Importance of Zinc for Human Health

Part Two in a Three-Part Series 

Consequences and Causes of Zinc Deficiency

This is the second article in the series on zinc nutrition. Background information on zinc metabolism and dietary requirements was provided in part 1. Functional effects and causes of zinc deficiency are discussed here.

Consequences of Zinc Deficiency

Due to multiple biologic functions of zinc and its ubiquitous distribution in human tissues, there is a broad range of physiological signs of zinc deficiency. These signs vary depending on the severity of the condition. Clinical signs of frank zinc deficiency are seen in acrodermatitis enteropathica, which is a rare autosomal recessive genetic disorder with zinc malabsorption (1). Iatrogenic causes of zinc deficiency such as prolonged parenteral nutrition with inadequate zinc content and long-term penicillamine therapy for Wilson’s disease, have produced similar clinical signs as those observed in acrodermatitis enteropathica.

Clinical manifestations of frank zinc deficiency may vary at different ages. In early infancy, diarrhea is a prominent symptom. Zinc deficiency leads to impaired cognitive function, behavioral problems, impaired memory, learning disability and neuronal atrophy (2). Skin problems become more frequent as the child grows older. Alopecia, growth retardation and recurrent infections are common in school-age children. Chronic non-healing skin ulcers and recurrent infections are common among the elderly. These effects are derived from controlled clinical trials showing positive response to supplemental zinc.

Unlike the situation with acrodermatitis enteropathica described above, where clinical signs reflect severe deficiency, functional impairments identified in community-based trials may be more representative of mild or moderate deficiency. The range of functional impairments reported from these trials is described below.

Risk of Infections

Diarrhea:
Several studies have demonstrated reductions in the incidence and duration of acute and persistent diarrhea in zinc-supplemented children compared with placebo controls. Recently, a pooled analysis of randomized, controlled trials of zinc supplementation performed in nine low-income countries in Asia and Latin America indicated that supplemental zinc led to a 25 percent reduction in the prevalence of diarrhea (3). This analysis did not find differences in the effect of zinc by age or baseline serum zinc status of children, suggesting that benefits of zinc supplementation are likely to occur in all subgroups living in areas where there is a high risk of zinc deficiency. More recently, two additional trials conducted in Africa demonstrated significant reductions in the incidence or number of days with diarrhea (4,5), confirming that the preventive effect of zinc on diarrheal morbidity is consistent across a wide range of geographic regions.

Respiratory infections:
Reductions in the incidence of acute lower respiratory infections in response to zinc supplementation have also been documented. The recent pooled analysis of trials conducted in India, Jamaica, Peru and Vietnam indicated an overall 41 percent reduction in the incidence of pneumonia among zinc supplemented children (3).

Malaria:
Intervention trials carried out in Gambia and Papua New Guinea suggest that zinc may play a role in morbidity reduction related to Plasmodium falciparum infections. The study conducted in Gambia demonstrated a 32 percent reduction in clinic visits attributable to malaria among those given 70 mg zinc, twice a week (6). Similarly, the study in Papua New Guinea showed a 38 percent reduction in clinic visits among children provided with 10 mg zinc daily (7). On the other hand, a study conducted in Burkina Faso did not find any reduction in malarial episodes among children given daily supplements of 10 mg zinc. However, in this study, malarial episodes were identified by household visits. Zinc may reduce the severity of infection, possibly resulting in fewer clinic visits, but not necessarily fewer infections.

Mortality

Only limited information is available concerning the impact of zinc supplementation on child mortality. A recent study of full-term, small-for-gestational-age infants in northern India indicated that daily supplementation of 5 mg zinc significantly reduced mortality by 67 percent (8). Another study of older children in Burkina Faso also found that mortality was reduced by more than 50 percent among children who received zinc supplements, although the difference was not statistically significant (4).

Growth and development

There is a large body of literature indicating that zinc depletion limits growth and development, though the mechanisms involved are not well understood. This effect is seen at different stages of life cycle.

Low birth weight infants:
Infants born small for gestational age are at greater risk of zinc deficiency. Two studies reported from Latin American countries showed increased weight gain in low birth weight infants receiving daily supplement of 5 mg zinc (9,10). Responses in linear growth have been less consistent; increased growth was noted in the study in Chile (9) but not in Brazil (10), possibly because the zinc supplement was given for only a short period (8 weeks) in the latter study.

Severely malnourished children:
Children with severe malnutrition suffer from multiple nutrient deficiencies including zinc deficiency. One of the early studies carried out in Jamaica showed that zinc supplementation increased weight gain in children recovering from severe malnutrition four to twelve weeks after hospital admission (11). Subsequent trials in Bangladesh (12) also found greater weight gain among severely malnourished children who received daily zinc supplements (10 mg/kg body weight) during the course of nutritional rehabilitation. However, in one study where severely malnourished children were provided zinc supplements (1.5-6 mg/kg body weight), starting immediately after hospital admission, a higher dose of zinc increased mortality, suggesting that excessive zinc may increase the risk of severe complications (13).

Stunted children:
A number of supplementation trials have been carried out in children to assess the effect of zinc on physical growth. A meta-analysis of 33 randomized intervention trials showed that zinc supplementation produced highly significant positive response in weight gain as well as linear growth (14). Growth responses were greater in children with low initial weight-for-age or height-for-age Z scores. Thus the beneficial effect of zinc on children’s growth may be limited to populations with pre-existing growth failure.

Zinc deficiency is also associated with impaired appetite and may thereby contribute to decreased food intake and growth failure. A controlled trial in children with evidence of mild zinc deficiency resulted in increased dietary intake of energy after one year of zinc supplementation (15). A significant reduction in anorexia was also observed in stunted Ethiopian children (5) However, because the high rates of morbidity were also responsive to zinc in this study, it is not possible to determine to what extent anorexia resulted primarily from zinc deficiency or was associated with morbidity. Nonetheless, the effects of zinc status on growth and appetite may be integrally related and both outcomes would likely be corrected simultaneously through improved zinc intakes.

Adolescents:
The first cases of human zinc deficiency reported in the 1960s were in male adolescents from the Middle East (16). In this group, zinc deficiency was characterized by delayed sexual development, short stature, anemia and abnormalities in skeletal maturation. Zinc supplementation resulted in significant increase in height and sexual maturation. Decreased sperm counts and testosterone levels were also observed during experimental zinc depletion among adolescent males.

Pregnancy outcome:
The results of zinc supplementation trials during pregnancy have been inconsistent. Of the thirteen published randomized placebo-controlled trials, six studies found no effect on pregnancy outcome. Two studies showed improved fetal growth, as measured by birth weight, one of which was carried out in African American women with low plasma zinc concentration (17) and the other in urban Indian women (18). A significant reduction in preterm deliveries was also observed in these supplementation trials. A study conducted in adult Hispanic women in California showed a significant reduction in pregnancy-induced hypertension (19). However, a similar study in pregnant teenagers did not show any effect of zinc supplementation on blood pressure (20). Possible reasons for these discrepancies include small sample sizes, varying degrees of zinc deficiency and different periods of supplementation. More controlled trials among pregnant women are needed in countries where there is elevated risk of zinc deficiency and high prevalence of low birth weight.

Changes in the Elderly

 Several of the degenerative changes associated with aging may partly be due to zinc deficiency. These include a decline in immunocompetence (21), delayed wound healing (22) and certain changes in neurologic and psychologic functions (23).

Causes of Zinc Deficiency

The general causes of zinc deficiency include inadequate intake, increased requirements, malabsorption, increased losses and impaired utilization. Inadequate dietary zinc of absorbable zinc is the primary cause of zinc deficiency in most situations. This may result from a combination of low dietary intake, heavy reliance on foods with low zinc content and/ or with zinc that is poorly absorbable. Several studies show that inadequate dietary intake is common in many parts of the world (24). Low intakes are further exacerbated by physiologic conditions associated with elevated zinc requirements, increasing the risk of zinc deficiency.

Malabsorption of zinc may occur in a number of situations. For example, acrodermatitis enteropathica is a rare genetic disorder that specifically affects zinc absorption (1). Malabsorption syndromes and inflammatory diseases of the bowel, resulting in poor absorption and loss of zinc, may lead to secondary zinc deficiency, particularly in the presence of marginal dietary intakes (25) Certain drugs such as phenytoin and tetracyclin may reduce zinc absorption (25). Several studies suggest that pharmacological doses of iron interfere with the absorption of zinc due to competitive interactions between these elements (26,27). Utilization of zinc is impaired in the presence of infection, and decreased circulating levels of zinc reduce the availability of zinc to the tissues.

Conditions that alter intestinal integrity not only reduce absorption, but also result in increased endogenous losses of zinc. For example, fecal excretion of zinc is increased during acute diarrhea (28), though it is not clear to what extent this represents unabsorbed zinc or zinc of endogenous origin. These findings are of practical significance because diarrheal diseases are common in many low-income countries. Not only does zinc deficiency increase the susceptibility to childhood diarrhea, but increased losses of endogenous zinc that occur during diarrhea may further deplete body zinc, setting up a vicious cycle.

Groups at High Risk

Infants and children

Young children are at greater risk of zinc deficiency because of the increased requirements during growth. Exclusively breast fed infants of mothers with adequate zinc nutriture can satisfy their zinc requirements for the first 5-6 months of life (29). However, after this age, complementary foods containing absorbable zinc are required to satisfy the requirements. In many low-income countries, complementary feeding is delayed and cereal foods used for feeding have low content of total and absorbable zinc. These foods fail to meet the needs for zinc. Conversely, early introduction of such foods with high phytate may interfere with the absorption of zinc from breast milk. (30).

Low birth weight infants have poor hepatic stores of zinc (31). In those who are born prematurely, zinc status will be further compromised because most of the zinc is transferred during the last trimester of pregnancy. Moreover, preterm infants may have reduced absorption because of their immature gastrointestinal tract. These impairments result in increased zinc requirements during the neonatal period, although specific requirements for these infants have not been established.

Zinc requirements of malnourished children are estimated to be between 2-4 mg/ kg body weight (32). These requirements are much higher than those for healthy children (0.17 mg/kg at 1-3 years), presumably due to prior zinc depletion and problems of malabsorption due to changes in the intestinal tract.

Adolescents

The physiological requirements for zinc peak during adolescence at the time of the pubertal growth spurt, which generally occurs in girls between 10-15 years and in boys between 12-15 years. Even after the growth spurt has ceased, adolescents may require additional zinc to replete tissue zinc pools depleted during puberty (33).

Pregnant and lactating women

Increased nutritional demands during pregnancy and lactation predispose women to developing zinc deficiency (34). These demands are greater during lactation, although physiological adjustments in zinc absorption help to meet the needs for lactation. Several studies have indicated that iron supplements reduce the absorption of zinc (26,27). Where dietary intakes of zinc are low, supplemental iron, in dosages as low as 60 mg/ day may prevent women from meeting their needs for zinc during pregnancy and lactation (27).

Elderly

Diet surveys indicate that zinc intakes in the elderly are often inadequate, even in high-income countries (35). Several factors may contribute to poor zinc nutrition among the elderly. These include reduction in food intake due to reduced mobility or depression, and poor access to zinc-rich foods. There is some evidence that the efficiency of zinc absorption may decrease with age (36).

Summary

In summary, zinc deficiency is widespread in many populations and the risk is greater in growing children and pregnant women because of higher requirements of zinc. Inadequate dietary intake of absorbable zinc is the primary cause of zinc deficiency. Intervention studies have confirmed the critical importance of adequate zinc nutriture to support normal growth, reduce the risk of infections, prevent adverse outcomes of pregnancy, and improve other aspects of human health and function. Efforts are on to define more precisely the risk of zinc deficiency in vulnerable populations and to develop appropriate strategies to control this condition. These will be discussed in the subsequent article on zinc.

See Also: Zinc, Part 1 and Zinc, Part 3.

References

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This material has been prepared by V. Reddy on behalf of the IFM's Advisory Committee on Child Health and Nutrition, February 2005.