Zinc Deficiency in Human Health

Jerome Nriagu, School of Public Health, University of Michigan

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
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

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 4060%, pulses about 2040% and dairy products about 1030% 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 1030%. 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

2 Zinc Deficiency in Human Health

Table 1 Etiology of zinc deficiency in human populations Factor Inadequate dietary intake Driver/Moderator 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) Crohns disease Wilsons 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 Downs syndrome Congenital hypoplasia Table 2 Typical zinc contents of common food items (from Typical Zinc Content (mg/100 g) <1

Food Item Chicken breast Chicken liver Tuna Salmon Other finfish White rice Vegetables: leaves, stems and flowers Dark chicken meats Pork loin Sword fish Mushrooms Whole milk White wheat flour/ white bread Veal Lamb Pork Turkey dark meat Lobster Clam Crab Skim milk Yogurt White bean Chicken pea Duck Beef Beef liver Pig liver 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)

Decreased bioavailability Deceased absorption

12

Excessive losses

24

410

Increased requirements

> 10

Iatrogenic

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

Genetic defects

specific gene polymorphisms which can up-regulate the expression of proteins and metalloenzymes that may induce conditioned zinc deficiency.

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

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 mothers 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

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 worlds population is a risk for zinc deficiency but the World Health Organization estimates that zinc deficiency affects one-third of the worlds 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
Table 3 Immunological effects and functions of zinc Effects of Zinc Deficiency 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 Impaired leucocyte functions (chemotaxis, phagocytosis and bacterial killing)

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

Decreased incidence of opportunistic infections in AIDS patients Increased CD4 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 CD4 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 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

weights and reduced pregnancy complications. Zinc deficiency in the mother can jeopardize a childs 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 childs 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 CD4 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 zincs 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.

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 childs diarrhea or dysentery. Wilsons 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 Wilsons 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 Wilsons 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: 243249 Fraker PJ and King LE (1994) Reprogramming of the immune system during zinc deficiency. Annual Reviews of Nutrition 24: 277298 Gray M (2003) Does oral zinc supplementation promote healing of chronic wound? Journal of Wound, Ostomy and Continence Nursing 30: 295299 Hambidge M (2000) Human zinc deficiency. Journal of Nutrition 130: 1344S1349S Hambidge M (2003) Biomarkers of trace mineral intake and status. Journal of Nutrition 133: 948S955S

Ho E (2004) Zinc deficiency: DNA damage and cancer risk. Journal of Nutritional Biochemistry 15: 572578 Hoogenraad TU (2005) Paradigm shift in treatment of Wilsons disease: zinc therapy now treatment of choice. Brain & Development 28: 141146 Hoque KM and Binder HJ (2006) Zinc in the treatment of acute diarrhea: current status and assessment. Gastroenterology 130: 22012205 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: 467471 McAleer MF and Tuan RS (2004) Cytotoxicant-induced trophoblast dysfunction and abnormal pregnancy outcomes: role of zinc and metallothionein. Birth Defects Research 72: 361370 Mocchegiani E, Bertoni-Freddari C, Marcellini F and Malavolta M (2005) Brain, aging and neurodegeneration: role of zinc ion availability. Progress in Neurobiology 75: 367390 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: 245255 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: 727631 Prasad AS (1985) Clinical, endocrinological and biochemical effects of zinc deficiency. Clinics in Endocrinology and Metabolism 14: 567585 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: 737755 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: 510519 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: 420433 Scheplyagina LA (2005) Impact of the mothers zinc deficiency on the womans and newborns health status. Journal of Trace Elements in Medicine and Biology 19: 2935 Walker CF and Black RE (2004) Zinc and the risks for infectious disease. Annual Review of Nutrition 24: 255275 Wellinghausen N, Kirchner H and Rink L (1997) Immunobiology of zinc. Trends in Immunology (formerly Immunology Today) 18: 519521

Web-based Resources
Office of Dietary Supplements, National Institutes of Health, Bethesda, Maryland 20892 USA Web: http://ods.od.nih.gov