Zinc deficiency and supplementation in children and adolescents

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Steven A Abrams, MD



UpToDate performs a continuous review of over 375 journals and other resources. Updates are added as important new information is published. The literature review for version 15.3 is current through August 2007; this topic was last changed on June*19,*2007. The next version of UpToDate (16.1) will be released in March 2008.

INTRODUCTION*—*Zinc is an essential trace element. Zinc intake is closely related to protein intake; as a result, it is an important component of nutritionally related morbidity worldwide. Symptoms attributable to severe zinc depletion include growth failure, primary hypogonadism, skin disease, impaired taste and smell, and impaired immunity and resistance to infection. Zinc supplementation in populations likely at risk for zinc deficiency appears to have beneficial effects on the incidence and outcome of serious childhood infectious diseases.

ZINC METABOLISM*—*The usual oral intake of zinc is approximately 4 to 14 mg/day; the recommended dietary allowance (RDA) is 8 mg/day for children ages 9 to 11 years; the RDA for adolescent and adult males is 11 mg/day [1]. Primary dietary sources of zinc include animal products such as meat, seafood, and milk (show table 1). Ready-to-eat cereal contains the greatest amount of zinc consumed from plant products [2]. Sufficient dietary zinc sources are available in a typical mixed diet, but lacto-ovovegetarians need more milk, eggs, grains, legumes, nuts, and seeds to achieve adequate levels [3,4]. (See "Vegetarian diets for children").

Ten to 40 percent of dietary zinc is absorbed in the small bowel; absorption is inhibited by the presence of phytates and fiber in the diet that bind to zinc, as well as dietary iron and cadmium [5]. Approximately 0.5 to 1.0 mg/day is secreted in the biliary tract and excreted in the stool.

Zinc circulates at a concentration of 70 to 120 mcg/dL with 60 percent loosely bound to albumin and 30 percent tightly bound to macroglobulin. Urinary excretion typically ranges from 0.5 to 0.8 mg/day. The primary stores of zinc include the liver and kidney.

Most of the body zinc stores are intracellular where zinc is bound to metalloproteins. Zinc is the intrinsic metal component or activating cofactor for more than 70 important enzyme systems, including carbonic anhydrase, the alkaline phosphatases, dehydrogenases, and carboxypeptidases. It is involved in the regulation of nucleoproteins and the activity of various inflammatory cells and plays a role in growth, tissue repair and wound healing, carbohydrate tolerance, and synthesis of testicular hormones.

Zinc also is involved in the immune response and the response to infection. Zinc deficiency is associated with impaired phagocytic function, lymphocyte depletion, decreased immunoglobulin production, a reduction in the T4+/T8+ ratio, and decreased interleukin (IL)-2 production [6-8].

ZINC DEFICIENCY*—*Zinc deficiency is an important problem in children and adolescents, particularly in developing countries. The true prevalence of mild zinc deficiency is not known because of the nonspecificity of symptoms and imprecise diagnostic methods.

Etiology

**Dietary zinc depletion*—*Zinc depletion was first described as a consequence of poor intake in adolescent males in Iran and Egypt [9]. The depletion was caused by both inadequate zinc intake and the binding of ingested zinc to fiber and phytates in unleavened bread and clay. Affected patients suffered from severe growth retardation, anemia, hypogonadism, rough skin, and apathy or general lethargy. The growth retardation and hypogonadism responded to zinc supplementation.

Experimental zinc deficiency has been produced in normal volunteers [10]. They developed primary hypogonadism with decreased serum androgens, increased serum gonadotropins, and oligospermia.

Inadequate dietary zinc intake and depletion is thought to be an important worldwide health problem affecting poor children in developing countries. The potential significance of this condition has been studied in randomized supplementation trials. (See "Zinc supplementation" below).

**Breastfeeding*—*Zinc deficiency occurs rarely in exclusively breast-fed infants (usually premature) whose mothers have a low level of zinc in their breastmilk. The clinical presentation is similar to that of acrodermatitis enteropathica (see next section) [11-14].

**Zinc malabsorption*—*Acrodermatitis enteropathica is a recessively inherited partial defect in intestinal zinc absorption. It is the result of mutations in the SLC39A4 gene on chromosome 8q24.3, which encodes a protein that appears to be involved in zinc transportation [15,16]. Affected infants develop an erythematous and vesiculobullous dermatitis (show picture 1), alopecia, ophthalmic disorders, diarrhea, severe growth retardation, delayed sexual maturation, neuropsychiatric manifestations, and frequent infections. The syndrome is associated with severe zinc depletion and responds to oral supplementation. Replacement doses of 3 mg/kg/day of elemental zinc (13.2 mg/kg/day of zinc sulfate) are recommended; zinc levels are measured every three to six months and the dose is adjusted up or down as needed [17,18].

**Other*—*Reduced zinc levels, at times symptomatic, have been reported in several other conditions: Crohn's disease — Low plasma zinc concentrations occur in a significant number of patients with active Crohn's disease [19]. The clinical significance of this observation is not known. Several cases of dermatitis resembling acrodermatitis enteropathica with alopecia and eczematous changes responding to zinc administration have been described [20-22]. Hypogonadism, growth retardation, and abnormalities in taste also have been reported [20]. Studies have suggested that zinc absorption is significantly reduced in children with Crohn's disease, whereas endogenous fecal zinc excretion and urinary zinc excretion are unchanged [23]. This results in much poorer zinc balance in the children with Crohn's disease. The long-term consequences of this, and the optimum level of zinc supplementation for children with Crohn's disease remains unclear. (See "Overview of the management of Crohn's disease in children and adolescents", section on Monitoring nutritional status). Sickle cell disease — Low zinc levels can occur in children and adolescents with sickle cell disease, particularly in association with poor or delayed growth [24,25]. Zinc depletion in this population appears to reflect increased urinary excretion caused by a renal tubular defect and perhaps chronic hemolysis or impaired absorption, not inadequate dietary intake [25,26].

In one study, for example, 44 percent of 104 children with sickle cell disease had low plasma zinc concentrations [24]. These children, when compared to those with normal plasma zinc levels, had significant reductions in height, weight, upper arm muscle area, and, in older children, delayed sexual maturation. Whether zinc deficiency promotes infection in children with sickle cell disease remains controversial [27]. Liver disease — Children and adults with severe, chronic liver disease have an increased incidence of low plasma zinc levels [28-30]. The mechanism may be multifactorial, including hypoalbuminemia, reduced intake, and increased urinary excretion. The low plasma concentration and the increased urinary excretion correct within seven days of liver transplantation [28,29]. Renal disease — Zinc deficiency caused by increased urinary excretion can complicate nephrotic syndrome in children [31]. In addition, uremic patients are often deficient in zinc, probably because of reduced dietary intake, zinc malabsorption, and/or possible leaching of zinc by dialysis equipment [32,33]. Adolescent athletes — One study found significantly low plasma zinc concentrations in adolescent gymnasts when compared to matched control sedentary children [34]. This finding probably is related to inadequate intake associated with overall dietary restrictions caused by a desire to maintain weight as well as possibly increased losses in sweat. Other studies have not found reduced zinc levels in adolescent athletes with normal zinc intakes [35,36].

Clinical manifestations*—*Numerous signs and symptoms have been associated with zinc depletion (show table 2). Mild zinc deficiency is associated with depressed immunity, impaired taste and smell, onset of night blindness, and decreased spermatogenesis. Severe zinc deficiency is characterized by severely depressed immune function, frequent infections, bullous pustular dermatitis, diarrhea, and alopecia [6,7,37].

In some situations, zinc depletion is documented by measurement of zinc concentration in plasma, lymphocytes, or neutrophils. Because zinc is a cofactor for alkaline phosphatase activity, alkaline phosphatase serves as a serologic marker for zinc depletion [38]. In other situations, the diagnosis of zinc depletion is inferred by the response to zinc supplementation in placebo-controlled intervention. (See "Zinc supplementation" below).

Diagnosis*—*Zinc status can be assessed by measurement of zinc in plasma, erythrocytes, neutrophils, lymphocytes, and hair. Measurement of zinc in the plasma is simple and readily available in many laboratories. A low plasma zinc usually is defined as a value less than 60 mcg/dL [39]. Because much of plasma zinc is bound to albumin, correcting values for the level of serum albumin in conditions associated with hypoalbuminemia is important.

[Dr.]

Some investigators argue that plasma zinc measurements are relatively insensitive and that mild zinc deficiency occurs with normal plasma levels [40]. Zinc levels in neutrophils or lymphocytes may be more sensitive [41]. The criteria for zinc deficiency are decreased zinc level in either lymphocytes (<50 mcg/10(10) cells) or granulocytes (<42 mcg/10(10) cells) [42]. Depressed serum alkaline phosphatase levels for age provide supportive evidence for zinc deficiency [38].

ZINC SUPPLEMENTATION*—*Zinc deficiency, associated with impaired immunity and propensity to infection, is thought to be common in children in developing countries in which children experience high rates of serious infections. Zinc supplementation has been evaluated both as a therapeutic agent and as a potential prophylactic agent in children in these populations [43].

Prevention of diarrhea and pneumonia*—*Numerous studies in developing countries have shown that routine oral zinc supplementation reduces the incidence of diarrheal disease and pneumonia [43-48].

In one meta-analysis, zinc supplementation for three or more months in children less than five years of age reduced episodes of diarrhea, respiratory tract infections, severe diarrhea or dysentery, persistent diarrhea, and lower respiratory tract infections or pneumonias, with rate ratios between 0.75 and 0.95 [48]. The effect size is small and probably enhanced by publication bias, suggesting that it would be helpful to identify subpopulations most likely to benefit from zinc supplementation.

One placebo controlled study described outcomes of zinc supplementation during the neonatal period. Brazilian infants with low birth weight were given 5 mg zinc/day or placebo for the first eight weeks of life. Infants who received zinc supplement had 48 percent less diarrhea than did a control group during their initial 26 weeks of life [49].

Treatment of acute diarrhea*—*Several randomized studies have shown that zinc supplementation reduces the duration and severity of acute diarrhea in children who are likely to be zinc deficient [43,44,50-54]. In the largest of these trials, 937 Indian children between the ages of 6 and 35 months with acute diarrhea received vitamin supplementation and were randomly assigned to receive placebo or 20 mg of zinc per day [51]. Children with malnutrition severe enough to require hospitalization were excluded. Zinc supplementation reduced the duration of diarrhea by 23 percent (95% CI 12-32 percent) and the number of watery stools per day by 39 percent (95% CI 6-70 percent). The reductions in duration and severity were greater in children with growth retardation than in those with normal growth. This observation has been confirmed in other studies [53].

In contrast, zinc supplementation did not appear to affect the duration or volume of diarrhea in Bangladeshi infants younger than 6 months who were hospitalized with acute diarrhea [55].

Treatment of persistent diarrhea*—*The World Health Organization defines diarrheal episodes of greater than 14 days as persistent diarrhea. Persistent diarrhea is associated with higher mortality and greater adverse growth effects than is acute diarrhea [56]. Randomized, controlled trials of zinc supplementation in children hospitalized for persistent diarrhea have shown inconsistent effects on disease duration [57,58]. In one, a reduction in plasma copper levels was noted in zinc-supplemented malnourished children, suggesting that caution be exercised in giving zinc alone to severely malnourished children [58].

Prevention or treatment of malaria*—*Trials examining whether zinc supplementation reduces morbidity or mortality from malaria have had conflicting results. A randomized trial in Papua, New Guinea showed that supplementation reduced clinic visits for malaria [59]. Several other trials reported non-significant reductions of morbidity from malaria [59-61]. A large placebo-controlled trial performed in a malaria-endemic area of Africa also failed to show a significant effect of zinc supplementation on overall mortality or malaria-related mortality [62]. However, the analysis raised the possibility that there may be benefit in subgroups of children. Zinc levels tend to decrease during the acute phase response in children with falciparum malaria [63]. However, zinc supplementation does not appear to have a beneficial effect when used as an adjunct to treatment of the disease [64]. (See "Epidemiology, pathogenesis, clinical features, and diagnosis of malaria").

Treatment of the common cold*—*Initial studies suggested that zinc lozenges could shorten the duration of symptoms of the common cold [65,66]. However, another controlled trial and a meta-analysis reviewing six trials found no benefit [67,68]. (See "The common cold in children").

Enhancement of growth*—*Some studies have described improved linear growth in infants who receive zinc supplementation, especially in those who were stunted or had low plasma zinc concentrations at baseline [61,69-73]. A meta-analysis of 33 randomized controlled trials confirmed the effects of zinc supplementation in enhancing linear growth and weight gain in children with growth retardation [74]. The doses of zinc used in these trials varied from 1 to 20 mg/day of elemental zinc. Because zinc has no pharmacologic effect on growth, a growth response to zinc is taken as evidence of a preceding growth-limiting zinc deficiency [75].

ZINC TOXICITY*—*Little toxicity occurs with zinc supplementation. Ingestion of up to ten times the recommended daily intake produces no symptoms. Intestinal absorption of copper is inhibited by zinc. Thus, chronic intake of zinc in excess of 100 mg per day may be associated with copper deficiency [76].

The acute ingestion of 1 to 2 g zinc sulfate produces nausea and vomiting associated with irritation and corrosion of the gastrointestinal tract. Large doses of zinc compounds also can produce acute renal failure caused by tubular necrosis or interstitial nephritis [77]. (See "Clinical presentation, evaluation and diagnosis of acute renal failure in children

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Сообщение от Dr.

Вот, случайно наткнулся
Steven A Abrams, MD
UpToDate performs a continuous review of over 375 journals and other resources. Updates are added as important new information is published. The literature review for version 15.3 is current through August 2007; this topic was last changed on June*19,*2007. The next version of UpToDate (16.1) will be released in March 2008.

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