The zinc is secreted primarily by the prostate, and one can infer that low zinc
status can have a significant impact on proper functioning
of this organ. High levels of zinc found in maturing
spermatozoa are believed to exercise some influence on
oxygen consumption by the spermatozoa, chromatin stabilization and acrosin activity. Clinical studies show that
zinc deficiency negatively affects the formation and
maturation of spermatozoa, testicular growth, and testicular steroidogenesis. Zinc supplementation has been
shown to be beneficial to infertility in female and improve
sperm count, motility and morphology in subfertile men
with idiopathic asthenozoospermia and/or oligozoospermia. Besides infertility, zinc deficiency can contribute to
the pathogenesis of other male reproductive dysfunction
such as hipogonadism and feminization. The mechanisms
for the effects are not fully understood.
Pregnancy and Prenatal Development
The conceptus requires zinc for normal growth and
development and is therefore at heightened risk when
the supply of zinc is suboptimal. Maternal zinc deficiency
can disrupt the normal function of trophoblast, the
embryonic-derived component of the placenta responsible for implantation, production and secretion of
hormones, establishment of the maternal-fetal barrier
and the mediation of metabolic exchanges across this
barrier. The trophoblast is important for establishing
and maintaining the fetoplacental unit and trophoblastic
dysfunction has been linked to improper fetal development and poor pregnancy outcomes including
spontaneous abortion, prolonged gestation, difficult
labor, low birth weight, and more complications during
delivery. Malformations associated with zinc deficiency
include abnormalities in brain and eye functions, audiometric performance, cleft lip and palate, and
abnormalities of the heart, lung and urogenital systems.
Fetuses in zinc-deficient mothers often show growth
retardation, and a high frequency of skeletal abnormalities. Biochemical and functional abnormalities can be
displayed in the lung and pancreatic systems. Evidence
that zinc deficiency is a teratogenic risk in humans
include (i) women with acrodermatitis enteropathica
tend to have complicated pregnancies if they do not
receive zinc supplements; (ii) low plasma zinc levels
have been associated with increased risk of malformations
and low birth weight; and (iii) several studies show that
zinc supplementation is associated with increased birth
5
weights and reduced pregnancy complications. Zinc deficiency in the mother can jeopardize a child’s health in two
ways. On the one hand, it increases the rate of pregnancy
and the risks of delivery complications, low birth weight
and other adverse birth outcomes. On the other hand,
maternal zinc deficiency can lead to adverse post-natal
development and latent effects which can persist throughout lifetime.
Neonates with zinc deficiency show higher rates of
congenital valvular defects, gastrointestinal tract atresia,
increased congenital malformations (such as wry-neck,
hernia, varus, valgus footstep, etc) and life-threatening
conditions including respiratory disorders, convulsive
syndrome and edematic syndrome and lower rate of physical development. Infants with zinc deficiency general
have higher disease morbidity marked by conditions such
as rickets, anemia, dystrophy, atopic dermatitis, various
types of allergic reactions, alimentary disorders such as
hypotrophy and paratrophy and increased susceptibility
to infectious diseases. Meta-analysis of the results from
randomized controlled trials of women receiving zinc
supplements during pregnancy in developing countries
provide a strong evidence that significant benefits can be
derived from maternal Zn supplementation in relation to
neonatal morbidity and infant infections.
A critical role for zinc in the development of the
central nervous system (CNS) is biologically plausible
because (i) zinc-dependent enzymes are involved brain
growth; (ii) zinc is involved in the production of neurotransmitters, (iii) zinc-dependent neurotransmitters are
involved in brain memory function, (iv) zinc finger
proteins play a role in the brain structure and
neurotransmission, (v) high concentrations of zinc in the
synaptic vesicles of the ‘‘zinc containing’’ neurons in the
forebrain serve as a moderator of neuronal excitability.
Clinical evidence for the impairment of the central nervous system (CNS) by zinc deficiency are two-fold: (a)
CNS dysfunction is a prominent clinical feature in most
cases of acrodermatitis enteropathica, a genetic defect
associated with zinc deficiency syndrome, and (b) marked
improvement in immune function is achieved with zinc
therapy. The treatment of acrodermatitis enteropathica
with zinc is rapidly attended by an increase in hedonic
tone, alertness, motivation and responsiveness along with
rapid decreases in nervousness, irritability and restlessness. The impairment of cognitive processes in infants
by zinc deficiency is well documented in the scientific
literature, but a consensus has not yet been reach.
Zinc has been used successfully to treat children with
attention deficit hyperactivity disorder (ADHD), a highincidence condition characterized by short attention
span, impulsivity, overactivity and inability to socialize.
Furthermore, many authors have reported significant
beneficial effects of zinc supplementation on the cognitive
functions of children from poor developing countries.
6 Zinc Deficiency in Human Health
In addition to effects on the child’s cognition, zinc deficiency also impairs the acquirement of motor skills,
locomotive development, speech, and ability to orient
himself or herself. These effects of zinc deficiency are
remarkably similar to those commonly associated with
childhood lead poisoning. Since zinc deficiency is much
more prevalent in childhood populations, one must wonder whether this condition is being misclassified for lead
poisoning in many (if not most) epidemiological studies.
Maternal zinc deficiency during early pregnancy can
influence the development of epigenetic marks at the Avy
locus in the early embryo thereby influencing all tissue
development and possibly the germ line. Subsequent
incomplete erasure of the epigenetic alterations at Avy
induced by zinc deficiency represents a plausible
mechanism by which adaptive evolution may occur in
animals. It is increasingly evident that epigenetic alterations at metastable epiallelles may be the mechanistic link
between early nutrition and zinc deficiency and chronic
disease susceptibility in adults. Zinc deficiency can be
considered an important contributory factor to the
‘‘Barker Effect’’ which posits that exposures in the womb
and postnatal environment can predispose one to the
heightened risk of certain autoimmune diseases such as
asthma, diabetes, hypertension and coronary heart disease
later in life. In this sense, the effects of maternal exposure
to zinc deficiency on birth defects may be more profound
than is generally realized.
Immune Function
Zinc is essential to most cell systems involved in the
immune function and its deficiency can diminish immunocompetence and resistance to infections (Table 3). Zinc
poor status impairs the activity of natural killer cells,
some neutrophil functions and phagocytosis by macrophages. Zinc is critically important for the maturation and
functioning of T cells since it is an essential co-factor for
the thymulin, a thymus hormone. Zinc deficiency reduces
the proliferation and cytokine secretion in mitogen-activated leukocytes. Thus, thymic atrophy and lymphopenia
are well-known hallmarks of zinc deficiency in humans.
Zinc is an essential constituent of HIV proteins required
for viral replication. The nucleocapsid protein p7 of HIV1 contains two retrovirus type ‘‘zinc finger’’ domains
which are necessary for multiple phases of viral replication. Both the ‘‘zinc-finger’’ domains of HIV- 49 and gagprecursor proteins containing such ‘zinc-fingers’ have
become attractive targets for antiviral therapeutics.
Cytokines are necessary for adequate development and
function of a range of cells involved in immune responses,
and reported changes in the production of cytokines such
as interleukin-1 (IL-1), IL-2, IL-3, IL-4, IL-6, interferon- (INF-), INF-, and tumor necrosis factor- (TNF-)
presumably reflect the attempt of cells of the genome to
adapt to the stress of suboptimal zinc. Zinc deficiency
affects the balance between the Th-1 and Th-2 cells, a
critical factor in cell-mediated immunity.
Zinc has been used successfully to restore immune
function in the zinc-specific malabsorption syndrome
known as acrodermatitis enteropathica as well as other
morbidities. Some immunological dysfunction in the
elderly such as decreased interferon- (IFN- ) production can be corrected with zinc. Impaired immune
response to diphtheria vaccination in hemodialysis
patients has been linked to zinc deficiency and is correctable with zinc therapy. The subject of zinc and
immunodeficiency has been extensively reviewed in a
number of publications. Hypozincuria is a clinical manifestation of HIV-AIDS and zinc therapy has been shown
to increase the CD4þ cell count and reduce the incidence
of bacteria infections in HIV-infected patients. Zinc salts
are increasingly gaining favor as non-prescription drug
for reducing the duration and severity of common colds.
Growth
The first recognized clinical presentations of zinc deficiency and the essential role of zinc in human nutrition
were growth retardation (the zinc-deficient dwarfs of the
Middle East) and hypogonadism; impairment of physical
growth remains one of the most studied clinical features
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
meta-analysis of 25 of the prospective intervention studies showed that zinc supplementation had a highly
significant effect on linear growth and body weight of
children. Since zinc has no pharmacological effect on
growth, the improvements on growth rates must stem
from a correction of pre-existing zinc deficiency. In addition to impaired growth of children, zinc deficiency can
retard intrauterine growth and the importance of adequate maternal zinc nutriture for normal fetal growth
and development has been documented in a number
studies.
Zinc can mediate growth through its influence on the
synthesis and secretion of growth hormones and activity
of insulin-like growth factors. Zinc is involved in DNA
and RNA syntheses which moderate critical metabolic
pathways involved in growth such as cell transcription
and replication; synthesis of collagen, osteocalcin, somatomedin-c, insulin and alkaline phosphatase; and
differentiation of chodrocytes, osteoblasts, and fibroblasts.
Zinc is intimately linked to bone growth through its
mediating influence on a number of hormones involved in
bone metabolism and the cross-talk with the calcium
metabolic pathways. It plays a role in collagen crosslinking and stimulates bone formation and mineralizatin
while reducing bone resorption. Furthermore, zinc
Zinc Deficiency in Human Health
concentration in the bone is elevated relative to those of
other tissues hence zinc has been considered to be an
essential component of calcified matrix.
The mediating effect of zinc on appetite may lead to
growth impairment. Zinc deficiency has been implicated
in the pathogenesis of anorexia nervosa. Animal studies
show that zinc deficiency can reduce total food intake by
up to 50% and when the anorexic animals were force-fed,
they became seriously sick and some even died. The
symptoms were reversed with zinc repletion. In human
populations, at least 5 trials have shown that zinc therapy
improved weight gain in anorexia. A 1994 randomized,
double-blind, placebo-controlled trial showed that zinc
(14 mg per day) doubled the rate of body mass increase in
the treatment of anorexia nervosa. A study of zinc levels
in five tissue and fluid samples collected from fifteen
anorexic patients to those from fifteen controls showed a
statistically significant reduction in zinc content in whole
blood, blood serum, plasma, urine and washed scalp hair
in anorexic patients compared to controls. Subsequent
zinc supplementation resulted in increased zinc levels in
all anorexic patients, attended by a subjective improvement in appetite. The molecular mechanisms involved in
zinc suppression of appetite are poorly understood and
recent studies have implicated zinc’s influence on gene
expression of appetite-related peptides including neuropeptide-Y (NPY), melanin-containing hormone, ghrelin,
calcitonin gene-related products and serotonin. In addition to anorexia and weight loss, other reported effects
linked to zinc deficiency include taste impairment, salivary secretion disorders and loss of smell all of which can
predispose an individual to greatly reduced appetite.
Anorexia nervosa is a poorly understood disorder of
unclear aetiology, associated with high morbidity and
mortality, for which most conventional therapies are
often to be very unsatisfactory. It has recently been
recommended that zinc supplementation should be tried
first for any patient with anorexia nervosa, particularly
since such therapy cannot cause the patient any harm.
Other Clinical Effects
Dermatological effects resulting from severe zinc deficiency and in patients suffering from acrodermatitis
enteropathica include erythematous scaling eruptions in
the naso-labial and retro-auricular folds, with the dermatitis extending to the trunk and becoming exudative upon
continued zinc deficiency, and bullous pustular dermatitis
of the extremities and the oral, anal and genital areas,
combined with paronychia and generalized alopecia
(acrodermatitis enteropathica).
Diarrhea is a prominent clinical feature in most cases
of acrodermatitis enteropathica, a zinc-deficiency syndrome. Diarrhea with severe zinc deficiency has been
reported in children in many developing countries.
7
There is a compelling body of data from clinical trials
that zinc supplementation, either alone or with oral rehydration solutions (ORSs), can significantly reduce the
duration and severity of both acute and persistent diarrhea and dysentery in children (see review by Hoque and
Binder, 2006). The beneficial effects of zinc supplementation on recovery from diarrhea are reported to be greater
in stunted children, a condition likely related to zinc
deficiency. Zinc can be effective because it corrects an
underlying zinc deficiency that may be contributing, in
some manner, to the child’s diarrhea or dysentery.
Wilson’s disease is a hereditary disorder associated
with copper overload in the body. Classic treatment
involves ‘‘decoppering’’ with penicillamine or other chelating agents. In recent years, zinc therapy has replaced
chelating agents as first-line therapy for Wilson’s disease.
The zinc induces the expression of metallothioneins
which are highly effective detoxification proteins able to
chelate free copper ions in the blood not bound to ceruloplasmin. The metallothionein-bound copper is stored
temporarily in the mucosa of the gut and subsequently
excreted via the stool. The reversal of copper poisoning
by normalization of free copper concentration in blood
with zinc therapy does link Wilson’s disease, in one way
or the other, to zinc deficiency or metabolic zinc
imbalance.
Zinc metabolism and homeostasis have been implicated in many processes related to brain aging and the
onset and development of age-related neurodegenerative
disorders. A number of recent studies have suggested that
zinc deficiency accompanies many cases of Parkinson
disease (PD) which can be correlated with vision problems, olfactory loss and taste loss. Studies of brain tissue
from PD patients have reported significantly lower levels
of zinc in the cerebrospinal fluid. The role of zinc in
pathogenesis of PD is highly speculative, and some people
have proposed that that a dyshomeostasis of zinc ions is
present in PD rather than zinc deficiency per se.
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
commercially available for treating wounds even though
we still do not know how zinc enhances wound healing or
to what extent the zinc is absorbed. In contrast to topical
applications, zinc deficiency is now recognized to have
adverse effect on the wound healing process and to prolong the time for tissue repair. Normal wound healing has
three phases (i) inflammation, (ii) cellular proliferation
and (iii) remodeling, all of which can involve zinc-dependent anabolic, endocrine and immune processes. It is
therefore not surprising that a large number of the studies
in animal models and humans have reported that zinc
deficiency is associated with increased risk for chronic
wound and delayed wound healing. At the same time,
studies of burn patients have reported low plasma zinc
8 Zinc Deficiency in Human Health
levels and increased urinary excretion of zinc which can
create a vicious cycle of zinc deficiency.
Sickle cell disease (SCD) is caused by a single mutation in the adult -globin gene which drastically reduces
the solubility of deoxygenated hemoglobin leading to
chronic hemolytic anemia. Growth retardation, delayed
sexual maturation, hyperammonaemia, abnormal dark
adaptation and cell-mediated immune disorder are presentations of sickle cell anemia that have been related to
zinc deficiency. Other studies have found that decreased
plasma zinc is common in children with SCD along with
decreased linear growth, skeletal growth, muscle mass,
and sexual and skeletal maturation. Some trials with
zinc supplementation have demonstrated significant
improvements in secondary sexual characteristics, reversal of dark adaptation abnormality and normalization of
plasma ammonia levels. Other reported beneficial effects
of zinc therapy for SCD patients include increased zinc
plasma, erythrocyte and neutraphil levels and enhanced
activities of zinc-dependent enzymes. Interestingly, a
novel therapeutic approach to sickle cell disease employs
engineered zinc-finger protein transcription factors
designed to activate and regulate the expression of the
-globin gene.
See also: 00001
Further Reading
ATSDR (1993). Toxicological Profile for Zinc. US Department of Health &
Human Services, Agency for Toxic Substances and Disease
Registry, Atlanta, Georgia
Bozalioglu S, Ozkan Y, Turan M and Simsek B (2005) Prevalence of zinc
deficieny and immune response in short-term hemodialysis. Journal
of Trace Elements in Medicine and Biology 18: 243–249
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
Hambidge M (2000) Human zinc deficiency. Journal of Nutrition
130: 1344S–1349S
Hambidge M (2003) Biomarkers of trace mineral intake and status.
Journal of Nutrition 133: 948S–955S
Ho E (2004) Zinc deficiency: DNA damage and cancer risk. Journal of
Nutritional Biochemistry 15: 572–578
Hoogenraad TU (2005) Paradigm shift in treatment of Wilson’s disease:
zinc therapy now treatment of choice. Brain & Development
28: 141–146
Hoque KM and Binder HJ (2006) Zinc in the treatment of acute diarrhea:
current status and assessment. Gastroenterology 130: 2201–2205
Leonard MB, Zemel BS, Kawchak DA, Ohene-Frempong K and
Stallings VA (1998) Plasma zinc status, growth and maturation in
children with sickle cell disease. Journal of Pediatrics 132: 467–471
McAleer MF and Tuan RS (2004) Cytotoxicant-induced trophoblast
dysfunction and abnormal pregnancy outcomes: role of zinc and
metallothionein. Birth Defects Research 72: 361–370
Mocchegiani E, Bertoni-Freddari C, Marcellini F and Malavolta M (2005)
Brain, aging and neurodegeneration: role of zinc ion availability.
Progress in Neurobiology 75: 367–390
Nriagu JO, editor (1980) Zinc in the Environment, Part 2: Health Effects.
Wiley, New York
Oteiza PI and Mackenzie GG (2005) Zinc, oxidant-triggered cell
signaling and human health. Molecular Aspects of Medicine
26: 245–255
Ozata M, Mergen M, Oktenli C, Aydin A, Sanisoglu SY, Bolu E,
Yilmaz MI, Sayal A, Isimer A and Ozdemir IC (2002) Increased
oxidative stress and hypozincemia in male obesity. Clinical
Biochemistry 35: 727–631
Prasad AS (1985) Clinical, endocrinological and biochemical effects of
zinc deficiency. Clinics in Endocrinology and Metabolism
14: 567–585
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
micronutrient: a review. Nutrition Research 20: 737–755
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
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
Scheplyagina LA (2005) Impact of the mother’s zinc deficiency on the
woman’s and newborn’s health status. Journal of Trace Elements in
Medicine and Biology 19: 29–35
Walker CF and Black RE (2004) Zinc and the risks for infectious disease.
Annual Review of Nutrition 24: 255–275
Wellinghausen N, Kirchner H and Rink L (1997) Immunobiology of
zinc. Trends in Immunology (formerly Immunology Today)
18: 519–521
Web-based Resources
Office of Dietary Supplements, National Institutes of Health,
Bethesda, Maryland 20892 USA Web: http://ods.od.nih.gov